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RELATED APPLICATIONS
This application is a national stage application under 35 U.S.C. §571 based on PCT Application No. PCT/US2014/013395, entitled “Visual Electrophyphysiology Device” and filed Jan. 28, 2014, which claims the benefit of U.S. Provisional Application Ser. No. 61/842,102, entitled “VISUAL ELECTROPHYSIOLOGY DEVICE” and filed Jul. 2, 2013. The entirety of the aforementioned applications are incorporated herein by reference.
GOVERNMENT RIGHTS
Inventions described herein were made with government support under grant 9R44EY021121 awarded by the National Institutes of Health, USA. Accordingly, per the terms and conditions of the grant, the U.S. government has certain rights in the present application.
FIELD
The embodiments described herein relate to improved devices and methods for assessing visual system function.
BACKGROUND
The electroretinogram (ERG) and visual evoked potentials (VEP) are diagnostic tests used to help assess visual system function. See, for example, the textbook Principles and Practice of Clinical Electrophysiology of Vision, 2 th edition, edited by Heckenlively and Arden (2006), which describes dozens of diseases that can be diagnosed with the aid of visual electrophysiology. Standards have been developed for the most common of these tests, as described in Marmor et al. (2009), Hood et al. (2012), Holder et al. (2007), and Odom et al. (2010). As a specific example, some features of the clinical ERG are strongly correlated with diabetic retinopathy (Bresnick and Palta (1987), Han and Ohn (2000) and Satoh et al. (1994)). As another example, Kjeka et al. (2013) showed greatly improved outcomes for the treatment of central retinal vein occlusion when basing treatment decisions on ERG results rather than ophthalmologic examinations alone.
Normally, ERG measurements are recorded using a large instrument (e.g., the LKC Technologies UTAS system) in a darkened room with electrodes placed directly onto the eye. Dilating drops are used to enlarge the pupil and anesthetic drops are used to numb the eye before placing the electrodes onto the eye. The eye is stimulated with light to elicit a response from the visual system which is recorded via the electrodes. The measurements are performed by a skilled technician, and the results are usually interpreted by an ophthalmologist or PhD expert in visual electrophysiology. The invasiveness and complexity described above have prevented the ERG from having widespread use in assessing diabetic retinopathy and other diseases.
The invention described in U.S. Pat. No. 7,540,613 helps prevent these disadvantages. Nevertheless, there still exists a need for visual electrophysiology devices that are easier to use and/or have improved performance.
SUMMARY
Described herein are embodiments of a device and method for providing an indication of visual system function. The improvements disclosed herein can be used separately or in combination, including improvements in stimulus generation, ease of use, and error condition monitoring. Embodiments overcome the problems described above.
An embodiment of a device to provide an indication of visual system function of a patient has a first light emitter having a first emission spectrum. The device also has an optical assembly arranged so that light emitted from the first light emitter reaches an eye of the patient. The device also has a camera arranged to image the eye of the patient and a controller. The controller modulates a light emission from the first light emitter to create a light stimulus that receives and analyzes an electrical signal from the visual system of the patient and that provides an indication of visual system function based on that analysis.
In some embodiments, the device further includes a second light emitter having a visible second emission spectrum that is distinct from the first emission spectrum, wherein the optical assembly is arranged so that light emitted from the second light emitter reaches an eye of the patient. In this case, the controller measures the eye's pupil area using images from the camera and adjusts the luminance of the light stimulus as a function of the eye's pupil area and wherein the controller modulates light emission from the first and second light emitters to create first and second flashes overlapping in time.
In another embodiment, the light stimulus comprises one or more flashes of light and the controller synchronizes the camera and the light stimulus so that the camera is only activated when there is no flash.
In another embodiment, the controller measures the eye's pupil area using images received from the camera and adjusts the luminance in the light stimulus through a non-linear, concave function of the eye's pupil area.
In another embodiment, the controller does not provide an indication of visual system function unless the eye's pupil has been identified.
In another embodiment, the device further includes a light detector adapted to measure light emitted from the first light emitter, wherein the controller does not provide an indication of visual system function if the signal from the light detector differs from a set of expected light detector signals that includes excessive external light.
In another embodiment, the controller measures the eye's pupil area using images from the camera and adjusts the luminance of the light stimulus as a function of the eye's pupil area. In addition, the device further includes an electrical impedance meter, wherein the controller does not provide an indication of visual system function unless the electrical impedance meter measures an impedance smaller than a target value.
In another embodiment, the controller modulates a light emission from the first light emitter so as to deliver to the eye a periodic visual stimulus that approximates a retinal illuminance that varies as one of a sinusoid, a square wave having a duty cycle between 30% and 70%, or a triangular wave.
In some embodiments, the controller modulates a light emission from the first light emitter to create a first flash of light having a duration less than 21 ms. The controller also modulates a light emission from the second light emitter to create a second flash of light having a duration less than 21 ms. The first and second flashes may overlap in time by at least 50% of the longer of the two flashes. The controller may receive images from the camera and uses those images to measure the eye's pupil area and adjusts the energy in the first flash as a function of the area. The controller can further receive and analyze an electrical signal from the visual system of the patient so as to provide an indication of visual system function.
In accordance with another embodiment, a device to provide an indication of visual system function of a patient has a first light emitter having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm. The device also has a camera arranged to image an eye of the patient. The device also has an optical assembly arranged so that light emitted from the first light emitter reaches the eye. The device also has a controller that modulates a light emission from the first light emitter to create a first flash of light having a flash frequency greater than 1 Hz. The controller receives images from the camera at a frame rate. The controller measures the eye's pupil area using the images and adjusts the energy in the first flash as a function of the area. The ratio of the flash frequency to the frame rate is an integer or one over an integer. The controller can further receive and analyze an electrical signal to provide an indication of visual system function.
In accordance with another embodiment, a device to provide an indication of visual system function of a patient has a first light emitter having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm. The device also has an infrared light emitter having a second emission spectrum that has at least 50% of its energy emitted at wavelengths longer than 710 nm. The device also has an optical assembly arranged so that light emitted from the first light emitter and the infrared light emitter reaches an eye of the patient. The device also has a controller. The controller modulates a light emission from the first light emitter to create a first flash of light having a duration less than 21 ms. The controller also modulates a light emission from the infrared light emitter to create an infrared flash of light having a duration less than 40 ms. The energy emitted by the first light emitter during the infrared flash of light is less than 50% of the energy emitted by infrared light emitter during the infrared flash of light. The controller can further receive and analyze an electrical signal from the visual system of the patient so as to provide an indication of visual system function.
In accordance with another embodiment, a device to provide an indication of visual system function of a patient includes an electrode array comprising three electrodes structurally adapted to be applied and removed from the skin as a single unit. The device also has an analog to digital converter that measures the electric potential difference between a first electrode and a second electrode in the electrode array. The device also has a common-mode attenuation circuit electrically connected to a third electrode in the electrode array. The distance between the first and second electrode is greater than the distance between the first electrode and third electrode and the distance between the first and second electrode is greater than the distance between the second electrode and third electrode. The device also has a controller.
In certain embodiments, the device has a first light emitter having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm and an optical assembly arranged so that light emitted from the first light emitter reaches an eye of the patient. The controller may modulate a light emission from the first light emitter to create a first flash of light having a duration less than 21 ms. The controller can further receive and analyze the electrical signal to provide an indication of visual system function based on that analysis.
In accordance with another embodiment, a device to provide an indication of visual system function of a patient has a first light emitter having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm. The device also has an optical assembly arranged so that light emitted from the first light emitter reaches an eye of the patient. The device also has a camera arranged to image the eye of the patient. The device also has a controller that modulates a light emission from the first light emitter to create a first flash of light having a duration less than 21 ms. The controller also receives images from the camera and can further receive and analyze an electrical signal from the visual system of the patient so as to provide an indication of visual system function. The controller does not provide the indication until after the eye's pupil has been identified.
In accordance with another embodiment, a device to provide an indication of visual system function of a patient has an electrode that receives an electrical signal from the visual system of the patient. The device also has a first light emitter having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm. The device also has an optical assembly arranged so that light emitted from the first light emitter reaches the eye. The device also has a light detector that measures light emitted from the first light emitter. The device also has a controller. The controller modulates a light emission from the first light emitter to create a first flash of light and can further receive and analyze the electrical signal to provide an indication of visual system function. The controller can also receive a signal from the light detector, and the controller does not provide the indication if the signal from the light detector differs from a set of expected light detector signals.
In accordance with another embodiment, a device to provide an indication of visual system function of a patient has a first light emitter having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm. The device also has an optical assembly arranged so that light emitted from the first light emitter reaches the eye. The device also has a light detector that measures light emitted from the first light emitter. The device also has a controller. The controller modulates a light emission from the first light emitter to create a first flash of light and can further receive and analyze an electrical signal from the visual system of the patient to provide an indication of visual system function. The controller can also receive a signal from the light detector, whereby the controller does not provide the indication if the signal from the light detector differs from a set of expected light detector signals.
In accordance with another embodiment, a device to provide an indication of visual system function of a patient has a first light emitter having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm. The device also has an optical assembly arranged so that light emitted from the first light emitter reaches an eye of the patient. The device also has a camera arranged to image the eye of the patient. The device also has a controller that modulates a light emission from the first light emitter to create a first flash of light having a duration less than 21 ms. The controller receives images from the camera, measures the eye's pupil area using images from the camera, and adjusts the energy in the first flash as a function of the area. The controller can also receive and analyze an electrical signal from the visual system of the patient so as to provide an indication of visual system function. The device also has an electrical impedance meter and the controller does not provide the indication until after the electrical impedance meter measures an impedance smaller than 1 GΩ.
In accordance with another embodiment, a method for providing an indication of visual system function of a patient includes illuminating an eye of the patient with a first flash of visible light having a duration of less than 21 ms and having a first emission spectrum. The method additionally includes illuminating the eye of the patient with a second flash of visible light having a duration of less than 21 ms and having a second emission spectrum distinct from the first emission spectrum. The first flash and second flash overlap in time by at least 50% of the longer of the two flashes. The method further includes measuring the eye's pupil area, adjusting the energy in the first flash as a function of the eye's pupil area and receiving and analyzing an electrical signal from the patient and providing an indication of visual system function based on that analysis. The method may further involve imaging the eye of the patient, receiving images from the camera, measuring the eye's pupil area using images from the camera, and adjusting the energy in the first flash as a function of the area.
In accordance with another embodiment, a method for providing an indication of visual system function of a patient includes the step illuminating an eye of the patient with a visible light stimulus comprising flashes of light having a flash frequency greater than 7 Hz. The method further includes measuring the eye's pupil area at a frame rate frequency, adjusting the luminance of the visible light stimulus as a function of the eye's pupil area, and receiving and analyzing an electrical signal from the patient and providing an indication of visual system function based on that analysis, wherein the ratio of the flash frequency to the frame rate frequency is within 1% of an integer or within 1% of the reciprocal of an integer.
The method may further involve illuminating the eye of the patient with infrared flashes of light that have at least 50% of their energy emitted at wavelengths longer than 710 nm and an infrared flash frequency greater than 1 Hz, wherein the energy in the first visible light stimulus emitted during the infrared flashes is less than 50% of the infrared energy emitted during the infrared flashes. The method may further involve measuring the eye's pupil area at a frame rate frequency, adjusting the luminance of the first visible light stimulus as a function of the eye's pupil area and illuminating the eye of the patient with a second visible light stimulus. In this case, the first visible light stimulus may include a first flash of visible light having a duration of less than 21 ms and a first emission spectrum. The second visible light stimulus may include a second flash of visible light having a duration of less than 21 ms and a second emission spectrum distinct from the first emission spectrum. Further, the first and second flashes of visible light may overlap in time by at least 50% of the longer of the two flashes of visible light, whereby the ratio of the infrared flash frequency to the frame rate frequency is within 1% of an integer or within 1% of the reciprocal of an integer.
In accordance with another embodiment, a method for providing an indication of visual system function of a patient involves placing an electrode array comprising three electrodes on the skin of the patient as a single unit, wherein the three electrodes include a first electrode, a second electrode and a third electrode, whereby the first and second electrode are more distant from each other than any other pairing of the first, second, and third electrodes and whereby the third electrode is electrically connected to a common-mode attenuation circuit. The method further includes the step of illuminating an eye of the patient with a first visible light stimulus, measuring the electric potential difference between the first electrode and the second electrode, and providing an indication of visual system function based on that measurement.
The method may further include the step of illuminating the eye of the patient with infrared flashes of light having at least 50% of their energy emitted at wavelengths longer than 710 nm and having an infrared flash frequency greater than 1 Hz, measuring the eye's pupil area at a frame rate frequency, and adjusting the luminance of the light stimulus as a function of the eye's pupil area, wherein the ratio of the flash frequency to the frame rate frequency is within 1% of an integer or within 1% of the reciprocal of an integer. The method may further includes the step of illuminating the eye of the patient with a second visible light stimulus. In this case, the first visible light stimulus may have a stimulus frequency greater than 7 Hz, including a first flash of visible light having a duration of less than 21 ms and having a first emission spectrum. The second visible light stimulus may include a second flash of visible light having a duration of less than 21 ms and a second emission spectrum distinct from the first emission spectrum. The energy in the first flash of visible light emitted during the infrared flashes may be less than 50% of the infrared energy emitted during the infrared flashes, and the first and second flashes of visible light may overlap in time by at least 50% of the longer of the two flashes,
In accordance with another embodiment, a method for providing an indication of visual system function of a patient involves emitting a first light from a first light emitter, having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm, so that the first light reaches an eye of the patient. The method also involves emitting an infrared light from an infrared light emitter, having an infrared emission spectrum that has at least 50% of its energy emitted at wavelengths longer than 710 nm, so that the second light reaches an eye of the patient. The method also involves controlling the first light emitter to modulate a first light to create a first flash of light having a duration less than 21 ms. The method also involves controlling the infrared light emitter to modulate an infrared light to create an infrared flash of light having a duration less than 40 ms, wherein the energy emitted by the first light emitter during the infrared flash of light is less than 50% of the energy emitted by infrared light emitter during the infrared flash of light. Finally, the method involves receiving and analyzing an electrical signal from the patient so as to provide an indication of visual system function.
In accordance with another embodiment, a method for providing an indication of visual system function of a patient involves placing an electrode array comprising three electrodes on the skin as a single unit, wherein the three electrodes include a first electrode, a second electrode and a third electrode, a distance between the first and second electrode is greater than the distance between the first electrode and third electrode, and a distance between the first and second electrode is greater than the distance between the second electrode and third electrode. The method also involves emitting a first light from a first light emitter, having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm, so that the first light reaches an eye of the patient. The method also involves controlling the first light emitting to modulate a first light to create a first flash of light having a duration less than 21 ms. The method also involves measuring the electric potential difference between the first electrode and the second electrode so as to provide an indication of visual system function.
In accordance with another embodiment, a method for providing an indication of visual system function of a patient involves emitting a first light from a first light emitter, having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm, so that the first light reaches an eye of the patient. The method also involves controlling the first light emitting to modulate a first light to create a first flash of light having a duration less than 21 ms. The method also involves imaging the eye of the patient, receiving images from the camera, measuring the eye's pupil area using images from the camera and adjusting the energy in the first flash through a non-linear, concave function of the area. Finally, the method involves receiving and analyzing an electrical signal from the patient so as to provide an indication of visual system function.
In accordance with another embodiment, a method for providing an indication of visual system function involves emitting a first light from a first light emitter, having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm, so that the first light reaches an eye of the patient. The method also involves controlling the first light emitting to modulate a first light to create a first flash of light having a duration less than 21 ms. The method also involves imaging the eye of the patient, receiving images from the camera; and receiving and analyzing an electrical signal from the patient so as to provide an indication of visual system function, wherein the indication is not provided until the eye's pupil has been identified.
In accordance with another embodiment, a method for providing an indication of visual system function of a patient involves emitting a first light from a first light emitter, having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm, so that the first light reaches an eye of the patient. The method also involves controlling the first light emitting to modulate a first light to create a first flash of light having a duration less than 21 ms. The method also involves measuring the light emitted from the first light emitter with a light detector and receiving a signal from the light detector. Finally, the method involves receiving and analyzing an electrical signal from the patient so as to provide an indication of visual system function, wherein the indication is not provided if the signal from the light detector differs from a set of expected light detector signals.
In accordance with another embodiment, a method for providing an indication of visual system function of a patient involves emitting a first light from a first light emitter, having a first emission spectrum that has at least 50% of its energy emitted between 400 nm and 710 nm, so that the first light reaches an eye of the patient. The method also involves controlling the first light emitting to modulate a first light to create a first flash of light having a duration less than 21 ms. The method also involves imaging the eye of the patient and receiving images from the camera. The method also involves receiving and analyzing an electrical signal from the patient so as to provide an indication of visual system function. Finally, the method involves measuring an electrical impedance associated with the electrical signal received from the patient, wherein the indication is not provided until after the electrical impedance meter measures an impedance smaller than 1 GΩ.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description, serve to explain the novel principles of the embodiments described herein. In the drawings:
FIG. 1 is a cross sectional view of an exemplary visual electrophysiology device.
FIG. 2 is a schematic view illustrating components contained within the visual electrophysiology device of FIG. 1
FIG. 3 shows three exemplary relations between luminance and pupil area, from the perspective of luminance emitted from the visual electrophysiology device ( FIG. 3A ) and of retinal illuminance ( FIG. 3B ).
FIG. 4 shows timing diagrams of light output versus time for exemplary embodiments described herein. FIG. 4A shows a periodic synthesized white light stimulus followed by an infrared flash. FIG. 4B shows a periodic synthesized white light stimulus followed by an infrared flash, with a superimposed higher-frequency synthesized white light background.
FIG. 5 shows timing diagrams of light output versus time for exemplary embodiments described herein. FIG. 5A shows a desired sinusoidal waveform and a pulse-width modulation (PWM) approximation thereof. FIG. 5B shows a desired triangular waveform and a PWM approximation thereof. FIG. 5C shows a square waveform and a PWM approximation thereof.
DETAILED DESCRIPTION
Disclosed herein are embodiments of improved visual electrophysiology devices and methods of improved visual electrophysiology. These devices and methods can be used to provide an indication of visual system function of a patient. There is an electrical circuit that controls a light stimulus directed toward the eye and measures the electrical signal the eye produces in response to the light. Device operation involves stimulating the eye with light and measuring an electrical response to the stimulus. By way of example, the time span between the flash of light and the time of the peak of the electrical response may be indicative of the degree of retinal ischemia in a patient.
Embodiments of the present invention may improve the measurements over existing visual electrophysiology device measurements, by making the stimulation more consistent, improving the data collection, and/or checking for error conditions. The stimulus to the eye can comprise flashes of light or other modulated light waveforms. The stimulus to the eye can comprise a single flash of light. The stimulus to the eye can comprise a background illumination that is perceptually constant or only slowly changing.
Embodiments may provide a first light emitter having a first emission spectrum. The first light emitter may have a first visible emission spectrum and may emit, for example, green, red, orange, blue, amber, or yellow light. The first light emitter may be a LED. Optionally, other (2, 3, 4, 5 or more) visible light emitters may be present with distinct spectra. For example, some embodiments may use 4 LEDs that each have red, green, and blue emitters. Some embodiments may have an infrared light emitter that emits at least 50% of its energy at wavelengths longer than 710 nm. Other light emitters may be provided.
Some embodiments may use a controller to modulate the emitters' output so that they emit light for periods of time (e.g., less than 6 ms, 21 ms or 40 ms) and so that the light emitted from at least some of the visible light emitters overlaps in time. In some embodiments, the emission duration for each emitter is different (e.g., the second light emitter emits light for a longer period of time than the first light emitter).
Some embodiments use a camera to measure the pupil size so the light stimulus luminance can be adjusted to reduce the effect of pupil size on the effective retinal stimulus; for example, the light stimulus luminance can be linearly related to the multiplicative inverse of the eye's pupil area or the light stimulus luminance can be related to the multiplicative inverse of the eye's pupil area through a non-linear, concave function.
The light emitters can be arranged to deliver retinal illuminances that are approximately sinusoidal, triangular, or square by for example continuously modulating the light output or by delivering flashes of light in a pulse-width modulation (PWM) fashion. In various embodiments, time or frequency synchronization between the light stimulus, optional infrared light flashes, and camera images may provide more consistent stimulation, image collection, light stimulus luminance adjustment, and the like. By varying the above-described characteristics of the light emitters as described herein, embodiments provide improved results over existing visual electrophysiology devices.
Embodiments may improve over existing visual electrophysiology devices by using electrode arrays and driving a middle electrode with a common-mode attenuation circuit while measuring electric potential differences between the more distantly separated outer electrodes. This electronic configuration maximizes the magnitude of the electric signals while providing the convenience of an easy to use electrode array.
Embodiments may improve over existing visual electrophysiology devices by checking for error conditions. Electrical impedance measurements may be used to confirm the device is electrically connected to the patient with a sufficiently low impedance. For example, it could determine if the electrode array does not stick sufficiently well to the patient to achieve an electrical connection. A light detector may be used for example to ensure undesired external light is sufficiently small and/or to ensure the desired light stimulus is in fact produced. Pupil detection may be used to ensure the patient's eye is present and open to ensure the light stimulus produced enters the patient's eye.
Combinations of the above description are also contemplated. Composition and methods of their use are contemplated. Embodiments improve over existing visual electrophysiology devices in other ways apparent from the detailed description herein.
DEFINITIONS
In order to more clearly understand the embodiments described herein, certain terms are defined as follows. Other terms are defined in other parts of this disclosure.
The term “light emitter” refers to anything that emits electromagnetic radiation in the UV, visible, and infrared (IR) range. Exemplary light emitters include LEDs, display devices, and gas-discharge devices such as xenon flash lamps and fluorescent bulbs. In some cases herein, the term “infrared” is abbreviated as “IR”.
The term “LED” refers to a light emitting diode. LED includes those comprising semiconductor, organic, and quantum-dots. The term LED includes those with integrated phosphors.
The term “patient” refers a human or other mammal from which physiological electrical signals are to be measured. It is contemplated that the device will be placed in proximity to the patient to enable stimulation of the patient's visual system and measurement of physiological response thereto.
The term “retinal illuminance” refers to the product of luminance and pupil area. The unit Troland (abbreviated Td) is a measure of retinal illuminance where luminance has units of cd/m 2 and pupil area has units of mm 2 .
The phrase “indication of visual system function” refers to the analysis of an electrical signal from the visual system of a patient in response to light. It is to be distinguished from other measures of the visual system based solely on e.g., imaging of the eye structure with fundus photography, OCT, or the like, or psychophysical measures such as visual acuity using a Snellen chart.
Description
Various embodiments, as well as additional objects, features, and advantages thereof, will be understood more fully from the following description.
FIG. 1 shows an exemplary device 100 used to provide an indication of visual system function of a patient. An eyecup 107 may contact the bony regions around the eye to keep the device against or near the patient. The light emitter 106 shines light into an optical assembly 104 , which directs the light to the patient's eye. In this example, the optical assembly 104 acts as an integrating sphere to deliver the light emitted from the light emitter 106 in a diffuse manner to the patient's eye. A diffuse light source enables interrogation of large portion of the retina and makes patient fixation less important. Other exemplary optical assemblies do not require light from the light emitter 106 to be reflected before reaching the patient's eye, for example, the light may be refracted, diffused, scattered, or may have a direct path between the light emitter and the patient's eye.
The light emitter 106 can have 1, 2, 3, 4, or more emission sources. For example, the light emitter 106 can be a first light emitter, which may be a LED or different type of light emitter. The first light emitter has a first emission spectrum. In some embodiments, the first light emitter may emit green, red, orange, blue, amber, or yellow light. The first light emitter may be, for example, a green LED. The light emitter 106 can also be a second light emitter. The optional second light emitter has a visible second emission spectrum that, for example, is distinct from the first emission spectrum. The second light emitter, if present, may emit green, red, orange, blue, amber, or yellow light as long as the emission spectrum is distinct from the first emission spectrum. The optional second light emitter may be an LED or a different type of light emitter and may be, for example, a red LED. The light emitter 106 can also be a third light emitter. The optional third light emitter has a visible third emission spectrum that, for example, is distinct from the first and second emission spectra. The third light emitter, if present, may emit green, red, orange, blue, amber, or yellow light as long as the emission spectrum is distinct from the first and second emission spectra. The optional third light emitter may be an LED or a different type of light emitter, and may be, for example, a blue LED. The device 100 may have additional (e.g., 4, 5, 6, 7, 8, or more) visible light emitters having distinct spectra; for example, having 4 different visible spectral sources enables independent stimulation of one of the three types of cones or rods in a human (Shapiro et al. (1996)).
The light emitter 106 can be, for example, an RGB LED, for example, a CREE CLV6Aa, an Avago ASMT-MT000-0001, or an Osram LRTD-C9TP. The light emitter 106 can be, for example, a red, green, blue, white LED such as CREE XLamp XM-L. Individual LEDs or other light sources may be used. Two components in the light emitter 106 are visible in the cross section of the device 100 ; two more are on the other half, for a total of four. The number of components in the light emitter 106 need not be 4; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more is contemplated. A larger number of components comprising the light emitter 106 gives improved light uniformity in the integrating sphere and a brighter possible light output; however, larger numbers are inconvenient is terms of manufacturing difficulty and cost.
As shown in FIG. 1 , a camera 101 can image the patient's eye through the hole in the optical assembly 104 and the eyecup 107 . The eyecup 107 can be designed to rest on regions around a patient's eye so as to reduce the amount of light originating outside of the device 100 from reaching the eye. Alternatively, the eyecup 107 can be designed not to contact the patient. An optional fixation light 102 can provide a target for the patient to fixate on during the testing process. When using an infrared light emitter 103 , at least 50% of its energy will be emitted at wavelengths longer than 710 nm. The infrared light emitter 103 can be used to illuminate the patient's eye during the exposure time of the camera 101 . In some embodiments, the device 100 has neither a camera 101 , nor an infrared light emitter 103 .
Patient connector 108 can be used to make a set of electrical connections to the patient so as to be able to receive an electrical signal from the patient. The electrical signals can be gathered from the patient using any number of electrodes (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) operationally connected to the device 100 via a cable. Exemplary locations to measure the response include on the surface of the eye (e.g., with electrodes such as Burian Allen electrodes, DTL electrodes, and ERG Jet electrodes), under the epithelium (e.g., with a needle electrode), on the skin near the eye (e.g., with LKC Sensor Strip electrodes as described in U.S. Patent application 61/696,499), on the back or top of the head (e.g., using gold cup electrodes).
FIG. 2 depicts a schematic illustration of components that may be contained within the device 100 of FIG. 1 as previously shown in U.S. Pat. No. 7,540,613. In FIG. 2 , the light emitter 106 provides a light stimulus to the eye 144 . Current high brightness LED's have sufficient brightness for carrying out the present invention with an efficient diffuser, however, in certain applications a plurality of LEDs may be used for a light emitter 106 .
A light emitter 106 is controlled by a controller 110 that provides the overall control of the device 100 . Controller 110 may be a microcontroller or microcomputer device with a processor, memory and other connections to other components of device 100 . Controller 110 may be a pre-programmed computer that is programmed to perform the functions and controls described herein. Alternatively, controller 110 may include wireless connections or wired connections that allow remote programming (e.g., for additional functions or updates). Those of ordinary skill in the art would understand how to program and operate controller 110 . Control of the light emitter 106 is by means of the controller 110 which can control the timing of the firing of the light and camera sources, as well as the intensity, frequency and synchronicity thereof as further described below. By way of example, the controller 110 can modulate the activity of the light emitter 106 , such as an LED to provide a series of brief flashes of light of predetermined duration, however, other stimulus waveforms or stimulus frequencies can also be utilized as further described below.
The light emitter 106 is positioned so as to emit light to the interior of a diffuse spheroidal reflector 142 so that the light from the light source is directed uniformly toward the eye 144 from all directions. In the illustrated embodiment, the diffuse spheroidal reflector 142 is spheroidal in configuration with a white interior surface to enhance the reflectivity. The white surface can be a coating (e.g., paint) or diffuse spheroidal reflector 142 can be made for example, from white plastic. The use of the diffuse spheroidal reflector 142 provides an even illumination to most of the retina of the eye 144 . Diffuse spheroidal reflector 142 is an exemplary optical assembly 104 .
Returning to FIG. 2 , as previously explained, the light stimulus by the light emitter 106 gives rise to an electrical signal from the eye 144 that can be sensed by e.g., electrodes 132 , 134 contacting the skin of the patient proximate to the eye 144 , whereby the electrical signal is communicated by wires 148 to an amplifier and an analog to digital (A/D) converter shown as block 150 . The A/D converter (located for example on the electronics board 109 in FIG. 1 ) can measure the electric signals on the electrodes and provide the information to the controller 110 . The controller 110 can analyze the electric signals so as to provide an indication of visual system function, using techniques described for example, in the references cited in the Background section above.
The analysis of the data from the electrical signals sensed by the electrodes 132 , 134 is, as described, carried out by the controller 110 . Algorithms for specifically assessing retinal ischemia in a patient have been published. See, for example, Severns et al. (1991), Severns and Joshson (1991), and Kjeka et al. (2013). For other diseases, algorithms are described in the references cited in the Background section above.
In exemplary embodiments, signals from the skin electrodes 132 , 134 are analyzed for the amount of noise present to determine if accurate and clinically meaningful measurements can be made. If the signal to noise ratio is marginal, additional data can be collected to improve the estimate. Next, a sine wave is fit to the data to determine the amount of elapsed time between the actuation of the stimulus and the maximal response of the eye. This measurement has been shown to be a highly sensitive measure of the extent of ischemia in the eye (Severns et al. (1991)).
As further components of the device 100 , ( FIG. 1 ) there are controls 120 that can be used to initiate each test and to enter customized settings. In addition, the device 100 can provide a visual readout 118 to the user of the results of each test, that is, the readout 118 provides a visual readout to the user that is related to the amount of retinal ischemia of the eye.
The amplifier can be a biomedical amplifier using 24 bit (or more) A/D converters that eliminates gain adjustment and the prolonged recovery from saturation of conventional amplifiers. Typically, conventional amplifiers have required some oversight by a technician during testing to assure that the gain setting was correctly matched to the input range of the A/D converter. Further, such conventional amplifiers could saturate (fail to respond to the input signal) and might take tens of seconds to recover the ability to respond to a signal. The saturation is difficult to distinguish from a lack of response from the patient making reliable automation of signal acquisition difficult.
To avoid such problems, the device 100 may utilize a low gain differential amplifier (no more than 32×) and a high resolution (typically 18 bits or greater) differential A/D converter to acquire the signal from the eye 144 by means of the skin electrodes 132 , 134 . Thus, the amplifier has a very high tolerance for noise and offsets, while producing highly faithful reproduction of the input waveform. The amplifier and A/D converter of block 150 are also immune to prolonged saturation caused by interfering signals. In some embodiments, the amplifier and A/D converter can be built into the same device (e.g., an ADS1220, ADS1248, ADS1292, ADS1294, ADS1298, or ADS1299 from Texas Instruments or an AD7195, AD7194, AD7193, AD7799, AD7738 from Analog Devices to name a few). Some embodiments do not use an amplifier. Input impedance of the system is very high (>10 MΩ) so that the relatively high impedance of the electrodes 132 , 134 contacting the skin does not affect the results. The output of the A/D converter in block 150 is connected to the controller 110 , which analyzes the data.
Conveniently, all the electrodes used for one eye can be located in a self-adhering electrode array such as those described in U.S. Provisional Patent Application Ser. No. 61/696,499, filed Sep. 4, 2012 and PCT Application Serial No. PCT/US13/58007, filed Sep. 4, 2013, the disclosures of which are expressly incorporated by reference herein. In some embodiments, three electrodes are used in an array for each eye. An A/D converter (located for example on electronics board 109 ) can measure the electric potential difference between a first electrode and a second electrode in the electrode array, and a common-mode attenuation circuit can be electrically connected to a third electrode in the electrode array. An advantageous and novel arrangement of these electrodes is where the distance between the first and second electrode is greater than both the distance between the first electrode and third electrode and the distance between the second electrode and third electrode. As a result, the common-mode attenuation circuit can be considered connected to the middle of the three electrodes.
In contrast, current practice (as described in the ISCEV standard Marmor et al. (2009)) uses remote locations such as the earlobe for a common-mode attenuation circuit electrode location. When electrodes are located on a small sensor array, however, the performance is improved by maximizing the distance between the first and second electrode. For example, in one embodiment, the first electrode can be located under the eye, the second electrode can be located near the temple, and the third electrode can be located in between the first electrode and the second electrode. The common-mode attenuation circuit can reduce the common-mode voltage difference between signals on the electrodes and the A/D converter caused, for example, by capacitive coupling between the power lines and the body. By reducing common-mode interference, potential measurements between electrodes can be made more accurately. Exemplary common-mode attenuation circuits include a right leg drive circuit and a constant potential with respect to a potential at the A/D converter.
An electronics board 109 may have a controller 110 modulating a light emission from the first light emitter to create a first flash of light having a duration less than 21 ms. The controller 110 may also modulate a light emission from the second light emitter to create a second flash of light having a duration less than 21 ms. The controller 110 may also modulate a light emission from the third light emitter to create a third flash of light having a duration less than 21 ms. Generally, the controller 110 modulates a light emission from one or more light emitters to create flashes of light having durations less than 21 ms, for example, less than 10 ms, 6 ms, 5 ms, 4 ms, or 3 ms.
When constructing flashes of light from multiple different colored sources, there are several alternative ways to do so. For example, if the first light emitter emits green and the second emitter emits blue, then to emit the color cyan, both emitters are needed. A common way is to control the flash duration for each source independently. For example, the green flash duration may be 2 ms and the blue flash duration 5 ms. The starting times for the two flashes may be aligned, or the ending times may be aligned, or to reduce the peak electrical power requirements, the second flash may begin soon after the first completes. Because the flashes are short, even though the durations differ, they are perceived by the brain as a cyan color. However, the retina responds to the light as it arrives, leading to millisecond-level uncertainties in when should the flash be considered to have occurred (in the present example). Analogous statements can be made if white light is synthesized from red, green, and blue LEDs. One common visual electrophysiology test, the 30 Hz flicker electroretinogram (Marmor et al. (2009)), has response times in the range of 20-40 ms, where a few milliseconds of uncertainty caused by the flash characteristics may produce errors in the measurements.
Nevertheless, appropriately synthesized colors have advantages over single LEDs. Two methods of creating a white flash, for example, are by using a white light source (e.g., a white LED or xenon bulb) or by synthesizing the color using, for example, red, green, and blue LEDs. The optical assembly 104 may reflect some wavelengths better than others, leading to deviations from the spectrum of a white light source. The color of the optical assembly 104 may also change from part-to-part due to manufacturing variation, leading to part-to-part deviations in the spectrum emitted if a white light source is used. In contrast, the color can be tuned to the desired color, independent of the exact color absorption of the optical assembly 104 , when using red, green, and blue LEDs.
One method to reduce the timing uncertainty caused by flash characteristics is to have the light waveforms overlap in time. In some embodiments, the independent visible light spectral sources overlap by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the longer of the flashes (whether it be 2, 3, 4, or more independent visible light spectral sources). FIG. 4 shows an overlap of 100%, where all the lights flash simultaneously. Some embodiments use light flashes that are symmetric about a center point. For example, a 2 ms blue flash can be combined with a 4 ms green flash by having the blue occur in the interval (t−1 ms, t+1 ms) and the green flash over the interval (t−2 ms, t+2 ms). Thus, the center of each flash occurs at the same time (t ms in this example). One method to achieve the desired color without affecting the percentage overlap is to individually adjust the current applied to each source. Brightness can be adjusted either by further current adjustments or the duration of the flash can be changed.
An infrared light emitter 103 may be optionally used to image the eye in the infrared spectrum. Contrast between the pupil and the iris may be improved with infrared illumination. The controller 110 modulates a light emission from an infrared light emitter 103 to create an infrared flash of light having a duration less than 40 ms, 30 ms, 20 ms, 10 ms, 5 ms, or 3 ms. The exact duration of the infrared flash may be constant, or may dynamically change in operation to provide varying exposures in camera 101 . A typical exposure time in some embodiments can be 2.6 ms. However, the exposure time may be varied by the controller 110 , for example, based on feedback from sensors.
Generally, a shorter exposure time can be better because images have less motion blur and are less affected by external light, but shorter exposure times also increase the peak electrical power demands of the device 100 and provide less light to the camera 101 .
In some embodiments, it is advantageous to minimize the energy emitted by the visible light stimulus to the retina when the infrared light is flashed on and off. First, peak power required by the device 100 is reduced by having light emitted from the light emitter 106 and infrared light emitter 103 occur at substantially different times. Additional advantages exist when the camera 101 acquires images during IR flashes. If the visible light during an IR flash is small, then chromatic aberrations in the images taken by the camera 101 are also small as the spectral content of the illumination is more limited. Moreover, if the visible light during an IR flash is small, the camera 101 can acquire images primarily in the infrared, which may improve contrast between the pupil and the iris, even if the camera 101 is sensitive to visible and IR light. It may be advantageous to have the camera 101 sensitive to both visible and infrared light in order to reduce cost and/or so that the camera 101 can provide visible-light features to the device 101 , such as reading information off of computer displays, smartphones, and the like.
Some embodiments with the optional infrared light emitter 103 do not have a camera 101 ; these embodiments may use the infrared light, for example, to trigger other devices by providing synchronization information.
The energy emitted by the first light emitter during the infrared flash of light can be less than 50%, 40%, 30%, 25%, 20%, 10%, 5%, or 1% of the energy emitted by infrared light emitter during the infrared flash of light. Similarly, in embodiments having a second light emitter, the energy emitted by the second light emitter during the infrared flash of light may be less than 50%, 40%, 30%, 25%, 20%, 10%, 5%, or 1% of the energy emitted by the infrared light emitter during the infrared flash of light.
In some embodiments, the first light emitter emits 0% of the energy emitted by the infrared light emitter during the infrared flash of light to minimize chromatic aberrations and to provide better contrast in the IR, as shown in FIG. 4A . If background illumination is used (e.g., as shown in FIG. 4B ), then some visible light during the infrared may be difficult to avoid and the percentage will be higher than 0%. Similarly, in embodiments having a third light emitter, the energy emitted by the third light emitter during the infrared flash of light may be less than 50%, 40%, 30%, 25%, 20%, 10%, 5%, or 1% of the energy emitted by infrared light emitter during the infrared flash of light.
The controller 110 can modulate a light emission from the first light emitter to create a light stimulus having a stimulus frequency greater than 7 Hz, including but not limited to the list of frequencies near 30 Hz enumerated below. The controller 110 may also modulate a light emission from the infrared light emitter 103 to create infrared flashes of light having durations less than 40 ms and an infrared flash frequency greater than 1 Hz.
In some cases, controlling the timing between the stimulus frequency and the infrared flash frequency can be advantageous so that, for example, the lighting created by the light stimulus interacts in a consistent manner with the infrared flashes. Other potential advantages of controlling the timing between the two frequencies include reduced peak power, better contrast with less chromatic aberration and less changes to lighting levels in embodiments using a camera sensitive to visible and IR light. Without time synchronization, lighting levels in embodiments using a camera sensitive to visible and IR light will vary at the beat frequency between the visible and infrared light frequencies.
In some embodiments, the energy emitted by the first light emitter during the infrared flashes of light is less than 50% of the energy emitted by infrared light emitter during the infrared flash of light, and the ratio of the stimulus frequency to the infrared flash frequency is within 1% of an integer or within 1% of the reciprocal of an integer, for example, the ratio can be 1.
The light emitter 106 generates visible light that can stimulate the visual system of a patient. In some embodiments, the light emitter 106 creates a light stimulus that occurs on a periodic basis having a stimulus frequency within 0.01 Hz of one of the following frequencies: 26.94, 27.13, 27.32, 27.51, 27.70, 27.90, 28.10, 28.31, 28.51, 28.72, 28.94, 29.15, 29.37, 29.59, 29.82, 30.05, 30.28, 30.52, 30.76, 31.00, 31.25, 31.50, 31.76, 32.02, 32.28, 32.55, 32.83, 33.10, 33.67 Hz, or integer multiples thereof. Other frequencies may be used.
In some embodiments, the light emitter 106 creates a light stimulus having a stimulus frequency within 0.1 Hz of 28.31, 28.72, or 32.55 Hz, or integer multiples thereof. The light emitter 106 , can creates flashes at a sufficiently large frequency (e.g., above about 50 Hz) so that the light appears to be constantly on. In some embodiments, the frequency is lower than 40 Hz and may appear to flash or flicker. In other embodiments, the light emitter 106 creates flashes at a frequency above about 50 Hz and additional light at a frequency lower than 40 Hz, creating the appearance of a flickering light on top of a constant background. For example, the device 100 can create a flickering light at a frequency within 0.01 Hz of 28.31 Hz and a perceptually-constant background at a frequency within 0.1 Hz of 283.06 Hz. In some embodiments, the light emitter 106 generates a light stimulus having a stimulus frequency greater than 7 Hz.
FIG. 4 shows exemplary timing diagrams for light waveforms described above. Plot 300 shows 1.5 periods of synthesized white light flash followed by an IR flash. Both the synthesized white light flash (also referred to as the stimulus) and IR flash occur at a stimulus frequency of about 28.306 Hz. Consequently, the ratio of the visible light flash frequency and the infrared light flash frequency is 1. Curve 301 depicts the luminance output of a green LED that is part of the light emitter 106 , as measured at the eyecup 107 . Curves 302 , 303 depict the corresponding luminance outputs from red and blue (respectively) LEDs that are also part of the light emitter 106 measured at the eyecup 107 . Curve 304 depicts output from the infrared light emitter 103 . In this example, there is no overlap between the output of visible light and infrared light.
Plot 310 is analogous to plot 300 , with the exception the addition of a background illumination. The background illumination is created in this example with 283.06 Hz flashes of the red, green, and blue LEDs, 7 of which are indicated by designator 315 . The 283.06 Hz background frequency is higher than the patient's critical fusion frequency and thus is perceived to be a constant illumination. While in this example, the background frequency is 10 times the stimulus frequency, other multiples are contemplated as well (including multiples of 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more). The red, green, blue, and infrared waveforms are indicated with the same dashing patterns as in plot 300 , and with the designators 312 , 311 , 313 , and 314 respectively. In the example shown in plot 310 , 2 of the background flashes occur during the infrared light emission and 1 of the background flashes occurs during the stimulus flash. The same or different light emitters can be used to create the background and stimulus illumination.
A camera 101 may be optionally used to image the eye of the patient periodically at a frame rate frequency. A controller 110 in the device 100 can use the images, for example, to detect the eye's pupil and measure its area. If the pupil cannot be detected, the device 100 may be configured to not present results as a safeguard to reduce the likelihood of presenting erroneous results. Alternatively, the device 100 may present results irrespective of a pupil being detected, which may be advantageous in cases such as stimulating the eye through a closed eyelid.
In certain embodiments, the controller 110 may modulate a light emission from the first light emitter creating a light stimulus having a stimulus frequency greater than 7 Hz, including but not limited to the list of frequencies near 30 Hz enumerated earlier in this disclosure. In some cases, controlling the timing between the stimulus frequency and the frame rate can be advantageous so that, for example, (a) the lighting created by the light stimulus interacts in a consistent manner with the image acquisition by the camera 101 , and/or (b) updates to stimulus luminance based on pupil area measurements happen in a consistent manner.
In some embodiments, the ratio of the stimulus frequency to the frame rate is within 1% of an integer or within 1% of the reciprocal of an integer, for example, the ratio can be 1. In some embodiments, the ratio of the stimulus frequency to the frame rate is greater than 7, for example, 8, 9, 10, 11, 12, 13, 14, 15, or more. High ratios can occur (but are not required to occur), for example, when using pulse-width modulation to create light stimuli that approximate a retinal irradiance that varying as a sinusoid, a square wave having a duty cycle between 30% and 70%, or a triangular wave. Further, when using a camera 101 with an infrared light emitter 103 to image the eye in the infrared, the frame rate may equal the flash rate from the infrared light emitter 103 (i.e., 1 IR flash per image) and the ratio of these rates to the stimulus frequency can be 1% of an integer or within 1% of the reciprocal of an integer (for example, 1).
Using the camera 101 , a controller 110 in the device 100 can measure the area of the patient's pupil. With this information, the controller 110 can adjust light stimulus as a function of the area. This adjustment may be useful, for example, to reduce the intra-patient and/or inter-patient variability that results from differences in retinal illumination caused by variations in pupil area. The adjustment of the light stimulus as a function of pupil area can occur at the frame rate frequency and/or other frequencies such as a frequency faster than 0.5 Hz, 1 Hz, 2 Hz, 5 Hz, 10 Hz or 20 Hz. The adjustment of the light stimulus as a function of the pupil area does not have to happen on a periodic basis; for example, a microprocessor on the controller may have a peak CPU load greater than 100% which causes an adjustment to be occasionally missed. As shown in Satoh et al. (1994), the timing of the response to a 30 Hz flicker stimulus depends on the intensity of the light. In Satoh et al. (1994), the eyes were dilated and an artificial pupil having a diameter of 5 mm was inserted so as to make the stimulus pupil size independent.
Exemplary relations between luminance of the visual stimulus and the pupil area are shown in FIG. 3 , where FIG. 3A shows the relation between the light emitted from the device 100 and pupil area; FIG. 3B shows the relation between retinal illuminance and pupil area. Curve 201 shows a flash luminance that is independent of pupil area. In this case, as shown by Curve 211 , the total amount of light entering the eye changes linearly with pupil area. In some embodiments, the light stimulus can be linearly related to the multiplicative inverse of the eye's pupil area. For example, the light stimulus can be made so that the energy entering the eye is constant, independent of pupil size. Curves 203 and 213 show this relation, where the amount of light entering the eye is constant.
In other embodiments, the light stimulus can be related to the multiplicative inverse of the eye's pupil area through a non-linear, concave function. Using a non-linear concave function can compensate for the eye's reduced sensitivity to light entering away from the center of the pupil (e.g., the Stiles-Crawford effect). In these cases, the amount the light is reduced as the area increases is smaller than the amount that the pupil area increased. Curves 202 and 212 show this relation, where the amount of light entering the eye increases slowly with pupil area, as the effectiveness of stimulating the retina is reduced for light not entering the center of the pupil.
In some embodiments, the device 100 may measure the area of the patient's pupil. In cases where the area of the pupil cannot be measured (for example, because the eyelids are closed), the controller 110 may estimate the pupil size based on previous measurements. If the pupil has not yet been identified, the controller may indicate so to the device operator and not provide a result (i.e., an indication of visual system function). The controller 110 may be arranged so as to wait indefinitely or for a predetermined amount of time before the initial pupil acquisition before proceeding with the remainder of the test process. This fail-safe procedure helps prevent erroneous results. Additionally, if the pupil size has been measured but has subsequently been lost and not been measured for at least a predetermined amount of time (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 second or more), the controller 110 may also indicate an error to the device operator and not provide a result.
In some embodiments, the device 100 has a light detector 105 that can monitor the output of the light emitter 106 . The light detector 105 can comprise, for example, a photodiode. The light detector 105 can also monitor the amount of light originating outside the device 100 that enters the optical assembly 104 (herein called “external light”). The light detector 105 can generate an expected set of signals, based for example on expected levels of external light and/or expected levels of the light emitter 106 . If these expectations are not met, the controller 110 may not provide a result.
Certain visual tests depend on the amount of background illumination. If the eyecup 107 is pressed against the skin surrounding the eye to be tested, the amount of external light is reduced. Nevertheless, some external light may be present and act as additional background illumination. If the amount of external light exceeds a threshold, the light detector 105 can be used to detect this case to prevent providing erroneous results. For example, the threshold can be between 1 cd/m 2 and 200 cd/m 2 . The threshold can be between 3 cd/m 2 and 30 cd/m 2 . The threshold can be between 10 cd/m 2 and 100 cd/m 2 .
The amount of external light may be combined with information regarding the pupil size of the eye being tested to determine if the amount of external light is too large. For example, the threshold can be a value between 10 Td and 1000 Td. The threshold can be a value between 30 Td and 300 Td. In some embodiments, the threshold can also depend on the stimulus. For example, dimmer stimuli may require a lower threshold.
In some embodiments, the amount of external light can be used to modify the stimulus in order to reduce the effect of external light on the electrical measurement.
The optional light detector 105 may be used to monitor the light stimulus so that the controller 110 can compensate for variations in the output of the light emitter 106 or the optical efficiency of the optical assembly 104 . The controller 110 can adjust, for example during a calibration phase of a test, the output of light emitter 106 in order to achieve a desired signal from light detector 105 . If the adjustment is too great, the device 100 may be configured to report an error rather than possibly providing erroneous results.
In some embodiments, the device 100 has an electrical impedance meter measuring the impedance associated with the electrical signal received from the visual system of the patient attached through the patient connector 108 . If the impedance is too large, the device 100 may not be electrically connected to the patient or the connection may be of such a poor quality as to comprise the signal quality. In some embodiments, the controller 110 does not provide an indication of visual system function unless the impedance is less than a target value, such as 1 GΩ, 500 MΩ, 150 MΩ, 15 MΩ, 1.5 MΩ, 150 kΩ, 100 kΩ, 50 kΩ, 25 kΩ, 10 kΩ, or 5 kΩ. The high end of these values (e.g., 1 GΩ, 500 MΩ, 150 MΩ, or similar) enables embodiments to reveal whether or not something is connected. If impedance down near the lower end is utilized, the embodiments may indicate that an effective connection with little noise has been made. However, achieving the lower end of impedance may not be reasonably practicable or worthwhile because of the skin preparations required to get that low of an impedance. In some embodiments, the impedance near the high end (150 MΩ) is sufficient. Other embodiments may require a lower impedance.
Turning to FIG. 5 , three exemplary timing diagrams for light waveforms are shown. In FIG. 5A , Plot 400 shows 2 periods of synthesized white light, occurring at a stimulus frequency of about 28.306 Hz. Curve 402 represents the desired sinusoidal stimulus while pulse train 401 represents a pulse-width modulation (PWM) approximation to curve 402 . In this example the PWM period is 10 times the stimulus period; however, other ratios of stimulus period to PWM period are contemplated, including ratios greater than or equal to 7. In some embodiments, integer ratios are preferred because each period is thereby more similar to each other. Curve 402 shows 2 periods, however, the amplitude of the 2 periods are not the same.
As described above, using the camera 101 , a controller 110 can measure the area of the patient's pupil. With this information, the controller 110 can adjust the luminance as a function of the area. Between the first and second period of curve 402 , the device 100 measured the pupil to be smaller and therefore increased the brightness of the desired light waveform in order to reduce the effect of pupil size on retinal stimulation.
In FIG. 5B , Plot 410 is analogous to Plot 400 , except the desired light waveform is a triangular wave. Curve 412 is the desired triangular wave and pulse train 411 is the PWM approximation thereof. In FIG. 5C , Plot 420 is also analogous to Plot 400 , except a square wave is the desired light waveform. Curve 422 is a 50% duty cycle square wave. Other duty cycles are also contemplated, for example square waves having a duty cycle between 30% and 70%, and square waves having a duty cycle between 40% and 60%. Short duty cycles (e.g., <20%) may be implemented with a single flash such as shown in FIG. 4 .
Pulse train 421 is a PWM approximation to Curve 422 . In this example, the stimulus period is 20 times the PWM period. Curve 422 has the second period being smaller in amplitude than the first, which may occur, for example, when the device 100 measures an increase in pupil area. In some embodiments, the device 100 directly synthesizes a continuous light waveform that approximates a retinal irradiance that varies as one of a sinusoid, a square wave having a duty cycle between 30% and 70%, or a triangular wave.
In some embodiments, the device 100 uses pulse-width modulation (PWM) to create a light stimulus approximating a retinal irradiance varying as one of a sinusoid, a square wave having a duty cycle between 30% and 70%, or a triangular wave. For example, the controller 110 can use PWM to control the output of a first light emitter and a second light emitter in order to deliver a periodic visual stimulus to the eye approximating a retinal irradiance varying as one of a sinusoid, a square wave having a duty cycle between 30% and 70%, or a triangular wave. For example, the controller 110 can use PWM to control the output of a first light emitter and a second light emitter in order to deliver a periodic visual stimulus to the eye approximating a retinal irradiance varying as a sinusoid.
The controller 110 in the electronics board 109 can be any of those known in the art. The controller 110 can be a single microprocessor, for example, one sold by Analog Devices, Atmel, Intel, Microchip, Texas Instruments, etc. Alternatively, the controller 110 can be distributed among many integrated circuits on one or more printed circuit boards in the device 100 . The controller 110 can be configured to modulate the light output of a first light emitter and to receive and analyze the electrical signal from a patient.
In some embodiments, the controller 110 can communicate with a camera and measure the pupil size in images taken with the camera. In some embodiments, the controller 110 can modulate the light output from additional light emitters, such as a second light emitter, a third light emitter, and/or an infrared light emitter. The controller 110 can provide to the operator an indication for visual system function of a human using a display and/or providing a means to communicate the information to a computer or other electronic device.
While the above descriptions have emphasized compositions, methods of their use are also contemplated. To provide an indication of visual system function, the methods involve illuminating an eye of the patient with a light stimulus. The methods also involve either receiving and analyzing an electrical signal from the patient so as to provide an indication of visual system function or measuring the electric potential difference between a first electrode and second electrode so as to provide an indication of visual system function.
Illuminating the eye may comprise visible flashes of light having a duration less than 21 ms from 1, 2, 3, or more distinct spectral sources. When these flashes of light come from a plurality of spectral sources, they can be configured to overlap in time by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the longest of the flashes so as to reduce the timing uncertainty as described earlier in this disclosure.
The methods may involve measuring the eye's pupil area and adjusting the energy in the first flash (or other light stimuli) as a function of the eye's pupil area, for example, wherein the energy in the first flash is linearly related to the multiplicative inverse of the eye's pupil area or wherein the energy in the first flash is related to the multiplicative inverse of the eye's pupil area through a non-linear, concave function. In some methods, the light stimulus comprises flashes of light having a flash frequency greater than 7 Hz and the measuring of the eye's pupil area occurs at a frame rate wherein the ratio of the flash frequency to the frame rate frequency is within 1% of an integer or within 1% of the reciprocal of an integer—these features may occur separately or together with the overlapping flashes described above. In some methods, the light stimulus comprises flashes of light having a flash frequency greater than 7 Hz and the eye is also illuminated with infrared flashes of light that have most of their energy emitted at wavelengths longer than 710 nm, wherein the infrared flash frequency is greater than 1 Hz, wherein the energy emitted by the first light emitter during the infrared flash of light is less than 50% of the energy emitted by infrared light emitter during the infrared flash of light, and wherein the ratio of the stimulus frequency to the infrared flash frequency is within 1% of an integer or within 1% of the reciprocal of an integer—these features may occur separately or in any combination of frame rate and overlapping flash methods described above.
Some methods involve placing an electrode array comprising three electrodes on the skin of the patient as a single unit, wherein the three electrodes include a first electrode, a second electrode and a third electrode, wherein the first and second electrode are more distant from each other than any other pairing of the first, second, and third electrodes, which can occur separately or in any combination with infrared flashing, frame rate, and overlapping flash methods described above.
Some methods involve measuring the eye's pupil area and adjusting the luminance of the light stimulus through a non-linear, concave function of the eye's pupil area, which can occur separately or in any combination with the electrode array, infrared flashing, frame rate, and overlapping flash methods described above. Some methods involve measuring the eye's pupil area and adjusting the luminance of the light stimulus as a function of the eye's pupil area, wherein the light stimulus that approximates a retinal irradiance that varies as one of a sinusoid, a square wave having a duty cycle between 30% and 70%, or a triangular wave, which can occur separately or in any combination with the electrode array, infrared flashing, frame rate, and overlapping flash methods described above.
Some methods include techniques to reduce erroneous results, each of which can be used separately or in combination with any of the other methods. Some methods include attempting to locate the eye's pupil in images taken by a camera and not returning an indication of visual system function unless the eye's pupil has been identified. Some methods include receiving a signal from the light detector and not returning an indication of visual system function if the signal from the light detector differs from a set of expected light detector signals, wherein the set of expected light detector signals comprises monitoring for external light exceeding a threshold. The threshold can be any of those described above, including those dependent and independent of pupil area. Some methods include measuring the eye's pupil area and adjusting the luminance of the light as a function of the eye's pupil area, and measuring an electrical impedance associated with the electrical signal received from the patient, wherein the indication is not provided unless the electrical impedance meter measures an impedance smaller than a target value. The target value can be any of those described above, including those in the GΩ, MΩ, and kΩ range.
All references cited herein are incorporated by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
All numbers expressing quantities used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
The above description of devices includes many novel and advantageous aspects. Combinations of the aspects are also contemplated. It will be apparent to those skilled in the art that various modifications and variations can be made in the disclosed detection device, components, and methods without departing from the scope of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope of the invention being indicated by the following claims and their equivalents.
The terms and descriptions used herein are set forth by way of illustration only and are not meant as limitations. Those skilled in the art will recognize that many variations are possible within the spirit and scope of the invention as defined in the following claims, and their equivalents, in which all terms are to be understood in their broadest possible sense unless otherwise indicated.
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Han, Young-Keun, and Young-Hoon Ohn. (2000) “Changes of ERG Parameters in Diabetic Retinopathy.” J Korean Ophthalmol Soc, 41:149-155.
Holder, Graham, et al. (2007) “ISCEV standard for clinical pattern electroretinography—2007 update.” Doc Ophthalmol, 114:111-116.
Hood, Donald, et al. (2012) “ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition).” Doc Ophthalmol, 124:1-13.
Kjeka, O, R W Jansson, C Bredru, and J Krohn. (2013) “Early panretinal photocoagulation for ERG-verified ischaemic central retinal vein occlusion.” Acta Ophthalmol, 37-41.
Marmor, M F, et al. (2009) “ISCEV standard for full-field clinical electroretinography (2008 update).” Doc Ophthalmol, 118:69-77.
Odom, Vernon, et al. (2010) “ISCEV standard for clinical visual evoked potentials. (2009 update).” Doc Ophthalmol, 120:111-119.
Satoh, S, H IIjma, M Imai, K Abe, and T Shibuya. (1994) “Photopic electroretinogram implicit time in diabetic retinopathy.” Japanese Journal of Ophthalmology, 38: 178-184.
Severns, M L, Johnson, M A and Merritt, S A. (1991) “Automated estimate of implicit time and amplitude of the flicker electroretinogram.” Applied Optics 30:2106-2112.
Severns, M L and Johnson, M A (1991) “Automated implicit time and amplitude determination for the 30 Hz flicker electroretinogram: performance prediction of neovascularization central retinal vein occlusion.” Technical Digest Series , Washington, D.C.; Optical Society of America, pp. 10-13.
Shapiro, A G, Pokorny J, and Smith V C. (1996). “Cone-rod receptor spaces with illustrations that use CRT phosphor and light-emitting-diode spectra.” J. Opt Soc. Am. A., 2319-2323.
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BACKGROUND OF THE INVENTION
This invention relates to the manual assessment of muscle strength. More particularly, the invention relates to a portable, manual muscle tester and to the method of using same.
Manual muscle testing is the most widely used method of physical examination for clinical evaluation of muscle strength. Manual tests are commonly used to monitor a patient's progress during an extended period of rehabilitation or recovery. These tests are also used to determine differences in strength between individuals and to determine strength deficits in a given individual. In the latter case, deficits are detected by the comparison of contralateral limb segments or muscle groups. Manual muscle tests are employed, as well, to locate weakness in areas not previously suspected by the patient. The area of weakness is often far removed from the site of pathology, and such weaknesses are related to the musclo-skeletal linkage systems of the body. Manual testing is also used in the design of rehabilitation or strengthening programs for individuals who have been injured or wish to undertake an activity for which they are not properly conditioned.
Typically an examiner (and by this is meant a physician, therapist, athletic trainer, or coach, for example) asks a patient to maintain a specific posture with the limb being tested. The examiner applies pressure downward with one or two hands and judges subjectively the patient's resistance. For example, the examiner may judge the force he must apply to a limb in order to lower it from a raised position. The resistance is quantified subjectively with a grade from 5 (maximal) to 0 (no contraction). For purposes of comparison, a patient's unaffected limb is similarly tested. From day to day or week to week, the examiner relies on a subjective determination to measure the patient's progress.
Manual muscle testing is essentially a subjective evaluation and is unreliable when performed by different individuals who may use different techniques. Several attempts to standardize manual testing procedures have been made and many devices to measure strength have been proposed. One of the earliest, which dates back to 1912, is a spring scale device. Lengthy reviews are now available on various devices and their use. Despite the obvious disadvantages of a subjective test of a muscle strength, manual muscle testing, without instrumentation, continues to be the predominant method used in the clinical setting. Until recently, few, if any, dynamometers (strength measuring devices) offered objective, accurate evaluation of dynamic muscle strength.
The patent literature proposes devices for measuring strength. For the most part, these are large, cumbersome, immobile, and specially adapted to test particular muscles, those of the legs, for example, or those of the arms. In one case, portability of a test device is recognized and a fluid filled cylinder and pressure gage arrangement is suggested. No provision is made for this device to retain the maximum pressure gage reading. A dial gage indicates force applied to the fluid cylinder plunger and typically these are much harder to read than a clear digital, numeric force indication, particularly when the indication quickly varies, as in all muscle testing procedures.
The physician, physical therapist, athletic trainer who tests a subject's strength is aware of what muscles contribute what forces and in what directions. A simple example clarifies the importance of selective measurement. A subject's leg is commonly tested by having the subject sit and raise his foot off the floor. The examiner applies pressure downward at the knee gradually until he overcomes the subject's resistance and the leg moves downward. The examiner is interested in those muscles resisting downward force. In this test, the examiner is not concerned, for example, with the forces resisting rotational movement from the hip to the knee, or those forces resisting movement of the leg from side to side. Likewise, the examiner does not want his measurement to include force components directed longitudinally along the upper leg to the hip. A manual muscle tester should permit the examiner to distinguish between the forces that are of interest, and those that are not.
For ease of operation, a portable manual muscle tester should be simply used, preferably in a manner closely akin to the testing that the examiner currently uses. The unit should be easy to operate without elaborate attachment to the patient or subject, should be easy to read, afford repeatability in its strength indications from one test to the next, should require no elaborate or time consuming setup procedure, and should be of a size, shape, and weight such that the examiner will readily keep it with him throughout the day.
BRIEF SUMMARY OF THE INVENTION
In accordance with this invention, an improved, manual muscle tester is provided. The unit is light weight, small enough to be held in one hand, accurate, and easily read. This instrument responds only to forces applied along an axis perpendicular to its face, it is battery operated, and its digital output freezes at the maximum measured force.
Under the direction of Dr. James A. Nicholas, a device for objectively quantifying muscle strength has been a longstanding goal of The Institute of Sports Medicine and Athletic Trauma (ISMAT). Dr. Nicholas began actively researching this problem when he realized the importance of measuring hip flexor strength in patients with osteoporosis. In this work, the following characteristics have been concluded to be important:
1. readily quantified muscle force outputs indicative of strength;
2. palm-sized, compact, and portable;
3. wireless;
4. not susceptible to eccentric loading.
The present invention meets the above objectives. It has a digital display that freezes at the peak force, and optionally an output analog signal as well. It is small and light. The unit is self contained, being battery operated and requiring no wires to a source or to auxiliary equipment. A uniquely constructed flexure to which the input force is applied and small integrated circuits contribute to the instrument's compactness. The flexure and a strain gage bridge circuit eliminate forces other than those applied in the chosen direction.
The size and weight of the instrument of this invention permit the examiner to use the same procedures with which he is familiar. In fact, since the examiner exerts force in much the same way as before, to test the patient's resistance, he or she need not entirely discard the subjective evaluations that may result from years of experience. In the test described above, for example, the examiner will still be aware of the force resisting downward movement of the leg when the force is applied through the instrument to the raised knee.
Because the subject unit is wireless as well as compact, it invites the examiner to carry it, to use it regularly, and to become accustomed to relying on the more objective indication of the patient's strength.
The input beam or "flexure" and the bridge circuit discard forces applied to the tester other than in a direction parallel the axis of movement of an actuator that the patient engages. The flexure is a cantilever beam connected to the manual actuator. The beam has four strain gages arranged thereon to form a bridge circuit. An output signal from the bridge circuit is proportional to force applied in the direction of actuator movement perpendicular to the beam. Forces other than the perpendicular forces are cancelled. The cantilever beam is constructed to prevent stresses being reflected back to the strain gages from the location where the beam is connected to its support. At its supported end, remote from the actuator, the beam is T-shaped. The arms of the T turn downward. At their down turned ends, the arms of the T-shaped beam adjoin a support block which supports the beam. The block is centrally recessed to allow the stem of the T-shaped beam to flex along its length from the actuator to its top where it joins the arms. By removing the support locations from the path of strain communicated along the stem from the actuator to the gages, this shape prevents reflected stress or stress introduced by the attachment of the beam and support block from contributing to the measurements made by the strain gages. The beam shape, moreover, contributes to the unit's compactness.
The output display of this manual muscle tester is located on the opposite side of its case from the actuator. This digital force indication faces away from the subject and towards the examiner for easy reading. Because, with each test, the digital force indication freezes at its maximum, the examiner can concentrate on properly testing his subject, rather than having to concentrate on reading the force indication during the test. In addition to the digital peak force indication, a force versus time analog signal is made available at an output jack and is suitable for recording or display.
Distinctly beneficial features reside in the circuitry that translates the force applied to the actuator into the digital display that the examiner reads. The digital meter circuit is ratiometric. It employs the same input or reference voltage as the strain gage bridge. Because the voltage being measured is derived from the same input voltage as the reference voltage applied to the meter, reference voltage changes do not contribute error, the ratio measured remains the same.
A calibration check is provided by switching a fixed resistance into parallel with one of the resistances of the bridge to provide an imbalance. If the electronics and batteries are in acceptable condition, a particular digital output will be displayed when the bridge is thus unbalanced.
The bridge output is supplied to an instrumentation amplifier. Its output supplies an operational amplifier of the peak freeze circuit. Special attention is given to preventing rapid discharge of a peak freeze capacitor storing the voltage from which the output display is derived. A second high input impedance operational amplifier connected in the feedback loop of the first operational amplifier helps maintain the charge on the peak freeze capacitor and compensates for the diode characteristics by including them in the feedback path of the amplifiers.
Depressing the reset switch has a two-fold purpose. It provides a discharge path for the peak freeze capacitor and it also connects the output of the peak freeze circuit to yet another amplifier which is wired as an integrator for automatically zeroing the electronics when there is zero force on the balance. The output of the integrator introduces a voltage to the reference input of the instrumentation amplifier with such a polarity that its output is driven to zero. During a test, the integrator maintains the proper no-load voltage to the instrumentation amplifier.
The above and further advantages of the invention will be better understood from the following detailed description of a preferred embodiment taken in consideration with the several figures of the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is a perspective view of a manual muscle tester in accordance with the invention.
FIG. 2 is a top view of the instrument of FIG. 1.
FIG. 3 is an exploded perspective view showing the shape of the flexure and the relationships of the parts of the instrument.
FIG. 4 is a diagrammatic illustration of the actuator, cantilever beam, and strain gage relationship.
FIG. 5 is a diagrammatic and shows one manner of using the manual muscle tester.
FIG. 6 is a schematic of the circuit that translates the input force to the digital display.
DESCRIPTION OF PREFERRED EMBODIMENT
In FIG. 1 a manual muscle tester 10 according to this invention includes a case 11 with a digital display 12 representing a force F applied to an actuator 13 parallel to the axis of movement 14 of the actuator. On the case of the instrument 10 can be seen, in FIG. 1, a switch 16. This is the unit's on-off switch. A switch 18 labeled "Reset" sets the meter back to zero as described more fully below. An adjusting screw 20 labeled "Zero" sets the display 12 at zero when no force is applied, and an adjustment screw 22 labeled "Cal" operates in cooperation with a switch 23 labeled "Cal" to calibrate the meter whose display is shown at 12.
The actuator 13 has a stem 24 (FIG. 3) extending into an opening 25 in the case 11. The stem terminates in a threaded end 26 of reduced diameter as shown in FIG. 3. In this figure, one sees a cantilever beam or flexure 28 bored and tapped at 29 to receive the threaded end 26 of the actuator stem. The cantilever beam 28 has a T shape with down-turned arms 31 and 32. These have tapped and threaded openings 33 and 34 aligning with openings 35 and 36 in a mounting block 38. A pair of bolts 41 and 42 extend upward through the openings 35 and 36 and thread into the openings 33 and 34 to secure the down-turned arms of the T-shaped beam to the block 38, thus supporting the block in cantilever fashion. A recess 39 in the block 38 aligns with the longer central stem 30 of the T-shaped cantilever beam 28 and permits the beam's central stem 30 to flex downward between its arms 31 and 32 without interference by the mounting block.
In addition to the mechanical components of the instrument, in FIG. 3 one sees a pair of nine volt batteries 44 and 45 that power the unit. The printed circuit card 47 that is the digital volt meter whose display is shown at 12 in FIG. 1 appears in this Figure, and a printed circuit card 48 that cooperates with a strain gage bridge to translate input force to the analog signal read by the digital volt meter 47 appears, as well. In FIG. 3 two of the strain gages 50 and 51 that make up the bridge can be seen. Two further gages are similarly positioned on the under surface of central stem 30 of the beam 28.
The diagram of FIG. 4 illustrates the manner in which the beam 28, the actuator 13, and the strain gage bridge translate force parallel the axis 14 (or perpendicular to the face of the beam) into an electrical signal indicative of that force only. That parallel force is designated F in FIG. 4 and a force component perpendicular to the axis 14 is designated S. The two additional strain gages 52 and 53 are seen located spaced apart lengthwise on the stem 30 of the beam 28 directly below the gages 50 and 51. The four gages are connected together in a bridge circuit 55, illustrated in FIG. 6. A reference or input voltage is applied across the bridge from a junction 56 of the gages 51 and 50 to a junction 57 of the gages 52 and 53. A force indicative output signal V is taken from the remaining junctions 58 and 59.
The strain measurement M 1 in the beam 28 at the location of the gages 50 and 52 is:
M.sub.1 =F(A+L)-SR,
where
F is the force normal to the beam (parallel the axis 14);
A is the distance between the two gage locations lengthwise of the beam;
L is the distance between the gages 51 and 53 and the stem 24;
S is the force parallel the beam (normal to the axis 14); and
R is the length of the stem.
The strain measurement M 2 at the gages 51 and 53 is:
M.sub.2 =FL-SR.
As connected, the bridge subtracts the two measurements to arrive at M 1 -M 2 . Substituting:
M.sub.1 -M.sub.2 =FA+FL-SR-FL+SR,
M.sub.1 -M.sub.2 =FA.
Therefore, the bridge output is directly proportional to F, the force normal to the beam.
In FIG. 5 a typical test procedure is shown. The patient or test subject sits, elevates his leg and resists the downward force F applied by the examiner. The peak force F which will appear and remain on the display of the meter of the unit 10 will be the force needed to overcome the patient's resistance and move the knee downward. The forces S transmitted substantially parallel the upper leg from knee to hip will not contribute to the force measured by the instrument. This force, communicated back along the femur to the hip, is only the resistance of the patient to movement backward on the table and is no part of the force F that the muscles exert in resistance to the examiner's downward force F.
FIG. 6 illustrates the circuitry of the manual muscle tester. The two small nine volt batteries 44 and 45 supply the circuit through the on-off switch 16. A commercial voltage regulator 65 (National Semiconductor LM330, for example) provides a positive five volts across a capacitor 66 connected between a positive input or supply line 67 and a zero volt reference or supply line 68. A voltage convertor 70 serves as a power supply. Connected in its conventional manner between the lines 67 and 68 a commercially available integrated circuit 72 (such as the ICL 7660 of Intersil) provides a negative five volts to a line 73. The ten volts between line 73 and the line 67 are supplied as the input to the strain gauge bridge 55.
The bridge output, at junctions 58 and 59, is applied, via lines 81 and 82 to input terminals of an instrumentation amplifier 85 (e.g. Analog Devices AD521). The amplifier 85 is connected to provide a gain of 200. The output of the instrumentation amplifier is fed via resistance 89 to a "peak freeze" or peak detection circuit 86. This output is made available, for example, at a jack 88, as an analog output suitable for recording and/or display. The analog representation represents force throughout the time of the test procedure and does not freeze at peak force.
The peak detection circuit 86 includes a first operational amplifier 87 (such as RCA's CA 3130). The amplifier is connected to have a gain of one. A pair of diodes 90 and 91 connect the output of the operational amplifier 87 to a 0.47 μf peak freeze capacitor 93. The diodes prevent discharge of the peak reading or peak freeze capacitor. The peak freeze capacitor 93 and a 330 ohm resistor are connected in series between the zero volt reference line 68 and an input to a second operational amplifier 97 (e.g., National Semiconductor LH0052). This amplifier 97 is provided in the feedback loop of the first operational amplifier 87 along with a 20KΩ resistance 98. It is the output of this second operational amplifier 97 that, through the potentiometer 22, supplies the digital meter that indicates input force.
Inclusion of the second amplifier 97 protects the peak freeze capacitor 93 from bleed-off by virtue of its high input impedance. Use of the two diodes 90 and 91 allows a high resistance 101 to be connected between the feedback from the second operational amplifier to the junction of the two diodes. The resistance 101, one MΩ for example, keeps the anode side of the diode 91 at the same high voltage as the output of amplifier 97 after the output voltage from the amplifier 87 has dropped. This prevents drain-off of the peak freeze capacitor 93 by slight reverse current back through the diodes 90 and 91 when the input force to the manual muscle tester has been reduced and the output of the operational amplifier 87 drops.
Connection of the two diodes 90 and 91 along with the operational amplifier 97 in the feedback loop of the amplifier 87 also removes the "knee" or nonlinear portion of the characteristic curve of the diodes to produce a much more linear relation between the input to the peak freeze circuit and its output. By virtue of the apparent lack of feedback the gain of the peak freeze circuit, which can be viewed as a single amplifier, increases dramatically in the low voltage region, where the diode "knee" is evident, until the output is clamped at the input voltage. A diode 99 connected from the output of the operational amplifier 87 to the feedback path connection that amplifier's inverter terminal prevents the output of that amplifier from going negative during the zeroing and meter resetting described below.
The adjustable arm 103 of the potentiometer 22 provides the input to the digital meter 47. The meter is a digital volt meter (e.g., Printed Circuit International's PCIM 176) with reference connections connected between the line 67 at positive five volts and the line 73 at negative five volts. The potentiometer 22 calibrates the meter. The meter connection is ratiometric; the meter reference voltage is the same ten volts as the bridge input. The meter compares the peak freeze output of the amplifier 97 with the ten volts across the bridge. Changes in the input or reference voltage affect proportionally the force indicative voltage applied to the meter and do not affect the ratio that the meter reads. Thus, such changes do not result in error in the displayed value.
Calibration of the meter is checked by closing a calibration switch 23. The switch is in series with a calibration resistance 106 and connects the resistance 106 in parallel with one of the strain gage resistances of the bridge. This imparts a standard imbalance to the bridge. Each time the calibrate switch 23 is closed, then, the same digital reading should appear on the meter. If this does not occur, correction is made at the potentiometer 22.
To reset the instrument to zero, having tested a patient and noted the force indicated by the meter, a double pole single throw reset switch 18 is closed. One pair of contacts 18' connects the output of the amplifier 97 through a resistance 109 to an input of yet another operational amplifier 110 (again, LH0052, for example). This amplifier is connected as an integrator. Its storage capacitor 112 in its feedback path stores the voltage necessary to produce a zero meter reading when no force is applied to the actuator 13. A variable resistance 20 is shown connected to the amplifier 110 in the manner that is conventional for adjusting offset voltage. This variable resistance has been adjusted initially, in the absence of any input force, to bring the meter 47 to zero. The adjusted offset voltage, stored by the capacitor 112, is the slight voltage needed to compensate, for example, slight error voltages such as may appear from the bridge or as offset voltages of the instrumentation and further operational amplifiers.
When the contacts 18' close, the negative integral that is the output of the zeroing amplifier 110 is supplied to pin 11 of the instrumentation amplifier 85. Pin 11 has a gain of one relationship with the output pin 7. Hence, the negative integral is applied as an input to the first of the operational amplifiers, amplifier 87. This drives the output of that amplifier 87 to zero and discharges the peak freeze capacitor 93 through a resistance 111 and the remaining contacts 18" of the double pole single throw reset switch 18. The output of the amplifier 97 becomes zero and the digital meter registers zero.
Thus it will be seen that a compact, easy to read, and accurate manual muscle tester is provided. The forces applied other than along the instrument actuator's axis of movement are cancelled. The circuitry translating the input force to the digital output display enhances easy reading through its peak detection "peak freeze" operation. An analog voltage is also provided so that a complete time history of a test may be recorded, written on a strip chart recorder, or otherwise displayed. The circuit is especially adapted to be largely impervious to input or reference voltage variations through its ratiometric meter operation. The size, arrangement of the physical package, and the few adjustments necessary make the instrument easy to use by physicians, physical therapists, trainers, and coaches, unskilled in the operation of complex instruments. Its manner of use is very much like the subjective manual muscle tests already familiar to many.
Although a specific, preferred embodiment has been described in detail, modifications within the spirit and scope of this invention will be readily apparent. For example, the analog peak reading circuiting of the "peak freeze" provisions can be accomplished digitally by, for example, analog to digital convention of the bridge output, storage of the peak value in memory and display or stored peak in units of force. Accordingly, the foregoing description of the preferred embodiment is not to be construed as limiting the scope of this invention as defined in the appended claims.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of application, Ser. No. 07/850,891, filed Mar. 13, 1992 now U.S. Pat. No. 5,469,492.
TECHNICAL FIELD
The subject invention is related to systems for operating medical X-ray equipment, such as that which is illustratively used in diagnostic or radiographic rooms.
BACKGROUND OF THE INVENTION
Conventional equipment for performing diagnostic X-rays on human patients comprises an X-ray source, usually a combination of an X-ray tube, a collimator, and various control mechanisms. The X-ray source generates and focuses X-rays. The patient is interposed between the X-ray source and an X-ray sensitive film, which is typically packaged in a cassette insertable into a holder.
The X-ray source and film holder are typically mounted on separate stands which allow the X-ray source and film to be manipulated and oriented with respect to patients of different sizes, and to allow X-rays to be taken of different parts of the body. Typically, a film holder for receiving an X-ray sensitive film cassette is mounted on a stationary stand. That stand includes siderails so that the film holder can be slidably vertically positioned along the stand. The X-ray source is also typically mounted on a stand for vertical motion. More specifically, an X-ray source may be mounted on a carriage which is adapted to slide up and down on a main column or tube stand. Accordingly, the height of the film and X-ray source can be adjusted by moving the respective vertically moveable carriages to the height which is appropriate for a particular patient or a particular exposure.
It is also necessary to adjust the distance between the film and the X-ray source. In the system described above, the tube stand for the X-ray source is mounted on a carriage. The carriage is adapted to slide back and forth along a track mounted in the floor, and the top of the tube stand travels along a rail, typically mounted to the wall. In this manner, the column along with the attached X-ray source may be moved in a horizontal direction so that the source may be set at the appropriate distance from the film.
In another type of prior art device, such as that disclosed in U.S. patent application Ser. No. 07/850,891, now U.S. Pat. No. 5,469,492 a wall-mounted frame for the X-ray source is stationary, and does not move horizontally. This frame does not include a central column, but rather includes spaced vertically extending side rails. A first carriage or tube slide is mountable on the side rails for vertical motion. This first carriage also includes top and bottom rails. A second carriage, to which the X-ray source is attached, is mountable on the tube slide for horizontal movement. Accordingly, vertical movement of the X-ray source is achieved by moving the tube slide on the side rails, and horizontal movement is achieved by moving this second carriage horizontally along the tube slide. A similar range of motion to the previously-described device is provided, but without the need for a floor-track, which may be undesirable for a variety of reasons.
Other prior art systems also exist which are adapted for use with a radiographic table. In a radiographic table, the X-ray film cassette is typically disposed underneath the table surface to allow X-rays to be taken of reclining patients. In such prior art devices, a stand similar to the latter one described above may be used. That is, a wall mounted frame includes side rails or other track means for receiving a tube slide which is moveable vertically on the stand. That tube slide, in turn, carries a second carriage which is horizontally moveable. In such a device, the radiographic table must be located in close proximity to the stand, since the X-ray source does not extend away from the second carriage to a great extent. This can be inconvenient in that the operator must often reach over the patient and the radiographic table for the purpose of adjusting the position of the X-ray source.
All the prior art systems just described include a support means for the X-ray source mounted adjacent to a wall. A slidably movable carriage or slide is supported on the support means such that this combination provides for vertical and horizontal translation of the X-ray source in a plane parallel to the wall for the purpose of properly positioning the source. While vertical and horizontal movement of the source are desirable, further ranges of motion for the X-ray source would also be desirable. For example, the possibility of moving the X-ray source vertically perpendicular away from and toward the wall would be advantageous. For the case of use of a radiographic table, such extension would allow the radiographic table to be placed a greater distance away from the stand upon which the source is mounted. This would lead to increased ease of movement both of the stand and of the reclining patient. Moveover, X-rays could be taken at a variety of positions away from the wall, wherein the same X-rays in prior art devices would need to be taken by means of moving the patient underneath the stationary X-ray source. With the X-ray source positioned away from the wall in this manner, the source could potentially become an obstacle to patients and medical personnel when not in use. Accordingly, another desirable range of motion for the X-ray source is rotation about a vertical axis so that the source, which normally extends away from the wall, could be folded to a position adjacent the wall.
An object of this invention, therefore, is to provide systems and assemblies for mounting X-ray equipment which allow for vertical and horizontal adjustment of an X-ray source, as well as additional ranges of motion. A further object of the invention is to provide such systems and assemblies which allow for such movement with a minimum of operator effort.
Another object of the subject invention is to provide systems and assemblies wherein all of the above-mentioned advantages are realized. These and other objects and advantages of the invention will be apparent to those skilled in the art upon reading the following detailed description and upon reference to the drawings and the dependent claims.
SUMMARY OF THE INVENTION
Those objects are achieved, in general, by utilizing certain new and useful assemblies for mounting an X-ray source. In accordance therewith, the subject invention provides for a source assembly for mounting an X-ray source, the assembly including a support means and carriage for providing movement of the X-ray source in a plane parallel to the plane of the mounting wall, the assembly comprising: a base member fixed to the carriage and horizontally projecting away from the carriage; a horizontally extending tubular member preferably square in cross-section pivotally mounted to the base member for rotation in a horizontal plane about the pivot point; a stem journalled within the tubular member for horizontal reciprocation with respect thereto; and a source mounting fixed to the X-ray source, the mounting including a collar journalled around the stem to provide rotational motion in a vertical plane about the stem.
The invention further provides for such mounting assemblies comprising various components to make operation smooth and reliable.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective drawing of a preferred embodiment of the operating system and mounting assemblies of the subject invention showing a film stand, a source stand, a mounting assembly for the source, and the environment in which the system is used;
FIG. 2 is an elevational view showing one position of the source assembly;
FIG. 3 is a further elevational view showing another position of the source assembly;
FIG. 4 is a top plan view showing the various ranges of motion of the source assembly;
FIG. 5 is a perspective view of the source assembly according to this embodiment; and
FIG. 6 is a side section view showing further detail of the source assembly according to the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 shows a representative embodiment and the environment of use of the source assembly according to the invention. The source assembly is indicated generally by reference numeral 10. An X-ray source 20 is mounted to the source assembly 10, which provides various ranges of motion and support to the source 20. The source 20 and the source assembly 10 are shown in a representative X-ray environment. That environment includes a first stand 30 which serves as a film stand. Film stand 30 includes side rails 31 and 32. Reciprocable vertically along siderails 31 and 32 is a film carrier 40, which may illustratively receive an X-ray film cassette. Stand 30 also advantageously includes a counterweight 35 as disclosed in co-pending 07/850,891 now U.S. Pat. No. 5,469,492. A second stand 50 is also included. This stand is mounted to a wall 60 which defines a reference plane of interest to the description of this invention. Stand 50 includes side rails 51 and 52. Vertically reciprocable along siderails 51 and 52 is a first carriage 70. In turn, a second carriage 80 is horizontally reciprocable along the first carriage 70 which includes rails 71 and 72. Stand 50 also advantageously includes a counterweight 75 as disclosed in co-pending 07/850,891 now U.S. Pat. No. 5,469,492. Through the combination of stand 50, carriage 70 and carriage 80, the X-ray source 20 can be moved to a variety of positions in a plane parallel to the plane of the wall 60. It should be noted that alternative means for moving the X-ray source 20 in this plane could also be used. For example, the above-described prior art system including a vertical column with a carriage vertically moveable thereon, and a floor-track for horizontal movement of the column could be used. One skilled in the art will appreciate that other means of for supporting and moving the X-ray source 20 in a plane parallel to the plane of the wall 60 are available.
The environment in FIG. 1 also includes a radiographic table 90. In a similar manner to stand 30, radiographic table 90 includes a means for receiving a film cassette, which is typically disposed underneath the top surface of the table 90.
With the environment of use thus established, reference is now made to FIG. 5 which shows the various ranges of motion provided to the X-ray source 20 by means of the source assembly 10. Source assembly 10, according to the invention, offers three ranges of motion. The first range of motion, depicted by reference number 100 is rotational motion about a horizontal axis. As will be discussed in greater detail below, a source mounting 110 is mountable to the source 20. This source mounting 110 is pivotable about a horizontal axis, thereby allowing the source 20 to be rotated between a position wherein the X-ray beam is aimed at the floor, and a position wherein it is aimed at a wall. Returning briefly to FIG. 1, it can be seen that this is advantageous in that the source 20 may be used either for taking X-rays of a patient disposed on a radiographic table 90, or of the patient standing in front of the X-ray stand 30.
The second range of motion made available by source assembly 10 is the reciprocable motion depicted by reference number 120. This motion is motion away from and toward the wall 60 serving as a reference point in this description. By means of such reciprocable motion, X-ray's may be taken of a stationary patient at varying distances from the wall 60. Since previous source mounting systems have not included such movement relative to the wall 60, the same images could be obtained only by moving the patient relative to the X-ray source. Such patient movement is no longer required with the source assembly 10 according to the invention.
The third range of motion offered by source assembly 10 is depicted by reference numeral 130. This motion is essentially a pivoting motion in a horizontal plane. When the source is pivoted in this plane, it can be folded back to a position where it is adjacent to either the wall 60, or to other components mounted on that wall. Such a position may be particularly advantageous in that the X-ray source 20 can be removed as an obstacle from the room, while still maintaining all the other advantageous functional features offered by source assembly 10.
In continuing reference to FIG. 5, the various components which provide for the advantageous ranges of motion can be seen. These components include a base member 150. Base member 150 is illustratively mounted to a carriage moveable on a stand, as seen in FIG. 1. The base member 150 horizontally projects away from that carriage, and away from the mounting wall 60. Member 150 includes a top plate on 152 and a bottom plate 153, and includes an open interior space 154. A tubular member 160, which in this embodiment has a square cross-section is pivotally mounted to base member 150 by means of pivot pin 162. The proximal end of tubular member 160 is received within opening 154 in the base 150. Opening 154 thus allows tubular member 160 to pivot about the pivot point 162. Tubular member 160 serves to extend the distance between the X-ray source, and the wall 60. This extension away from wall may become an obstacle under certain circumstances, and accordingly the tubular member 160 is pivotable about pivot point 162 to a position wherein X-ray source 120 is adjacent the wall 60. Such a position of tubular member 160, and X-ray source 120 is shown in FIG. 4.
Returning to FIG. 5, further extension of source 20 away from wall 60 is provided by means of a stem 170. Stem 170 is journalled within an interior passage way 165 within tubular member 160 for reciprocable motion with respect thereto. Thus, the distance of source 20 from wall 60 may be adjusted by means of adjusting the relative position of stem 170 and tubular member 160.
Rotational motion about a horizontal axis is provided to source 20 by means of source mounting 110. In addition to a face plate 180 for mounting to the X-ray source, source mounting 110 also includes a cylindrical collar 185. The cylindrical collar is journalled over the distal end of stem 170, to provide rotational motion with respect thereto.
To provide for a reliable fixing of the source 20 at a variety of positions, source assembly 10 includes a position retaining system. Each range of motion of source assembly 10 has its own latch or other position-retaining device associated with it. In reference to FIG. 5, for the range of motion 100, a three component position retention assembly 200 is used. Assembly 200 first includes a T-shaped handle 201. T-shaped handle 201 is threaded and received within a threaded collar 202 by means of rotation of the handle 201, the distal end of T-shaped member 201 engages one of several angularly spaced detents 203 in stem 170 as shown in FIG. 6, thus preventing collar 185 from being able to rotate on stem 170. A spring loaded, electrically actuable solenoid 193 is also part of assembly 200. Solenoid 193, also shown in FIG. 6 includes a central spindle biased into engagement with a series of angularly spaced detents 194. Electrical actuation of solenoid 193, by means of a switch (not shown) pulls the spindle out of engagement with detents 194 to allow rotation of the collar 185 stem 170. Since both solenoid 193 and T-shaped handle 201 engage detents on stem 170, both must be disengaged to provide for rotation of collar 185. Typically, solenoid 193 is first energized to release the spindle from detents 194. The operator then unscrews T-shaped handle 201 and uses the T-shaped handle as a gripping point for rotating source 20. As an alternative the end of handle 201 could be spring biased into engagement with detents 203, instead of threaded in.
The third component of assembly 200 is a magnetic clutch. Three magnets 192 are mounted on a support 194 fixed to collar 185. A clutch plate 191 is fixed to stem 170. Engagement of magnets 192 with clutch plate 191 prevents unrestrained rotation of collar 185 about stem 170 when both solenoid 193 and T-shaped handle 201 are disengaged. Rather, the magnetic clutch offers smooth rotation of collar 185 between positions.
Similarly, the range of motion in FIG. 5 depicted by reference numeral 120 is controlled by means of assembly 220. 220 includes a T-shaped handle 221 which is threaded at its distal end and received within a threaded collar 222. Rotation of T-shaped handle 221 causes engagement of the distal end of member 221 with one of a plurality of longitudinally spaced detents 223, in stem 170 (FIG. 6), thus locking it against further horizontal reciprocation within tubular member 160. Alternatively, handle 220 may be spring--biased as opposed to threaded into engagement with detents 223. A spring loaded solenoid 225 also controls the reciprocating movement of stem 170. Solenoid 225 includes a spindle 226 biased by a spring into engagement with detents 227 spaced in stem 170. Actuation of solenoid 225 by a switch (not shown) causes spindle 226 to disengage detents 227. As with assembly 200, electrical solenoid 225 is typically first actuated to disengage spindle 226 from detents 227. Thereafter, the operator can manually disengage handle 220 from detents 223 to allow movement of the stem 170.
The range of motion indicated by reference numeral 130 in FIG. 5 is restricted by means of an engageable latch mechanism 230 the operation of which can be better understood by reference to FIG. 4. Base member 150 includes receiving notches 152. Although only three receiving notches 152 are shown in the present embodiment, any plurality of such notches could be used. Latch mechanism 230 includes a horizontally disposed latch member 231 which selectively engages in a receiving notch 152 to lock tubular member 160 in a given orientation. Movement of the latch member 231 is controlled by a finger tab 232. To positively lock latch 230 into position, latch member 231 is biased into engagement with slots 152 by means of a coil spring 235 which surrounds the stem of latch member 231.
Source assembly 10 also includes means for insuring smooth operation of the apparatus as source 20 is moved through the various ranges of motions provided by source assembly 10. In reference to FIG. 5, the smooth nature of the reciprocal movement of stem 170 with respect to tubular member 160 is provided by complimentary blocks, illustratively formed of nylon, and designated by reference numerals 270 and 280. Each block 270, 280 includes a central circular cross-sectional recess for receiving circular stem 170. Moreover, each block 270, 280 is journalled for sliding movement relative to the interior surface of tubular member 160. While block 270 is so journalled, it does not move with respect to 160. Rather, it is fixed in place at the distal end of tubular member 160 by means of screws 272. In reference to FIG. 6, it can be seen that block 270 also includes through-passages which allow access by the latching mechanisms to detents 223 and 227, respectively. Returning to FIG. 5, it can be seen that rear block 280 is adapted for slidable movement within tubular member 160. Stem 170 is fixed within the central hole in block 280 by means of a pin 285. Thus, as stem 170 moves outward in the sense of FIG. 5, block 280 slides outwardly along with it. The snug journalling of block 280 within tubular member 160 insures smooth and well supported motion of the stem 170 in both outward and inward directions. Blocks 280 and 270 also combine to present a limit to the outward motion of stem 170. When the front face of block 280 engages the rear face of block 270, further outward movement of the stem 170 is prevented.
Smooth operation of source assembly 10 is also facilitated by the magnetic clutch mechanism previously described. Magnets 192 engage a circular plate 191 to prevent sudden rotational movement of mounting 110 after solenoid 193 and handle 201 are disengaged from the stem 170.
Similarly, vertical movement of the source 20 is made smoother and less jerky by inclusion of the counter weight 75 shown in FIG. 1 and previously discussed. Overall, the functioning of source assembly 10, and the carriages to which it is attached, provide a smooth and reliable operation and movement without the need for undue exertion on the part of the operator.
The ranges of motion provided to source 20 by means of the source assembly 10 allow a wider variety of X-ray images to be taken by a single X-ray source. In the environment view of FIG. 1, the source 20 is shown directed toward the top of a radiographic table 90. Various images of a patient reclining on table 90 could be taken by taking advantage of the various ranges of motion provided for by assembly 10. Moreover, by rotation of the source 20 about a horizontal axis, the source could be directed at stand 40, for the purpose of taking an X-ray of a standing patient in that position.
FIG. 2 shows an elevational view of the position of source 20 as shown in FIG. 1. FIG. 2 also shows the location of the X-ray film cassette 250 as is necessary for taking X-ray images of a patient reclined on radiographic table 90.
FIG. 3 shows an alternative position for source 20, made possible by means of the source assembly 10. In the position of FIG. 3, the source assembly has been rotated in the horizontal plane so that it is in the position shown in the plan view of FIG. 4 wherein the source is disposed adjacent to the wall 60. At the same time, source 20 is rotated so that the X-rays are emitted from the source 20 in a path roughly parallel to the floor. Accordingly, a film stand 251 may now be placed on radiographic table 90. This would allow, for example, X-ray of an arm resting on the top surface of radiographic table 90. Advantageously, this X-ray may be taken with the patient seated near the table, as opposed to having to be taken with the patient either standing or reclining on the table 90.
It will be appreciated by one skilled in the art that the ranges of motion provided by source assembly 10, according to the invention, make possible the taking of X-rays at a variety of positions which were not available by previous designs. Further, various modifications to the disclosed source assembly 10 will be apparent to those skilled in the art. All such modifications and equivalents are considered to be included in the scope of the invention as defined by the following claims.
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BACKGROUND OF THE INVENTION
This application claims priority of German Application No. 101 18 464 6 filed Apr. 7, 2001, the complete disclosures of which is hereby incorporated by reference.
a) Field of the Invention
The invention is directed to an electrical probe. A probe of this kind can preferably be used in ophthalmological surgery for electrosurgical cutting, ablation or coagulation of tissue.
b) Description of the Related Art
The use of electrosurgical procedures in ophthalmology is known per se and is disclosed, for example, in U.S. Pat. Nos. 6,135,998 and 5,755,716. U.S. Pat. No. 6,135,998 describes a probe in which an outer electrode is constructed coaxially around an inner wire-shaped electrode. The space between the electrodes is filled with an insulating material, e.g., also glass or fused silica.
Further, combined probes used for electrosurgical operation and laser operation are also known from general surgery (e.g., U.S. Pat. Nos. 5,011,483 and 5,509,916). In these cases, the laser light of correspondingly high-power lasers is guided in the vicinity of the ends of the electrodes of the electrosurgical probe by means of separate light-conducting fibers in order to treat the tissue with laser radiation as needed.
In operative use of an electrosurgical probe in ophthalmology, ensuring sufficient illumination of the interior of the eye and the fundus oculi is problematic. Therefore, illumination which is supplied via a second incision is often used in addition to the surgical tool. This additionally complicates performance of the operation and considerably increases stress and risk for the patient.
OBJECT AND SUMMARY OF THE INVENTION
Therefore, it is the primary object of the invention to provide a novel probe which makes the use of the probe more economical and improves the illumination conditions at the working location of the probe.
According to the invention, this object is met in an electrosurgical probe comprising a first electrode, a second electrode arranged coaxial to the first electrode and an isolator located between the electrodes. The isolator is constructed as a light guide. By light guides is meant in the following also optical waveguides which are suitable for components of the spectrum other than visible components. In this respect, it is advantageous to connect the light guides in an optically active manner with a light generating unit. This light generating unit can be a suitable lamp, e.g., a halogen lamp, as well as a laser. The radiation is advantageously coupled into the light guide by suitable optical systems, e.g., lenses or optical gratings, known to the person skilled in the art. According to the invention, the light guide can also comprise a bundle of light-conducting fibers. The electrodes have corresponding contacts for connecting to a power supply unit. It is particularly advantageous when the light guide comprises a flexible light guide which is constructed continuously from the probe tip to the light generating unit. Alternatively, the invention can also be realized in that the probe is constructed as a separable unit which is connected with the light generating unit via a flexible light guide with corresponding coupling points.
The light can be conducted in the light guide by the principle of total reflection. Alternatively, it may also be favorable to provide the jacket surfaces of the light guide with a reflective coating.
It has proven advantageous when the electrodes do not closely contact the insulator, but rather have a clearance of several hundredths of a millimeter. This increases the flexibility of the light guide; moreover, it has been shown that there is less light loss as a result of this step.
In realizing the invention, it has turned out that the probe according to the invention can also be used advantageously in other areas of technology. Its use is particularly advantageous when the measurements or treatments to be carried out require the combination of optical and electrical methods. For example, in cell biology, electric potentials or changes in potential are measured directly at the location of optical stimulation. For this purpose, light of suitable intensity, wavelength and/or signal duration is directed via the light guide to the relevant location on the specimen and simultaneously or subsequently detects a possible change in potential by means of the electrodes using measurement techniques. It is likewise possible to carry out electrical and optical stimulation simultaneously or with a delay in time in that the electrodes are acted upon by voltage and corresponding light pulses are directed via the light guide to the active point of the electrodes or into the vicinity thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is a partly sectional side view of the inventive light guide constructed continuously from the probe to a power supply/light generating unit; and
FIG. 2 shows a partly sectional side view of an assembled probe.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention will be described more fully in the following with reference to two preferred embodiment examples.
FIG. 1 shows an implementation of the invention in which the light guide is constructed continuously from the probe to a power supply/light generating unit. The probe comprises an inner electrode 1 which is enclosed coaxially by a flexible light guide 2 and an outer electrode 3 which at least partially envelopes the light guide. The light guide comprises a suitable high-index, flexible, insulating material such as PMMA, but can also be constructed as gradient fiber. The light conduction is realized in a known manner by total internal reflection of the light at the interfaces of the fibers. An insulating handle 4 which partially surrounds the outer electrode 3 is used for stabilizing and handling the probe. The light guide 2 tapers to a point 5 . The inner electrode 1 can terminate at the point 5 of the light guide 2 or can project beyond the latter by a small distance. The outer electrode 3 ends at a certain distance before the inner electrode exits from the light guide acting as an isolator. The outer electrode is surrounded by another isolator 6 between the handle and supply unit. The outer electrode is surrounded by another isolator 6 between the handle and supply unit. A connector 7 in which the inner electrode 1 , outer electrode 3 and light guide 2 are guided out to separate connections is used to connect to the power supply unit. The inner electrode is guided at the end face of the light guide transverse to the side and to a contact. This has been shown to result in only a negligible reduction in the in-coupling efficiency of the light in the light guide. A protective cap 14 serves only to protect the probe during transport; it is removed before using the probe. The following dimensions were realized in a preferred embodiment form for ophthalmological surgery:
inner electrode 1 : Ø0.010 . . . 0.1 mm
light guide 2 : Ø0.7 . . . 0.75 mm
outer diameter of probe: 0.9 mm
However, when used as a measurement probe, other dimensional ratios can also be realized. For purposes of deliberate influencing of a specimen with laser light, it is better not to let the light guide taper to a point, but to provide a smooth termination of the light-conducting fiber, beyond which the inner electrode projects by some hundredths or tenths of a millimeter.
FIG. 2 shows an assembled probe. The probe likewise comprises an inner electrode 1 which is surrounded coaxially by a light guide 2 and an outer electrode 3 which at least partially surrounds the light guide. Aside from suitable plastics, glass or fused silica can also be considered for light guides.
The electrodes 1 and 3 and the light guide 2 are held by an insulating handle 4 . A connection piece 8 by which the probe is connected with a light/power generating unit, not shown, via a flexible light guide 9 and power supply cables 10 , 11 of the two electrodes 1 and 2 engages in the handle 4 . The connection between the power supply cables 10 , 11 and the electrodes 1 , 3 is effected via corresponding contacts 12 , 13 . In the simplest case, the light from the flexible light guide 9 can be coupled into the light guide 2 of the probe, as is shown, by joining the ends of the two light guides; it is equally possible to provide a corresponding optical imaging system in this case.
For purposes of illustration, an enlarged view of the probe tip is shown in FIG. 3 and a section through the probe according to the invention is shown in FIG. 4 . The inner electrode 1 is surrounded coaxially by the insulating light guide 2 which is surrounded by the outer electrode 3 . The light guide 2 terminates in a tip 5 and the inner electrode 1 projects beyond the tip 5 by a small distance.
With regard to the handling of the probe, the probe tip is advanced to the location of the intended action upon the tissue. Light is guided through the light guide 2 and is radiated diffusely or directly from the tip 5 so that the area surrounding the probe tip is illuminated. Observation can be carried out, for example, by means of an operation microscope. A halogen lamp or other suitable lighting can be used as light source. The relevant tissue can now be treated in a known manner by applying electrical pulses of suitable shape and intensity to the electrodes. Suitable electrical parameters are described in detail in U.S. Pat. No. 6,135,998.
It is also possible to replace the second electrode by a separate ground line which is connected to the patient at a suitable location. In this way, the probe according to the invention is simplified to form a monopolar probe, as it is called.
The realization of the invention is not restricted to the embodiment examples shown herein; in particular, other geometric dimensions can also be provided or the insulator can also be used for the transmission of other optical radiation in the ultraviolet or infrared spectral range.
While the foregoing description and drawings represent the present invention, it will be obvious to those skilled in the art that various changes may be made therein without departing from the true spirit and scope of the present invention.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No. 10/152,535 filed on May 20, 2002 and claims priority under 35 U.S.C. 119 of Danish application no. 0317/97 filed on Mar. 20, 1997, of U.S. provisional application No. 60/041,390 filed on Mar. 27, 1997 and the benefit of application Ser. Nos. 09/045,038, 09/836,496 and 10/152,535 filed on Mar. 20, 1998, Apr. 17, 2001 and May 20, 2002 respectively, in the U.S. is claimed under 35 U.S.C. 120, the contents of all of which are fully incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to zinc free insulin crystals having a diameter below 10 μm and to therapeutic powder formulations suitable for pulmonary administration comprising such insulin crystals.
BACKGROUND OF THE INVENTION
[0003] Diabetes is a general term for disorders in man having excessive urine excretion as in diabetes mellitus and diabetes insipidus. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is more or less completely lost. About 2% of all people suffer from diabetes.
[0004] Since the introduction of insulin in the 1920's, continuous strides have been made to improve the treatment of diabetes mellitus. To help avoid extreme glycaemia levels, diabetic patients often practice multiple injection therapy, whereby insulin is administered with each meal.
[0005] Insulin is usually administrated by s.c. or i.m. injections. However, due to the adherent discomfort of injections alternative ways of administration such as nasal and pulmonary has been extensively investigated. For a review on alternative routes of administration of insulin, see Danielsen et al. New routes and means of insulin delivery, in: Childhood and Adolescent Diabetes (Ed. Kelnar), Chapman & Hall Medical, London 1994, pp. 571-584.
[0006] In order to circumvent injections, administration of insulin via the pulmonary route could be an alternative way to provide absorption profiles which mimic the endogenous insulin without the need to inject the insulin.
DESCRIPTION OF THE BACKGROUND ART
[0007] Administration of insulin via the pulmonary route can be accomplished by either an aqueous solution or a powder preparation. A description of the details can be found in several references, one of the latest being by Niven, Crit. Rev. Ther. Drug Carrier Sys, 12(2&3): 151-231 (1995). One aspect covered in said review is the stability issue of protein formulations, aqueous solutions being less stable than powder formulation. So far, all powder formulations have been described as mainly amorphous.
[0008] A review of the permeation enhancers useful for the promotion of trans-mucosal absorption is found in Sayani et al., Crit. Rev. Ther. Drug Carrier Sys, 13(1&2): 85-184 (1996).
[0009] Patton et al., Inhale Therapeutic Systems, PCT WO 95/24183, claim a method for aerosolising a dose of insulin comprising providing the insulin as a dry powder dispersing an amount of the dry powder in a gas stream to form an aerosol capturing the aerosol in a chamber for subsequent inhalation.
[0010] It has been found that when insulin is combined with an appropriate absorption enhancer and is introduced into the lower respiratory tract in the form of a powder of appropriate particle size, it readily enters the systemic circulation by absorption through the layer of epithelial cells in the lower respiratory tract as described in U.S. Pat. No. 5,506,203. The manufacturing process described in said patent, comprising dissolution of insulin at acid pH followed by a pH adjustment to pH 7.4 and addition of sodium taurocholate before drying the solution by vacuum concentration, open drying, spray drying, or freeze drying, results in a powder composed of human insulin and absorption enhancer. The powder is characterized as mainly amorphous determined under a polarized light microscope. The desired particle size distribution is achieved by micronizing in a suitable mill, such as a jet mill, and the components may be mixed before or after micronizing. The biological effect of the powder obtained according to the methods described in this patent is only seen in the presence of a substantial amount of enhancer.
[0011] Platz et al., Inhale Therapeutic Systems, PCT WO 96/32149, describes spray drying of zinc insulin from a solution containing mannitol and a citrate buffer, pH 6.7. The inlet temperature is 120 to 122□C, the outlet temperature 80-81□C. The mass median aerodynamic diameter, MMAd, of the obtained insulin particles was determined to 1.3 to 1.5 μm.
[0012] In his thesis, “Insulin Crystals”, Munksgaard Publisher 1958, p. 54-55, Schlichtkrull describes crystallisation of zinc free, recrystallised porcine insulin from a solution comprising 0.01 M sodium acetate and 0.7% ˜0.12 M sodium chloride and 0.1% methyl-parahydroxybenzoate and using a pH of 7.0. The crystals obtained were 10-50 μm rhombic dodecahedral crystals showing no birefringence.
[0013] Jackson, U.S. Pat. No. 3,719,655 describes a method of purification of crude porcine and bovine insulin by crystallisation. Zinc free crystals of insulin are obtained by crystallisation at pH 8.2 (range 7.2-10) in the presence of 0.5 M (range 0.2 M-1 M) of a sodium, potassium, lithium or ammonium salt. Crystallisation is achieved by addition of 1 N alkali metal hydroxide or 1 N ammonia to a solution of crude insulin in 0.5 N acetic acid to a pH of 8.2 is obtained. Alternatively, crystallisation is achieved in an aqueous solution of impure insulin at pH 8.2 by addition of solid sodium chloride to a concentration of sodium ions of 0.45 M. The crystals appear in the octadecahedral or dodecahedral forms, i.e. crystals belonging to the cubic crystal system.
[0014] Baker et al., Lilly, EP 0 709 395 A2 (filed Oct. 31, 1994) describe a zinc free crystallisation process for Lys B28 -Pro B29 human insulin characterised by adjustment of the pH of a strongly buffered acid solution containing metal cations or ammonium ions and a preservative with metal hydroxide or ammonia to a value between 8.5 and 9.5.
[0015] The known methods for the manufacture of insulin particles of the desired size for pulmonary administration are cumbersome, generates problems with insulin dust and the investments in equipment are large. Furthermore, insulin is exposed to conditions where some denaturation is likely to take place. Thus WO 96/32149 disclose spray drying in a temperature range of 50□C to 100□C, followed by milling of the particles to achieve to desired particle size.
[0016] Furthermore, the known powder formulations for pulmonary administration which have been described as mainly amorphous have a tendency to associate into aggregates in the dry powder.
DESCRIPTION OF THE INVENTION
[0000] Definitions
[0017] The expression “enhancer” as used herein refers to a substance enhancing the absorption of insulin, insulin analogue or insulin derivative through the layer of epithelial cells lining the alveoli of the lung into the adjacent pulmonary vasculature, i.e. the amount of insulin absorbed into the systemic system is higher than the amount absorbed in the absence of enhancer.
[0018] In the present context the expression “powder” refers to a collection of essentially dry particles, i.e. the moisture content being below about 10% by weight, preferably below 6% by weight, and most preferably below 4% by weight.
[0019] The diameter of the crystals is defined as the Martin's diameter. It is measured as the length of the line, parallel to the ocular scale, that divides the randomly oriented crystals into two equal projected areas
BRIEF DESCRIPTIONS OF THE INVENTION
[0020] It is an object of the present invention to provide an insulin powder suitable for pulmonary delivery which has a reduced tendency to associate into aggregates in the dry powder compared to the pulmonary insulin particles described in the prior art.
[0021] According to the present invention this object has been accomplished by providing zinc free insulin crystals having a diameter below 10 μm.
[0022] The crystals of the present invention furthermore exhibit a better stability profile than powders of essentially the same composition prepared by spray drying, freeze-drying, vacuum drying and open drying. This is probably due to the amorphous state of powders prepared by the other methods described. By this means it is possible to store the powder formulations based on the crystals of the present invention at room temperature in contrary to human insulin preparations for injections and some amorphous insulin powders without stabilizing agent which have to be stored between 2□C to 8□C.
[0023] Furthermore, therapeutical powder formulations comprising the insulin crystals of the invention elucidates better flowing properties than corresponding amorphous powder formulations.
Preferred Embodiments
[0024] The zinc free insulin crystals of the invention are advantageously provided in a crystal structure belonging to the cubic crystal system, preferably in the octadecahedral or dodecahedral crystal forms, since these crystal forms result in readily soluble product having excellent flowing properties.
[0025] The diameter of the insulin crystals is advantageously kept in the range of 0.2 to 5 μm, preferably in the range of 0.2 to 2 μm, more preferably in the range of 0.5 and 1 μm, to ensure high bioavailability and suitable profile of action, see PCT application No. WO 95/24183 and PCT application No. WO 96/32149.
[0026] In a preferred embodiment the insulin used is selected from the group consisting of human insulin, bovine insulin or porcine insulin, preferably human insulin.
[0027] In another preferred embodiment the insulin used is selected from the group consisting of rapid-acting insulins, preferably des(B30) human insulin, Asp B28 human insulin or Lys B28 Pro B29 human insulin.
[0028] In another preferred embodiment the insulin used is an insulin derivative, preferably selected from the group consisting of B29-N ε -myristoyl-des(B30) human insulin, B29-N ε -palmitoyl-des(B30) human insulin, B29-N ε -myristoyl human insulin, B29-N ε -palmitoyl human insulin, B28-N ε -myristoyl Lys B28 Pro B29 human insulin, B28-N ε -palmitoyl Lys B28 Pro B29 human insulin, B30-N ε -myristoyl-Thr B29 Lys B30 human insulin, B30-N ε -palmitoyl-Thr B29 Lys B30 human insulin, B29-N ε -(N-palmitoyl-γ-glutamyl)-des(B30) human insulin, B29-N ε -(N-lithocholyl-γ-glutamyl)-des(B30) human insulin, B29-N ε -(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N ε -(ω-carboxyheptadecanoyl) human insulin, more preferably Lys B29 (N-ε acylated) des(B30) human insulin.
[0029] The insulin derivatives has a protracted onset of action and may thus compensate the very rapid increase in plasma insulin normally associated with pulmonary delivery. By carefully selecting the type of insulin, the present invention enables adjustment of the timing and to obtain the desired biological response within a defined time span.
[0030] In order to avoid irritation of the lungs and to eliminate immunological reactions, the employed insulin is preferably insulin which has been purified by chromatography, such as MC insulin (Novo), Single Peak insulin (E. Lilly) and RI insulin (Nordisk).
[0031] In a preferred embodiment the zinc free insulin crystals according to the invention further comprise a stabilizing amount of a phenolic compound, preferably m-cresol or phenol, or a mixture of these compounds.
[0032] The present invention is furthermore concerned with a therapeutic powder formulation suitable for pulmonary administration comprising the zinc free crystals described above.
[0033] In a preferred embodiment this therapeutic powder formulation further comprises an enhancer which enhances the absorption of insulin in the lower respiratory tract.
[0034] The enhancer is advantageously a surfactant, preferably selected from the group consisting of salts of fatty acids, bile salts or phospholipids, more preferably a bile salt.
[0035] Preferred fatty acids salts are salts of C 10-14 fatty acids, such as sodium caprate, sodium laurate and sodium myristate.
[0036] Lysophosphatidylcholine is a preferred phospholipid.
[0037] Preferred bile salts are salts of ursodeoxycholate, taurocholate, glycocholate and taurodihydrofusidate. Still more preferred are powder formulations according to the invention wherein the enhancer is a salt of taurocholate, preferably sodium taurocholate.
[0038] The molar ratio of insulin to enhancer in the powder formulation of the present invention is preferably 9:1 to 1:9, more preferably between 5:1 to 1:5, and still more preferably between 3:1 to 1:3.
[0039] The powder formulations of the present invention may optionally be combined with a carrier or excipient generally accepted as suitable for pulmonary administration. The purpose of adding a carrier or excipient may be as a bulking agent, stabilizing agent or an agent improving the flowing properties.
[0040] Suitable carrier agents include 1) carbohydrates, e.g. monosaccharides such as fructose, galactose, glucose, sorbose, and the like; 2) disaccharides, such as lactose, trehalose and the like; 3) polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; 4) alditols, such as mannitol, xylitol, and the like; 5) inorganic salts, such as sodium chloride, and the like; 6) organic salts, such as sodium citrate, sodium ascorbate, and the like. A preferred group of carriers includes trehalose, raffinose, mannitol, sorbitol, xylitol, inositol, sucrose, sodium chloride and sodium citrate.
[0041] The crystals of the present invention are advantageously produced according to the following procedure:
providing a solution of insulin having a pH between 7.0 and 9.5; mixing said solution with a solution of a salt of an alkali metal or an ammonium salt; and recovering the formed crystals.
[0045] The salt of an alkali metal or ammonium is preferably selected from the group consisting of the hydrochloride or acetate of sodium, potassium, lithium or ammonia, or mixtures thereof, more preferably sodium acetate.
[0046] In order to suppress the solubility of the crystals formed, the solution of insulin and/or the solution of a salt of an alkali metal or an ammonium salt preferably comprises a water miscible organic solvent in an amount which corresponds to 5 to 25% (v/v) in the solution obtained after mixing.
[0047] The water miscible organic solvent is preferably selected from the group consisting of ethanol, methanol, acetone and 2-propanol, more preferably ethanol.
[0048] A very uniform distribution of crystal sizes and crystals of the same crystallographic form are obtained when the two solutions are mixed within a period of less than 2 hours, preferably less than 1 hour, more preferably less than 15 minutes, still more preferably less than 5 minutes.
[0049] The crystallisation process by which uniformly sized, small, zinc free crystals is obtained directly, without the use of milling, micronizing, sieving and other dust generating steps, is much to be preferred from the present state of the art in the manufacture of insulin powders for inhalation.
[0050] The concentration of insulin after mixing is preferably between 0.5% and 10%, more preferably between 0.5% and 5%, still more preferably between 0.5% and 2%.
[0051] The concentration of salt after mixing is preferably between 0.2 M and 2 M, more preferably about 1 M.
[0052] The method according to the present invention may further comprise a washing step, in which the crystals obtained are washed with a solution comprising auxiliary substances to be included in the final dry powder, preferably an enhancer and/or a carbohydrate, and optionally comprising 5-25% of an alcohol, preferably ethanol, 5-50 mM of a preservative preferably phenol, and 0.1-2 M of a salt such as sodium acetate.
[0053] This invention is further illustrated by the following examples which, however, are not to be construed as limiting.
EXAMPLE 1
[0000] Crystallisation in 1 M Sodium Acetate.
[0054] 2 g of highly purified human insulin is dissolved in 100 ml 10 mM tris buffer, pH 8.0 in 20% (v/v) of ethanol in water. To this solution is added 100 ml 2 M sodium acetate under stirring. A precipitate forms immediately. After 2 days at room temperature microscopy shows small crystals having a diameter between 0.5 and 1 μm. The crystals are collected by centrifugation at −10□C, washed once with 20 ml ice cold 10% ethanol (v/v) in water, isolated by centrifugation and dried by lyophilization. The obtained crystals are shown in FIG. 1 .
EXAMPLE 2
[0000] Crystallisation in the Presence of Taurocholic Acid Sodium Salt.
[0055] 10 mg of human insulin and 5 mg of taurocholic acid sodium salt are dissolved in 500 μl 10 mM tris buffer, pH 8.0 in 20% (v/v) of ethanol in water. To this solution is added 500 μl 2 M sodium acetate. Microscopy after 1 hour and after 24 hours shows identically appearance of the crystals, i.e. uniformly sized crystals having diameters between 0.5 and 1 μm. The crystals were washed three times with 100 μl 10% (v/v) ethanol in water at −10□C and dried in vacuo. HPLC of the crystals showed that the washings had removed the taurocholic acid sodium salt from the insulin crystals.
EXAMPLE 3
[0000] Crystallisation in the Presence of Tween 80, bis(2-ethylhexyl) Sulfosuccinate Sodium Salt, Chitosan, L-α-lysophosphatidylcholine Myristoyl and Polyoxyethylene Sorbitan Monolaurate.
[0056] Crystallisation was performed as described in Example 2 except that taurocholic acid sodium salt was replaced by 0.6% (w/v) Tween 80, 0.56% (w/v) bis(2-ethylhexyl) sulfosuccinate sodium salt, 0.32% (w/v) chitosan, 0.52% (w/v) L-αlysophosphtidylcholine myristoyl, and 1% (w/v) polyoxyethylene sorbitan monolaurate, respectively. All five examples resulted in uniformly sized crystals having diameters between 0.5 and 1 μm.
EXAMPLE 4
[0057] Crystallisation in 10% (v/v) Ethanol.
[0058] Crystallisation was performed in 10% (v/v) ethanol as described in Example 1, using 4 combinations of pH and concentration of sodium acetate:
4.1: pH 7.5 and 1 M sodium acetate 4.2: pH 7.5 and 1.5 M sodium acetate 4.3: pH 9.0 and 1 M sodium acetate 4.4: pH 9.0 and 1.5 M sodium acetate
[0063] All 4 combinations yielded uniformly sized crystals having diameters between 0.5 and 1 μm.
EXAMPLE 5
[0000] Crystallisation in 15% (v/v) Ethanol.
[0064] Crystallisation was performed in 15% (v/v) ethanol, using 6 combinations of pH and concentration of sodium acetate:
5.1: pH 7.5 and 1 M sodium acetate 5.2: pH 7.5 and 1.5 M sodium acetate 5.3: pH 7.5 and 2 M sodium acetate 5.4: pH 9.0 and 1 M sodium acetate 5.5: pH 9.0 and 1.5 M sodium acetate 5.6: pH 9.0 and 2 M sodium acetate
[0071] All 6 combinations yielded uniformly sized crystals having diameters between 0.5 and 1 μm.
EXAMPLE 6
[0000] Crystallisation in 20% (v/v) Ethanol.
[0072] Crystallisation was performed in 20% (v/v) ethanol using 4 combinations of pH and concentration of sodium acetate:
6.1: pH 7.5 and 1 M sodium acetate 6.2: pH 7.5 and 1.5 M sodium acetate 6.3: pH 7.5 and 2 M sodium acetate 6.4: pH 9.0 and 1 M sodium acetate
[0077] All 4 combinations yielded uniformly sized crystals having diameters between 0.5 and 1 μm.
EXAMPLE 7
[0000] Crystallisation at pH 7.5, 8.0, 8.5 and 9.0 in 20% Ethanol (v/v) Using Slow Addition of Sodium Acetate.
[0078] Crystallisation was performed using solutions as described in Example 1, except that the 2 M sodium acetate was dissolved in 20% (v/v) ethanol in water. The pH of the insulin solutions were adjusted to 7.5, 8.0, 8.5 and 9.0, respectively. The sodium acetate solution was added in aliquots over a period of 2 hours, using 10 min between additions. At all 4 pH values uniformly sized crystals having diameters between 0.5 and 1 μm were obtained.
EXAMPLE 8
[0000] Crystallisation of Lys B29 (ε-myristoyl) des(B30) Human Insulin in the Presence of Taurocholic Acid Sodium Salt.
[0079] 10 mg of Lys B29 (ε-myristoyl) des(B30) human insulin and 5 mg of taurocholic acid sodium salt are dissolved in 500 μl 10 mM tris buffer, pH 8.0 in 20% (v/v) of ethanol in water. To this solution is added 500 μl 2 M sodium acetate. Microscopy after 1 hour and after 24 hours shows identically appearance of the crystals, i.e. uniformly sized crystals having diameters between 0.5 and 1 μm. The crystals were washed once with 300 μl 10% (v/v) ethanol in water at −10□C and dried in vacuo. HPLC of the crystals showed that the washings had removed the palmitoyl-Thr B29 Lys B30 human insulin, B29-N ε -(N-palmitoyl-γ-glutamyl)-des(B30) human insulin, B29-N ε -(N-lithocholyl-γ-glutamyl)-des(B30) human insulin, B29-N ε -(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N ε -(ω-carboxyheptadecanoyl) human insulin.
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CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No. 12/364,327 (Attorney Docket No. 021356-003210US), filed on Feb. 2, 2009, which was a continuation-in-part of application Ser. No. 11/027,912 (Attorney Docket No. 021356-001110US), filed on Dec. 29, 2004, now U.S. Pat. No. 7,695,437, which claimed the benefit of provisional application No. 60/534,036 (Attorney Docket No. 021356-001100US), filed on Dec. 30, 2003, the full disclosures of which are incorporated herein by reference. The text of the present application is identical to that of application Ser. No.11/027,912 (Attorney Docket No. 021356-001110US).
[0002] The subject matter of the present application is related to that of the following applications: Ser. No. 10/750,370, entitled “Medical Device Inline Degasser” (Attorney Docket No. 02356-000500US); Ser. No. 10/751,344, entitled “Articulating Arm for Medical Procedures” (Attorney Docket No. 02356-000600US); Ser. No. 10/750,369, entitled “Disposable Transducer Seal” (Attorney Docket No. 02356-000700US); 60/533,528, entitled “Position Tracking Device” (Attorney Docket No. 021356-000900US); 60/533,988, entitled “Method for Planning and Performing Ultrasound Therapy” (Attorney Docket No. 021356-001000US); 60/533,958, entitled “Systems and Methods for the Destruction of Adipose Tissue” (Attorney Docket No. 021356-001200US); 60/534,034, entitled “Component Ultrasound Transducer” (Attorney Docket No. 021356-001300US); the full disclosure of each of these applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to a handheld medical device for delivering energy in precise locations into the human body. The device is principally for non-invasive therapies.
[0005] 2. Background of the present invention
[0006] A general problem in the application of high intensity focused ultrasound (HIFU) for therapeutic purposes is that it is often necessary to hold the therapeutic means stationary for some significant amount of time over the tissue to be treated. Alternatively, it may be necessary to scan the therapy beam at a slow, constant rate through the tissue to be treated. Both of these requirements present a barrier to a hand-held therapeutic device, as it is often difficult or impossible for a person to either hold the device steady, or to scan at an acceptably slow and steady rate for the desired therapeutic effect.
[0007] A HIFU procedure may require that the ultrasound beam be scanned over the treatment volume at a constant rate (e.g. 5 mm/sec+/−1 mm/sec) to achieve the desired therapeutic effect. Additionally, the treatment volume must be scanned so that there is never more than a 2 mm spacing between adjacent focal lines of treatment. These requirements are beyond the capabilities of human beings. The solution in the past has been to incorporate a computer controlled motion device rigidly mounted to something that is stationary with respect to the patient (e.g. the floor, wall or bed). Such a device is either absolutely stationary, or is able to scan at a precise rate in a precise pattern without any human intervention. Such an arrangement has the disadvantages of size and bulk, complexity and reliability of the overall device.
[0008] Thus there remains a need in the art for a HIFU applicator that can be easily manipulated by a user while still providing reliable and uniform treatment.
[0009] There is also a need for a HIFU transducer that can keep track of the tissue volumes treated so as to prevent re-treatment of those same volumes.
[0010] There is still further a need for a therapy device that can assist the operator in identifying regions of tissue to be treated.
BRIEF SUMMARY OF THE INVENTION
[0011] It is an objective of the present invention to provide for a therapy head usable in HIFU procedures that can be easily manipulated and provide reliable and uniform treatment.
[0012] It is another object of the presenting invention to track tissue in a library or map of the tissue to be treated.
[0013] It is still further an objective of the present invention to provide a means for alerting a physician to any problems or difficulties associated with a procedure using a HIFU generator of the present invention.
[0014] At least some of the objectives of the present invention are realized through an ultrasound therapy head comprising an enclosure having a window, at least one energy applicator suspended within the enclosure and a means for maneuvering the energy applicator within the enclosure such that the energy applicator radiates energy through the window.
[0015] Preferably the energy applicator is an ultrasound transducer however a variety of other energy applicator may be used in combination with an ultrasound transducer.
[0016] The means for maneuvering the energy applicator preferably includes a means for determining the position of the energy applicator within the enclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 illustrates a therapy head.
[0018] FIG. 2 shows a therapy head on an articulating arm with external control elements.
[0019] FIGS. 3A-3B show internal views of actuators and motors in the therapy head.
[0020] FIG. 4 provides a schematic of the elements of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Described herein is a device for use primarily in high intensity ultrasound procedures. A therapy head is disclosed having an enclosure with a window. The enclosure contains one or more energy applicators, and a means of moving the energy applicators within the enclosure. The energy applicators are positioned so the radiant energy passes through the window to a patient.
[0022] The enclosure is preferably small enough to be manipulated by hand. It can be operated by itself with a physician carrying the load of the therapy head, or it can be supported by an articulating arm or other mechanical device. The enclosure has a window that is oriented toward a patient. The window may be made from any material so long as it is essentially transparent to the energy applicator. The window may be incorporated into the enclosure, or it may be a removable device. If the window is a removable device, then the window will cover an access port through which the interior components of the enclosure may be accessed. The window may also be a disposable device, such as a disposable transducer seal.
[0023] Within the enclosure is at least one energy applicator. Preferably this energy applicator is an ultrasound transducer. More preferably the ultrasound transducer is a high intensity focused ultrasound transducer. However the transducer may be a component transducer assembly, or a device that incorporates multiple energy applicators, some of which may not be ultrasound transducers.
[0024] There is a means for maneuvering the energy applicator within the enclosure. The means for maneuvering the energy applicator requires two components. A first component is one or more actuators. The energy applicator is attached to the actuators. The attachment may be a slidable engagement, rotational engagement or through a series of traveler rods. The actuators are driven by a force generating device, like an electric motor or the equivalent. Electric motors are preferred for their small size and reliability. One or more position sensing devices, such as rotational or optical encoders, are built into either the motor assembly, or the actuators, so the movement of the energy applicator within the enclosure is known. Alternatively the energy applicator may also contain a miniature location device (e.g. like mini-GPS system) that an external sensor can identify to determine the location of the energy applicator within the enclosure.
[0025] The second component of the maneuvering means is a driver or controller. The driver or controller directs the movement of the motors, and thus the movement of the actuators and the maneuvering of the energy applicator. The controller may be a medical appliance, a computer, or a specialized medical procedure controller. The controller may be positioned within the enclosure, or it may be a device outside the enclosure providing signal to the motors.
[0026] In operation, the controller has a library of data used to coordinate the movement of the energy applicator and the dosage of the radiant energy into the patient. By controlling the movement of the energy applicator while radiant energy is emitted through the window, a precise energy dosage may be delivered into the patient. The controller can be programmed with the parameters needed to perform the task. Parameters may include the type of therapy to be administered and the maximum safe dosage that may be applied to a patient for a given area, volume or mass of tissue.
[0027] Once the therapy head has been completely prepared for a procedure, a physician can place the therapy head on a patient. The therapy head can move the energy applicator within the enclosure to treat the patient according to the procedure parameters programmed into the controller. If the procedure area is small, then the controller can move and activate the energy emitter without any additional input from a user.
[0028] If the treatment area exceeds the window of the enclosure, or exceeds the range of motion of the energy applicator within the enclosure, the therapy head must be moved to cover as much area as needed. Movement of the therapy head can be done manually, or through a mechanical device. Data from the encoders is relayed to the controller so that the controller can identify the position of the energy applicator within the confines of the enclosure. This position information can be combined with a Position Tracking Device (Co-pending application, serial number unassigned), and an Articulating Arm (Co-pending application, serial number un-assigned). The controller can utilize position data from the present invention, combined with the data derived from the two aforementioned co-pending applications, to produce precise position data for the energy applicator with respect to the enclosure, the patient and a fixed external reference point. During the procedure if the controller reads the position or motion information from the encoders and other sensors and determines the energy applicator is not in the proper position, the controller can use the means for maneuvering the applicator, to correct the energy applicator's position.
[0029] Similarly the controller can identify the dosage of energy delivered with great precision to any particular area. The controller can track the amount of energy transmitted into the patient through out the treatment area and can cause the energy applicator to radiate or not radiate depending on the amount of energy already deposited into the patient at the particular place in the procedure.
[0030] Turning now to the drawings, in FIG. 1 there is a therapy head 50 having an energy applicator 600 within an enclosure 500 . The enclosure has a window 590 for allowing radiant energy to pass from the enclosure to a patient. The therapy head 50 is preferably small and light enough for a physician to move it comfortably with one hand. The therapy head 50 may increase in both size and weight if the physician is assisted by an articulating arm 200 in bearing the weight of the therapy head 50 . There is a data link 572 extending between the therapy head 50 and an external computer 400 or a therapy controller 450 .
[0031] The therapy head 50 may be mounted ( FIG. 2 ) on an articulated arm 200 supported by a base 100 . The articulating arm 200 would also have its movements and functions monitored or controlled by a computer 400 or therapy controller 450 .
[0032] The enclosure 500 contains motor drives 508 , 510 for moving the energy applicator 600 within the enclosure ( FIG. 3A ). The motor drives are connected directly, or through a gear assembly, to a pair of traveler rods 520 , 528 . The traveler rods in turn move a pair of slotted actuators 520 ′, 528 ′. The slotted actuators travel along the traveler rods carrying the energy applicator at the intersection of the two slotted actuators. As the traveler rods rotate in response to movement from the motors, the slotted actuators carry the energy applicator throughout the range of motion of the slotted traveler rods. Rotational encoders 530 are positioned on the traveler rods 520 , 528 so that the movement of the energy applicator can be accurately measured.
[0033] Alternatively, the motor drives 508 , 510 can directly drive rotational actuators 514 , 516 to move the energy applicator 600 within the enclosure ( FIG. 3B ). In this embodiment there is no need for a gear mechanism. As the motor drives move the axis of the motor assemblies back and forth, the actuators 514 , 516 move in direct correlation to the motors. The sensitivity of the positioning of the energy applicator can be controlled through the motor drives, or the actuators used in response to the energy applicator. Three motors (not shown) may also be used to drive three articulating arms.
[0034] FIG. 4 illustrates a schematic of the present invention. The therapy head 50 is shown in cross section with a partition 504 separating an upper enclosure from a lower enclosure. The partition is water tight so that fluid in the lower partition does not seep into the upper enclosure. There are a pair of motor drive units 508 , 510 within the upper enclosure. The motor drive units pass rotational energy to the energy applicator 600 through a series of mechanical actuators 514 , 516 , 518 . The actuators extend through the water tight partition 504 and are themselves water resistant. An acoustic window 590 is displaced at the bottom of the enclosure.
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TECHNICAL FIELD
The present invention relates to an electric vacuum cleaner including first and second dust separation devices for separating vacuumed dust.
BACKGROUND
There is conventionally known an electric vacuum cleaner including a first dust separation device for separating dust and a second dust separation device for separating dust which has passed through the first dust separation device (refer to JP2006-6383A).
The electric vacuum cleaner includes the first dust separation device for separating dust vacuumed by a negative pressure of an electric fan, a first dust collection section for collecting the dust separated by the first dust separation device, the second dust separation device for separating the dust which has passed through the first dust separation device, a dust removing device for removing the dust adhering to the second dust separation device and a second dust collection section provided in the lower portion of the second dust separation device, for accumulating the dust removed by the dust removing device. An introduction opening provided in the upper portion of the second dust collection section is provided with an openable and closable opening and closing member. The opening operation and closing operation of the opening and closing member are conducted in conjunction with a pulling-out operation and a retracting operation of a power source cord.
More particularly, the opening and closing member closes the introduction opening of the second dust collection section, when pulling-out the power source code and the opening and closing member opens the introduction opening, when retracting the power source code.
In addition, when the power source cord is retracted, the dust removing device for removing the dust adhering to the second dust separation device is operated, disposing the dust removed by the second dust separation device into the second dust collection section from the introduction opening.
In operation of the electric fan, i.e., when the power source cord is pulled out, the introduction opening of the second dust collection section is closed by the opening and closing member. Accordingly, the dust accumulated in the second dust collection section is prevented from rising to adhere again to the second dust collection section.
However, the above electric vacuum cleaner has a problem in that its structure is complex, because the opening and closing operation of the opening and closing member requires an interlocking mechanism which operates in conjunction with the pulling-out operation and retracting operation of the power source cord.
SUMMARY
It is, therefore, an object of the present invention to provide an electric vacuum cleaner capable of opening and closing an introduction opening of a second dust collection section by means of a simple structure.
One aspect of the invention relates to an electric vacuum cleaner including a first dust separation device configured to separate dust vacuumed by a negative pressure of an electric fan, a first dust collection section for collecting the dust separated by the first dust separation device, a second dust separation device configured to separate the dust which has passed through the first dust separation device, a dust removing device configured to remove the dust adhering to the second dust separation device, a second dust collection section positioned in an upstream side of the second dust separation device and provided in a lower portion of the second dust separation device, for accumulating the dust removed by the dust removing device, a partition wall for zoning the first dust collection section and the second dust collection section, and an introduction opening for introducing the dust removed by the dust removing device into the second dust collection section, wherein the partition wall is provided with a communication opening for communicating the first dust collection section to the second dust collection section, the partition wall is provided with an opening and closing member for closing either of the introduction opening or the communication opening and switching the closing to the other by rotating, and the opening and closing member closes the introduction opening with the negative pressure by driving of the electric fan and closes the communication opening by its own weight when the electric fan is not driven.
Preferably, the communication opening is formed in an upper portion of the second dust collection section.
Advantageously, a bottom portion of the first dust collection section and a bottom portion of the second dust collection section are simultaneously opened, so as to simultaneously discharge the dust accumulated in the first dust collection section and the second dust collection section.
In a preferred embodiment, the dust removing device removes the dust adhering to the second dust separation device, when operation of the electric fan is stopped.
Advantageously, the second dust separation device comprises a pleated filter body.
In a preferred embodiment, the dust removing device removes the dust adhering to the pleated filter body by vibrating the pleated filter body.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view showing an external appearance of an electric vacuum cleaner according to the present invention.
FIG. 2 is a perspective view showing a body of the electric vacuum cleaner.
FIG. 3 is a vertical cross-sectional view showing the structure of the electric vacuum cleaner body.
FIG. 4 is a perspective view illustrating a dust collection container.
FIG. 5 is a perspective view illustrating the dust collection container shown in FIG. 4 seen from another direction.
FIG. 6 is an explanatory view showing a structure of a round air path section of the dust collection container.
FIG. 7 is an explanatory view illustrating a fine dust collection section.
FIG. 8 is a cross-sectional view showing the electric vacuum cleaner body with an introduction opening closed by an opening and closing plate.
FIG. 9 is an explanatory view showing a fine dust collection section with the introduction opening closed by the opening and closing plate.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Hereinafter, an embodiment of an electric vacuum cleaner according to the present invention will be described with reference to the drawings.
Embodiment
An electric vacuum cleaner 10 shown in FIG. 1 includes a vacuum cleaner body 20 . The front portion of the vacuum cleaner body 20 is provided with a hose connection port 21 . A dust collection hose 12 has one end detachably connected to the hose connection port 21 and has the other end provided with a hand operation unit 13 . An extension wand 14 is detachably connected to the hand operation unit 13 . A suction port 15 is detachably connected to the leading end portion of the extension wand 14 . The hand operation unit 13 is provided with an operation part 13 A including a plurality of operation switches S.
The vacuum cleaner body 20 includes a body case 30 , a dust collection container 50 detachably mounted on the body case 30 and a cover body 40 having the back portion connected to the body case 30 by a hinge so as to be openable and closable in the up and down direction, as illustrated in FIG. 2 .
In addition, an electric fan 33 (refer to FIG. 3 ) is built in a back portion 30 A of the body case 30 , and a cord reel 34 is disposed below the electric fan 33 . A plate-like mounting section 35 is provided in front of the body case 30 (on the left side in FIG. 3 ). The dust collection container 50 is detachably mounted on the mounting section 35 . The cover body 40 and the mounting section 35 enclose the dust collection container 50 , so as to fasten the dust collection container 50 when the cover body 40 is closed.
The cover body 40 is provided with a tube portion 22 as shown in FIG. 3 . The leading end of the tube portion 22 is the hose connection port 21 and the back end of the tube portion 22 is a connection opening 23 .
A front opening (not shown) is formed in a front wall portion 31 (reference to FIG. 2 ) of the back portion 30 A. The front opening communicates with a suction opening 33 A of the electric fan 33 via a communication air path (not shown). The communication air path opposed to the front opening is provided with a dust removing device 90 .
The dust removing device 90 includes a reciprocating body (not shown) for reciprocating in the width direction of the body case 30 (in the direction orthogonal to the page space of FIG. 3 ) and a projection 91 provided in the reciprocating body. The projection 91 shallowly engages with a top portion of a pleat of an after-mentioned pleated filter body 100 , and the projection 91 moves over the top portions of the pleat by the reciprocating of the reciprocating body. The dust removing device 90 thereby removes the dust adhering to the pleated filter body 100 by vibrating the pleated filter body 100 .
The reciprocating body reciprocates for a predetermined time every time the driving of the electric fan 33 is stopped.
As shown in FIGS. 4 , 5 , the dust collection container 50 includes a round air path section 51 formed on the upper portion thereof, a dust collection section (a first dust collection section) 60 formed below the round air path section 51 , a negative pressure room 70 formed at the back of the dust collection section 60 , and a bottom pad 80 .
The round air path portion 51 includes a dust separation section (a first dust separation device) 52 provided in the central portion thereof and a circular arc round air path 53 provided around the dust separation section 52 , as shown in FIG. 6 . A leading end opening 54 of the leading end of the round air path 53 is connected to the connection opening 23 of the tube portion 22 of the cover body 40 as shown in FIG. 3 . The round air path 53 communicates into the dust collection section 60 via a back end opening 55 . Moreover, the round air path 53 includes an opening 57 which is formed in the bottom portion in the middle of the round air path 53 and communicates with the negative pressure room 70 . A net filter F 2 is stretched to the opening 57 .
The dust separation section 52 includes a frame (not show) having an almost cylindrical shape and a net filter F 1 stretched to the frame. The bottom portion of the dust separation section 52 opens, such that the dust separation section 52 communicates with the negative pressure room 70 via an opening 56 .
A dividing wall 61 provided in the back portion of the dust collection section 60 includes an opening 62 which communicates with the negative pressure room 70 . A lower portion wall 61 A of the dividing wall 61 includes a communication hole (communication opening) 63 positioned in an upper portion of a fine dust collection section 74 . More particularly, the communication hole 63 is formed below the opening 62 . A net filter (the first dust separation device) F 3 is stretched to the opening 62 .
A frame 71 for detachably installing a pleated filter body (a second dust separation device) 100 is integrally formed in the back portion of the negative pressure room 70 (on the right side in FIG. 5 ). A back end opening 72 of the frame 71 is connected to the front opening (not shown) of the body case 30 shown in FIG. 3 .
A lower portion back wall 73 is formed in the lower portion of the frame 71 . The fine dust collection section (the second dust collection section) 74 includes a space surrounded by the lower portion back wall 73 , the lower portion wall 61 A of the dividing wall (partition wall) 61 of the dust collection section 60 and the bottom pad 80 . The fine dust collection section 74 communicates with the dust collection section 60 via the communication hole 63 of the dividing wall 61 . In addition, as shown in FIG. 7 , an introduction opening 75 is formed between a lower frame wall 71 A of the frame 71 and the lower portion wall 61 A of the dividing wall 61 as shown in FIG. 7 .
In addition, one end portion (upper portion in FIG. 7 ) of an opening and closing plate (opening and closing member) 76 for closing the introduction opening 75 is supported by the lower portion of the dividing wall 61 of the dust collection section 60 . The opening and closing plate 76 is rotatable upon one end portion of the opening and closing plate 76 . The opening and closing plate 76 closes the communication hole 63 of the dividing wall 61 by its own weight and opens the introduction opening 75 of the fine dust collection section 74 , when the electric fan 33 is not driven. The opening plane of the communication hole 63 is configured such that the opening and closing plate 76 rotates to close the introduction opening 75 (refer to FIG. 9 ), if the pressure in the negative pressure room 70 becomes negative by the driving of the electric fan 33 .
The bottom pad 80 is a rotatable in the clockwise direction about an axis 81 illustrated in FIG. 3 . If a button B provided in a holding portion 58 of the dust collection container 50 is pressed, the bottom portion of the dust collection section 60 and the bottom portion of the fine dust collection section 74 are opened. Accordingly, the dust accumulated in the dust collection section 60 and the fine dust collection section 74 can be disposed.
[Operation]
Next, the operation of the electric vacuum cleaner having the above structure will be explained.
At first, as shown in FIG. 2 , the dust collection container 50 is mounted on the mounting section 35 of the body case 30 , and the cover body 40 is closed. As shown in FIG. 1 , one end of the dust collection hose 21 is connected to the hose connection port 21 of the cover body 40 .
In this state, as illustrated in FIGS. 3 , 7 , the opening and closing plate 76 of the dust collection container 50 closes the communication hole 63 of the dividing wall 61 by its own weight.
If the switch S of the operation part 13 A is operated, the electric fan 33 is driven. By the driving of the electric fan 33 , air is sucked from the suction opening 33 A of the electric fan 33 , creating a negative pressure in the negative pressure room 70 of the dust collection container 50 . Thereby, the opening and closing plate 76 rotates by this negative pressure so as to close the introduction opening 75 as shown in FIGS. 8 , 9 .
If the introduction opening 75 is closed by the opening and closing plate 76 , the fine dust accumulated in the fine dust collection section 74 is prevented from rising to adhere to the pleated filter body 100 .
In addition, since the communication hole 63 of the dividing wall 61 of the dust collection container 50 is formed in the upper portion of the fine dust collection section 74 , the air flows as illustrated by the arrows in FIGS. 7 , 9 when the opening and closing plate 76 rotates to close the introduction opening 75 . Accordingly, the dust accumulated in the fine dust collection section 74 is not raised by this air.
As described above, the opening and closing plate 76 rotates by the driving of the electric fan 33 so as to close the introduction opening 75 ; thus, the structure of the opening and closing plate 76 is simplified.
On the other hand, a negative pressure is created in the dust collection section 60 and the round air path 53 by the negative pressure of the negative pressure room 70 of the dust collection container 50 . This negative pressure acts on the tube portion 22 , the dust collection hose 12 , the extension wand 14 and the suction port 15 , so as to vacuum the dust together with air from the suction port 15 .
The vacuumed dust and air are sucked into the hose connection port 21 of the cover body 40 via the extension wand 14 and the dust collection hose 12 . The dust and air sucked into the hose connection port 21 is sucked into the dust collection section 60 through the round air path 53 of the dust collection container 50 .
A part of the air is separated from the dust by the round air path 53 , and the separated air is sucked to the negative pressure room 70 through the net filters F 1 , F 2 .
The dust and air sucked into the dust collection section 60 are separated, and the separated air is sucked to the negative pressure room 70 through the net filter F 3 and also the dust is collected in the dust collection section 60 .
The air sucked to the negative pressure room 70 is sucked to the suction opening 33 A of the electric fan 33 via the pleated filter body 100 or the like. The sucked air is discharged from a discharging port 33 B of the electric fan 33 , and is discharged outside from a discharging port (not shown) of the body case 30 . If the driving of electric fan 33 is stopped, the sucking of dust and air from the suction port 15 is stopped. The degree of vacuum of the negative pressure room 70 of the dust collection container 50 is thereby increased to atmospheric pressure. The opening and closing plate 76 of the dust collection container 50 rotates by its own weight, so as to close the communication hole 63 of the dividing wall 61 as shown in FIGS. 3 , 7 , opening the introduction opening 75 of the fine dust collection section 74 .
On the other hand, the reciprocating body (not shown) of the dust removing device 90 reciprocates for a predetermined time by stopping the driving of the electric fan 33 ; thus, the dust adhering to the pleated filter body 100 is removed. The dust removed from the pleated filter body 100 is disposed into the fine dust collection section 74 because the introduction opening 75 is opened as shown in FIG. 7 .
In order to dispose of the dust accumulated in the dust collection section 60 and the fine dust collection section 74 of the dust collection container 50 , the dust collection container 50 is removed from the body case 30 , and the bottom pad 80 rotates in the clockwise direction about the axis 81 to open the bottom portion of the dust collection section 60 and the fine dust collection section 74 . Accordingly, the dust accumulated in the dust collection section 60 and the fine dust collection section 74 is disposed.
According to one embodiment of the present invention, the introduction opening of the second dust collection section can be opened and closed by means of a simple structure; thus, the re-adhesion of dust can be prevented.
The present application is based on and claims priority from Japanese application No. 2006-99862 filed on Mar. 31, 2006, the disclosure of which is hereby incorporated by reference herein in its entirety.
Although the present invention has been described in terms of an exemplary embodiment, it is not limited thereto. It should be appreciated that variations may be made in the embodiment described by persons skilled in the art without departing from the scope of the present invention as defined by the following claims. In addition, the number, position, shape, or the like of the components are not limited to the above embodiment, and can be changed to the number, position, shape or the like of components preferable for conducting the present invention. Moreover, no element or component in the present disclosure is intended to be dedicated to the public regardless of whether the element or component is explicitly recited in the following claims.
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FIELD OF THE INVENTION
This invention relates to an artificial biocompatible vertebral device and, more particularly, to an intervertebral spinal implant for use in the treatment of back pain.
BACKGROUND OF THE INVENTION
A number of medical conditions such as compression of spinal cord nerve roots, degenerative disc disease, tumor, and trauma can cause severe back pain. Intervertebral fusion is one surgical method of alleviating back pain. In intervertebral fusion, two adjacent vertebral bodies are fused together by removing the affected intervertebral disc and inserting an implant that would allow for bone to grow between the two vertebral bodies to bridge the gap left by the disc removal. Another surgical method of relieving back pain is by corpectomy. In corpectomy, a diseased or damaged vertebral body along with the adjoining intervertebral discs are removed and replaced by a spinal implant that would allow for bone to grow between the closest two vertebral bodies to bridge the gap left by the spinal tissue removal.
A number of different implant materials and implant designs have been used for interbody fusion and for vertebral body replacement with varying success. Current implant materials used include metals, radiolucent materials including plastics, elastic and polymeric materials, ceramic, and allografts. Current implant designs vary from threaded cylindrical implants to rectangular cages with teeth-like protrusions.
For example, U.S. Pat. No. 5,782,919 to Zdeblick et. al. discloses an interbody fusion device which has a tapered body defining a hollow interior for receiving a bone graft or bone substitute material. Furthermore, the body of the device defines exterior threads for gripping the adjacent vertebrae and has a series of vascularization openings for promoting bony ingrowth. A variant on this design is shown in U.S. Pat. No. 4,961,740 to Ray et. al. The Ray patent illustrates a hollow, cylindrical fusion cage having a helical thread disposed on the outer surface of the cage with a plurality of holes leading to the hollow center between the threads.
U.S. Pat. No. 5,766,252 to Henry et. al. discusses a rectangular interbody spinal spacer that has vertically opposite upper and lower load bearing surfaces spaced apart a distance corresponding to the desired spacing. The rigid member has a wedge-shaped configuration with an ogival tip at the front end of the member.
While each of the foregoing prosthesis, address some problems relating to intervertebral disc replacements or vertebral body and intervertebral disc replacements, they present others. Thus, there is a need for an intervertebral implant whose design takes into consideration the anatomy and geometry of the intervertebral space sought to be filled by the intervertebral prosthesis as well as the anatomy and geometry of the end plates of the adjacent vertebral bodies. There is also a need for a spinal disc implant which integrates well with the vertebral bone tissue of the adjacent vertebral bodies between which the implant is to be inserted.
SUMMARY OF THE INVENTION
The present invention relates to an intervertebral implant for use when surgical fusion of vertebral bodies is indicated. The implant may be used to replace a diseased or damaged intervertebral disc or may be used to replace a diseased or damaged partial or complete vertebral body, or may be used to replace a diseased or damaged vertebral body and adjacent intervertebral discs.
In one embodiment, the implant comprises a body made from a biocompatible metal, radiolucent material, allograft, or resorbable material conforming substantially in size and shape with the end plates of the vertebrae, has a wedge-shaped profile, and has a central bore for receiving an osteoconductive material to promote the formation of new bone. The top and bottom surfaces may be flat planar surfaces, wedged, or curved surfaces. Preferably, the top and bottom surfaces mimic the topography of the vertebral end plates. The top and bottom surfaces each may have areas extending from an outer periphery of the implant to the central bore having a plurality of teeth for engaging the end plates of adjacent vertebra and each may also have areas extending from the outer periphery of the implant to the central bore that are substantially smooth for receiving a surgical instrument. The substantially smooth areas may extend in an anterior-posterior direction, a lateral direction, or may run in both directions. In addition, the substantially smooth area may run in an anterio-lateral direction.
The implant may have at least one channel on at least one side of the implant for receiving a surgical tool or instrument. This channel may also extend in at least an anterior-posterior direction, a lateral direction, or in both directions.
In another embodiment, instead of instrument receiving channels, the implant may have a threaded hole on the anterior, anterio-lateral, or lateral side of the implant for receiving a threaded arm of an insertion tool.
In yet another embodiment, the implant may have a stackability feature wherein the implant is modular and comprises an upper endcap, and a lower endcap; or an upper endcap, a lower endcap, and at least one body portion.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top view of a first embodiment of the implant according to the present invention;
FIG. 2 is a cross-sectional side view of the implant of FIG. 1 ;
FIG. 3 is an axial cross-sectional view of the implant of FIG. 1 ;
FIG. 4 is a front or anterior view of the implant of FIG. 1 ;
FIG. 4A is a top view of a another embodiment of the implant of FIG. 1 ;
FIG. 4B is a top view of a another embodiment of the implant of FIG. 1 ;
FIG. 5 is a top view of a second embodiment of the present invention;
FIG. 6 is a cross-sectional side view of the implant of FIG. 5 ;
FIG. 7 is an axial cross-sectional view of the implant of FIG. 5 ;
FIG. 8 is a front or anterior view of the implant of FIG. 5 ;
FIG. 9 is a top view of a third embodiment of the present invention;
FIG. 10 is a side view of the implant of FIG. 9 ;
FIG. 11 is an axial cross-sectional view of the implant of FIG. 9 ;
FIG. 12 is a front or anterior view of the implant of FIG. 9 ;
FIG. 13 is a top view of a fourth embodiment of the present invention;
FIG. 14 is a side view of the implant of FIG. 13 ;
FIG. 15 is an axial cross-sectional view of the implant of FIG. 13 ;
FIG. 16 is a front or anterior view of the implant of FIG. 13 ;
FIG. 16A is a perspective view of a fifth embodiment of the present invention;
FIG. 17 is a top view of an upper endcap of the implant of FIG. 16A ;
FIG. 18 is a bottom view of the upper endcap of FIG. 17 ;
FIG. 19 is a cross-sectional view taken at line A—A of the upper endcap of FIG. 17 ;
FIG. 20 is a cross-sectional view taken at line B—B of the upper endcap of FIG. 17 ;
FIG. 21 is a front or anterior view of the upper endcap of FIG. 17 ;
FIG. 22 is a top view of a lower endcap of the implant of FIG. 16A ;
FIG. 23 is a bottom view of the lower endcap of FIG. 22 ;
FIG. 24 is a cross-sectional view taken at line A—A of the lower endcap of FIG. 22 ;
FIG. 25 is a cross-sectional view taken at line B—B of the lower endcap of FIG. 22 ;
FIG. 26 is a front or anterior view of the lower endcap of FIG. 22 ;
FIG. 27 is a top view of an alternate upper endcap of a fifth embodiment of the present invention;
FIG. 28 is a bottom view of the upper endcap of FIG. 27 ;
FIG. 29 is a cross-sectional view taken at line A—A of the upper endcap of FIG. 27 ;
FIG. 30 is a cross-sectional view taken at line B—B of the upper endcap of FIG. 27 ;
FIG. 31 is a front or anterior view of the upper endcap of FIG. 27 ;
FIG. 32 is a top view of an alternate lower endcap of a fifth embodiment of the present invention;
FIG. 33 is a bottom view of the lower endcap of FIG. 32 ;
FIG. 34 is a cross-sectional view taken at line A—A of the lower endcap of FIG. 32 ;
FIG. 35 is a cross-sectional view taken at line B—B of the lower endcap of FIG. 32 ;
FIG. 36 is a front or anterior view of the lower endcap of FIG. 32 ;
FIG. 37 is a front or anterior view of a body portion of the implant of FIG. 16A ;
FIG. 38 is a cross-sectional view taken at line A—A of the body portion of FIG. 37 ;
FIG. 39 is a top view of the body portion of FIG. 37 ;
FIG. 40 is a bottom view of the body portion of FIG. 37 ;
FIG. 41 is a cross-sectional view taken at line B—B of the body portion of FIG. 37 ;
FIG. 42 is a top view of an endcap of a sixth embodiment of the present invention;
FIG. 43 is a bottom view of the endcap of FIG. 42 ;
FIG. 44 is a cross-sectional view taken at line A—A of the endcap of FIG. 42 ;
FIG. 45 is a side or lateral view of the endcap of FIG. 42 ;
FIG. 46 is a front or anterior view of the endcap of FIG. 42 ;
FIG. 47 is a top view of an alternate endcap of a sixth embodiment of the present invention;
FIG. 48 is a bottom view of the endcap of FIG. 47 ;
FIG. 49 is a cross-sectional view taken at line A—A of the endcap of FIG. 47 ;
FIG. 50 is a side or lateral view of the endcap of FIG. 47 ;
FIG. 51 is a front or anterior view of the endcap of FIG. 47 ;
FIG. 52 is a top view of an alternate endcap of a sixth embodiment of the present invention;
FIG. 53 is a bottom view of the endcap of FIG. 52 ;
FIG. 54 is a cross-sectional view taken at line B—B of the endcap of FIG. 52 ;
FIG. 55 is a side or lateral view of the endcap of FIG. 52 ;
FIG. 56 is a front or anterior view of the endcap of FIG. 52 ;
FIG. 57 is a top view of a body portion of a sixth embodiment of the present invention;
FIG. 58 is a bottom view of the body portion of FIG. 57 ;
FIG. 59 is a cross-sectional view of the body portion of FIG. 57 ;
FIG. 60 is a cross-sectional view taken at line B—B of the body portion of FIG. 57 ;
FIG. 61 is a front or anterior view of the body portion of FIG. 57 ;
FIG. 62 is a side or lateral view of the body portion of FIG. 57 ;
FIG. 63 is a top view of an endcap of a seventh embodiment of the present invention;
FIG. 64 is a bottom view of the endcap of FIG. 63 ;
FIG. 65 is a cross-sectional view taken at line A—A of the endcap of FIG. 63 ;
FIG. 66 is a side or lateral view of the endcap of FIG. 63 ;
FIG. 67 is a top view of a body portion of a seventh embodiment of the present invention;
FIG. 68 is a bottom view of the body portion of FIG. 67 ;
FIG. 69 is a side or lateral view of the body portion of FIG. 67 ; and
FIG. 70 is a perspective view of an implant of a seventh embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows a top view of a first embodiment of intervertebral spacer or implant 10 according to the present invention. Implant 10 has a generally kidney-bean shaped footprint which includes anterior side 12 , posterior side 14 , and first and second lateral sides 16 , 18 . Anterior side 12 and lateral sides 16 , 18 are all substantially arcuate, preferably convex, in shape while posterior side 14 is substantially arcuate, preferably concave, in shape.
Implant 10 further includes central bore 26 which can be filled with bone growth inducing substances to allow bony ingrowth and to further assist in the fusion of the adjacent vertebrae and the implant. Central bore 26 has a generally kidney-bean shape that substantially conforms to the kidney-bean shaped footprint of implant 10 . The radius of curvature 23 of the arcuate, preferably convex, sides of central bore 26 may be about 6.5 mm to about 8.5 mm, preferably about 7.5 mm, and the radius of curvature 25 of the areas between the preferably convex and concave sides are about 3 mm to about 3.4 mm, preferably about 3.2 mm.
In addition, implant 10 , on its upper 15 and lower 30 surfaces, has sections or areas having teeth 20 , spikes, or similar gripping structures to facilitate engagement of implant 10 with the end plates of the adjacent vertebra. The teeth may be pyramidal, saw toothed or other similar shapes. Ridges may also be used to facilitate gripping adjacent vertebrae. Implant 10 may also have sections or areas 22 or 24 or both which are essentially smooth and devoid of any protrusions. Sections 22 , 24 are provided to assist the surgeon in implantation of the spacer as will be discussed below.
As mentioned above, implant 10 has a generally kidney-bean shaped footprint. This footprint is designed to conform in size and shape with the general perimeter and shape of the end plates of the vertebrae between which implant 10 is to be implanted thereby providing maximum support while avoiding the intravertebral foramen of the vertebral bodies. The intravertebral foramen or the spinal canal is the portion of the vertebral body that houses the spinal cord and nerve roots. Generally, a portion of the intravertebral foramen extends into the body portion or end plate portion of the vertebra. This portion of the intravertebral foramen, in effect, changes the perimeter of the body portion of the vertebra from substantially an oval shape to substantially a kidney-bean shape. Accordingly, the footprint of implant 10 is kidney-bean shaped to emulate the general shape and perimeter of the body portion of the adjacent vertebrae.
Implant 10 preferably also has a generally wedge-shaped, side-view profile that is designed to restore the natural curvature or lordosis of the spine after the affected disc or affected vertebral body and adjoining discs have been removed. As shown in FIGS. 2 and 4 , this wedge shape results from a gradual increase in height from anterior side 12 followed by a decrease in height as posterior side 14 is approached. The implant has a generally constant height from lateral side 16 to lateral side 18 . In another preferred embodiment, the implant may have a gradual increase in height followed by a gradual decrease in height from lateral side 16 to lateral side 18 . The substantially convex curvature of upper surface 15 and lower surface 30 change the height of implant 10 in the anterior to posterior direction. In another preferred embodiment, the substantially convex curvature of upper surface 15 and lower surface 30 change the height of implant 10 in the lateral direction. Implant 10 preferably has the greatest height generally midway between anterior side 12 and the center of implant 10 . In an exemplary embodiment, upper surface 15 and lower surface 30 may also be flat planar surfaces or flat angled surfaces. Alternatively, the upper surface 15 and lower surface 30 may be substantially curved surfaces, preferably shaped to mimic the topography of the vertebral end plates.
In order to facilitate insertion of implant 10 , posterior side 14 and anterior side 12 transition to upper and lower surfaces 15 , 30 with rounded edges 40 . Rounded edges 40 may enable implant 10 to slide between the end plates while minimizing the necessary distraction of the end plates. In a preferred embodiment, rounded edges 40 have a radius of curvature ranging from about 0.75 mm to 1.75 mm, but preferably is about 1.25 mm. In another preferred embodiment, rounded edges 40 may extend around the periphery of implant 10 . Rounded edges 40 may also be used as a means to clean the edges of the implant 10 by eliminating any half or partial teeth located on or near the edge of the implant 10 .
As shown in FIG. 2 and FIG. 3 , channel 32 runs through implant 10 from anterior side 12 through central bore 26 to posterior side 14 . Channel 32 is sized to receive a surgical instrument such as an inserter for implantation of implant 10 . In addition, located along the side of channel 32 , near anterior side 12 , are retaining grooves 34 which further assist with coupling the implantation instrument to implant 10 . Using the implantation instrument with channel 32 and retaining grooves 34 , implant 10 can be inserted in an anterior approach where posterior end 14 is the first side to be introduced to the intervertebral space.
Extending from a first lateral side 16 to a second lateral side 18 may be a second instrument receiving channel 38 . Channel 38 is also sized to receive a surgical instrument such as an inserter for implantation of implant 10 and has retaining grooves 36 and 37 to further assist with coupling the implantation instrument to implant 10 . Using the implantation instrument with channel 38 and retaining grooves 36 , implant 10 can be inserted in a lateral approach where lateral side 16 is the first side to be introduced into the intervertebral space. Alternatively, using the implantation instrument with channel 38 and retaining grooves 37 , implant 10 can be inserted in a lateral approach where lateral side 18 is the first side to be introduced into the intervertebral space.
Although spinal spacer insertion instruments are well known in the art, an inserter used with implant 10 may be modified to optionally include releaseable engaging members configured and dimensioned to mate with retaining grooves 34 , 36 , 37 to further assist with holding the implant during the insertion and installation procedure.
As can be seen in FIGS. 2 and 3 , channel 32 is shown extending the entire length of the lateral sides 16 , 18 of the implant 10 . However, in an exemplary embodiment, channel 32 may extend only a portion of the length of lateral sides 16 , 18 , or may extend the length of only one of the lateral sides 16 , 18 . Likewise, channel 38 may extend only a portion of the length of sides 12 , 14 or may extend along one of the sides 12 , 14 .
To further assist with the insertion and implantation of implant 10 , implant 10 has areas 22 and 24 , located on the upper 15 and lower 30 surface of implant 10 , which are substantially smooth and are sized to receive an instrument such as a distractor, which is well known in the art. In this particular embodiment, area 22 extends in an anterior-posterior direction helping facilitate anterior implant insertion and area 24 extends in a transverse or lateral direction helping facilitate transverse implant insertion. Although in FIG. 1 area 22 is shown as extending along the entire longitudinal length of implant 10 , from the perimeter edge of anterior side 12 to the perimeter edge of posterior side 14 , area 22 may extend only partially along the longitudinal length of implant 10 . The preceding is also applicable to area 24 . Area 24 is shown to extend along the entire transverse length of implant 10 , however, area 24 may extend only partially along the transverse length of implant 10 . Furthermore, in an exemplary embodiment, only area 22 , as shown in FIG. 4A , or only area 24 , as shown in FIG. 4B , may be present on upper and lower surfaces 15 , 30 of implant 10 .
Implant 10 may be fabricated from pure titanium or an alloy thereof, preferably anodized to increase its biocompatiblity by making it more inert. Implant 10 may also be fabricated from a radiolucent material, such as polyetheretherketone or polyetherketoneketone, and may include a radiopaque marker, such as a titanium alloy pin. The radiopaque marker may be located along any of the implant sides such as anterior side 12 , posterior side 14 , or lateral sides 16 , 18 . By using a radiolucent material, the progression and status of the fusion can be tracked through the use of X-rays or similar devices while the radiopaque marker will indicate the position of the implant with respect to the adjacent vertebral bodies. Implant 10 may also be fabricated from other biocompatible materials, such as allografts, and/or other resorbable materials.
The dimensions of the implant 10 may vary depending on where in the spine the implant will be inserted. The vertebral bodies in the lumbar area of the spine, for example, are larger than the vertebral bodies in the thoracic area. Therefore, an implant intended for the thoracic region would be smaller than one for the lumbar region. Likewise, lower lumbar disc replacements would be larger than upper ones. A person of ordinary skill could adapt the basic dimensions of the implant to make them occupy the space formerly occupied by the particular vertebral disc which needs replacement. Implant 10 is generally sized for anterior, lateral, or anterio-lateral approaches where inserting the implant around the spinal cord or spinal dural sac is not necessary as in a posterior approach. An exemplary embodiment of implant 10 may have a width (extending from anterior side 12 to posterior side 14 ) ranging from 15 mm–40 mm, but preferably about 22–26 mm, and most preferably about 24 mm, and a length (extending from lateral side 16 to lateral side 18 ) ranging from 20 mm–50 mm, but preferably about 28–32 mm, and most preferably about 30 mm. In addition, in an exemplary embodiment, the height of implant 10 , measure as the distance between upper surface 15 and lower surface 30 , when used as an intervertebral spacer, may be in the range of about 5 mm to about 25 mm. When using implant 10 as a corpectomy device, the height of implant 10 may range from about 17 mm to about 100 mm. Furthermore, in an exemplary embodiment, the radius of curvature 19 (shown in FIG. 1 ) of the concave and the radius of curvature 17 (shown in FIG. 1 ) of the convex sides may range from about 8 mm to about 30 mm, but preferably are about 13 mm. The radius of curvature 21 (shown in FIG. 1 ) of transition areas 13 which connect concave side 14 with convex sides 16 , 18 may be about 4 mm to about 8 mm, but preferably are about 6 mm. Also, in an exemplary embodiment, the radius of curvature of the upper and lower surfaces of implant 10 from anterior side 12 to posterior side 14 may range from about 40 mm to about 100 mm, but preferably about 50 mm. The upper and lower surfaces 15 , 30 are preferably flat between lateral sides 16 , 18 .
FIG. 5 shows a top view of a second embodiment of an implant 100 . In general, most of the structure of implant 100 is similar or comparable to the structure of implant 10 . Accordingly, the equivalent structures of implant 100 have been numbered the same as implant 10 and discussion of the similar components and features is not believed necessary. In this particular embodiment, located on upper surface 15 and lower surface 30 of implant 100 , is area 110 . Area 110 extends simultaneously in a longitudinal and lateral direction diagonally across implant 110 to facilitate anterio-lateral implant insertion. Although in FIG. 5 area 110 is shown as extending along the entire length of implant 100 , area 110 may extend only partially along the length of implant 100 .
Similar to implant 10 discussed above, implant 100 has the two sets of instrument receiving channels to increase surgical flexibility when inserting implant 100 and to facilitate the insertion process by creating more surgical insertion alternatives. In the case of an anterio-lateral insertion, either channel 38 with retaining grooves 36 and 37 may be used or channel 32 with retaining grooves 34 may be used.
FIG. 9 shows a top view of a third embodiment of an implant 200 . In general, most of the structure of implant 200 is similar or comparable to the structure of implant 10 . Accordingly, the equivalent structures of implant 200 have been numbered the same as implant 10 and discussion of the similar components and features is not believed necessary. In this particular embodiment, instead of having instrument receiving channels, implant 200 has threaded bores 210 , 212 . Threaded bores 210 , 212 are sized to receive an implantation instrument such as a threaded inserter.
As can best be seen in FIGS. 10 and 11 , threaded bore 210 is located on lateral side 18 . This location allows for insertion of implant 200 in a lateral fashion. Although, threaded bore 210 is located on lateral side 18 , it may also be located on lateral side 16 . This location also allows for insertion of implant 200 in a lateral direction. FIGS. 11 and 12 show threaded bore 212 which is located on anterior side 12 of implant 200 . This location allows for insertion of implant 200 in an anterior direction with posterior side 14 being the first side to be introduced to the intervertebral space.
FIG. 13 shows a top view of a fourth embodiment of an implant 300 . In general, most of the structure of implant 300 is similar or comparable to the structure of implant 100 . Accordingly, the equivalent structures of implant 300 have been numbered the same as implant 100 and discussion of the similar components and features is not believed necessary. In this particular embodiment, instead of having instrument receiving channels, implant 300 has threaded bore 310 . Threaded bore 310 , is sized to receive an implantation instrument such as a threaded inserter.
As can best be seen in FIGS. 15 and 16 , threaded bore 310 is located on an anterio-lateral side (between anterior side 12 and lateral side 16 ) of implant 300 . This location allows for insertion of implant 200 in an anterio-lateral fashion. Although, threaded bore 310 is located on an anterio-lateral side (between anterior side 12 and lateral side 16 ), it can also be located on an opposite anterio-lateral side (between anterior side 12 and lateral side 18 ) also allowing for an anterio-lateral implantation.
In a fifth embodiment, implant 400 is similar to the previously disclosed embodiment but now has a stackability feature. As will be further explained below, implant 400 includes an upper endcap and a lower endcap which may be stacked to form the spacer or implant. As shown in FIG. 16A , implant 400 may also include at least one body portion which may be stacked between the upper endcap and the lower endcap to form the spacer or implant. FIG. 17 shows a top view of upper endcap 402 of implant 400 . Upper endcap 402 has a generally kidney-bean shaped footprint which includes anterior side 403 , posterior side 404 , and first and second lateral sides 406 , 408 . Anterior side 403 and lateral sides 406 , 408 are all substantially arcuate, preferably convex, in shape while posterior side 404 is substantially arcuate, preferably concave, in shape.
As shown in FIGS. 17–20 , upper endcap 402 also includes two elongated bores 410 which can be filled with bone growth inducing substances to allow bony ingrowth and to further assist in the fusion of the adjacent vertebrae. Upper endcap 402 further includes a central bore 411 for receiving a fastening member, such as a screw. In addition, upper endcap 402 , on its upper surface 405 , has sections or areas having teeth 412 or similar gripping means to facilitate engagement of implant 400 with the end plates of the adjacent vertebra, and has sections or areas 414 , 416 which are substantially smooth and devoid of any protrusions. Although in FIG. 17 sections 414 , 416 are shown as extending along the entire length of upper endcap 402 , from perimeter edge to perimeter edge, sections 414 , 416 may extend only partially along the length of upper endcap 402 . Sections 414 , 416 are provided to assist the surgeon in anterior or lateral implantation of the implant as was discussed above with respect to sections 22 , 24 . As can be seen in FIGS. 18 and 21 , upper endcap 402 has a generally rectangular protrusion 418 configured and dimensioned to interface and mate with a recess portion of the implant body or with the lower endcap. While protrusion 418 has been shown and described as generally rectangular, it can be appreciated that protrusion 418 can be any shape desired. A lower surface 407 surrounds the protrusion 418 . Lower surface 407 is illustrated as surrounding and encircling completely protrusion 418 , but it can be appreciated that lower surface 407 may only partially surround protrusion 418 .
Upper endcap 402 may have a generally wedge-shaped, side profile that is designed to restore the natural curvature or lordosis of the spine after the affected disc or affected vertebral body and adjoining discs have been removed. As shown in FIG. 19 , this wedge shape results from a gradual increase in height from anterior side 403 followed by a decrease in height as posterior side 404 is approached. The substantially convex curvature of upper surface 405 changes the height of implant 400 along its width. In an exemplary embodiment, upper surface 405 may also be a flat planar surface, a flat angled surface, or a substantially curved surface, preferably shaped to mimic the topography of the adjacent vertebral end plates. The radius of curvature for upper surface 405 may be the same as described for the one-piece implant described earlier.
FIG. 22 shows a top view of a lower endcap 420 . In general, most of the structure of endcap 420 is similar or comparable to the structure of endcap 402 . Accordingly, the equivalent structures of endcap 420 have been numbered the same as endcap 402 and discussion of the similar components and features is not believed necessary. As discussed with endcap 402 , endcap 420 also has a generally kidney-bean shaped footprint which includes anterior side 403 , posterior side 404 , and first and second lateral sides 406 , 408 . Anterior side 403 and lateral sides 406 , 408 are all substantially arcuate, preferably convex, in shape while posterior side 404 is substantially arcuate, preferably concave, in shape. As can be seen in FIGS. 37–41 , on lower surface 407 , lower endcap 420 has a shoulder 424 defining a cavity 422 configured and dimensioned to interface and mate with a portion of the implant body. Shoulder 424 has been shown as surrounding cavity 422 entirely, but it should be appreciated that shoulder 424 may only partially surround cavity 422 .
Turning now to FIGS. 27–31 , an alternative embodiment of upper endcap 430 can be seen. In general, most of the structure of upper endcap 430 is similar or comparable to the structure of upper endcap 402 . Accordingly, the equivalent structures of upper endcap 430 have been numbered the same as upper endcap 402 and discussion of the similar components and features is not believed necessary. In this particular embodiment, located on upper surface 405 of upper endcap 430 , is area 432 . Area 432 extends simultaneously in a longitudinal and lateral direction diagonally across upper endcap 430 to facilitate anterio-lateral implant insertion. Although in FIGS. 27–31 , area 432 is shown as extending along the entire length of upper endcap 430 , area 432 may extend only partially along the length of upper endcap 430 .
FIG. 32 shows a top view of a lower endcap 440 . In general, most of the structure of lower endcap 440 is similar or comparable to the structure of lower endcap 420 . Accordingly, the equivalent structures of lower endcap 440 have been numbered the same as lower endcap 420 and discussion of the similar components and features is not believed necessary. As can be seen in FIGS. 32–36 , located on lower surface 405 of lower endcap 440 , is area 432 . Area 432 extends simultaneously in a longitudinal and lateral direction diagonally across lower endcap 440 to facilitate anterio-lateral implant insertion. Although in FIGS. 32–35 , area 432 is shown as extending along the entire length of lower endcap 440 , area 432 may extend only partially along the length of upper endcap 440 .
FIG. 37 shows a front or anterior view of a body portion 450 . In general, some of the structure of body portion 450 is similar or comparable to the structure of upper and lower endcaps 402 , 420 , 430 , 440 . Accordingly, the equivalent structures of body portion 450 have been numbered the same as upper and lower endcaps 402 , 420 , 430 , 440 and discussion of the similar components and features is not believed necessary. As can be seen in FIGS. 37–40 , body portion 450 has a generally kidney-bean shape footprint. Located on upper surface 455 , body portion 450 has a shoulder 462 defining a cavity 464 and located on lower surface 457 , body portion 450 has a generally rectangular protrusion 456 . While shoulder 462 is shown as completely enclosing and surrounding cavity 464 , shoulder 462 may only partially surround cavity 464 . Likewise, lower surface 457 is shown as completely surrounding protrusion 456 , but it can be appreciated that lower surface 457 may only partially surround protrusion 456 . Shoulder 462 and cavity 464 are configured and dimensioned to interface and mate with either rectangular protrusion 418 of upper endcaps 402 , 430 or rectangular protrusion 456 of another body portion 450 . Protrusion 456 of body portion 450 is configured and dimensioned to interface and mate with either cavity 422 of lower endplates 420 , 440 or cavity 464 of another body portion 450 . Again, while the protrusions have been described as rectangular, any geometric shape is contemplated.
As mentioned above, implant 400 is a stackable implant comprising an upper endcap 402 , 430 , a lower endcap 420 , 440 , and, if necessary, at least one body portion 450 . It is also possible for implant 400 to include an upper endcap 402 , 430 and a lower endcap 420 , 440 . The modularity of implant 400 , allows implant 400 to have a variable height, thereby allowing a surgeon to create an implant sized to appropriately fit the surgical space. In use, once the implant height that will be needed for the surgical procedure is determined, the desired implant can be created from the endcaps and, if necessary, one or more body portions. If a smaller implant is needed, implant 400 may comprise upper endcap 402 , 430 , and lower endcap 420 , 440 . If a larger implant is needed, implant 400 may comprise upper endcap 402 , 430 , lower endcap 420 , 440 and at least one body portion 450 . Body portions 450 may be the same size or of various sizes. Upper and lower endcaps 402 , 420 , 430 , 440 and body portion 450 are configured and dimensioned to mate with each other via an interference or similar fit. For further fixation of the endcaps and body portion together, a fixation screw may be threaded into central bore 411 . Additional screws and bores my also be used.
Body portion 450 also may include channels 464 , 466 or threaded bores 458 , 460 for implantation of the assembled implant 400 . Channel 464 runs anterior to posterior through body portion 450 from anterior side 403 to posterior side 404 . Channel 464 is sized to receive a surgical instrument such as an inserter for implantation of implant 400 . Using the implantation instrument, implant 400 can be inserted in a lateral approach where the contra-lateral side is the first side to be introduced into the intervertebral space. Alternatively, using the implantation instrument with channel 464 , implant 400 may be inserted in a lateral approach where lateral side 408 is the first side to be introduced to the intervertebral space.
Extending from a first lateral side 406 to a second lateral side 408 may be a second instrument receiving channel 466 (not shown). Channel 466 is also sized to receive a surgical instrument such as an inserter for implantation of implant 400 . Using the implantation instrument with channel 466 , implant 400 may be inserted in an anterior approach where posterior end 404 is the first side to be introduced to the intervertebral space.
Although channel 464 is described as extending the entire length of the lateral sides 406 , 408 of the implant 400 , channel 464 may extend only a portion of the length of lateral sides 406 , 408 , or may extend the length of only one of the lateral sides 406 , 408 . Likewise, channel 466 may extend the length of one of the sides 403 , 404 or may extend only a portion of the length of sides 403 , 404 .
Implant 400 , instead of having instrument receiving channels, may have threaded bores 458 , 460 . Threaded bores 458 , 460 are sized to receive an implantation instrument such as a threaded inserter.
As can best be seen in FIGS. 37 and 41 , threaded bore 458 is located on lateral side 406 . This location allows for insertion of implant 400 in a lateral fashion. Although, threaded bore 458 is located on lateral side 406 , it may also be located on lateral side 408 . This location also allows for insertion of implant 400 in a lateral direction. FIG. 41 shows threaded bore 460 which is located on anterior side 403 of implant 400 . This location allows for insertion of implant 400 in an anterior direction with posterior side 404 being the first side to be introduced to the intervertebral space.
In a sixth embodiment, implant 500 is similar to the previously disclosed stackable embodiment, however implant 500 has a different coupling configuration for stacking. As will be further explained below, implant 500 includes a plurality of endcaps which may be stacked to form the spacer or implant. Implant 500 may also include at least one body portion which may be stacked between the endcaps to form the implant. FIG. 42 shows a top view of endcap 502 of implant 500 . Endcap 502 has a generally kidney-bean shaped footprint which includes anterior side 503 , posterior side 504 , and first and second lateral sides 506 , 508 . Anterior side 503 and lateral sides 506 , 508 are all substantially arcuate, preferably convex, in shape while posterior side 504 is substantially arcuate, preferably concave, in shape.
As shown in FIGS. 42–46 , endcap 502 also includes two elongated bores 510 which can be filled with bone growth inducing substances to allow bony ingrowth and to further assist in the fusion of the adjacent vertebrae. Endcap 502 further includes a central bore 511 for receiving a fastening member, such as a screw, sleeve, or nut. In addition, endcap 502 , on its upper surface 505 , has sections or areas having gripping structures 512 to facilitate engagement of implant 500 with the end plates of the adjacent vertebra, and has sections or areas 516 which are substantially smooth and devoid of any protrusions. Although in FIG. 42 sections 516 are shown as extending along the entire length of endcap 502 , from perimeter edge to perimeter edge, sections 516 may extend only partially along the length of endcap 502 . Sections 516 are provided to assist the surgeon in anterior or lateral implantation of the implant as was discussed above with respect to section 22 . As can be seen in FIGS. 43 and 46 , endcap 502 has a generally rectangular protrusion 518 configured and dimensioned to interface and mate with a recess portion of the implant body or another endcap. While protrusion 518 has been shown and described as generally rectangular, it can be appreciated that protrusion 518 can be any shape desired. A lower surface 507 surrounds the protrusion 518 . Lower surface 507 is illustrated as surrounding and encircling completely protrusion 518 , but it can be appreciated that lower surface 507 may only partially surround protrusion 518 . Located proximate to protrusion 518 , on lower surface 507 , is a shoulder 515 defining a cavity 513 . Cavity 513 is configured and dimensioned to interface and mate with a portion of the implant body or another endcap. Shoulder 515 has been shown as surrounding cavity 513 entirely, but it should be appreciated that shoulder 515 may only partially surround cavity 513 . This different coupling configuration allows for interchangeability of the endcaps.
Endcap 502 may have a generally wedge-shaped, side profile that is designed to restore the natural curvature or lordosis of the spine after the affected disc or affected vertebral body and adjoining discs have been removed. As shown in FIG. 44 , this wedge shape results from a gradual increase in height from anterior side 503 followed by a decrease in height as posterior side 504 is approached. The substantially convex curvature of upper surface 505 changes the height of implant 500 along its width. In an exemplary embodiment, upper surface 505 may also be a flat planar surface, a flat angled surface, or a substantially curved surface, preferably shaped to mimic the topography of the adjacent vertebral end plates. The radius of curvature for upper surface 505 may be the same as described for the one-piece implant described earlier.
FIG. 47 shows a top view of another endcap 520 . In general, most of the structure of endcap 520 is similar or comparable to the structure of endcap 502 . Accordingly, the equivalent structures of endcap 520 have been numbered the same as endcap 502 and discussion of the similar components and features is not believed necessary. As discussed with upper endcap 502 , endcap 520 also has a generally kidney-bean shaped footprint which includes anterior side 503 , posterior side 504 , and first and second lateral sides 506 , 508 . Anterior side 503 and lateral sides 506 , 508 are all substantially arcuate, preferably convex, in shape while posterior side 504 is substantially arcuate, preferably concave, in shape. As can be seen in FIGS. 47–51 , endcap 520 also includes two elongated bores 510 which can be filled with bone growth inducing substances to allow bony ingrowth and to further assist in the fusion of the adjacent vertebrae. Endcap 520 further includes a central bore 511 for receiving a fastening member, such as a screw, sleeve or nut. In addition, endcap 520 , on its upper surface 505 , has sections or areas having gripping structures 512 to facilitate engagement of implant 500 with the end plates of the adjacent vertebra, and has sections or areas 517 which are substantially smooth and devoid of any protrusions. Although in FIG. 47 sections 517 are shown as extending along the entire length of endcap 520 , from perimeter edge to perimeter edge, sections 517 may extend only partially along the length of endcap 520 . Sections 517 are provided to assist the surgeon in transverse implantation of the implant as was discussed above with respect to section 24 . As can be seen in FIGS. 48 and 51 , endcap 520 has a generally rectangular protrusion 518 configured and dimensioned to interface and mate with a recess portion of the implant body or another endcap. While protrusion 518 has been shown and described as generally rectangular, it can be appreciated that protrusion 518 can be any shape desired. A lower surface 507 surrounds the protrusion 518 . Lower surface 507 is illustrated as surrounding and encircling completely protrusion 518 , but it can be appreciated that lower surface 507 may only partially surround protrusion 518 . Located proximate to protrusion 518 , on lower surface 507 , is a shoulder 515 defining a cavity 513 . Cavity 513 is configured and dimensioned to interface and mate with a portion of the implant body or another endcap. Shoulder 515 has been shown as surrounding cavity 513 entirely, but it should be appreciated that shoulder 515 may only partially surround cavity 513 .
Endcap 520 may have a generally wedge-shaped, side profile that is designed to restore the natural curvature or lordosis of the spine after the affected disc or affected vertebral body and adjoining discs have been removed. As shown in FIG. 49 , this wedge shape results from a gradual increase in height from anterior side 503 followed by a decrease in height as posterior side 504 is approached. The substantially convex curvature of upper surface 505 changes the height of implant 500 along its width. In an exemplary embodiment, upper surface 505 may also be a flat planar surface, a flat angled surface, or a substantially curved surface, preferably shaped to mimic the topography of the adjacent vertebral end plates. The radius of curvature for upper surface 505 may be the same as described for the one-piece implant described earlier.
Turning now to FIGS. 52–56 , an alternative embodiment of endcap 530 can be seen. In general, most of the structure of endcap 530 is similar or comparable to the structure of endcap 502 . Accordingly, the equivalent structures of endcap 530 have been numbered the same as endcap 502 and discussion of the similar components and features is not believed necessary. In this particular embodiment, located on upper surface 505 of endcap 530 , is area 519 . Area 519 extends simultaneously in a longitudinal and lateral direction diagonally across endcap 530 to facilitate anterio-lateral implant insertion. Although in FIGS. 52–56 , area 519 is shown as extending along the entire length of endcap 530 , area 519 may extend only partially along the length of endcap 530 .
FIG. 57 shows a top view of a body portion 550 . In general, some of the structure of body portion 550 is similar or comparable to the structure of endcaps 502 , 520 , and 530 . Accordingly, the equivalent structures of body portion 550 have been numbered the same as endcaps 502 , 520 , and 530 and discussion of the similar components and features is not believed necessary. As can be seen in FIGS. 57–62 , body portion 550 has a generally kidney-bean shape footprint. Located on upper surface 555 and lower surface 557 , body portion 550 has a shoulder 562 defining a cavity 564 and a generally rectangular protrusion 556 . While shoulder 562 is shown as completely enclosing and surrounding cavity 564 , shoulder 562 may only partially surround cavity 564 . Likewise, upper surface 555 and lower surface 557 are shown as completely surrounding protrusions 556 , but it can be appreciated that upper surface 555 and lower surface 457 may only partially surround protrusions 556 . Shoulder 562 and cavity 564 are configured and dimensioned to interface and mate with either rectangular protrusion 518 of endcaps 502 , 520 , 530 or rectangular protrusion 556 of another body portion 550 . Protrusion 556 of body portion 550 is configured and dimensioned to interface and mate with either cavity 513 of endcaps 502 , 520 , 530 or cavity 564 of another body portion 550 . Again, while the protrusions have been described as rectangular, any geometric shape is contemplated.
As mentioned above, implant 500 is a stackable implant comprising two endcaps 502 , 520 , 530 , and, if necessary, at least one body portion 550 . The modularity of implant 500 , allows implant 500 to have a variable height, thereby allowing a surgeon to create an implant sized to appropriately fit the surgical space. In use, once the implant height that will be needed for the surgical procedure is determined, the desired implant can be created from the endcaps and, if necessary, one or more body portions. If a smaller implant is needed, implant 500 may comprise two endcaps 502 , 520 , 530 . If a larger implant is needed, implant 500 may comprise endcaps 502 , 520 , 530 , and at least one body portion 550 . Body portions 550 may be the same size or of various sizes. Endcaps 502 , 520 , 530 , and body portion 550 are configured and dimensioned to mate with each other via an interference or similar fit. For further fixation of the endcaps or the endcaps and body portion together, a fixation screw may be threaded into central bore 511 . Additional screws and bores my also be used.
Body portion 550 also may include channels 563 , 566 and/or threaded bores 558 , 560 for implantation of the assembled implant 500 . Channel 563 runs anterior to posterior through body portion 550 from anterior side 503 to posterior side 504 . Channel 563 is sized to receive a surgical instrument such as an inserter for implantation of implant 500 . Using the implantation instrument, implant 500 can be inserted in a lateral approach where the contra-lateral side is the first side to be introduced into the intervertebral space. Alternatively, using the implantation instrument with channel 563 , implant 500 may be inserted in a lateral approach where lateral side 508 is the first side to be introduced to the intervertebral space.
Extending from a first lateral side 506 to a second lateral side 508 may be a second instrument receiving channel 566 . Channel 566 is also sized to receive a surgical instrument such as an inserter for implantation of implant 500 . Using the implantation instrument with channel 566 , implant 500 may be inserted in an anterior approach where posterior end 504 is the first side to be introduced to the intervertebral space.
Although channel 563 is described as extending the entire length of the lateral sides 506 , 508 of the implant 500 , channel 563 may extend only a portion of the length of lateral sides 506 , 508 , or may extend the length of only one of the lateral sides 506 , 508 . Likewise, channel 566 may extend the length of one of the sides 503 , 504 or may extend only a portion of the length of sides 503 , 504 .
Implant 500 , instead of or in addition to having instrument receiving channels, may have threaded bores 558 , 560 . Threaded bores 558 , 560 are sized to receive an implantation instrument such as a threaded inserter.
As can best be seen in FIGS. 59 , 61 , and 62 , threaded bore 558 is located on lateral sides 506 , 508 . This location allows for insertion of implant 500 in a lateral fashion. FIG. 59 shows threaded bore 560 which is located on anterior side 503 of implant 500 . This location allows for insertion of implant 500 in an anterior direction with posterior side 504 being the first side to be introduced to the intervertebral space.
As can best be seen in FIG. 59 , body portion 550 may also include openings 561 , which preferably extend from the outer surface of body portion 550 to elongated bores 510 . Openings 561 may be packed with bone growth inducing substances to further aid in the fixation and fusion of the implant.
In a seventh embodiment, implant 600 is similar to the previously disclosed stackable embodiment, however implant 600 has a slightly different structure and footprint. Preferably, the structure and footprint of implant 600 allows implant 600 to be particularly suited for implantation in the cervical region of the spine. FIG. 63 shows a top view of endcap 602 of implant 600 . Endcap 602 has a generally oblong octagonal shaped footprint which includes anterior side 603 , posterior side 604 , and first and second lateral sides 606 , 608 .
As shown in FIGS. 63–66 , endcap 602 also includes an elongated bore 610 which can be filled with bone growth inducing substances to allow bony ingrowth and to further assist in the fusion of the adjacent vertebrae. Endcap 602 further includes a central bore 611 for receiving a fastening member, such as a screw. In addition, endcap 602 , on its upper surface 605 , has sections or areas having gripping structures 612 to facilitate engagement of implant 600 with the end plates of the adjacent vertebra, and has sections or areas 616 which are substantially smooth and devoid of any protrusions. Although in FIG. 63 section 616 is shown as extending along a partial length of endcap 602 , sections 616 may extend along the entire length of endcap 602 , from perimeter edge to perimeter edge. Section 616 may be provided to provide a recess allowing a screw head to be recessed so as not to extend upwardly beyond the upper ends of the gripping structures 612 . As can be seen in FIGS. 65 and 66 , endcap 602 has a protrusion 618 configured and dimensioned to interface and mate with a recess portion of the implant body or another endcap. It can be appreciated that protrusion 618 may be any shape desired. A lower surface 607 surrounds the protrusion 618 . Lower surface 607 is illustrated as surrounding and encircling completely protrusion 618 , but it can be appreciated that lower surface 607 may only partially surround protrusion 618 . Located proximate to protrusion 618 , on lower surface 607 , is a shoulder 615 defining a cavity 613 . Cavity 613 is configured and dimensioned to interface and mate with a portion of the implant body or another endcap. Shoulder 615 has been shown as surrounding cavity 613 entirely, but it should be appreciated that shoulder 615 may only partially surround cavity 513 .
Endcap 602 may have a generally wedge-shaped, side profile that is designed to restore the natural curvature or lordosis of the spine after the affected disc or affected vertebral body and adjoining discs have been removed. As shown in FIG. 66 , this wedge shape results from a gradual increase in height from anterior side 603 to the posterior side 604 . In an exemplary embodiment, upper surface 605 may also be a flat planar surface, a convexly-curved surface, or a substantially curved surface, preferably shaped to mimic the topography of the adjacent vertebral end plates. The radius of curvature for upper surface 605 may be the same as described for the one-piece implant described earlier.
FIG. 67 shows a top view of a body portion 650 . In general, some of the structure of body portion 650 is similar or comparable to the structure of endcap 602 . Accordingly, the equivalent structures of body portion 650 have been numbered the same as endcap 602 and discussion of the similar components and features is not believed necessary. As can be seen in FIGS. 67–69 , body portion 650 has a generally oblong octagonal shape footprint. Located on upper surface 655 and lower surface 657 , body portion 650 has a shoulder 662 defining a cavity 664 and a protrusion 656 . While shoulder 662 is shown as completely enclosing and surrounding cavity 664 , shoulder 662 may only partially surround cavity 664 . Likewise, upper surface 655 and lower surface 657 are shown as completely surrounding protrusions 656 , but it can be appreciated that upper surface 655 and lower surface 657 may only partially surround protrusions 656 . Shoulder 662 and cavity 664 are configured and dimensioned to interface and mate with either protrusion 618 of endcap 602 , or protrusion 656 of another body portion 650 . Protrusion 656 of body portion 650 is configured and dimensioned to interface and mate with either cavity 613 of endcaps 602 or cavity 664 of another body portion 650 . Again, the protrusions may be any contemplated geometric shape.
As mentioned above, implant 600 is a stackable implant comprising two endcaps 602 , and, if necessary, at least one body portion 650 . The modularity of implant 600 , allows implant 600 to have a variable height, thereby allowing a surgeon to create an implant sized to appropriately fit the surgical space. In use, once the implant height that will be needed for the surgical procedure is determined, the desired implant can be created from the endcaps and, if necessary, one or more body portions. If a smaller implant is needed, implant 600 may comprise two endcaps 602 . If a larger implant is needed, implant 600 may comprise endcaps 602 , and at least one body portion 650 . Body portions 650 may be the same size or of various sizes. Endcap 602 , and body portion 650 are configured and dimensioned to mate with each other via an interference or similar fit. For further fixation of the endcaps or the endcaps and body portion together, a fixation screw may be threaded into central bore 611 . Additional screws and bores my also be used.
Body portion 650 also may include windows 665 , 666 which can be filled with bone growth inducing substances to further allow for bony ingrowth and to further assist in the fusion of the adjacent vertebrae. Windows 665 , 666 may also be used to mate with the implant holder to assist with the implantation of the implant.
Body portion 650 may also have a threaded bore 658 . Threaded bore 658 is sized to receive an implantation instrument such as a threaded inserter for implantation of the assembled implant 600 . As can best be seen in FIG. 69 , threaded bore 558 is located on lateral sides 606 , 608 . This location allows for insertion of implant 600 in a lateral fashion.
FIG. 70 shows a perspective view of one embodiment of implant 600 which includes two endcaps 602 and one body portion 650 .
The embodiments disclosed herein are illustrative and exemplary in nature and it will be appreciated that numerous modifications and other embodiments of the implant disclosed may be devised by those skilled in the art.
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[0001] The present application is a continuation-in-part of U.S. patent application Ser. No. 10/772,964 filed Feb. 4, 2004, which is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention relates generally to a formulation for the controlled release of hormones to the systemic circulation and/or to the brain (by bypassing the blood-brain barrier) after nasal application and for the modulation of brain functioning. More specifically, the invention relates to the treatment of neuroendocrinologic disorders, such as Female Sexual Disorder (FSD) by nasally administering a formulation comprising a hormone drug.
BACKGROUND
[0003] A growing body of evidence suggests a modulatory role of brain-acting compounds, such as neurosteroids (e.g., androgens, progestins) or neurotransmitters in the regulation of disorders influenced by receptors in the brain, such as depression, Parkinson's disease, Alzheimer's, or even loss of libido.
[0004] Considerable importance has been placed on the measurement of receptor concentrations in the brain. However, the underlying mechanisms of action are still poorly understood. Much of the confusion about the wide range of effects and side effects is due to various non-genomic actions. Tissues traditionally considered non-targets for clinical action are today found to be vividly regulated by non-genomic mechanisms.
[0005] Generally, genomic actions are typically due to compounds binding to intracellular receptors, traveling to the nucleus of the cell, and binding to DNA to initiate expression of various proteins. These various proteins exert a wide range of effects. The compounds may also induce transcription-independent signaling, thus modulating non-genomic responses. These second messenger pathways involve kinase pathways, including ion flux as well as cAMP or lipase. In contrast to the genomic effects, most of the non-genomic effects are immediate.
[0006] Thus, the mechanisms mediating the effects of a molecule can be both genomic and non-genomic. The clinical relevance of the genomic effects often is understood. However, there is very little knowledge of the possible differential relevance of a molecule's non-genomic actions in different cell types. It is hypothesized that non-genomic signaling mechanisms might be more of a pharmacological phenomenon. At the very best, these can be influenced by the way a molecule is administered.
[0007] Nasal drug delivery offers many advantages that include rapid adsorption due to the abundant presence of capillary vessels in the nose, fast onset of action, avoidance of hepatic first-pass metabolism, utility for chronic medication, and ease of administration. It is also known that, in contrast to large and/or ionized molecules, lipophilic pharmaceutical compounds having a sufficiently low molecular weight generally are readily absorbed by the mucous membrane of the nose. For such drugs, it is possible to obtain pharmacokinetic profiles similar to those obtained after intravenous injection.
[0008] However, maintaining constant in vivo therapeutic drug concentrations for an extended period of time has been problematic. The rapid mucociliary clearance of a therapeutic agent from the site of deposition and the presence of enzymes in the nasal cavity (that may cause degradation of the therapeutic agent) result in a short time span available for absorption.
[0009] Many efforts have been made in the art in attempt to overcome these limitations. GB 1987000012176 describes the use of bioadhesive microspheres to increase residence time in the nasal cavity. It has also been found that the use of enhancers improves permeability of the nasal membrane and stabilizers prevent drug degradation. PCT/GB98/01147 (U.S. Pat. No. 6,432,440) describes the use of in situ gelling pectin formulations.
[0010] Investigations on the nasal absorption of sexual steroids, which are rather small and lipophilic compounds, have shown that sexual steroids are readily absorbed by the mucous membrane of the nose and are found very quickly in serum. Due to this fact, the short half-life of sexual steroids, and the limited possibilities for formulating nasal application forms with sustained release, the use of sexual steroids in clinical practice has been limited because hormone replacement therapy, in general, is a long-term application.
[0011] Several formulations have been proposed for sexual steroid drugs. Testosterone is nearly water-insoluble and somewhat more soluble in vegetable oil. Hussain et al., J. Pharm. Sci. 91(3): 785-789 (2002), concluded that testosterone would be an ideal candidate for nasal administration if its solubility in water could be increased. Hussain et al. proposed using a water-soluble pro-drug, testosterone 17β-N,N-dimethylglycinate, and found serum levels equal to intravenous administration with peak plasma concentrations within twelve minutes (25 mg dose) and twenty minutes (50 mg dose) and elimination half-lives of about fifty-five minutes. It should be noted, however, that this speed is not necessary or desirable because sex hormone replacement is not an emergency therapy.
[0012] Ko et al., J. Microencaps., 15(2): 197-205 (1998), proposed the use of charged testosterone submicron O/W emulsion formulations (water/Tween80, soybean oil/Span80) based on the hypothesis that increased absorption is possible upon solubilization of the drug and/or prolongation of the formulation residence time in the nose. Ko et al. found higher relative bioavailability for the positively (55%) and negatively (51%) charged emulsions compared to the neutral one (37%). T max was observed in every case at about twenty minutes after administration. However, because Ko et al. did not take blood samples before application, it is not possible to evaluate the differences in the decrease of serum levels, although from a graph it seems that after intravenous application (hydroalcoholic solution) the level shows the longest elimination half time. In practice, however, such an emulsion is not suitable for nasal application because of the droplet size (approximately 430 nm).
[0013] The solubility of progesterone in water and oil is somewhat comparable to that of testosterone but investigators have taken different approaches. It has been that progesterone dissolved in almond oil (20 mg/ml) and administered by nasal spray lead to higher bioavailability than that provided by progesterone dissolved in dimethicone or a PEG-based ointment (Fertil Steril 56(1): 139-141 (1991); Maturitas 13(4): 313-317 (1991); Gynecol Endocrinol 6(4): 247-251 (1992); Fertil Steril, 60(6): 1020-1024 (1993); and Maturitas 19(1): 43-52 (1994)).
[0014] After nasal application of progesterone in almond oil, C max levels were observed after thirty to sixty minutes, decreasing significantly six to eight hours after a single administration. Steege et al., Fertil Steril, 46(4): 727-729 (1986), dissolved progesterone in polyethylene glycol (200 mg/ml) and found T max at thirty minutes. The duration of serum levels was at least eight hours but with high variations. When progesterone was formulated in ethanol/propylene glycol/water, however, T max was at only 5.5 minutes (Kumar et al, Proc. Natl. Acad. Sci. U.S.A., 79: 4185-9 (1982)). Provasi et al., Boll. Chim. Farm. 132(10): 402-404 (1993), investigated powder mixtures (co-ground and co-lyophilized progesterone/cyclodextrin) containing progesterone. Provasi et al. found T max at within two to five minutes with serum levels decreasing after only twenty minutes.
[0015] The results for progesterone described above are quite similar to that found for testosterone and for an already marketed aqueous nasal spray containing estradiol, formulated in cyclodextrin (commercially available as AERODIOL® from Servier Laboratories, France). Maximum plasma levels are reached within ten to thirty minutes and decrease to 10% of the peak value after two hours. Again, this speed is not necessary for sex hormone replacement therapy and is not desirable in view of the short elimination half-life of hormones.
[0016] Apart from the “liberation/adsorption” problem shown above in connection with sexual hormones and bioavailability, the focus of research has centered on the crucial liver metabolism and the short half-life of the compounds. However, high protein-binding also presents a problem because only the unbound fraction is biologically active. Approximately 40% of circulating plasma testosterone binds to sex hormone binding globulin (SHBG)—2% in men and up to 3% in women remains unbound (free)—and the remainder binds to albumin and other proteins. The fraction bound to albumin dissociates easily and is presumed to be biologically active, whereas the SHBG fraction is not. It should be noted that the amount of SHBG in plasma determines the distribution of testosterone in free and bound forms, whereas free testosterone concentrations determine (limit) the drug's half-life.
[0017] Additional research has shown that pharmacokinetics (and the resulting efficacy) may be determined by the route of testosterone administration. Previous research has shown that sublingual application of testosterone undecanoate results in a very fast and high testosterone peak that triggers sexual arousal. Apperloo et al., J Sex Med, 3:541-549 (2006), recently found that a single dose of a vaginally-applied testosterone propionate results in a slower rising and lower testosterone peak that does not trigger sexual arousal. Apperloo et al. found an acute and prolonged rise in testosterone and free testosterone above physiological levels with a peak at 5.5 hours is not sufficient to influence the female sexual response. Recently, it was hypothesized that some effects of hormones are typically mediated by their neurobiological activity. Thus, these application forms probably lack a sufficient CNS effect. In order to achieve a corresponding efficacy, the therapeutic agent has to cross the blood-brain barrier. The therapeutic agent, however, not only has to cross the blood-brain barrier in a certain concentration, it additionally has to stay in the brain long enough to exert its desired action.
[0018] Accordingly, there has remained a need for a sexual hormone drug formulation system that is therapeutically effective when administered to the nose of a patient and is safe, stable and easily manufactured.
SUMMARY OF THE INVENTION
[0019] The inventor has surprisingly found that the incorporation of various hormone drugs, such as sexual hormones, into a special lipophilic or partly lipophilic system not only leads to a higher bioavailability in general caused by sustained serum levels in plasma but also to a more favorable serum level profile. In an especially important aspect, the lipophilic or partly lipohilic system of the invention allows hormones to cross the blood-brain-barrier in such a way as to achieve efficacy in medicines for disorders of the central nervous system (CNS).
[0020] The invention comprises a formulation for nasal application comprising: (a) at least one active ingredient; (b) at least one lipophilic or partly lipophilic carrier; and (c) a compound or a mixture of compounds having surface tension decreasing activity in an amount effective for in situ generation of an emulsion upon contact of the formulation with water.
[0021] While not wishing to be bound by theory, it is believed that nasal administration of the formulation of the invention may be able to recruit selective actions of a molecule which, in turn, may provide new clinical applications. Of particular interest is the use of formulations to modulate brain functioning. Application of the formulation of the invention to the nose results in surprising and different action of compounds to the brain as compared to what is seen with conventional formulations. While not wishing to be bound by theory, it is believed that this effect is due to new, possibly also non-genomic, mechanisms that are made available by the gel formulation of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 shows a comparison of DHT levels after application of different doses of testosterone as a dermal or nasal gel to hypogonadal men.
[0023] FIG. 2 shows the serum levels of free testosterone at baseline and after nasal application of testosterone.
[0024] FIG. 3 shows the effect of a single nasal dose of 0.9 mg testosterone in women.
[0025] FIG. 4 shows the fMRI data indicating the brain response to emotional faces after nasal administration of testosterone.
[0026] FIG. 5 shows the fMRI data indicating the brain response to emotional faces after nasal administration of placebo.
[0027] FIG. 6 shows the serum concentration of testosterone in women over time during fMRI.
[0028] FIG. 7 Percentage (±SEM) of frequency of Eyebrow Raising (A), Chest Rubbing (B), Masturbation (C), Head Cocking (D) and Mutual Gaze (E), measured by instantaneous sampling in the different phases (Baseline, Treatment 1, Wash Out, Treatment 2) for the Group 1 (G1: Placebo-Noseafix) and Group 2 (G2: Noseafix-Placebo). *p<0.05 vs. baseline.
[0029] FIG. 8 Percentage (±SEM) of frequency in the Baseline (A), Treatment 1 (B), Wash Out (C) and Treatment 2 (D), of behaviors measured by instantaneous sampling (Eyebrow Raising, Chest Rubbing, Masturbation, Head Cocking and Mutual Gaze). For Group 1 (G1: Placebo-Noseafix) and Group 2 (G2: Noseafix-Placebo). *p<0.05 vs. Placebo.
[0030] FIG. 9 Percentage (±SEM) of observation time of grooming (A), courtship (B) and agonistic behavior (C), measured by continuous recording in different phase (Baseline, Treatment 1, Wash Out, Treatment 2) for the Group 1 (G1: Placebo-Noseafix) and Group 2 (G2: Noseafix-Placebo). *p<0.05 vs. Baseline, Treatment 1 and Wash Out. The total Observation Time was: 224 minutes for Baseline and 140 minutes for each Treatment and Wash Out phase.
[0031] FIG. 10 Percentage (+SEM) of observation time in Baseline (A), Treatment 1 (B), Wash Out (C) and Treatment 2(D), of grooming, courtship and agonistic behavior, measured by continuous recording for Group 1 (01: Placebo-Noseafix) and Group 2 (G2: Noseafix-Placebo). *p.<0.05 vs. Placebo. The total Observation Time was: 224 minutes for Baseline and 140 minutes for each Treatment and Wash Out phase.
[0032] FIG. 11 shows the plasma testosterone levels in different phases of the study for the animals treated with placebo and the product Noseafix.
DETAILED DESCRIPTION OF THE INVENTION
[0033] The formulation of the invention is chemically and physically stable and can be in the form of a suspension or a solution of the pharmacologically active substance. The formulation of the invention may be filled into a preservative-free device able to accurately deliver doses of the above formulation, even at higher viscosities.
[0034] After nasal application of the formulation of the invention, the active ingredient or active ingredient particles are efficiently trapped at the deposition site and are absorbed at a predictable rate across the mucous membrane of the patient, thereby limiting possible deactivation by metabolizing enzymes and/or protein-binding.
[0035] It will also be understood that the terms and expressions used herein have the ordinary meaning as is accorded to such terms and expressions with respect to their corresponding respective areas of inquiry and study except where specific meanings have otherwise been set forth herein.
[0036] The term “higher availability” shall mean that after a single application a serum level of hormone significantly higher than baseline is maintained for six hours, more preferably for eight hours and most preferably for at least ten hours. The term “higher availability” shall also mean that, after a single application, a cerebral spinal fluid (CSF) level significantly higher than baseline can be achieved and maintained long enough to exert the desired action.
[0037] The term “hormone” shall mean polypeptide hormones, oligopeptide hormones, amine hormones, steroid hormones (such as sexual hormones, including testosterone), and lipid and phospholipids-derived hormones.
[0038] The term “sexual hormone drug” shall mean a sexual hormone (such as testosterone), a biologic pro-drug of a sexual hormone (such as androstenedione, progesterone, 17-α-hydroxyprogesterone), a derivative of a sexual hormone (such as mestanolone and 4-chloro-1-dehydromethyltestosterone), or a combination thereof.
[0039] The inventive formulation for nasal application comprises (a) at least one active ingredient; (b) at least one lipophilic or partly lipophilic carrier; and (c) a compound or mixture of compounds having surface tension decreasing activity in an amount effective for in situ generation of an emulsion upon contact of the formulation with water.
[0040] The active ingredient is generally a hormone drug. Preferably, the hormone drug is comprised within the formulation in an amount up to about 0.2 to about 6% by weight, preferably 0.2 to 4% by weight. In one aspect of the invention, the hormone drug is a sexual hormone drug. Preferably, the sexual hormone drug is testosterone.
[0041] In one aspect, the active ingredient may be introduced into the formulation in a processed form, such as nano- or microparticles, liposomes, bilayer vesicles, and micelles, among others.
[0042] The formulation of the invention also comprises at least one lipophilic or partly lipophilic carrier. The formulation of the invention comprises oil in a range of about 30% to about 98% by weight, preferably about 60 to about 98% by weight, more preferably about 75% to about 95% by weight, even more preferably about 85% to about 95% by weight, and most preferably about 90% by weight. In a preferable aspect, the lipophilic carrier comprises an oil or a mixture of oils, such as a vegetable oil, such as castor oil, soybean oil, sesame oil, or peanut oil, fatty acid esters such as ethyl- and oleyloleat, isopropylmyristate, medium chain triglycerides, glycerol esters of fatty acids, or polyethylene glycol, phospholipids, white soft paraffin, hydrogenated castor oil, or a mixture thereof. More preferably, the oil is a vegetable oil. Most preferably, the oil is castor oil. In one aspect, the lipophilic carrier may comprise a mixture of oils. In a preferable aspect, the vegetable oil is castor oil.
[0043] The formulation of the invention also comprises a compound or mixture of compounds having surface tension decreasing activity in an amount effective for in situ generation of an emulsion upon contact of the formulation with water in an amount of about 1 to about 20% by weight, preferably about 1 to about 10% by weight, more preferably about 1 to about 5% by weight, and most preferably at about 4% by weight. The surface tension decreasing component generally comprises at least one surfactant selected from the group consisting of anionic, cationic, amphoteric, and non-ionic surfactants, including, but not limited to, lecithin, fatty acid ester of polyvalent alcohols, fatty acid ester of sorbitanes, fatty acid ester of polyoxyethylensorbitans, fatty acid ester of polyoxyethylene, fatty acid ester of sucrose, fatty acid ester of polyglycerol, oleoyl macrogolglycerides, and/or at least one humectant such as sorbitol, glycerine, polyethylene glycol, macrogol glycerol fatty acid ester, or mixture thereof. Preferably, the surface tension decreasing component is an oleoyl macrogolglyceride (such as LABRAFIL® M 1944 CS, as available from Gattefossé (Saint-Priest, France)). In another aspect, the surface tension decreasing component may comprise a surfactant mixture. In a preferable aspect, the surface tension decreasing component comprises an oleoyl macrogolglyceride or a mixture of oleoyl macrogolglycerides.
[0044] The particular amount of surface tension decreasing component that constitutes an effective amount is dependent on the particular oil or oil mixture used in the formulation. Generally, depending on the carrier component selected for the formulation, particularly where the carrier component is an oil or oil mixture, it is necessary to select surfactants with compatible hydrophilic/lipophilic balance (HLBF) values to form the most stable emulsions.
[0045] While it is not practical to enumerate specific amounts of surface tension decreasing components for use with a variety of different carrier components, Table 1 below provides a general guide for providing the formulation of the invention.
[0000]
TABLE 1
Typical composition of lipid formulation.
Content of formulation (% w/w)
Excipient
Type 1
Type 2
Type 3
Type 4
Type 5
Oil
100
40-100
40-100
<20
—
Surfactant
—
0-60
—
—
0-20
HLB ≦ 12
Surfactant
—
—
20-40
20-50
30-80
HLB ≦ 12
Hydrophilic
—
—
0-40
20-50
0-50
co-solvent
[0046] The formulation may optionally further comprise a viscosity regulating agent, such as a thickener or gelling agent. While the amount of the viscosity regulating agent used in the formulation is dependent on the carrier used in the formulation, the formulation generally comprises the viscosity regulating agent in an amount of from about 0.5 to about 10% by weight, preferably about 0.5 to about 7% by weight, more preferably about 1 to about 4% by weight, and most preferably about 4% by weight. Examples of viscosity regulating agents include, but are not limited to, cellulose and derivatives thereof, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides, lanolin, the like, or mixture thereof. A preferred viscosity regulating agent is colloidal silicon dioxide (such as ACROSIL 200®, as available from Degussa).
Optional Components
[0047] In another aspect of the invention, the formulation may optionally comprise a viscosity regulating agent in an amount of from about 0.5 to about 10% by weight, preferably about 0.5 to about 7% by weight, more preferably about 1 to about 4% by weight, and most preferably about 4% by weight. Preferably, the viscosity regulating agent comprises a thickener or gelling agent, such as cellulose and cellulose derivatives, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides and lanolin, or a mixture thereof. More preferably, the viscosity regulating agent is colloidal silicon dioxide.
[0048] In another aspect, the viscosity regulating agent may comprise a mixture of viscosity regulating agents. In a preferred aspect, the mixture of viscosity regulating agents together with an ointment base such as oleo gel or PEG-, lanolin alcohol-, or petrolatum-ointment and about 0.5 to about 40% (w/w) of lanolin, hydroxypropyl methylcellulose, petrolatum, PEG 300-6000, glyceryl monostearate, beeswax, or CARBOPOL® (Noveon, Inc).
[0000]
Constituents
%-wt
Useful
Preferably
Preferred
Active
—
0.2-0.6
0.2-4
Carrier
60-98
75-95
85-95
Surfactant
1-20
1-10
1-5
Viscosity Builder
0.5-10
0.5-7
1-4
[0049] Processing.
[0050] Generally, the formulation of the invention can be prepared very easily. The lipophilic carrier and surface tension decreasing component are filled into a stirrer vessel and about 75% of the viscosity regulating agent is mixed in. The active ingredient is added under stirring to obtain a homogenous dispersion of the active ingredient. Next, the formulation is adjusted to the necessary viscosity with the remainder of the viscosity regulating agent. The formulation is preferably filled into a preservative-free unit-dose container.
[0051] Because some hormones have lower levels of solubility in water, liberation from the formulation is the speed-limiting step for adsorption. It has been surprisingly found that the incorporation of a hormone drug such as testosterone in the oily formulation of the invention containing a suitable surfactant leads to physiologic serum levels and to a steady, sustained action of the hormone over time, as well as to increased levels in the CSF.
[0052] It is believed that the special release of the hormone is due to the oily carrier and because the formulation remains on the mucous membrane for a prolonged period of time due to its viscosity. Upon contact of the formulation with the humidity of the mucous membrane, precipitation of the active ingredient is hindered by the ability of the surface tension decreasing component to form oil drops containing the active ingredient. Thus, by adding a surface tension decreasing component to the formulation, the dissolution pattern of the active ingredient becomes more favorable and effective because there is no big variability in dissolution, which ensures bioequivalence.
[0053] Treatment.
[0054] The steroid hormone testosterone exerts its effects in tissues before or after testosterone is reduced by 5-alpha reductase to dihydrotestosterone (DHT). Since DHT has stronger binding properties than testosterone, DHT produces different actions in the body. As shown in FIG. 1 , although the testosterone level in serum of hypogonadal men is comparable, application of the nasal gel of the invention results in a much lower level of DHT as compared to application of a dermal gel on the market. Formulations resulting in low levels of DHT are particularly desired because there is some evidence that DHT promotes cell growth in the prostate gland and is linked to promoting the spread and growth of prostate cancer cells.
[0055] The formulation described below in Table 2 was selected for treatment of hypogonadism because of the serum/CSF level achieved for the active ingredient but also because of skin care properties, such as moistening of the nasal membrane, which are important for long term applications.
[0000]
TABLE 2
Representative Formulation
Compound
Concentration
Delivery per nostril
Testosterone
4%
≈4 mg
Colloidal silicon dioxide
4%
≈4 mg
Oleoyl macrogol-glycerides
4%
≈4 mg
Castor oil
88%
≈88 mg
[0056] In another aspect of the invention, the formulation according to the invention may also be processed into powder form, such as by lyophilization or spray-drying.
[0057] Referring now to FIG. 2 and the preferred formulation containing testosterone described above in Table 2, C max is clearly decreased in the special formulation of the invention, which is desirable in view of toxicological considerations. Further the level of unbound testosterone is very constant over at least ten hours, which mimics the physiologic daily rhythm of testosterone release. The dotted line shows the serum level after application of one spray per nostril of the preferred formulation.
[0058] It can be concluded that the inventive formulation for nasal application is different from conventional formulations, especially those designed for sustained release, because the inventive formulation mimics the physiologic daily rhythm of testosterone release. The invention also avoids supra- and sub-normal testosterone levels, which is easier for the patient to tolerate and, importantly, is suitable for hormone replacement therapy. As shown in FIG. 2 (upper line), a simple nasal spray containing testosterone is unsatisfactory in this sense.
[0059] As shown in FIG. 3 , application of testosterone in the inventive nasal gel formulation to women results in peak level (C max ) after about fifteen and before at least seventy-five minutes. Previous data regarding other forms of testosterone administration indicate: (1) a testosterone patch provides peak levels of testosterone at 24-36 hours (Advisory Committee Briefing Document, 2 Dec. 2004, P&G, p. 128); (2) a transdermal spray administered to the abdomen or forearm results in a peak level at 14-18 hours (Humberstone, A. J., et al., Poster No. P2-218; (3) a vaginal gel results in peak level at 5.5 hours (Apperloo et al.); and (4) an oral capsule of testosterone results in peak level at 5-7 hours (Houwing, N. S., et al., Pharmacotherapy 23(10): 1257-65 (2003)).
WORKING EXAMPLES
[0060] The following examples are intended to further illustrate, and not limit, embodiments in accordance with the invention.
Example 1
Nasal Administration of Testosterone to Women
[0061] The rapid and relatively high peak concentration of testosterone after application of testosterone was shown to correspond to a signal in the brain. Fourteen healthy, premenopausal women, between thirty-five and forty-five years of age during early follicular phase and who were not taking hormonal contraceptives, received the inventive nasal gel containing 0.9 mg testosterone or a placebo forty minutes before scanning. Scanning was done with functional magnetic resonance imaging (fMRI) using a 1.5 T Siemens Sonata MR scanner (TR 2.29 s, TE 30 ms, 3.5×3.5×3.5 mm voxels) to investigate the regional cerebral blood flow. During scanning, the subjects had to match the emotional expression with faces of different individuals expressing either anger or fear. As shown in FIG. 4 , the fMRI data shows that application of the nasal testosterone gel formulation produces rapid effects on the neural emotion circuitry. Although not wishing to be bound by theory, it is believed that the rapid effects on the neural emotion circuitry are mediated by non-genomic mechanisms.
[0062] Previous data has shown that the amygdala response is important to sexual arousal. Karama et al., Hum. Brain. Mapp. 16:1-13 (2002), has shown that female sexual arousal is associated with increased amygdala activation and Baird et al., Ann. Neurol. 55: 87-96 (2004), has shown that increased sexual drive is associated with larger amygdala volume. As shown in FIG. 4 , the nasally applied testosterone gel formulation leads to an amygdala response after not more than forty minutes. The fMRI results show that a single dose of nasal administration of the inventive formulation is able to restore the activation of amygdala region. The nasally applied testosterone gel formulation therefore is useful for the treatment of Female Sexual Dysfunction (FSD) or female sexual arousal disorder.
[0063] As shown in FIG. 5 , young women between nineteen to thirty years of age have a higher amygdala response than that seen in middle-aged women between thirty-five to forty-five years of age when both groups are given placebos. A comparison of FIG. 4 with FIG. 5 demonstrates that treatment with the testosterone nasal gel of the invention increases the emotional reactivity of the middle-aged women to a level similar to that seen with the young women in the placebo group.
[0064] In addition to the fast response seen in the brain, the nasal gel formulation also triggers a long lasting effect. Further fMRI data and serum concentration levels, as shown in FIG. 6 , show that the response lasts for 2.5 hours. Therefore, both genomic and non-genomic signaling mechanisms can be assumed. Because it is not sufficient for a neurotherapeutic agent to cross the blood-brain barrier (the neurotherapeutic agent must also stay in the brain long enough to exert its action), a prolonged serum level is desirable for the action in the periphery.
[0065] It was also found that an intermittent nasal application of the inventive gel promotes female sexual proceptivity, which, for safety reasons, is extremely favorable in women.
Example 2
Effects of Nasal Administered Testosterone on the Sexual Behavior of Female Capuchin Monkeys ( Cebus Apella )
[0066] The objective of the study was to investigate the effects of nasal administered testosterone on the sexual behavior of female capuchin monkeys ( Cebus apella ).
[0067] Ten brown tufted capuchins ( Cebus apella ) were used as subjects as focal animals in this study. Animals were all adult females (>5 years old). All animals were weighted prior to and following the experimental procedures as described in Table 1.
[0000]
TABLE 1
Weight of Female Capuchins
Monkeys in the Noseafix Experiment.
Female
Baseline
Treat. 1
Treat. 1
Washout
Treat. 2
Treat. 2
Number
September 23
September 30
October 3
October 8
October 10
October 13
1
2.120
2.070
2.205
2.140
2.175
2.115
2
2.265
2.330
2.545
2.520
2.370
2.390
3
2.390
2.360
2.355
2.390
2.350
2.340
4
2.390
2.330
2.385
2.395
2.320
2.345
5
2.500
2.195
2.225
2.315
2.310
2.245
6
2.510
2.490
2.640
2.315
2.480
2.615
7
2.500
2.445
2.610
2.600
2.450
2.465
8
1.740
1.725
1.795
1.765
1.755
1.760
9
2.610
2.595
2.695
2.740
2.700
2.745
10
2.520
2.370
2.325
2.430
2.410
2.325
[0068] Females were housed in heterosexual pairs, see Table 2:
[0000]
TABLE 2
N°
Housing Condition
Females' Number
Females' Name
n = 4
Family Groups
2
Rosa
(reproductive pair and
4
Drica
offspring)
7
Salomé
9
Chiquinha
n = 2
Adult Male
1
Maneca
6
Cida
n = 2
Adult male and young
3
Mila
female
8
Salete
n = 2
Adult male and one
5
Delia
adult female
10
Aurora
[0069] The ten subjects were assigned to the two groups based on age and on the housing condition. They never had experienced exogenous testosterone before. Females were randomly assigned to the treatment and placebo group, comprising five animals, see Table 3.
[0000]
TABLE 3
Design of the Female
Capuchin Groups in the Noseafix Experiment.
Animal
Treatment 1 (A)
Treatment 2 (B)
Number
Animal Name
(September 9-October 3)
(October 9-October 13)
(1)
Maneca
Placebo
Noseafix
(2)
Rosa
Placebo
Noseafix
(3)
Mila
Noseafix
Placebo
(4)
Drica
Placebo
Noseafix
(5)
Delia
Placebo
Noseafix
(6)
Cida
Noseafix
Placebo
(7)
Salomé
Noseafix
Placebo
(8)
Salete
Placebo
Noseafix
(9)
Chiquinha
Noseafix
Placebo
(10)
Aurora
Noseafix
Placebo
[0070] The monkeys were housed and tested at the Primate Center of the University of Brasilia, Brazil, under natural light, temperature and humidity conditions. The Primate Center is located within the grounds of an ecological reserve, such that home cages are surrounded by nearby native tropical semideciduos gallery forest. Subjects were housed in the Cebus Colony room of the Primate Center, which contains two species of cebids: Brown tufted capuchins— Cebus apella and Squirrel monkeys— Saimiri ustus . The colony room consists of two rows of 6 cages (4 m length, 2, 9 width,×2 m height, each cage respectively) consist of two concrete walls, separating adjacent cages, and a wire mesh front, back and ceiling forming an outdoor/semi-indoor housing system. Each cage consist of two concrete walls, separating adjacent cages, and a wire mesh front, back and ceiling forming an outdoor/semi-indoor housing system.
[0071] Each home cage contains a suspended wood nest-box, several wood perches at different heights, a food tray (where food bowl is placed) and a thick layer of natural dry leaves and twigs on the floor. Olfactory and acoustic contact is possible between all members of the colony, but not visual contact.
[0072] Food is provided once a day at 7:30 am., remaining in the home cages until 5:30 pm. The provisions include a variety of fresh fruits and vegetables. Dry pellets and fresh water are available ad libitum. Animals are weighted and clinically evaluated by a veterinary once a month.
[0073] The study was a randomized, double-blinded, cross-over with a non-treatment run-in. The experimental procedure was divided into 23 days in 4 consecutive phases:
[0074] Baseline=8 days (−7, −6, −5, −4, −3, −2, −1, 0)
[0075] Treatment 1 (A)=5 days (1 to 5)
[0076] Wash out=5 days (6 to 10) Treatment 2 (B)=5 days (11 to 15)
[0077] The study started with a no-treatment run-in. In this study phase, the non-influenced (sexual) behavior of the female capuchin monkeys was observed and recorded as baseline. Behavioral observations were carried out daily during 23 experimental days (between 8 am and 5 pm). During all the phases, the behavior of the females' capuchin monkeys was individually observed throughout the day by four experienced observers. The behaviors were scored using a combination of continuous recording and instantaneous sampling (point samples every 7 minutes), (Martin and Bateson, 1986). The description of sexual behaviors is based on studies on capuchins sexual behavior, (Carosi et al., 1999; Carosi and Visalberghi, 2002). All behaviors were scored manually on spreadsheets and chronometers.
[0078] Each animal was observed four times a day (two sessions in the morning and two sessions in the afternoon). Each observation session lasted 14 min (7 min for instantaneous sampling and 7 min for continuous recording). The total amount of hours observed throughout the four phases of the experiment were 214.6.
[0079] Reliability for behavior identifications was assessed using data from three observations' days previous to the beginning of the study. Interaobserver (between the four observers) and intraobserver reliability were calculated as the sum of agreements between observers divided by the sum of disagreements. The concordance′ index was up to 85%.
[0080] The behaviors observed were classified in sexual: eyebrow raising, mutual gaze, head cocking, chest rubbing, masturbation, extended arm(s), body touching mounting attempt, mounting, courtship, and non-sexual behaviors: resting, repetitive behavior, grooming, activity, and agonistic. Their operational definitions are presented in Table 4.
[0000]
TABLE 4
Behavioral Definitions and Recording Techniques Used
Behavior
(recording technique)
Definition
Eyebrow raising (I)
F's eyebrows are raised up and backwards and
the fur over the crown is flattened.
Mutual gaze
F and M maintain mutual eye contact for at
least 2-3 s. It involves eyebrow raising.
Head cocking (I)
F's head is tilted to one side (approx. 45°). The
head may gently change side every few
seconds.
Chest rubbing (I)
F's hand(s) are slowly rubbed back and forth
on the fur of its own chest. The movements
are usually upward and/or downward and
repeated several times in a row.
Masturbation (I)
F rubs its own genital with hands.
Extended arm(s) (CR)
F slowly moves/stretches one or both arms
toward M, without contacting M. Individuals
are in proximity usually seated, facing and
looking at each other.
Body touching (CR)
F's hand gently reaches out and touches M's
body for at least a few seconds.
Mounting attempt (CR)
M tries to mount F, but F moves away.
Mounting (CR)
M mounts F in a position which allows for
copulation. Thrusting usually occurs. A
mounting bout starts when M gains a mounting
position and ends when it dismounts. Bouts
can be isolated or form a mounting sequence. F
may also mount M.
Courtship (CR)
F seeks the M attention or the observer
attention. The courtship includes all the
behaviors described for instantaneous
sampling: eyebrow raising, mutual gaze, head
cocking, chest rubbing and masturbation.
Resting (CR)
F is still on a substrate without doing anything
else.
Stereotypy behavior (CR)
F goes, moves repeatedly to one place to
another without any other behavior associated.
Grooming (CR)
F cleans its hair, another animal hair or it is
cleaned by another animal.
Activity (CR)
It includes all the non-sexual female behaviors
that were not described before such as
foraging, playing, drinking, eating and moving.
Agonistic (CR)
Aggressive behavior including threat, chase
way, grab with or without vocalization.
*Abbreviations: I, instantaneous sampling (-s intervals);
CR, continuous recording;
F, female;
M, male.
[0081] Measurements.
[0082] The following measurements were done during the study:
Baseline phase: Body weight
Testosterone morning concentration Behavior
Wash-out phase: Body weight
Testosterone morning concentration Behavior
Treatment phases: Body weight
Testosterone morning concentration Behavior
[0092] The daily dose of the respective study drug was administered in the morning by study staff using the original recipient for a single dose. The test drug and the placebo were administered at the same interval time in the morning by the same experimenter in all days during the treatment 1 and 2. The drug was administered after the blood has been collected by the same experimenter in both nostrils of each animal.
[0093] The study staff filled out a treatment protocol for each animal and confirmed the administration with date and signature.
[0094] In order to obtain the blood samples during all the phases of experience, the animals were captured by a caretaker with the aid of a net, removed with leather gloves, anesthetized with isoflurano nasal and then transported to a table where the procedure was done. The order of capture of the females was maintained for all the days of the experiment. Time between the capture, blood collection and recovery of the females varies from 5 to 30 minutes depending on the animal.
[0095] Blood samples were drawn between 08:15 to 10:40 a.m. six times throughout the total time of experiment during the baseline, wash-out and treatment phases (Days=−5, 2, 5, 10, 12 and 15, respectively). The isoflurano 1 ml was administered nasally in a cotton ball placed at the nose of the animals until that sedation effect was observed. Once the animal is anesthetized, 1.5 ml of the venous blood was drawn from each female. On day 10 th we could not get a blood sample of the female number 4, Drica.
[0096] The transport of the analytical samples (plasma samples) from the Primate Center to the analytical laboratory at the Pharmacology Department at the University of Brasilia, was performed in thermo-isolated boxes contained dry ice. The temperature during the transport was not warmer than −20° C. Each blood sample containing heparin was immediately centrifuged at 2000 rpm for 10 minutes. The plasma was separated and put in duplicate test tubes labeled with the protocol number, study period, animal number, animal name, date and time of sampling. The test tubes with the blood were safely closed. The plasma samples were safely racked and immediately frozen for storage at −80° C.
[0097] Samples were stored in labeled tubes containing heparin as anticoagulant. The label of the blood collecting tubes contained information about protocol number, study period, animal number, animal name, date and time of sampling.
[0098] Phase 1: Baseline.
[0099] This first phase consisted of 8 consecutive days (from −7 to 0 day) where the baseline values of sexual and non-sexual female behaviors were recorded for 10 animals. During this phase, the non-influenced (sexual) behavior of the females' capuchin monkeys was individually observed through the day by 04 independent observers. The behaviors were scored using focal animal's continuous recording and focal instantaneous sampling methods. On the day −5, the first blood sample was collected for each female. After the blood has been collected, the animal was placed back into their home cage and released.
[0100] Phase 2: Treatment 1(A).
[0101] This phase consisted of 5 consecutive days (day 1 to day 5) with the nasal administration as single doses of 0.48 mg of testosterone (Noseafix®) 0.48 mg of testosterone (0.24 mg per nostril), once daily for 5 female capuchin monkeys (animal numbers 3, 6, 7, 9 and 10) as presented in Table 3. The 5 other females received gel for nasal administration with content identical to Noseafix. On day 2 and 5, blood samples were collected for the animals. Sexual and non-sexual behavior were recorded by the same observers of the previous phase for all days and according to the behavior categories described before. The blood samples were obtained using the same procedure described in the general description of protocol.
[0102] Phase 3: Wash Out.
[0103] During five consecutive days (day 6 to day 10), sexual and non-sexual behavior were recorded by the same observers of the previous phases using the same behavioral categories already described. On day 10 th for nine females we draw 1, 5 ml of venous blood. It was not possible to get a blood sample of the animal 4 on this day.
[0104] Phase 4: Treatment 2(B).
[0105] This phase was equal to the Treatment 1 except by the fact that the animals that got drug received placebo and vice-versus. All the procedures to capture the animals, collect blood, administer the drug or placebo and recording the behavior were the same as described previously. On the days 12 th and 15 th , new sample blood were taken from all the capuchin females.
[0106] Noseafix®.
[0107] Name of the drug: Noseafix® (0.48 mg of testosterone/vial)
Pharmaceutical form: gel for nasal administration Content: active ingredient: testosterone Excipients: according to the analytical certificate Mode of administration: nasal, as single doses of 0.48 mg of testoterone (0.24 mg per nostril), once daily for 5 days Manufacturer: HOLOPACK GmbH—Abtsgmünd/Germany for Mattern Research AG-Stans/Switzerland
[0114] Noseafix® Placebo.
[0115] Name of the drug: Placebo
Pharmaceutical form: gel for nasal administration Content: identical to the gel base of Noseafix® Mode of administration: nasal, single dose (same volume as measured for Noseafix®), once daily for 5 days Manufacturer: HOLOPACK GmbH—Abtsgmünd/Germany for Mattern Research AG-Stans/Switzerland
[0121] Behavioral Analysis.
[0122] Behavioral raw data were transformed for the analysis as a function of the length of time of the observational sessions. Individually daily frequencies or durations were divided by the duration (in seconds) of each observational session. Thus, rates and percentages of time spent in each behavior were obtained. Daily scores of the behaviors sampled with the instantaneous technique were expressed as a proportion of the total number of point samples of the sessions.
[0123] Statistical Analysis
Data are expressed as the mean±SEM Results are based in two-tailed statistical tests Significance level was set at p≦0,05
[0127] Comparisons were done within each group to evaluate if the variables measured for each behavior were significantly modified by the treatment. With this purpose, we carried out one-way Analysis of Variance (ANOVA), taking each behavior as dependent variable, and the experiment's phase as independent variable, followed by post hoc analysis with Tukey's all-pair wise comparisons when applicable.
[0128] The results are presented separately for data collected using the Scan and the Continuous Recording methods.
[0129] Eyebrow Raising.
[0130] In female tufted capuchins “eyebrow raising”, “touching and running”, “nuzzling”, and, to a lesser extent, “headcocking” are displays strongly correlated to the periovulatory phase and represent female proceptivity (Carossi, et al., 1999).
[0131] Statistical comparisons within Group 1 (Placebo in the treatment 1 phase—Noseafix in the treatment 2 phase) indicated significant differences between treatments [F 3 , 366=3.692, p=0,012] (see FIG. 7 ). Post hoc tests demonstrated differences between Treatment 1 and Treatment 2 [p=0,029], and between Wash-Out phase and Treatment 2 [p=0,022]. These results indicate that animals treated with Noseafix at treatment phase 2 showed increased frequency of “eyebrow raising” when compared to treatment phase 1 (placebo).
[0132] Also, comparisons within Group 2 (Noseafix-Placebo) treatments showed significant difference between phases [F 3, 454 =2,786, p=0,040]. Post hoc analysis indicated an increase of the frequency of this behavior during the treatment phase 1 (Noseafix), although not significant, the Wash-Out phase when compared with Baseline [p=0,022] ( FIG. 7A ), and during the treatment phase 2 (Noseafix). It is interesting to note that these increases reach significance during the Wash-Out phase which could be interpreted as a long lasting effect of Noseafix.
[0133] The frequency of eyebrow raising behavior was not different between groups during Baseline [t=1,691, p=0,093] ( FIG. 8A ), Treatment 1 [t=1,916, p=0,057] ( FIG. 8B ) and Treatment 2 [t=−1,140, p=0,256] ( FIG. 8D ). During the Wash-Out phase ( FIG. 8C ) the groups differed significantly [t=2,972, p=0,004], where Group 2 shown more frequently this behavior than the Group 1. These results suggest a long lasting effect of Noseafix treatment.
[0134] Chest Rubbing.
[0135] This behavior in Capuchin monkeys has been reported as one of the most prominent indication of female courtship (Carosi and Visalberghi, 2002). When multiple comparison within Group 2 (Noseafix-Placebo) were done, differences between phases were observed [F 3, 454 =3,439, p=0,017] (see FIG. 7B ). Post hoc tests showed a significant increase during Treatment 1 phase when compared to both Baseline [p=0,049] and Treatment 2 [p=0,02]. Multiple comparisons within Group 1 did not show any significant difference due to the experimental phase [F 3, 366 =0,652] ( FIG. 7B ). These results indicate an effect of Noseafix treatment increasing the “chest rubbing” behavior. The placebo treatment had no effect at all. During Baseline [t=0,505, p=0,614] and Treatment 2 [t=−1,186, p=0,239], the frequency of the Chest Rubbing behavior ( FIGS. 8A and 8D ) did not differ between the groups. Group 2 had a greater frequency for this behavior compared to Group 1 in both Treatment 1 [t=−2,046, p=0,043] and Wash-Out [t=−2,811, p=0,006] phases ( FIGS. 8B and 8C ). These results again indicate an increase of “chest rubbing” by Noseafix. Moreover, the incidence of this behavior during the Wash-Out phase suggests a long lasting effect of the compound.
[0136] Masturbation.
[0137] Female capuchin monkeys perform mounting on adult males lasting from a few seconds up to 1-2 min.
[0138] They usually stay on the male back in a position resembling that of an infant on its mother. However, the female can also take up a more proper mounting position, perform pelvic thrusts, and rub her genitals on the male's fur, as if masturbating. She can also perform a masturbation-like behavior by rubbing her genitals with the hands. This type of behavior typically occurs when the female is proceptive and she persistently solicits the male (Carosi and Visalberghi, 2002).
[0139] Multiple comparisons within each group did not find differences in Group 1 [F3, 366=0,822, p=0,482]. However, comparisons within Group 2 revealed differences due to phase [F3, 454=3,329, p=0,020]. Post hoc analysis indicated differences between Baseline and Treatment 1 [p=0,049], where during Treatment 1 an increase of the frequency of this behavior was found ( FIG. 7C ). This result suggests an effect of Noseafix treatment on the frequency of this behavior. No significant increase of masturbation was observed during treatment with placebo.
[0140] Comparisons for this behavior within phases between groups did not show significant differences [Baseline: t=1.467, p=0,145; Treatment 1: t=0,721, p=0,472; Wash-Out: t=0,925, p=0,358; Treatment 2: t=0,894, p=0,373] ( FIG. 8A to 8D ).
[0141] Head Cocking.
[0142] This behavior is characterized by the head tilted to one side (approximately 45°). The head may gently switch side every few seconds. The actor is constantly gazing at the recipient while cocking the head. This is performed by both sexes. Head cocking is performed by several prosimian and platyrrhine species during explorative activities, such as visual inspection of objects and unfamiliar persons (possibly to improve visual and auditory perception). The head cocking observed during capuchins' sexual interactions is unlikely to be related to the functions reported in other species (Carosi and Visalberghi, 2002).
[0143] Multiple comparisons within each group for the different phases, neither comparisons between the two groups within each phase showed any significant difference in the frequency of this behavior [Group 1: F 3, 366 =0,508, p=0,677; Group 2: F 3, 454 =0,891, p=0,446] ( FIG. 7D ), [Baseline: t=0,011, p=991; Treatment 1: t=−0.894, p=0,373; W-O: the behavior was not observed; Treatment 2: t=0,791, p=0,430] ( FIG. 8A to 8D ).
[0144] Mutual Gaze.
[0145] The monkeys may move repeatedly closer and farther apart while mutual gazing. Regardless of the distance between them, they try to regain mutual gaze. The mutual gaze usually lasts for several minutes, with occasional interruptions of a few seconds.
[0146] It is usually accompanied by one or all of the following behavioral patterns: eyebrow raising with grin and vocalizations, head cocking, and chest rubbing (Carosi and Visalberghi, 2002).
[0147] Comparisons for Mutual Gaze behavior between phases within each group did not show any significant difference [Group 1: F 3, 366 =0,837, p=0,474; Group 2: F 3, 454 =1,264, p=0,268] ( FIG. 7E ). Comparisons between groups within each phase also did not show significant differences for this behavior [Baseline: t=1,779, p=0,078; Treatment 1: t=−1,388, p=0,168; Wash-Out: t=−0,652, p=0,515; Treatment 2: t=−0,459, p=0,647] ( FIG. 8A to 8D ).
[0148] Grooming.
[0149] Differences between treatment phases were observed within Group 1 [F 3, 366 =3,246, p=0,022]. Post hoc analysis demonstrated significant difference between Baseline and Treatment 2 [p=0,017], due to an increase of this behavior during Treatment 2 (when the subjects were under Noseafix treatment, see FIG. 9A ). No such differences were observed within Group 2 [F 3, 454 =2,153, p=0,093].
[0150] Comparisons within each phase did not show any difference in the time spent in Grooming between groups [Baseline: t=0, 7, p=0,485; Treatment 1: t=0,674, p=0,501; Wash-Out: t=0,138, p=0, 89; Treatment 2: t=1,131, p=0,259] ( FIG. 10A to 10D ).
[0151] Courtship.
[0152] This category includes the following behaviors: extended arm(s), sexual display, body touching, courtship and mounting.
[0153] Multiple comparisons within each group between phases revealed significant differences for Group 1 [F3, 366=5,71, p=0,001] during Treatment 2 due to an increase of this category when compared to Baseline [p=0,03], Treatment 1 [p=0,005] and Wash-Out [0,001]; and for Group 2 [F3, 454=2,455, p=0,063] between Baseline and Wash-Out [p=0,043] ( FIG. 9B ). These results indicate that treatment with Noseafix increase courtship in female capuchin monkeys.
[0154] Comparisons of the time spent in courtship behaviors within each phase between groups shown significant differences during Treatment 1 [t=−2,007, p=0,047] and during Wash-Out [t=−3,08, p=0,003]. In both situations Group 2 spent more time than Group 1 ( FIGS. 10B and 10C ). During Baseline [t=0,975, p=0,33] and Treatment 2 [t=−1,654, p=0,101] no differences were observed between groups ( FIGS. 10A and 10C ).
[0155] Stereotypy.
[0156] Differences in the time spent in stereotyped behavior between phases within each group were not found [Group 1: F3, 366=1,878, p=0,133; Group 2: F3, 454=0,549, p=0,649] (Data not shown in figures).
[0157] Comparisons between groups within each phase demonstrated that Group 1 shown significantly higher percentage of time in this behavior than Group 2 in all the phases [Baseline: t=3,138, p=0,002; Treatment 1: t=3,538, p=0,001; Wash-Out: t=4,379, p<0,001; Treatment 2: t=−3,188, p=0,002] (Data not shown in figures).
[0158] Agonistic Behavior. (Chase Away).
[0159] Multiple comparisons between phases within each group did not show significant differences in the observation time [Group 1: F3, 366=0,079, p=0,971; Group 2: F3, 454=1,703, p=0,166] ( FIG. 9C ).
[0160] Comparisons of Agonistic Behavior within each phase between groups shown significant difference between them during the Wash-Out phase [t=−2,356, p=0,02], where the Group 2 shown more agonistic behavior than Group 1 ( FIG. 10C ). For the remaining phases significant differences were not observed [Baseline: t=−1,719, p=0,087; Treatment 1: t=−0,859, p=0,391; Treatment 2: t=0,265, p=0,792] ( FIGS. 10A , 10 B and 10 D). It is worth to mention that this Chase Away behavior was observed only in one animal, although during a long time. It is not possible to be sure that this behavior observed during the Wash-Out period was elicited by the effect of testosterone (Noseafix) administered during treatment 1 phase (long lasting effect). However, it seems not likely since in capuchin monkeys, high levels of testosterone were not associated with aggressive behavior (Lynch, et al., 2002).
[0161] FIG. 11 shows the plasma testosterone levels in different phases of the study for the animals treated with placebo (blue squares) and Noseafix (red squares). As can be observed, the administration of Noseafix induced an increase in plasma testosterone level. It is interesting to observe that the high magnitude effect was observed when the animals were at the Wash-Out phase. This effect fits perfectly with the higher frequency of sexual arousal behaviors observed during the Wash-Out phase. Therefore, behavioral and plasma testosterone level shows a close relationship.
[0162] The two yellow squares in the Figure-Treatment 2 phase, illustrates the “possible” residual effect of Noseafix treatment during Treatment 1 phase. It would be interesting in other study to introduce a second Wash-Out phase (after treatment 2) in order to confirm this residual (long lasting) effects of Noseafix treatment on plasma testosterone levels and the proceptivity of female capuchin monkeys.
[0163] In summary, the results obtained indicate that administration of Noseafix seem to promote female sexual proceptivity in the tufted capuchin monkey ( Cebus apella ), which characterizes this species mating system. These effects are in close relationship to the plasma testosterone levels measured during this study. The following aspects summarize the major findings and the results that corroborate this conclusion:
The frequency of Eyebrow Raising, Chest Rubbing and Masturbation were enhanced by the administration of Noseafix. These behaviors are an indicative of female's sexual solicitation and are frequent displayed during the preiovulatory period ( FIG. 1 ). It is important to mention that none of these behaviors were significantly observed in animals under placebo administration. Therefore, the females' proceptivity can not be related to the natural ovulatory cycle, although we can not rule out a possible interaction between Noseafix and ovulatory cycle in some animals. In order to exclude this possibility would be necessary to conduct another experiment in females where the natural cycle is blocked by the administration of a contraconceptive drug. The female sexual appetitive activities such as invitational patterns and active initiative in approaching, investigating, and sexually soliciting the male were only observed in animals under Noseafix treatment ( FIGS. 7 to 10 ). It is worth to mention that some of these behaviors were also observed during the Wash-Out phase, but only for the animals that have received Noseafix before. Therefore, it is possible that Noseafix has a long lasting effect. Since we did not do a PK study, it is not possible to know how long are the Noseafix effects in capuchin monkeys. Moreover, a second Wash-Out phase, after Treatment 2, would be interesting to observe possible occurrence of sexual display behaviors in animals treated with Noseafix during Treatment 2 phase. The compound tested did not exert a significant effect upon the frequency of exploratory activity or stereotyped behaviors in the monkeys tested. Therefore, the effects of Noseafix were not due to changes in the subject's level of activity.
[0166] The features disclosed in the foregoing description, in the claims and/or in the drawings may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a device for holding a plurality of documents and for readily displaying one of the documents. More particularly, if it is desired to display a document located within a stack of documents, the documents on top of the one to be displayed are supported and retained in a position whereby the desired document may be readily viewed.
2. Description of Related Art Including Information Disclosed under 35 C.F.R. 1.97 and 1.98
Particularly when working at a desk or table, there is usually more than ample room available for two stacks of letter size, 81/2"×11", or legal size, 81/2"×14" documents. That is, pages may be flipped from one pile to another to bring into view the desired document. However, when working with stacks of larger size documents, handling the documents in the same way, i.e., from pile to pile, quickly takes up all of the room on the disk or table, making it difficult to also have available for use other reference and work materials. Building plans, mechanical drawings utilized in the specification of parts, assembly drawings, architectural plans, and electrical and electronic schematics are frequently prepared on larger sized sheets of paper. To some extent the following standard paper sizes have been established for engineering type drawings or prints:
______________________________________SIZE DIMENSION (INCHES)______________________________________A 81/2 × 11B 11 × 17C 17 × 22D 22 × 34E 36 × 44______________________________________
Standard sizes for architectural drawings are somewhat different. For instance, the "D" size is 24"×36".
When viewing documents or prints of the larger sizes, B through E, it is desirable to have a mechanism for holding and displaying them in an upright position with respect to a horizontal work surface, such that the major portion of the work surface will be available for supporting other materials such as reference books. It is further desirable that the sheets in a stack of sheets above the sheet which is to be displayed be supported as well as those sheets below the sheet to be displayed. Such an apparatus in the form of a holder or display device which can be set on top of a desk or hung on a wall in an office is also desirable at a construction site where it might be hung on a wall, or placed on an easel or on another work surface such as the top of a large tool container which are frequently used at construction sites.
The applicant is unaware of such an apparatus or holder existing in the prior art. Devices utilized for holding multiple sheets of paper in the past include easels such as disclosed in U.S. Pat. Nos. 861,722, issued Jul. 30, 1907 and 4,877,213 issued Oct. 31, 1989. Such easels are most typically designed to hold documents in a somewhat vertical position wherein the longer dimension extends in the vertical direction. The documents above the one to be viewed are typically folded over the top of the easel so as to rest behind the easel. Somewhat similar to easels is the copy holder shown in U.S. Pat. No. 2,194,019, issued Mar. 19, 1940. The copy holder is a hinged stand with a spring means for retaining documents on an inclined table 17. The applicant is also aware of U.S. Pat. No. 4,531,642, issued Jul. 30, 1985 which reveals a portable desk having a pair of clips for supporting documents on an inclined surface. The portable desk also includes a bookrest along the lower edge of the inclined surface. Finally, U.S. Pat. No. 4,925,143 , issued May 15, 1990 discloses a document holding assembly having two vertical and two inclined support surfaces, all of which are essentially the same size and each of which is provided with a clip means for holding documents on its surface. None of the above-mentioned patents disclose, nor is the applicant aware of an apparatus suitable for retaining a stack of large size documents or prints wherein both sheets above and below a sheet to be displayed are retained, and which may be used on a desk top, hung on a wall, or supported by an easel.
SUMMARY OF THE INVENTION
It is an object of this invention to provide an apparatus or device for holding a plurality of documents or prints, for displaying one of the documents, and for holding and supporting both the documents on top of and the document below the document to be displayed. It is a further object of this invention to provide a device for holding a plurality of documents and for displaying one of the documents which is readily supported on a flat surface, hung on a vertical surface or supported by an easel. It is a further object of this invention to provide a device for holding a plurality of documents, for displaying one of the documents, and which is readily carried by hand with the documents secured thereon.
In accordance with this invention., a device for holding a plurality of documents, and displaying one of the documents, is formed of two support members. A first support member is formed with a generally rectangular flat surface, the dimensions of which are slightly larger than the dimensions of the size document to be supported thereon. In describing a preferred embodiment of this invention, the longer sides will be referred to as the top and bottom and the shorter dimensions as the sides. A second support member is also formed with a generally rectangular flat surface one dimension of which is essentially the same as that of the sides of the first support member and will be referred to as the sides, and the other dimension of which is approximately one half of the length of the top and bottom of the first support member and will be referred to as the top and bottom. Retaining means, such as U-shaped channels, are provided along the top and bottom edges of both the first and second members. Adjacent side edges of the first and second members are hinged to each other. A releasable securing means, such as a spring loaded clamp, for securing the documents to the first support member is located adjacent to the hinged side edge of the first member.
With the first and second support members hinged to each other, and the second support member laying on top of the first support member, the retaining means on both members extend over their upper surfaces. When it is desired to view a document or a print, other than the top print, in a stack of prints retained on the first member, those prints above the print to be viewed are pulled out of the U-shaped channels on the first member. They are then folded around the free side edge of the second member, which is opposite the hinged side edge, and placed in the U-shaped channels on the second member.
In a preferred embodiment, the hinges are provided with detent means, whereby the second member may be held in predetermined positions at various angles to the first member. Thus, when it is desirable to view documents retained on the device at a desk, the first member may be placed in a vertical position directly in front of the user and the second member positioned at an angle of 90° or somewhat greater angle to the first member such that it extends on the left side toward the viewer. Since the two members are at a significant angle with respect to each other, they will stand in a vertical position on a flat horizontal surface without the need for additional support.
A pair of apertures are provided near the upper edge of the first member such that they may engage nails or similar devices projecting from a wall or other vertical surface, so as to hang the device thereon. Further, the device may be supported by an easel if an appropriate retaining means is provided at the top of an easel to prevent the device from tipping forward due to the weight of the second member.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 a perspective view of the device for holding a plurality of documents and for displaying one of the documents in accordance with this invention, with the hinged members of the device in a first position with respect to each other.
FIG. 2 is a perspective view of the device of this invention with the hinged members at approximately right angles to each other.
FIG. 3 is a view taken along the lines 3--3 in FIG. 2.
FIG. 4 is a cross-section taken along the lines 4--4 in FIG. 2.
FIG. 5 a perspective view showing the hinges on the first and second members disengaged from each other.
FIG. 6 is an enlarged elevation view, partially in sections, showing one of the hinges utilized to secure the first and second members to each other.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIGS. 1 and 2, a device 10 in accordance with this invention is illustrated. The device includes a first support member 12, and a second support member 14, connected to each other by a pair of hinges 16 and 18. The first support member 12 is formed with a generally rectangular flat surface 20 having height and width dimensions slightly larger than those of the documents or prints 22 to be supported thereon.
In the embodiment of the invention illustrated in the figures of the drawings the support members 12 and 14 are formed of sheets of translucent or clear plastic material. The first support member 12 is formed of a sheet of material the width of which is sufficiently greater than that of the prints 22 such that the top and bottom edges may be bent at right angles to form side members 24 and 26 to confine and protect the top and bottom edges of the prints. On the right half of the first support member 12, the side members 24 and 26 are provided with retaining portions 28 and 30 which are bent at right angles to the side members 24 and 26 to form U-shaped channels 32 and 34 to retain the loose ends of the prints 22.
The second support member 14 is approximately one half as long as the first support member 12. The upper and lower edges of support member 14 are also provided with side members 36 and 38 and retaining portions 40 and 42 at right angles thereto so as to form U-shaped channels 44 and 46.
As illustrated in FIG. 5, each of the hinges 16 and 18 consist of two portions, 48 and 50, one of which, 50, includes a stem and the other of which, 48, includes an aperture for receiving the stem. The abutting surfaces of hinged portions 48 and 50 are provided with saw tooth like surfaces as shown in FIG. 6. By varying the positions in which the saw tooth like surfaces engage each other, the relative angular positions of the first and second support members 12 and 14 with respect to each other may be adjusted.
The portion of the first support member 12 on which the hinge portions 48 are mounted is bent at 49 and 51 at an obtuse angle to the flat surface 20 of the first member. Because of the bends, portions of the fastening means located on the back side of the first support member 12 (not shown) will not engage the surface on which, the first support member is resting. Further, with the particular type of hinges shown in the figures, the angular position of the portion of the first support member 12 on which the hinged portions 48 are mounted permits the members 12 and 14 to close upon each other as shown in FIG. 1.
Referring again to FIG. 1, a plurality of prints 22 are shown to be clipped to the first support member 12 by a spring loaded clip 52 positioned between the hinges 16 and 18 with their top and bottom edges retained in the U-shaped channels 32 and 34. With the second support member 14 rotated to be positioned over and parallel to the first support member 12, as shown in FIG. 1, the device 10 and the prints 22 retained thereon may be readily carried by a user engaging his hand in a hand hole 54 provided in the first support member 12.
Referring to FIGS. 2 and 3, to view a print other than the top one, the prints above the print to be viewed are pulled out of the U-shaped channels 32 and 34 on first support member 12 and folded over outer edge 56 of the second support member 14 and directed into the U-shaped channels 44 and 46 formed on the second support member. As illustrated in FIG. 2, several of the prints are retained by the U-shaped channels 32 and 34 on the first support member 12, while other prints are shown retained by the U-shaped channels 44 and 46 on the second support member 14. Referring to FIG. 4, it will be observed that prints are positioned on each side of the second support member 14, and are retained on the left side by the U-shaped channels 44 and 46 at the bottom and top of member 14. A print 58 is shown to be free from the U-shaped channels on both support members and positioned to be moved in the direction of the arrow A in FIGS. 2 and 3 to be supported by the second support member 14.
The device 10 as shown in FIG. 2 is readily self-supporting in a vertical position on a flat horizontal surface for viewing the top print retained on the first support member 12. The first support member 12 is also provided with apertures 60 and 62 which may be utilized to receive pins or nails extending from a vertical surface, such as a wall in an office or at a construction site, to hang the device 10 in a vertical position, whereby the prints may be retained and the top print on the first support member 12 observed. The device 10 for retaining and displaying prints may also be supported on an easel, with the lower side member 24 of the first support member 12 resting on the shelf of the easel. However, due to the weight of the second support member 14 and of the documents wrapped around it, it is necessary that the top of the first support member 12 be secured to the easel such that the print device 10 does not tip off of the easel.
In an alternate embodiment of the invention it may be desirable to more securely hold the prints on support members 12 and 14. This may be accomplished by extending the retaining portions 28 and 30 on support member 12 and retaining portions 40 and 42 on support member 14 toward each other as shown by the phantom lines in FIG. 5.
While the U-shaped channels 32 and 34 on the first support member 12 and 44 and 46 on the second support member 14 are shown to be formed by bending flat sheets forming those members, they may also be formed as separate channels which are secured to the flat portions of the support members 12 and 14 by rivets, adhesive or other fastening means. While in the preferred embodiment, the support members 12 and 14 are formed from transparent plastic sheets, it may be desirable, particularly when the device is intended for use on construction sites, to form the support members of a metal such as aluminum or magnesium, which are desirable because of their lighter weight.
While a particular type of spring loaded clip 52 and a particular type of hinge, 16 and 18, are illustrated, it is of course within the purview of the invention to use other types of clips and hinges.
Since it is desirable that prints be retained in the channels at both the top and the bottom of the first and second support members, it is desirable to provide a device of suitable size for each document size which is to be supported. While it is preferable that the length of the second support member 14 be one half of that of the support member 12, such that the documents will extend the full length of the U-shaped channels 44 and 46, but not project beyond the channels, it is of course within the purview of this invention to vary the relative length of the second support member 14 with respect to the first support member 12. In a particular embodiment of this invention, that is one intended to support documents which are approximately 24" wide by 36" long, i.e. the previously mentioned architectural D size document, the first support member 12 is made 37 inches long and the height between the bases of the U-shaped channels 32 and 34 is made 241/4". Further, the U-shaped channels 32 and 34 on the first support member are made approximately 151/4" long. The U-shaped channels 32, 34 and 44, 46 on the top and bottom edges of the first and second members are typically made 3/4" wide and 3/4 " deep. It should also be noted that the hand hole 54 is located closer to the left end of the first support member 12 than to the right, so as to balance the weight of the device to the right and left of the hand hole. This takes into consideration the additional weight of the clip hinges and second support member 14.
While in accordance with the U. S. Patent statues, the preferred embodiment of the invention has been shown and described, various changes may be made in the device of this invention without parting from the true spirit and scope of this invention. The appended claims are intended to cover all such changes and modifications which fall within the true spirit and scope of this invention.
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RELATED US PATENT APPLICATION DATA
[0001] This patent application is a Continuation-In-Part Application, which claims priority to Non-Provisional application Ser. No. 13/019,732 filed on Feb. 2, 2011, which claims priority to Non-Provisional application Ser. No. 12/658,109 filed on Feb. 3, 2010 and Non-Provisional application Ser. No. 12/658,110, also filed on Feb. 3, 2010, which are both incorporated in their entireties by reference.
FIELD OF THE INVENTION
[0002] The present disclosure generally relates to an apparatus and method of use for presentation of a sterile cover for a medical device. More particularly, the present disclosure relates to a dispensing apparatus that presents, stages by expansion, and singulates a sterile cover for a stethoscope head.
BACKGROUND OF THE INVENTION
[0003] A stethoscope is a well known and widely used acoustic medical device for auscultation, or listening, to internal sounds in a human or animal body. The diaphragm is placed upon a patient, where body sounds vibrate the diaphragm creating acoustic pressure waves that travel through a tubing and are conveyed into a listener's ears. In use, the stethoscope head is often contaminated with skin bacteria and like contaminants that may undesirably be transmitted to the next patient. One means to avoid the undesirable transfer of unwanted organisms and other contaminants would be to sterilize the stethoscope head between each use. The transmission of bacterial infections among patients, particularly in a hospital setting, has been aggravated by the development of antibiotic-resistant strains of staphylococcal infections and other harmful microorganisms. It is this problem that the apparatus of the present invention seeks to overcome by providing a novel stethoscope cover and a dispensing apparatus for quickly and easily dispensing the stethoscope cover.
[0004] A number of different types of stethoscope covers and apparatus for dispensing the same have been suggested in the past.
[0005] A first exemplary proposed solution discloses stethoscope head cover that overlies the diaphragm and the surrounding rim of the stethoscope, the cover being fabricated from a thin sheet of plastic with a discontinuous layer of peelable adhesive on one surface of the plastic. The discontinuous layer of adhesive is in a predetermined pattern and the pattern is selected so that air passageways are provided from the regions between the cover and the diaphragm and past the rim to regions external the stethoscope. The cover generally comprises a flat, thin plastic sheet with the discontinuous layer of a peelable adhesive applied to one surface of the sheet. The adhesive adheres to both the diaphragm and the rim of the stethoscope leaving the aforesaid air passages for eliminating trapped air pockets or bubbles between the diaphragm and the cover.
[0006] A second exemplary disposable stethoscope cover diaphragm is removably attached over the outer edge of a stethoscope high frequency pickup in order to isolate the pickup from pathogens contacted when the stethoscope is used to examine a person. The cover diaphragm can be used as the diaphragm of a stethoscope pickup and can be used with a diaphragm supplied with the stethoscope. After the cover diaphragm has been used it can discarded and destroyed or, alternatively, can be cleaned for reuse.
[0007] An exemplary dispenser for use in dispensing disposable stethoscope diaphragms for removable attachment to a stethoscope head, supplies a series of diaphragms in a stacked array in a tube. The diaphragms are dispensed by a plate slidably mounted on the base for movement between retracted and extended positions. A cradle formed in the plate receives a single diaphragm through the opening when the dispensing plate is in its retracted position. Movement of the dispensing plate from its retracted to extended position is effective to place a diaphragm in the plate cradle into a position that allows the diaphragm to be attached to the stethoscope head by pressing the stethoscope head against the diaphragm.
[0008] What is desired is a disposable stethoscope diaphragm cover capable of being dispensed and presented for placement over a stethoscope head while minimizing any risk of contamination.
SUMMARY OF THE INVENTION
[0009] This invention relates to stethoscope cover staging and dispensing apparatus, and more particularly to a stethoscope cover staging and dispensing apparatus which provides a medical professional an ability to place a sterile cover onto a stethoscope head.
[0010] In a first aspect of the present invention, a stethoscope cover and respective dispensing configuration, the stethoscope cover and respective dispensing configuration comprising:
[0011] a carrier strip fabricated of an elastically deformable material;
[0012] a plurality of stethoscope covers detachably coupled to the carrier strip in a linear, spatial arrangement, each cover being fabricated having a thin, elastically deformable membrane-like central portion defined by a peripheral edge;
[0013] wherein the plurality of stethoscope covers and carrier strip stretch in unison for staging and placement of each stethoscope cover onto one of a stethoscope head and a stethoscope diaphragm.
[0014] In a second aspect of the present invention, the carrier strip and plurality of stethoscope covers are fabricated of the same material during the same forming process.
[0015] In yet another aspect, the carrier strip and plurality of stethoscope covers are fabricated having a unitary structure.
[0016] In yet another aspect, each stethoscope cover is removably attached to the carrier strip by singulation webbing.
[0017] In yet another aspect, each stethoscope cover is removably attached to the carrier strip by a singulation groove formed about a periphery of the respective stethoscope cover.
[0018] In yet another aspect, the stethoscope covers are fabricated of a size and shape to cover a stethoscope head.
[0019] In yet another aspect, the stethoscope covers are fabricated of a size and shape to cover a diaphragm of a stethoscope head.
[0020] In yet another aspect, the stethoscope covers utilize an elastic property of the cover to attach to the entire stethoscope head or the diaphragm portion.
[0021] In yet another aspect, the carrier strip is rolled into a coil for distribution and dispensing.
[0022] In yet another aspect, the carrier strip is folded into a serpentine format for distribution and dispensing.
[0023] In yet another aspect, a stethoscope diaphragm cover dispensing apparatus inventories, feeds, and stages the stethoscope cover.
[0024] In yet another aspect, the carrier strip is drawn by either a manually operated advancing mechanism or an automated advancing mechanism.
[0025] In yet another aspect, the stethoscope diaphragm cover dispensing apparatus draws each of a first and a second carrier strip apart to expand the stethoscope cover during a staging step.
[0026] In yet another aspect, the stethoscope diaphragm cover dispensing apparatus draws each of a first and a second carrier strip outward, expanding the stethoscope cover into a staging configuration.
[0027] In yet another aspect, the stethoscope diaphragm cover dispensing apparatus comprises a cover clamping member, which temporarily retains the diaphragm cover in position during a step of inserting the stethoscope into the cover. This deters any contact with the cover to minimize any contamination prior to use.
[0028] In yet another aspect, the stethoscope diaphragm cover dispensing apparatus comprises a cover shearing mechanism which singulates the diaphragm cover from the carrier strip.
[0029] In yet another aspect, a method for individually staging a stethoscope cover from a series of stethoscope covers stored within a carrier strip, the method comprises the steps of:
[0030] providing a stethoscope cover and carrier strip assembly, the stethoscope cover and carrier strip assembly comprising:
a carrier strip fabricated of an elastically deformable material and a plurality of stethoscope covers detachably coupled to the carrier strip in a linear, spatial arrangement, each cover being fabricated having a thin, elastically deformable membrane-like central portion defined by a peripheral edge, wherein the plurality of stethoscope covers and carrier strip stretch in unison for staging and placement of each stethoscope cover onto one of a stethoscope head and a stethoscope diaphragm;
[0034] placing the stethoscope cover and carrier strip assembly into a stethoscope diaphragm cover dispensing apparatus;
[0035] advancing the stethoscope cover dispensing apparatus to position an individual stethoscope cover into a staging location;
[0036] stretching an opening of the stethoscope cover to allow insertion of at least a portion of a stethoscope head into the stethoscope cover;
[0037] simulating the stethoscope cover from the carrier strip; and
[0038] allowing the stethoscope cover to return towards a relaxed configuration, wherein the relaxed configuration secures the stethoscope cover to the respective portion of the stethoscope head.
[0039] In yet another aspect, the method further comprises the step of applying a longitudinal tension to the stethoscope cover and carrier strip assembly to expand the stethoscope cover in a longitudinal direction.
[0040] In yet another aspect, the method further comprises the step of applying a lateral tension to the stethoscope cover and carrier strip assembly to expand the stethoscope cover in a lateral direction.
[0041] An advantage of the invention allows the protective stethoscope head cover to be quickly and easily removed from the stethoscope head following examination of the patient and then suitably disposed of so as to prevent skin bacteria and like contaminants that may have contaminated the protective cover during patient examination from undesirably being transmitted to the next patient.
[0042] These and other advantages of the invention will be further understood and appreciated by those skilled in the art by reference to the following written specification, claims and appended drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0043] The invention will now be described, by way of example, with reference to the accompanying drawings, in which:
[0044] FIG. 1 presents an isometric view of an exemplary embodiment of a stethoscope diaphragm cover dispensing apparatus;
[0045] FIG. 2 presents a side elevation view of the exemplary stethoscope diaphragm cover dispensing apparatus, originally introduced in FIG. 1 ;
[0046] FIG. 3 presents a top plan view of the exemplary stethoscope diaphragm cover dispensing apparatus, originally introduced in FIG. 1 , detailing an exemplary stethoscope diaphragm cover presentation configuration;
[0047] FIG. 4 presents a side elevation view of a second exemplary stethoscope diaphragm cover dispensing apparatus;
[0048] FIG. 5 presents a side elevation view of the second exemplary stethoscope diaphragm cover dispensing apparatus, originally introduced in FIG. 1 , detailing a cover application process;
[0049] FIG. 6 presents a sectioned side elevation view of the second exemplary stethoscope diaphragm cover dispensing apparatus, originally introduced in FIG. 1 , detailing a cover staging, the cover application process, and a cover singulation process;
[0050] FIG. 7 presents an isometric view of the operational components interacting with a stethoscope diaphragm cover array;
[0051] FIG. 8 presents a side view illustrating the stethoscope diaphragm cover as installed onto a stethoscope head;
[0052] FIG. 9 presents a sectioned side view taken across a central diameter of an alternate exemplary stethoscope diaphragm cover shown in a relaxed state;
[0053] FIG. 10 presents a sectioned side view taken across a central diameter of the stethoscope diaphragm cover of FIG. 8 shown in an extended, staging state;
[0054] FIG. 11 presents an isometric view of another exemplary stethoscope diaphragm cover dispensing apparatus for dispensing a stacked carrier strip.
[0055] Like reference numerals refer to like parts throughout the various views of the drawings.
DETAILED DESCRIPTION OF THE INVENTION
[0056] The following detailed description is merely exemplary in nature and is not intended to limit the described embodiments or the application and uses of the described embodiments. As used herein, the word “exemplary” or “illustrative” means “serving as an example, instance, or illustration.” Any implementation described herein as “exemplary” or “illustrative” is not necessarily to be construed as preferred or advantageous over other implementations. All of the implementations described below are exemplary implementations provided to enable persons skilled in the art to make or use the embodiments of the disclosure and are not intended to limit the scope of the disclosure, which is defined by the claims. For purposes of description herein, the terms “upper”, “lower”, “left”, “rear”, “right”, “front”, “vertical”, “horizontal”, and derivatives thereof shall relate to the invention as oriented in FIG. 1 . Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description. It is also to be understood that the specific devices and processes illustrated in the attached drawings, and described in the following specification, are simply exemplary embodiments of the inventive concepts defined in the appended claims. Hence, specific dimensions and other physical characteristics relating to the embodiments disclosed herein are not to be considered as limiting, unless the claims expressly state otherwise.
[0057] A stethoscope 300 , as best illustrated in FIG. 8 , is utilized in the medical profession for a multitude of applications. Sound can be utilized in diagnosing an ailment of a patient. The stethoscope 300 includes a stethoscope head 310 comprising at least one diaphragm 312 , 314 which acquires and amplifies sounds emanating from within a patient. A pair of tubes in acoustical communication with the at least one diaphragm 312 , 314 , wherein the tubes transfer the amplified sounds to the medical professional's ears, audio equipment, and the like. The contact surface of the stethoscope head 310 often becomes contaminated with skin bacteria and like contaminants that must be disinfected to ensure against any undesirable transmission of the contaminants to the next patient. The present invention provides a stethoscope head cover 212 and a respective stethoscope diaphragm cover dispensing apparatus 100 to ensure the contacting surface of the stethoscope head 310 remains free from contaminants between patients.
[0058] A stethoscope diaphragm cover dispensing apparatus 100 is provided for dispensing, staging, and placing a stethoscope head cover 212 onto a stethoscope head 310 . Details of the stethoscope diaphragm cover dispensing apparatus 100 are presented in FIGS. 1 through 6 , with the operational mechanisms being detailed in FIG. 8 .
[0059] The stethoscope diaphragm cover dispensing apparatus 100 is designed to store, dispense, stage, and aid in a placement of a stethoscope head cover 212 onto a stethoscope head 310 as illustrated in FIGS. 3 , 5 , and 6 . A 200 includes a series of stethoscope head covers 212 , which are carried by a stethoscope carrier strip 210 as illustrated in FIGS. 7 through 9 . Each stethoscope head cover 212 is fabricated having a thin, elastically deformable membrane-like central portion defined by a stethoscope head cover peripheral edge 213 . The material selection ensures bacteria and other harmful microorganisms remain on the contacting (outer) surface of the stethoscope head cover 212 . The stethoscope head cover 212 is formed having a size and shape to receive the stethoscope head 310 . The interface between the stethoscope carrier strip 210 and the stethoscope head cover peripheral edge 213 can be defined to aid in separation of the stethoscope head cover 212 from the stethoscope carrier strip 210 , but would be of a sufficient strength to allow the stethoscope carrier strip 210 to convey an expansion force onto the stethoscope head cover 212 . This allows for the expansion of the stethoscope head cover 212 into an expanded stethoscope cover 222 for staging and insertion of the stethoscope head 310 thereinto. The stethoscope head cover 212 and the stethoscope carrier strip 210 can be formed simultaneously or separately and subsequently mated together. The stethoscope carrier strip 210 can be configured and stored in a rolled arranged referred to as a rolled carrier strip 214 and illustrated in FIGS. 6 and 7 , or in a stacked serpentine configuration referred to as a serpentine carrier strip 614 and illustrated in FIG. 11 .
[0060] The stethoscope diaphragm cover dispensing apparatus 100 includes a dispenser housing 110 , which is fabricated having a pair of housing sidewalls 114 extending downward from each elongated edge of a housing top member 112 creating an inventory storage region 116 therein. The dispenser housing 110 is preferably fabricated of a sheet metal, plastic, a composite material, and the like. The stethoscope diaphragm cover dispensing apparatus 100 includes a pair of cover staging arms 118 extending forward from each outer edge of the dispenser housing 110 creating a cover staging clearance area 119 . An upper surface of the cover staging arms 118 is preferably planar with the housing top member 112 . A strip presentation aperture 122 can be provided through the housing top member 112 for passage of the stethoscope carrier strip 210 therethrough (as illustrated in FIG. 3 ). It is understood that the strip presentation aperture 122 can be alternatively located through a front member (not shown) of the dispenser housing 110 . Alternatively, the strip presentation aperture 122 can be omitted, where the stethoscope carrier strip 210 would extend from underneath the housing top member 112 . An excess strip material return port 124 is provided through an upper surface of each respective cover staging arm 118 for returning and collecting spent strip material 216 of the stethoscope cover and carrier strip assembly 200 . The forward section of the housing top member 112 and the upper surfaces of each cover staging arm 118 can be used to create a platform for supporting the stethoscope head cover 212 during staging and placement upon the stethoscope head 310 . An optional inventory viewing port 120 can be provided through any reasonable location of the dispenser housing 110 to determine the remaining inventory within the stethoscope diaphragm cover dispensing apparatus 100 .
[0061] The internal operating mechanisms of the stethoscope diaphragm cover dispensing apparatus 100 are presented in FIGS. 6 and 7 . The rolled carrier strip 214 is placed upon an inventory management axle 140 and inserted into the inventory storage region 116 . The stethoscope carrier strip 210 is routed towards the cover staging clearance area 119 . The rolled carrier strip 214 is preferably provided with a pair of leader strips, which emulate the spent strip material 216 and allow for preparation for use without wasting any stethoscope head covers 212 . The spent strip material 216 is fed through each respective excess strip material return port 124 , around a distal free wheel pulley 142 , then returning and secured to a strip advance mechanism 134 . The leader strip may include a feature to aid in engagement with the strip advance mechanism 134 . Examples include a loop and pin or clip configuration, a slot within the strip advance mechanism 134 , an adhesive, and the like. The strip advance mechanism 134 rotates to advance the stethoscope carrier strip 210 . The strip advance mechanism 134 can be operated by any reasonable operating mechanism. In a first exemplary embodiment, a strip advancing control lever 130 ( FIGS. 1 and 2 ) can operationally engage with the strip advance mechanism 134 using a ratcheting interface, wherein the medical professional would push/pull a lever handle 131 in a respective direction, causing the strip advancing control lever 130 to pivot accordingly. The pivotal motion of the strip advancing control lever 130 rotates the strip advance mechanism 134 , which draws the stethoscope carrier strip 210 forward. A set of optional gears (not shown, but well understood) may be integrated between the strip advancing control lever 130 and the strip advance mechanism 134 . The gear set can relate the pivotal direction of the strip advancing control lever 130 to the rotational direction of the strip advance mechanism 134 into either a like or an opposite direction. Additionally, the gear set can provide a torque conversion between the strip advancing control lever 130 and the strip advance mechanism 134 .
[0062] An alternative exemplary mechanical drive means is a strip advancing control wheel 132 attached to the strip advance mechanism 134 in a manner similar to the engaging interface between the strip advancing control lever 130 and the strip advance mechanism 134 previously described herein. The medical professional would rotate the strip advancing control wheel 132 to rotate the strip advance mechanism 134 , which draws the stethoscope carrier strip 210 forward.
[0063] An optional registration control system may be integrated into the stethoscope diaphragm cover dispensing apparatus 100 . This can include a pin, a series of pins, and the like which engage with a notch, aperture, and the like spatially provided along the stethoscope carrier strip 210 . The combination control the motion of the strip advance mechanism 134 ensuring the stethoscope head cover 212 is properly positioned within the cover staging clearance area 119 during the staging process.
[0064] It is understood that the advancing mechanism may be automated, integrating an electrically driven motor. At least one sensor can be integrated into the stethoscope diaphragm cover dispensing apparatus 100 to ensure proper registration of the stethoscope head cover 212 during the advancement process.
[0065] A tensioning member 144 is located rearward of the cover staging clearance area 119 and applies a longitudinal tension force to the stethoscope carrier strip 210 . The tensioning member 144 illustrated is exemplary, where it is understood that tension may be applied by any reasonable mechanism. The excess strip material return ports 124 are positioned wider than a width between the edges of the stethoscope carrier strip 210 in a relaxed state. As the stethoscope carrier strip 210 is drawn into the excess strip material return port 124 , the motion creates a lateral tensile force between the longitudinal edges of the stethoscope carrier strip 210 . The tension applied to the stethoscope carrier strip 210 between the tensioning member 144 and the distal free wheel pulley 142 and by the distance between each of the excess strip material return ports 124 expands the stethoscope head cover peripheral edge 213 of the stethoscope head cover 212 into an expanded stethoscope cover 222 . The expanded stethoscope cover 222 is a presented in a staged configuration of the stethoscope head cover 212 for insertion of the stethoscope head 310 thereinto.
[0066] An optional enlarged carrier edge 230 can be incorporated along each edge (or other portion) of the stethoscope carrier strip 210 . The carrier rail feature or an enlarged carrier edge 230 can be any form factor having a thickness greater than the thickness of the stethoscope carrier strip 210 , including a circular cross section, a “T” shaped cross section, an “L” shaped cross section, a “C” shaped cross section, and the like. The shape provides a mechanical interface to support the lateral tension. The enlarged carrier edge 230 would aid in providing the lateral tension to the stethoscope cover and carrier strip assembly 200 . It is understood that the lateral stretching of the stethoscope cover and carrier strip assembly 200 can be created by any means of drawing each of a first edge and a second edge (understood by description) of the stethoscope carrier strip 210 apart from each other by positioning a first and a second distal draw location separated by a distance that is greater than a dimension between the a first edge and a second edge of the stethoscope carrier strip 210 when in a relaxed state.
[0067] An optional strip clamp 150 may be hingebly attached to the dispenser housing 110 by a strip clamp hinge 154 . A cover shearing mechanism 152 may be integrated into a contacting surface of the strip clamp 150 . The cover shearing mechanism 152 would be shaped to contour to an outline of the stethoscope head cover peripheral edge 213 respective to the stethoscope head cover 212 in an extended configuration and located in registration therewith. The medical professional advances the rolled carrier strip 214 positioning one stethoscope head cover 212 into a staging position within the cover staging clearance area 119 and subsequently inserts the stethoscope head 310 through the stretched stethoscope head cover peripheral edge 213 and into the expanded stethoscope cover 222 . The medical professional can pivot the strip clamp 150 to temporarily hold the expanded stethoscope cover 222 in place during the insertion of the stethoscope head 310 thereinto. The medical professional can pivot the strip clamp 150 downward and applies a pressure thereon, which causes the cover shearing mechanism 152 to shear the stethoscope head cover 212 from the stethoscope carrier strip 210 . Alternatively, the cover shearing mechanism 152 can be designed to apply a clamping force to the stethoscope carrier strip 210 , where the stethoscope head cover 212 is separated from the stethoscope carrier strip 210 by applying a tensile force between the stethoscope head cover 212 and the stethoscope carrier strip 210 by moving the stethoscope head 310 accordingly. This provides an additional means to ensure the expanded stethoscope cover 222 remains untouched during placement onto the stethoscope head 310 . The illustrated embodiment detailed in FIG. 8 places the stethoscope head cover 212 over the entire stethoscope head 310 .
[0068] The stethoscope cover can be shaped in a second exemplary configuration referred to as a stethoscope diaphragm cover 412 and illustrated in FIGS. 9 and 10 . The stethoscope diaphragm cover 412 includes a cover diaphragm engagement flange 415 formed about a peripheral edge. The stethoscope diaphragm cover 412 is carried by a stethoscope carrier strip 410 (collectively referred to as a stethoscope cover and carrier strip assembly 400 ) in a manner similar to that of the stethoscope head cover 212 and respective stethoscope carrier strip 210 previously described herein. The stethoscope diaphragm cover 412 is shaped to engage with and be retained upon a large diaphragm 312 or a small diaphragm 314 of the stethoscope head 310 . The stethoscope diaphragm cover dispensing apparatus 100 draws the cover diaphragm engagement flange 415 radially outward allowing the medical professional to insert the diaphragm 312 , 314 into the stethoscope diaphragm cover 412 . A carrier rail feature or enlarged carrier edge 430 may be included along each of the distal edges of the stethoscope carrier strip 410 to mechanically aid in applying the lateral tension. The enlarged/shaped carrier edge 430 can be guided through a track, wherein the track is formed using any means known by those skilled in the art. The extended cover diaphragm engagement flange 415 retracts into a relaxed configuration when the stethoscope diaphragm cover 412 is separated from the stethoscope carrier strip 410 . A cover singulation aid feature 417 may be included as a demarcation between the cover diaphragm engagement flange 415 and the stethoscope carrier strip 410 . The cover singulation aid feature 417 can be designed to aid in the singulation process.
[0069] The above illustrates a stethoscope diaphragm cover dispensing apparatus 100 used in conjunction with the rolled carrier strip 214 . Alternatively, a stethoscope diaphragm cover dispensing apparatus 500 may be used to dispense a stethoscope cover and carrier strip assembly 600 provided in a serpentine format. The stethoscope diaphragm cover dispensing apparatus 500 stores and dispenses a plurality of stethoscope head cover 612 from a serpentine carrier strip 614 . Like features of stethoscope cover and carrier strip assembly 600 and stethoscope cover and carrier strip assembly 200 are numbered the same except preceded by the numeral ‘6’. A bead or other enlarged section of material may be provided about a stethoscope head cover edge 613 of the stethoscope head cover 612 .
[0070] The stethoscope diaphragm cover dispensing apparatus 500 includes a dispenser housing 510 , which can be formed having a pair of housing sidewalls 514 extending rearward from each elongated, vertical edge of a housing front member 512 creating an inventory storage section 516 therein. The dispenser housing 510 is preferably fabricated of a sheet metal, plastic, a composite material, and the like. The inventory storage section 516 is sized to receive the serpentine carrier strip 614 . The stethoscope diaphragm cover dispensing apparatus 500 includes a pair of cover staging arms 518 extending forward from each outer edge of the dispenser housing 510 creating a cover staging clearance 519 . The general conception and operational mechanisms are similar to those described for the stethoscope diaphragm cover dispensing apparatus 100 . In the exemplary embodiment, the stethoscope carrier strip 610 is guided through a track or groove within an interior sidewall of each cover staging arm 518 . An inventory viewing port 520 may be provided through the housing sidewall 514 or housing front member 512 , allowing a service person to determine the remaining inventory within the inventory storage section 516 . The stethoscope carrier strip 210 is drawn forward by any reasonable means. As the stethoscope carrier strip 210 is drawn forward, the stethoscope head cover 612 is expanded into a staged or expanded stethoscope cover 622 configuration, in accordance with the expansion process previously described herein.
[0071] It is understood that an optional protective layer may be adhered to at least one of the surfaces of the stethoscope cover and carrier strip assembly 200 , 400 , 600 to ensure sanitized delivery of the covers 212 , 412 , 612 .
[0072] The stethoscope diaphragm cover dispensing apparatus 100 , 500 can be provided in a variety of sizes and form factors, including a hand-held dispensing unit of type described that is of simple compact construction and one that can be inexpensively manufactured in quantity, a wall mounted unit, and the like. The system can include a manually advancing system, an automated advancing system, and the like.
[0073] Since many modifications, variations, and changes in detail can be made to the described preferred embodiments of the invention, it is intended that all matters in the foregoing description and shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense. Thus, the scope of the invention should be determined by the appended claims and their legal equivalence.
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RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application No. 61/833,414, filed on Jun. 10.2013, the entire contents of which are hereby incorporated by reference.
BACKGROUND
[0002] Merkel Cell Polyomavirus (MCPyV) is a member of the Polyomaviridae virus family.
[0003] Merkel cells are found in hair follicles, certain mucosal tissue and in the areas of skin involved with sensation of touch and are located in the basal level of the epidermis (Sidhu, G.S. et al. (2005) Ultrastruct. Pathol. 29: 287-294). Merkel Cell Carcinoma (MCC) is a malignancy of cutaneous neuroendocrine cells and is hypothesized to originate from the transformation of Merkel cells. It is one of the most lethal and aggressive skin cancers, and its incidence has tripled in the past 20 years and continues to climb (Hodgson, N. C. (2005) J. Surg. Oncol. 89:1-4; Lemos, B. and Nghiem, P. (2007) J. Invest. Dermatol. 127: 2100-2103.) An increase in the incidence of MCC has been noted in HIV-infected individuals (Engels, E. A. et al. (2002) Lancet 359: 497-498.), chronic lymphocytic leukemia patients (Vlad, R. and Woodlock, T. J. (2003) Am. J. Clin. Oncol. 26: 531-534.), and organ transplant patients (Buell, J. F. et al. (2002) Transplant. Proc. 34: 1780-1781.). It is prevalent in the elderly with the mean age of onset being in the 70s (Agelli, M. and Clegg, L. X. (2003) J. Am. Acad. Dermatol. 49: 832-841.) MCC also occurs almost exclusively in Caucasians at sites of the body that are frequently exposed to the sun. This link between MCC and immunosuppression led researchers to suspect an infectious origin of MCC, and MCPyV was subsequently isolated from an MCC tumor (Feng, H. et al. (2008) Science 319: 1096-1100.)
[0004] Portions of the MCPyV capsid have been shown to bind sialic acid components of the ganglioside Gt1b (Erickson, K. D. et al (2009) J. Virol. 83:10275-10279.) It has also been shown that the virus requires sulfated glycosaminoglycans, particularly heparan sulfate, for infectious entry. Although MCPyV pseudovirions efficiently bind to cells not expressing sialylated glycans like Gt1b, these particles are deficient in gene transduction. Crystal structure analysis has supported the hypothesis that the MCPyV infectious entry process requires glycosaminoglycans for initial attachment and subsequent association with sialic acid for gene transduction (Neu, U. et al (2012) PLoS Pathog. 8: e1002738.)
SUMMARY
[0005] The present disclosure provides new compositions and methods for treating Merkel Cell Polyomavirus (MCPyV) infection and disorders associated with MCPyV infection. Specifically, it provides compounds which can act extracellularly to reduce or prevent infection of a cell by a MCPyV. Some preferred embodiments of the disclosure include therapeutic compounds having an anchoring domain that facilitates association of the compound with the surface of a target cell and a sialidase domain that can act extracellularly to reduce or prevent infection of the target cell by a pathogen, such as a virus. In some embodiments the compound comprises, consists of or consists essentially of all or a catalytically active portion of a sialidase.
[0006] In the above method, administration of the agent having sialidase activity leads to an improvement in the parameters resulting from the infection.
[0007] Disclosed herein is a method of treating an infection by a Merkel Cell Polyomavirus (MCPyV) or MCPyV related disorder, the method comprising administering to the skin of the patient a therapeutically effective amount of an agent having sialidase activity. In various embodiments: the patient is immunocompromised; the patient is infected with HIV; the patient is suffering from chronic lymphocytic leukemia; the patient has undergone organ transplant or is being treated in preparation for organ transplant; the patient has undergone liver, heart, bone marrow or kidney transplant or is being treated in preparation for liver, heart, bone marrow or kidney transplant. In some embodiments, the agent having sialidase activity is a polypeptide comprising all or a portion of a sialidase having sialidase activity (e.g., the agent comprises a fusion protein wherein the fusion protein comprises at least a first portion comprising a portion of a sialidase having sialidase activity and a second portion that binds to a glycosaminoglycan (GAG)); or the agent comprises a fusion protein wherein the fusion protein comprises at least a first portion comprising a portion of a sialidase having sialidase activity and a second portion that has a net positive charge at physiological pH). In some cases, the second portion that binds to a GAG is selected from the group consisting of: human platelet factor 4 (SEQ ID NO: 2), human interleukin 8 (SEQ ID NO: 3), human antithrombin III (SEQ ID NO: 4), human apoprotein E (SEQ ID NO: 5), human angio associated migratory protein (SEQ ID NO: 6), and human amphiregulin (SEQ ID NO: 7). In some cases, the agent having sialidase activity is a bacterial sialidase; the bacterial sialidase is derived from a bacterium selected from the group consisting of: Vibrio cholera, Arthrobacter ureafaciens, Clostridium perfringens, Actinomyces viscosus , and Micromonospora viridifaciens . In some cases, the agent having sialidase activity is a human sialidase. The agent can be topically administered to the skin; e.g., the infected skin or the skin most frequently exposed to the sun. The agent can be administered by subdermal injection, or as a lotion or a transdermal patch. The administration of the agent having sialidase activity causes one or more of: a decrease in malignant lesions on the skin, and a reduction of MCPyV viral load. In some cases, the infection of the skin is associated with an event selected from the group consisting of an HIV infection and commencement of immunosuppressive therapy.
[0008] In some cases the agent having sialidase activity comprises, consists of, or consists essentially of DAS181 (SEQ ID NO:13 or SEQ ID NO:14). In some cases, the method comprises administering a topical composition comprising microparticles comprising a compound that comprises, consists of, or consists essentially of DAS181 (SEQ ID NO:13 or SEQ ID NO:14).
[0009] In some cases, the agent having sialidase activity is DAS181. In some cases the method comprises administering composition comprising microparticles comprising DAS181.
DETAILED DESCRIPTION
[0010] In general, the present disclosure relates to methods for treating MCPyV virus infection using agents having sialidase activity. Suitable aunts are described in U.S. Pat. Nos. 8,084,036 and 7,807,174 which are both hereby incorporated by reference in their entirety. The agents having sialidase activity can remove sialic acid residues from the surface of cells and reduce in infection by certain viruses that binding to sialic acid residues, e.g., MCPyV.
[0011] In some embodiments, the severity of the infection is reduced with the treatment of the compounds. The reduction of the severity of the infection can be measured by the reduction of the symptoms which present with the infection.
[0012] The compounds of the present disclosure have sialidase activity. In some instances, the compounds having sialidase activity are a fusion protein in which the portion having sialidase activity is fused to a protein or protein fragment not having sialidase activity. In some instances the portion having sialidase activity is fused to an anchoring domain. In some instances the anchoring domain is GAG.
[0013] DAS181 (SEQ ID NOs: 13 and 14) is a fusion protein compound comprising the catalytic domain of a sialidase ( A. viscous ) and an anchoring domain that is a human amphiregulin GAG-binding domain. In some instances of the present disclosure, DAS181 could be used to treat the infection by MCPyV virus and disorders associated therewith (e.g., Merkel Cell Carcinoma).
[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Generally, the nomenclature used herein and the manufacture or laboratory procedures described below are well known and commonly employed in the art. Conventional methods are used for these procedures, such as those provided in the art and various general references. Where a term is provided in the singular, the inventors also contemplate the plural of that term. Where there are discrepancies in terms and definitions used in references that are incorporated by reference, the terms used in this application shall have the definitions given herein. As employed throughout the disclosure, the following teams, unless otherwise indicated, shall be understood to have the following meanings:
[0015] A “target cell” is any cell that can be infected by MCPyV virus, such as a merkel cell.
[0016] A “domain that can anchor said at least one sialidase domain to the membrane of a target cell”, also called an “extracellular anchoring domain” or simply, “anchoring domain” refers to a moiety that can interact with a moiety that is at or on the exterior of a cell surface or is in close proximity to the surface of a cell. An extracellular anchoring domain can be reversibly or irreversibly linked to one or more moieties, such as, preferably, one or more sialidase domains, and thereby cause the one or more attached therapeutic moieties to be retained at or in close proximity to the exterior surface of a eukaryotic cell. Preferably, an extracellular anchoring domain interacts with at least one molecule on the surface of a target cell or at least one molecule found in close association with the surface of a target cell. For example, an extracellular anchoring domain can bind a molecule covalently or noncovalently associated with the cell membrane of a target cell, or can bind a molecule present in the extracellular matrix surrounding a target cell. An extracellular anchoring domain preferably is a peptide, polypeptide, or protein, and can also comprise any additional type of chemical entity, including one or more additional proteins, polypeptides, or peptides, a nucleic acid, peptide nucleic acid, nucleic acid analogue, nucleotide, nucleotide analogue, small organic molecule, polymer, lipids, steroid, fatty acid, carbohydrate, or a combination of any of these.
[0017] As used herein, a protein or peptide sequences is “substantially homologous” to a reference sequence when it is either identical to a reference sequence, or comprises one or more amino acid deletions, one or more additional amino acids, or more one or more conservative amino acid substitutions, and retains the same or essentially the same activity as the reference sequence. Conservative substitutions may be defined as exchanges within one of the following five groups:
[0018] I. Small, aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, Gly
[0019] II. Polar, negatively charged residues and their amides: Asp, Asn, Glu, Gln
[0020] III. Polar, positively charged residues: His, Arg, Lys
[0021] IV. Large, aliphatic nonpolar residues: Met, Leu, Ile, Val, Cys
[0022] V. Lame aromatic residues: Phe, Try, Trp
[0023] Within the foregoing groups, the following substitution are considered to be “highly conservative”: Asp/Glu, His/Arg/Lys, Phe/Tyr/Trp, and Met/Leu/Ile/Val. Semi-conservative substitutions are defined to be exchanges between two of groups (I)-(V) above which are limited to supergroup (A), comprising (I), (II), and (III) above, or to supergroup (B), comprising (IV) and (V) above. In addition, where hydrophobic amino acids are specified in the application, they refer to the amino acids Ala, Gly, Pro, Met, Leu, Ile, Val, Cys, Phe, and Trp, whereas hydrophilic amino acids refer to Ser, Thr, Asp, Asn, Glu, Gln, His, Arg, Lys, and Tyr.
[0024] As used herein, the phrase “therapeutically effective amount” refers to the amounts of active compounds or their combination that elicit the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
[0025] (1) inhibiting the disease and its progression; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) such as in the case of MCPyV virus infection, and
[0026] (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as in the case of MCPyV virus infection.
[0027] As used herein, the phrase “treating (including treatment)” includes one or more of the following:
[0028] (1) inhibiting the disease and its progression; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and
[0029] (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder.
[0030] A “sialidase” is an enzyme that can remove a sialic acid residue from a substrate molecule. The sialidases (N-acylneuraminosylglycohydrolases, EC 3.2.1.18) are a group of enzymes that hydrolytically remove sialic acid residues from sialo-glycoconjugates. Sialic acids are alpha-keto acids with 9-carbon backbones that are usually found at the outermost positions of the oligosaccharide chains that are attached to glycoproteins and glycolipids. One of the major types of sialic acids is N-acetylneuraminic acid (NeuSAc), which is the biosynthetic precursor for most of the other types. The substrate molecule can be, as nonlimiting examples, an oligosaccharide, a polysaccharide, a glycoprotein, a ganglioside, or a synthetic molecule. For example, a sialidase can cleave bonds having alpha (2,3)-Gal, alpha(2,6)-Gal, or alpha (2,8)-Gal linkages between a sialic acid residue and the remainder of a substrate molecule. A sialidase can also cleave any or all of the linkages between the sialic acid residue and the remainder of the substrate molecule. Two major linkages between NeuSAc and the penultimate galactose residues of carbohydrate side chains are found in nature, NeuSAc alpha (2,3)-Gal and NeuSAc alpha (2,6)-Gal. Both NeuSAc alpha (2,3)-Gal and NeuSAc alpha (2,6)-Gal molecules can be recognized by influenza viruses as the receptor, although human viruses seem to prefer NeuSAc alpha (2,6)-Gal, avian and equine viruses predominantly recognize NeuSAc alpha (2,3)Gal. A sialidase can be a naturally-occurring sialidase, an engineered sialidase (such as, but not limited to a sialidase whose amino acid sequence is based on the sequence of a naturally-occurring sialidase, including a sequence that is substantially homologous to the sequence of a naturally-occurring sialidase). As used herein, “sialidase” can also mean the active portion of a naturally-occurring sialidase, or a peptide or protein that comprises sequences based on the active portion of a naturally-occurring sialidase.
[0031] A “fusion protein” is a protein comprising amino acid sequences from at least two different sources. A fusion protein can comprise amino acid sequence that is derived from a naturally occurring protein or is substantially homologous to all or a portion of a naturally occurring protein, and in addition can comprise from one to a very large number of amino acids that are derived from or substantially homologous to all or a portion of a different naturally occurring protein. In the alternative, a fusion protein can comprise amino acid sequence that is derived from a naturally occurring protein or is substantially homologous to all or a portion of a naturally occurring protein, and in addition can comprise from one to a very large number of amino acids that are synthetic sequences.
[0032] A “sialidase catalytic domain protein” is a protein that comprises the catalytic domain of a sialidase, or an amino acid sequence that is substantially homologous to the catalytic domain of a sialidase, but does not comprises the entire amino acid sequence of the sialidase the catalytic domain is derived from, wherein the sialidase catalytic domain protein retains substantially the same activity as the intact sialidase the catalytic domain is derived from. A sialidase catalytic domain protein can comprise amino acid sequences that are not derived from a sialidase, but this is not required. A sialidase catalytic domain protein can comprise amino acid sequences that are derived from or substantially homologous to amino acid sequences of one or more other known proteins, or can comprise one or more amino acids that are not derived from or substantially homologous to amino acid sequences of other known proteins.
I. Composition for Preventing or Treating Infection by a Pathogen
[0033] The present disclosure relates to compounds (agents) that include a peptide. The compounds include all or a catalytic portion of a sialidase. In some cases the compound includes at least one domain that can associate the sialidase or portion thereof with a eukaryotic cell. By “peptide or protein-based” compounds, it is meant that a compound that includes a portion having an amino acid framework, in which the amino acids are joined by peptide bonds. A peptide or protein-based compound can also have other chemical compounds or groups attached to the amino acid framework or backbone, including moieties that contribute to the anchoring activity of the anchoring domain, or moieties that contribute to the infection-preventing activity or the sialidase domain. For example, the protein-based therapeutics of the present disclosure can comprise compounds and molecules such as but not limited to: carbohydrates, fatty acids, lipids, steroids, nucleotides, nucleotide analogues, nucleic acid molecules, nucleic acid analogues, peptide nucleic acid molecules, small organic molecules, or even polymers. The protein-based therapeutics of the present disclosure can also comprise modified or non-naturally occurring amino acids. Non-amino acid portions of the compounds can serve any purpose, including but not limited to: facilitating the purification of the compound, improving the solubility or distribution or the compound (such as in a therapeutic formulation), linking domains of the compound or linking chemical moieties to the compound, contributing to the two dimensional or three-dimensional structure of the compound, increasing the overall size of the compound, increasing the stability of the compound, and contributing to the anchoring activity or therapeutic activity of the compound.
[0034] The peptide or protein-based compounds of the present disclosure can also include protein or peptide sequences in addition to those that comprise anchoring domains or sialidase domains. The additional protein sequences can serve any purpose, including but not limited to any of the purposes outlined above (facilitating the purification of the compound, improving the solubility or distribution or the compound, linking domains of the compound or linking chemical moieties to the compound, contributing to the two-dimensional or three-dimensional structure of the compound, increasing the overall size of the compound, increasing the stability of the compound, or contributing to the anchoring activity or therapeutic activity of the compound). Preferably any additional protein or amino acid sequences are part of a single polypeptide or protein chain that includes the sialidase domain or domains, but any feasible arrangement of protein sequences is within the scope of the present disclosure.
[0035] The anchoring domain and sialidase domain can be arranged in any appropriate way that allows the compound to bind at or near a target cell membrane such that the therapeutic sialidase can exhibit an extracellular activity that prevents or impedes infection of the target cell by a pathogen. The compound will preferably have at least one protein or peptide-based anchoring domain and at least one peptide or protein-based sialidase domain. In this case, the domains can be arranged linearly along the peptide backbone in any order. The anchoring domain can be N-terminal to the sialidase domain, or can be C-terminal to the sialidase domain.
[0036] It is also possible to have one or more sialidase domains flanked by at least one anchoring domain on each end. Alternatively, one or more anchoring domains can be flanked by at least one sialidase domain on each end. Chemical, or preferably, peptide, linkers can optionally be used to join some or all of the domains of a compound. It is also possible to have the domains in a nonlinear, branched arrangement. For example, the sialidase domain can be attached to a derivatized side chain of an amino acid that is part of a polypeptide chain that also includes, or is linked to, the anchoring domain.
[0037] A compound of the present disclosure can have more than one anchoring domain. In cases in which a compound has more than one anchoring domain, the anchoring domains can be the same or different. A compound of the present disclosure can have more than one sialidase domain. In cases in which a compound has more than one sialidase domain, the sialidase domains can be the same or different. Where a compound comprises multiple anchoring domains, the anchoring domains can be arranged in tandem (with or without linkers) or on alternate sides of other domains, such as sialidase domains. Where a compound comprises multiple sialidase domains, the sialidase domains can be arranged in tandem (with or without linkers) or on alternate sides of other domains, such as, but not limited to, anchoring domains.
[0038] A peptide or protein-based compound of the present disclosure can be made by any appropriate way, including purifying naturally occurring proteins, optionally proteolytically cleaving the proteins to obtain the desired functional domains, and conjugating the functional domains to other functional domains. Peptides can also be chemically synthesized, and optionally chemically conjugated to other peptides or chemical moieties. Preferably, however, a peptide or protein-based compound of the present disclosure is made by engineering a nucleic acid construct to encode at least one anchoring domain and at least one sialidase domain together (with or without nucleic acid linkers) in a continuous polypeptide. The nucleic acid constructs, preferably having appropriate expression sequences, can be transfected into prokaryotic or eukaryotic cells, and the therapeutic protein-based compound can be expressed by the cells and purified. Any desired chemical moieties can optionally be conjugated to the peptide or protein-based compound after purification. In some cases, cell lines can be chosen for expressing the protein-based therapeutic for their ability to perform desirable post-translational modifications (such as, but not limited to glycosylation).
[0039] A great variety of constructs can be designed and their protein products tested for desirable activities (such as, for example, binding activity of an anchoring domain or catalytic activity of a sialidase domain). The protein products of nucleic acid constructs can also be tested for their efficacy in preventing or impeding infection of a target cell by a pathogen. In vitro and in vivo tests for the infectivity of pathogens are known in the art.
Anchoring Domain
[0040] As used herein, an “extracellular anchoring domain” or “anchoring domain” is any moiety that interact with an entity that is at or on the exterior surface of a target cell or is in close proximity to the exterior surface of a target cell. An anchoring domain serves to retain a compound of the present disclosure at or near the external surface of a target cell. An extracellular anchoring domain preferably binds 1) a molecule expressed on the surface of a target cell, or a moiety, domain, or epitope of a molecule expressed on the surface of a target cell, 2) a chemical entity attached to a molecule expressed on the surface of a target cell, or 3) a molecule of the extracellular matrix surrounding a target cell.
[0041] An anchoring domain is preferably a peptide or protein domain (including a modified or derivatized peptide or protein domain), or comprises a moiety coupled to a peptide or protein. A moiety coupled to a peptide or protein can be any type of molecule that can contribute to the interaction of the anchoring domain to an entity at or near the target cell surface, and is preferably an organic molecule, such as, for example, nucleic acid, peptide nucleic acid, nucleic acid analogue, nucleotide, nucleotide analogue, small organic molecule, polymer, lipids, steroid, fatty acid, carbohydrate, or any combination of any of these.
[0042] Target tissue or target cell type includes the sites in an animal or human body where a pathogen invades or amplifies. For example, a target cell can be a kidney cell that can be infected by a MCPyV virus. A compound or agents of the present disclosure can comprise an anchoring domain that can interact with a cell surface entity, for example, that is specific for the target cell type.
[0043] A compound for treating infection by a pathogen can comprise an anchoring domain that can bind at or near the surface of a target cell. For example, heparin/sulfate, closely related to heparin, is a type of GAG that is ubiquitously present on cell membranes, including the surface of respiratory epithelium. Many proteins specifically bind to heparinIheparan sulfate, and the GAG-binding sequences in these proteins have been identified (Meyer, F A, King, M and Gelman, R A. (1975) Biochimica et BioophysicaActa 392: 223-232; Schauer, S. ed., pp 233. Sialic Acids Chemistry, Metabolism and Function. Springer-Verlag, 1982). For example, the GAG-binding sequences of human platelet factor 4 (PF4) (SEQ ID NO:2), human interleukin 8 (IL8) (SEQ ID NO:3), humanantithrombin III (AT III) (SEQ ID NO:4), human apoprotein E (ApoE) (SEQ ID NO:5), human angio-associated migratory cell protein (AAMP) (SEQ ID NO:6), or human amphiregulin (SEQ ID NO:7) have been shown to have very high affinity (in the nanomolar range) towards heparin (Lee, M K and Lander, A D. (1991) Pro Natl Acad Sci USA 88:2768-2772; Goger, B, Halden, Y, Rek, A, Mosl, R, Pyre, D. Gallagher, J and Kungl, A J. (2002) Biochem. 41:1640-1646; Witt, D P and Lander A D (1994) Curr Bio 4:394-400; Weisgraber, K H, Rail, S C, Mahley, R W, Milne, R W and Marcel, Y. (1986) J Bio Chem 261:2068-2076). These sequences, or other sequences that have been identified or are identified in the future as heparin/heparan sulfate binding sequences, or sequences substantially homologous to identified heparin/heparan sulfate binding sequences that have heparin/heparan sulfate binding activity, can be used as epithelium-anchoring-domains in compounds of the present disclosure that can be used.
Sialidase Domain
[0044] A sialidase that can cleave more than one type of linkage between a sialic acid residue and the remainder of a substrate molecule, in particular, a sialidase that can cleave both α(2, 6)-Gal and α(2, 3)-Gal linkages can be used in the compounds of the disclosure. Sialidases include are the large bacterial sialidases that can degrade the receptor sialic acids Neu5Ac alpha(2,6)-Gal and Neu5Ac alpha(2,3)-Gal. For example, the bacterial sialidase enzymes from Clostridium perfringens (Genbank Accession Number X87369), Actinomyces viscosus, Arthrobacter ureafaciens , or Micromonospora viridifaciens (Genbank Accession Number D01045) can be used. Sialidase domains of compounds of the present disclosure can comprise all or a portion of the amino acid sequence of a large bacterial sialidase or can comprise amino acid sequences that are substantially homologous to all or a portion of the amino acid sequence of a large bacterial sialidase. In one preferred embodiment, a sialidase domain comprises a sialidase encoded by Actinomyces viscosus , such as that of SEQ ID NO: 12, or such as sialidase sequence substantially homologous to SEQ ID NO: 12. In yet another preferred embodiment, a sialidase domain comprises the catalytic domain of the Actinomyces viscosus sialidase extending from amino acids 274-666 of SEQ ID NO:12, or a substantially homologous sequence.
[0045] Additional sialidases include the human sialidases such as those encoded by the genes NEU2 (SEQ ID NO:8; Genbank Accession Number Y16535; Monti, E, Preti, Rossi, E., Ballabio, A and Borsani G. (1999) Genomics 57:137-143) and NEU4 (SEQ ID NO:9; Genbank Accession Number NM080741; Monti, E, Preti, A, Venerando, Band Borsani, G. (2002) Neurochem Res 27:646-663). Sialidase domains of compounds of the present disclosure can comprise all or a portion of the amino acid sequences of a sialidase or can comprise amino acid sequences that are substantially homologous to all or a portion of the amino acid sequences of a sialidase. Preferably, where a sialidase domain comprises a portion of the amino acid sequences of a naturally occurring sialidase, or sequences substantially homologous to a portion of the amino acid sequences of a naturally occurring sialidase, the portion comprises essentially the same activity as the intact sialidase. The present disclosure also includes sialidase catalytic domain proteins. As used herein a “sialidase catalytic domain protein” comprises a catalytic domain of a sialidase but does not comprise the entire amino acid sequence of the sialidase from which the catalytic domain is derived. A sialidase catalytic domain protein has sialidase activity. Preferably, a sialidase catalytic domain protein comprises at least 10%, at least 20%, at least 50%, at least 70% of the activity of the sialidase from which the catalytic domain sequence is derived. More preferably, a sialidase catalytic domain protein comprises at least 90% of the activity of the sialidase from which the catalytic domain sequence is derived.
[0046] A sialidase catalytic domain protein can include other amino acid sequences, such as but not limited to additional sialidase sequences, sequences derived from other proteins, or sequences that are not derived from sequences of naturally occurring proteins. Additional amino acid sequences can perform any of a number of functions, including contributing other activities to the catalytic domain protein, enhancing the expression, processing, folding, or stability of the sialidase catalytic domain protein, or even providing a desirable size or spacing of the protein.
[0047] A preferred sialidase catalytic domain protein is a protein that comprises the catalytic domain of the A. viscosus sialidase. Preferably, an A. viscosus sialidase catalytic domain protein comprises amino acids 270-666 of the A. viscosus sialidase sequence (SEQ ID NO:12). Preferably, an A. Viscosus sialidase catalytic domain protein comprises an amino acid sequence that begins at any of the amino acids from amino acid 270 to amino acid 290 of the A. visco sus sialidase sequence (SEQ ID NO: 12) and ends at any of the amino acids from amino acid 665 to amino acid 901 of said A. viscosus sialidase sequence (SEQ ID NO: 12), and lacks any A. viscosus sialidase protein sequence extending from amino acid 1 to amino acid 269. (As used herein “lacks any A. viscosus sialidase protein sequence extending from amino acid 1 to amino acid 269” means lacks any stretch of four or more consecutive amino acids as they appear in the designated protein or amino acid sequence.)
[0048] In some preferred embodiments, an A. viscosus sialidase catalytic domain protein comprises amino acids 274-681 of the A. viscosus sialidase sequence (SEQ ID NO: 12) and lacks other A. viscosus sialidase sequence. In some preferred embodiments, an A. viscosus sialidase catalytic domain protein comprises amino acids 274-666 of the A. viscosus sialidase sequence (SEQ ID NO: 12) and lacks any other A. viscosus sialidase sequence. In some preferred embodiments, an A. viscosus sialidase catalytic domain protein comprises amino acids 290-666 of the A. viscosus sialidase sequence (SEQ ID NO: 12) and lacks any other A. viscosus sialidase sequence. In yet other preferred embodiments, an A. viscosus sialidase catalytic domain protein comprises amino acids 290-681 of the A. viscosus sialidase sequence (SEQ ID NO: 12) and lacks any other A. viscosus sialidase sequence.
Linkers
[0049] A compound of the present disclosure can optionally include one or more linkers that can join domains of the compound. Linkers can be used to provide optimal spacing or folding of the domains of a compound. The domains of a compound joined by linkers can be sialidase domains, anchoring domains, or any other domains or moieties of the compound that provide additional functions such as enhancing compound stability, facilitating purification, etc. A linker used to join domains of compounds of the present disclosure can be a chemical linker or an amino acid or peptide linker. Where a compound comprises more than one linker, the linkers can be the same or different. Where a compound comprises more than one linker, the linkers can be of the same or different lengths.
[0050] Many chemical linkers of various compositions, polarity, reactivity, length, flexibility, and cleavability are known in the art of organic chemistry. Preferred linkers of the present disclosure include amino acid or peptide linkers. Peptide linkers are well known in the art. Preferably linkers are between one and one hundred amino acids in length, and more preferably between one and thirty amino acids in length, although length is not a limitation in the linkers of the compounds of the present disclosure. Preferably linkers comprise amino acid sequences that do not interfere with the conformation and activity of peptides or proteins encoded by monomers of the present disclosure. Some preferred linkers of the present disclosure are those that include the amino acid glycine. For example, linkers having the sequence: (GGGGS (SEQ ID NO:10))n, where n is a whole number between I and 20, or more preferably between I and 12, can be used to link domains of therapeutic compounds of the present disclosure.
[0051] The present disclosure also includes nucleic acid molecules that encode protein-based compounds of the present disclosure that comprise at least one sialidase domain and at least one anchoring domain. The nucleic acid molecules can have codons optimized for expression in particular cell types, such as, for example E. coli or human cells. The nucleic acid molecules or the present disclosure that encode protein-based compounds of the present disclosure that comprise at least one sialidase domain and at least one anchoring domain can also comprise other nucleic acid sequences, including but not limited to sequences that enhance gene expression. The nucleic acid molecules can be in vectors, such as but not limited to expression vectors.
Administration
[0052] The compound is administered so that it comes into contact with the target cells, but is preferably not administered systemically to the patient. Thus, a composition comprising a sialidase (e.g., a composition comprising DAS181) can be topically administered to the skin, e.g., the infected skin or the skin most frequently exposed to the sun. The composition can be administered by subdermal injection, or as a lotion or a transdermal patch to the infected skin The administration of the agent having sialidase activity causes one or more of: a decrease in malignant lesions on the skin, and a reduction of MCPyV viral load.
Nucleic Acid Molecules
[0053] The present disclosure also comprises nucleic acid molecules that encode protein-based compounds of the present disclosure that comprise a catalytic domain of a sialidase. The nucleic acid molecules can have codons optimized for expression in particular cell types, such as, for example E. coli or human cells. The nucleic acid molecules or the present disclosure that encode protein-based compounds of the present disclosure that comprise at least one catalytic domain of a sialidase can also comprise other nucleic acid sequences, including but not limited to sequences that enhance gene expression. The nucleic acid molecules can be in vectors, such as but not limited to expression vectors.
II. Pharmaceutical Compositions
[0054] The present disclosure includes compounds of the present disclosure formulated as pharmaceutical compositions. The pharmaceutical compositions comprise a pharmaceutically acceptable carrier prepared for storage and preferably subsequent administration, which have a pharmaceutically effective amount of the compound in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990)). Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid can be added as preservatives. In addition, antioxidants and suspending agents can be used.
[0055] The pharmaceutically effective amount of a test compound required as a dose will depend on the route of administration, the type of animal or patient being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. In practicing the methods of the present disclosure, the pharmaceutical compositions can be used alone or in combination with one another, or in combination with other therapeutic or diagnostic agents. These products can be utilized in vivo, preferably in a mammalian patient, preferably in a human, or in vitro. In employing them in vivo, the pharmaceutical compositions can be administered to the patient in a variety of ways, preferably topically to the target cells, topically to the locus of infection or topically to tissue comprising the target cells.
[0056] Accordingly, in some embodiments, the methods comprise administration of the agent and a pharmaceutically acceptable carrier. In some embodiments, the ophthalmic composition is a liquid composition, semi-solid composition, insert, film, microparticles or nanoparticles.
III. Method of Treating an Infection by a Pathogen
[0057] The method of the present disclosure includes: treating a subject that is infected with a pathogen or at risk of being infected with a pathogen with a pharmaceutical composition of the present disclosure that comprises a protein-based compound that comprises a sialidase activity. In some preferred embodiments the method includes applying a therapeutically effective amount of a pharmaceutical composition of the present disclosure to target cells of a subject. The sialidase activity can be an isolated naturally occurring sialidase protein, or a recombinant protein substantially homologous to at least a portion of a naturally occurring sialidase. A preferred pharmaceutical composition comprises a sialidase with substantial homology to the A. viscosus sialidase (SEQ ID NO:12). The subject to be treated can be an animal or human subject. In yet another aspect, the method includes: treating a subject that is infected with a pathogen with a pharmaceutical composition of the present disclosure that comprises a protein-based compound that comprises a sialidase catalytic domain. In some preferred embodiments, the method includes applying a therapeutically effective amount of a pharmaceutical composition of the present disclosure to epithelial cells of a subject. The sialidase catalytic domain is preferably substantially homologous to the catalytic domain of a naturally occurring sialidase. A preferred pharmaceutical composition comprises a sialidase catalytic domain with substantial homology to amino acids 274-666 the A. viscosus sialidase (SEQ ID NO: 12). The subject to be treated can be an animal or human subject. In some cases the compound is DAS181.
Dosage
[0058] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and type of patient being treated, the particular pharmaceutical composition employed, and the specific use for which the pharmaceutical composition is employed. The determination of effective dosage levels, that is the dose levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods as discussed above. In non-human animal studies, applications of the pharmaceutical compositions are commenced at higher dose levels, with the dosage being decreased until the desired effect is no longer achieved or adverse side effects are reduced or disappear. The dosage for a compound of the present disclosure can range broadly depending upon the desired affects, the therapeutic indication, route of administration and purity and activity of the compound. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the test compound. Typically, dosages can be between about 1 ng/kg and about 10 mg/kg, preferably between about 10 ng/kg and about 1 mg/kg, and more preferably between about 100 ng/kg and about 100 micrograms/kg.
[0059] In one preferred regimen, appropriate dosages are administered to each patient by subdermal injection, or as a lotion or a transdermal patch to the infected skin. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient maybe varied and will depend upon a variety of factors including the activity of the specific salt or other form employed, the metabolic stability and length of action of that compound, the age of the patient, body weight of the patient, general health of the patient, sex of the patient, diet of the patient, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
EXAMPLES
Example 1: Preparation of a Suspension of DAS181 Microparticles for use in Treating Infections
[0060] Purification of DAS181
[0000] DAS181 is a fusion protein containing the heparin (glycosaminoglycan, or GAG) binding domain from human amphiregulin fused via its N-terminus to the C-terminus of a catalytic domain of Actinomyces Viscosus (e.g., sequence of amino acids set forth in SEQ ID NO: 13 (no amino terminal methionine) and SEQ ID NO: 14 (including amino terminal methionine). The DAS 181 protein used in the examples below was purified as described in Malakhov et al., Antimicrob. Agents Chemother., 1470-1479 (2006), which is incorporated in its entirety by reference herein. Briefly, the DNA fragment coding for DAS181 was cloned into the plasmid vector pTrc99a (Pharmacia) under the control of an IPTG (isopropyl-β-D-thiogalactopyranoside)-inducible promoter. The resulting construct was expressed in the BL21 strain of Escherichia Coli ( E. Coli ). The E. coil cells expressing the DAS181 protein were washed by diafiltration in a fermentation harvest wash step using Toyopearl buffer 1, UFP-500-E55 hollow fiber cartridge (GE Healthcare) and a Watson-Marlow peristaltic pump. The recombinant DAS181 protein was then purified in bulk from the cells as described in US 20050004020 and US 20080075708, which are incorporated in their entirety by reference herein.
[0061] Activity of DAS181
[0000] The sialidase activity of DAS181 was measured using the fluorogenic substrate 4-methylumbelliferyl-N-acetyl-α-D-neuraminic acid (4-MU-NANA; Sigma). One unit of sialidase is defined as the amount of enzyme that releases 10 nmol of MU from 4-MU-NANA in 10 minutes at 37° C. (50 mM CH 3 COOH—NaOH buffer, pH 5.5) in a reaction that contains 20 nmol of 4-MU-NANA in a 0.2 ml volume (Potier et al., Anal. Biochem., 94:287-296, 1979). The specific activity of DAS 181 was determined to be 1,300 U/mg protein (0.77 μg DAS181 protein per unit of activity).
[0062] Microparticle Preparation
[0000] The following ingredients were then combined to form DAS181 microparticles in a large scale batch process:
[0063] (a) 75 mg/ml Histidine, 0.107M citric acid, pH 5.0 and 1M Trehalose stock solutions were sterile filtered into and combined in an Excipient Bottle.
[0064] (b) The contents of the Excipient Bottle were added, with mixing, to a Compounding Vessel containing 125 mg/ml DAS181 protein prepared as described in Example 1.
[0065] (c) Isopropanol was sterile filtered into an Isopropanol Bag
[0066] (d) The content of the Isopropanol Bag was pumped into the Compounding Vessel while mixing vigorously to form the Feedstock Solution. The final composition of the Feedstock Solution was as follows: 70 mg/ml DAS181, 26% isopropanol, 9.8 mg/ml histidine, 9.8 mg/ml trehalose, 2.69 mg/ml citric acid, pH 5.0. The time between initiating the addition of isopropanol and starting the lyophilization cycle was between 90 minutes and 120 minutes
[0067] (e) Stainless Steel trays that had undergone depyrogenation were each filled with 950 g of the Feedstock Solution, using a metering pump
[0068] (f) The filled Stainless Steel trays were subjected to a Lyophilization Cycle as follows:
a. the feedstock solution in the lyophilization trays were gasketed and placed in the lyophilizer shelves at 25° C. for 5 minutes; b. the temperature of the shelves was lowered to −55° C. at a ramp rate of −0.4° C./minute; c. the trays were held at −55° C. for between 60 and 180 minutes; d. primary drying was accomplished by setting the condenser to <−60° C., applying a vacuum of 125 mTorr with 250 mTorr dead band and increasing the temperature to −40° C. at a ramp rate of 0.125° C./minute and further to a temperature of −30° C. at 0.167° C./minute; e. the temperature was held at −30° C. for between 5000 and 6500 minutes; f. secondary drying was accomplished by increasing the temperature to 15° C. at a ramp rate of 0.5° C./minute, holding at 15° C. for 30 minutes, then further ramping up to a temperature of 30° C. at a ramp rate of 0.5° C./minute; g. the temperature was held at 30° C. for between 300 and 500 minutes; and h. the vacuum was released and the lyophilizer was backfilled with nitrogen to prevent oxidation of the microparticle formulations before transferring into bottles for bulk mixing and aliquoting the bulk powder for storage at ≦−15° C.
[0077] Physical Parameters:
[0000] The DAS181 dry powder microparticles prepared according to the above method have a mass median aerodynamic diameter (MMAD) of about 10 microns and a GSD of between 1 and 2.
Suspension of Microparticles
[0078] To prepare 1 ml of a 100 mg DAS181/ml suspension, 125 mg of microparticles prepared as described were placed in a vial in a controlled RH environment (typically 10-30% RH). Next, 450 μL of PEG 300 was added to the vial and gently mixed with the microparticles. The mixture was held for 5 minutes to allow the microparticles to interact with the PEG 300. Next, 450 μL of water is added to the vial and the contents are gently mixed for 2-3 minutes or until a homogeneous suspension is achieved.
Injectability was measured using a NE-1010 syringe pump with a DPM-3 digital mount meter attached to the plunger rail. Standard 1 mL BD syringes are used with 27 G×½ PrecisionGlide BD needles. Injectability values are reported in unit of lbs of force measured. Viscosity was measured using a Brookfield DV-1 Prime with a CPE-44PY cup and a CPE-40 cone spindle. Injection force of less than 50N is considered as injectable. The conversion unit of lbs to N is 1 lbs=4.4 N.
The above method produced suspensions with good injectability. Good results were obtained when the ratio of PEG 300 to water was: 50:50, 65:35 and 75:25. When PEG 200 was used, good results were obtained when the ratio of PEG 300 to water was 65:35 and 75:25.
In addition to polyethylene glycol (PEG 200, PEG 300, PEG 400, PEG 500, PEG 600), polysorbate 80, polysorbate 20 (Polyoxyethylene (20) sorbitan monooleate), propylene glycol, thioglycerol, tricaprylin, triolein, and versetamide are useful first media for adding to the protein microparticles.
The second media is water that can include salts, buffers, preservatives and other pharmaceutically acceptable excipients.
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BACKGROUND OF THE INVENTION
The present invention concerns a nutrient composition suitable for enteral feeding (tube feeding). The word "enteral feeding (tube feeding)" used herein means a kind of methods of so-called surgical nutrition used for nutritive care of patients before and after their surgical operation, and it is a method of injecting nutrients via a feeding tube into the gastrointestinal tract of a patient to whom oral feeding of the nutrients is impractical.
The nutrient composition for use in enteral feeding has been classified into elemental diet or chemically defined diet, synthetic low-residue diet and standard blenerized diet.
Elemental diet contains purified crystalline amino acids as the nitrogen source, and nutrient components such as essential fatty acids and vitamins are combined with them. Standard blenderized diet is prepared by combining milk or fruit juice with a fluidized mixture of various kinds of natural food. Synthetic low-residue diet has an intermediate composition of the above-mentioned two categories, and is in a powdery or a liquid state obtained by combining milk casein or egg-albumin as a protein source with fat source, carbohydrate source, inorganic salts and vitamins. It is used after dissolving into water or in an original liquid state.
The nutrient composition of the present invention belongs to the category of the above-mentioned synthetic low-residue diet.
Although various products have hitherto been commerciallized as the nutrient composition for use in enteral feeding, they have the following demerits: (1) they have many side effects causing diarrhea, abdominal pains, feeling of abdominal distension, etc., (2) they cause a raise of transaminase activity, however, only temporarily after administration, (3) their nitrogen balance is not favourable, (4) they taste bad and so are not suitable for oral administration, etc. Indeed, there are some compositions commerciallized with the intention of solving such demerits. For instance, the addition of lipids has been restricted to an extremely low level for control of diarrhea. However, in the case of insufficiency of nutrient supply as a result of aiming the prevention of side effects, such a composition lacks the aptitude as a nutrient.
It is for this reason that the nutrient composition suitable for enteral feeding without causing any side effects such as diarrhea, etc. and with a good taste, which can supply the necessary nutrients sufficiently, has not yet been developed.
On the other hand, the nutrient composition for enteral feeding is also used in the case where the patient is suffering from impairment of deglutition, impassableness through the digestive tracts, etc. in which case there is a necessity of early nutrient supplement after surgical operation, and it is further used in the case where the long term care should be taken on the patient's nutritive state. Accordingly, the provision of a nutrient composition without having the above-mentioned demerits has been strongly demanded.
For reference, the nutrient compositions for enteral feeding hitherto reported or commerciallized are exemplified as follows:
A composition is prepared by combining soy-bean, egg, skim milk, casein and essential amino acids as a protein source; vegetable fats and oils or medium chain triglyceride (MCT, powdery or liquid triglyceride of fatty acid of the medium chain length) as a fat source; and alpha-starch, bread and dextrin as a carbohydrate source, and after adding minerals and vitamins to the composition, it is made to be a liquid state with an addition of water ("SHOKUHIN KOGYO" (Food Industry), Vol. 22(12), page 41, 1979). A composition is prepared by combining skim milk powder, whole milk powder, dextrin, maltose, electrolytes and vitamin. Another composition is prepared by combining dextrin, starch syrup solid, medium chain triglycerides and natural foods. Still another composition is prepared by combining skim milk powder, tricaprylin, lactose and dextrin. (Refer to "RINSHO-EIYOGAKU (Clinical Science of Nutrition) by OKABE, Kazuhiko et al., page 90, published in 1979").
As a result of examination and studying the above-mentioned demerits seen in the publicly known nutrient composition for use in the above-mentioned enteral feeding, the present inventors have confirmed that these dermerits are caused by lactose which is contained in high amount (generally about 52 to 58% by weight) in the skim milk powder used generally as a protein source, the unbalance of amino acid within the protein source in the composition and the insufficiency of the fat content in the composition.
Further, it has been found by the present inventors that the lactose content in the nutrient composition could be reduced by combining 20 to 40% by weight of low-lactose skim milk powder containing a reduced amount of lactose which is obtained by decomposing 50 to 90% by weight of the originally contained lactose, as a kind of protein source and 5 to 15% by weight of medium chain triglyceride (MCT) as a kind of fat source, and that by doing so, the retention of the amino acid balance and the increase of fat content of the composition could be easily carried out by the combination of other protein sources and fat sources. The present invention is based on these findings.
The present invention will be explained in detail as follows:
DETAILED DESCRIPTION OF THE INVENTION
An object of the present invention is to provide a novel nutrient composition for use in enteral feeding, which has been accompanied by almost none of the demerits seen in the publicly known nutrient compositions for tube feeding, has an extremely low tendency of causing lactose intolerance and is capable to supply a high energy at a predetermined dose rate. The other objects of the present invention will be elucidated by the following description.
The characteristic feature of the present invention lies in a nutrient composition of a low-residue diet state containing a protein source, a fat source and a carbohydrate source as the base material, and having various trace nutrient components, in that the nutrient composition contains 20 to 40% by weight of skim milk powder which contains a reduced amount of lactose by decomposing 50 to 90% by weight of lactose as a kind of protein source and 5 to 15% by weight of medium chain triglyceride as a fat source.
The low-lactose skim milk powder which is one of the main components of the composition of the invention and in which the content of lactose has been reduced by decomposing 50 to 95% by weight of lactose, can be prepared by subjecting a mixture of skim milk powder and water to the action of lactose to decompose a part of lactose in the skim milk powder. It is necessary that the extent of decomposition of lactose in skim milk powder is controlled to be 50 to 90% by weight, preferably, 70 to 85% by weight. In the case of the extent of decomposition of larger than 95%, the lactose content in the composition becomes so small that the maintenance of the necessary amount of lactose in the human body necessary for absorption of calcium becomes impossible. On the other hand, in the case of the extent of decomposition of lactose of less than 50%, the lactose content of the composition becomes excess and causing diarrhea, abdominal pains and feeling of abdominal distension.
Medium chain triglyceride which is another main component of the composition of the present invention includes triglycerides of the fatty acids of 6 to 10 carbon atoms. Such triglyceride of the fatty acids of 6 to 10 carbon atoms shows the following specific properties as compared with triglycerides of the fatty acids of longer chain length of more than 12 carbon atoms: more rapid absorption in human body, no accumulation in the liver and reduction of cholesterol level in the body.
In addition, since the medium chain triglycerides can be easily mixed and emulsified with other fat sources such as vegetable oil such as corn oil, soybean oil, cotton-seed oil, safflower oil and sunflower oil or animal fats as milk fat or lard, it is possible to raise the fat content in the composition to the desired extent by combining the triglyceride with these fat sources.
The reason why the content of the skim milk powder which contains a reduced amount of lactose is defined in the range of 20 to 40% by weight in the composition is based on the easiness of retatining the amino acid balance in the composition by combining with other protein sources. As the protein sources used herein, milk casein and whole milk powder are suitable because of their good digestibility. In addition, purified crystalline essential amino acids may be combined with the composition, when necessary.
The reason why the content of the medium chain triglycerides (MCT) is defined to 5 to 15% by weight is to provide a nutrient composition with high calorie. In the case of the MCT content of less than 5% by weight, it is difficult to provide a nutrient composition with the desired high calorie even when other fat sources are combined, from the viewpoint of the absorption into the body, because the absorption of the fat sources other than the above-mentioned triglycerides are poorer. However, on the other hand, in the case of the content of larger than 15% by weight, the total content of fat source in the composition becomes in excess (more than 20% by weight) at the time when other fat source is combined for the supply of essential fatty acid such as linoleic acid. There is fear of causing diarrhea in the patient administered with such a composition.
Accordingly, it is necessary in the nutrient composition of the present invention to decide the combined amount of other fat source in connection with the content of the medium chain triglycerides.
Although in the composition of the present invention, both lactose remaining in the skim milk powder in which the content of lactose has been reduced and monosaccharides formed by the decomposition of lactose by lactase are present as carbohydrate, the amount of carbohydrate-supply due to them is insufficient and so it is necessary to combine separately another carbohydrate source with the composition.
The carbohydrate source used in the present invention includes various highly digestible carbohydrates, and since polysaccharide such as dextrin and starch syrup solid comprising water-soluble polysaccharides and dextrin restrain the raise of osmotic pressure of the composition of an aqueous solution type caused by the above-mentioned monosaccharides, they are preferable particularly. It is preferable to combine these carbohydrates in amount of 40 to 50% by weight of the nutrient composition.
In the present invention, in addition to the above-mentioned substances, inorganic salts, for instance, calcium salts, and iron salts and vitamins, for instance, vitamins A, B 1 , B 6 , C, D and E, nicotinamide, calcium pantothenate, folic acid, etc. as trace nutrient components may be added to the composition, and further, essential amino acids such as L-methionine, L-cystine and L-tryptophane may be added. Since in the composition of the present invention, essential amino acids derived from the above-mentioned protein sources are contained, in the time of adding the above-mentioned amino acids, it is preferable to control the amount of addition so that essential amino acid index (CAA index) becomes higher than 90. Further, as the above-mentioned inorganic salts, it is preferable to add in the form of calcium carbonate or iron and sodium succinate citrate. In addition, since the addition of other inorganic salts than calcium salt and iron salt raises the osmotic pressure of the composition of the present invention in the state of an aqueous solution, it is preferable to avoid such an addition.
Furthermore, since the nutrient composition of the present invention is applicable in oral feeding, components such as a fruit juice or flavor may be added.
In the case where the composition of the present invention is fed via a feeding tube to a patient who cannot orally ingest because of various impairments, the composition is mixed with water and the concentration of the composition in the aqueous mixture is adjusted to about 25% by weight so that the mixture can flow smoothly through a thin tube. In this case, since it is desirable that the above-mentioned mixture has an energy of a little higher than about 1 kcal/ml, the energy of the nutrient composition at a solid state is preferably made to be 400 to 500 kcal/100 g of the solid composition. Taking the nutritive balance into consideration, it is preferable that about 15 to 25 g of protein component, about 13 to 18 g of fat component containing about 4 to 6 g of oil as the source of essential fatty acid and about 40 to 65 g of carbohydrate component are contained in 100 g of the nutrient composition in a solid state. It is preferable that about 2.5 to 3.5 g of inorganic mineral component and suitable amounts of vitamins and amino acids are further contained in the composition. The above-mentioned formulation can be altered in meeting the requirement of the patient's body.
The important merits of the nutrient composition of the present invention over the commerciallized nutrient composition for enteral feeding are as follows:
(1) The composition of the present invention has very few side effects of causing diarrhea, abdominal pain and feeling of abdominal distention.
(2) A supply of the nutritive material of high contents of protein and fat can be prepared by the composition, and a high energy can be supplied by a single administration of a limited amount.
(3) The raise of transaminase activity by the administration of the composition of the present invention is a little, and the administration of the present composition does not exert any harmful influence on the hepatic function.
(4) On ingesting the present composition, nitrogen balance becomes positive from just after the surgical operation and the nutritive state of the patient becomes favourable.
(5) The absorption of calcium contained in the present composition is favourable and the occurrence of lactose-intorelance due to the administration of the present composition is very rare.
The constitution and the effects of the present invention will be concretely explained by the following examples of execution and test:
EXAMPLE 1
Preparation of the Skim Milk Powder Containing a Reduced Amount of Lactose
After introducing 900 liters of water and 100 kg of skim milk powder into a decomposing vessel of a capacity of 2000 liters and mixing the content uniformly by stirring, 400 g of lactase was further added to the mixture uniformly. Lactose in the skim milk powder was subjectd to decomposition by maintaining the temperature of the liquid mixture at about 7° C. About 200 liters of the specimen of the liquid mixture was collected three times, namely, after 7, 15 and 30 hours from the beginning of the decomposition, and each specimen was immediately spray-dried.
The extent of decomposition of lactose in each specimen was as follows:
______________________________________ Hours of Extent of decompositionSpecimen No. decomposition of lactose (%)______________________________________1 7 552 15 753 30 90______________________________________
EXAMPLE 2
Preparation of the Nutrient Composition of the Present Invention
An aqueous mixture amounting to 1000 kg was obtained by adding 584 kg of water to 62 kg of milk casein, 1.3 kg of sodium carbonate for dissolving milk casein, 273 kg of starch syrup solid, 61 kg of medium chain triglyceride corresponding to 10% by weight of the product, 19 kg of corn oil, 13 g of vitamin A and D oil (containing both 500,000 I.U. of vitamin A and 50,000 I.U. of vitamin D per gram) and 15 g of dl-alpha-tocopherol (vitamin E). The solid content of the mixture thus prepared was 40% by weight. After pasteurizing and homogenizing the mixture, it was spray-dried to obtain 320 kg of the primary powder.
In the next place, by powder-to-powder mixing of 65 kg of the primary powder, 28 kg of the specimen No. 2 obtained in Example 1 (skim milk powder in which lactose has been decomposed to the extent of 75% by weight) corresponding to 28% by weight of the product, 6 kg of whole milk powder, 150 g of L-methionine, 150 g of L-cystine, 60 g of L-tryptophan, 140 g of calcium carbonate, 50 g of iron and sodium succinate citrate, 0.5 g of vitamin B 1 , 1 g of vitamin B 6 , 10.2 g of vitamin C, 4.5 g of nicotinic acidamide, 3.4 g of calcium pantothenate and 90 mg of folic acid, a product of the present invention was obtained. The analysis of 100 g of the product thus obtained was as follows:
20 g of protein, 15 g of fat (consisting of 9.8 g of medium chain triglyceride, 3 g of corn oil and others), 59 g of carbohydrate, 3.2 g of ash (consisting of 440 mg of calcium, 5 mg of iron and others), 1000 I.U. of vitamin A, 0.5 mg of vitamin B 1 , 0.8 mg of vitamin B 2 , 1 mg of vitamin B 6 , 0.68 mg of vitamin B 12 , 10.2 mg of vitamin C, 100 I.U. of vitamin D, 3.4 I.U. of vitamin E, 4.5 mg of nicotinamide, 3.4 mg of calcium pantothenate and 90 micrograms of folic acid, the presence of vitamin B 2 and vitamin B 12 in the product being derived from raw materials.
The calorific value of this product was 444 Kcal/100 g.
EXAMPLE 3
Preparation of the Nutrient Composition of the Present Invention
Another primary powder was prepared by at first making 1000 kg of an aqueous mixture of a solid content of 40% by weight by adding 584 kg of water to 64 kg of milk casein, 1.3 kg of sodium carbonate for dissolving milk casein, 275 kg of starch syrup solid, 31 kg of medium chain triglyceride corresponding to 5% by weight of the product, 45 kg of corn oil, 13 g of vitamin A and D oil (containing both 500,000 I.U. of vitamin A and 50,000 I.U. of vitamin D per gram) and 16 g of dl-alpha-tocopherol. After pasteurizing and homogenizing, the aqueous mixture was spray-dried.
In the next step, powder-to-powder mixing was carried out on 66 kg of thus prepared primary powder, 25 kg of the specimen No. 1 obtained in Example 1 of the extent of decomposition of lactose of 55% by weight (corresponding to 25% by weight of the product), 8 kg of whole milk powder, 190 g of L-cystine, 190 g of L-methionine, 60 g of L-tryptophane, 220 g of calcium carbonate, 50 g of sodium-iron succinate-citrate, 0.5 g of vitamin B 1 , 1 g of vitamin B 6 , 10.2 g of vitamin C, 4.5 g of nicotinamide, 3.4 g of calcium pantothenate and 90 mg of folic acid to obtain 100 kg of a product.
EXAMPLE 4
Preparation of the Nutrient Composition of the Present Invention
In the first step, a primary powder was prepared by making 1000 kg of an aqueous mixture of a solid content of 40% by weight by adding 586 kg of water to 42 kg of milk casein, 800 g of sodium carbonate for dissolving milk casein, 273 kg of starch syrup solid, 76 kg of medium chain triglycerides (corresponding to 10% by weight of the product), 22 kg of corn oil, 13 g of vitamin A and D oil containing 500,000 I.U. of vitamin A and 50,000 I.U. of vitamin D per gram, and 15 g of dl-alpha-tocopherol. After pasteurizing and homogenizing, the aqueous mixture was spray-dried.
In the next step, powder-to-powder mixing was carried out on 56 kg of the thus prepared primary powder, 40 kg of the specimen No. 3 obtained in Example 1 of the extent of decomposition of lactose of 90% by weight (corresponding to 40% by weight of the product), 3 kg of whole milk powder, 190 g of L-cystine, 190 g of L-methionine, 60 g of tryptophan, 50 g of iron and sodium succinate citrate, 0.5 g of vitamin B 1 , 1 g of vitamin B 6 , 10.2 g of vitamin C, 4.5 g of nicotinamide, 3.4 g of calcium pantothenate and 90 mg of folic acid to obtain 100 kg of a product.
EXAMPLE OF CLINICAL TEST 1
On administering each 150 ml of a 25% by weight aqueous mixture of the nutrient composition obtained in Example 2 to each of 30 postoperative patients via a feeding tube, no abnormal findings were observed except one case of diarrhea. However, according to the results of the same kind of experiment while using a commerciallized product of the same kind, in 19 cases out of 30 total cases, abnormal findings such as diarrhea, abdominal pain and feeling of abdominal distention were observed.
From these results, it is understood that the nutrient composition of the present invention does not cause any conspicuous side effect and is excellent in effectiveness.
EXAMPLE OF CLINICAL TEST 2
The organoleptic tests were carried out on the 100 hospitalized patients capable of oral ingestion. The samples were orally administered as each 150 ml of both of the two aqueous 25% by weight mixture at 38° C. of the nutrient composition obtained in Example 2 and a commerciallized composition of the same kind. According to the tests, the numbers of the patients who evaluated each of the solutions as preferable was as follows on every item of the question:
______________________________________ Composition of present CommercializedItem invention composition______________________________________1. Easiness in drinking 81 192. Taste 86 143. Flavor 87 134. Mouth feel 78 225. Aftertaste 79 21______________________________________
According to the above-mentioned results, it is seen that the composition of the present invention is superior to the commerciallized composition in all the items of evaluation and is also suitable for oral administration.
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CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a U.S. National Phase Application pursuant to 35 U.S.C. §371 of International Application No. PCT/EP2013/057270 filed Apr. 8, 2013, which claims priority to European Patent Application No. 12163800.1 filed Apr. 11, 2012 and U.S. Provisional Patent Application No. 61/665,421, filed Jun. 28, 2012. The entire disclosure contents of these applications are herewith incorporated by reference into the present application.
TECHNICAL FIELD
The present invention is directed to a cartridge holder for a drug delivery device with snap fastening connection means to fasten the cartridge holder to a housing of the drug delivery device, wherein the fastening connection means are provided with at least one basically rectangular window for receiving a locking element of said housing. The invention further refers to a pen-type injector equipped with a respective snap fastening connection for the cartridge holder.
BACKGROUND
Such injectors are regularly used by persons who do not have formal medical training. Accordingly, the application comes along with circumstances that set a number of requirements for drug delivery devices of this kind. In case of improper use such as unauthorized disassembly actions there is the risk of contamination of the medicament stored in the cartridge. Also mechanical parts of the device could be damaged. Therefore, the device must be robust in construction in order to prevent fatal manipulation of the components. Especially with regard to the cartridge holder, which is connected to the housing of the drug delivery device, there is demand for a reliable connection easy to manufacture and to assemble but also safe regarding to any kind of manipulation.
US 2001/0034507 A1 discloses a cartridge holder in which a cartridge is accommodated, the cartridge holder being mechanically coupled to a sleeve-shaped mechanism holder by means of a bayonet lock. The cartridge holder shown in EP 1 855 743 B1 is provided with snap fastening connection means to couple a sleeve-like cartridge holder to a housing. The fastening connection means include a pair of apertures provided in the wall of the sleeve-like cartridge holder at a section facing the housing of the drug delivery device and for receiving a locking element of the housing. The apertures are formed as rectangular windows continuously reaching through the cartridge holder. However, rectangular windows generally have walls intersecting at an angle of 90°, which means they have acute-angled edges, respectively corners. In case of improper use or unauthorized disassembly efforts, e.g. by trying to pull or lever out the cartridge holder from the housing, mechanical pressures in the material, especially in the connection means area arise. As a result of the sharp edges and corners of the windows, notch effects occur that cause local stress concentrations in the corner area. Often, plastic materials are used for producing drug delivery devices. Especially at low temperatures, materials of this kind can tend to become brittle. In this case, the concentrated stress distribution in the corner area may result in tear or breakage of the window geometry and the material surrounding the window.
SUMMARY
It is an object of the present invention to conceive a suitable solution in terms of stress resistance, especially at low temperature conditions. This is obtained by a cartridge holder as defined in claim 1 and a drug delivery device as defined in claim 9 .
The present invention is based on the idea that each of the corners of the window is provided with a round contour. The round contour can come along with a curved shape of the intersection of two adjacent walls. Preferably, the round contour is designed as a clearance or recess in the material surrounding or being adjacent to the respective corners. In this respect it is not necessary that the whole clearance or recess is rounded, e.g. a circular clearance. Moreover, the clearance or recess may comprise at least one straight or rectangular section and at least one rounded section, e.g. a segment of a circle, ellipse or oval. Further, it is preferred to provide the rounded corners such that the rectangular opening area of the window is not affected or reduced, i.e. the rounded corners do not interfere in the region in which the snap protrusions (locking elements) of the housing engage.
The mechanical forces the connection means between cartridge holder and drug delivery device are subjected to and the flux of force in the area of the corners of the window is redirected more smoothly. Due to the geometry, notch effects are minimized. Especially at low temperatures, the geometry reduces critical stress peaks in the corner area as local stress is distributed over a greater range. The connection means benefit from a significant less breakage tendency and higher breakage strength. In the field of drug delivery devices, materials such as Bormed RF825MO have proved to be effective. In regard of the specifications emerging from the patient's use and material properties, all requirements concerning mechanical and thermal load capacities can be met by the specific window design.
According to a first embodiment of the present invention, the round contour may be formed into at least one of the corners of the window in a notch-like manner. The curved corner may for example be set back a distance with respect to the adjacent side walls of the window, respectively the basic rectangular shape of the window. A suitable locking element such as a bayonet locking element or a radially projecting tab-like element may preferably have a basically rectangular shape, too. A direct application of force into the corner area is avoided because the locking element is substantially supported by the side walls of the window and does not contact the corner area.
Preferably, the rounded notch extends in a circumferential direction and/or axial direction with respect to a longitudinal axis of the cartridge holder. The stress forces in the material are distributed over a large area thus reducing local stress peaks to a minimum.
Preferably, in each of the corners on one side of the basically rectangular window in a circumferential direction first notches are provided that extend in circumferential direction and in each of the corners on the opposite side of the window second notches are provided that extend in axial direction. The second notches can be provided such that one of the second notches extends towards a distal end of the device where a needle arrangement can be attached while the other of the second notches extends towards a proximal end of the device having actuating or comparable means to induce a force for discharging a medicament from the cartridge.
In another preferred embodiment of the invention, at least a portion of each of the first notches is formed as an extension of respectively one of two opposite sides of the window. Further, at least a portion of each of the second notches is formed as an extension of a third side of the window. By this arrangement, stress concentrations and local stress peaks are kept away from the corners in a very efficient way. Further, the extensions provide a large contact surface for the locking element received in the window. Forces transmitted through the locking element are mainly supported by the sides of the window while keeping the stress forces away from the corners.
In order to maintain a fixed position of the locking element in the window and to prevent unintended relative movement between locking element and window, e.g. due to manufacturing tolerances, the first notches may be arranged in such way that an intermediate section between the first notches constitutes a lug which is preferably resilient and which is adapted to exert a force toward the locking element. This embodiment also meets the requirements concerning an easy and convenient assembly. The basic dimensions of the window can be wider than the dimensions of the locking element thereby enabling an easy snapping action without any jamming effects. The lug is adapted to bias the locking element toward the side wall opposite to the lug. A reliable locking with a tight fit combined with a simple attachment of the cartridge holder to the housing is thus achieved. The lug can be arranged on either side of the window, exerting a force in proximal, distal or any other direction.
An absolutely firm seat of the locking element in the window can be achieved by adapting the dimensions of the basically rectangular shape of the window to receive the locking element which is associated with the housing in a tight manner. Even when high forces are applied to the connection between cartridge holder and housing, relative movement between those two elements is prevented by what impact loads and stresses in the connection are eliminated.
Preferably, according to a further embodiment of the invention, on at least a portion of the outer surface of the cartridge holder at least one axially elongated spline element, preferably integrally formed with a cartridge holder, is disposed which is adapted to engage a corresponding groove associated with or formed into the housing. For example, a multiplicity of parallel ribs that extend in the longitudinal direction of the cartridge holder can be spaced at regular or irregular intervals over the outer circumference of the cartridge holder. The ribs act as guidance means and facilitate the insertion of the cartridge holder into the housing. Further, they prevent relative rotational movement between the cartridge holder and the housing. In a further improvement of the invention, a plurality of spline elements is provided around the periphery of the cartridge holder distributed in such manner, that the cartridge holder can only be fastened to the drug delivery device when the cartridge holder and the drug delivery device are in a predetermined relative rotational position to each other. For this purpose, the plurality of spline elements is preferably distributed around the periphery of at least a section of the cartridge holder in a non rotationally symmetric manner. In this context, the arrangement of the spline element on the cartridge holder can serve as coding. The cartridge holder can only be connected to a housing with spline grooves, said spline grooves being arranged in a corresponding distribution which means both of the parts are encoded and the coding of each of the elements is compatible to the other. In regard of manufacturing issues, this feature ensures that only the dedicated cartridge holder is attached to the drug delivery device and that drug delivery device and cartridge holder are in the correct relative position to each other.
The object of the present invention is further achieved by a pen-type injector, having a housing and a cartridge holder for a cartridge containing a medical product such as a medicament, wherein the housing and the cartridge holder are held together by a snap fastening connection as described above. In particular, the advantages of the present invention make a positive difference when the pen-type injector is a disposable injection device. Such devices can be thrown away or recycled after the content of the medicament has been exhausted. Preferably, the snap fastening connection is designed such that the housing of the pen-type injector and the cartridge holder cannot be separated without causing damage and/or destroying same. The pen-type injector may be designed similar to that known from EP 1 603 610.
Tables 1 to 9 as illustrated in FIGS. 5-13 show in exemplary form the improved strength capacity and stress resistance of a drug delivery device that is provided with the connection means of invention, the window of the cartridge holder being referred to as clip window. The enhanced absorption of impact stresses acting on the drug delivery device at different locations, varied temperature conditions and under different preload condition is displayed in comparison to comparative examples that relate to drug delivery devices provided with regular connection means.
Tables 1 to 4 present impact test results at very low temperature conditions (2° Celsius) under different preload conditions with the impact forces applied directly onto the clip window (tables 1 and 2), respectively between clip windows (tables 3 and 4). In each series of testing, the new window design shows an improved absorbance of short-time stress peaks, while as to state-of-the-art designed windows a higher breakage tendency is indicated at the same time.
But not only at low temperature condition, where plastic materials are regularly more susceptible to breakage effect, also under normal, respectively room temperature conditions, drug delivery devices significantly benefit from the inventive window design. Especially when impact forces directly act onto the window, stress absorption is more efficient (tables 5 to 8). Hence, under all conditions, the present invention offers a reliable and resistant connection between cartridge holder and the injector.
As to the influence of the inventive connection means on manipulation safety, table 9 displays the result of a testing series representing an unauthorized disassembly action with 800 mm/min disassembly movement. Compared to state-of-the-art designs, the new window design results in significantly higher forces necessary to successfully manipulate the connection. Thus, under all conditions and manipulation actions, the connection means of the invention ensure a high degree of safety for a drug delivery device regarding to any kind of manipulation.
The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly- Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2, H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2, des Pro36 Exendin-4(1-39), des Pro36 [Asp28] Exendin-4(1-39), des Pro36 [IsoAsp28] Exendin-4(1-39), des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or des Pro36 [Asp28] Exendin-4(1-39), des Pro36 [IsoAsp28] Exendin-4(1-39), des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group-Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010), H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2, des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2, H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2, H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2, des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2, H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (C H ) and the variable region (V H ). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H-H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
BRIEF DESCRIPTION OF THE FIGURES
In the following, the invention will be described by a way of an example and with reference to the schematic drawings in which:
FIG. 1 shows a perspective view of a housing of a drug delivery device;
FIG. 2 shows a perspective view of a cartridge holder in accordance with a first embodiment of the present invention;
FIG. 3 shows a perspective view of the cartridge holder shown in FIG. 2 from the opposite direction;
FIG. 4 shows a side view of the connection section of the cartridge holder shown in FIGS. 2 and 3 .
FIGS. 5-12 shows Tables 1-8 listing impact test results; and
FIG. 13 shows Table 9 listing testing series representing an unauthorized disassembly action.
DETAILED DESCRIPTION
FIG. 1 shows a housing 1 of a drug delivery device for receiving a cartridge holder ( FIG. 2 ) containing a medicinal product for example a medicament such as insulin. The housing 1 is of sleeve-like shape. At the distal end 2 of the housing 1 a section 3 is formed as an opening to receive a cartridge holder and to be locked therewith. On the inner surface of the receiving section 3 of the housing 1 , a set of locking elements 4 is disposed projecting radially inwardly from the inner surface of the inner wall of the housing 1 and being basically of rectangular shape with a tapered or chamfered edge facing towards the distal end and the cartridge holder. In the inner wall, there is also formed a set of spline grooves 5 extending in longitudinal direction from the distal end 2 of the housing 1 in the opposite direction toward a proximal end.
The spline grooves 5 are arranged such as to establish a keyed connection with corresponding spline elements on the cartridge holder. The same applies to the locking elements 4 that are adapted to be received in respective receptacles in the cartridge holder.
FIG. 2 shows the cartridge holder 6 adapted to be connected with the housing 1 shown in FIG. 1 . The cartridge holder 6 has a proximal end 7 and a distal end 8 . The proximal end 7 is adapted to be connected to the receiving section 3 of the housing 1 shown in FIG. 1 . The cartridge holder 6 has an elongated tube-like shape, i.e. it is substantially designed as a cylindrical body for receiving a cartridge or an ampoule (not shown) and having a longitudinal axis 9 . At the distal end 8 of the cartridge holder 6 , there is a section onto which a needle arrangement can be mounted. For this purpose, the section is provided with a helical thread 10 arranged on the outside of the distal end section 8 . Other suitable attachment means could be used instead of or in addition to a thread.
On a substantially cylindrical section of the cartridge holder 6 , a continuous opening 11 extending an axial direction is formed into the cartridge holder. A similar opening is provided on the radially opposite side of the cartridge holder 6 , which can be best seen in FIG. 3 . The cartridge can be inserted into the cartridge holder 6 through its proximal end. For the patient's convenience and in regard to safety requirements, the filling level of the cartridge and other important information can be visually checked through the opening 11 . In addition or as an alternative to the openings 11 , the cartridge holder 6 may be made at least partly of a transparent or translucent material.
The cartridge holder 6 and the housing 1 can be connected by snap fastening connection means that fasten the cartridge holder 6 to the housing 1 . For this purpose, on its proximal end 7 , the cartridge holder 6 is provided with an insertion section 12 . The insertion section 12 is separated from the cylindrical section with the openings 11 by a collar 13 , the collar being formed on the outer circumference of the holder 6 and extending radially outwardly. The collar 13 is adapted to abut the distal end of housing 1 when the insertion section is inserted into the receiving section 3 of housing 1 .
On the outer surface of the insertion section 12 , four longitudinal spline elements or ribs 14 extending in axial direction from the proximal end 7 toward the collar 13 are disposed. The longitudinal ribs 14 are adapted to engage the spline grooves 5 formed in the receiving section 3 of housing 1 to establish a keyed connection in radial direction to prevent relative rotational movements between the housing 1 and the cartridge holder 6 but to allow relative axial movement e.g. for the assembly process. The insertion section 12 also has a number of irregularly spaced windows 15 close to the proximal end 7 . As the opening 11 , the windows 15 are continuous openings through which the inner section of the cartridge holder 6 can communicate with the outside.
An enlargement of section 12 is shown in a side view in FIG. 4 revealing the specific geometry of the windows 15 . The window 15 is basically of a rectangular shape as indicated by a broken line 16 . The basic shape of the window 15 conforms in its dimensions to the locking elements 4 which means that the locking elements 4 that are basically of an rectangular shape as well conform to the size of the rectangular shape in their dimensions. Given the basic rectangular shape 16 of the window 15 FIG. 4 shows that each of the four corners of the window 15 is provided with a round contour diverting from the basic rectangular shape 16 of the window 15 .
The round contour is formed into the corners in a notch-like manner, which means the round contour of the edge is set back a distance from respective edge of the basic rectangle. Accordingly, on one side of the window 15 in circumferential direction, there are first notches 17 a , 17 b formed into the window 15 . Opposite the first notches 17 a , 17 b , there are second notches 18 a , 18 b formed into the window 15 . A distal section of the first notch 17 a is an extension 19 a of a distal side 20 a of the rectangle 16 of the window 15 . One proximal section of the first notch 17 b is an extension 19 b of an opposite proximal side 20 b of the rectangle 16 of the window 15 . One section of each of the second notches 18 a , 18 b is formed as an extension 19 c of a third side 20 c of the window 15 .
The first notches 17 a , 17 b are substantially arranged in a parallel relationship so as to form an intermediate section in-between said section constituting a resilient lug 21 .
In order to connect and to fasten the cartridge holder 6 to the housing 1 , the cartridge holder 6 is inserted with its insertion section 12 into the receiving section 3 of the housing 1 . The longitudinal splines 14 engage with the spline grooves 5 of the receiving section 3 and the locking elements 4 are received in the window 15 . In the window 15 , the lug 21 exerts a force toward the locking element 4 with the tendency to bias the locking element 4 toward the third side 20 c of the window 15 thereby securing a firm seat of the locking element 4 in the window 15 . In case, an inexperienced user now tries to pull the cartridge holder 6 out of the housing 1 or accidentally buckles the cartridge holder relative to the housing 1 , the connection between the cartridge holder and the housing is loaded with mechanical forces. Due to the notches 17 a , 17 b , 18 a , 18 b and the way the locking element is received in the window, local stress peaks in the corners of the window 15 are avoided.
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CROSS REFERENCES TO RELATED APPLICATIONS
Not Applicable
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
Not Applicable
REFERENCE TO APPENDIX
Not Applicable
BACKGROUND OF THE INVENTION
Currently, when one desires to clean a bathroom, it is necessary to have multiple tools to reach the various regions of the room. In addition, when mopping the floor or cleaning the walls, the user often is required to use a separate sponge and bucket. When one wishes to clean the bathtub, one must operate on his knees with his back bent over. In all, cleaning a room, especially a bathroom, is not a comfortable or practical endeavor but very necessary.
A. Field of the Invention
The present invention relates to a device for cleaning. It further relates to a device for cleaning multiple regions of a room.
B. Prior Art
Prior art exists which aids in the act of cleaning regions of a room. An example of such prior art is Jurkanis U.S. Pat. No. 2,955,311. However, this prior art patent fails to perform the same function as the present invention. This prior art patent also does not have the same structure as the present invention.
Prior art also exists which relates to the simple cleaning of objects. Examples of such prior art are Vosbikian U.S. Pat. No. 5,454,659, Rothweiler U.S. Pat. No. 4,826,340, Richard U.S. Pat. No. 6,491,463, Smith U.S. Pat. No. D447,635, Kelly U.S. Pat. No. D384,436, Holberg U.S. Pat. No. 4,225,254, and Lynch U.S. Pat. No. D434,911. However, these prior art patents are dissimilar in structure in that they are generally smaller and handheld objects of a fixed design. The present invention rests on a fixed surface, such as a floor, and has swivel capabilities. In addition, the present invention utilizes separate tubes to transfer cleaning fluids from the handle to the cleaning device. The prior art patents do not have such a feature.
BRIEF SUMMARY OF THE INVENTION
The present invention is a cleaning tool that would be used to clean the bathtub, shower, walls, and surrounding area. It consists of a handle with several buttons which lead to a series of internal, refillable tubes to be filled with cleaning fluids. At the other end of the device is an interchangeable and detachable swivel sponge head. The sponge head receives the cleaning fluids through connection tubes. The fluid is released by the user pressing one of the buttons on the handle. This device will be large enough so that the user may stand in an erect position and clean the floor, similar to the method for using a mop. In addition, the device will be light enough to use when cleaning a wall. The sponge head will also swivel so as to allow the user to clean the interior of a bathtub.
It is an object of this device to create one tool to clean multiple areas of a room. It is a further object of this device to store and dispense cleaning fluids for the purpose of cleaning, if that is desired or necessary.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the device as it would look in use.
FIG. 2 is an isometric exploded view of the device.
FIG. 3 a is a view of the handle taken along line 3 — 3 on FIG. 1 showing the button on the handle not depressed.
FIG. 3 b is a view of the handle taken along line 3 — 3 on FIG. 1 showing the button on the handle depressed.
FIG. 4 is a view of the cleaning head taken along line 4 — 4 on FIG. 1 .
FIG. 5 is a view of the cleaning canister according to line 5 — 5 on FIG. 1 .
DETAILED DESCRIPTION OF THE EMBODIMENTS
DRAWING REFERENCE NUMERALS
5 Device
10 Sponge
12 Holes
14 Clasping Balls
15 Plate
20 Swivel Point
25 Arm
30 Hose
31 Opening to Tubes
32 Second Hose Barb
34 First Hose Barb
35 Activation buttons
36 Spring
37 Piston
40 Handle/Canister
41 Cleaning solution
42 Liquid cleaning fluid/cleaning canister
43 Cleaning solution
45 Cap
50 Tie
The present invention is a device 5 to be used as a replacement for a mop when cleaning a room, specifically a bathroom. At the bottom end of the device 5 will be a sponge 10 . FIG. 1 The sponge 10 will be removable and interchangeable. The sponge 10 will contain a central plate or piece with holes 12 and several clasping mechanism or clasping balls 14 . The sponge 10 will be attached to a solid and flat plate 15 . FIG. 2 The plate 15 will have several holes around its periphery and the clasping balls 14 will be securely inserted through these holes to lock the sponge in place. A swivel 20 will be attached to the center of the plate 15 on the side opposite the sponge 10 and allow the direction of the sponge to conform to the shape or contour of the surface to be cleaned. FIG. 1
Secured to and extending upwardly from the swivel 20 is an elongated arm 25 . This arm 25 will be rigid and provide support and shape to the device 5 . A pair of hoses 30 will extend alongside the arm 25 from the plate 15 . The hoses 30 will connect to the plate 15 on a first pair of hose barbs 34 . FIGS. 2 , 4 The hose barbs 34 are hollow and extend from one side of the plate 15 to the other. The hoses 30 will be secured to the arm 25 through the use of ties 50 . At the end of the arm 25 and hoses 30 on the opposite end of the device 5 will be a handle/cleaning canister 40 . The arm 25 will be securely attached to the front side of the handle/canister 40 . The handle/canister 40 will be hollow and will allow a cleaning fluid within the canister 40 and also act as a handle for the device. FIGS. 1 , 2
A second pair of hose barbs 32 will be stationed at and extend from the external side of the front of the handle/canister 40 to the interior side. The pair of hoses 30 will attach to the second pair of hose barbs 32 on the external side. On the top of the handle/canister 40 are a pair of activation buttons 35 . On the rear surface of the handle/canister 40 is one or more caps 45 . FIG. 2
Within the interior of the handle/canister 40 is the liquid cleaning fluid 42 . FIGS. 3 a , 3 b , 5 The pair of activation buttons 35 are connected to a piston 37 which sits on a spring 36 . FIGS. 3 a , 3 b An opening is provided in the piston 37 to allow cleaning fluid 42 to travel from the interior of the canister 40 to the second hose barb 34 through the opening 31 in the canister. FIG. 5 When one of the buttons 35 is depressed, the piston 37 pushes the spring 36 down and exposes the second hose barbs 32 to the cleaning fluid 42 such as depicted in FIG. 3 b . When the button 35 is released, the spring 36 pushes the piston 37 upward and closes the opening of the second hose barbs 32 thus preventing the flow of liquid cleaning fluid 42 into the hoses 30 such as depicted in FIG. 3 a . It is anticipated that the cleaning canister 40 will have two separate compartments in which to store two different cleaning solutions 41 , 43 if desired. FIG. 5 There are two separate canisters which are operated by two separate piston and spring arrangements. This will enable the user to put different kinds of cleaning solutions in the respective canister if so desired.
The cleaning fluid 42 is placed in the handle/canister 40 by removing the caps 45 . Once the handle/canister 40 is full, the cap 45 is replaced. The device 5 should be made of durable and lightweight material, such as plastic. The approximate size of the device 5 is a length of between three and four feet long.
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FIELD OF THE INVENTION
The present invention relates generally to the assessment of the responsiveness of a subject with lowered level of consciousness.
BACKGROUND OF THE INVENTION
Neuromonitoring is a subfield of clinical patient monitoring focused on measuring various aspects of brain function and on changes therein caused by drugs commonly used to induce and maintain anesthesia in an operation room or sedation in patients under critical or intensive care.
Electroencephalography (EEG) is a well-established method for assessing brain activity. When measurement electrodes are attached on the skin of the skull surface, the weak biopotential signals generated in the pyramid cells of the cortex may be recorded and analyzed. The EEG has been in wide use for decades in basic research of the neural systems of the brain as well as in the clinical diagnosis of various central nervous system diseases and disorders.
Electromyography (EMG) is a method for recording electrical biopotentials of muscles. In an EMG measurement, the electrodes are attached onto the surface of the skin overlying a muscle. When a biopotential signal is recorded from the forehead of a subject, the recorded signal indicates both the activity of the facial muscles (fEMG) and the brain (EEG).
One of the special applications of the EEG, which has received attention recently, is the use of a processed EEG signal for objective quantification of the amount and type of brain activity for the purpose of determining the level of consciousness of a patient. In its simplest form, the utilization of an EEG signal allows the automatic detection of the alertness of an individual, i.e. if he or she is awake or asleep. This has become an issue of increased interest, both scientifically and commercially, in the context of measuring the depth of unconsciousness induced by anesthesia during surgery.
Another important component of balanced anesthesia is analgesia, i.e. prevention of pain reactions of a patient by administration of pain medication. Adequate analgesia reduces surgical stress and there is firm evidence that it decreases postoperative morbidity. Awareness during surgery with insufficient analgesia may lead to a post-traumatic stress disorder. Low quality pre- and intra-operative analgesia makes it difficult to select the optimal pain management strategy later on. More specifically, it may cause exposure to unwanted side effects during the recovery from the surgery. If the anesthesia is too light and involves insufficient hypnosis, it may cause traumatic experiences both for the patient and for the anesthesia personnel. From an economical point of view, if the anesthesia is too deep, it may cause increased perioperative costs through extra use of drugs and time, and extend the time required for post-operative care.
Virtually every patient being cared for in an intensive care unit (ICU), for example, receives some form of sedation. However, the control of the depth of the sedation administered to a patient is still problematic, and therefore oversedation and undersedation are both common occurrences in intensive care units. At present, monitoring the level of sedation is mainly handled by using subjective observations from the patient. Various sedation assessment scales have been developed for subjectively assessing the level of sedation, the Ramsay Score being one of the most widely used tools for this purpose.
The depth of hypnosis is not directly measurable. Therefore, drug delivery systems have to derive the level of hypnosis from a surrogate signal or from indirectly measured parameters. The most common and popular surrogate signal for this purpose is the EEG, from which several parameters may be determined. The basic reason for the insufficiency of a single parameter is the variety of drugs and the complexity of the drug effects on the EEG signal in human brains. However, during the past few years, some commercial validated devices for measuring the level of consciousness and/or awareness in clinical set-up during anesthesia or sedation have become available. Such devices, which are based on a processed EEG signal and examine the signal as a whole with its multiple features, are marketed by GE Healthcare Finland Oy, Kuortaneenkatu 2, FIN-00510 Helsinki (Entropy Index) and by Aspect Medical Systems, Inc., 141 Needham Street, Newton, Mass. 02464, U.S.A. (Bispectral Index, BIS™).
In addition to the EEG signal data, EMG signal data obtained from facial muscles (fEMG) of the forehead is used for monitoring purposes during anesthesia and intensive care. Recovering facial muscle activity is often the first indicator of the patient approaching consciousness. When this muscle activity is sensed by electrodes placed appropriately, it provides an early indication that the patient is emerging from anesthesia. Similarly, these electrodes can sense pain reactions when the anesthesia is not adequate due to inadequate analgesia. So, the EMG signals give an early warning of the arousal of the patient, and they may also be indicative of inadequate analgesia.
Several factors affect the state of the central nervous system (CNS) of an ICU patient: sedative drugs, natural sleep cycles, and brain disorders all have their effect on the EEG signal. So far, no methods exist to distinguish these components from each other to provide a clinician an overall picture of the CNS state of the patient. The development of such a method is challenging due to the non-specificity of the EEG signal. A slow wave EEG pattern, for example, may be associated with a high level of a sedative, deep natural sleep, or a severe stage of encephalopathy. Correspondingly, low EEG entropy or BIS levels may be associated with any of these causes. Furthermore, natural variations of vigilance cause high fluctuations of entropy or BIS that tend to mask any underlying information of the sedative drug effect. Therefore, the above-mentioned devices for measuring the level of (un)consciousness and/or (un)awareness are not suitable for distinguishing the different causes giving rise to the level measured.
The clinician can distinguish between the different causes by including contextual information and by stimulating the patient. For example, if a patient with a slow wave EEG has not received substantial amounts of sedative drugs and has normally functioning liver/kidneys, he cannot be too deeply sedated. If the patient in such a situation anyway does not respond to a strong external stimulus, the clinician may conclude that the patient has developed a brain disorder. To estimate the sedative drug effect and particularly to avoid too deep levels of sedation, it is recommended that some kind of stimulus-response-based scoring is regularly performed by the nursing staff. Such scores are, however, often imprecise and subjective and do not provide continuous information. Furthermore, stimulus-response-based scoring is difficult to implement in automatic monitoring.
The present invention seeks to alleviate or eliminate the above-mentioned drawbacks.
SUMMARY OF THE INVENTION
The present invention seeks to provide a novel mechanism for estimating the responsiveness of a patient with lowered level of consciousness. The lowered level of consciousness is typically induced by one or more sedative drugs, but it may also be caused by a neurological disorder. The invention further seeks to provide a mechanism that provides an objective measure of the responsiveness to be obtained automatically and improves the specificity of the patient monitoring with respect to the underlying causes giving rise to a certain level of unconsciousness.
The idea of improving the specificity of the patient monitoring by monitoring naturally occurring arousal of a patient with lowered level of consciousness is based on two discoveries. First, in a clinical environment a patient is continually exposed to some sort of unintentional stimuli that may cause arousals of different magnitudes. Second, deepening sedation of the patient tends to suppress these naturally occurring arousals, while test persons in natural sleep remain relative responsive.
In the present invention, a measure indicative of the level of (un)consciousness of a patient is first determined. For this purpose, any measure suitable for quantifying the level of (un)consciousness may be used. The measure may also be an indirect measure of the level of (un)consciousness, such as a measure based on the EMG level, movements, or opening of the eyes of the patient. Based on a recorded time series of the first measure, a second measure is then derived, which is indicative of the responsiveness of the patient. The time series of the first measure is recorded without intentionally producing arousals in the patient, i.e. all arousals that may be seen in the first measure occur naturally without proactive actions of the clinical staff. The determination of the second measure may be continuous and independent of the occurrence of the stimuli causing the arousals or the said determination may be synchronized with the occurrence of the stimuli by monitoring when such stimuli occur in the clinical environment of the patient.
Thus one aspect of the invention is providing a method for measuring the responsiveness of a subject with lowered level of consciousness The method includes the steps of obtaining physiological signal data from a subject with lowered level of consciousness and deriving a first measure from the physiological signal data, the first measure being indicative of the level of consciousness of the subject. The method further includes the steps of recording a sequence of the first measure and determining, based on the sequence, a second measure indicative of a responsiveness of the subject, wherein the method is performed without inducing arousals in the subject.
Another aspect of the invention is that of providing an apparatus for measuring the responsiveness of a subject with lowered level of consciousness. The apparatus includes means for recording a sequence of a first measure, the first measure being indicative of the level of consciousness of the subject and first calculation means for determining, based on the sequence, a second measure indicative of the responsiveness of the subject, wherein the apparatus is devoid of any stimulation means for inducing arousals in the subject.
The apparatus of the invention may be implemented as a combinatory monitor indicating both the level of consciousness and the responsiveness of the patient or as a supplementary unit of a conventional patient monitor intended for measuring the level of consciousness.
The invention enables an objective and reliable measure of the responsiveness of a patient under sedation or suffering from a neurological disorder to be obtained without additional and proactive stimulation of the patient. Thus, the measurement does not interfere with the clinical procedures.
The implementation of the determination of the second measure may vary depending on whether or not the stimuli that may cause arousals in the patient are detected. If stimulus detection is not employed, it is preferable to monitor the first measure over a time period long with respect to the typical frequency of the unintentionally occurring arousals. However, if stimulus detection is used, the second measure may be defined faster, especially if the intensity of the stimulus causing the arousal is also measured. In an extreme case, this may allow the second measure to be defined based on one arousal only.
A further aspect of the invention is that of providing a computer program product by means of which known patient monitoring devices may be upgraded and thus their applicability extended. The program product includes-a first program code portion configured to record a sequence of a first measure, the first measure being indicative of the level of consciousness of the subject and a second program code portion configured to determine, based on the sequence, a second measure indicative of the responsiveness of the subject.
Other features and advantages of the invention will become apparent by reference to the following detailed description and accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
In the following, the invention and its preferred embodiments are described more closely with reference to the examples shown in FIG. 1 to 6 in the appended drawings, wherein:
FIG. 1 is a flow diagram illustrating one embodiment of the method of the invention;
FIG. 2 illustrates the calculation of the high-frequency EEG power change in the embodiment of FIG. 1 ;
FIG. 3 shows the responsiveness index as calculated with one embodiment of the invention as a function of the Ramsay Score;
FIG. 4 illustrates another embodiment of the invention;
FIG. 5 illustrates one embodiment of the apparatus/system according to the invention; and
FIG. 6 illustrates another embodiment of the apparatus/system of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention rests on the idea that in a clinical environment a patient is continually exposed to stimuli caused by various unintentional stimulation sources. Unintentional stimulation here refers to stimulation that occurs naturally without proactive actions whose only purpose is to generate stimulus-response pairs. As discussed in Freedman, N., et al., “Abnormal Sleep/Wake Cycles and the Effect of Environmental Noise on Sleep Disruption in the Intensive Care Unit”, Am. J. Respir Crit Care Med Vol 163:451-457, 2001, abrupt noise in an ICU environment causes sleep disruptions leading to arousals and awakenings. In an ICU environment, such unintentional stimuli may also be caused by various other sources external to the patient, such as lights, sounds, caregiving procedures, or the ventilation of the patient. An unintentional stimulus may also be internal, such as pain or anxiety.
In the present invention, a first measure indicative of the level of consciousness of the patient is determined. The time series of the first measure is examined to detect the raises or other changes caused by arousals resulting from unintentional stimuli. A second measure indicative of the responsiveness of the patient is then determined based on a selected sequence of the time series. The second measure may be calculated based on the frequency and/or intensity of at least one such change detected, and the number of data points in the sequence may vary depending on the implementation. The ability of the second measure to differentiate between natural sleep and unconsciousness induced by sedatives is based on the discovery that deepening sedation tends to suppress naturally occurring arousals, while test persons in natural sleep remain relative responsive. The invention therefore provides a selective mechanism for differentiating between sedation and natural sleep.
In one embodiment of the invention, the first measure represents high-frequency EEG power measured from the patient and the second measure is indicative of the occurrence of raises in the first measure. This embodiment is discussed in the following with reference to FIG. 1 , which represents the continuous state of the process, i.e. it is assumed that the process has already gathered enough signal data from the patient to be able to calculate the required values over the time windows used.
The EEG signal measured from a patient (step 11 ) is first digitized and the sampled EEG signal is filtered to exclude high- and low-frequency artifacts (step 12 ). As is common in the art, the digitized signal samples are processed as sets of sequential signal samples representing finite time blocks or time windows, commonly termed “epochs”. Based on the signal data, the process then calculates the current high-frequency EEG power at step 13 and stores the calculated value. The high-frequency EEG power is derived by calculating the power of the signal data in a frequency band comprising high-frequency EEG components. In this example, the said band extends from 20 Hz to 35 Hz and the length of the time window within which the power is determined corresponds to one epoch (5 seconds). The high-frequency EEG power may be derived from a power spectrum. The Fast Fourier Transform, for example, is a computationally effective algorithm for this purpose. Alternatively, the high-frequency EEG power may be calculated straight from the time-domain signal, by utilizing appropriate filters. A time series representing the first measure, which is the high-frequency EEG power in this case, is thus obtained from step 13 .
The process then determines a change variable indicative of the changes in the high-frequency EEG power. For this, the process first finds the minimum high-frequency EEG power defined within a preceding time window of a predetermined length (step 14 ). In this example, the length of the time window from which the minimum is searched is 1 minute. The change variable is then determined by subtracting the minimum value from the current value (step 15 ).
The values of the change variable obtained during another, longer time window are then used to obtain a final index indicative of the mean/cumulative high-frequency EEG power changes with respect to time (step 16 ). The said another time window is long with respect to the typical frequency of the unintentionally caused arousals of the patient. In this example, the final index is calculated over a time window of 30 minutes, i.e. the window extends 30 minutes backwards from the current moment. Nevertheless, steps 13 to 16 may be performed for each epoch.
The determination of the change variable is illustrated in FIG. 2 , in which curve 20 represents the power values obtained during the preceding time window from which the minimum is retrieved. If the current high-frequency EEG power determined at step 13 is Vc, for example, the value of the change variable corresponds to Vc−Vm. Since the absolute value of the change variable may be great, the usability of the variable may be enhanced by calculating the logarithm of the difference.
In the above embodiment, the responsiveness index R of the patient is thus determined according to equation (1) as follows:
R
(
t
)
=
1
T
2
∫
t
-
T
2
t
log
(
P
arousal
(
u
)
)
ⅆ
u
,
where
P
arousal
(
u
)
=
PEEG
(
u
)
-
min
(
u
-
T
1
)
≤
v
≤
u
PEEG
(
v
)
,
(
1
)
and where PEEG(ti) refers to high-frequency EEG power in a short time window ti computed over the frequency range of 20 Hz to 35 Hz. In the above example, the length of this time window corresponds to one epoch (5 seconds), while T 2 =30 minutes and T 1 =1 minute, as discussed above. However, the values may change.
Due to the above subtraction, the final index does not depend on the absolute level of the background high-frequency EEG. This is an important property as the absolute high-frequency EEG power level varies substantially between different patients. For the same reason, the index is robust against stationary artifacts, such as ECG or pacemaker artifacts. On the other hand, due to the long time window the index is also relatively robust against isolated transient artifacts, such as those occurring during care procedures. Low-frequency artifacts such as eye movements obviously do not affect the index either.
The particular embodiment disclosed above uses both the amplitude and the frequency of the arousals, but the implementation of the second measure may also be based on the frequency or the amplitude of the arousals only. Requirements for artifact detection procedures depend on the choice of the frequency range used. The second measure may also indicate the frequency or the total number of substantial changes occurred within a certain preceding time window, where substantial changes refer to changes exceeding a predetermined change limit.
FIG. 3 illustrates the responsiveness calculated in the above-described manner as a function of the responsiveness level assessed by a clinician using the Ramsay Score. The Ramsay Score includes six levels, and the value of the responsiveness that corresponds to each level represents the mean value of the patients of the level concerned. As can be seen from the figure, the calculated index conforms to the assessment of the clinician.
In the above embodiment, the values of the high-frequency EEG power are continuously examined to find the abrupt raises associated with the arousals of the patient. FIG. 4 illustrates another embodiment of the present invention, in which the determination of the responsiveness is synchronized with the natural stimuli that cause the arousals. Therefore, the first measure needs to be examined only when a stimulus occurs. In this embodiment, the first measure may be obtained as discussed above (steps 41 and 42 ). Concurrently, the clinical environment is monitored to detect the natural stimuli that may cause arousals of the patient (step 43 and 44 ). As noted above, the natural stimuli may be originated from various sources, and one or more such sources may be monitored at step 43 . For example, the noise level may be recorded through a microphone and/or the airway pressure of a ventilator may be monitored to detect patient/ventilator dyssynchrony. Furthermore, if a non-invasive blood pressure monitor is used, the cuff pressurization may be used as a standard disturbance that may cause an arousal of the patient.
When detecting a disturbance that may cause an arousal of the patient, a trigger message is supplied to an analysis process (step 44 /yes). The analysis process also receives the time series representing the first measure. The trigger message acts as a trigger notifying the analysis process of the occurrence of a stimulus, and the message may further include information about the type and/or magnitude (intensity) of the stimulus.
In response to the trigger message, the analysis process determines (step 45 ) the corresponding change in the first measure. The changes occurring within a certain time period may then be used to calculate the final index. For example, a variable indicative of the sum or mean of the changes occurring within the said time period may be calculated. The length of the period depends on the practical implementation; if the responses in the first measure are clear, the number of stimuli in the time window may be low. In an extreme case, the final index may be determined from a sequence of two measures obtained based on a single stimulus. The length of the period over which the final index is defined may thus be defined in time units or in the number of detected stimuli. If several stimulus sources are monitored, the changes caused by different sources may be weighted differently when calculating the final index.
As noted above, the EEG entropy may also be used instead of high-frequency EEG power as the first measure indicative of the level of consciousness of the patient. Instead of entropy, the evaluation of the level of consciousness may also be based on another parameter that characterizes the amount of disorder or irregularity in the EEG signal data measured from the patient. Other possible quantifications that may be used include fractal spectrum analysis, Lempel-Ziv complexity, or bispectral or multispectral analyses. A further parameter that may be employed as the first measure is the above-mentioned Bispectral Index, BIS™. The BIS involves the calculation of three parameters: Burst Suppression Ratio, Beta Ratio, and SynchFastSlow, and the resulting BIS value is a combination of the three parameters. The principles of the BIS algorithm are described in Ira J. Rampil, A Primer for EEG Signal Processing in Anesthesia , Anesthesiology, Vol. 89(4) October 1998, pp. 980-1002. If BIS is employed as the first measure, the present invention includes monitoring the BIS values and deriving a second measure, which is indicative of the magnitude and/or frequency of the BIS changes within a certain period. As discussed above, the second measure may indicate the mean or sum of the changes within a period of a predetermined length or the mean or sum of the changes within a period comprising a predetermined number of stimuli. The second measure may also be indicative of the rate of changes that exceed a certain limit value.
FIG. 5 illustrates one embodiment of the system or apparatus according to the invention. The physiological signal(s) obtained from one or more sensors attached to a patient 10 are supplied to an amplifier stage 51 , which amplifies the signal(s) before they are sampled and converted into digitized format in an A/D converter 52 . The digitized signals are supplied to a computer unit 53 which may comprise one or more processors. As noted above, the signal data measured from the patient is typically EEG signal data, which is measured through electrodes applied to the forehead of the patient. The electrodes also receive high-frequency EEG signal data from the patient.
The computer unit is provided with a memory or database 54 holding the digitized signal data obtained from the sensor(s). The memory or database may also store first and second calculation algorithms that the computer unit executes in order to obtain the first and second measures, respectively. The resulting index of responsiveness may be displayed on the screen of a monitor 56 . Although one computer unit or processor may perform the above steps, the processing of the data may also be distributed among different units/processors (servers) within a network, such as a hospital LAN (local area network). The apparatus of the invention may thus also be implemented as a distributed system.
If the index determination is synchronized with the occurrence of the stimuli, the apparatus/system is further provided with a detection system 58 for detecting the stimuli that may cause the arousals in the clinical environment. As discussed above, the detection system may detect one or more stimulus types, in which case it is provided with one or more detection interfaces for receiving signals indicative of the stimuli. For example, if audio stimuli occurring in the clinical environment are detected, the corresponding detection interface may be provided with a microphone M for measuring the noise level. Some of the detection interfaces may be connected to desired clinical equipment, such as to a ventilator for measuring the airway pressure for detecting patient/ventilator dyssynchrony or to a blood pressure cuff for detecting when the cuff is pressurized.
The computer unit may further act as a controlling entity controlling the administration of the drugs from the delivery system 57 to the patient. The computer unit may also supply the values of the responsiveness index to another computer unit or microprocessor (not shown), which then acts as the controlling entity controlling the drug delivery system. The said controlling entity may be provided with the control data needed for the administration, such as the pharmacodynamic and pharmacokinetic properties of the drugs to be administered. The drug delivery system may comprise separate delivery units for one or more drugs to be administered, such as a delivery unit for an analgesic drug and/or a delivery unit for a hypnotic drug.
The computer unit may also act as a decision-support tool for the physician, such as an anesthesiologist, who may control the operation of the drug delivery system through an appropriate user input device 55 , such as a keyboard or a bar code reader. Various parameters possibly needed in the calculation of the first and second measures may also be supplied through the input device, if the computer unit has no access to such data.
A conventional patient monitor intended for measuring the level of consciousness may also be upgraded to enable the monitor to determine the responsiveness index of the invention. Such an upgrade may be implemented by delivering to the patient monitor a plug-in software module that enables the device to calculate the responsiveness index based on the time series of the first measure defined in the device. The software module may be delivered, for example, on a data carrier, such as a CD or a memory card. As discussed above, the patient monitor may be an entropy-based monitor or a BIS monitor, for example. The plug-in software module has access to the time series of the entropic indicators or the BIS values, whereby it may calculate the responsiveness index in the above-described manner.
The software module may also comprise a new version of the software, which replaces the existing software of the patient monitor.
A responsiveness monitor of the invention may also be implemented as a separate module connectable to a conventional patient monitor intended for measuring the level of consciousness. As is shown in FIG. 6 , such a responsiveness monitor 60 may comprise a data processing unit 63 which receives the time series of the first measure from the conventional patient monitor and derives the second measure from the said time series. The responsiveness monitor may comprise a display of its own for displaying the calculated responsiveness index to the user, and it may optionally include the above-described detection system 58 .
Although the invention was described above with reference to the examples shown in the appended drawings, it is obvious that the invention is not limited to these, but may be modified by those skilled in the art without departing from the scope of the invention.
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BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The subject antidotal food product containing activated charcoal is generally directed to an antidotal substance to be administered to poisoning victims for decontamination of various poisonous substances that they may have ingested. More specifically, the antidotal food product containing activated charcoal is an orally administered antidotal substance having the visual appearance and physical properties to enable proper oral administration to even young children.
Poisonings by the ingestion of toxic substances have historically been and continue to be a significant problem today. With the ongoing proliferation of an expansive variety of commercially-available household products, access to a plethora of toxic substances just in the average home is currently at or near an all time high. While efforts in recent years, such as conspicuous labelling, tamper-proof sealing campaigns, and limiting the number of tablets in bottles of children's medicines as well as a concerted informational program appear to have been successful in preventing dramatic growths in the number of poisoning incidents that occur annually, significant numbers of poisoning incidents continue to occur, an overwhelming percentage of those incidents occurring at a residence, and the majority of the victims being young children. In 1993 alone, for instance, there were 1,751,476 human poisoning cases reported to recognized poison centers, over 90% of which occurred at a residence, according to the 1993 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Children under the age of six made up approximately 56% of the victims in these cases. Considering that only about 70% of the American population actually had access at the time to a poison center recognized in the study, the number of incidents that actually occurred in 1993 is likely to have been significantly higher than these numbers would indicate, with the total number of cases more realistically having been on the order of 2.5 million.
In the emergency treatment of poisoning victims, the effort centers around two main objectives: general support and stabilization of the victim, and decontamination of the victim. As decontamination and treatment must begin immediately in such toxicologic emergencies, often without the benefit of full and thorough clinical information on the patient, it is particularly important that any drug or therapeutic substance administered to the patient be substantially free of unwanted side effects that may cause unforeseen complications, or even death. For this reason, sorbents which, when introduced into the patient's gastro-intestinal tract, resist decomposition and adsorb the ingested toxins until eventual excretion by the patient have been employed for decontamination. Of those sorbents, activated charcoal has emerged in the field of emergency toxicological treatment as the decontaminant of choice. Its routine use in the treatment of poison victims did not become widespread until the 1980s; however, its administration to poisoning victims has now surpassed the administration of syrup of ipecac as the single most important toxicological treatment measure.
Activated charcoal is a fine, black, powdery substance which is tasteless, odorless, and non-toxic. Activated charcoal is generally formed by oxidation (activation) of combustion residue derived from a controlled combustion process performed on wood, peat, or another organic material. The oxidation and controlled combustion steps combine to yield a substance composed of extremely porous particles which give it extraordinarily high internal surface area, typically ranging between 900 and 2000 m 2 /g. Due to its extraordinary surface area, activated charcoal exhibits great adsorptivity and, thus, has proven to be quite effective as a decontaminant when introduced in sufficient quantities into the gastro-intestinal tract of a poisoning victim. The highly adsorptive activated carbon particles within the gastro-intestinal tract are capable of adsorbing toxin, not only from the contents of the gastro-intestinal tract but even from the blood stream (by "intestinal dialysis") through the blood vessels which supply the gastro-intestinal tract. These toxins, now bound to the activated charcoal, are excreted in the stool.
Activated charcoal is currently available in several forms to be orally administered to poisoning victims. In the most widely used form, activated charcoal is contained in a liquid suspension such as the commercially-available Actidose Aqua and Charcoaid 2000 suspensions. Activated charcoal is also available extensively in Europe, and to a more limited extent in the United States, simply in its powdered or granulated form for mixture within a drinkable liquid prior to ingestion. In yet another form, activated charcoal is contained in over-the-counter tablets or capsules widely available in Europe for the treatment of gas and upset stomach. Use of these tablets or capsules for decontamination in toxicological treatment, however, is not readily feasible. Even if all active ingredients other than activated charcoal were removed therefrom, the relatively high dosages required in most poisoning incidents would necessitate the ingestion of many such tablets or capsules, a daunting task even for the average adult, let alone for the average young child.
In whatever form activated charcoal is delivered to the gastro-intestinal tract, suspended in a liquid, compressed within a tablet or capsule, or simply in its raw powdery state, the activated charcoal is likely to have significantly beneficial, if not life-saving, effects on the poisoning victim - that is, if it can be properly delivered in the necessary quantities to the gastro-intestinal tract of that victim. Therein lies the single greatest obstacle to optimal utilization of activated charcoal as a decontaminant in toxological treatment. Each of the currently available forms in which activated charcoal is available for oral ingestion utterly fails to adequately induce or at least encourage proper ingestion of a sufficient dose of the activated charcoal by the victim. Essentially, except in the tablet or capsule form (which presents its own obstacles to ingestion), the antidotal substances are extremely unpalatable and, in fact, quite noxious. Liquid antidotal suspensions containing activated charcoal, for instance, form a black, gritty liquid bearing a striking resemblance to expended engine crankcase oil and lacks the pleasant taste which, theoretically, might cause the ingesting individual to even momentarily forget the unpleasant appearance, texture, and consistency of that which he or she is ingesting.
Whereas to a mature adult poisoning victim, the noxiousness of an activated charcoal-containing antidote may simply represent a trivial, though unpleasant, consequence that must be tolerated to avoid the far greater consequences of his or her serious predicament, it would hardly be such a trivial matter to a young child victim. To that young child or any other victim lacking the mental or emotional capacity to fully appreciate the magnitude of the situation and therefore incapable of seeing beyond the overbearing experience of ingesting the given antidote, the palatability of the antidote, both in appearance and taste, will not only determine how pleasant the ingestion experience is, but will actually determine whether or not that ingestion occurs in the first place. That might, in part, explain why with 1,751,476 reported poisoning incidents in 1993, activated charcoal was administered in that year to only 127,857 victims, despite the fact that the relatively risk-free benefits of activated charcoal and toxological treatment had been widely recognized by emergency care providers since well before 1993. Children, especially very young children, who represent the class of individuals most vulnerable to accidental poisonings and who, in fact, make up the majority of the victims in poisoning incidents, are loathe to ingest activated charcoal in the various forms in which it may currently be presented to them.
This fact is borne out by empirical studies performed on the subject, and by the first hand experiences of seasoned emergency health care professionals. For instance, in a 1987 study, Grbcich, et al., "Administration of Charcoal in the Home," Vet. Hum. Toxicology, 29, 458 (1987), the authors studied the cases of six children between the ages of one and five years who were given a liquid suspension containing 1 gm/kg of activated charcoal after they had accidentally ingested a toxic substance in amounts that did not necessitate hospitalized treatment. Of those children, none ingested the full amount of the suspension given to him or her, and only one ingested as much as half of the amount given. The authors observed that "all parents had considerable difficulty getting the child to drink the charcoal suspension,! and most indicated they would not choose this method of oral decontamination in the event of a future poisoning." The experiences in the emergency room have been, by and large, no different from the experiences of these parents, for most health care providers currently consider themselves extremely fortunate if they are able to coax, trick, or otherwise prompt a young child poisoning victim to ingest any amount of an activated charcoal antidote.
Faced with this obstacle, forced ingestion is not a viable option. Aside from its moral and legal implications, forced ingestion would pose a substantial collateral health risk. The direct health risks of activated charcoal therapy are nominal, if any, but one indirect risk, the serious occurrence of which has been reported in a few cases, is that of activated charcoal aspiration by the victim. While the risk of aspiration accompanies any oral ingestion of a substance, that risk is greatly amplified where ingestion of the substance is imposed upon a non-cooperative child who is instinctively resisting that ingestion. The risk becomes even greater where the ingestion is being forced by the child's parent, guardian, or any other individual having a personal relationship with the child, who might himself or herself understandably be in an excited, agitated, or even bewildered state given the exigencies surrounding a typical poisoning incident.
In cases where activated charcoal must be administered to an uncooperative patient, there is no choice but to introduce it through a nasogastric or orogastric tube. This procedure often requires physically restraining the patient. It also carries the risks of trauma to the mouth, pharynx, esophagus and stomach. Inadvertent placement into the tracheo-bronchial tree can result not only in trauma to these areas but in massive charcoal aspiration which can be fatal.
Efforts have been made to render the currently available forms of activated charcoal antidotes more palatable, but those efforts have at best yielded only antidotes that may be somewhat less noxious, but certainly not palatable, especially to young children. What is more, those efforts have often led to the introduction into the antidote of components which actually diminish the adsorptivity of the activated charcoal, thereby undermining the singular essential function of the antidote.
What is currently needed, therefore, is an antidotal product containing ample quantities of activated charcoal which is palatable to young children and in which the adsorptivity of the activated charcoal is not diminished in any substantial measure. It is absolutely essential that the antidotal product not only be palatable enough to entice the average young child to place it into his or her mouth, but that the product also be palatable enough to encourage the child to willingly swallow and continue to willingly swallow relatively large quantities thereof.
The antidotal food product containing activated charcoal of the present invention is an antidotal product which uniquely provides the necessary palatability not heretofore seen in prior art antidotes. In its preferred embodiment, the subject antidotal food product is in the form of a readily recognizable cookie sandwich having a pair of black wafers sandwiching a creamy filling. The subject antidotal food product in this form has the appearance, weight, and feel of very common and popular cookie treats. To the average young child, the subject antidotal food product is, thus, indistinguishable from the delectable cookie treats he or she is accustomed to eating.
The subject antidotal food product also incorporates a number of component compositions which give it a pleasant flavor and a texture not unlike that of the commonly-available cookie treats. Thus, a child would not only be enticed to place the subject antidotal food product into his or her mouth, he or she would actually be encouraged thereafter to chew and swallow the product. The pleasant taste would encourage the child to so ingest additional portions of the product if necessitated by the required activated charcoal dosage.
An important factor in the proper use of activated charcoal or any other decontaminant in toxological treatment is, in addition to its ingestion in sufficient doses by the victim, the promptness with which that ingestion occurs. Ideally, the activated charcoal ought to be administered at the site at which the poisoning incident occurs (which in most cases is the victim's home) immediately following the accidental ingestion, before the ingested toxins have had the opportunity to be extensively absorbed into the blood stream. Yet, most likely due to the difficulty of administering them arising from their unpalatability, currently available activated charcoal antidotes are almost exclusively administered in medical institutions, often many precious minutes, if not hours, after the accidental toxic ingestion has occurred. Given its inherent palatability, the subject antidotal food product, in contrast, could easily be administered in the home or any other setting outside a medical institution. Hence, the subject antidotal food product would not only expand the usage of activated charcoal as a decontaminant, it would actually enhance in a significant manner the effectiveness of that usage.
While the subject antidotal food product successfully incorporates with activated charcoal other component compositions which combine therewith to yield heretofore unsurpassed palatability without diminishing the decontaminating function of the activated charcoal; it must be recognized that due to the properties and characteristics of activated charcoal, developing the proper combinations was hardly a trivial task. One cannot simply blend a pleasant tasting composition with activated charcoal to form a useful antidotal product. Many substances will tend in varying degrees to bind with the activated charcoal particles and significantly diminish, even completely nullify, its adsorptivity. An end product would then result which is either devoid of a decontaminating capability, or which requires the ingestion of much too great a quantity to be of any practical use.
Realization of the unique combination of component compositions that essentially form the subject antidotal food product was the result of extensive testing and research. That testing and research is described in great detail in following paragraphs.
SUMMARY OF THE INVENTION
A primary object of the present invention is to provide an antidotal food product for decontaminating a user of a toxin ingested by him or her.
It is another object of the present invention to provide an antidotal food product which exhibits sufficient palatability to entice and encourage ingestion thereof even by young children.
It is another object of the present invention to provide an antidotal food product incorporating a substantial quantity of a sorbent composition for adsorbing toxins contained in and around the gastro-intestinal tract of the user.
It is another object of the present invention to provide an antidotal food product incorporating a substantial quantity of an activated charcoal composition.
It is another object of the present invention to provide an antidotal food product which contains a substantial quantity of an activated charcoal composition, yet exhibits the appearance, texture, and taste substantially similar to that of a cookie treat commonly consumed by children.
It is another object of the present invention to provide an antidotal food product which co-mingles with an activated carbon composition incorporated therein a flavoring composition which does not substantially diminish the adsorptivity of the activated charcoal composition.
It is yet another object of the present invention to provide an antidotal food product having a pair of wafer portions, each incorporating substantial quantities of an activated charcoal composition blended with a flavoring composition, and a flavored, creamy filling portion sandwiched therebetween.
It is another object of the present invention to provide an antidotal food product which may be conveniently stored and safely administered at a site outside a medical institution.
These and other objects are attained by the subject antidotal food product which is adapted for ingestion by a user for decontaminating that user of a toxin ingested by him or her, and which emulates in taste, texture, and appearance a readily identifiable food product. The antidotal food product includes a solid wafer portion having an outer contour substantially equivalent to that of the identifiable food product, the wafer portion being characterized by an outer texture and a friability that is also substantially equivalent to the outer texture and friability that characterize the identifiable food product. The wafer portion includes a sorbent composition having a predetermined adsorptivity for adsorbing the user-ingested toxin. The wafer portion also includes a flavored binding composition blended with the sorbent composition which adds to the antidote a flavor substantially equivalent to that of the identifiable food product. This flavoring composition is such that it mixes with the sorbent composition without substantially abating the sorbent composition's predetermined adsorptivity; thus, without interfering therewith.
In a preferred embodiment, the sorbent composition of the antidotal food product is an activated charcoal composition having an approximate internal surface area of 2,000 m 2 /g. The flavored binding composition in that preferred embodiment, includes a corn syrup solids component, a compressible sucrose component, a chocolate cream flavor component, a vanilla dry flavor component, and a sweetener component.
At least a pair of wafer portions are included in the preferred embodiment along with a flavored, creamy filling portion sandwiched therebetween to emulate a readily-identifiable cookie treat. The filling portion includes a powdered sugar component, a high fructose corn syrup component, a vanilla flavoring component, and a salt component.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graphical representation of adsorption kinetics test data for the preferred embodiment of the decontaminant food product of the present invention;
FIG. 2 is a graphical representation of equilibrium adsorption test data illustrating the interfering effects of a composition tested during development of the preferred embodiment of the subject decontaminant food product; and,
FIG. 3 is a block diagram illustrating the sequence of steps in the preferred method of forming the preferred embodiment of the subject decontaminant food product.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the preferred embodiment, the subject antidotal food product is provided generally in the form of a cookie sandwich treat commonly consumed by and quite popular with young children. It generally exhibits the appearance, the texture, the friability, and the sweet flavor which typically characterize such cookie sandwich treats. Accordingly, one antidotal food product formed in accordance with the overall invention concept as herein described may comprise a pair of biscuit-like wafers and a creamy, preferably white, filling sandwiched therebetween. The wafers may have a coloring resembling popular cookie or wafer like products commercially sold and easily identified by young children to obviously entice them to eat the antidotal food product of the subject invention. Each wafer includes activated charcoal, corn syrup solids, compressible sucrose, chocolate cream flavor, vanilla dry flavor, and sweetener in the approximate weight range proportions indicated in Table 1.
TABLE 1______________________________________ APPROXIMATE WEIGHT PREFERRED WEIGHTCOMPOSITION PERCENTAGE RANGE PERCENTAGE______________________________________Activated 20.0%-60.0% 40.0%CharcoalCorn Syrup 0.0%-78.0% 28.8%SolidsCompressible 0.0%-78.0% 28.8%SucroseChocolate 0.5%-2.0% 1.0%Cream FlavorVanilla Dry 0.5%-2.0% 1.0%FlavorAdditive 0.1%-1.0% 0.3%Sweetener______________________________________
Preferably, a pair of disk-shaped black wafers are formed in accordance with the proportions indicated in Table 1. The wafers exhibit a compressed granular texture and a degree of friability akin to that of a class of cookie treats quite popular with children. The degree of friability is such that the wafers are easily crumbled by the average biting force generated by even a very young child. The degree of friability is also such that the crumbled wafers may thereafter be effectively disintegrated by the subsequent chewing action generated by the given young child.
Subject to the allowable ranges of their component composition weight percentages, the wafers exhibit a degree of rich, sweet flavor to accompany their graham cracker-like crumbly texture. It is important that the sweet flavor of the wafers be sufficient to encourage substantial chewing prior to ingestion into the user's gastro-intestinal tract.
To enhance both the sweet flavor of the wafers, and to enhance the emulation of that readily identifiable class of cookie treats, a creamy white filling is sandwiched between a pair of wafers. The precise consistency, color, and taste of the filling is not important to the invention; however, it is preferable that the filling be of a consistency similar to that found in commonly-consumed cookie sandwich treats, that its color is not one that is non-existent in a commonly consumed cookie sandwich treat, and that its flavor exhibit a sufficient sweet component to supplement or augment the sweet flavor of the wafers. The component compositions and their corresponding proportional weights of one suitable filling composition exhibiting such attributes are indicated in Table 2.
TABLE 2______________________________________ APPROXIMATE WEIGHT PREFERRED WEIGHTCOMPOSITION PERCENTAGE RANGE PERCENTAGE______________________________________Powdered 70%-90% 76.34%SugarHigh Fructose 10%-30% 22.90%Corn SyrupVanilla 0%-2% 0.63%FlavorSalt 0%-1% 0.13%______________________________________
Turning now to each of the component compositions shown in Table 1 for each wafer, the preferred sorbent composition is activated charcoal, a black, powdery substance characterized by an extraordinary porosity which gives its particles a high internal surface area. A medicinal grade of this activated charcoal is commercially available from a limited number of manufacturers worldwide in forms respectively exhibiting various levels of internal surface area. One line of medicinal grade activated charcoals is manufactured by American Norit Company having designations A Supra, B Supra, and USP XXII, respectively with characteristic surface areas of 2,000, 1,400, and 900 m 2 /g. Medicinal grade activated charcoal characterized by even greater internal surface areas have been available in the past in the United States but are currently not available commercially. Any medicinal activated charcoal may be used in the subject composition. A Supra was chosen in the preferred embodiment since it represents the largest surface area charcoal currently commercially available in the United States. This may translate into a lesser quantity of charcoal product required.
Lab tests verify that activated charcoal of greater surface area exhibits greater adsorptivity per unit gram thereof. To the extent possible, therefore, it is preferable that activated charcoal of maximum surface area be incorporated into the subject wafer. This would not only tend to decrease the minimum weight percentage necessary in each wafer to enable the incorporation in greater proportional quantities of the other flavor-enhancing compositions, but would also quite simply lessen the dosage that must be ingested for decontamination of a given quantity of ingested toxin.
Referring to the other compositions accompanying activated charcoal in the subject wafer, several factors are of paramount importance in their selection. First, the accompanying compositions must provide for the otherwise tasteless, gritty activated charcoal, a friable, yet chewable texture and a pleasant degree of sweet flavor reminiscent of, if not identical to, a sweet cookie treat. The accompanying compositions must provide such attributes without substantially abating the adsorptivity of the activated charcoal; that is, without interfering therewith. As will be discussed in following paragraphs, that is no trivial matter, as a number of component compositions incorporated into early prototypes of the subject wafer were found to unexpectedly diminish in significant manner the overall adsorptivity of the activated charcoal. The component compositions shown in Table 1, when combined in the proportional quantities indicated, were found to reduce the overall adsorptivity of activated charcoal in its pure form by only approximately 6%. This was determined to be an acceptable tradeoff given the exceptional flavor, texture, and friability level attained in the wafer.
The corn syrup solids composition is a solid form of a corn or glucose syrup which is generally a mixture of D-glucose, maltose, and maltodextrins derived by hydrolysis of corn starch from the action of various acids and enzymes. The composition serves both as a sweetener and a binding agent for binding the activated charcoal particles together in a compressed solid. The particular type of corn syrup solids composition is not important to the present invention, and any one of various corn syrups commercially available may be utilized.
The compressible sucrose composition also serves both as a sweetener and a binding agent. It is preferably of the type commercially-available and known as Di-Pac. While it is not necessary to include both a compressible sucrose composition and a corn syrup solids composition, as indicated in Table 1, it was found that wafers incorporating only compressible sucrose as its binding agent exhibited an undesirably great degree of friability tending to crumble much too readily to retain the appearance and feel of a cookie or biscuit. Wafers incorporating only corn syrup solids as their binding agent were found to exhibit an undesirably low degree of friability, appearing to be much too hard to be comfortably chewed by young children. A mixture, however, in substantially equal amounts of the two compositions proved to exhibit a desirable level of both friability and taste. The resulting wafers incorporating substantially equal amounts of compressible sucrose and corn syrup solids compositions exhibited the richness in flavor characteristic of the compressible sucrose coupled with enough wafer cohesiveness to prevent premature crumbling at the wafer edges.
The remaining compositions in Table 1, namely the chocolate cream flavor, the vanilla dry flavor, and the additive sweetener, are commercially available flavor enhancers included to optimize the taste emulation of popular cookie products. Although the chocolate cream flavor, the vanilla dry flavor, and the additive sweetener are not therapeutically active, they do provide an important function of the overall antidotal food product in that their combined presence optimizes the probability that the young child will ingest the antidotal food product in emergency conditions and thereby allow the therapeutically active ingredients to take effect. Thus, such ingredients are important in the overall concept since they render the therapeutically active ingredients functional in a particular environment. Other suitable flavoring composition may be incorporated to serve this purpose; however, it is important to maintain the proportional quantities of such flavor enhancers at the low levels indicated in Table 1 to prevent the occurrence of unexpected levels of adsorptivity interference with respect to the activated charcoal. Accordingly, care must be taken not to introduce into the wafer in any amount a flavoring composition which, by its inherent properties, exhibits an inordinate tendency to interfere with activated charcoal adsorptivity. It was found in an early prototype of the subject wafer, for instance, that the incorporation of melted chocolate as a flavor enhancer caused a noticeable decrease in the activated charcoal's adsorptivity. This was likely due to the inherent tendency of the melted chocolate to adhere to the charcoal particles and plug their pores to thereby measurably reduce the available adsorption surface area.
Regarding the component compositions of the filling composition shown in Table 2, such is important in that they combine in the indicated proportions to form a sweet, creamy filling which complements the dry, somewhat diluted sweetness of the wafers, tending thereby to prompt the user to chew the wafers over a longer period of time. This increased chewing time is important, for the more the wafer is chewed, the more the activated charcoal is dispersed. Kinetics tests performed with various wafer prototypes, as discussed in following paragraphs, indicate that greater dispersement of the activated charcoal effects measurably faster rates of toxin adsorption.
Observations from numerous other tests indicate that the component compositions of the filling present no significant threat to adsorptivity of the activated charcoal contained in the wafers. Accordingly, the choice of component compositions and their respective weight percentages are important to the present invention to the extent that they affect the consistency, color, and taste of the resulting filling. The particular choice of component compositions and their corresponding weight percentages are determined primarily by these considerations. The component compositions shown in Table 2 are each devoid of a fat component, a feature desirable in light of interference tests. Interference tests for various component compositions indicate that fat-containing compositions observably interfere with the activated charcoal contained in the wafers.
Referring now to the tests performed for the subject decontaminant food product, extensive tests were performed on each of the more than forty prototypes developed in the process of realizing a workable decontaminant food product that overcomes the shortcomings of the prior art. Comparative kinetics tests to determine the rate at which a given prototype adsorbed a. toxin, equilibrium adsorption tests to determine the adsorption capacity of the given prototype, and, where necessary, interference tests to determine the degree by which isolated component compositions tend to diminish the adsorptivity of the activated charcoal in the given prototype were performed for each prototype under simulated conditions. The tested prototypes varied widely in their component compositions and the corresponding proportional quantities, and the most instructive of the test results obtained are discussed in following paragraphs.
All tests were conducted in vitro by mixing a predetermined amount of a test substance into a stock solution. The in vitro stock solution used in each test consisted of 1 g/L of sodium salicylate dissolved in a simulated gastric fluid solution containing 2.0 g/L of NaCl, 7.0 mL/L of 12 N strength concentrated HCl, and distilled water. The simulated gastric fluid was characterized in this form by a pH level of 1.2, the salicylate at this pH level being more than 99.99% in the form of undissociated salicylic acid, which is very similar in its properties to aspirin, or acetylsalicylic acid.
Equilibrium adsorption tests for determining the total amount of salicylate that a given test substance may potentially adsorb if allowed to attain equilibrium conditions was conducted with the following procedures. First, a predetermined amount of the substance to be tested was placed in a glass vial, and 20 mL of the stock solution was added to that vial. The vial was thereafter continuously shaken by placement on a shaking table for approximately 15 hours. This caused the test substance to fully disintegrate such that the activated charcoal contained therein attained virtually perfect adsorption equilibrium with the salicylate in the stock solution.
The kinetics tests were conducted generally by performing the following steps. Approximately 500 mL of the stock solution was poured into a one liter glass container. A predetermined quantity of the given test substance was then introduced into the solution in the glass container. The container was then placed on a shaking table and shaken thereby at a 60 cycles per minute oscillation frequency. Samples were taken at various times. Activated charcoal was filtered from each sample and the solution analyzed colorimetrically to determine the salicylate concentration corresponding to the given sample time.
Comparative kinetics test results for a cookie product formed by sandwiching a pair of wafers formulated in accordance with the preferred combination indicated in Table 1 sandwiched about a filling formulated in accordance with Table 2 are shown in FIG. 1. For this test, a cookie weighing 6.80 g (5.15 g wafers and 1.65 g filling) was chewed vigorously by the individual conducting the test, then introduced into a given volume of the stock solution. At 40% of the wafer weight, approximately 2.06 g of A Supra activated charcoal was thereby introduced into the solution. As shown by curve 10, the concentration of salicylate in the solution decreased from 1.0 g/L to under 0.2 g/L within 2.5 minutes after the cookie's introduction into the solution. After this dramatic initial decrease, the rate of salicylate concentration decrease gradually declined until equilibrium conditions were reached (not shown).
The superior adsorption performance of the subject decontaminant food product is apparent when curve 10 is compared with curve 20 plotting the decrease in salicylate concentration upon introduction therein of a commonly available prior art activated charcoal liquid suspension. Curve 20 was obtained by introducing 11 g of ACTIDOSE AQUA, a liquid suspension commercially marketed by Paddock Labs, Inc., Minneapolis, MN. That amount of ACTIDOSE AQUA was determined to contain approximately the equivalent amount of activated charcoal as contained in the cookie sample from which curve 10 was derived. Comparison of the two curves indicates that the cookie formed in accordance with the present invention not only reduced the salicylate concentration in the simulated gastric fluid solution at a significantly faster rate, but also yielded a significantly greater overall reduction in that concentration than a comparable amount of ACTIDOSE AQUA suspension. At the five minute point, for instance, the salicylate concentration, upon introduction of the subject cookie, was slightly below 0.1 g/L, whereas the salicylate concentration upon introduction of ACTIDOSE AQUA into the solution was observed to be slightly below 0.5 g/L at that time. After 30 minutes, the salicylate concentration had diminished to approximately 0.03 g/L with the subject cookie, whereas it had begun to level off at approximately 0.15 g/L with ACTIDOSE AQUA.
The degree of interference with the adsorptivity of the activated charcoal in the cookie sample corresponding to curve 10 may be determined by comparison with the adsorption performance of an appropriate quantity of the same activated charcoal alone. That adsorption performance is indicated by curve 30, derived by introducing into the stock solution approximately 2.0 g of pure A Supra activated charcoal powder. Comparison of curves 10 and 30 does indicate a measure of interference with the charcoal's adsorptivity; and, while the resolution of the curves in FIG. 1 is not sufficient to quantifiably represent that measure of interference, separately conducted equilibrium adsorption tests show that the interference is not at a significant level. Those equilibrium adsorption tests conducted with pure A Supra activated charcoal yielded an approximate 75% adsorption compared to the 68.5% adsorption obtained with a sample of the subject cookie. That equates to a reduction of approximately 6.5% in the resulting adsorption of salicylate. In light of the vital benefits derived from the enticing flavor and friability of the subject decontaminant food product, the cost in adsorptivity would be found by most toxicological treatment professionals to be quite insignificant.
The pleasant flavor introduced into each wafer by the additional component compositions not only encourage thorough and complete chewing which enhances the adsorption kinetics by dispersing the activated charcoal contained in the wafer, it also has a more direct effect on the charcoal dispersion. The pleasant flavor induces the user's salivary glands to produce more saliva than it would otherwise produce in the absence of such a pleasant flavor. The additional saliva, in turn, serves as a vehicle for more efficient dispersion of the charcoal particles.
Referring now back to Table 1, it is preferable that A Supra activated charcoal be incorporated into each wafer at a 40% weight percentage. A reduction in the weight percentage of A Supra activated charcoal leads to a corresponding reduction in the adsorptivity of the resulting cookie. This was borne out in equilibrium adsorption tests conducted with a 30 weight percent A Supra powdered wafer wherein adsorption values in the range of 61.1% to 64.9% were observed. In tests with a 20 weight percent A Supra powdered wafer sample, the range of adsorption values observed decreased to 44.9% to 46.3%.
An increase in the weight percentage of A Supra beyond 40%, while possible without excessively detrimental effects on the resulting wafer's flavor and friability, would nevertheless tend to reduce the wafer's palatability to younger children who are more inclined than older consumers to reject a food product for lack of sweetness.
Other than the activated charcoal component, the other primary components of each wafer, the corn syrup solids (CSS) and the DiPac compositions may be varied in their proportional quantities. Those two compositions combine to form the main components of the flavored binding composition, and variations in their relative proportional quantities in that binding composition notably affect the flavor and friability of the resulting wafer. As shown in Table 3, the relative proportions of the CSS and DiPac compositions, however, do not appear to affect the adsorptivity of the activated charcoal.
TABLE 3______________________________________RELATIVE PROPORTIONS PERCENT SALICYLATE ADSORBED______________________________________100% CSS, 0% DiPac 68.49%75% CSS, 25% DiPac 68.49%50% CSS 50% DiPac, 68.22%0% CSS, 100% DiPac 68.49%______________________________________
Comparative evaluation of the wafers resulting from each binding composition formulation shown in Table 3 indicates that the corn syrup solids component is a stronger binding agent than the DiPac component. Accordingly, a wafer incorporating the 100% CSS--0% DiPac formulation was more resistant to finger-abrasion than was a wafer incorporating the 75% CSS--25% DiPac formulation, which, in turn, was more resistant to finger abrasion than a wafer incorporating the 50% CSS--50% DiPac formulation, or one incorporating the 0% CSS--100% DiPac formulation. The resistance to abrasion of wafers incorporating the 50% CSS--50% DiPac and the 0% CSS--100% DiPac formulations were qualitatively, at least, indistinguishable.
Comparative flavor evaluation of wafers incorporating the formulations shown in Table 3 indicates that a wafer incorporating the 100% CSS--0% DiPac formulation had little, if any, sweet flavor. A wafer incorporating the 75% CSS--25% DiPac formulation had a mildly sweet, subtle chocolate flavor. A wafer incorporating the 50% CSS--50% DiPac formulation had a more defined sweet chocolate flavor, and a wafer incorporating 0% CSS--100% DiPac had an even more distinct sweet chocolate flavor. It is thus preferable for the optimal combination of friability level and flavor to incorporate into each wafer a 50% corn syrup solids--50% DiPac binding composition formulation.
The filling composition formulated in accordance with Table 2 offers a concentrated sugary flavor which supplements and augments the flavor of the wafers. Often, however, consumed cookie sandwich treats are consumed in parts by children who first disassemble the sandwich by separating at least one wafer from the filling, then proceed to consume the separated parts in sequence rather than in toto. It is, therefore, preferable that the wafers in and of themselves exhibit substantial flavor to be desirable to the average young child's palate separate and apart from any filling composition.
The combination of component compositions shown in Table 1 for each wafer of the subject decontaminant food product was obtained only after extensive testing of numerous formulations incorporating a wide variety of component compositions and in varying proportional quantities. One flavored binding agent considered in place of the corn syrup solids and DiPac compositions was a composition commercially marketed as Maltrin 700, a tabletting agent. Adsorbance tests conducted by combining the Maltrin 700 with a sample of A Supra activated charcoal, however, indicated that the Maltrin 700 significantly interferes with the adsorptivity of the activated charcoal. In those tests, 0.0203 g of A Supra activated charcoal was combined with 0.0779 g of Maltrin 700 and introduced into a predetermined volume of the stock solution. A separate 0.0203 g sample of A Supra activated charcoal was introduced into a second separate sample of the same stock solution. In a third separate sample of the stock solution, 0.0203 g of A Supra activated charcoal and 0.0779 g of Maltrin 700 combined and compressed into a tableted wafer form was introduced after the wafer had been sufficiently crushed. The comparative adsorption results obtained are shown in Table 4.
TABLE 4______________________________________ PERCENT SALICYLATE RELATIVETEST SUBSTANCE ADSORBED PERFORMANCE______________________________________Pure A Supra 58.24% 100.0%Activated CharcoalA Supra Activated 51.92% 89.1%Charcoal and Maltrin 700A Supra Activated 40.50% 69.5%Charcoal and Maltrin700 in Tableted WaferForm______________________________________
As the results in Table 4 show, Maltrin 700, when simply blended with A Supra powder interfered with the activated charcoal's adsorptivity by approximately 11%. More importantly, the Maltrin 700, when thoroughly blended and tightly compressed with the A Supra activated charcoal powder as it would be in the tableted wafer form of the subject decontaminant food product, interfered by more than an alarming 30%. Maltrin 700 was eliminated as a preferable component composition on this basis, as were numerous other possible compositions.
Among the many prototype wafer formulations tested was that for which the component compositions and their proportional quantities are shown in Table 5. Equilibrium adsorption tests conducted for this prototype wafer formulation yielded adsorptivity measures that were significantly less than expected. Interference tests were conducted for each of the components outside of activated charcoal to isolate the cause of the reduced adsorptivity. Those tests indicated that the reduction in adsorptivity was due primarily to the inordinate levels of interference attributable to the melted chocolate and the emulsifier composition used in the formulation commercially marketed as Dur-Lo.
For comparison purposes, prototype wafers were formulated, as shown respectively in Tables 6 and 7, first without the melted chocolate composition, then without either of the melted chocolate and the Dur-Lo emulsifier compositions. Equilibrium adsorption tests were then performed for each prototype formulation. The isotherms for these prototype wafer formulations (of Table 5, Table 6, and Table 7) are shown in FIG. 2 as curves 100, 110, and 120, respectively. The melted chocolate component in Table 5 was replaced for the Table 6 and 7 prototypes with a cocoa powder composition, as a chocolate flavor is a desirable characteristic of the resulting wafer, regardless of the formulation used.
TABLE 5______________________________________COMPONENT COMPOSITION QUANTITY (g)______________________________________Granulated Sugar 0.550Non-Fat Dry Milk 0.175Salt 0.050Baking Soda 0.075Monocalcium Phosphate 0.025Vanilla Flavor 0.100Sorbitol Liquid 2.600Glycerine 1.300Melted Chocolate 0.700Cake Flour 1.300Dur-Lo Emulsifier 0.400A Supra Activated Charcoal 2.025______________________________________
TABLE 6______________________________________COMPONENT COMPOSITION QUANTITY (g)______________________________________Granulated Sugar 0.550Non-Fat Dry Milk 0.175Salt 0.050Baking Soda 0.075Monocalcium Phosphate 0.025Vanilla Flavor 0.100Sorbitol Liquid 2.600Glycerine 1.300Brown Cocoa Powder 1.400Cake Flour 1.300Dur-Lo Emulsifier 0.400A Supra Activated Charcoal 2.025______________________________________
TABLE 7______________________________________COMPONENT COMPOSITION QUANTITY (g)______________________________________Granulated Sugar 0.550Non-Fat Dry Milk 0.175Salt 0.050Baking Soda 0.075Monocalcium Phosphate 0.025Vanilla Flavor 0.100Sorbitol Liquid 2.600Glycerine 1.300Brown Cocoa Powder 1.400Cake Flour 1.300A Supra Activated Charcoal 2.025______________________________________
Referring to FIG. 2, isotherm 110 (corresponding to Table 6) clearly shows that the absence of melted chocolate but with the use of Dur-Lo affords a significant increase in the adsorptivity observed when taken with respect to isotherm 100 (corresponding to Table 5). Isotherm 120 without Dur-Lo and melted chocolate shows, further, that the absence of both melted chocolate and the Dur-Lo emulsifier in the tested wafer affords an even greater increase in the observed adsorptivity over that of isotherm 100. It is not readily apparent why this marked increase in interference is attributable to the melted chocolate and Dur-Lo emulsifier compositions in such an inordinate measure relative to the levels of interference attributable to the other component compositions. Whatever the specific cause, it is likely that the unique physical properties of the melted chocolate and Dur-Lo components in some measure cause them to bind with the activated charcoal particles, filling many of the pores that otherwise would give each activated charcoal particle a greater internal surface area. The adsorptivity of the given activated charcoal particle is thus severely curtailed.
Referring now to FIG. 3, there is shown a preferred method for forming the decontaminant food product of the present invention, in its preferred cookie sandwich form. Appropriate quantities of the base wafer ingredients in the approximate weight percentage ranges of Table 1: activated charcoal 210, corn syrup solids 211, Di-Pac 212, chocolate cream flavor 213, vanilla dry flavor 214, and sweetener 215, are evenly blended at step 220 into a paste. As necessary, a limited quantity of water 216 is mixed into the paste to facilitate the malleability of the paste and thereby enhance the homogeneity obtained in the blend. After sufficient blending, the paste is allowed to dry at step 230, at room temperature approximating 70° F., for approximately 12 hours resulting in a dry paste composition. The dried paste 240 is then ground at step 250 in a Wiley mill, employing preferably a 20 or 40 mesh screen. The ground preparation is then compressed at step 260 in, preferably, a one inch punch and die assembly set to impart at least 15,000 psi compression pressure when a 1.0" diameter wafer is compressed and may be set at 40,000 psi compression pressure when a larger wafer in the order of 1.75" diameter is used. A plurality of wafers are formed by the aforementioned steps.
The wafer may then be sprayed with an anti-dusting spray film in step 262 in order to cover the activated charcoal particulates in order to minimize the smearing of the activated charcoal when being grasped by a user. The spray film is a sugar film formed of sucrose or dextrose or some like composition to form an encapsulation.
The filling is then prepared by mixing and evenly blending at step 280 appropriate quantities of powdered sugar 270, preferably having a 6X granularity, high fructose corn syrup 271, vanilla flavor 272, and salt 273. An appropriate quantity of the resulting creamy mixture is then placed between a pair of wafers to assemble at step 300 a cookie sandwich decontaminant food product.
Although this invention has been described in connection with specific forms and embodiment thereof, it will be appreciated that various modifications other than those discussed above may be resorted to without departing from the spirit or scope of the invention. For example, functionally equivalent elements may be substituted for those specifically shown and described, proportional quantities of the elements shown and described may be varied, and in the formation method steps described, particular steps may be reversed or interposed, all without departing from the spirit or scope of the invention as defined in the appended Claims.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to fitness machine technology, and more particularly to an incline angle adjustable stair climbing machine.
2. Description of the Related Art
Because modern people are busy with work and do not have much time to engage in outdoor sports and outdoor sport activities are susceptible to weather, in order not to be constrained by time and weather, office workers who love to exercise usually will prepare a fitness machine at home for use any time when desired to achieve the effect of fitness. In order to meet the needs of different users, various fitness machines with different functions are commercially available for selection, such as treadmills, steppers, elliptical machines, or stair climbing machines. In a stair climbing machine, the circulation of tread boards enables the user to simulate a stair climbing exercise, strengthening the muscle strength and improving the functions of the heart and the lungs. However, the climb gradient of regular stair climbing machines it normally fixed, not adjustable according to user training needs. Therefore, the fitness effect the user can get from a conventional stair climbing machine is very limited.
SUMMARY OF THE INVENTION
The present invention has been accomplished under the circumstances in view. It is the main object of the present invention to provide a stair climbing machine, which allows adjustment of the incline angle to change the climb gradient, satisfying different training needs.
To achieve this and other objects of the present invention, an incline angle adjustable stair climbing machine comprises a base frame, a tilting seat, a tilting seat adjuster, a staircase, and a tread board adjuster. The tilting seat has a rear end thereof pivotally connected to a rear end of the base frame. The tilting seat adjuster is mounted between an opposing front end of the base frame and an opposing front end of the tilting seat, and adapted for adjusting the incline angle of the tilting seat. The staircase is mounted at the tilting seat, comprising a plurality of tread boards biasable relative to the tilting seat. The tread board adjuster is mounted at the tilting seat and connected with the tread boards of the staircase, and adapted for adjusting the angle of each tread board relative to the tilting seat, maintaining each tread board constantly in horizontal. Thus, when using the incline angle adjustable stair climbing machine, operate the tilting seat adjuster to adjust the incline angle of the tilting seat and then operate the tread board adjuster to adjust the angle of each tread board, enabling the user to conduct stair-climbing exercises at different climb gradients accurately and comfortably.
Preferably, the incline angle adjustable stair climbing machine further comprises a handrail and a handrail adjuster. The handrail has a rear end thereof pivotally connected to the rear end of the base frame. The handrail adjuster is mounted between the front end of the tilting seat and an opposing front end of the handrail, and adapted to adjust the incline angle of the handrail, enabling the handrail to be synchronously adjusted with the tilting seat.
Preferably, the staircase further comprises a tread board adjustment frame. The tread board adjustment frame is vertically movably mounted at the tilting seat and connected with each tread board. The tread board adjuster is mounted between the tilting seat and the tread board adjustment frame for enabling the tread board adjuster to adjust the angle of each tread board via the tread board adjustment frame.
Other and further benefits, advantages and features of the present invention will be understood by reference to the following specification in conjunction with the accompanying drawings, in which like reference characters denote like elements of structure.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an oblique top elevational view of an incline angle adjustable stair climbing machine in accordance with the present invention.
FIG. 2 corresponds to FIG. 1 when viewed from another angle.
FIG. 3 is a side view of the incline angle adjustable stair climbing machine in accordance with the present invention.
FIG. 4 is an elevational view of a part of the present invention, illustrating the structure of the tread board adjuster.
FIG. 5 is a partial elevational view of the present invention, illustrating an operating status of the tread board adjuster.
FIG. 6 is an enlarged view of a part of the linkage of the incline angle adjustable stair climbing machine in accordance with the present invention.
FIG. 7 is a partial sectional view of the present invention, illustrating the structural relationship between the tread board, the tread board adjustment frame and the bracket.
FIG. 8 is similar to FIG. 6 , illustrating the linkages operated and the tread boards lifted.
FIG. 9 is similar to FIG. 3 , illustrating the incline angle of the stair climbing machine adjusted.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIGS. 1, 2 and 4 , a stair climbing machine 10 in accordance with the present invention is shown. The stair climbing machine 10 comprises a base frame 20 , a tilting seat 30 , a tilting seat adjuster 40 , a handrail 50 , a handrail adjuster 60 , a staircase 70 , and a tread board adjuster 80 .
The base frame 20 is adapted to be positioned on a floor to provide a supporting effect.
The tilting seat 30 has a rear end thereof pivotally connected to a rear end of the base frame 20 .
The tilting seat adjuster 40 comprises a first motor 41 , a first screw rod 42 , and a first sleeve 43 . The first motor 41 is pivotally mounted at an opposing front end of the tilting seat 30 . The first screw rod 42 has a top end thereof connected to the first motor 41 . The first sleeve 43 is threaded onto the first screw rod 42 with a bottom end thereof affixed to the base frame 20 . Thus, when the first motor 41 is started to rotate the first screw rod 42 clockwise or counter-clockwise, the first screw rod 42 causes the first motor 41 to move axially upward or downward along the first screw rod 42 , thereby turning the tilting seat 30 upward or downward relative to the base frame 20 .
The handrail 50 has a rear end thereof pivotally connected to an opposing rear end of the base frame 20 for holding by user's both hands.
The handrail adjuster 60 comprises a second motor 61 , a second screw rod 62 , and a second sleeve 63 . The second motor 61 is pivotally connected to an opposing front end of the handrail 50 . The second screw rod 62 has a top end thereof connected to the second motor 61 . The second sleeve 63 is threaded onto the second screw rod 62 with a bottom end thereof pivotally connected to the front end of the tilting seat 30 . Thus, as shown in FIG. 3 and FIG. 9 , when the second motor 61 is started to rotate the second screw rod 62 clockwise or counter-clockwise, the second screw rod 61 causes the second motor 61 to move axially upward or downward along the second screw rod 62 , thereby turning the handrail 50 upward or downward relative to the tilting seat 30 .
The staircase 70 comprises two opposing front chain wheels 72 , two opposing rear chain wheels 73 , two chains 74 , and a plurality of tread boards 75 that are arranged in a front-rear parallel manner. The two front chain wheels 72 are mounted at the front end of the tilting seat 30 in opposing left and right positions with a front wheel axle 722 . The two rear chain wheels 73 are mounted at the rear end of the tilting seat 30 in opposing left and right positions with a rear wheel axle 732 . Each chain 74 is mounted around one respective front chain wheel 72 and one respective rear chain wheel 73 at one same side, enabling the respective chain wheels 72 , 73 to be rotated synchronously. Each tread board 75 is pivotally connected between the two chains 74 with a respective tread board axle 752 so that each tread board 75 can be carried by the chains 74 to cycle, and can also be biased up and down relative to the tilting seat 30 . The staircase 70 further comprises a tread board adjustment frame 76 (see FIG. 7 ). The tread board adjustment frame 76 comprises two opposing side plates 77 , and two support rods 78 connected between the two side plates 77 . Each side plate 77 has an elongated slot 772 (see FIG. 2 ) located near a front end thereof for the passing of the front wheel axle 722 , and a rectangular hole 774 (see FIG. 1 ) located near an opposing rear end thereof for the passing of the rear wheel axle 732 . The elongated slot 772 is larger than the outer diameter of the front wheel axle 722 . The rectangular hole 774 is larger than the outer diameter of the rear wheel axle 732 . Thus, when the side plates 77 are driven by an external force, they can be moved alternatively up and down relative to the tilting seat 30 . As shown in FIG. 7 , each side plate 77 further has a guide groove 776 located at an inner wall thereof. Each tread board 75 is coupled between the guide grooves 776 of the two side plates 77 by a guide rod 754 . The guide rod 754 has two opposite ends thereof respectively mounted with a guide roller 756 that is rotatably coupled to the guide groove 776 of one respective side plate 77 to enhance tread board moving stability, allowing the respective tread board 75 to be moved synchronously with the tread board adjustment frame 76 .
Referring to FIGS. 4-8 , the tread board adjuster 80 comprises a third motor 81 , a third screw rod 82 , a third sleeve 79 , and an interlocking seat 83 . The third motor 81 is mounted at the tilting seat 30 . The third screw rod 82 has a front end thereof connected to the third motor 81 . The third sleeve 79 is threaded onto the third screw rod 82 with a bottom end thereof affixed to the interlocking seat 83 . Thus, when the third motor 81 is started to rotate the third screw rod 82 clockwise or counter-clockwise, the third sleeve 79 is caused by the third screw rod 82 to carry the interlocking seat 83 axially forwards or backwards along the third screw rod 82 . The tread board adjuster 80 further comprises two opposing linkages 84 . As illustrated in FIG. 4 , FIG. 6 and FIG. 8 , each linkage 84 comprises a front sliding rail 85 , a rear sliding rail 86 , a front sliding seat 87 , a rear sliding seat 88 , a bracket 89 , an upper sliding rail 90 , a lower sliding rail 91 , an upper sliding seat 92 , a lower sliding seat 93 , a first link 94 , and a second link 95 . The front sliding rail 85 is affixed to the tilting seat 30 . The rear sliding rail 86 is affixed to the tilting seat 30 opposite to the front sliding rail 85 . The front sliding seat 87 and the rear sliding seat 88 are respectively mounted on the front sliding rail 85 and the rear sliding rail 86 . The bracket 89 comprises a first prop rod 892 , and two second prop rods 894 arranged in parallel. The first prop rod 892 has opposing front and rear ends thereof respectively connected to the front sliding seat 87 and the rear sliding seat 88 . The second prop rods 894 have respective opposing front and rear ends thereof respectively connected to respective outer walls of the side plates 77 of the tread board adjustment frame 76 and the first prop rod 892 . The upper sliding rail 90 is affixed to a bottom side of the first prop rod 892 of the bracket 89 between the front sliding rail 85 and the rear sliding rail 86 . The lower sliding rail 91 is affixed to the tilting seat 30 to face toward the upper sliding rail 90 . The upper sliding seat 92 and the lower sliding seat 93 are respectively mounted at the upper sliding rail 90 and the lower sliding rail 91 . Further, the lower sliding seat 93 is connected to one end of the interlocking seat 83 (see FIG. 4 ). Thus, the lower sliding seat 93 can be carried to move by the interlocking seat 83 . The first link 94 has opposing top and bottom ends thereof respectively pivotally connected to the first prop rod 892 of the bracket 89 and the lower sliding seat 93 . The second link 95 has opposing top and bottom ends thereof respectively pivotally connected to the upper sliding seat 92 and the tilting seat 30 . Further, the first link 94 and the second link 95 are pivotally connected together in a crossed manner.
Based on the above-described structural composition, if the user wishes to adjust the climb gradient, start up the first motor 41 to rotate the first screw rod 42 , thereby biasing the tilting seat 30 relative to the base frame 20 . At this time, subject to angular position change of the tilting seat 30 , the climb gradient is relatively changed. After reached the desired angle, turn off the first motor 41 to keep the tilting seat 30 in the adjusted angular position, and the user can thus step on the tread boards 75 to perform stair-climbing exercises on the desired climb gradient.
Because the angular position of the tilting seat 30 can be changed relative to the base frame 20 , in order to let the user hold the handrail 50 with the two hands under the ergonomic posture during the process the user is stepping on the tread boards 75 , the second motor 61 can be started up to rotate the second screw rod 62 in biasing the handrail 50 relative to the tilting seat 30 to a suitable angular position. After the tilting seat 30 reaches the desired angular position, turn off the second motor 61 , keeping the handrail 50 in the optimal angular position suitable for holding by the user's both hands.
On the other hand, the tread boards 75 can be slightly tilted with the change of the tilting seat 30 in the incline angle. In order to let the tread boards 75 to be constantly maintained in horizontal for stepping by the user as the angle of the tilting seat 30 is changed, the third motor 81 can be started up to rotate the third screw rod 82 in moving the lower sliding seat 93 via the interlocking seat 83 . When the lower sliding seat 93 is moved, the first link 94 and the second link 95 are biased relative to each other to move the bracket 89 upwards. At this time, the bracket 89 moves the tread board adjustment frame 76 upwards relative to the tilting seat 30 subject to matching between the front sliding seat 87 and the front sliding rail 85 and matching between the rear sliding seat 88 and the rear sliding rail 86 . During movement of the tread board adjustment frame 76 , the slide plates 77 are forced to bias the tread boards 75 relative to the tilting seat 30 , enabling the tread boards 75 to be maintained in horizontal after change of the incline angle of the tilting seat 30 , and allowing the user to conduct a stepping exercise with less effort.
In order to let the stair climbing machine 10 to be operated efficiently and conveniently, the tilting seat adjuster 40 , the handrail adjuster 60 and the tread board adjuster 80 can be controlled to work synchronously through an electronic control measure so that when changing the incline angle of the tilting seat 30 , the tread boards 75 or the handrail 50 can be relatively biased to the optimal angular position suitable for exercise.
In conclusion, the stair climbing machine 10 of the invention uses the tilting seat adjuster 40 to adjust the incline angle of the tilting seat 30 and the tread board adjuster 80 to adjust the horizontal angle of the tread boards 75 , enabling the user to conduct stair-climbing exercises at different climb gradients accurately and comfortably. Further, the stair climbing machine 10 uses the handrail adjuster 60 to adjust the incline angle of the handrail 50 , or employs an electronic control measure to actuate the tilting seat adjuster 40 , the tread board adjuster 80 and the handrail adjuster 60 synchronously, enabling the user to get good support in the operation, and achieving the objects of the present invention.
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FIELD OF THE INVENTION
[0001] The present invention generally relates to a device and a method of use which includes insertion of the device into anatomical structures associated with blood circulation. In particular, the invention relates to myocardial revascularization by partial arterialization of structures associated with the coronary sinus.
BACKGROUND OF THE INVENTION
[0002] A consequence of coronary heart disease and the related narrowing or occlusion of coronary vessels is that coronary heart disease is a leading cause of death in industrialized countries. In fact, coronary heart disease is responsible for approximately 30% of deaths in these countries. In Germany, more than 340,000 persons die each year as a result of coronary heart disease. Aortocoronary bypass surgery is a conventional procedure for treating coronary heart disease, in particular if several coronary arteries are affected by the disease. Approximately 70,000 bypass operations are performed in Germany annually. About 60 per cent of the patients undergoing first-time bypass surgery are between 50 and 69 years of age.
[0003] As a general rule, aortocoronary bypass surgery is performed after opening the patient's thorax and connecting the patient to a heart-lung machine. Typically, the patient's heart is stopped during surgery for approximately 30 to 50 minutes once the principal artery has been clamped.
[0004] In spite of successful primary surgical treatment, coronary heart disease, in most cases, cannot be stopped and can spread even to the bypass graft. Typically, 30% of all bypasses are clogged again within 15 years after they were put in. This results in a second bypass being required in order to correct the clogged first bypass. This second bypass procedure includes a significantly increased surgical risk and a mortality rate of approximately 10%. The relatively high surgical risk associated with a secondary bypass surgical procedure is due to the following two factors: 1) possible lesion of the heart muscle or the larger vessels when the heart that is embedded in scar tissue is exposed, and 2) possible lesion of a still functional bypass during exposure of the heart, resulting in heart failure.
[0005] In addition, in the event of advanced coronary heart disease, it is possible that the path of the coronary vessels becomes altered to such an extent that it is impossible to sew a bypass to the coronary artery. Conventionally, there is not any established treatment for this group of patients. One attempted treatment is heart laser treatment, for example transynyocardial revescularization, for patients who could no longer be helped with conventional measures (bypass surgery), and is carried out only in exceptional cases. At the present time, there has been no evidence of any possible benefit for the patient.
[0006] In a study carried out at the Cleveland Clinic in 1999, the patient records of 500 angina pectoris patients who had undergone left heart catheter surgery during the three months of the study period were evaluated. Out of 500 patients, 59 (12 per cent) were not eligible for conventional treatment, i.e. bypass surgery (ACVB) or balloon dilatation (PTCA). Out of the 59, 21 received laser treatment. It is speculated that if the inclusion criteria for this study were expanded (patients with EF<25 per cent), the number of patients not eligible for treatment with traditional procedures would be greater.
[0007] Arterialization of heart veins was first described in 1948 by Beck as a possible treatment for patients who could no longer be treated with conventional surgery at the time. The principle was again taken up by Moll, who had already sutured a venous bypass on the coronary sinus. Surgery was performed using a heart lung machine. Consequently, the risks inherent in aortocoronary bypass surgery were not eliminated. Although Moll's initial description appeared to be promising, the technique was not widely accepted and was abandoned. The main argument against the technique described by Beck et al. was the development of a pronounced myocardial edema caused in Beck's technique by the total occlusion of the coronary sinus.
[0008] Presently, conventional application of this procedure involves advancing a tube into the coronary sinus and an end of the tube is anchored there. The free end of the tube is then drawn back through the right atrium. Following this, the free led out end of the conduit is connected with a central arterial blood supply. Thereby a blood flow is established from a central artery to the coronary sinus. This results in a blood flow whose direction is opposite that normally present in the coronary sinus.
[0009] However, for the conduit to fulfill its function, it is necessary to reliably anchor its distal end in a coronary vein. For this purpose one can use catheters of the type referred to in, for example, U.S. Pat. No. 6,406,491 B1. The catheter is inserted in the vein. Once it has reached its right position, the jacket is drawn back, thereby exposing the anchoring elements that anchor the distal end in the wall. The problem occurring in this case is that the anchor has to withstand the pulling force exerted when the jacket is drawn back. Occasionally, however, the sensitive vein is injured or the distal end of the conduit is torn from its anchoring place in the vein.
[0010] Catheters are known that comprise an actuator, a sheath and spreading elements, for example, U.S. Pat. No. 6,241,738 B1. However, these types of catheters are tools used for removing objects that have been inserted or are to be inserted in the vein. The spreading elements as taught and suggested by these catheters are not designed to engage the vein. In addition, those catheters are not conceived to remain in the body.
SUMMARY OF THE INVENTION
[0011] Briefly stated, a catheter according to the present invention in a preferred form can be inserted in the coronary sinus or vein on a previously introduced guiding wire as would be done using catheters known in the art. When the jacket is withdrawn in order to expose the anchoring element(s), the pusher keeps the distal end of the conduit in place, such that pulling forces acting on the anchor are reduced. The pusher can then be pulled out of the conduit. In addition, strong pulling forces are reduced or eliminated since the pusher can slide on a guiding wire and inside the conduit without much resistance through use of, for example, suitable surface coating(s).
[0012] The catheter also includes a conduit with at least one expandable anchoring element at its distal end for anchoring in the vessel wall and a jacket that is associated with the conduit and which can be at least partially retracted in a proximal direction once the conduit has been inserted into the coronary sinus. The retraction thereby releases the at least one anchoring element, so that it can, for example, expand.
[0013] The anchoring elements can incorporate elastic elements, for example, elastic hooks that engage with the wall of the coronary sinus or vein once the jacket is withdrawn. The hooks may extend distally and outward from the conduit such that repositioning is possible by pushing the jacket and pressing the hooks together, following which the catheter may then be pushed in further or pulled out. The hook may alternatively extend proximally and outward. In compensation, one obtains greater safety against unintentional withdrawal, since the hooks, in this case, claw more firmly into the wall of the coronary sinus.
[0014] The hooks may have a rounded front end such that damage to the coronary sinus is reduced or avoided. In addition the hooks may be provided on only one side of the circumference of the conduit. This way they can be well anchored in, for example, the myocardium, whereas the other side of the coronary sinus, that is very thin, is not damaged.
[0015] The anchoring element may also be configured as a spiral that expands once the jacket has been withdrawn.
[0016] The pusher element may be made of plastic or carbon-like material, in particular polytetrafluorethylene; this has the advantage of especially low friction forces. Another advantageous embodiment is characterized in that the pusher is made of metal, in particular a very flexible, thin-walled metal tube, for example, similar to a canulla tube.
[0017] An engagement surface, for example a bottleneck, may be formed as part of the conduit and utilized as the engagement surface. The bottleneck may also be in the shape of a headpiece that is placed on the distal end of the conduit. In both cases, the bottleneck and the distal end of the pusher may be advantageously provided with complementary coupling devices. These coupling devices, by turning the pusher, allow the pusher to be coupled with the engagement surface, so that the pusher can apply not only a distally directed force, but also a proximally directed force for repositioning the catheter. The rotating coupling devices may be, for example, threads or bayonet couplings. The coupling part of the pusher with the conduit and/or a headpiece of said conduit can also be, for example, a unilateral eccentric shape.
[0018] The conduit may associate tightly at its distal end against the wall of the vein, so that no blood may flow in the opposite direction. In other cases, the conduit may be configured attached, and/or positioned to allow at least a certain backflow of blood in the opposite direction. For example, the distal end of the conduit may be positioned such that it does not tightly engage against the wall of the coronary sinus.
[0019] An object of the present invention in a preferred form is to create a catheter that will reduced the risk of disengaging the anchoring and thereby damage the vein when the jacket is withdrawn.
[0020] Another object of the invention is to provide a conduit with an engagement surface proximate its distal end, and to provide the catheter with a pusher that can be pushed on a guiding wire, a front portion of the pusher engaging with the engagement surface.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Other objects and advantages of the invention will be evident to one of ordinary skill in the art from the following detailed description with reference to the accompanying drawings in which:
[0022] FIGS. 1A and 1B are respectively schematic representations of the anterior and the posterior of a heart with its relevant blood vessels;
[0023] FIG. 2 is a schematic representation of an inserted conduit in relation to anatomical features consistent with the present invention;
[0024] FIG. 3 is a transverse cross-section of a distal end area of a catheter that is inserted in a coronary sinus before the jacket is withdrawn consistent with the present invention;
[0025] FIG. 4 is a transverse cross-section of a distal end area of a catheter as shown in FIG. 3 after the jacket has been partially withdrawn for releasing the anchoring elements consistent with the present invention;
[0026] FIG. 5 is a transverse cross-section of a distal end area of a catheter, showing an alternative embodiment of the anchoring elements consistent with the present invention;
[0027] FIG. 6 is a cut away side view of a headpiece with anchoring elements consistent with the present invention;
[0028] FIG. 7 is a transverse cross-section of a distal end area of a catheter having an alternative anchoring element consistent with the present invention;
[0029] FIG. 8 is a cut away side view of a conduit with a narrowed distal end consistent with the present invention;
[0030] FIG. 9 is a cut away side view of a rotating coupling device, a pusher and a headpiece consistent with the present invention;
[0031] FIG. 10 is a transverse cross-section of the distal end of a conduit consistent with the present invention; and
[0032] FIGS. 11-12 show a transverse cross-section and side view respectively of an alternative of the bottleneck and/or the rotating coupling device consistent with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0033] For patients who can no longer be treated with conventional surgery techniques or for whom the risk involved in bypass surgery is extremely high, the invention in one embodiment includes a procedure of continuous retrograde coronary perfusion. In continuous retrograde coronary perfusion, excluding the use of a heart-lung machine, a small incision is made on the right side of the neck through which a catheter system is inserted in the cervical vein and advanced into the right atrium of the heart. The catheter system carries a conduit (plastic or autologous material) that is anchored in the coronary sinus by means of a special anchoring system. Following secure anchoring, the free end of the conduit is drawn back through the right atrium. Following this, the free led out end of the conduit is connected with the cervical artery that lies directly next to the cervical vein. Thereby blood flow is established from a central artery to the coronary sinus.
[0034] The present inventive surgical technique in one embodiment of the present invention provides partial arterialization of the coronary sinus. The conduit may be attached, for example, in or past the center third of the coronary sinus. This way, veinous inlets, for example, the V. interventricularis posterior (middle cardiac vein), the major vein draining blood from the right coronary vein and discharging only a few mm behind the ostium into the coronary sinus, remains open and continues to drain into the coronary sinus.
[0035] FIGS. 1A and 1B depict schematically a typical heart. From the aorta 1 , blood flows, among other routes, through an opening into the coronary vessels 3 , thereby supplying the heart muscles with among other things oxygenated blood. The blood flowing back from the heart muscle travels through the coronary vein 5 and various lateral branches 6 , into the coronary sinus 4 , and then into the right atrium 30 . In cases of advanced coronary heart disease or surgery for recurrence, the paths of the coronary vessels may be altered to such an extent that it is technically no longer possible to sew a bypass on the coronary vein 5 . For such patients it is possible to achieve revascularization of the coronary vessels by supplying the coronary vessels with arterial blood “from the rear”, i.e. via the coronary sinus. 4
[0036] This revascularization can be achieved, in one embodiment of the present invention, as shown in FIG. 2 , by a conduit 7 inserted through the ostium 32 of the coronary sinus 4 . The conduit 7 extends from the coronary sinus into a large central and peripheral artery 10 . For example, the cervical artery can be utilized. However, it should be understood that other arterial structures could be utilized. The conduit 7 passes through, for example, the right atrium and the superior vena cava 9 . The transition from venous to arterial vessel is a well known surgical practice and as such does not have to be dealt with in detail in the present disclosure. However, the conduit 7 must be anchored by the distal end 8 of the conduit 7 so as to secure it in position.
[0037] It should be noted that this anchoring of the conduit 7 may be a tight association, since other veinous inlets, for example, small veins 6 lead into the coronary sinus 4 , or may be of a less tight association, so as to maintain a certain backflow of venous blood.
[0038] The invention includes several types of distal end 8 attachments. For example, as shown in FIG. 3 , the distal end 8 of a conduit 7 is inserted in the coronary sinus 4 . For this insertion, a guide wire 11 had previously been inserted in the coronary sinus 4 . The conduit 7 is provided with a headpiece 12 at its distal end 8 . Anchoring elements 13 , for example, hook shaped anchoring elements, are provided on the outer circumference of the headpiece 12 . A pusher 15 bears on said headpiece 12 . The headpiece 12 may extend as far as the proximal end of the catheter. The pusher 15 , for example, exerts a counter force on the headpiece 12 when a jacket 14 associated with the anchoring elements 13 is withdrawn in order to release the anchoring elements 13 . This, among other things, prevents the distal end 8 of the conduit 7 from unintended withdrawal at the same time the jacket 14 is withdrawn. Unintended withdrawal of the anchoring elements 13 could, among other things, lead to the wall of the coronary sinus 4 being damaged and/or the distal end 8 being removed from its desired location. It should be noted that the conduit 7 may be anchored proximate to or in the vein 5 in embodiments of the present invention.
[0039] In one embodiment of the present invention, as is shown in FIG. 4 , the anchoring elements 13 have elastic properties such that they may spread apart through utilization of the elastic properties. Upon spreading out, the anchoring elements 13 associate with the wall of the coronary sinus 4 . In operation, for example, once the jacket 14 is proximally retracted far enough that the conduit is exposed, the pusher 15 may also be pulled out. By choosing suitable materials and/or surface treatments of the various elements, friction against the guide wire 11 and the conduit 7 can be sufficiently reduced. This can enhance the prevention of a damaging pull force being exerted on the anchoring elements 13 .
[0040] In one embodiment of the present invention, as shown in FIGS. 3 and 4 , the anchoring elements 13 spread apart in a substantially distal direction. This allows for the jacket 14 to be brought into association with the anchoring elements such that the anchoring elements 13 are compressed toward the headpiece 12 . This allows for the distal end 8 of the conduit 7 to be, for example, repositioned.
[0041] In one embodiment of the present invention, as shown in FIG. 5 , the anchoring elements 13 spread laterally in a substantially proximal direction. This proximal spreading, for example, provides a better hold which provides, among other things, greater resistance to withdrawal. The disadvantage of this backward spreading is, for example, that the anchoring elements 13 cannot generally be pressed together again by pushing the jacket 14 over them.
[0042] In one embodiment of the present invention, as shown in FIG. 6 , the ends 100 of the anchoring elements 13 are rounded so that, for example, the risk of damaging the wall of the coronary sinus 4 is lessened.
[0043] In one of the embodiment present invention, as shown in FIG. 7 , an anchoring element 13 positioned in the headpiece 12 is provided in the form of a spiral. In operation, wherein the jacket 14 is retracted in a proximal direction, the spiral formed anchoring element 13 a expands laterally outward from the headpiece 12 such that coils of the spiral formed anchoring element contact the adjacent coronary sinus 4 . Among other things, the spiral formed anchoring element 12 a distributes contact pressure along a length of the coronary sinus 4 via the coil contact points. This can reduce or eliminate damage to the coronary sinus 4 .
[0044] In one embodiment of the present invention, as shown in FIG. 8 , the distal end 8 of the conduit 7 includes a narrowed portion 17 against which the pusher 15 may come to bear. The narrowed portion 17 allows for, among other things, a positive control surface upon which the pusher 15 can engage and be disengaged from.
[0045] In one embodiment of the present invention, as shown in FIG. 9 , the device includes a rotating coupling device 16 which couples the pusher 15 to the headpiece 12 . The coupling device allows for an engagement of the pusher 15 and the headpiece 12 such that the pusher 15 can also exert a proximally directed force on the headpiece 12 . This rotating coupling 16 can include, for example, a thread or a bayonet coupling (shown in FIGS. 11 and 12 ). The pusher 15 and headpiece 12 may be disengaged by a selective rotation of the pusher 15 relative to the headpiece 12 .
[0046] In one embodiment of the present invention, as shown in FIG. 9 , the anchoring elements 13 may be arranged on selected portions of the headpiece 12 , for example, on substantially only one side of the headpiece 12 . This arrangement allows for the anchoring elements 13 to, for example, be anchored into the myocardium with the other side being proximate to delicate structures, such as thin coronary sinus or vein walls. This aids in reducing damage to the delicate structures which might otherwise occur if they were contacted by the anchoring elements 13 .
[0047] In one embodiment of the present invention, the distal end 8 of the conduit 7 is shown in FIG. 10 . The narrowed portion 17 a does not extend around the entire inner circumference of the conduit, but substantially consists of two stops against which the pusher 15 comes to bear. This way, the portion 17 a restricts the lumen 34 of the conduit 7 to a lesser degree which results in a lessened resistance to the blood flow entering the conduit.
[0048] In one embodiment of the present invention, as shown in FIG. 11 , the narrowed portion 17 b consists substantially of peg-like stops 16 of a bayonet coupling whose complementary recesses at the end of the pusher 15 are shown in FIG. 12 .
[0049] It should be understood that the following examples are included for purposes of illustration so that the invention may be more readily understood and are in no way intended to limit the scope of the invention unless otherwise specifically indicated.
[0000] Exemplary Experimental Procedures
[0050] Four experimental procedures were carried out in a manner consistent with the present invention. The experimental procedures were carried out using domestic pigs. Experimentally several pigs were obtained and anesthetized and monitored:
[0051] Five experiments were performed, three of which were successful (cf. below). In two animals the experiment had to be aborted. In both animals, coronary sinus perfusion was unable to sufficiently perfuse the myocardium following occlusion of the coronary arteries. Both animals died of acute heart pump failure shortly after extra-corporal circulation was stopped.
[0052] The detailed inspection of the coronary arteries and veins of the animals which died of heart pump failure showed that in both cases, the animals had an anomaly in their coronary veins. In either animal, only two coronary sinus ostia were identified in the atrium. The coronary veins of the R. interventricularis drained into one ostium, the vein of the A. circumflexa into the other. During the experiment, coronary perfusion occurred only through one ostium. This anomaly explains the failure of the experiments.
[0053] Subsequently 20 pig hearts were examined from butchered animals. All 20 pig hearts had a coronary sinus in atypical location into which drain all three major heart veins. One can assume that the anatomical variation of the coronary sinus discovered in the pilot test was an accidental result. Such variations have so far not been reported in humans.
[0054] The pilot tests showed that retrograde perfusion of the coronary veins alone, using arterialized blood is sufficient for adequate myocardial perfusion.
[0055] A phase 1 surgery was performed in order to create chronic ischemia. The Phase 1 surgery was performed by the surgical steps which included:
[0056] Placing a pig in lateral position; putting in an arterial pressure line in A. femoralis; putting in a venous shunt for flow-directed insertion of a pulmonary catheter; placing a Millar catheter; performing a lateral thoracotomy; exposing the RIVA immediately below bifurcation of a first diagonal branch; applying a circular stenosis of the coronary artery by means of a Dacron™ band wrapped around the vessel and sutured to itself so as to reduce the blood flow through the coronary artery by approximately 50% (controlled by flow measurement).
[0057] In addition, the following parameters were measured: RR interval (syst/mean/diast); ZVD; HF; Cl; HZV; PAP (syst/mean/diast); PCWP; PVR; SVR; and Blood gas analysis (lactate, pH).
[0058] Furthermore, laboratory chemical analyses were conducted which included testing LDH, HBDH, lactate, and Epicardial echocardiography were measured.
[0059] Next, injection of microspheres was carried out along with (Time 1) measuring with first color for initial reference value, 5 million (first color) in LA as bolus for 30 sec; reference sample from A. carotis: 5 sec. before start of bolus injection; aspiration for 90 sec., 7.5 mL/min.). Other tests included measuring (catecholamines, defibrillation, instability, etc.)
[0060] A Phase 2 surgery was subsequently performed in order to place a coronary sinus bypass. The Phase 2 surgery was performed by surgical steps which included:
[0061] Placing the pig in a supine position, putting arterial pressure line in A. femoralis; putting in a venous shunt for flow-directed insertion of a pulmonary catheter; placing a Millar catheter; performing a median sternotomy; creating a longitudinal opening of the pericardium; disposing a ligature on left side in permanent V. cava superior; administering systemic heparinization (ACT approximately 500 sec); connecting to a pig heart-lung machine (HLM) with canullation of A. ascendens and direct canullation of V. cava superior (SVC) and V. cava inferior (IVC); starting cardiopulmonary bypass (routine CPB priming with crystalloid solution); harnessing SVC and IVC; opening up right atrium in the beating heart; inserting a 5 mm PTFE tubular prosthesis about 3 to about 4 cm into the coronary sinus (a Palmas stent is attached to distal end of a prosthesis); attaching a prosthesis in coronary sinus following ballooning of stent with a balloon catheter; adjusting the length of tubular prosthesis, tangentially clamping A. descendens or Truncus brachiocephalicus; end-side anostomosing of the tubular prosthesis with A. ascendens or Truncus brachiocephalicus with a continuous suture; prosthesis initially remains clamped; suture closure of right atrium; opening coronary sinus bypass; and disconnecting HLM. The following parameters were measured: RR (syst/mean/diast); ZVD; HF; Cl; HZV; PAP (syst/mean/diast); PCWP; PVR; SVR; and Blood gas analysis (lactate, pH).
[0062] In addition, chemical analyses were carried out in the laboratory, for example, LDH, HBDH, lactate. Also measured was the flow in the coronary sinus bypass, Epicardial echocardiography results before and after placement of coronary sinus and bypass
[0063] There was an injection of microspheres, (Time 1) measuring with one color each time, 5 million in LA as bolus for 30 sec; reference sample from A. carotis: 5 sec. before start of bolus injection; aspiration for 90 sec., 7.5 mL/min.). In addition, the following time point actions were taken:
[0064] Time 2: myocardial perfusion only through native coronary system (coronary sinus open); Time 3: myocardial perfusion only through native coronary system after insertion of CS bypass in coronary sinus; Time 4: myocardial perfusion only through CS bypass after occulsion of native coronary arteries; and other (catecholamines, defibrillation, instability, etc.)
[0065] A Phase 3 surgery was subsequently carried out in order to access cadial function, analyze perfusion, and remove selected organs.
[0066] The phase 2 surgery was performed by surgical steps which included:
[0067] Placing the pig in a lateral position; putting in an arterial pressure line in the A. femoralis; putting in a venous shunt for flow-directed insertion of a pulmonary catheter; placing a Millar catheter; performing a median thoracotomy; creating a longitudinal opening in the pericardium; exposing the heart; measuring the following parameters: RR (syst/mean/diast), ZVD, HF, Cl, HZV, PAP (syst/mean/diast), PCWP, PVR, SVR, Blood gas analysis (lactate, pH).
[0068] In addition, chemical analyses in laboratory (LDH, HBDH, lactate); measuring flow in coronary sinus bypass; and Epicardial echocardiography.
[0069] An injection of microspheres was made, wherein at Time 1 a reference value was determined by measuring with one color, 5 million (fifth color) in LA as bolus for 30 sec; reference sample from A. carotis: 5 sec. before start of bolus injection; aspiration for 90 sec. 7.5 mL/min.)
[0070] The pig was then euthanized with a KCL infusion at end of test.
[0071] Removal of organs and sample storage/processing was then done as follows: Heart: analysis of microsperes; Lung; and Kidney.
[0072] In summer 2004, we carried out four pilot tests on pigs with partial arterialization of the coronary sinus were performed.
[0000] Additional Exemplary Experimental Procedures
[0073] Additional experimental procedures which included a longer follow-up period were performed on pigs. For this, the first step was to create chronic ischemia of the heart muscle by creating a severe stenosis of the R. interventricularis and R. circumflexus. The degree of stenosation of the coronary artery is measured by means of flow monitoring and angiography.
[0074] Subsequently, the animals were monitored for seven days. After seven days, the animals were operated on a second time. As described below, the coronary sinus bypass was then put in place by means of median sternotomy using the HLM. After weaning from HLM, function analyses was carried out on the still anesthesized animals (cf. below). Following this, the animals, after a monitoring period of four weeks, were again anesthesized for another series of measurements for cardiac function and perfusion. The animals were then euthanized for organ removal for pathological evaluation.
[0075] The additional exemplary experimentation was divided in three phases as follows:
[0076] A Phase 1 surgery wherein chronic myocardial ischemia was created. After surgery, the animals woke up and were monitored for seven days. The animals were given post-operative analgesics. In the further course of the test, the animals were monitored on a daily basis. In the event of severe cardiac complications or other life-threatening impairments, the animals were immediately euthanized by a veterinarian;
[0077] A Phase 2 surgery wherein after seven days, the animals were operated on once more with the coronary sinus bypass being put in place. While the animals were still under anesthesia, the necessary function analyses was performed. The animals were given post-operative analgesics. After this surgery, the animals were also checked up on daily; in the event of life-threatening impairments, the animals were euthanized by a veterinarian; and
[0078] A Phase 3 surgery wherein after a convalescence phase of four weeks, the third and last surgery was performed under anesthesia, also for performing function analyses. The animals were then euthanized. At the end of the examination, the animals did not awaken from the anesthesia; irreversible heart failure was induced by potassium injection.
[0079] It should be noted that the anatomy of the heart of the domestic pig is closest to that of humans. Findings from experiments on pig hearts can generally be transferred to clinical practice in humans.
[0080] The present animals test project was carried out on 20 domestic pigs of a size ranging from about 30 kg to about 40 kg.
[0081] Initially, the impact of the above-mentioned surgical procedure was to visually examine the open heart. Following a median sternotomy, the animals were hooked up to the HLM. Following an opening of the right atrium, a plastic conduit (5 mm tubular prosthesis) is inserted in the beating heart. The distal end of the conduit was attached in the coronary sinus with an anchoring element. The conduit was then led out of the atrium and anastomosed with the A. ascendens. The atrium is closed again. The permanent V. cava superior, located in pigs on the left, draining into the coronary sinus, is ligated. Once the blood flow is opened through the coronary sinus conduit, the left and right coronary veins are progressively closed by means of clips. Disconnection of HLM is made wherein there is a termination of extra-corporal circulation.
[0082] All surgical steps were carried out in sterile conditions. After a 12 hours without feeding, the animals were anesthesized with midolazam (Dormicum®) (intravenous infusion of 0.2 mg/kg/h), fentanyl (intravenous infusion of 5-10 μg/kg/h) and vecuronium (Norcuronh®) (intravenous infusion of 0.05-0.1 mg/kg/h) and endotracheally entubated. 10 mL/kg/h of Ringre's bicarbonate solution were infused as a basal volume substitution. The respiratory minute volume and respiratory frequency were set in such way that the arterial PO2 was between 90 mmHg and 110 mmHg and the arterial PO2 between 38 mmHg and 42 mmHg. During mechanical ventilation, a positive endexpiratory pressure (PEEP) of 5 mmHg was applied. When a CPB was put in, the lung was not ventilated, but PEEP of 5 mmHg was applied to prevent an alveolar collapse. During surgery, the animals were placed on a heating pad. Rectal temperature was maintained at between 36° C. and 37° C. During the entire surgery, arterial blood pressure (catheter in A. carotis), heart frequency, ECG, and blood gas parameter were continuously monitored. At the end of the experiments, the animals were euthanized by intravenous injection of potassium chloride (20 mmol/kg).
[0083] Phase 1 surgery wherein chronic ischemia was induced included the surgical steps of placing the pig in a lateral position; performing a lateral thoracotomy; exposing the R. interventricularis anterior immediately below the bifurcation of first diagonal branch; creating a circular stenosis of coronary artery by means of a Dacron™ band wrapped around the vessel and sutured to itself in order to reduce blood flow by approximately 50% (controlled by flow measurement).
[0084] It should be noted that in order to evaluate changes in contractility and hemodynamics prior to and after stenosation of the coronary artery, the following parameters were determined in each anesthesized animal in each case prior to and after surgery:
1) Laboratory analyses (LDH, HBDH, lactate) 2) Hemodynamics: Measurement of contractility by means of impedance and Millar catheter Pulmonary catheter for determining heart-time volume, cardiac index, peripheral and pulmonary vessel resistance Epicardial echocardiography 3) Microspheres, Time 1: measuring with one color as initial reference value.
[0091] This data served as process parameters for cardiac function for subsequent surgery.
[0092] Phase 2 surgery wherein a coronary sinus bypass was created included the surgical steps of placing the pig in a supine position, median sternotomy; creating a longitudinal opening in pericardium; placing a ligature on left side in permanent of the V. cava superior; administering systemic heparinization (ACT approximately 500 sec); connecting pig to heart-lung machine (HLM) with canullation of A. ascendens and direct canullation of V. cava inferior (SVC) and V. cava inferior (IVC); starting cardiopulmonary bypass (routine CPB priming with crystalloid solution); harnessing SVC and IVC; opening up right atrium in beating heart; inserting a 5 mm PTFE tubular prosthesis 3 to 4 cm into coronary sinus (a Palmas stent is attached to distal end of prosthesis); attaching prosthesis in coronary sinus following ballooning of stent with balloon catheter; adjusting length of tubular prosthesis, tangentially clamping of A. descendens or Truncus brachiocephalicus; end-side anostomosing of tubular prosthesis with A. ascendens or Truncus brachiocephalicus by means of continuous suture; prosthesis initially remains clamped; suture closure of right atrium; opening coronary sinus bypass.
[0093] In addition, the animals were connected to the CPB for 30 min. During this period, the coronary sinus bypass was anastomosed. At the end of the CPB, the animals were monitored. Experimental parameters included Survival after CPB; Hemodynamic measurements (Measurement of contractility by means of impedance and Millar catheter; Pulmonary catheter for determining heart-time volume, cardiac index, peripheral and pulmonary vessel resistance; and Epicardial echocardiography); Laboratory analyses (LDH, HBDH, lactate); and Determination of regional myocardial perfusion by means of fluorescent microspheres prior to and after placement of coronary sinus bypass.
[0094] The measurement of myocardial perfusion using fluorescent microspheres was performed during the CPB according to the described technique. Measurement of blood flow using ms was based on the principle that the microspheres, after a single passage through the system cling to the terminal capillary vessel. When they are removed from the respective tissue, they can be counted. Based on the ration of circulating microspheres in the blood (blood reference value) and the number of microspheres in the tissue, one can determine regional blood flow. During CPB, the microspheres are injected at three moments:
1) Time 2 (second color): myocardial perfusion only through native coronary system (coronary veins are stenosed; coronary sinus is open) 2) Time 3 (third color): myocardial perfusion only through native coronary system following placement of coronary sinus bypass in the coronary sinus. Coronary sinus still occluded. 3) Time 4 (fourth color): myocardial perfusion through open coronary sinus bypass.
[0098] Each microsphere injection contains 2 million microspheres. Three different colors were used for each of the three measuring periods (“blue-green”, “orange”, “yellow”). The microspheres were dissolved in 4 mL of NaCl/TWEEN 80 (solution ratio: 1 drop of TWEEN 80 per 100 mL of NaCl) and injected into the left atrium as bolus over a period of 5 sec. Aspiration of blood sample from the A. descendens (blood reference sample) was started five minutes prior to injection of microspheres. Aspiration was done for 90 sec at a flow of 7.5 mL/min using a mechanical precision pump (Harvard pump 22, FMI GmbH, Ober Beerbach, Germany). The blood was aspirated through a 40 cm long Teflon-coated catheter and collected in a 20 mL glass syringe (Hero, Germany). Prior to this, the Teflon catheter was advanced to the level of the A. descendens through a shunt system lying in the abdominal aorta. The flask of the glass syringe had previously been coated with TWEEN 80 (polyoxyethylene sorbital mono-oleate, Sigma Chemical, St. Louis, USA). In addition, 2 mL of heparin (10,000 I.E.) were put in the syringe. This prevented both the aggregation of the microspheres within and at the needle, and coagulation of the aspirated blood. The syringe was weighed prior to and after aspiration in order to calculate the amount of aspirated blood with reference to blood density (1.055). The actual microsphere concentration per mL of blood was then calculated using the blood reference value.
[0099] For calculating myocardial blood flow for each sample, the following formula was used (MS=microspheres; HTV=heart-time volume; reference=blood reference sample):
Blood flow [mL/min]= MS myocardium× HTV [mL/min/ MS reference
[0100] The sum total of blood flow readings from all myocardial samples was the total blood flow in the myocardium.
[0101] Phase 3 surgery wherein cardiac function, perfusion analysis, and organ removal was accomplished included the steps of placing the pig in supine position; performing a median sternotomy; creating a longitudinal opening in pericardium; exposing the heart; performing function and perfusion analysis.
[0102] At the end of the experiment, the entire heart was removed and divided into three parts: right ventricle, septum, left ventricle. The number of microspheres in each of the three muscle preparations was analyzed (Fa. Perfusion Technologies Ltd., Freiburg, Germany).
[0103] After removal, the heart muscle tissue was weighed, dried for 48 hours at 80° C. in a drying furnace, and then weighed again. The ratio of moist to dry matter was calculated and used as marker for water content in the heart muscle.
[0104] As a final measure, the following parameters were determined for evaluating cadiac contraction and perfusion:
1) Laboratory analyses (LDH, HBDH, lactate) 2) Hemodynamic measurements: Measurement of contractility by means of impedance and Millar catheter Pulmonary catheter for determining heart-time volume, cardiac index, peripheral and pulmonary vessel resistance Epicardial echocardiography 3) Determination of regional myocardial perfusion using fluorescent microspheres.
[0111] It should be noted as observational validation of the technique that intraoperative findings in the coronary arteries and coronary veins of a pig following ligature of R. interventricularis and R. circumflexus and initiation of coronary sinus perfusion showed that the observed bright red vessels are the coronary veins through which arterialized blood was flowing, and that the observed dark red vessels were the coronary arteries through deoxygenated blood was flowing into the aortic root.
[0112] While preferred embodiments of the foregoing invention have been set forth for purposes of illustration, the foregoing description should not be deemed a limitation of the invention herein. Accordingly, various modifications, adaptations and alternatives may occur to one skilled in the art without departing from the spirit and the scope of the present invention.
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RELATED APPLICATION DATA
[0001] This application claims priority to U.S. Provisional Patent Application No. 61/379,146, filed Sep. 1, 2010.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] Exemplary embodiments of the present invention relate to systems and methods for delivering a prosthesis to a desired location in the body. More particularly, the present invention relates to a delivery system for deploying a prosthesis within a body lumen and to methods of delivering a prosthesis to a desired location in a body. The delivery system can be operated with one hand while maintaining accuracy and providing mechanical advantage in deployment of a prosthesis in a body lumen.
[0004] 2. Background
[0005] Vascular aneurysms are the result of abnormal dilation of a blood vessel, usually resulting from disease and/or genetic predisposition that weakened the arterial wall and allowed it to expand. While aneurysms could occur in any blood vessel, most occur in the aorta and peripheral arteries, with the majority of aortic aneurysms occurring in the abdominal aorta, usually beginning below the renal arteries and often extending into one or both of the iliac arteries.
[0006] Aortic aneurysms were commonly treated in open surgical procedures where the diseased vessel segment was bypassed and repaired with an artificial vascular graft. While considered to be an effective surgical technique, particularly considering the alternative of a fatal ruptured abdominal aortic aneurysm, conventional vascular graft surgery suffered from a number of disadvantages. The surgical procedure was complex and required experienced surgeons and well-equipped surgical facilities. Even with the best surgeons and equipment, however, patients frequently were elderly and weakened from cardiovascular and other diseases, reducing the number of eligible patients.
[0007] Even for eligible patients prior to rupture, conventional aneurysm repair had a relatively high mortality rate, usually from 2% to 10%. Morbidity related to the conventional surgery included myocardial infarction, renal failure, impotence, paralysis, and other conditions. Additionally, even with successful surgery, recovery took several weeks, and often required a lengthy hospital stay.
[0008] In order to overcome some or all of these drawbacks, endovascular prosthesis placement for the treatment of aneurysms has been used. Although promising, many of the proposed methods and apparatuses suffered from undesirable limitations. In particular, accurate delivery and placement of the endovascular prosthesis within the vasculature was problematic.
[0009] Stent-grafts (endovascular prostheses) are resilient structures, usually biased to expand against a surrounding luminal wall. Such resiliently-expanding stent-grafts may be tightly compressed within a catheter for delivery, imposing significant radial expansion forces against the surrounding catheter sheath. This may lead to high levels of friction between the stent-graft and the sheath, particularly if the resiliently-expanding structure becomes partially embedded in the sheath material. Thus, a delivery system must be capable of imparting a significant, yet controlled, force to retract the sheath and deploy the stent-grafts.
[0010] U.S. Pat. No. 7,419,501 to Chiu et al., which is incorporated herein by reference in its entirety, discloses a delivery system that attempts to address these issues by providing a delivery system having a handle that allows for accurate placement of a stent-graft in a body lumen. The delivery system includes a sheath and a handle. The handle includes: a slide shaft having a threaded outer surface; and a hub assembly coupled to the sheath. The hub assembly includes: an inner slider having a thread tooth pivot support; a thread tooth pivotably mounted to the thread tooth pivot support; and a sleeve having a thread tooth press member pressing on the thread tooth, where motion of the sleeve relative to the inner slider pivots the thread tooth on the thread tooth pivot support to engage and disengage the hub assembly with the threaded outer surface.
[0011] U.S. application Ser. No. 13/106,110, filed May 12, 2011, which is incorporated herein by reference in its entirety, discloses a delivery system having an improved handle that allows for operation of the delivery system with one hand while maintaining accuracy in delivery and deployment of a prosthesis in a body lumen. The delivery system includes a sheath and a handle. The handle includes: a slide shaft having a threaded outer surface; and a hub assembly coupled to the sheath. The hub assembly includes: an inner slider having a thread tooth pivot support; a thread tooth pivotably mounted to the thread tooth pivot support; a distal sleeve having a thread tooth press member pressing on the thread tooth; and a proximal sleeve. Motion of the distal sleeve relative to the inner slider pivots the thread tooth on the thread tooth pivot support to engage and disengage the hub assembly with the threaded outer surface. The distal sleeve is rotatably coupled to the proximal sleeve, and the proximal sleeve is prevented from rotating in order to provide a stable grip to allow operation of the catheter with one hand.
BRIEF SUMMARY OF THE INVENTION
[0012] Some embodiments of the present invention provide improved delivery systems that allow for operation of the delivery system with one hand while maintaining accuracy in delivery and deployment of a prosthesis in a body lumen.
[0013] Some embodiments of the present invention also provide methods of using an improved delivery system that allows for operation of the delivery system with one hand while maintaining accuracy in delivery and deployment of a prosthesis in a body lumen.
[0014] Additional features of the invention will be set forth in the description that follows, and in part will be apparent from the description, or may be learned by practice of the invention
[0015] Some embodiments of the present invention provide a delivery system for delivering a prosthesis to a location in a body, the delivery system including a housing having a longitudinal axis and a distal end hole, a sheath extending from within the housing through and outwardly beyond the distal end hole, wherein the sheath contains the prosthesis at a distal end thereof, a first sheath control disposed on the housing so as to be accessible from the exterior of the housing, wherein the first sheath control is operatively engaged with the sheath, a stop disposed within the housing, the stop being engagable and disengagable with respect to the sheath and configured to, when engaged, confine axial motion of the sheath with respect to the housing within set parameters, and a stop control accessible from the exterior of the housing and operatively connected to the stop, wherein actuation of the stop control causes the stop to disengage or engage with respect to the sheath, wherein a first actuation of the first sheath control causes the sheath to move axially proximally with respect to the housing, thereby releasing at least a portion of the prosthesis.
[0016] Some embodiments of the present invention also provide a method of delivering a prosthesis to a desired location in a body, the method including introducing a sheath of a delivery system into a patient's vasculature, wherein a distal tip of the sheath contains the prosthesis, advancing the distal tip of the sheath to the desired location in the body, actuating, in a first direction, a sheath control of the delivery system to cause the sheath to move axially proximally with respect to the housing until further motion of the sheath is prevented by a stop, thereby releasing at least a portion of the prosthesis, actuating a stop control to disengage the stop, and continuing to actuate the sheath control in the first direction until the prosthesis is fully released, wherein the sheath control is disposed on a housing of the delivery system so as to be accessible from the exterior of the housing, and wherein the sheath control is operatively engaged with the sheath, and wherein the stop control is disposed on the housing of the delivery system so as to be accessible from the exterior of the housing, and wherein actuation of the stop control causes the stop to disengage or engage with respect to the sheath.
[0017] Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
BRIEF DESCRIPTION OF THE FIGURES
[0018] The accompanying figures, which are incorporated herein, form part of the specification and illustrate embodiments of prosthetic delivery systems and methods of delivering a prosthesis to a desired location in a body. Together with the description, the figures further serve to explain the principles of and to enable a person skilled in the relevant art(s) to make and use the delivery systems and methods described herein. In the drawings like reference characters indicate identical or functionally similar elements.
[0019] FIG. 1 is a perspective view of a delivery system according to an exemplary embodiment of the present invention.
[0020] FIG. 2 is a top view of a delivery system according to an exemplary embodiment of the present invention.
[0021] FIG. 3 is a side view of a delivery system according to an exemplary embodiment of the present invention.
[0022] FIG. 4 is a perspective view of a delivery system according to an exemplary embodiment of the present invention.
[0023] FIG. 5 is a perspective view of a delivery system according to an exemplary embodiment of the present invention.
[0024] FIG. 6 is a perspective view of a delivery system according to an exemplary embodiment of the present invention.
[0025] FIG. 7 is a perspective view of a delivery system according to an exemplary embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The following detailed description of prosthetic delivery systems and methods of delivering a prosthesis to a desired location in a body refers to the accompanying figures that illustrate exemplary embodiments. Other embodiments are possible and may fall within the scope of the present invention. Modifications can be made to the exemplary embodiments described herein without departing from the spirit and scope of the present invention. Therefore, the following detailed description is not meant to be limiting. Further, it would be apparent to one of skill in the art that the systems and methods described below can be implemented in many different embodiments of hardware. Any actual hardware described is not meant to be limiting. The operation and behavior of the systems and methods presented are described with the understanding that various modifications and variations of the exemplary embodiments may be within the scope of the present invention.
[0027] FIG. 1 is a perspective view of a delivery system 100 according to an exemplary embodiment of the present invention. FIG. 2 is a top view of an exemplary embodiment of delivery system 100 . FIG. 3 is a side view of an exemplary embodiment of delivery system 100 . Delivery system 100 includes a housing 120 , a first sheath control 150 , a stop control 152 , and a sheath 170 . Housing 120 can include proximal portion 110 (sometimes referred to as a “handle” or “grip”) and distal portion 130 . Distal portion 130 can include a distal end hole 138 .
[0028] A distal tip of sheath 170 can releasably contain a prosthesis (not shown). A user can operate delivery system 100 by inserting sheath 170 containing the prosthesis in its distal tip into a body lumen of a patient. The user can then position the distal tip of sheath 170 within the patient's body lumen in a desired location. The user can then operate delivery system 100 to withdraw sheath 170 , thereby releasing the prosthesis at the desired location in the patient's body lumen.
[0029] Sheath 170 extends from within housing 120 through and outwardly beyond distal end hole 138 . Sheath 170 can removably contain a prosthesis (not shown) within its distal end. The prosthesis can be held in position by a prosthesis retainer (not shown) mounted to a delivery shaft (not shown) connected to housing 120 .
[0030] U.S. application Ser. No. 13/106,110, filed May 12, 2011, which is hereby incorporated by reference in its entirety, discloses systems and methods of controlling motion of a sheath with respect to a housing. As one skilled in the art would appreciate, similar systems and methods can be used in conjunction with the present invention. The present invention, however, is not limited to such use.
[0031] First sheath control 150 is mounted to housing 120 so as to be accessible and operable from the exterior of housing 120 . First sheath control 150 can be selectively engaged and disengaged with sheath 170 . When engaged, first sheath control 150 can be operated to move sheath 170 axially with respect to housing 120 . When first sheath control 150 is operated to move sheath 170 proximally with respect to housing 120 , sheath 170 can gradually release the prosthesis from its distal end, because the prosthesis will be held axially stationary with respect to housing 120 by the prosthesis retainer and/or delivery shaft. If the prosthesis is only partially released, first sheath control 150 can be operated to move sheath 170 distally with respect to housing 120 , thereby recapturing the prosthesis within the distal end of sheath 170 .
[0032] First sheath control 150 can operatively engage with sheath 170 in a variety of ways that would be apparent to one of skill in the art. For example, first sheath control 150 can include interior threads or other engagement members that align with exterior threads or other engagement members on sheath 170 such that rotation of first sheath control 150 causes axial translation of sheath 170 with respect to housing 120 , or sheath 170 can be fixed to a slide shaft that engages first sheath control 150 to cause axial translation of sheath 170 in response to operation of first sheath control 150 . Preferably first sheath control 150 can engage with sheath 170 so as to provide mechanical advantage and precise control to a user of sheath control 150 in order to facilitate release or recapture of the prosthesis.
[0033] In an exemplary embodiment, first sheath control 150 includes a wheel-shaped control member aligned coaxially with housing 120 and rotatable thereabout. First sheath control 150 can be positioned between proximal portion 110 and distal portion 130 so as to be easily accessible to a user of delivery system 100 . First sheath control 150 can cover a portion of housing 120 where proximal portion 110 and distal portion 130 meet, or first sheath control 150 can itself form a part of housing 120 by itself joining proximal portion 110 and distal portion 130 . A user will typically grasp proximal portion 110 in one hand such that the forefinger and thumb of the user are positioned proximate to first sheath control 150 . Because of the location of first sheath control 150 relative to proximal portion 110 (i.e., grip), as well as the mechanical advantage and precision control provided by first sheath control 150 , the user can operate first sheath control 150 to release or recapture the prosthesis with the forefinger and thumb of the user's hand while grasping proximal portion 110 with the remaining fingers and the palm, without the need to employ the user's other hand. First sheath control 150 can be configured such that it does not travel in an axial direction with respect to housing 120 .
[0034] Delivery system 100 can also include a sheath stop that, when engaged, limits the axial motion of sheath 170 with respect to housing 120 . The sheath stop can be configured to allow axial motion of sheath 170 to release only a portion of the prosthesis. Such a feature can provide an indication of how much of the prosthesis has been released, or indicate the point after which recapture of the prosthesis cannot effectively take place. Stop control 152 (sometimes referred to as “stop release” or “⅔ stop release”) can be actuated to disengage the sheath stop, thereby allowing axial motion of sheath 170 beyond the limits imposed when the sheath stop is engaged (e.g., allowing axial motion of sheath 170 to its full proximal position). Typically a user would operate stop control 152 to release the sheath stop once the user is certain of proper placement of the prosthesis. Thereafter, the user can operate first sheath control 150 to further and fully release the prosthesis. As shown in FIG. 1 , in an exemplary embodiment stop control 152 is a ring located at the distal end of first sheath control 150 . To actuate stop control 152 and thereby disengage the sheath stop, a user applies pressure to stop control 152 in a distal direction.
[0035] First sheath control 150 can include gripping enhancements 154 on its surface to assist a user in turning first sheath control 150 . FIGS. 1-3 depicts ridges extending longitudinally and disposed around the exterior of the wheel of first sheath control 150 . Other gripping enhancements can also be used. For example, raised bumps, circular ridges, surface texture, or indents can be disposed on a surface of first sheath control 150 . Such gripping enhancements decrease the likelihood that a user's fingers will slip while operating first sheath control 150 , and increase the ease with which the user can operate first sheath control 150 .
[0036] Additionally, first sheath control 150 can include a control indicator 156 . Control indicator 156 also can enhance a user's grip on first sheath control 150 , however it is shaped differently from gripping enhancements 154 . The different shape of control indicator 156 provides tactile feedback to a user operating first sheath control 150 , and can thereby indicate to the user the degree to which the first sheath control 150 has rotated.
[0037] In some situations, it may be desirable to have more direct control over the movement of sheath 170 than may be provided by first sheath control 150 . In an exemplary embodiment, housing 120 includes a second sheath control 112 (also referred to as a “proximal indicator”) accessible through a proximal slot 114 extending longitudinally along and through a portion of proximal portion 110 . Second sheath control 112 can be fixed to sheath 170 and axially slidable with respect to housing 120 . Second sheath control 112 moves within slot 114 during operation of first sheath control 150 as a consequence of first sheath control 150 moving sheath 170 . Because second sheath control 112 is accessible through slot 114 , it can be viewed by a user, thereby providing to the user an indication of the extent of movement of sheath 170 . As an alternative to moving sheath 170 using first sheath control 150 , a user can choose instead to move sheath 170 using second sheath control 112 . As the user grips proximal portion 110 , the user can position his or her thumb (or other portion of his or her hand) on second sheath control 112 and slide second sheath control 112 proximally or distally within proximal slot 114 , thereby causing a corresponding movement of sheath 170 . Such use of second sheath control 112 to control sheath 170 may be desirable to a user for a variety of reasons. For example, the user can withdraw sheath 170 more quickly with second sheath control 112 than operation of first sheath control 150 would allow.
[0038] Depending on the configuration of first sheath control 150 , a user's control of the movement of sheath 170 by way of second sheath control 112 may be inhibited by the engagement of first sheath control 150 with sheath 170 . To alleviate this difficulty, an exemplary embodiment of the present invention includes a sheath engagement control 118 , operable to disengage or engage first sheath control 150 with sheath 170 . As shown in FIG. 1 , in an exemplary embodiment sheath engagement control 118 coexists with second sheath control 112 . This configuration allows a user to apply pressure to sheath engagement control 118 (e.g., by pressing down on sheath engagement control 118 with his or her thumb) to disengage first sheath control 150 from sheath 170 , at which point the user can slide second sheath control 112 so as to control movement of sheath 170 . The user can release the pressure applied to sheath engagement control 118 in order to re-engage first sheath control 150 with sheath 170 . In some exemplary embodiments, sheath engagement control 118 need not be held down to keep first sheath control 150 disengaged with sheath 170 , but need only be pressed once to disengage, and once again to re-engage.
[0039] Housing 120 can optionally include a proximal flush port 116 in proximal portion 110 , and/or a distal flush port 136 in distal portion 130 . Proximal flush port 116 and distal flush port 136 can be used to flush cavities within sheath 170 with fluid in order to prevent introducing air into a patient during delivery of the prosthesis.
[0040] Distal portion 130 can include a distal slot 134 extending longitudinally along and through distal portion 130 . A distal indicator 132 may be viewable to a user through distal slot 134 . Distal indicator 132 is connected to sheath 170 and slidable within distal portion 130 along with motion of sheath 170 . As such, distal indicator 132 can indicate to a user the extent to which sheath 170 has moved in response to the user's operation of either first sheath control 150 or second sheath control 112 .
[0041] FIG. 4 is a perspective view of a delivery system 400 according to an exemplary embodiment of the present invention. Description of elements of the exemplary embodiment depicted in FIG. 4 that are the same or operate similarly as those described above with reference to FIGS. 1-3 may be omitted or abbreviated.
[0042] In an exemplary embodiment of the present invention, a delivery system 400 includes a first sheath control 450 that includes a wheel-shaped control member rotatably mounted to a housing 420 (housing 420 including a proximal portion 410 and a distal portion 430 ). First sheath control 450 can be positioned on housing 420 so as to be easily accessible to a user of delivery system 400 . A user will typically grasp proximal portion 410 (i.e., grip) in one hand such that the forefinger and thumb of the user are positioned proximate to first sheath control 450 . Because of the location of first sheath control 450 relative to proximal portion 410 , as well as the mechanical advantage and precision control provided by first sheath control 450 , the user can operate first sheath control 450 to release or recapture the prosthesis with the forefinger and/or thumb of the user's hand that is grasping proximal portion 410 , without the need to employ the user's other hand. In order to facilitate such operation, first sheath control 450 can be provided with grip enhancers 454 , which, in the embodiment of FIG. 4 , are grooves extending around the circumference of first sheath control 450 in an axial direction with respect to first sheath control 450 .
[0043] Delivery system 400 can also include a sheath stop that, when engaged, limits the axial motion of sheath 170 with respect to housing 420 . A stop control 452 can be actuated to disengage the sheath stop, thereby allowing axial motion of sheath 170 beyond the limits imposed when the sheath stop is engaged (e.g., allowing axial motion of sheath 170 to its full proximal position). Typically a user would operate stop control 452 to release the sheath stop once the user is certain of proper placement of the prosthesis. Thereafter, the user can operate first sheath control 450 to further and fully release the prosthesis. As shown in FIG. 4 , in an exemplary embodiment stop control 452 is a button located in the center of first sheath control 450 . To actuate stop control 452 and thereby disengage the sheath stop, a user applies pressure to stop control 452 .
[0044] Delivery system 400 can also include a sheath engagement control 418 that is separate from second sheath control 112 and is slidably disposed on the exterior surface of housing 420 . Sheath engagement control 418 is located proximate to first sheath control 450 so as to allow for single-handed access by a user. Sheath engagement control 418 is slidable in an axial direction with respect to housing 420 between a proximal position and a distal position. Sliding sheath engagement control 418 from one position to the other disengages or engages first sheath control 450 with sheath 170 . For example, sliding sheath engagement control from the proximal position to the distal position can cause sheath engagement control 418 to disengage first sheath control 450 with sheath 170 , at which point a user can slide second sheath control 112 so as to control movement of sheath 170 . The user can slide sheath engagement control 418 from the distal position to the proximal position in order to re-engage first sheath control 450 with sheath 170 . In some exemplary embodiments, sheath engagement control 418 is spring-loaded such that it resists sliding from the proximal position to the distal position. In such an exemplary embodiment, a user who has slid sheath engagement control 418 to a distal position in order to disengage first sheath control 450 with sheath 170 need only release sheath engagement control 418 in order to allow sheath engagement control 418 to return to the proximal position and re-engage first sheath control 450 with sheath 170 .
[0045] FIG. 5 is a perspective view of a delivery system 500 according to an exemplary embodiment of the present invention. Description of elements of the exemplary embodiment depicted in FIG. 5 that are the same or operate similarly as those described above may be omitted or abbreviated.
[0046] In the embodiment shown in FIG. 5 , a delivery system 500 includes a first sheath control 550 that includes a wheel-shaped control member rotatably mounted to a housing 520 (housing 520 including a proximal portion 510 and a distal portion 530 ) such that the axis of the wheel is offset from the longitudinal axis of housing 520 . First sheath control 550 can be partially recessed within housing 520 such that a portion of the exterior surface of first sheath control 550 extends through the surface of housing 520 so as to be accessible from the exterior of housing 520 . A user can operate first sheath control 520 by rotating the portion of first sheath control 520 that extends outside housing 520 . A user will typically grasp proximal portion 510 in one hand such that the thumb of the user is positioned proximate to first sheath control 550 . Because of the location of first sheath control 550 relative to proximal portion 510 (i.e., grip), as well as the mechanical advantage and precision control provided by first sheath control 550 , the user can operate first sheath control 550 to release or recapture the prosthesis with the thumb of the user's hand that is grasping proximal portion 510 , without the need to employ the user's other hand. In order to facilitate such operation, first sheath control 550 can be provided with grip enhancers 554 , which, in the exemplary embodiment of FIG. 5 , are grooves extending around the circumference of first sheath control 550 in an axial direction with respect to first sheath control 550 .
[0047] Delivery system 500 can also include a combination stop control and sheath engagement control 556 . Combination stop control and sheath engagement control 556 can be a three-position switch, with a middle position, a left position, and a right position. Combination stop control and sheath engagement control 556 can be a cylindrical element extending through a portion of housing 520 so as to protrude from opposing sides of housing 520 , where a user can operate combination stop control and sheath engagement control 556 by pressing on either end. Combination stop control and sheath engagement control 556 is not limited to a cylindrical element. For example, combination stop control and sheath engagement control 556 can be rectangular, triangular, or hexagonal.
[0048] Combination stop control and sheath engagement control 556 is shown in FIG. 5 in the middle position. When in the middle position, pressing on a right side of combination stop control and sheath engagement control 556 will cause combination stop control and sheath engagement control 556 to slide from the middle position to the left position, and pressing on the left side of combination stop control and sheath engagement control 556 will cause combination stop control and sheath engagement control 556 to slide from the middle position to the right position. When in the left position, pressing on a left side of combination stop control and sheath engagement control 556 will cause combination stop control and sheath engagement control 556 to slide from the left position to either the middle position or the right position, depending on how far combination stop control and sheath engagement control 556 is pressed. When in the right position, pressing on a right side of combination stop control and sheath engagement control 556 will cause combination stop control and sheath engagement control 556 to slide from the right position to either the middle position or the left position, depending on how far combination stop control and sheath engagement control 556 is pressed.
[0049] Of the three potential positions for combination stop control and sheath engagement control 556 , one will be a first position in which first sheath control 550 is engaged with sheath 170 and a sheath stop is engaged. Another will be a second position in which first sheath control 550 is disengaged with sheath 170 and the sheath stop is engaged. Another will be a third position in which first sheath control 550 is engaged with sheath 170 and the sheath stop is disengaged. As will be appreciated by one of skill in the art, more or fewer than three positions are possible for combination stop control and sheath engagement control 156 , and combinations of first sheath control 550 and sheath stop states other than those described are possible.
[0050] In some exemplary embodiments, combination stop control and sheath engagement control 556 can be spring-loaded so as to naturally tend to remain in a neutral position. The neutral position can correspond to the middle position. In such an exemplary embodiment, the portions of combination stop control and sheath engagement control 556 that extend on either side of housing 520 can each correspond independently to one of a stop control and a sheath engagement control. For example, a user can depress and release the left side of combination stop control and sheath engagement control 556 in order to engage or disengage the sheath stop, regardless of the state of engagement of the first sheath control 550 with the sheath 170 . Correspondingly, the user can depress and release the right side of combination stop control and sheath engagement control 556 in order to engage or disengage first sheath control 550 with the sheath 170 , regardless of the state of the sheath stop. Alternatively, rather than a single member protruding from opposing sides of housing 520 , combination stop control and sheath engagement control 556 can include two separate protrusions, acting as buttons extending from either side of housing 520 , each independently performing the functions of either a stop control or a sheath engagement control.
[0051] It should be noted that although the terms “left” and “right” are used above in relation to the position of combination stop control and sheath engagement control 556 , these terms are used for convenience of description only, and are not meant to be limiting. As one of skill in the art would appreciate, the described positions can be oriented other than left and right, for example “top” and “bottom”, “proximal” and “distal”, and the like.
[0052] FIG. 6 is a perspective view of a delivery system 600 according to an exemplary embodiment of the present invention. Description of elements of the exemplary embodiment depicted in FIG. 6 that are the same or operate similarly as those described above may be omitted or abbreviated.
[0053] In an exemplary embodiment of the present invention, a delivery system 600 includes a first sheath control 650 that includes a lever-based control member mounted to a housing 620 (housing 620 including a proximal portion 610 and a distal portion 630 ) such that the lever extends in a substantially axial direction with respect to housing 620 , albeit angled thereto, depending on its state. First sheath control 650 is shown in FIG. 6 as being mounted near a midpoint of housing 620 , with its lever extending in a distal direction with respect to housing 620 . The lever of first sheath control 650 can be moved toward or away from housing 620 . Movement of the lever in one direction will cause the sheath to move proximally with respect to the housing, thereby at least partially releasing the prosthesis. Movement of the lever in the other direction will cause the sheath to move distally with respect to the housing, thereby recapturing at least a portion of the prosthesis, if the prosthesis has not already been fully released.
[0054] Because of the location of first sheath control 650 on housing 620 , as well as the mechanical advantage and precision control provided by first sheath control 650 , the user can operate first sheath control 650 using his or her thumb and index finger while holding housing 620 with the palm and remaining fingers. to release or recapture the prosthesis with the fingers of the user's hand that is grasping 620 , without the need to employ the user's other hand. In order to facilitate such operation, first sheath control 650 can be provided with grip enhancers 654 , which, in the embodiment of FIG. 6 , are grooves extending across the lever of first sheath control 650 .
[0055] It should be noted that although the lever of first sheath control 650 is shown in FIG. 6 as being mounted near a midpoint of housing 620 , with its lever extending in a distal direction with respect to housing 620 , this configuration is exemplary, and is not meant to be limiting. As one of skill in the art would appreciate, sheath control 650 can be positioned in a variety of configurations with respect to housing 620 . For example, first sheath control 650 could be mounted near a midpoint of housing 620 with its lever extending in a proximal direction with respect to housing 620 , or it could be mounted near an endpoint (either proximal or distal) of housing 620 with its lever extending toward the opposing endpoint of housing 620 .
[0056] Delivery system 600 can also include a sheath stop that, when engaged, limits the axial motion of sheath 170 with respect to housing 620 . A stop control 652 can be actuated to disengage the sheath stop, thereby allowing axial motion of sheath 170 beyond the limits imposed when the sheath stop is engaged (e.g., allowing axial motion of sheath 170 to its full proximal position). Typically a user would operate stop control 652 to release the sheath stop once the user is certain of proper placement of the prosthesis. Thereafter, the user can operate first sheath control 650 to advance and fully release the prosthesis. As shown in FIG. 6 , in an exemplary embodiment stop control 652 is a slidable control member disposed on the exterior surface of housing 620 . Stop control 652 can be located on housing 620 under or proximate to the lever of first sheath control 650 . This positioning facilitates easy single-handed access by a user. As described above, a user can grasp delivery system 600 with one hand such that his or her fingers wrap around housing 620 and are positioned on or proximate to the lever of first sheath control 650 . In such a position, the user's fingers would be positioned proximate to stop control 652 . Stop control 652 is slidable in an axial direction with respect to housing 620 between a proximal position and a distal position. Sliding stop control 652 from one position to the other disengages or engages the sheath stop. For example, sliding sheath stop control 652 from the distal position to the proximal position can cause sheath stop control 652 to disengage, at which point a user can continue to operate first sheath control 650 to move sheath 170 beyond the limits otherwise imposed by the sheath stop.
[0057] Delivery system 600 can also include a sheath engagement control 618 that is separate from second sheath control 112 and is slidably disposed on the exterior surface of housing 620 . Sheath engagement control 618 can be located on a side of housing 620 opposite to that of first sheath control 650 . This positioning facilitates single-handed access by a user. Sliding sheath engagement control 618 from one position to the other disengages or engages first sheath control 650 from sheath 170 . For example, sliding sheath engagement control 618 from the proximal position to the distal position can cause sheath engagement control 618 to disengage first sheath control 650 with sheath 170 , at which point a user can slide second sheath control 112 to control movement of sheath 170 . The user can slide sheath engagement control 618 from the distal position to the proximal position in order to re-engage first sheath control 650 with sheath 170 . In some exemplary embodiments, sheath engagement control 618 is spring-loaded such that it resists sliding from the proximal position to the distal position. In such an exemplary embodiment, a user who has slid sheath engagement control 618 to a distal position in order to disengage first sheath control 450 with sheath 170 need only release sheath engagement control 618 in order to allow sheath engagement control 618 to return to the proximal position and re-engage first sheath control 650 with sheath 170 .
[0058] FIG. 7 is a perspective view of a delivery system 700 according to an exemplary embodiment of the present invention. Description of elements of the exemplary embodiment depicted in FIG. 7 that are the same or operate similarly as those described above may be omitted or abbreviated.
[0059] In an exemplary embodiment of the present invention, a delivery system 700 can include a first sheath control 750 aligned coaxially with respect to a housing 720 . First sheath control 750 includes gripping enhancements 754 . First sheath control 720 will operate similarly to first sheath control 150 , described above with reference to FIGS. 1-3 . Delivery system 700 can also include a combination stop control and sheath engagement control 756 positioned near a distal end of housing 720 . Such combination stop control and sheath engagement control 756 will operate similarly to combination stop control and sheath engagement control 556 , described above with reference to FIG. 5 .
[0060] Delivery system 700 can also include a second sheath control 712 extending longitudinally from a proximal end of housing 720 . Second sheath control 712 can be fixed to sheath 170 and axially slidable with respect to housing 720 . Second sheath control 712 can move proximally or distally with respect to housing 720 during operation of first sheath control 750 as a consequence of first sheath control 750 moving sheath 170 . Because second sheath control 712 extends from the proximal end of housing 720 , it can be viewed by a user, thereby providing to the user an indication of the extent of movement of sheath 170 . As an alternative to moving sheath 170 by way of first sheath control 750 , a user can choose instead to move sheath 170 by way of second sheath control 712 . As the user grips housing 720 , the user can position a rear portion of his or her hand on second sheath control 712 , and can slide second sheath control 712 proximally or distally with respect to housing 720 , thereby causing a corresponding movement of sheath 170 and at least partial release or recapture of the prosthesis.
[0061] While various exemplary embodiments of the present invention have been described above, they have been presented by way of example only, and not limitation. The elements of the exemplary embodiments presented above are not necessarily mutually exclusive, but can be interchanged to meet various needs as would be appreciated by one of skill in the art. Although the exemplary embodiments presented above allow a user to operate the delivery devices with one hand, it would be appreciated by one of skill in the art that the exemplary embodiments can also be operated with multiple hands, or with a single hand and another body part or implement.
[0062] It therefore will be apparent to one skilled in the art that various changes in form and detail can be made to the exemplary embodiments disclosed herein without departing from the spirit and scope of the present invention. The phraseology or terminology herein is used for description and not for limitation. Thus, it is intended that the present invention cover modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application makes reference to and thereby incorporates all information found in U.S. Pat. Nos. 6,421,763; 6,312,460; 6,475,237; 6,451,051 which describe stents and attachment means having hinges and struts. This patent application also makes reference and thereby incorporates all information found in U.S. patent application Ser. No. 12/378,081 by Joseph M. Thielen and William J. Drasler, filed 11 Feb. 2009 entitled Peripheral Overlap Stent. This patent application makes reference to and includes all information found in the provisional patent application No. 61/463,969 entitled Large Vessel Closure Device and Method, filed 25 Feb. 2011 by William J. Drasler and Joseph M. Thielen.
FIELD OF THE INVENTION
[0002] This invention relates to an interventional catheter that is placed into a lumen of the body to deliver a stent device to an artery, vein, or other tubular member of the body in a smaller diameter configuration and allows it to expand to a larger diameter configuration. Additionally, the invention relates to providing a very low profile catheter that is able to percutaneously deliver a covered stent to the body vessel to cover or close an opening in the wall of the vessel.
BACKGROUND OF THE INVENTION
[0003] Delivery of stents or covered stents to the vasculature is often provided via percutaneous delivery that involves the Seldinger approach. Following access to the vasculature via a needle, a guidewire is entered through the needle and the needle is removed. With the guidewire in place in the vessel, a dilator with an external introducer sheath is then advanced over the wire into the vessel. Upon removal of the dilator, the introducer sheath is left in place to provide an access channel for entry of an interventional catheter. This introducer sheath enlarges the vessel to a diameter that is larger than the interventional catheter, and makes the diameter of the access site larger than necessary in some cases. Closure of the access site can then present a problem for large diameter access sites that are intended for large diameter interventional catheters, particularly when the patient is being heparinized.
[0004] Transcatheter Aortic Valve Implantation (TAVI), Abdominal Aortic Aneurysm repair, and other minimally invasive procedures require that large introducer sheaths be placed percutaneously into the vasculature in order to provide passage for these devices intended to repair or replace the damaged vessel or body tissue. Often the catheters have profiles that range from 16 to 21 French or larger. Vascular closure of such large arteriotomy sites following the removal of the large introducer sheath can be very difficult and often can require surgical intervention. Most percutaneous closure device do not perform well to close such large arteriotomy sites where the diameter of the arteriotomy is almost as large as the diameter of the vessel. One closure device that utilizes an anchor material on the inside of the vessel attached to a plug material on the outside works well for smaller diameter access closure but is not reliable for larger diameter access site closure. Other percutaneous closure devices that utilize sutures also have difficulty ensuring that the large diameter arteriotomy site is consistently closed. Manual compression of the large diameter access site can require a long period of time and can be associated with continued blood oozing and the formation of a hematoma.
[0005] What is needed is a device that can easily and consistently close a large diameter access site. The device should allow closure of the access site within only a few seconds after removal of the large introducer that provided access to the large interventional catheter. Since the femoral access site often contains plaque deposit, the closure device should not be limited by such plaque. Also, since the femoral artery is generally the access site of preference, the device should not be prone to kinking or collapse due to external pressure that may be applied to the skin or due to bending that can occur at the femoral arterial access site. The profile of a vascular closure device should have a profile that allows its use without requiring excessive or complicated delivery.
SUMMARY
[0006] The present invention is well suited to use as a closure device for closure of an access site following a TAVI procedure or other percutaneous procedure that requires a large interventional catheter wherein the access site is not easily sealed using standard manual compression via thumb pressure or the current percutaneous closure devices. The present invention can also be used to percutaneously deliver a stent or a covered stent to the lumen of a vessel for any purpose such as enlarging a stenotic region of the vessel or repairing a dissected or injured vessel using a very low profile delivery catheter.
[0007] The delivery catheter of the present invention is a very low profile catheter that is able to deliver a self-expanding or balloon expandable stent device to the interior of a vessel. An external sheath or case holds the self-expanding stent device into a small diameter configuration on the outside of a balloon that has a very low profile. A molded plastic tapered cone at the distal end of the balloon serves as a dilator. The external sheath or case serves as an introducer sheath to hold the second smaller arteriotomy site outwards. The distal tip end of the cone is configured to be attached to the proximal end of a guidewire configured to receive it. A special guidewire of the present invention can be introduced into the vessel and can subsequently be attached to the catheter cone for introduction directly into the vessel. The low profile of the device potentially obviates the need for a vascular closure device to close the opening created by the delivery device of this invention.
[0008] Although the present delivery device is intended primarily for closing a large opening in an artery using a self-expanding stent device that has a covering, it is understood that the invention can also be used to deliver a self-expanding stent without a covering. Also, a balloon expanding stent can be used with the present invention instead of a self-expanding stent device. For sealing an access site in the femoral artery, a self-expanding stent device offers the advantage that it will not crush by exposure to external forces and it is able to flex from exposure to external forces. A balloon expandable stent offers the advantage of compressing any luminal plaque and thereby providing tight apposition of the stent device against the vessel wall to form a tight seal without leakage.
[0009] In one embodiment of the delivery catheter a low profile balloon at the distal end has a covered self-expanding stent positioned around the deflated balloon. The balloon membrane is wrapped around a portion of the stent struts to hold the stent adjacent to the balloon and prevent it from embolizing or moving axially until desired. The covering on the self-expanding stent can be a thin-walled (less than 0.001 inch wall) expanded polytetrafluoroethylene (ePTFE) membrane, a thin fibrous polyurethane, or other thin porous membrane of similar thickness. The covered stent is held into a small diameter configuration by an external sheath or case that can move proximally to expose the stent for delivery.
[0010] Bonded to the distal end of the balloon is a nondeformable plastic tip or cone with a gradual taper that is similar to a taper found on a dilator catheter; the taper on one side of the cone can be approximately 15-25 degrees off of the axis. A gradual taper will allow the cone to easily dilate or “Dotter” the arteriotomy site as it is advanced into the vessel. At the distal end of the cone is located an attachment feature or element that allows the cone to become attached without unwanted release to a receiving element that is located on a special guidewire that is an element of the present invention.
[0011] In one embodiment for the method of use of the present invention, a standard introducer sheath of approximately 16-21 French size has been previously inserted into the femoral artery or other blood vessel and is directed towards the aorta for use in delivery of a TAVI catheter or other large catheter. For the method of use for the present invention the standard Seldinger approach is used to gain access to the femoral artery at a location just distal (approximately 1 to 3 cm) to the large TAVI access site and a needle access is directed into the vessel in a direction toward the large diameter TAVI introducer sheath. A guidewire of the present invention ranging in diameter from 0.010 to 0.038 inches is introduced into the needle and advanced into the vessel and the needle is removed. The guidewire has a receiving element located at its proximal end. The attachment element at the distal end of the cone is attached to the receiving element of the guidewire. The attachment of the guidewire to the cone can be accomplished via a swaging step or by forming an interlocking coupling. The delivery catheter which includes the guidewire are together advanced through the arteriotomy site and into the vessel. The cone dilates the arteriotomy site as the catheter is advanced into the vessel and the external sheath or case holds the arteriotomy site outwards as the delivery catheter is advanced further into the vessel. The delivery catheter is advanced until the cone comes into contact with the large TAVI introducer sheath. The cone and case of the delivery catheter of the present invention obviate the need for a separate dilator and introducer sheath and thereby reduces the size of arteriotomy access site.
[0012] Upon removal of the larger diameter TAVI introducer sheath, the delivery catheter is advanced a prescribed distance to position the stent device across the large diameter arteriotomy site. The case is retracted proximally to expose the stent device and the balloon is inflated to place the stent device into contact with the arteriotomy and close the access site. As the balloon is inflated the wrap attachments of the balloon with the struts of the self-expanding stent device will unwrap and allow the stent to be released into contact with the vessel wall. The balloon inflation ensures that the stent device is placed into intimate contact with the vessel wall and ensure that any plaque deposits on the vessel wall are dilated, crushed, or covered. After delivery of the covered stent device, the delivery catheter is removed from the vessel.
[0013] The delivery catheter of the present invention is intended to deliver a self-expanding stent device that can extend up to 10 mm with its external sheath or case having a diameter of approximately 4-5 French (F). At this low profile it is not expected that this additional access site for delivery of the present invention will require a closure device and is expected to close with minimal or no manual compression requirement. The low profile of the present device is attained in part by having none or minimal internal structures in the balloon. Furthermore, there is no additional dilator or introducer sheath for the present delivery catheter invention to pass through. The cone and the case of the present invention act as the dilator and the low profile introducer sheath. The separate guidewire element of the invention allows the guidewire to be placed via the standard Seldinger approach, but the subsequent guidewire attachment to the cone obviates the need for the standard dilator and introducer sheath. The delivery catheter which includes the guidewire can be accessed directly into the vessel with direct contact of the cone and case with the low profile arteriotomy site, and advanced easily for short distances as a fixed wire catheter. The short distance from the access site for the present invention to the location of the deployment of the stent device is very short, 2-10 cm, and less than 4 cm in most cases. For these cases where the delivery catheter of the present invention is used to provide closure to a large arteriotomy site, the entire catheter can be very short in length ranging from approximately 6 to 20 inches long.
[0014] One element of the present embodiment of the present invention is the stent device. The stent device can be a stent such as a balloon expandable stent or a self-expanding stent; alternately, the stent device can have a cover attached to it. In one embodiment of the stent device, a Nitinol stent is formed into a zigzag pattern although any stent pattern can be used with the present invention. A cover formed of ePTFE can be located on the outside and inside surface ( 230 ) of the stent and bonded together. Various configurations of the stent zigzag pattern can be used and a variety of linkage or connection patterns can be used to attach one zigzag ring to a neighboring ring to form a generally cylindrically shaped stent. Alternately, a small length ringlet can be placed at each end of the stent device with a covering extending in between. The stent and its covering can be formed from biodegradable polymers or metals, the covering can be a biodegradable tissue material obtained from an animal source or formed from processed collagen or other tissue materials. The cover for the stent can extend throughout the entire length of the stent or it can occupy only a central portion of the stent.
[0015] As the external sheath or case is retracted it can be important to hold onto the self-expanding sent device such that it does not jump axially or embolize uncontrolled into the artery. To address this issue, the present invention provides an option of a temporary attachment of the balloon with the struts of the stent device. The balloon can be wrapped around a portion of some struts of the stent. As the balloon wraps around the struts, the stent can be temporarily held to the balloon such that as the balloon is inflated the balloon is required to let go of the stent device. By providing the wrap attachments, the stent device can be delivered accurately to the desired site.
[0016] In an alternate embodiment of the present invention a small guidewire lumen extends throughout the length of the delivery catheter and out of distal cone. The ID of the guidewire lumen ( 300 ) can range from 0.010 to 0.040 inches. Following Seldinger approach to obtain access to the vessel, a guidewire can be placed into the vessel. The delivery catheter of this embodiment can then be used to follow over a standard guidewire and enter the vessel. The device and method of use is thereafter similar to that described for the last embodiment; the profile is not quite as favorable due to the presence of the internal guidewire tube.
[0017] It is understood that the device of the present invention is not limited to vascular closure and is not limited to only its use as a low profile delivery catheter. When used for large diameter stent device delivery, the dimensions of delivery catheter elements can be altered proportionally and accordingly. Also, the use of the present invention for delivery of balloon expanding stents or stent devices can also accomplish many of the benefits described for the self-expanding stent device.
[0018] In yet another embodiment a self-expanding stent either with or without a covering can be located within the external sheath or case of the delivery catheter without positioning it onto a balloon of a balloon catheter. A pusher tube placed over the catheter shaft can ensure that the stent device is pushed out of the case as the case is being withdrawn. A control fiber attached to the stent device ensures that the self-expanding stent is not allowed to embolize within the blood vessel. A post dilation of the self-expanding stent device may be necessary to ensure that it is fully engaged with the vessel wall to prevent blood leakage through the arteriotomy site. The pusher tube and the control fiber can be used with the embodiments that contain a balloon catheter.
[0019] In a further embodiment the stent or the stent used in the stent device can be a hinge stent similar to the balloon expandable hinge stent described in the patents and patent application cross referenced in this patent application. The balloon expandable hinge stent has hinge and strut features that allow the stent to be expanded by a balloon but is not susceptible to forming a permanently crushed shape due to exposure to external forces or forces imposed by muscle groups. The hinge stent design can be securely mounted and delivered on a deflated balloon at the distal end of a balloon catheter. The balloon expandable stent or stent device is not able to embolize upon release of the external sheath or case due to its tight crimped fit over the balloon.
[0020] In yet a further embodiment the stent or stent device can be a self-expanding hinge stent as described in the US patents and US application cross referenced in this application. The material of construction for a self-expanding stent can be the same as that used for standard self-expanding stents used in the industry. Alternately, it can be made using stainless steel and rely on dimensions of the hinges and struts to provide it with the self-expanding characteristics. A stent or stent device formed with the hinge structure described can have one portion of the stent that is self-expanding and another portion that is balloon expandable; both portions can be formed from the same material; the balloon expandable portion can assist in holding the stent device onto a balloon of a balloon delivery catheter.
[0021] In yet another embodiment a locator balloon is placed through the large diameter introducer sheath used to deliver the TAVI device. The locator balloon can serve to locate the position of the delivery catheter such that it is positioned directly adjacent to the large diameter arteriotomy site prior to release of the stent device. The locator balloon can have a tether located on its inner surface that allows the balloon to be inwardly folded such that passage of the delivery catheter can be accomplished without risk of bleeding or hematoma until the stent device has been significantly or fully deployed at the arteriotomy site.
[0022] Another embodiment provides an implantable locator balloon. The locator balloon provides a positioning benefit for the delivery catheter and holds the arteriotomy site from leakage. As the stent device is released and expanded into place via either a balloon expandable version or a self-expanding version, the locator balloon is pushed into the arteriotomy site and serves as a plug material to ensure that the arteriotomy site will not encounter blood leakage.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1A is a plan view of the delivery catheter with the guidewire unattached.
[0024] FIG. 1B is a plan view of the delivery catheter with the guidewire attached via a threaded joint.
[0025] FIG. 1C is a plan view of the delivery catheter with the guidewire attached via a swage joint.
[0026] FIG. 2A is a longitudinal plan view of the stent device with the stent and covering.
[0027] FIG. 2B is a transverse plan view of the stent device with the stent and covering.
[0028] FIG. 2C is a longitudinal plan view of the stent device with the stent and covering with individual ringlets and overlapping of struts in a circumferential direction.
[0029] FIG. 2D is a longitudinal plan view of the stent device with the stent and covering with ringlets that are connected.
[0030] FIG. 3A is a transverse plan view of the balloon with wrap attachments to the stent and located within the case.
[0031] FIG. 3B is a longitudinal plan view of the balloon with wrap attachments to the stent and located within the case.
[0032] FIG. 3C is a transverse plan view of the balloon with wrap attachments to the stent and a balloon bond.
[0033] FIG. 3D is a longitudinal plan view of the balloon with wrap attachments to the stent around an end strut.
[0034] FIG. 3E is a transverse plan view of the fully inflated balloon showing release of the stent device.
[0035] FIG. 3F is a longitudinal plan view of the fully inflated balloon showing the released stent device having two covering layers and blood coagulant material.
[0036] FIG. 4A is a plan view of the guidewire introduced into the blood vessel a small distance distal to the arteriotomy site with the large introducer sheath.
[0037] FIG. 4B is a plan view of the delivery catheter advancing into contact with the large introducer sheath.
[0038] FIG. 4C is a plan view of the delivery catheter positioned in the blood vessel with the stent device adjacent to arteriotomy site.
[0039] FIG. 4D is a plan view showing the case being withdrawn and exposing the stent device to the arteriotomy site.
[0040] FIG. 4E is a plan view of the stent device being expanded into apposition with the blood vessel via a dilatation balloon.
[0041] FIG. 4F is a plan view showing the stent device creating hemostasis at the arteriotomy site.
[0042] FIG. 5A is a plan view of another embodiment of the delivery catheter having a guidewire tube and providing passage for a standard guidewire.
[0043] FIG. 5B is a plan view showing advancement of the delivery catheter over a standard guidewire into contact with a large introducer sheath.
[0044] FIG. 6 is a plan view of a delivery catheter without a balloon and having a control fiber to hold the stent device.
[0045] FIG. 7A is a perspective view of one embodiment for a hinge and strut geometry for a balloon expandable stent having with one hinge with a short hinge length joining two struts to be used in the stent device.
[0046] FIG. 7B is a perspective view of one embodiment for a hinge and strut geometry for a balloon expandable stent having with two hinges each with short hinge lengths joined to a node and joining two struts to be used in the stent device.
[0047] FIG. 8 is a perspective view of one embodiment for a hinge and strut geometry for a self-expanding stent having a long hinge length to be used in the stent device.
[0048] FIG. 9A is a perspective view of the stent used in the stent device having one portion that is balloon expandable located in the central region of the stent and self-expanding portions located at each end of the stent.
[0049] FIG. 9B is a plan view of the stent used in the stent device having one portion that is self-expanding located in the central region of the stent and balloon expandable portions located at each end of the stent.
[0050] FIG. 10A is a plan view of the locator balloon advanced through the introducer sheath and positioned in the blood vessel.
[0051] FIG. 10B is a plan view of the locator balloon inflated to fill the blood vessel lumen.
[0052] FIG. 10C is a plan view of the locator balloon forming inner folds from traction place on a tether fiber thereby allowing for passage of the delivery catheter into position adjacent the arteriotomy site.
[0053] FIG. 10D is a plan view of the locator balloon being fully retracted into the locator balloon shaft and the stent device being placed into apposition with the wall of the blood vessel.
[0054] FIG. 11A is a plan view of an implantable locator balloon located within the arteriotomy site.
[0055] FIG. 11B is a plan view of an implantable locator balloon located within the arteriotomy site and having a stent device placed into apposition with the locator balloon to generate hemostasis.
DETAILED DESCRIPTION OF THE INVENTION
[0056] The present invention as shown in FIGS. 1A-1C is a delivery catheter ( 10 ) for delivering a stent device ( 20 ) percutaneously to a vessel lumen. The use of this invention can be for delivering a stent device ( 20 ) following angioplasty or during the angioplasty procedure. The stent device ( 20 ) can be a drug eluting stent such as a balloon expandable stent or a self-expanding stent or it can be a stent graft or covered stent. One of the more advantageous applications for the delivery catheter ( 10 ) of the present invention is for the closure of a large arteriotomy site such as one made in the femoral artery for delivery of a large catheter such as a TAVI device or an AAA device. Since the standard introducer sheath used in these procedures are approximately the same size as the vessel diameter, i.e., 16-21 French, the normal vascular closure devices and methods do not work well. The present delivery catheter ( 10 ) is intended to gain access in the same femoral artery or other artery that is typically entered for the TAVI procedure only at a new access site that is just a small distance distal to the TAVI access site. Since the present invention has a very small profile, providing this new second access site does not create a significant drawback and provides a definite device and method for sealing the large TAVI access opening easily, quickly, and consistently which currently is a source of vascular complications using existing sealing devices and methods.
[0057] An embodiment of the delivery catheter ( 10 ) is shown in FIGS. 1A-2B . A balloon tube or shaft ( 30 ) with a balloon inflation lumen ( 40 ) extends from the balloon manifold ( 50 ) through the delivery catheter ( 10 ) to the balloon ( 60 ). The distal end of the balloon ( 60 ) is closed by thermal methods, adhesive, solvent, bonding a plastic filler or other method. The balloon ( 60 ) can be formed from polyethylene terephthalate, polyethylene, or any material commonly used for making an angioplasty balloon. It is anticipated but not required that the same tubing that is use to form the balloon ( 60 ) can be used for the balloon tube or shaft ( 30 ).
[0058] On the outside of the balloon ( 60 ) is mounted a stent device ( 20 ); the stent device ( 20 ) can be a stent ( 80 ) or a covered stent ( 90 ). In the preferred embodiment for providing a vascular closure device the stent device ( 20 ) can be a self-expanding stent that has a covering ( 100 ); alternately the stent ( 80 ) can be either balloon expandable or self-expanding and it does not require a covering ( 100 ). The distal end of the balloon ( 60 ) is bonded to a conical dilator or cone ( 110 ) that is formed from a hard plastic, or metal, or other nondeformable material that is generally lubricious and can serve as a dilator. Materials for the cone ( 110 ) include polyethylene, delrin, fluorinated polymers, and other plastics, composites, or metals. At the distal end of the cone ( 110 ) is an attachment feature or attachment element ( 120 ). The attachment element ( 120 ) can be a stud that has a locking feature, a plastic or metal stud that has a lock snap that springs shut on a receiving element ( 130 ), a threaded stud ( 140 ) (as shown in FIG. 1A ) that can be used to form a threaded joint ( 150 ) as shown in FIG. 1B , a metal stud that can receive a mating cylinder that can be swaged upon to form a swage joint ( 160 ) as shown in FIG. 1C , or an indented receptacle that has a non-slip material on its surface, a threaded receptacle ( 180 ), or other locking receptacle.
[0059] Another element of the invention is a guidewire ( 170 ) having a receiving element ( 130 ) that is able to be attached to the attachment element ( 120 ) at the distal end of the cone ( 110 ). The receiving element ( 130 ) of the guidewire ( 170 ) can be a stud, a threaded joint ( 150 ), a threaded receptacle ( 180 ) as shown in FIGS. 1A and 1B and can be used to form a threaded joint ( 150 ) as shown in FIG. 1B , a snapping feature that mates with the attachment element ( 120 ) of the cone ( 110 ) or other mating member that allows the guidewire ( 170 ) to be readily but securely joined to the cone ( 110 ) of the delivery catheter ( 10 ).
[0060] Providing the guidewire ( 170 ) as a separate but connectable element allows the guidewire ( 170 ) to be advanced into the vessel through an initial needle puncture and allows removal of the needle; this obviates the need for a separate dilator and introducer sheath. The guidewire ( 170 ) can range in diameter from 0.014-0.038 inch diameter and can have a length ranging from 3 cm to 40 cm. Once the guidewire ( 170 ) is attached to the cone ( 110 ), the delivery catheter ( 10 ), which includes the guidewire ( 170 ), can then be advanced together to the site of interest in the vessel.
[0061] The delivery catheter ( 10 ) of the invention has a movable external sheath or case ( 190 ) that extends over the stent device ( 20 ) and holds the stent device ( 20 ) down onto the balloon ( 60 ). The case ( 190 ) comes into contact with the cone ( 110 ) to form a smooth surface such that the combination of the cone ( 110 ) and the case ( 190 ) act in a manner similar to a standard dilator and introducer sheath. Thus with the guidewire ( 170 ) attached to the cone ( 110 ), the delivery catheter ( 10 ) can be advanced through an arteriotomy site by holding onto the case ( 190 ) and advancing the delivery catheter ( 10 ) distally. When the case ( 190 ) is retracted in a proximal direction toward the balloon manifold ( 50 ) as shown in FIG. 1B , the stent device ( 20 ) is exposed to the vessel wall. In the case of a self-expanding stent device ( 20 ), the stent device ( 20 ) can be deployed immediately upon retraction of the case ( 190 ). The stent device ( 20 ) can then be post dilated by inflating the balloon ( 60 ) as shown in FIG. 1C to ensure definite contact of the stent device ( 20 ) and the vessel wall. The present invention provides that a self-expanding stent device ( 20 ) can remain attached to the balloon ( 60 ) even after retraction of the case ( 190 ) as shown in FIG. 1B ; this feature will be described further in FIGS. 2A-2D . In the femoral artery and many regions of the leg and the carotid arteries of the neck, a self-expanding stent device ( 20 ) is preferred to reduce the chances for crush deformation of the stent device ( 20 ) due to external forces applied to the stent device ( 20 ) through the skin or from muscle groups. For the case where external crush is not a significant detriment, such as for coronary stenting, a balloon expandable stent device ( 20 ) can be used; the balloon expandable stent device ( 20 ) is mounted onto the balloon ( 60 ) and is deployed upon inflation of the balloon ( 60 ). The case ( 190 ) can be used for the balloon expandable stent ( 80 ) or stent device ( 20 ) but is not required if a standard introduce sheath is used to provide entry for the stent device ( 20 ) mounted on a standard balloon dilation catheter such as used in the medical device industry.
[0062] The stent device ( 20 ) of the present invention can include any stent ( 80 ) or covered stent ( 90 ) that is currently found in the industry. The stent ( 80 ), for example, can be formed of zigzag rings or a zigzag spiral, or it can be formed from any open or close cell patterns used in stent design, some of which are shown in FIGS. 2A-2D . The stent struts ( 200 ) can have overlapped struts ( 210 ) to help gain a lower profile as shown in FIG. 2C . The connectors ( 220 ) or links of various patterns can connect individual ringlets ( 225 ) to provide a stent device ( 20 ) with multiple connected ringlets. Ringlets ( 225 ) can overlap neighboring ringlets ( 225 ) as described in the cross-referenced patent application. The self-expanding stent ( 80 ) can be formed from Nitinol, elgiloy, or other elastic metals, composites, biodegradable materials, or elastomeric plastics. The balloon expandable stent ( 80 ) can be formed from stainless steel, Cobalt-Chrome, or other materials commonly used for stents including biodegradable materials. Biodegradable polymeric materials or biodegradable metals can be used for the stent ( 80 ) or stent device ( 20 ) construction; such materials include polyglycolic acid, polylactic acid, polyethylene glycol, tissue or collagen materials, magnesium, or other biodegradable materials used in the medical device industry.
[0063] The stent device ( 20 ) can have a thin covering ( 100 ) placed on the inside surface ( 230 ), outside surface ( 240 ) or both. One embodiment as shown in FIG. 2B has an ePTFE cover with a thickness of approximately 0.0005 inches placed on both the outside and inside surface ( 230 )s of the stent struts ( 200 ) and bonded together around the stent struts ( 200 ) to hold it in place. The ePTFE covering ( 100 ) or other fibrous covering ( 100 ) such as polypropylene, polyurethane, or other fibrous or porous polymeric structure is porous to allow cellular penetration to enhance tissue healing but not allow significant bleeding to occur through the cover. Alternately, a tissue covering ( 100 ) such as a porcine pericardium or other biodegradable material can be used, including collagen, fibrin, or other tissue materials. The pore size for a polymeric covering should range between 2-30 microns, but this pore size is dependent upon the wall thickness.
[0064] The coverering ( 100 ) can extend along the entire surface of the stent ( 80 ) or it can cover only a portion of the stent ( 80 ) leaving the strut end ( 250 ) uncovered by the ePTFE or other cover material. Allowing the strut end ( 250 ) to remain uncovered allows the stent device ( 20 ) to be attached to the balloon ( 60 ) as shown in FIGS. 3A-3D . The stent ringlets ( 225 ) can be located, for example, at each end of the covering ( 100 ) leaving the central portion of the covering ( 100 ) without support from a stent ( 80 ), thereby having the flexibility that is desired and having the ability to be punctured again at a later time for vascular access.
[0065] The balloon ( 60 ) of the present invention is shown in a nondeployed configuration in FIGS. 3A and 3B . The balloon ( 60 ) can be wrapped around a portion of the stent strut ( 200 ) such as a strut end ( 250 ) to form a wrap attachment ( 260 ) as shown in FIGS. 3A-3D . This wrapping feature is not required by the present invention but provides a potential benefit for holding the self-expanding stent device ( 20 ) in position with respect to the balloon ( 60 ) such that the stent device ( 20 ) cannot embolize or become displaced in the vessel. In FIG. 3A a portion of the balloon ( 60 ) is wrapped around a stent strut. As the balloon ( 60 ) wraps around the strut, it can form a balloon bond ( 270 ) to another portion of the balloon ( 60 ) and form a wrap attachment ( 260 ). When the balloon ( 60 ) becomes partially inflated as shown in FIGS. 3C and 3D , the stent device ( 20 ) is still attached to the balloon ( 60 ). Further inflation of the balloon ( 60 ) as shown in FIGS. 3E and 3F causes the stent device ( 20 ) to become released from the balloon ( 60 ) as the balloon wrap attachments ( 260 ) are forced to let go of the strut ends ( 250 ). For the case where the stent device ( 20 ) is a covered stent ( 90 ), the strut ends ( 250 ) are held by the wrap attachments ( 260 ) and are released as shown in FIG. 3F . A small amount of thrombin, blood coagulant, or clotting agent ( 280 ) can be placed on the outside of the covering ( 100 ) or between the layers of the cover as shown in FIG. 3F if desired to assist in forming a clot when the stent device ( 20 ) is a covered stent ( 90 ) use to provide vascular closure.
[0066] The method of use of the delivery catheter ( 10 ) for vascular closure is shown in FIGS. 4A-4F . The method for delivery of a stent ( 80 ) or covered stent ( 90 ) to the vasculature for a different purpose is identical to this except that the site of delivery for the stent device ( 20 ) may not be for the closure of a large diameter arteriotomy site from a large catheter.
[0067] Access is made with a needle to the femoral artery at a site approximately 1-10 cm (preferably 1-3 cm) distal to a large introducer sheath, IS, being used for passage of a large diameter interventional catheter such as a TAVI or AAA catheter. The small diameter access site, SAS, for the delivery catheter ( 10 ) of the present invention could be greater than 3 cm from the large introducer for the large interventional catheter without deviating from the present invention. A guidewire ( 170 ) of the present invention having a receiving element ( 130 ) at its proximal end is advanced through the needle and past the site of the large diameter introducer sheath, IS, as shown in FIG. 4A . The needle is removed and the receiving element ( 130 ) of the guidewire ( 170 ) is firmly attached to the attachment element ( 120 ) at the distal end of the cone ( 110 ) of the delivery catheter ( 10 ). This attachment can be via screwing, swaging, via a snap fit, a one-way joint, or other joint. The cone ( 110 ) acts as a dilator to enter the arteriotomy and the case ( 190 ) acts as an introducer to hold the arteriotomy site outwards. The delivery catheter ( 10 ) is advanced along with the guidewire ( 170 ) into the vessel until the cone ( 110 ) comes into contact with the large diameter introducer. The large diameter introducer sheath, IS, can then be removed and the delivery catheter ( 10 ) is advanced a small prescribed distance if necessary to place the stent device ( 20 ) adjacent to the arteriotomy site as shown in FIG. 4C . The case ( 190 ) is then retracted in a proximal direction as shown in FIG. 4D thereby exposing the stent device ( 20 ) to the vessel, V, and the balloon ( 60 ) is inflated to press the self-expanding stent device ( 20 ) up against the vessel wall thereby covering the arteriotomy site as shown in FIG. 4E . The covering ( 100 ) on the stent device ( 20 ) covers the opening causing the blood leakage out of the arteriotomy site to cease. A small amount of thrombin or other clotting agent placed on the surface of the covering ( 100 ) or between layers of the ePTFE covering ( 100 ) can help to ensure that the blood clots quickly and leakage is maintained at a minimum. The balloon ( 60 ) is deflated and the delivery catheter ( 10 ) is then removed as shown in FIG. 4F .
[0068] In an alternate embodiment, a guidewire tube ( 290 ) with a separate guidewire lumen ( 300 ) can be placed through the balloon tube ( 30 ), the balloon ( 60 ), and through the cone ( 110 ) as shown in FIG. 5A . This device allows a standard guidewire ( 310 ) to be placed into the vessel, V, using a standard Seldinger approach. A guidewire ( 170 ) could range from 0.010 to −0.038 inches but it would be preferred to use the smaller diameter guidewire ( 170 ) to minimize the profile of the delivery catheter ( 10 ). After the standard guidewire ( 310 ) is in place across the arteriotomy site, AS, the delivery catheter ( 10 ) can be advanced over the standard guidewire ( 310 ) with cone ( 110 ) dilating the small diameter arteriotomy site, SAS, and the case ( 190 ) holding the small arteriotomy site, SAS, outwards. The delivery catheter ( 10 ) is advanced until the cone ( 110 ) comes into contact with the large diameter introducer sheath that is being used for passage of a large therapeutic device such as the TAVI or AAA catheters as shown in FIG. 5B . The large diameter introducer is removed and the delivery catheter ( 10 ) is positioned adjacent to the large diameter arteriotomy site, AS, and the stent device ( 20 ) is delivered in a manner that is similar to that described for the previous embodiment.
[0069] The present invention does not require that a balloon ( 60 ) (as shown in FIG. 1A ) be used to deliver a self-expanding stent device ( 20 ). As seen in FIG. 6 a self-expanding stent device ( 20 ) can be positioned toward the distal end of a catheter shaft ( 320 ) having a cone ( 110 ) positioned at its distal end. The stent device ( 20 ) is contained by an external sheath or case ( 190 ) that can be withdrawn to release the stent device ( 20 ). A pusher tube ( 330 ) located on the catheter shaft ( 320 ) can be used to hold the stent device ( 20 ) in place along the catheter shaft ( 320 ) while the case ( 190 ) is being withdrawn. A control fiber ( 340 ) can form a loop ( 350 ) around one of the struts ( 200 ) of the stent ( 80 ) of the stent device ( 20 ) to hold the stent device ( 20 ) from embolizing or moving out of position within the blood vessel after it has been released. A secondary step could be implemented after the stent device ( 20 ) has been released and the catheter shaft ( 320 ) has been removed from the vessel. A standard balloon dilatation catheter can be introduced into the external sheath or case ( 190 ) to provide a post dilatation to the self-expanding stent device ( 20 ) to ensure that it is in full apposition with the vessel wall.
[0070] In another embodiment a stent ( 80 ) or stent device ( 20 ) can have a stent structure with a hinge ( 360 ) and strut ( 200 ) geometry as described in the cross referenced US patents and US patent application indicated earlier in this application. A balloon expandable hinge ( 360 ) and strut ( 200 ) structure is shown in FIGS. 7A and 7B . The hinge ( 360 ) is the portion of the stent ( 80 ) that undergoes deformation as the stent ( 80 ) is expanded from nondeployed state to a deployed expanded diameter state. The hinge ( 360 ) has a short hinge length ( 380 ) that undergoes all of the deformation as the hinge ( 360 ) is bent along the hinge length ( 380 ) during expansion deformation. The hinge length ( 380 ) for the balloon expandable stent is very short ranging from 1-3 times a hinge width. The hinge length ( 380 ) should be shorter than the hinge width to provide the maximum focus for hinge ( 360 ) deformation during the expansion deformation. The hinge length ( 380 ) is also smaller than the hinge radial dimension ( 400 ). The hinge radial dimension ( 400 ) extends in the radial direction of the stent ( 80 ) and is larger than the strut radial dimension ( 410 ) such that the hinge ( 360 ) will not bend if the stent ( 80 ) of the stent device ( 20 ) is placed into an oval cross section or crush deformation due to exposure to an external force or due to exposure imposed by neighboring muscle groups of the body. The strut radial dimension ( 410 ) is smaller than the hinge radial dimension ( 400 ) such that the strut ( 200 ) will flex easily to allow the stent ( 80 ) to form an oval shape during a crush deformation and will return elastically to its normal shape to provide the stent ( 80 ) with a round shape when the crush deformation force has been removed. The strut width ( 420 ) is larger than the hinge width such that during the expansion deformation, the strut ( 200 ) does not bend and instead forces all of the expansion deformation to occur at the hinges ( 360 ).
[0071] In FIG. 7A the hinge ( 360 ) is connected to two struts ( 200 ) via two transition regions ( 430 ). The transition regions ( 430 ) do not flex in either the expansion deformation or a crush deformation. The transition region radial dimension for this embodiment tapers from the strut radial dimension ( 410 ) to the hinge radial dimension ( 400 ). The cross sectional area (defined by the radial direction and width direction) of the transition region ( 430 ) is larger than that of the strut ( 200 ) or the hinge ( 360 ). The embodiment of FIG. 7B has two hinges ( 360 ) each of which connect to a strut ( 200 ) via a transition region ( 430 ). Each hinge ( 360 ) of this embodiment connect to the other hinge ( 360 ) via a node ( 440 ) that does not bend during the expansion deformation and does not bend in the radial direction during a crush deformation. The other reference numerals used in FIG. 7B represent similar components as found in FIG. 7A .
[0072] The use of a balloon expandable stent device ( 20 ) of the present embodiment either with or without a covering ( 100 ) allows the stent device ( 20 ) to be crimped onto the balloon ( 60 ) of the present invention as described in FIG. 1A-1C . Upon removal of the external sheath or case ( 190 ), the stent ( 80 ) will remain in position adjacent to the arteriotomy site and held onto the balloon via a crimping mechanism. Expansion of the balloon ( 60 ) will place the stent device ( 20 ) into direct apposition with the vessel wall such that the stent ( 80 ) or stent device ( 20 ) will generate hemostasis. If the femoral artery is exposed to external forces, the stent ( 80 ) will bend elastically along the struts ( 200 ) to an oval shape and will return to a round shape. The wall structure for the stent ( 80 ) of the stent device ( 20 ) of this embodiment can be an open structure, closed structure, a zigzag structure; it can have individual zigzag ringlets ( 225 ), or connectors ( 220 ) that join individual stent ringlets ( 225 ), or a spiral shaped zigzag structure; the stent ( 80 ) can be formed from a single ringlet ( 225 ) located and attached to each end of the covering ( 100 ), or it can extend throughout most or all of the covered stent device ( 20 ).
[0073] A self-expanding stent device ( 20 ) of still another embodiment provides a stent ( 80 ) that has a self-expanding hinge structure as shown in FIG. 8 . The difference in this embodiment from that described in FIGS. 7A and 7B is that the hinge length ( 380 ) is longer. The expansion deformation of this embodiment is not focused as it was in the balloon expandable hinge geometry shown in FIGS. 7A and 7B . Instead the expansion deformation is spread along a hinge length ( 380 ) that extends from the junction of the hinge ( 360 ) from one transition region ( 430 ) to another transition region ( 430 ) as shown in FIG. 8 . The hinge length ( 380 ) for the self-expanding stent device ( 20 ) is larger than 3 times the hinge width ( 390 ). The hinge length ( 380 ) for materials such as stainless steel or other generally plastically deformable metals is greater than twice the strut width ( 420 ). The long hinge length ( 380 ) allows the hinge ( 360 ) to undergo a deformation during compression for delivery within the external sheath in a smaller diameter state and undergo expansion deformation elastically to an enlarged expanded diameter upon release into the blood vessel. Thus the long hinge length ( 380 ) provides the stent device ( 20 ) with its self-expanding character. Other reference numerals describe similar components described in FIGS. 7A and 7B .
[0074] The self-expanding hinge stent ( 80 ) of FIG. 8 can be used in the stent device ( 20 ) of the present invention to provide a stent ( 80 ) that has very soft flex in a crush deformation by forming a strut ( 200 ) with a strut radial dimension ( 410 ) that is relatively small (i.e., 0.002-0.003 inches) in comparison to existing femoral stents, (i.e., 0.004-0.005 inches). The hinge radial dimension ( 400 ) can be relatively larger (i.e., 0.006 inches) than existing femoral stent (0.004-0.005 inches) to provide a stronger stent that resists reduction in diameter.
[0075] The balloon expandable hinge stent ( 80 ) of FIGS. 7A and 7B can be combined with any self-expanding stent including the self-expanding hinge stent ( 80 ) of FIG. 8 to form a stent having both a self-expanding portion ( 450 ) and a balloon expandable portion ( 460 ) as shown in FIGS. 9A and 9B . Balloon expandable ringlets ( 225 ) can be placed at each end of the stent device ( 20 ) such that the stent device ( 20 ) is firmly attached to the balloon ( 60 ) as shown in FIG. 9B ; the central stent portion of the stent device ( 20 ) can be formed from self-expanding ringlets ( 225 ). The ringlets ( 225 ) can be attached directly to the covering ( 100 ) or can be attached to each other via connectors ( 220 ) or via one or more biodegradable fibers ( 480 ). Alternately, one or more balloon expandable ringlets ( 225 ) can be place in the central portion of the stent device ( 20 ) and one or more self-expanding ringlets ( 225 ) can be placed at the end portions of the stent device ( 20 ) as shown in FIG. 9A . The self-expanding ringlets ( 225 ) provide a soft and flexible deformation that is desirable in the femoral artery near the arteriotomy site.
[0076] In a further embodiment a locator balloon ( 490 ) is placed into the large introducer sheath, IS, prior to introduction of the delivery catheter ( 10 ) of the present invention to help position the delivery catheter ( 10 ) as shown in FIGS. 10A-10D . The locator balloon ( 490 ) is placed into the blood vessel, V, and inflated via a locator balloon inflation port ( 495 ) with an inflation medium that can include saline, air, CO2, contrast medium, or a cross-linkable polymer. The locator balloon ( 490 ) is pulled back to the arteriotomy site, AS, along with the large introducer sheath, IS. The locator balloon ( 490 ) provides hemostasis to the arteriotomy site and also can be used to occlude or partially occlude the vessel lumen, VL, as shown in FIG. 10B . As the delivery catheter ( 10 ) is introduced into the vessel lumen, VL, as shown in FIGS. 4A-4D , the delivery catheter ( 10 ) impinges upon the locator balloon ( 490 ), thereby stopping the delivery catheter ( 10 ) from further advancement past the locator balloon ( 490 ).
[0077] A tether fiber ( 500 ) of one embodiment is attached to the distal end ( 510 ) of the locator balloon ( 490 ). Applying tenstion to the tether fiber ( 500 ) via a tensioning spool ( 515 ) will cause the locator balloon ( 490 ) to form inward folds ( 520 ) and advance inside of the locator balloon shaft ( 525 ) thereby providing a passage for the delivery catheter ( 10 ) at a location adjacent to the arteriotomy site, AS, as shown in FIG. 10C . The locator balloon ( 490 ) still provides hemostasis of blood at the arteriotomy site. The stent device ( 20 ) of the delivery catheter ( 10 ) is then released adjacent to the arteriotomy site, AS, and into contact with the locator balloon ( 490 ). The locator balloon ( 490 ) can fully withdrawn into the locator balloon ( 490 ) shaft and out of the arteriotomy site, AS, as the balloon ( 60 ) from the delivery catheter ( 10 ) is delivered into apposition with the vessel wall at the arteriotomy site as shown in FIG. 10D . The locator balloon ( 490 ) can be formed with more than one tether or with a shape that enhances its ability to provide positioning for the delivery catheter ( 10 ) and also to provide hemostasis for the arteriotomy site.
[0078] The locator balloon ( 490 ) can alternately be partially implanted and serve as a plug for the arteriotomy site as shown in FIGS. 11A and 11B . In FIG. 11A the locator balloon ( 490 ) has been filled with a cross-linking polymer such as polyurethane, silicone, or a biodegradable material such as polyethylene glycol, or other biodegradable gel or fluid including saline. A balloon valve ( 530 ) is located near the junction of the locator balloon ( 490 ) with the locator balloon ( 490 ) distal shaft such that the inflation fluid can enter but cannot leak out of the locator balloon ( 490 ) and through the locator balloon shaft ( 525 ). A temporary passage (not shown) can be provided to allow inflation fluid to leak out of the locator balloon ( 490 ) and through a temporarily placed passage tube that extends through the balloon valve ( 530 ), for example. As the stent device ( 20 ) is dilated via the delivery catheter ( 10 ) to provide apposition of the stent device ( 20 ) with the vessel wall, the inflation fluid within the locator balloon ( 490 ) is forced to push the locator balloon ( 490 ) into forming a seal with the arteriotomy site. The locator balloon proximal shaft ( 550 ) is separated from the locator balloon distal shaft ( 540 ) via a threaded uncoupling or any other uncoupling mechanism that can be used to uncouple two tubings with a common lumen. The balloon valve ( 530 ) remains implanted in the arteriotomy site along with the locator balloon ( 490 ). The stent device ( 20 ) in this embodiment could include the stent ( 80 ) either with or alone without a covering ( 100 ) and depend upon the locator balloon ( 490 ) to provide the seal for the arteriotomy site.
[0079] The material of construction for the locator balloon ( 490 ) include nylon, pebax, polyethylene terephthalate (PET), polyurethane, silicone, or other compliant, semicompliant, or noncompliant materials used for balloon, stent ( 80 ), or implanted medical device manufacture in the medical device industry. The locator balloon ( 490 ) can also be formed from thin-walled ePTFE, a thin tissue material, or a flexible biodegradable tissue or film. The tether fiber ( 500 ) can be formed from a thin metal or polymeric fiber and can also be formed from a biodegradable material. The locator balloon distal shaft ( 540 ) can be formed from a polymeric material including a biodegradable materials indicated for the locator balloon ( 490 ). The tether valve can be a standard duck-billed valve formed from a thin polymeric leaflets or tissue leaflets; the tether valve can also be formed from biodegradable materials indicated for the locator balloon ( 490 ).
[0080] The dimensions for the locator balloon ( 490 ) as it is being used is further described during the following method steps. The locator balloon ( 490 ) is folded during entry into the large introducer sheath, IS, and into the vessel lumen, VL, of the blood vessel, V. The locator balloon ( 490 ) is then inflated via the locator balloon inflation port ( 495 ) with inflation medium to a volume or pressure that causes it to expand to a diameter that is 10-50% larger than the arteriotomy site, AS, and the inside diameter of the IS; this diameter can range from 4-11 mm; the locator balloon inflated diameter is approximately 6-9 mm for a TAVI procedure access site arteriotomy. The locator balloon shaft ( 525 ) is withdrawn proximally until the locator balloon ( 490 ) is in full contact with the arteriotomy site and the IS has its distal end adjacent the locator balloon ( 490 ). The locator balloon ( 490 ) is then inflated to a diameter that fills the lumen of the femoral artery, approximately 7-10 mm to provide an inflated locator balloon ( 490 ) into which the delivery catheter ( 10 ) will contact when it is inserted. The locator balloon ( 490 ) can have traction applied to the tether fiber ( 500 ) to cause the distal end of the locator balloon ( 490 ) to inwardly fold into the locator balloon shaft ( 525 ) and provide a space in the lumen of the blood vessel, V, for passage of the delivery catheter ( 10 ).
[0081] The embodiments of the present invention include both self-expanding and balloon expandable stents and covered stents ( 90 ) that form the stent device ( 20 ). The stents ( 80 ) can be formed from single ringlets ( 225 ) located at the end of the covering ( 100 ) or can extend throughout the stent device ( 20 ). The delivery catheter ( 10 ) and stent device ( 20 ) can be used with a balloon dilatation catheter or without, and can be used with or without the locator balloon ( 490 ). Each of the embodiments can be interchanged with other aspect of other embodiments and still are included in the present invention.
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TECHNICAL FIELD
[0001] The instant invention relates to accessory holders, particularly, holders designed to hold personal grooming accessories.
BACKGROUND OF THE INVENTION
[0002] Personal accessories, such as hair clips, barrettes, annular elastic hair ties, and various items of jewelry are most commonly stored in a drawer or tray, where they are likely to become entangled or mislaid. Additionally, items like hair clips or earrings, which a wearer might use in pairs or as multiple items, become separated from matching items when stored loosely. This requires time consuming searching for the match for a particular item. Also, items such as the above often have sharp projections that can injure a person rifling through a messy drawer, or pose an unseen hazard to the feet when inadvertently dropped to the floor. Small, loose, scattered objects pose a risk to children and pets that may ingest them. As these types of items are frequently stored in bathrooms, the small object may pose retrieval or drain clogging dangers if they fall into a sink or become unhygienically contaminated upon falling onto a bathroom floor or into other appliances.
[0003] Various devices have attempted to deal with aspects of these problems, although none as reasonably and effectively as the instant invention. U.S. Pat. No. 5,031,758 to Gonzalez is typical of those devices which utilize a hanging braid type device to hold items. The braid may tend to swing away from the user attempting to mount items, possibly requiring the use of two hands to affix or release items. Additionally, the braid, being of a soft and absorbent material, is inherently more difficult to clean than the instant invention. Elastic items, such as annular elastic hair ties, cannot be easily fastened to a braid, and must be stored, in the '758 device, in bins, thus decreasing the utility of the display feature. Similar problems affect other braid like display devices, such as those of U.S. Pat. No. 6,076,685 and U.S. Pat. No. 5,452,806.
[0004] Rigid or semi-rigid accessory holders have different problems, as can be illustrated by U.S. Pat. No. 5,626,503. This single pole accessory holder has a small base and would be top-heavy, making it unsuitable for use as a free standing unit, as it is, in fact, designed to be hung from a hook. Accessories such as hair clips and annular elastic hair ties may be mixed on top of and below other items on the holder, leading to the possibility of knocking various items off of the display when attempting to retrieve others. Additionally, elastic items such as annular elastic hair ties are held in a partially stretched position, such that, over time, storage on such a device lo will tend to fatigue the elastic members upon which these annular ties depend for their functioning.
[0005] Accordingly, the art has needed a means for improving the art of accessory storage. While some of the prior art devices attempted to improve the state of the art of accessory storage, none has achieved the unique and novel configurations and capabilities of the present invention. The present invention makes many improvements over the current state of the art. First, the plurality of grippable surfaces makes it easy and convenient to store a wide range of items. Second, paired or multiple items may be easily stored in proximity to each other. The grippable surfaces themselves are easily cleaned. In some embodiments, the accessory holder is enclosed, preventing accumulation of dust upon the stored items. Additionally, the present invention may accommodate widely varying sizes of clips without causing fatigue to the spring and elastic elements. With these capabilities taken into consideration, the instant invention addresses many of the shortcomings of the prior art and offers significant benefits heretofore unavailable. Further, none of the above inventions and patents, taken either singly or in combination, is seen to describe the instant invention as claimed.
SUMMARY OF INVENTION
[0006] In its most general configuration, the instant invention is an accessory device holder capable of holding a plurality of accessory devices, such as, by way of example and not limitation, hair clips, bows, barrettes, ties, and other hair accessories; as well as various items of jewelry. A plurality of internal attachment members hold clip type devices, while various posts, suspension devices, flexible attachment members, drawers, and retainers are provided in different embodiments to accommodate a wide array of items.
[0007] The device may be relatively open, being formed only with a base and at least one side or it may be more enclosed with the addition of top, back, and face plates, as well as doors, in differing embodiments. The device may be free-standing, and may be supplied with suction grips to enhance adhesion to various surfaces. It may also be provided with a mounting device so that the entire device may be hung on the wall, back of door, or other surface. The device may have mirrors on various front surfaces to make it easier for the user to adjust accessories and appearance, and it may be fitted with an interior light to make it easier to see small items within the device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] Without limiting the scope of the present invention as claimed below and referring now to the drawings and figures:
[0009] [0009]FIG. 1 shows an accessory holding device of the instant invention in elevated perspective view, in reduced scale;
[0010] [0010]FIG. 2 shows the accessory holding device of FIG. 1, in front elevation view, in reduced scale;
[0011] [0011]FIG. 3 shows a variation in the accessory holding device in elevated perspective view, in reduced scale;
[0012] [0012]FIG. 4 shows a variation in the accessory holding device of FIG. 3 in front elevation view, in reduced scale;
[0013] [0013]FIG. 5 shows a variation in the accessory holding device in elevated perspective view, in reduced scale;
[0014] [0014]FIG. 6 shows a variation in the accessory holding device of FIG. 5, in front elevation view, in reduced scale;
[0015] [0015]FIG. 7 shows a variation in the accessory holding device, in elevated perspective view, in reduced scale;
[0016] [0016]FIG. 8 shows a variation in the accessory holding device of FIG. 7 in front elevation view, in reduced scale;
[0017] [0017]FIG. 9 shows a variation in the accessory holding device, in elevated perspective view, in reduced scale; and
[0018] [0018]FIG. 10 shows a variation in the accessory holding device of FIG. 10, in elevated perspective view, in reduced scale.
[0019] Also, in the various figures and drawings, the following reference symbols and letters are used to identify the various elements described herein below in connection with the several figures and illustrations: C, T, N, B.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The accessory holder of the instant invention enables a significant advance in the state of the art. The preferred embodiments of the apparatus, seen in FIGS. 1 through 10, accomplish this by new and novel arrangements of elements that are configured in unique and novel ways and which demonstrate previously unavailable but preferred and desirable capabilities.
[0021] The detailed description set forth below in connection with the drawings is intended merely as a description of the presently preferred embodiments of the invention, and is not intended to represent the only form in which the present invention may be constructed or utilized. The description sets forth the designs, functions, means, and methods of implementing the invention in connection with the illustrated embodiments. It is to be understood, however, that the same or equivalent functions and features may be accomplished by different embodiments that are also intended to be encompassed within the spirit and scope of the invention.
[0022] These variations, modifications, alternatives, and alterations of the various preferred embodiments, arrangements, and configurations may be used alone or in combination with one another as will become more readily apparent to those with skill in the art with reference to the following detailed description of the preferred embodiments and the accompanying figures and drawings.
[0023] In a basic embodiment, seen in FIG. 1 and 2 , an accessory holding device 50 comprises at least one sidewall 100 having an inner surface 140 and an outer surface 150 , and a base plate 200 , wherein the base plate 200 is attached to the at least one sidewall 100 . There are a plurality of internal attachment members 300 , wherein the members 300 are releasably attached to the at least one sidewall 100 , and are adapted to hold, by way of example and not limitation, such items as hair clips C. The plurality of internal attachment members 300 may vary in shape and size to accommodate varying sizes and configurations of hair clips C.
[0024] Numerous variations are possible on this theme. By way of example and not limitation, as seen in FIGS. 3 and 4, at least one of the plurality of internal attachment members 300 may have a grip enhancing surface 310 . The grip enhancing surface 310 may include a variety of surface texture variations on the plurality of internal attachment members 300 , or they may be externally applied. Common externally applied grip enhancing surfaces 310 may include corrugated plastic and rubber coatings that may additionally include antimicrobial characteristics. In the case of corrugated coatings, the corrugations may be sized to cooperate with the teeth spacing of common hair clips C.
[0025] Additionally, there may be at least one suspension device 220 attached to the base plate 200 . The suspension devices 220 may be as simple as common hooks in some variations, yet may incorporate cushioned cleat type devices for use with particular articles of jewelry.
[0026] Further, the at least one sidewall 100 may have a plurality of sidewall recesses 110 in the inner surface 140 of the at least one sidewall 100 that are formed to receive the plurality of internal attachment members 300 . The plurality of sidewall recesses 110 may simply be smooth recesses sized and configured to cooperate with the plurality of attachment members 300 , or they may be fitted with a number of mechanical joining means. For instance, one embodiment may include sidewall recesses 110 that are internally threaded to mate with corresponding threads on the plurality of attachment members 300 . Alternatively, the sidewall recesses 110 may include quick-turn mechanical lock fittings to securely retain the plurality of attachment members 300 .
[0027] With further reference to FIGS. 3 and 4, the device 50 may have the at least one sidewall 100 configured with a plurality of attachment member receivers 120 that are formed to communicate between the at least one sidewall inner surface 140 and the at least one sidewall outer surface 150 , and further formed to releasably receive the plurality of internal attachment members 300 . One skilled in the art will realize that such a plurality of attachment member receivers 120 will allow great flexibility in the possible arrangement of the internal attachment members 300 within the device 50 .
[0028] Utility is not confined to the internal aspects of the device 50 , as it is easily possible to configure the device 50 with a wide variety of external attachments, as seen in FIGS. 3 through 9. The at least one sidewall 100 outer surface 150 may have at least one auxiliary sidewall recess 130 formed to releasably receive at least one external attachment member 400 , as seen in FIGS. 3, 4, and 7 . Further, the at least one external attachment member 400 may have a grip enhancing surface 410 similar to that previously described in relation to the plurality of internal attachment members 300 . The at least one external attachment member 400 may be formed, by way of example and limitation, as an accessory retainer 420 , seen in FIG. 9, formed to hold such items, by way of example and not limitation, necklaces N and bracelets B. There may be a flexible attachment member 430 suspended from the at least one external attachment member 400 , as seen in FIGS. 7 and 8. Such a flexible attachment member 430 facilitates the attachment and retention of various pinned or clipped articles, such as, by way of example and not limitation, earrings and pins. As one with skill in the art can appreciate, the at least one external attachment member 400 may be integral with one of the plurality of internal attachment members 300 .
[0029] Directing attention now to FIGS. 5, 7, and 10 , the base plate 200 may have at least one auxiliary base plate recess 250 , formed to releasably receive at least one base plate post 230 and, there may be at least one base plate extension 210 extending laterally beyond the point wherein the base plate 200 intersects the at least one sidewall 100 . The base plate extension 210 may have at least one auxiliary base plate recess 250 , as seen in FIG. 5, formed to releasably receive at least one base plate post 230 . Such posts 230 are formed to hold a plurality of accessories, such as, by way of example and not limitation, annular elastic hair ties T. Storing various elastic devices on the post 230 has the advantage of not storing these elastic devices in a stretched position, and therefore such storage does not contribute to eventual elastic fatigue of the accessory.
[0030] In yet another embodiment, seen in FIG. 9, the base plate 200 may be formed as a base box 240 . The base box 240 may contain at least one suction grip 244 , seen in FIG. 8, to give the device 50 more secure attachment to a plurality of surfaces, as may be desired when locating the device 50 on a countertop or the top surface of the tank of a water closet. To facilitate the storage of various items, in another embodiment, as seen in FIG. 9, the base box 240 may further include at least one drawer 242 .
[0031] In an additional embodiment, seen in FIGS. 3 through 10, the device may further include a back plate 500 , connected to at least one of the at least one sidewalls 100 . There may be a mounting device 510 , seen in FIGS. 3 and 4, attached to at least a portion of the back plate 500 . The mounting device 510 may be formed in an over the door type configuration shown in FIG. 3, or may be formed to secure to towel racks and hangers, or simple mechanical fasteners secured to a wall.
[0032] Further, the back plate 500 may further include a mirror 520 , seen in FIGS. 5 and 6, on at least a portion of the back plate 500 . Similarly functioning to the auxiliary base plate recess 250 described above, the back plate 500 may include at least one auxiliary back plate recess 530 , seen in FIG. 10, formed to releasably receive at least one back plate post 540 .
[0033] Various embodiments enclose the device 50 further, as seen in FIGS. 3 through 6 and 9 . The device 50 may include a top plate 700 , connected to at least one of the at least one sidewalls 100 , as seen in FIG. 9. Additionally, there may be a face plate 600 , seen in FIGS. 3 through 6, connected to at least one of the at least one sidewalls 100 . Further, there may be a mirror 520 on at least a portion of the face plate 600 , as seen in FIGS. 5 and 6, and there may be at least one auxiliary retainer 620 attached to the face plate 600 , seen in FIGS. 3 and 4, formed to releasably retain a plurality of accessories. The at least one auxiliary retainer 620 may be formed as an elastic member designed to stretch and retain items such as brushes and combs.
[0034] As seen in FIG. 9, the device 50 may be further enclosed by employing at least one door 610 , rotably attached to at least one of the at least one sidewalls 100 . To enhance the user's ability to locate items within the device 50 , the device 50 may be fitted with an interior light 800 , as seen in FIG. 10.
[0035] The device 50 may be crafted of a wide variety of materials, including but not limited to wood, metal, plastics and various composites thereof. While for illustrative purposes, the device 50 is shown illustrated with rectangular sidewalls 100 , base plates 200 , back plates 500 , face plates 600 and top plates 700 , such members may be crafted in a wide variety of aesthetically pleasing shapes, and may bear artistic or informative indicia.
[0036] Numerous alterations, modifications, and variations of the preferred embodiments disclosed herein will be apparent to those skilled in the art and they are all anticipated and contemplated to be within the spirit and scope of the instant invention. For example, although specific embodiments have been described in detail, those with skill in the art will understand that the preceding embodiments and variations can be modified to incorporate various types of substitute and or additional or alternative materials, relative arrangement of elements, and dimensional configurations. Accordingly, even though only few variations of the present invention are described herein, it is to be understood that the practice of such additional modifications and variations and the equivalents thereof, are within the spirit and scope of the invention as defined in the following claims.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. patent application Ser. No. 12/592,237, filed Nov. 21, 2009, which is a Continuation-In-Part of U.S. patent application Ser. No. 11/811,911 filed Jun. 12, 2007, which is a Divisional application of U.S. patent application Ser. No. 10/292,732 filed Nov. 12, 2002, which claims benefit of priority to New Zealand provisional patent No. 515432 filed Nov. 13, 2001, and U.S. provisional patent application Ser. No. 60/405,909 filed Aug. 26, 2002, each of which is incorporated by reference herein in their entirety.
[0002] Inventor Lloyd Hung Loi Tran reflects a legal name change from Loi H. Tran.
SUMMARY OF THE INVENTION
[0003] One aspect the invention provides cyclic Prolyl Glycine compounds suitable for the treatment or prevention of disease and injury in animals and humans. The cyclic PG being selected from the group that includes cPG, cPG analogues, cPG peptidomimetics and relating compounds which promote or cause the formation of cPG or cPG analogues in vivo.
[0004] One example of cPG analogues is cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) or being abbreviated as cyclic(tri(Pro-Gly)) or referred herein as c(PG)3.
[0005] Another example of the cPG analogues is cyclic Glycyl-2-Allyl Proline, referred herein as cGAL.
[0006] Collectively the cPG, c(PG)3 and cGAL are referred herein collectively as the “cPG compounds”.
[0007] Preferably the cPG compounds are administered in a pharmaceutically acceptable composition.
[0008] More preferably the composition additionally includes a therapeutic amount of a cPG compound in combination with a compound selected from growth factors and associated derivatives (insulin-like growth factor-I [IGF-I], insulin-like growth factor-II GPE, transforming growth factor-ill, activin, growth hormone, nerve growth factor, growth hormone binding protein, JQF-binding proteins [especially JGFBP-3], basic fibroblast growth factor, acidic fibroblast growth factor, the hst/Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor. Additional members of the FGF family include, for example, int-2, fibroblast growth factor homologous factor-I (FHF-1) FHF-2 FHF-3 and FHF-4, karatinocyte growth factor 2, glial-activating factor, FGF-10 and FGF-16, ciliary neurotrophic factor, brain derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 [BMP-2], glial-cell line derived neurotrophic factor, activity-dependant neurotrophic factor, cytokine leukaemia inhibiting factor, oncostatin M, interleukin), β,α,χ or consensus interferon, TNF-α; clomethiazole; kynurenic acid, Semax, FK506 [tacrolimus], L-threo-1-pheyl-2-decanoylamino-3-morpholino-1-propanol, andrenocorticotropin-(4-9 — analogue [ORG2766] and dizolcipine [MK-801], selegiline; glutamate antagonists such as, NPS15O6, GV1505260, MK-801, GV150526; AMPA antagonists such as 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (f)quinoxaline (NBQX), LY303070 and LY300164; anti-inflammatory agents directed against the addressin MAdCAM-1 and/or it integrin α4 receptors (α4β1 and α4β7), such as anti-MAdCAM-11mAb MECA-367 (ATCC accession no. (HB-9478), interferons including interferon beta 1b and interferon alfacon-1.
[0009] Preferably the cPG compounds may be used in the treatment or prevention of cell damage or cell death in response to diseases and injury resulting from septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, gastritis, ulcerative colitis, Crohn's disease, diabetes, rheumatoid arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, cirrhosis, allograft rejection, transplant rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis glomerulonephritis, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcer, keratitis, cataract, retinal disorders, age-related macular degeneration, optic neuritis ileitis, inflammation induced by overproduction of inflammatory cytokines, hemorrhagic shock, anaphylactic shock, burn, infection leading to the overproduction of inflammatory cytokines induced by bacteria, virus, fungus, and parasites, hemodialysis, chronic fatigue syndrome, stroke, cancers, cardiovascular diseases associated with overproduction of inflammatory cytokines, heart disease, cardiopulmonary bypass, ischemic/reperfusion injury, ischemic/reperfusion associated with overproduction of inflammatory cytokines, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune disorders, eczema, psoriasis, heart failure, dermatitis, urticaria, cerebral ischemia, systemic lupus erythematosis, AIDS, AIDS dementia, chronic neurodegenerative disease, chronic pain, priapism, cystic fibrosis, amyotrophic lateral sclerosis, schizophrenia, depression, premenstrual syndrome, anxiety, addiction, migraine, Huntington's disease, epilepsy, gastrointestinal motility disorders, obesity, hyperphagia, neuroblastoma, malaria, hematologic cancers, myelofibrosis, lung injury, graft-versus-host disease, head injury, CNS trauma, hepatitis, renal failure, chronic hepatitis C, paraquat poisoning, transplant rejection and preservation, fertility enhancement, bacterial translocation, circulatory shock, traumatic shock, hemodialysis, hangover, and combinations of two or more thereof.
[0010] Preferably the cPG compounds may be used in the restoration of myelination of axons in mammals where myelin depleted due to neural injury or disease.
[0011] Preferably cPG compound may be used in the restoration of myelination where depletion due to trauma, toxin exposure, asphyxia or hypoxia-ischemia, perinatal hypoxic-ischemic injury, injury to or disease of the white matter of the CNS, acute brain injury, chronic neurodegenerative disease including multiple sclerosis, and demyelinating diseases and disorders including acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, Devic's disease, the leucodystrophies; non-inflammatory involvement; progressive multifocal leukoencephalopathy, and central pontine myelinolysis.
[0012] Preferably the cPG compound will be administered in combination with IGF-1 or an interferon.
[0013] Another related aspect the invention relates to a method of treating or preventing cell damage or cell death in response to injury and disease by administering at least one cPG compound.
[0014] Preferably the cPG compound will be administered at between about 1 μg to about 150 mg per kilogram of bodyweight. A suitable dosage for administration of cPG may be, for example, at between 0.1 mg to about 100 mg per kilogram of body weight, at between about 1 mg to about 75 mg per kilogram of body weight, at between 10 mg to about 50 mg per kilogram of body weight, or at between about 20 mg to about 40 mg per kilogram of bodyweight.
[0015] A further aspect the invention relates to a method of restoring the myelination of axons in a mammal in need of restored myelination due to neural injury or disease, comprising administering a therapeutic amount of a cPG compound, where a cPG compound comprises cPG, a biologically active cPG analogue such as c(PG)3 and cGAL, a biologically active cPG peptidomimetic, a compound that increases the concentration of cPG, or a compound that increases the concentration of cPG analogues, effective to restore myelination of axons in a mammal. In one aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of a cPG compound comprises stimulation of astrocytes to promote remyelination. In another aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of a cPG compound comprises stimulation of oligodendrocytes to produce myelin.
[0016] In yet another aspect of the invention, the method of restoring myelination of axons to a mammal in need of restored myelination further comprises administering a therapeutic amount of a cPG compound in combination with a compound selected from IGF-I or an interferon. In one aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of a cPG compound in combination with IGF-I or an interferon to stimulate astrocytes to promote remyelination. In another aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of cPG in combination with IGF-I or an interferon to stimulate oligodendrocytes to produce myelin. In preferred embodiments, the interferon comprises interferon beta lb (Betaseron). In a further most preferred embodiment, the interferon comprises consensus interferon (Infergen®, interferon alfacon-1).
[0017] In still a further aspect of the invention, the methods to treat or prevent cell damage and death in response to injury and disease, comprises administration of a therapeutic amount of a cPG compound in an amount from about 1 μg to about 150 mg of cPG per kg of body weight of the mammal.
[0018] In yet another aspect of the invention, the method of restoring myelination of axons to a mammal in need of restored myelination further comprises administering a therapeutic amount of a cPG compound in combination with IGF-I from about 1 to 10 mg of IGF-I per 1 Kg body weight of the mammal or an interferon from about 0.1 to 1000 μg of IGF-I per 100 g of body weight of the mammal. In a preferred embodiment, the interferon is interferon beta. In the most preferred embodiment, the interferon is interferon beta 1b (Betaseron). In a further most preferred embodiment, the interferon comprises consensus interferon (Infergen®, interferon alfacon-1).
[0019] In a further preferred embodiment of the methods to treat or prevent cell damage and death in response to injury and disease, comprising administration of a cPG compound, the cPG compound is administered to the mammal through a shunt into a ventricle of the mammal.
[0020] In a further preferred embodiment of the methods to treat or prevent cell damage and death in response to injury and disease, comprising administration of a cPG compound, the cPG compound is administered to the mammal by peripheral administration.
[0021] The present invention provides a method of treatment for stimulating mature astrocytes to promote myelin production after hypoxic-ischemic injury including the step of increasing the active concentration of cPG and/or the concentration of analogues of cPG in the CNS of mammals.
[0022] Most preferably, it is the effective amount of IGF-I itself that is increased within the CNS of the mammal. This can be effected by direct administration of a cPG compound such as cPG, c(PG) 3 or cGAL and indeed this is preferred. However, the administration of compounds that indirectly increase the effective amount of IGF-I (for example a pro-drug which, within the patient is cleaved to release cPG) is in no way excluded.
[0023] The active compound (IGF-I or its analogue or its mimetic) can be administered alone, or as is preferred, a part of a pharmaceutical composition.
[0024] The composition can be administered directly to the CNS. The latter route of administration can involve, for example, lateral cerebro-ventricular injection, focal injection or a surgically inserted shunt into the lateral cerebro-ventricle of the brain of the patient.
[0025] Conveniently, the stimulation and promotion of myelin production in oligodendrocytes and the support, stimulation and promotion of remyelination by mature astrocytes is promoted through the administration of cPG compounds in the prophylaxis or therapy of demyelinating diseases such as multiple sclerosis.
BRIEF DESCRIPTION OF DRAWINGS
[0026] A better understanding of the invention will be gained from reference to the following examples and drawings wherein:
[0027] FIG. 1 illustrates the proposed metabolism pathway of cis-GPE to cyclic Prolyl Glycine and glutamic acid.
[0028] FIG. 2 illustrates the proposed mechanism by which cyclic Prolyl Glycine may act to bind metal ions.
[0029] FIG. 3 illustrates in graphic form Glutamate toxicity in cerebellar microexplants (P4) and rescue effect by cyclic GP.
[0030] FIG. 4 illustrates in graphic form prevention of glutamate toxicity by cyclic GP monitored within P4-cerebellar microexplants.
[0031] FIG. 5 illustrates in graphic form effects of cPG on functional recovery after 6-OHDA lesion
DETAILED DESCRIPTION OF THE INVENTION
[0032] The following examples are given by way of illustration only and shall not be taken as limiting the scope of the invention.
[0033] It has been surprisingly discovered that the process of the metabolism of IGF1 to the tripeptide GPE and des IGF is only a part of the process.
[0034] The cis-isomer of the GPE can further break down to form a cyclic Prolyl Glycine and glutamic acid. This is shown in FIG. 1 .
[0035] The cyclic PG structure is sufficiently small to allow it to cross the blood-brain barrier.
[0036] In addition, as shown in FIG. 2 the structure of the molecule is such that it is able to provide ligands for binding metal ions such as Mg 2 +, Ca 2t , Co 2 + and the like and as such can act as a chelating agent.
[0037] The possible role of cPG as an agent is further supported by the companion break down product, glutamic acid.
[0038] Glutamic acid is known to be associated with brain disease. (Johnston, G. A. R. in Roberts P. J. et al Editors, Glutamate: Transmitter in the Central Nervous System, John Wiley & Sons, 1981, pp. 77-87).
[0039] As used herein, a cPG compound is a compound with biological activity similar or identical to the biological activity of cPG; cPG compounds comprise cPG, biologically active cPG analogues, biologically active cPG mimetics, and compounds that increase the concentration of cPG and cPG analogues in a mammal. cPG compounds include cPG agonist molecules such as truncated portions of IGF-I compounds as well as other chemical and biological analogues and mimetics.
[0040] As used herein, “cPG analogue” is any analogue of cPG, naturally occurring analogue of cPG, or any variants thereof, which are capable of effectively binding to mGluR receptors in the CNS and of promoting an equivalent neuroprotective effect on CNS nerve cells, Examples of cPG analogues are c(PG)3 and cGAL
[0041] The term “cPG agonist molecules” includes peptide fragments and truncated portions of longer IGF-I compounds as well as other chemical and biological analogues and mimetics. cPG compounds can be used in the treatment of mammals, suffering from neutral injury or disease. In particular the cPG compounds can be used to treat human patients, suffering from neural injury or disease. Still more generally, the compositions and methods of the invention find use in the treatment of mammals, such as human patients, suffering from nerve damage or potential apoptotic and/or necrotic cell death, due to injuries and diseases such as septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, gastritis, ulcerative colitis, Crohn's disease, diabetes, rheumatoid arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, cirrhosis, allograft rejection, transplant rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomerulonephritis, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcer, keratitis, cataract, retinal disorders, age-related macular degeneration, optic neuritis ileitis, inflammation induced by overproduction of inflammatory cytokines, hemorrhagic shock, anaphylactic shock, bum, infection leading to the overproduction of inflammatory cytokines induced by bacteria, virus, fungus, and parasites, hemodialysis, chronic fatigue syndrome, stroke, cancers, cardiovascular diseases associated with overproduction of inflammatory cytokines, heart disease, cardiopulmonary bypass, ischemic/reperfusion injury, ischemic/reperfusion associated with overproduction of inflammatory cytokines, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune disorders, eczema, psoriasis, heart failure, dermatitis, urticaria, cerebral ischemia, systemic lupus erythematosis, AIDS, AIDS dementia, chronic neurodegenerative disease, chronic pain, priapism, cystic fibrosis, amyotrophic lateral sclerosis, schizophrenia, depression, premenstrual syndrome, anxiety, addiction, migraine, Huntington's disease, epilepsy, gastrointestinal motility disorders, obesity, hyperphagia, neuroblastoma, malaria, hematologic cancers, myelofibrosis, lung injury, graft-versus-host disease, head injury, CNS trauma, hepatitis, renal failure, chronic hepatitis C, paraquat poisoning, transplant rejection and preservation, fertility enhancement, bacterial translocation, circulatory shock, traumatic shock, hemodialysis, hangover, and combinations of two or more thereof.
[0042] In addition, cPG and its analogues, c(PG)3 and cGAL may be used to treat mammals suffering from white matter insult as the result of acute brain injury, such as perinatal hypoxic-ischemic injury; or from chronic neural injury or neurodegenerative disease, such as multiple sclerosis, or from other demyelinating diseases and disorders including inflammatory involvement, such as acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, Devic's disease, the leucodystrophies; non-inflammatory involvement; progressive multifocal leukoencephalopathy, central pontine myelinolysis. Patients suffering from such diseases or injuries will benefit greatly by a treatment protocol able to initiate re-myelination.
[0043] The present invention has application in the induction of myelin production following insult in the form of trauma, toxin exposure, asphyxia or hypoxia-ischemia, and has application in the treatment or prevention of apoptosis in response to injury or disease in the form of cancers, viral infections, autoimmune diseases, neurological diseases and injuries and cardiovascular diseases.
[0044] Ttreatment with cPG or its analogues, c(PG)3 and cGAL may be given before (as well as alter) an injury—as for example before elective surgery. Examples of relevant elective procedures include neural surgery, in which retraction of lobes of the brain may lead to cerebral oedema, or heart operations, such as valve replacement, in which inevitable small emboli are said to lead to detectable impairment of brain function in some 75% of cases.
Pharmacology and Utility
[0045] cPG can act as an anti-necrotic and anti-apoptotic in a process of cell death. Its anti-apoptotic and anti-necrotic activity in vivo can be measured by cell counts. cPG can also be measured in vitro. (Gudasheva T. A. et al. FEBS Letters, Vol. 391, Issues 1-2, 5 Aug. 1996, pp. 149-152). CNS damage may for example be measured clinically by the degree of permanent neurological deficit cognitive function, and/or propensity to seizure disorders. (Rakic L. J. et al, in Rakic L. J et al Peptide and Amino Acid Transport Mechanisms in The Central Nervous System, 1988, The MacMillan Press Ltd. (London) pp. 167-181).
Pharmaceutical Compositions and Administration
[0046] CPG itself is used to prevent or treat cell damage and death and the induction of myelin production. Usually this is effected through the direct administration of cGP to the patient. If desired, a combination of the cPG compounds and its analogues can be administered in a pharmaceutically acceptable composition.
[0047] Those skilled in the art will appreciate there is no intention on the part of the applicants to exclude administration of other forms of cPG. By way of example, the effective amount of cPG in the CNS can be increased by administration of a pro-drug from of cPG, which comprises cPG and a carrier, cPG and the carrier being joined by a linkage which is susceptible to cleavage or digested within the patient. Any suitable linkage can be employed which will be cleaved or digested to release cPG following administration.
[0048] In addition, it is envisaged cPG levels may be increased through an implant that includes a cell line capable of expressing cPG in an active from within the CNS of the patient.
[0049] cPG and its analogues, c(PG)3 and cGAL can be administered as part of a medicament or pharmaceutical preparation. This can involve combining cPG with any pharmaceutically appropriate carrier, adjuvant or excipient. The selection of the carrier, adjuvant or excipient will of course usually be dependent upon the route of administration to be employed.
[0050] The administration route can vary widely. An advantage of cPG is that it can be administered peripherally. This means it need not be administered directly to the CNS of the patient in order to have effect in the CNS.
[0051] Any peripheral route known in the art can be employed. These can include parenteral routes for example injection into the peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracisternal, topical, infusion (using e.g., controlled release devices or minipumps such as osmotic pumps or skin patches), implant, aerosol, inhalation, scarification, intraperitoneal, intracapsular, intramuscular, intranasal, oral, buccal, pulmonary, rectal or vaginal. The compositions can be formulated for parenteral administration to humans or other mammals in therapeutically effective amounts (e.g., amounts which eliminate or reduce the patient's pathological condition) to provide therapy for the neurological diseases described above.
[0052] Two of the preferred administration routes will be by subcutaneous injection (e.g., dissolved in 0.9% sodium chloride) or orally (in a capsule).
[0053] It will also be appreciated that on occasion it may desirable to directly administer IGF-I compounds to the CNS of the patient. Again, this can be achieved by any appropriate direct administration route. Examples include administration by lateral cerebroventricular injection or through a surgically inserted shunt into the lateral cerebroventricle of the brain of the patient.
[0054] The calculation of the effective amount of cPG compounds to be administered is within the skill of one of ordinary skill in the art, and will be routine to those persons skilled in the art. Needless to say, the final amount to be administered will be dependent upon the route of administration and upon the nature of the neurological disorder or condition that is to be treated. Preferably the cPG compound will be administered at between about 1 μg to 100 mg of cPG compound per 100 g of body weight where the dose is administered centrally. A suitable dosage for administration of cPG may be, for example, at between 0.1 mg to about 10 mg per 100 g of body weight, or at between about 1 mg to about 5 mg per 100 g body weight.
[0055] For inclusion in a medicament, cPG compounds can be obtained from a suitable commercial source such as Bachem AG of Bubendorf, Switzerland. Alternatively, cPG can be directly synthesized by conventional methods such as the stepwise solid phase synthesis method of Merrifield et al. 1963 J. Amer. Chem. Soc.: 85, 2149-2156. Alternatively synthesis can involve in the use of commercially available peptide synthesizers such as the Applied Biosystems model 430A.
[0056] cGAL may be prepared by methods such as are well-known to those of ordinary skill in the art of the synthesis of peptides and analogues. Example: “Principles of Peptide Synthesis” by Bodanzsky, published by Springer-Verlag 1993.
[0057] As a general proposition, the total pharmaceutically effective amount of the cPG agonist compound administered parenterally per dose will be in a range that can be measured by a dose response curve. One can administer increasing amounts of the cPG agonist compound to the patient and check the serum levels of the patient for cPG. The amount of cPG agonist to be employed can be calculated on a molar basis based on these serum levels of cPG.
[0058] Specifically, one method for determining appropriate dosing of the compound entails measuring cPG levels in a biological fluid such as a body or blood fluid. Measuring such levels can be done by any means, including RIA and ELISA. After measuring cPG levels, the fluid is contacted with the compound using single or multiple doses. After this contacting step, the cPG levels are re-measured in the fluid. If the fluid cPG levels have fallen by an amount sufficient to produce the desired efficacy for which the molecule is to be administered, then the dose of the molecule can be adjusted to produce maximal efficacy. This method can be carried out in vitro or in vivo. Preferably, this method is carried out in vivo, i.e., after the fluid is extracted from a mammal and the cPG levels measured, the compound herein is administered to the mammal using single or multiple doses (that is, the contacting step is achieved by administration to a mammal) and then the cPG levels are remeasured from fluid extracted from the mammal.
[0059] The compound may also be suitably administered by a sustained-release system. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919; EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., 1983), poly(2-hydroxyethyl methacrylate) (Langer et al, 1981), ethylene vinyl acetate (Langer et al., supra), or poly-D-(−)-3-hydroxybutyric acid (EP 133,988). Sustained-release compositions also include a liposomally entrapped compound. Liposomes containing the compound are prepared by methods known per se: DE Patent 3,218,121; Epstein et al., 1985; Hwang et al., 1980; EP Patent 52,322; EP Patent 36,676; EP Patent 88,046; EP Patent 143,949; EP Patent 142,641; Japanese Pat. Appln. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (from or about 200 to 800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the most efficacious therapy.
[0060] PEGylated peptides having a longer life can also be employed, based on, e.g., the conjugate technology described in WO 95/32003 published Nov. 30, 1995.
[0061] If parenteral administration is preferred, the compound is formulated generally by mixing each at the desired concentration, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically, or parenterally, acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
[0062] Generally, the formulations are prepared by contacting the compound with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, a buffered solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used.
[0063] The carrier may additionally contain additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; glycine; amino acids such as glutamic acid, aspartic acid, histidine, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, trehalose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counter-ions such as sodium; non-ionic surfactants such as polysorbates, poloxamers, or polyethylene glycol (PEG); and/or neutral salts, e.g., NaCl, KCl, MgCl.sub.2, CaCl.sub.2, etc.
[0064] The cPG compound is typically formulated in such vehicles at a pH of between about 5.5 to 8. Typical adjuvants which may be incorporated into tablets, capsules, and the like are a binder such as acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent like corn starch or alginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose or lactose; a flavoring agent such as peppermint, wintergreen, or cherry. When the dosage form is a capsule, in addition to the above materials, it may also contain a liquid carrier such as a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. A syrup or elixir may contain the active compound, a sweetener such as sucrose, preservatives like propyl paraben, a coloring agent, and a flavoring agent such as cherry. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants, and the like can be incorporated according to accepted pharmaceutical practice.
[0065] The compound to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutic compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
[0066] The compound ordinarily will be stored in unit or multi-dose containers, for example, sealed glass ampules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-mL vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous solution of compound, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized compound using bacteriostatic Water-for-Injection.
[0067] Combination therapy with the cPG agonist compound herein and one or more other appropriate reagents that increase total cPG in the blood or enhance the effect of the cPG agonist is also contemplated. These reagents generally allow the cPG agonist compound herein to release the generated cPG.
[0068] In addition, it is envisaged using gene therapy for treating a mammal, using nucleic acid encoding the cPG agonist compound, if it is a peptide. Generally, gene therapy is used to increase (or overexpress) cPG levels in the mammal. Nucleic acids, which encode the cPG agonist peptide can be used for this purpose. Once the amino acid sequence is known, one can generate several nucleic acid molecules using the degeneracy of the genetic code, and select which to use for gene therapy.
[0069] There are two major approaches to getting the nucleic acid (optionally contained in a vector) into the patient's cells for purposes of gene therapy: in vivo and ex vivo. For in vivo delivery, the nucleic acid is injected directly into the patient, usually at the site where the cPG agonist compound is required. For ex vivo treatment, the patient's cells are removed, the nucleic acid is introduced into these isolated cells, and the modified cells are administered to the patient either directly or, for example, encapsulated within porous membranes which are implanted into the patient. See, e.g., U.S. Pat. Nos. 4,892,538 and 5,283,187.
[0070] There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. A commonly used vector for ex vivo delivery of the gene is a retrovirus.
[0071] The currently preferred in vivo nucleic acid transfer techniques include transfection with viral vectors (such as adenovirus, Herpes simplex I virus, or adeno-associated virus) and lipid-based systems (useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Chol, for example). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell-surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins which bind to a cell-surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g., capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, and proteins that target intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., 1987; Wagner et al., 1990). For review of the currently known gene marking and gene therapy protocols, see Anderson 1992. See also WO 93/25673 and the references cited therein.
[0072] Kits are also contemplated for this invention. A typical kit would comprise a container, preferably a vial, for the cPG agonist compound formulation comprising cPG agonist compound in a pharmaceutically acceptable buffer and instructions, such as a product insert or label, directing the user to utilize the pharmaceutical formulation.
EXAMPLES
Experiment 1
[0073] Cyclic PG prevents glutamate induced neuronal death in vitro in a dose related manner.
Materials and Methods:
Cerebellar Cell Culture Preparing and Coating of Cover Slips
[0074] Ten coverslips were placed into a large petri dish and washed in 70% alcohol for 5 minutes, then washed with Millipore H 2 O. The coverslips were air dried, then coated with Poly-D-Lysine (1 mg/ml stock solution in PBS, 90-100 μl) and incubated for 2 hours at 34° C.
Extraction
[0075] Postnatal day 4 Wistar rats were used for the study. Rats were placed in ice for 1 minute, the heads were decapitated and the cerebellum removed on ice. Cerebellum tissue was placed in 1 ml of 0.65% glucose supplemented PBS (10 μl 65% stock D (+)glucose/1 ml PBS) in a large petri dish, chopped up into smaller sections and triturate with a 1 ml insulin syringe via a 23 G (0.4 mm) needle, and then squirted back into the glucose solution on the large petri dish. The tissue was sieved through (125 μm pore size gaze) and centrifuged (2 minutes at 60 g) two times for a medium exchange into serum-free BSA-supplemented START V medium (Biochrom). The second centrifugation step was done with 1 ml of START V medium. The microexplants were reconstituted into 500 μl of START V medium and put on ice
Cultivation and Fixation of Cerebellar Cells
[0076] Two hours after PDL-coating, the slides were washed with Millipore H 2 O and air dried. Each slide was placed into a small 35 mm petri dish and 40 μl of START V/cell suspension added. The tissue was incubated for 2 hours at 34° C. (settlement period). START V-medium (1 ml) was then added to the petri dish and cultivated at 34° C./5% CO2/100% humidity for 48 hours. Cells were rinsed in PBS and then fixed for 2-3 minutes in increasing concentrations of paraformaldehyde (5000 μl of 0.4% PFA was applied; then 1.2% PFA; then 3% PFA and finally 4% PFA—all fixation solutions contain 0.2% glutardialdehyde). Finally, the microexplants were rinsed in PBS.
Drug Application
[0077] 0 μl of toxin (L-glutamate-100 mM in Millipore water) was applied simultaneously with cPG (from bachem, 10 mM stock prepared in PBS and diluted to final concentrations between 1-100 nM) for Study 1. A delay in administration of cPG at 6 hours after glutamate treatment was performed for Study 2.
Result:
[0078] Study 1: Glutamate treatment resulted in 85% loss of cerebellum neurons. Cyclic PG significantly reduced the glutamate induced neuronal death in a dose response manner when administered simultaneously with glutamate ( FIG. 3 ). The treatments with lower doses of cPG (10-100 nM) showed significant recovery from glutamate-induced neurotoxicity.
[0079] Study 2: Cyclic PG showed a significantly recovery from glutamate induced neurotoxicity in a dose range of 1-100 nM when given 6 hours after the glutamate treatment compared to the vehicle treated group ( FIG. 4 ).
[0080] A further lower dose of cPG also showed a significant increase in neuron number compared to the normal control group, suggest a role for cPG in neuronal proliferation and differentiation.
CONCLUSIONS
[0081] Excessive glutamate can cause neuronal excitotoxicity by active NMDA receptors. Cyclic PG completely prevented the glutamate-induced neurotoxicity, when given either immediately or 6 hours after the glutamate treatment by acting as a direct or indirect NMDA antagonist. Given that cPG can agonise mGlu2/3 receptor, which can inhibit NMDA activity. GPE, the pre-hormone for cPG has been shown to be partial NMDA receptor agonist in promoting pCREB, probably due to its antagonistic effect on mGlu2/3 receptors. CPG may be involved in preventing neurons undergoing apoptosis because cPG appeared to be still effective as a delayed treatment, and promoted the neuronal proliferation.
Experiment 2
[0082] cyclic(tri(prolylglycyl)) or c(PG)3 prevents glutamate induced neuronal death in vitro in a dose related manner.
Materials and Methods: (See Above)
Drug Application
[0083] 10 μl of toxin (L-glutamate-100 mM in Millipore water) was applied simultaneously with cyclic(tri(prolylglycyl)) (from NeuroBiomed chemical synthetic group, 10 mM stock prepared in PBS and diluted to final concentrations between 1-100 nM) for Study 1. A delay in administration of cPG at 6 hours after glutamate treatment was performed for Study 2.
Result:
[0084] Study 1: Glutamate treatment resulted in 85% loss of cerebellum neurons. eye lic(tri(prolylglycyl)) significantly reduced the glutamate induced neuronal death by 57% in a dose response manner when administered simultaneously with glutamate. The treatments with lower doses of cyclic(tri(prolylglycyl)) (10-100 nM) showed significant recovery from glutamate-induced neurotoxicity.
[0085] Study 2: cyclic(tri(prolylglycyl)) showed an improvement of approximately 43% significantly recovery from glutamate induced neurotoxicity in a dose range of 1-100 nM when given 6 hours after the glutamate treatment compared to the vehicle treated group.
[0086] A further lower dose of cyclic(tri(prolylglycyl)) also showed a significant increase in neuron number compared to the normal control group, suggest a role for cPG in neuronal proliferation and differentiation.
Experiment 3
[0087] Cyclic Glycyl-2-Allyl Proline or cGAL prevents glutamate induced neuronal death in vitro in a dose related manner.
Materials and Methods: (See Above)
Drug Application
[0088] 10 μl of toxin (L-glutamate-100 mM in Millipore water) was applied simultaneously with cyclic Glycyl-2-Allyl Proline (obtained NeuroBiomed chemical synthetic group, 10 mM stock prepared in PBS and diluted to final concentrations between 1-100 nM) for Study 1. A delay in administration of cPG at 6 hours after glutamate treatment was performed for Study 2.
Result:
[0089] Study 1: Glutamate treatment resulted in 85% loss of cerebellum neurons. cyclic Glycyl-2-Allyl Proline significantly reduced the glutamate induced neuronal death by 63% in a dose response manner when administered simultaneously with glutamate. The treatments with lower doses of cyclic(tri(prolylglycyl)) (10-100 nM) showed significant recovery from glutamate-induced neurotoxicity.
[0090] Study 2: cyclic Glycyl-2-Allyl Proline showed an improvement of approximately 58% significantly recovery from glutamate induced neurotoxicity in a dose range of 1-100 nM when given 6 hours after the glutamate treatment compared to the vehicle treated group.
[0091] A further lower dose of cyclic Glycyl-2-Allyl Proline also showed a significant increase in neuron number compared to the normal control group, suggest a role for cPG in neuronal proliferation and differentiation.
CONCLUSIONS
[0092] Excessive glutamate can cause neuronal excitotoxicity by active NMDA receptors. Cyclic PG analogues, cyclic(tri(prolylglycyl)) and cyclic Glycyl-2-Allyl Proline significantly prevented the glutamate-induced neurotoxicity, when given either immediately or 6 hours after the glutamate treatment by acting as a direct or indirect NMDA antagonist.
[0093] Cyclic PG and its analogues, cyclic(tri(prolylglycyl)) and cyclic Glycyl-2-Allyl Proline may be involved in preventing neurons undergoing apoptosis because cPG appeared to be still effective as a delayed treatment, and promoted the neuronal proliferation.
Experiment 4
[0094] Effects of cPG after 6-OHDA induced nigral-striatal lesion.
Materials and Methods
[0095] Twenty male Wistar rats (280-310 g) were used. After exposing the skull, 6-OHDA (8 μg in a base of 2 μl 0.9% saline containing 1% ascorbic acid) was administered into the right medial forebrain bundle (MFB) using co-ordinates AP+4.7 mm, R 1.6 mmv−8 mm under 3% halothane anaesthesia. 6-OHDA was injected through a 25G needle connected via a polyethylene catheter to a 1000 μl Hamilton syringe, The 6-OHDA was infused by a microdialysis infusion pump at a rate of 0.5 μl/min. The needle was left in the brain for a further 3 minutes before being slowly withdrawn. The skin was sutured with 2.0 silk and the rats were allowed to recover from anaesthesia. The rats were housed in a holding room with free access to food and water at all times except during behavioural testing.
[0096] Cyclic PG was dissolved in saline. Four different doses of cPG (0, 0.1 0.5 1 mg/kg, Bachem) were administered intraperitoneally 2 h post lesion.
[0097] At 7 days post-lesion, rats were injected with 0.1 mg/kg apomorphine and the number of contralateral rotations/hour was recorded and calculated using a computerised Rotameter (St Diego Instruments). Experimenter was blinded from the treatment groups.
Result:
[0098] The group treated with lmg cPG (n=5, 154±64.1) showed a trend toward a reduction in the number of rotations compared to the vehicle treated group (n=5, 290.08±18.9) indicating a role for cPG in improving functional recovery in 6-OHDA induced nigrostriatal injury. ( FIG. 5 )
Experiment 5
[0099] Effects of cyclic(tri(prolylglycyl)) after 6-OHDA induced nigral-striatal lesion.
Materials and Methods (See Above)
[0100] Cyclic(tri(prolylglycyl)) was dissolved in saline solution. Four different doses of Cyclic(tri(prolylglycyl)) (0, 0.1 0.5 1 mg/kg, NeuroBiomed) were administered intraperitoneally 2 h post lesion.
[0101] The group treated with 1 mg cyclic(tri(prolylglycyl)) (n=5, 172+69) showed a trend toward a reduction in the number of rotations compared to the vehicle treated group (n=5, 290.08+18.9) indicating a role for cyclic(tri(prolylglycyl)) in improving functional recovery in 6-OHDA induced nigrostriatal injury.
CONCLUSIONS
[0102] Cyclic(tri(prolylglycyl)) improved the functional recovery after 6-OHDA induced nigral-striatal lesions in a dose related manner.
[0103] This data suggested Cyclic(tri(prolylglycyl)) has potential as a treatment for Parkinson's disease.
Experiment 6
[0104] Effects of Cyclic Glycyl-2-Allyl Proline or cGAL after 6-OHDA induced nigral-striatal lesion.
Materials and Methods (See Above)
[0105] cGAL was dissolved in saline solution. Four different doses of cGAL (0, 0.1 0.5 1 mg/kg, NeuroBiomed) were administered intraperitoneally 2 h post lesion.
[0106] The group treated with lmg cGAL (n=5, 134±69) showed a trend toward a significant reduction in the number of rotations compared to the vehicle treated group (n=5, 292±21) indicating a role for cGALin improving functional recovery in 6-OHDA induced nigrostriatal injury.
CONCLUSIONS
[0107] Cyclic Glycyl-2-Allyl Proline improved the functional recovery after 6-OHDA induced nigral-striatal lesions in a dose related manner.
[0108] This data suggested Cyclic Glycyl-2-Allyl Proline has potential as a treatment for Parkinson's disease.
ADVANTAGES
[0109] Some advantages offered by the present invention with the cyclic peptides, especially over IGF-I and the GPE include:
[0110] The active ingredients are easy to synthesise either in vitro or by other means such as recombinant techniques.
[0111] The peptide as a small molecule can diffuse readily through the body and between compartments (e.g. the blood-brain barrier, and mucous membranes), aiding in the choice of methods for its administration and its ability to reach sites where injury has occurred.
[0112] cPG, c(PG)3 and cGAL are very stable molecule and is unlikely to present a challenge to the immune system, so it may be administered over extended periods and it may be administered prophylactically.
[0113] With their antagonistic and agonistic effects, GPE/cPG, the present invention provides a novel therapeutic method for preventing brain injury and degenerative diseases by regulating mGluRs particularly ⅔ leading to long-term benefits of brain recovery.
[0114] With a role in regulating IGF-I induction, cPG will provide further neuroprotection with less potential for growth side-effects.
[0115] While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of examples only, and not limitation. It will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the present invention as defined in the appended claims. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined in accordance with the following claims and their equivalents.
[0116] All publication, including patent documents and scientific articles, referred to in this application, including any bibliography, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.
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RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 11/442,483, filed May 26, 2006, which is a continuation of U.S. application Ser. No. 10/055,504, filed on Oct. 25, 2001, now issued as U.S. Pat. No. 7,258,700, which claims benefit to U.S. Provisional Application No. 60/311,586 filed Aug. 10, 2001 and is a continuation-in-part of U.S. application Ser. No. 09/696,636 filed on Oct. 25, 2000, now issued as U.S. Pat. No. 6,508,839, which is a continuation-in-part of U.S. application Ser. No. 09/642,450 filed on Aug. 18, 2000, now issued as U.S. Pat. No. 6,482,235, which is a continuation-in-part of U.S. application Ser. No. 09/608,797 filed on Jun. 30, 2000, now issued as U.S. Pat. No. 6,425,919, which claims benefit to U.S. Provisional Application No. 60/172,996 filed Dec. 21, 1999, U.S. Provisional Application No. 60/161,085 filed Oct. 25, 1999, and U.S. Provisional Application No. 60/149,490 filed Aug. 18, 1999, the entire teachings of these applications being incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the surgical treatment of intervertebral discs in the lumbar, cervical, or thoracic spine that have suffered from tears in the anulus fibrosis, herniation of the nucleus pulposus and/or significant disc height loss.
2. Description of the Related Art
The disc performs the important role of absorbing mechanical loads while allowing for constrained flexibility of the spine. The disc is composed of a soft, central nucleus pulposus (NP) surrounded by a tough, woven anulus fibrosis (AF). Herniation is a result of a weakening in the AF. Symptomatic herniations occur when weakness in the AF allows the NP to bulge or leak posteriorly toward the spinal cord and major nerve roots. The most common resulting symptoms are pain radiating along a compressed nerve and low back pain, both of which can be crippling for the patient. The significance of this problem is increased by the low average age of diagnosis, with over 80% of patients in the U.S. being under 59.
Systems and methods for repairing tears in soft tissues are known in the art. Also, disclosed in the art are methods of augmenting the intervertebral disc. However, the efficacious treatment of intervertebral discs has not been adequately addressed using the systems and methods in the art. Accordingly, there still remains a need for devices and methods to treat intervertebral discs that have been compromised, including, but not limited to, discs that have suffered from tears in the anulus fibrosis, herniation of the nucleus pulposus and/or significant disc height loss.
SUMMARY OF THE INVENTION
Various embodiments of the present invention seek to exploit the individual characteristics of various anulus and nuclear augmentation devices to optimize the performance of both within the intervertebral disc. A primary function of anulus augmentation devices is to prevent or minimize the extrusion of materials from within the space normally occupied by the nucleus pulposus and inner anulus fibrosus. A primary function of nuclear augmentation devices is to at least temporarily add material to restore diminished disc height and pressure. Nuclear augmentation devices can also induce the growth or formation of material within the nuclear space. Accordingly, the inventive combination of these devices can create a synergistic effect wherein the anulus and nuclear augmentation devices serve to restore biomechanical function in a more natural biomimetic way. Furthermore, according to the invention both devices may be delivered more easily and less invasively. Also, the pressurized environment made possible through the addition of nuclear augmentation material and closing of the anulus serves both to restrain the nuclear augmentation and anchor the anulus augmentation in place.
One or more of the embodiments of the present invention also provide non-permanent, minimally invasive and removable devices for closing a defect in an anulus and augmenting the nucleus.
One or more of the embodiments of the present invention additionally provide an anulus augmentation device that is adapted for use with flowable nuclear augmentation material such that the flowable material cannot escape from the anulus after the anulus augmentation device has been implanted.
There is provided in accordance with one aspect of the present invention, a disc augmentation system configured to repair or rehabilitate an intervertebral disc. The system comprises at least one anulus augmentation device, and at least one nuclear augmentation material. The anulus augmentation device prevents or minimizes the extrusion of materials from within the space normally occupied by the nucleus pulposus and inner anulus fibrosus. In one application of the invention, the anulus augmentation device is configured for minimally invasive implantation and deployment. The anulus augmentation device may either be a permanent implant, or removable.
The nuclear augmentation material may restore diminished disc height and/or pressure. It may include factors for inducing the growth or formation of material within the nuclear space. It may either be permanent, removable, or absorbable.
The nuclear augmentation material may be in the form of liquids, gels, solids, or gases. It may include any/or combinations of steroids, antibiotics, tissue necrosis factors, tissue necrosis factor antagonists, analgesics, growth factors, genes, gene vectors, hyaluronic acid, noncross-linked collagen, collagen, fibren, liquid fat, oils, synthetic polymers, polyethylene glycol, liquid silicones, synthetic oils, saline and hydrogel. The hydrogel may be selected from the group consisting of acrylonitriles, acrylic acids, polyacrylimides, acrylimides, acrylimidines, polyacrylnitriles, and polyvinyl alcohols.
Solid form nuclear augmentation materials may be in the form of geometric shapes such as cubes, spheroids, disc-like components, ellipsoid, rhombohedral, cylindrical, or amorphous. The solid material may be in powder form, and may be selected from the group consisting of titanium, stainless steel, nitinol, cobalt, chrome, resorbable materials, polyurethane, polyesther, PEEK, PET, FEP, PTFE, ePTFE, PMMA, nylon, carbon fiber, Delrin, polyvinyl alcohol gels, polyglycolic acid, polyethylene glycol, silicone gel, silicone rubber, vulcanized rubber, gas-filled vesicles, bone, hydroxy apetite, collagen such as cross-linked collagen, muscle tissue, fat, cellulose, keratin, cartilage, protein polymers, transplanted nucleus pulposus, bioengineered nucleus pulposus, transplanted anulus fibrosis, and bioengineered anulus fibrosis. Structures may also be utilized, such as inflatable balloons or other inflatable containers, and spring-biased structures.
The nuclear augmentation material may additionally comprise a biologically active compound. The compound may be selected from the group consisting of drug carriers, genetic vectors, genes, therapeutic agents, growth renewal agents, growth inhibitory agents, analgesics, anti-infectious agents, and anti-inflammatory drugs.
In accordance with another aspect of the present invention, there is provided a method of repairing or rehabilitating an intervertebral disk. The method comprises the steps of inserting at least one anulus augmentation device into the disc, and inserting at least one nuclear augmentation material, to be held within the disc by the anulus augmentation device. The nuclear augmentation material may conform to a first, healthy region of the anulus, while the anulus augmentation device conforms to a second, weaker region of the anulus.
In another aspect of the invention, a method of closing a defect in an anulus fibrosus of an intervertebral disc is provided. In one embodiment, a barrier is inserted through an opening into a disc and positioned relative to the defect such that the barrier obstructs passage of material from the interior of the disc into the defect. In one embodiment, the opening is spatially separated from said defect. In one embodiment, the opening is the defect.
In one embodiment, the barrier is larger than in area than the defect. In one aspect of the invention, the barrier is expandable. In another aspect, the barrier is expanded from a compressed state after insertion to the interior of the disc. In one embodiment, the barrier is expand within the intervertebral disc, but not inside said defect.
In one aspect of the invention, a method of repairing an annular defect in an intervertebral disc is provided. In one embodiment, a first barrier is inserted into an interior of the disc and positioned proximate to an interior aspect of the defect. A second barrier is positioned proximate to the exterior aspect of the defect and the first barrier is affixed to the second barrier using a fixation device. In one aspect, a suture and/or anchoring device is used to affix the first and second barriers.
Further features and advantages of the present invention will become apparent to those of skill in the art in view of the detailed description of preferred embodiments which follows, when taken together with the attached drawings and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.
FIG. 1A shows a transverse section of a portion of a functional spine unit, in which part of a vertebra and intervertebral disc are depicted.
FIG. 1B shows a sagittal cross section of a portion of a functional spine unit shown in FIG. 1A , in which two lumbar vertebrae and the intervertebral disc are visible.
FIG. 1C shows partial disruption of the inner layers of an anulus fibrosis.
FIG. 2A shows a transverse section of one aspect of the present invention prior to supporting a herniated segment.
FIG. 2B shows a transverse section of the construct in FIG. 2A supporting the herniated segment.
FIG. 3A shows a transverse section of another embodiment of the disclosed invention after placement of the device.
FIG. 3B shows a transverse section of the construct in FIG. 3A after tension is applied to support the herniated segment.
FIG. 4A shows a transverse view of an alternate embodiment of the invention.
FIG. 4B shows a sagittal view of the alternate embodiment shown in FIG. 4A .
FIG. 5A shows a transverse view of another aspect of the present invention.
FIG. 5B shows the delivery tube of FIG. 5A being used to displace the herniated segment to within its pre-herniated borders.
FIG. 5C shows a one-piece embodiment of the invention in an anchored and supporting position.
FIG. 6 shows one embodiment of the invention supporting a weakened posterior anulus fibrosis.
FIG. 7A shows a transverse section of another aspect of the disclosed invention demonstrating two stages involved in augmentation of the soft tissues of the disc.
FIG. 7B shows a sagittal view of the invention shown in FIG. 7A .
FIG. 8 shows a transverse section of one aspect of the disclosed invention involving augmentation of the soft tissues of the disc and support/closure of the anulus fibrosis.
FIG. 9A shows a transverse section of one aspect of the invention involving augmentation of the soft tissues of the disc with the flexible augmentation material anchored to the anterior lateral anulus fibrosis.
FIG. 9B shows a transverse section of one aspect of the disclosed invention involving augmentation of the soft tissues of the disc with the flexible augmentation material anchored to the anulus fibrosis by a one-piece anchor.
FIG. 10A shows a transverse section of one aspect of the disclosed invention involving augmentation of the soft tissues of the disc.
FIG. 10B shows the construct of FIG. 10A after the augmentation material has been inserted into the disc.
FIG. 11 illustrates a transverse section of a barrier mounted within an anulus.
FIG. 12 shows a sagittal view of the barrier of FIG. 11 .
FIG. 13 shows a transverse section of a barrier anchored within a disc.
FIG. 14 illustrates a sagittal view of the barrier shown in FIG. 13 .
FIG. 15 illustrates the use of a second anchoring device for a barrier mounted within a disc.
FIG. 16A is an transverse view of the intervertebral disc.
FIG. 16B is a sagittal section along the midline of the intervertebral disc.
FIG. 17 is an axial view of the intervertebral disc with the right half of a sealing means of a barrier means being placed against the interior aspect of a defect in anulus fibrosis by a dissection/delivery tool.
FIG. 18 illustrates a full sealing means placed on the interior aspect of a defect in anulus fibrosis.
FIG. 19 depicts the sealing means of FIG. 18 being secured to tissues surrounding the defect.
FIG. 20 depicts the sealing means of FIG. 19 after fixation means have been passed into surrounding tissues.
FIG. 21A depicts an axial view of the sealing means of FIG. 20 having enlarging means inserted into the interior cavity.
FIG. 21B depicts the construct of FIG. 21 in a sagittal section.
FIG. 22A shows an alternative fixation scheme for the sealing means and enlarging means.
FIG. 22B shows the construct of FIG. 22A in a sagittal section with an anchor securing a fixation region of the enlarging means to a superior vertebral body in a location proximate to the defect.
FIG. 23A depicts an embodiment of the barrier means of the present invention being secured to an anulus using fixation means.
FIG. 23B depicts an embodiment of the barrier means of FIG. 23A secured to an anulus by two fixation darts wherein the fixation tool has been removed.
FIGS. 24A and 24B depict a barrier means positioned between layers of the anulus fibrosis on either side of a defect.
FIG. 25 depicts an axial cross section of a large version of a barrier means.
FIG. 26 depicts an axial cross section of a barrier means in position across a defect following insertion of two augmentation devices.
FIG. 27 depicts the barrier means as part of an elongated augmentation device.
FIG. 28A depicts an axial section of an alternate configuration of the augmentation device of FIG. 27 .
FIG. 28B depicts a sagittal section of an alternate configuration of the augmentation device of FIG. 27 .
FIGS. 29A-D depict deployment of a barrier from an entry site remote from the defect in the anulus fibrosis.
FIGS. 30A , 30 B, 31 A, 31 B, 32 A, 32 B, 33 A, and 33 B depict axial and sectional views, respectively, of various embodiments of the barrier.
FIG. 34A shows a non-axisymmetric expansion means or frame.
FIGS. 34B and 34C illustrate perspective views of a frame mounted within an intervertebral disc.
FIGS. 35 and 36 illustrate alternate embodiments of the expansion means shown in FIG. 34 .
FIGS. 37A-C illustrate a front, side, and perspective view, respectively, of an alternate embodiment of the expansion means shown in FIG. 34 .
FIG. 38 shows an alternate expansion means to that shown in FIG. 37A .
FIGS. 39A-D illustrate a tubular expansion means having a circular cross-section.
FIGS. 40A-D illustrate a tubular expansion means having an oval shaped cross-section.
FIGS. 40E , 40 F and 40 I illustrate a front, back and top view, respectively of the tubular expansion means of FIG. 40A having a sealing means covering an exterior surface of an anulus face.
FIGS. 40G and 40H show the tubular expansion means of FIG. 40A having a sealing means covering an interior surface of an anulus face.
FIGS. 41A-D illustrate a tubular expansion means having an egg-shaped cross-section.
FIG. 42A-D depicts cross sections of a preferred embodiment of sealing and enlarging means.
FIGS. 43A and 43B depict an alternative configuration of enlarging means.
FIGS. 44A and 44B depict an alternative shape of the barrier means.
FIG. 45 is a section of a device used to affix sealing means to tissues surrounding a defect.
FIG. 46 depicts the use of a thermal device to heat and adhere sealing means to tissues surrounding a defect.
FIG. 47 depicts an expandable thermal element that can be used to adhere sealing means to tissues surrounding a defect.
FIG. 48 depicts an alternative embodiment to the thermal device of FIG. 46 .
FIGS. 49A-G illustrate a method of implanting an intradiscal implant.
FIGS. 50A-F show an alternate method of implanting an intradiscal implant.
FIGS. 51A-C show another alternate method of implanting an intradiscal implant.
FIGS. 52A and 52B illustrate an implant guide used with the intradiscal implant system.
FIG. 53A illustrates a barrier having stiffening plate elements.
FIG. 53B illustrates a sectional view of the barrier of FIG. 53A .
FIG. 54A shows a stiffening plate.
FIG. 54B shows a sectional view of the stiffening plate of FIG. 54A .
FIG. 55A illustrates a barrier having stiffening rod elements.
FIG. 55B illustrates a sectional view of the barrier of FIG. 55A .
FIG. 56A illustrates a stiffening rod.
FIG. 56B illustrates a sectional view of the stiffening rod of FIG. 56A .
FIG. 57 shows an alternate configuration for the location of the fixation devices of the barrier of FIG. 44A .
FIGS. 58A and 58B illustrate a dissection device for an intervertebral disc.
FIGS. 59A and 59B illustrate an alternate dissection device for an intervertebral disc.
FIGS. 60A-C illustrate a dissector component.
FIGS. 61A-D illustrate a method of inserting a disc implant within an intervertebral disc.
FIG. 62 depicts a cross-sectional transverse view of a barrier device implanted within a disc along the inner surface of a lamella. Implanted conformable nuclear augmentation is also shown in contact with the barrier.
FIG. 63 shows a cross-sectional transverse view of a barrier device implanted within a disc along an inner surface of a lamella. Implanted nuclear augmentation comprised of a hydrophilic flexible solid is also shown.
FIG. 64 shows a cross-sectional transverse view of a barrier device implanted within a disc along an inner surface of a lamella. Several types of implanted nuclear augmentation including a solid geometric shape, a composite solid, and a free flowing liquid are also shown.
FIG. 65 illustrates a sagittal cross-sectional view of a barrier device connected to an inflatable nuclear augmentation device.
FIG. 66 depicts a sagittal cross-sectional view of a functional spine unit containing a barrier device unit connected to a wedge shaped nuclear augmentation device.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention provides for an in vivo augmented functional spine unit. A functional spine unit includes the bony structures of two adjacent vertebrae (or vertebral bodies), the soft tissue (anulus fibrosis (AF), and optionally nucleus pulposus (NP)) of the intervertebral disc, and the ligaments, musculature and connective tissue connected to the vertebrae. The intervertebral disc is substantially situated in the intervertebral space formed between the adjacent vertebrae. Augmentation of the functional spine unit can include repair of a herniated disc segment, support of a weakened, torn or damaged anulus fibrosis, or the addition of material to or replacement of all or part of the nucleus pulposus. Augmentation of the functional spine unit is provided by herniation constraining devices and disc augmentation devices situated in the intervertebral disc space.
FIGS. 1A and 1B show the general anatomy of a functional spine unit 45 . In this description and the following claims, the terms ‘anterior’ and ‘posterior’, ‘superior’ and ‘inferior’ are defined by their standard usage in anatomy, i.e., anterior is a direction toward the front (ventral) side of the body or organ, posterior is a direction toward the back (dorsal) side of the body or organ; superior is upward (toward the head) and inferior is lower (toward the feet).
FIG. 1A is an axial view along the transverse axis M of a vertebral body with the intervertebral disc 15 superior to the vertebral body. Axis M shows the anterior (A) and posterior (P) orientation of the functional spine unit within the anatomy. The intervertebral disc 15 contains the anulus fibrosis (AF) 10 which surrounds a central nucleus pulposus (NP) 20 . A Herniated segment 30 is depicted by a dashed-line. The herniated segment 30 protrudes beyond the pre-herniated posterior border 40 of the disc. Also shown in this figure are the left 70 and right 70 ′ transverse spinous processes and the posterior spinous process 80 .
FIG. 1B is a sagittal section along sagittal axis N through the midline of two adjacent vertebral bodies 50 (superior) and 50 ′ (inferior). Intervertebral disc space 55 is formed between the two vertebral bodies and contains intervertebral disc 15 , which supports and cushions the vertebral bodies and permits movement of the two vertebral bodies with respect to each other and other adjacent functional spine units.
Intervertebral disc 15 is comprised of the outer AF 10 which normally surrounds and constrains the NP 20 to be wholly within the borders of the intervertebral disc space. In FIGS. 1A and 1B , herniated segment 30 , represented by the dashed-line, has migrated posterior to the pre-herniated border 40 of the posterior AF of the disc. Axis M extends between the anterior (A) and posterior (P) of the functional spine unit. The vertebral bodies also include facet joints 60 and the superior 90 and inferior 90 ′ pedicle that form the neural foramen 100 . Disc height loss occurs when the superior vertebral body 50 moves inferiorly relative to the inferior vertebral body 50 ′.
Partial disruption 121 of the inner layers of the anulus 10 without a true perforation has also been linked to chronic low back pain. Such a disruption 4 is illustrated in FIG. 1C . It is thought that weakness of these inner layers forces the sensitive outer anulus lamellae to endure higher stresses. This increased stress stimulates the small nerve fibers penetrating the outer anulus, which results in both localized and referred pain.
In one embodiment of the present invention, the disc herniation constraining devices 13 provide support for returning all or part of the herniated segment 30 to a position substantially within its pre-herniated borders 40 . The disc herniation constraining device includes an anchor which is positioned at a site within the functional spine unit, such as the superior or inferior vertebral body, or the anterior medial, or anterior lateral anulus fibrosis. The anchor is used as a point against which all or part of the herniated segment is tensioned so as to return the herniated segment to its pre-herniated borders, and thereby relieve pressure on otherwise compressed neural tissue and structures. A support member is positioned in or posterior to the herniated segment, and is connected to the anchor by a connecting member. Sufficient tension is applied to the connecting member so that the support member returns the herniated segment to a pre-herniated position. In various embodiments, augmentation material is secured within the intervertebral disc space, which assists the NP in cushioning and supporting the inferior and superior vertebral bodies. An anchor secured in a portion of the functional spine unit and attached to the connection member and augmentation material limits movement of the augmentation material within the intervertebral disc space. A supporting member, located opposite the anchor, may optionally provide a second point of attachment for the connection member and further hinder the movement of the augmentation material within the intervertebral disc space.
FIGS. 2A and 2B depict one embodiment of device 13 . FIG. 2A shows the elements of the constraining device in position to correct the herniated segment. Anchor 1 is securely established in a location within the functional spine unit, such as the anterior AF shown in the figure. Support member 2 is positioned in or posterior to herniated segment 30 . Leading from and connected to anchor 1 is connection member 3 , which serves to connect anchor 1 to support member 2 . Depending on the location chosen for support member 2 , the connection member may traverse through all or part of the herniated segment.
FIG. 2B shows the positions of the various elements of the herniation constraining device 13 when the device 13 is supporting the herniated segment. Tightening connection member 2 allows it to transmit tensile forces along its length, which causes herniated segment 30 to move anteriorly, i.e., in the direction of its pre-herniated borders. Once herniated segment 30 is in the desired position, connection member 3 is secured in a permanent fashion between anchor 1 and support member 2 . This maintains tension between anchor 1 and support member 2 and restricts motion of the herniated segment to within the pre-herniated borders 40 of the disc. Support member 2 is used to anchor to herniated segment 30 , support a weakened AF in which no visual evidence of herniation is apparent, and may also be used to close a defect in the AF in the vicinity of herniated segment 30 .
Anchor 1 is depicted in a representative form, as it can take one of many suitable shapes, be made from one of a variety of biocompatible materials, and be constructed so as to fall within a range of stiffness. It can be a permanent device constructed of durable plastic or metal or can be made from a resorbable material such as polylactic acid (PLA) or polyglycolic acid (PGA). Specific embodiments are not shown, but many possible designs would be obvious to anyone skilled in the art. Embodiments include, but are not limited to, a barbed anchor made of PLA or a metal coil that can be screwed into the anterior AF. Anchor 1 can be securely established within a portion of the functional spine unit in the usual and customary manner for such devices and locations, such as being screwed into bone, sutured into tissue or bone, or affixed to tissue or bone using an adhesive method, such as cement, or other suitable surgical adhesives. Once established within the bone or tissue, anchor 1 should remain relatively stationary within the bone or tissue.
Support member 2 is also depicted in a representative format and shares the same flexibility in material and design as anchor 1 . Both device elements can be of the same design, or they can be of different designs, each better suited to being established in healthy and diseased tissue respectively. Alternatively, in other forms, support member 2 can be a cap or a bead shape, which also serves to secure a tear or puncture in the AF, or it can be bar or plate shaped, with or without barbs to maintain secure contact with the herniated segment. Support member 2 can be established securely to, within, or posterior to the herniated segment.
The anchor and support member can include suture, bone anchors, soft tissue anchors, tissue adhesives, and materials that support tissue ingrowth although other forms and materials are possible. They may be permanent devices or resorbable. Their attachment to a portion of FSU and herniated segment must be strong enough to resist the tensional forces that result from repair of the hernia and the loads generated during daily activities.
Connection member 3 is also depicted in representative fashion. Member 3 may be in the format of a flexible filament, such as a single or multi-strand suture, wire, or perhaps a rigid rod or broad band of material, for example. The connection member can further include suture, wire, pins, and woven tubes or webs of material. It can be constructed from a variety of materials, either permanent or resorbable, and can be of any shape suitable to fit within the confines of the intervertebral disc space. The material chosen is preferably adapted to be relatively stiff while in tension, and relatively flexible against all other loads. This allows for maximal mobility of the herniated segment relative to the anchor without the risk of the supported segment moving outside of the pre-herniated borders of the disc. The connection member may be an integral component of either the anchor or support member or a separate component. For example, the connection member and support member could be a length of non-resorbing suture that is coupled to an anchor, tensioned against the anchor, and sewn to the herniated segment.
FIGS. 3A and 3B depict another embodiment of device 13 . In FIG. 3A the elements of the herniation constraining device are shown in position prior to securing a herniated segment. Anchor 1 is positioned in the AF and connection member 3 is attached to anchor 1 . Support member 4 is positioned posterior to the posterior-most aspect of herniated segment 30 . In this way, support member 4 does not need to be secured in herniated segment 30 to cause herniated segment 30 to move within the pre-herniated borders 40 of the disc. Support member 4 has the same flexibility in design and material as anchor 1 , and may further take the form of a flexible patch or rigid plate or bar of material that is either affixed to the posterior aspect of herniated segment 30 or is simply in a form that is larger than any hole in the AF directly anterior to support member 4 . FIG. 3B shows the positions of the elements of the device when tension is applied between anchor 1 and support member 4 along connection member 3 . The herniated segment is displaced anteriorly, within the pre-herniated borders 40 of the disc.
FIGS. 4A and 4B show five examples of suitable anchoring sites within the FSU for anchor 1 . FIG. 4A shows an axial view of anchor 1 in various positions within the anterior and lateral AF. FIG. 4B similarly shows a sagittal view of the various acceptable anchoring sites for anchor 1 . Anchor 1 is secured in the superior vertebral body 50 , inferior vertebral body 50 ′ or anterior AF 10 , although any site that can withstand the tension between anchor 1 and support member 2 along connection member 3 to support a herniated segment within its pre-herniated borders 40 is acceptable.
Generally, a suitable position for affixing one or more anchors is a location anterior to the herniated segment such that, when tension is applied along connection member 3 , herniated segment 30 is returned to a site within the pre-herniated borders 40 . The site chosen for the anchor should be able to withstand the tensile forces applied to the anchor when the connection member is brought under tension. Because most symptomatic herniations occur in the posterior or posterior lateral directions, the preferable site for anchor placement is anterior to the site of the herniation. Any portion of the involved FSU is generally acceptable, however the anterior, anterior medial, or anterior lateral AF is preferable. These portions of the AF have been shown to have considerably greater strength and stiffness than the posterior or posterior lateral portions of the AF. As shown in FIGS. 4A and 4B , anchor 1 can be a single anchor in any of the shown locations, or there can be multiple anchors 1 affixed in various locations and connected to a support member 2 to support the herniated segment. Connection member 3 can be one continuous length that is threaded through the sited anchors and the support member, or it can be several individual strands of material each terminated under tension between one or more anchors and one or more support members.
In various forms of the invention, the anchor(s) and connection member(s) may be introduced and implanted in the patient, with the connection member under tension. Alternatively, those elements may be installed, without introducing tension to the connection member, but where the connection member is adapted to be under tension when the patient is in a non-horizontal position, i.e., resulting from loading in the intervertebral disc.
FIGS. 5A-C show an alternate embodiment of herniation constraining device 13 A. In this series of figures, device 13 A, a substantially one-piece construct, is delivered through a delivery tube 6 , although device 13 A could be delivered in a variety of ways including, but not limited to, by hand or by a hand held grasping instrument. In FIG. 5A , device 13 A in delivery tube 6 is positioned against herniated segment 30 . In FIG. 5B , the herniated segment is displaced within its pre-herniated borders 40 by device 13 A and/or delivery tube 6 such that when, in FIG. 5C , device 13 A has been delivered through delivery tube 6 , and secured within a portion of the FSU, the device supports the displaced herniated segment within its pre-herniated border 40 . Herniation constraining device 13 A can be made of a variety of materials and have one of many possible forms so long as it allows support of the herniated segment 30 within the pre-herniated borders 40 of the disc. Device 13 A can anchor the herniated segment 30 to any suitable anchoring site within the FSU, including, but not limited to the superior vertebral body, inferior vertebral body, or anterior AF. Device 13 A may be used additionally to close a defect in the AF of herniated segment 30 . Alternatively, any such defect may be left open or may be closed using another means.
FIG. 6 depicts the substantially one-piece device 13 A supporting a weakened segment 30 ′ of the posterior AF 10 ′. Device 13 A is positioned in or posterior to the weakened segment 30 ′ and secured to a portion of the FSU, such as the superior vertebral body 50 , shown in the figure, or the inferior vertebral body 50 ′ or anterior or anterior-lateral anulus fibrosis 10 . In certain patients, there may be no obvious herniation found at surgery. However, a weakened or torn AF that may not be protruding beyond the pre-herniated borders of the disc may still induce the surgeon to remove all or part of the NP in order to decrease the risk of herniation. As an alternative to discectomy, any of the embodiments of the invention may be used to support and perhaps close defects in weakened segments of AF.
A further embodiment of the present invention involves augmentation of the soft tissues of the intervertebral disc to avoid or reverse disc height loss. FIGS. 7A and 7B show one embodiment of device 13 securing augmentation material in the intervertebral disc space 55 . In the left side of FIG. 7A , anchors 1 have been established in the anterior AF 10 . Augmentation material 7 is in the process of being inserted into the disc space along connection member 3 which, in this embodiment, has passageway 9 . Support member 2 ′ is shown ready to be attached to connection member 3 once the augmentation material 7 is properly situated. In this embodiment, connection member 3 passes through an aperture 11 in support member 2 ′, although many other methods of affixing support member 2 ′ to connection member 3 are possible and within the scope of this invention.
Augmentation material 7 may have a passageway 9 , such as a channel, slit or the like, which allows it to slide along the connection member 3 , or augmentation material 7 may be solid, and connection member 3 can be threaded through augmentation material by means such as needle or other puncturing device. Connection member 3 is affixed at one end to anchor 1 and terminated at its other end by a support member 2 ′, one embodiment of which is shown in the figure in a cap-like configuration. Support member 2 ′ can be affixed to connection member 3 in a variety of ways, including, but not limited to, swaging support member 2 ′ to connection member 3 . In a preferred embodiment, support member 2 ′ is in a cap configuration and has a dimension (diameter or length and width) larger than the optional passageway 9 , which serves to prevent augmentation material 7 from displacing posteriorly with respect to anchor 1 . The right half of the intervertebral disc of FIG. 7A (axial view) and FIG. 7B (sagittal view) show augmentation material 7 that has been implanted into the disc space 55 along connection member 3 where it supports the vertebral bodies 50 and 50 ′. FIG. 7A shows an embodiment in which support member 2 ′ is affixed to connection member 3 and serves only to prevent augmentation material 7 from moving off connection member 3 . The augmentation device is free to move within the disc space. FIG. 7B shows an alternate embodiment in which support member 2 ′ is embedded in a site in the functional spine unit, such as a herniated segment or posterior anulus fibrosis, to further restrict the movement of augmentation material 7 or spacer material within the disc space.
Augmentation or spacer material can be made of any biocompatible, preferably flexible, material. Such a flexible material is preferably fibrous, like cellulose or bovine or autologous collagen. The augmentation material can be plug or disc shaped. It can further be cube-like, ellipsoid, spheroid or any other suitable shape. The augmentation material can be secured within the intervertebral space by a variety of methods, such as but not limited to, a suture loop attached to, around, or through the material, which is then passed to the anchor and support member.
FIGS. 8 , 9 A, 9 B and 10 A and 10 B depict further embodiments of the disc herniation constraining device 13 B in use for augmenting soft tissue, particularly tissue within the intervertebral space. In the embodiments shown in FIGS. 8 and 9A , device 13 B is secured within the intervertebral disc space providing additional support for NP 20 . Anchor 1 is securely affixed in a portion of the FSU, (anterior AF 10 in these figures). Connection member 3 terminates at support member 2 , preventing augmentation material 7 from migrating generally posteriorly with respect to anchor 1 . Support member 2 is depicted in these figures as established in various locations, such as the posterior AF 10 ′ in FIG. 8 , but support member 2 may be anchored in any suitable location within the FSU, as described previously. Support member 2 may be used to close a defect in the posterior AF. It may also be used to displace a herniated segment to within the pre-herniated borders of the disc by applying tension between anchoring means 1 and 2 along connection member 3 .
FIG. 9A depicts anchor 1 , connection member 3 , spacer material 7 and support member 2 ′ (shown in the “cap”-type configuration) inserted as a single construct and anchored to a site within the disc space, such as the inferior or superior vertebral bodies. This configuration simplifies insertion of the embodiments depicted in FIGS. 7 and 8 by reducing the number of steps to achieve implantation. Connection member 3 is preferably relatively stiff in tension, but flexible against all other loads. Support member 2 ′ is depicted as a bar element that is larger than passageway 9 in at least one plane.
FIG. 9B depicts a variation on the embodiment depicted in FIG. 9A . FIG. 9B shows substantially one-piece disc augmentation device 13 C, secured in the intervertebral disc space. Device 13 C has anchor 1 , connection member 3 and augmentation material 7 . Augmentation material 7 and anchor 1 could be pre-assembled prior to insertion into the disc space 55 as a single construct. Alternatively, augmentation material 7 could be inserted first into the disc space and then anchored to a portion of the FSU by anchor 1 .
FIGS. 10A and 10B show yet another embodiment of the disclosed invention, 13 D. In FIG. 10A , two connection members 3 and 3 ′ are attached to anchor 1 . Two plugs of augmentation material 7 and 7 ′ are inserted into the disc space along connection members 3 and 3 ′. Connection members 3 and 3 ′ are then bound together (e.g., knotted together, fused, or the like). This forms loop 3 ″ that serves to prevent augmentation materials 7 and 7 ′ from displacing posteriorly. FIG. 10B shows the position of the augmentation material 7 after it is secured by the loop 3 ″ and anchor 1 . Various combinations of augmentation material, connecting members and anchors can be used in this embodiment, such as using a single plug of augmentation material, or two connection members leading from anchor 1 with each of the connection members being bound to at least one other connection member. It could further be accomplished with more than one anchor with at least one connection member leading from each anchor, and each of the connection members being bound to at least one other connection member.
Any of the devices described herein can be used for closing defects in the AF whether created surgically or during the herniation event. Such methods may also involve the addition of biocompatible material to either the AF or NP. This material could include sequestered or extruded segments of the NP found outside the pre-herniated borders of the disc.
FIGS. 11-15 illustrate devices used in and methods for closing a defect in an anulus fibrosis. One method involves the insertion of a barrier or barrier means 12 into the disc 15 . This procedure can accompany surgical discectomy. It can also be done without the removal of any portion of the disc 15 and further in combination with the insertion of an augmentation material or device into the disc 15 .
The method consists of inserting the barrier 12 into the interior of the disc 15 and positioning it proximate to the interior aspect of the anulus defect 16 . The barrier material is preferably considerably larger in area than the size of the defect 16 , such that at least some portion of the barrier means 12 abuts healthier anulus fibrosis 10 . The device acts to seal the anulus defect 16 , recreating the closed isobaric environment of a healthy disc nucleus 20 . This closure can be achieved simply by an over-sizing of the implant relative to the defect 16 . It can also be achieved by affixing the barrier means 12 to tissues within the functional spinal unit. In a preferred aspect of the present invention, the barrier 12 is affixed to the anulus surrounding the anulus defect 16 . This can be achieved with sutures, staples, glues or other suitable fixation means or fixation device 14 . The barrier means 12 can also be larger in area than the defect 16 and be affixed to a tissue or structure opposite the defect 16 , i.e. anterior tissue in the case of a posterior defect.
The barrier means 12 is preferably flexible in nature. It can be constructed of a woven material such as Dacron™ or Nylon™, a synthetic polyamide or polyester, a polyethylene, and can further be an expanded material, such as expanded polytetrafluroethylene (e-PTFE), for example. The barrier means 12 can also be a biologic material such as cross-linked collagen or cellulous.
The barrier means 12 can be a single piece of material. It can have an expandable means or component that allows it to be expanded from a compressed state after insertion into the interior of the disc 15 . This expandable means can be active, such as a balloon, or passive, such as a hydrophilic material. The expandable means can also be a self-expanding elastically deforming material, for example.
FIGS. 11 and 12 illustrate a barrier 12 mounted within an anulus 10 and covering an anulus defect 16 . The barrier 12 can be secured to the anulus 10 with a fixation mechanism or fixation means 14 . The fixation means 14 can include a plurality of suture loops placed through the barrier 12 and the anulus 10 . Such fixation can prevent motion or slipping of the barrier 12 away from the anulus defect 16 .
The barrier means 12 can also be anchored to the disc 15 in multiple locations. In one preferred embodiment, shown in FIGS. 13 and 14 , the barrier means 12 can be affixed to the anulus tissue 10 in or surrounding the defect and further affixed to a secondary fixation site opposite the defect, e.g. the anterior anulus 10 in a posterior herniation, or the inferior 50 ′ or superior 50 vertebral body. For example, fixation means 14 can be used to attach the barrier 12 to the anulus 10 near the defect 16 , while an anchoring mechanism 18 can secure the barrier 12 to a secondary fixation site. A connector 22 can attach the barrier 12 to the anchor 18 . Tension can be applied between the primary and secondary fixation sites through a connector 22 so as to move the anulus defect 16 toward the secondary fixation site. This may be particularly beneficial in closing defects 16 that result in posterior herniations. By using this technique, the herniation can be moved and supported away from any posterior neural structures while further closing any defect in the anulus 10 .
The barrier means 12 can further be integral to a fixation means such that the barrier means affixes itself to tissues within the functional spinal unit.
Any of the methods described above can be augmented by the use of a second barrier or a second barrier means 24 placed proximate to the outer aspect of the defect 16 as shown in FIG. 15 . The second barrier 24 can further be affixed to the inner barrier means 12 by the use of a fixation means 14 such as suture material.
FIGS. 16A and 16B depict intervertebral disc 15 comprising nucleus pulposus 20 and anulus fibrosis 10 . Nucleus pulposus 20 forms a first anatomic region and extra-discal space 500 (any space exterior to the disc) forms a second anatomic region wherein these regions are separated by anulus fibrosis 10 .
FIG. 16A is an axial (transverse) view of the intervertebral disc. A posterior lateral defect 16 in anulus fibrosis 10 has allowed a segment 30 of nucleus pulposus 20 to herniate into an extra discal space 500 . Interior aspect 32 and exterior aspect 34 are shown, as are the right 70 ′ and left 70 transverse processes and posterior process 80 .
FIG. 16B is a sagittal section along the midline intervertebral disc. Superior pedicle 90 and inferior pedicle 90 ′ extend posteriorly from superior vertebral body 95 and inferior vertebral body 95 ′ respectively.
To prevent further herniation of the nucleus 20 and to repair any present herniation, in a preferred embodiment, a barrier or barrier means 12 can be placed into a space between the anulus 10 and the nucleus 20 proximate to the inner aspect 32 of defect 16 , as depicted in FIGS. 17 and 18 . The space can be created by blunt dissection. Dissection can be achieved with a separate dissection instrument, with the barrier means 12 itself, or a combined dissection/barrier delivery tool 100 . This space is preferably no larger than the barrier means such that the barrier means 12 can be in contact with both anulus 10 and nucleus 20 . This allows the barrier means 12 to transfer load from the nucleus 20 to the anulus 10 when the disc is pressurized during activity.
In position, the barrier means 12 preferably spans the defect 16 and extends along the interior aspect 36 of the anulus 10 until it contacts healthy tissues on all sides of the defect 16 , or on a sufficient extent of adjacent healthy tissue to provide adequate support under load. Healthy tissue may be non-diseased tissue and/or load bearing tissue, which may be micro-perforated or non-perforated. Depending on the extent of the defect 16 , the contacted tissues can include the anulus 10 , cartilage overlying the vertebral endplates, and/or the endplates themselves.
In the preferred embodiment, the barrier means 12 comprises two components—a sealing means or sealing component 51 and an enlarging means or enlarging component 53 , shown in FIGS. 21A and 21B .
The sealing means 51 forms the periphery of the barrier 12 and has an interior cavity 17 . There is at least one opening 8 leading into cavity 17 from the exterior of the sealing means 51 . Sealing means 51 is preferably compressible or collapsible to a dimension that can readily be inserted into the disc 15 through a relatively small hole. This hole can be the defect 16 itself or a site remote from the defect 16 . The sealing means 51 is constructed from a material and is formed in such a manner as to resist the passage of fluids and other materials around sealing means 51 and through the defect 16 . The sealing means 51 can be constructed from one or any number of a variety of materials including, but not limited to PTFE, e-PTFE, Nylon™, Marlex™, high-density polyethylene, and/or collagen. The thickness of the sealing component has been found to be optimal between about 0.001 inches (0.127 mm) and 0.063 inches (1.6 mm).
The enlarging means 53 can be sized to fit within cavity 17 of sealing means 51 . It is preferably a single object of a dimension that can be inserted through the same defect 16 through which the sealing means 51 was passed. The enlarging means 53 can expand the sealing means 51 to an expanded state as it is passed into cavity 17 . One purpose of enlarging means 53 is to expand sealing means 51 to a size greater than that of the defect 16 such that the assembled barrier 12 prevents passage of material through the defect 16 . The enlarger 53 can further impart stiffness to the barrier 12 such that the barrier 12 resists the pressures within nucleus pulposus 20 and expulsion through the defect 16 . The enlarging means 53 can be constructed from one or any number of materials including, but not limited to, silicon rubber, various plastics, stainless steel, nickel titanium alloys, or other metals. These materials may form a solid object, a hollow object, coiled springs or other suitable forms capable of filling cavity 17 within sealing means 51 .
The sealing means 51 , enlarging means 53 , or the barrier means 12 constructs can further be affixed to tissues either surrounding the defect 16 or remote from the defect 16 . In the preferred embodiment, no aspect of a fixation means or fixation device or the barrier means 12 nor its components extend posterior to the disc 15 or into the extradiscal region 500 , avoiding the risk of contacting and irritating the sensitive nerve tissues posterior to the disc 15 .
In a preferred embodiment, the sealing means 51 is inserted into the disc 15 proximate the interior aspect 36 of the defect. The sealing means 51 is then affixed to the tissues surrounding the defect using a suitable fixation means, such as suture or a soft-tissue anchor. The fixation procedure is preferably performed from the interior of the sealing means cavity 17 as depicted in FIGS. 19 and 20 . A fixation delivery instrument 110 is delivered into cavity 17 through opening 8 in the sealing means 51 . Fixation devices 14 can then be deployed through a wall of the sealing means 53 into surrounding tissues. Once the fixation means 14 have been passed into surrounding tissue, the fixation delivery instrument 110 can be removed from the disc 15 . This method eliminates the need for a separate entryway into the disc 15 for delivery of fixation means 14 . It further minimizes the risk of material leaking through sealing means 51 proximate to the fixation means 14 . One or more fixation means 14 can be delivered into one or any number of surrounding tissues including the superior 95 and inferior 95 ′ vertebral bodies. Following fixation of the sealing means 51 , the enlarging means 53 can be inserted into cavity 17 of the sealing means 51 to further expand the barrier means 12 construct as well as increase its stiffness, as depicted in FIGS. 21A and 21B . The opening 8 into the sealing means 51 can then be closed by a suture or other means, although this is not a requirement of the present invention. In certain cases, insertion of a separate enlarging means may not be necessary if adequate fixation of the sealing means 51 is achieved.
Another method of securing the barrier 12 to tissues is to affix the enlarging means 53 to tissues either surrounding or remote from the defect 16 . The enlarging means 53 can have an integral fixation region 4 that facilitates securing it to tissues as depicted in FIGS. 22A , 22 B, 32 A and 43 B. This fixation region 4 can extend exterior to sealing means 51 either through opening 8 or through a separate opening. Fixation region 4 can have a hole through which a fixation means or fixation device 14 can be passed. In a preferred embodiment, the barrier 12 is affixed to at least one of the surrounding vertebral bodies ( 95 and 95 ′) proximate to the defect using a bone anchor 14 ′. The bone anchor 14 ′ can be deployed into the vertebral bodies 50 , 50 ′ at some angle between 0° and 180° relative to a bone anchor deployment tool. As shown the bone anchor 14 ′ is mounted at 90° relative to the bone anchor deployment tool. Alternatively, the enlarging means 53 itself can have an integral fixation device 14 located at a site or sites along its length.
Another method of securing the barrier means 12 is to insert the barrier means 12 through the defect 16 or another opening into the disc 15 , position it proximate to the interior aspect 36 of the defect 16 , and pass at least one fixation means 14 through the anulus 10 and into the barrier 12 . In a preferred embodiment of this method, the fixation means 14 can be darts 25 and are first passed partially into anulus 10 within a fixation device 120 , such as a hollow needle. As depicted in FIGS. 23A and 23B , fixation means 25 can be advanced into the barrier means 12 and fixation device 120 removed. Fixation means 25 preferably have two ends, each with a means to prevent movement of that end of the fixation device. Using this method, the fixation means can be lodged in both the barrier 12 and anulus fibrosis 10 without any aspect of fixation means 25 exterior to the disc in the extradiscal region 500 .
In another aspect of the present invention, the barrier (or “patch”) 12 can be placed between two neighboring layers 33 , 37 (lamellae) of the anulus 10 on either or both sides of the defect 16 as depicted in FIGS. 24A and 24B . FIG. 24A shows an axial view while 24 B shows a sagittal cross section. Such positioning spans the defect 16 . The barrier means 12 can be secured using the methods outlined.
A dissecting tool can be used to form an opening extending circumferentially 31 within the anulus fibrosis such that the barrier can be inserted into the opening. Alternatively, the barrier itself can have a dissecting edge such that it can be driven at least partially into the sidewalls of defect 16 , annulotomy 416 , access hole 417 or opening in the anulus. This process can make use of the naturally layered structure in the anulus in which adjacent layers 33 , 37 are defined by a circumferentially extending boundary 35 between the layers.
Another embodiment of the barrier 12 is a patch having a length, oriented along the circumference of the disc, which is substantially greater than its height, which is oriented along the distance separating the surrounding vertebral bodies. A barrier 12 having a length greater than its height is illustrated in FIG. 25 . The barrier 12 can be positioned across the defect 16 as well as the entirety of the posterior aspect of the anulus fibrosis 10 . Such dimensions of the barrier 12 can help to prevent the barrier 12 from slipping after insertion and can aid in distributing the pressure of the nucleus 20 evenly along the posterior aspect of the anulus 10 .
The barrier 12 can be used in conjunction with an augmentation device 11 inserted within the anulus 10 . The augmentation device 11 can include separate augmentation devices 42 as shown in FIG. 26 . The augmentation device 11 can also be a single augmentation device 44 and can form part of the barrier 12 as barrier region 300 , coiled within the anulus fibrosis 10 , as shown in FIG. 27 . Either the barrier 12 or barrier region 300 can be secured to the tissues surrounding the defect 16 by fixation devices or darts 25 , or be left unconstrained
In another embodiment of the present invention, the barrier or patch 12 may be used as part of a method to augment the intervertebral disc. In one aspect of this method, augmentation material or devices are inserted into the disc through a defect (either naturally occurring or surgically generated). Many suitable augmentation materials and devices are discussed above and in the prior art. As depicted in FIG. 26 , the barrier means is then inserted to aid in closing the defect and/or to aid in transferring load from the augmentation materials/devices to healthy tissues surrounding the defect. In another aspect of this method, the barrier means is an integral component to an augmentation device. As shown in FIGS. 27 , 28 A and 28 B, the augmentation portion may comprise a length of elastic material that can be inserted linearly through a defect in the anulus. A region 300 of the length forms the barrier means of the present invention and can be positioned proximate to the interior aspect of the defect once the nuclear space is adequately filled. Barrier region 300 may then be affixed to surrounding tissues such as the AF and/or the neighboring vertebral bodies using any of the methods and devices described above.
FIGS. 28A and 28B illustrate axial and sagittal sections, respectively, of an alternate configuration of an augmentation device 38 . In this embodiment, barrier region 300 extends across the defect 16 and has fixation region 4 facilitating fixation of the device 13 to superior vertebral body 50 with anchor 14 ′.
FIGS. 29A-D illustrate the deployment of a barrier 12 from an entry site 800 remote from the defect in the anulus fibrosis 10 . FIG. 29A shows insertion instrument 130 with a distal end positioned within the disc space occupied by nucleus pulposus 20 . FIG. 29B depicts delivery catheter 140 exiting the distal end of insertion instrument 130 with barrier 12 on its distal end. Barrier 12 is positioned across the interior aspect of the defect 16 . FIG. 29C depicts the use of an expandable barrier 12 ′ wherein delivery catheter 140 is used to expand the barrier 12 ′ with balloon 150 on its distal end. Balloon 150 may exploit heat to further adhere barrier 12 ′ to surrounding tissue. FIG. 29D depicts removal of balloon 150 and delivery catheter 140 from the disc space leaving expanded barrier means 12 ′ positioned across defect 16 .
Another method of securing the barrier means 12 is to adhere it to surrounding tissues through the application of heat. In this embodiment, the barrier means 12 includes a sealing means 51 comprised of a thermally adherent material that adheres to surrounding tissues upon the application of heat. The thermally adherent material can include thermoplastic, collagen, or a similar material. The sealing means 51 can further comprise a separate structural material that adds strength to the thermally adherent material, such as a woven Nylon™ or Marlex™. This thermally adherent sealing means preferably has an interior cavity 17 and at least one opening 8 leading from the exterior of the barrier means into cavity 17 . A thermal device can be attached to the insertion instrument shown in FIGS. 29C and 29D . The insertion instrument 130 having a thermal device can be inserted into cavity 17 and used to heat sealing means 51 and surrounding tissues. This device can be a simple thermal element, such as a resistive heating coil, rod or wire. It can further be a number of electrodes capable of heating the barrier means and surrounding tissue through the application of radio frequency (RF) energy. The thermal device can further be a balloon 150 , 150 ′, as shown in FIG. 47 , capable of both heating and expanding the barrier means. Balloon 150 , 150 ′ can either be inflated with a heated fluid or have electrodes located about its surface to heat the barrier means with RF energy. Balloon 150 , 150 ′ is deflated and removed after heating the sealing means. These thermal methods and devices achieve the goal of adhering the sealing means to the AF and NP and potentially other surrounding tissues. The application of heat can further aid the procedure by killing small nerves within the AF, by causing the defect to shrink, or by causing cross-linking and/or shrinking of surrounding tissues. An expander or enlarging means 53 can also be an integral component of barrier 12 inserted within sealing means 51 . After the application of heat, a separate enlarging means 53 can be inserted into the interior cavity of the barrier means to either enlarge the barrier 12 or add stiffness to its structure. Such an enlarging means is preferably similar in make-up and design to those described above. Use of an enlarging means may not be necessary in some cases and is not a required component of this method.
The barrier means 12 shown in FIG. 25 preferably has a primary curvature or gentle curve along the length of the patch or barrier 12 that allows it to conform to the inner circumference of the AF 10 . This curvature may have a single radius R as shown in FIGS. 44A and 44B or may have multiple curvatures. The curvature can be fabricated into the barrier 12 and/or any of its components. For example, the sealing means can be made without an inherent curvature while the enlarging means can have a primary curvature along its length. Once the enlarging means is placed within the sealing means the overall barrier means assembly takes on the primary curvature of the enlarging means. This modularity allows enlarging means with specific curvatures to be fabricated for defects occurring in various regions of the anulus fibrosis.
The cross section of the barrier 12 can be any of a number of shapes. Each embodiment exploits a sealing means 51 and an enlarging means 53 that may further add stiffness to the overall barrier construct. FIGS. 30A and 30B show an elongated cylindrical embodiment with enlarging means 53 located about the long axis of the device. FIGS. 31A and 31B depict a barrier means comprising an enlarging means 53 with a central cavity 49 . FIGS. 32A and 32B depict a barrier means comprising a non-axisymmetric sealing means 51 . In use, the longer section of sealing means 51 as seen on the left side of this figure would extend between opposing vertebra 50 and 50 ′. FIGS. 33A and 33B depict a barrier means comprising a non-axisymmetric sealing means 51 and enlarger 53 . The concave portion of the barrier means preferably faces nucleus pulposus 20 while the convex surface faces the defect 16 , annulotomy 416 , or access hole 417 and the inner aspect of the anulus fibrosis 10 . This embodiment exploits pressure within the disc to compress sealing means 51 against neighboring vertebral bodies 50 and 50 ′ to aid in sealing. The ‘C’ shape as shown in FIG. 33A is the preferred shape of the barrier wherein the convex portion of the patch rests against the interior aspect of the AF while the concave portion faces the NP. Used in this manner, the barrier or patch 12 serves to partially encapsulate the nucleus puposus 20 by conforming to the gross morphology of the inner surface of the anulus 10 and presenting a concave or cupping surface toward the nucleus 20 . To improve the sealing ability of such a patch, the upper and lower portions of this ‘C’ shaped barrier means are positioned against the vertebral endplates or overlying cartilage. As the pressure within the nucleus increases, these portions of the patch are pressurized toward the endplates with an equivalent pressure, preventing the passage of materials around the barrier means. Dissecting a matching cavity prior to or during patch placement can facilitate use of such a ‘C’ shaped patch.
FIGS. 34 through 41 depict various enlarging or expansion devices 53 that can be employed to aid in expanding a sealing element 51 within the intervertebral disc 15 . Each embodiment can be covered by, coated with, or cover the sealing element 51 . The sealing means 51 can further be woven through the expansion means 53 . The sealing element 51 or membrane can be a sealer which can prevent flow of a material from within the anulus fibrosis of the intervertebral disc through a defect in the anulus fibrosis. The material within the anulus can include nucleus pulposus or a prosthetic augmentation device, such as a hydrogel.
FIGS. 34 through 38 depict alternative patterns to that illustrated in FIG. 33A . FIG. 33A shows the expansion devices 53 within the sealing means 51 . The sealing means can alternatively be secured to one or another face (concave or convex) of the expansion means 53 . This can have advantages in reducing the overall volume of the barrier means 12 , simplifying insertion through a narrow cannula. It can also allow the barrier means 12 to induce ingrowth of tissue on one face and not the other. The sealing means 51 can be formed from a material that resists ingrowth such as expanded polytetraflouroethylene (e-PTFE). The expansion means 53 can be constructed of a metal or polymer that encourages ingrowth. If the e-PTFE sealing means 51 is secured to the concave face of the expansion means 53 , tissue can grow into the expansion means 53 from outside of the disc 15 , helping to secure the barrier means 12 in place and seal against egress of materials from within the disc 15 .
The expansion means 53 shown in FIG. 33A can be inserted into the sealing means 51 once the sealing means 51 is within the disc 15 . Alternatively, the expansion means 53 and sealing means 51 can be integral components of the barrier means 12 that can be inserted as a unit into the disc.
The patterns shown in FIGS. 34 through 38 can preferably be formed from a relatively thin sheet of material. The material may be a polymer, metal, or gel, however, the superelastic properties of nickel titanium alloy (NITINOL) makes this metal particularly advantageous in this application. Sheet thickness can generally be in a range of 0.1 mm to 0.6 mm and for certain embodiments has been found to be optimal if between 0.003″ to 0.015″ (0.0762 mm to 0.381 mm), for the thickness to provide adequate expansion force to maintain contact between the sealing means 51 and surrounding vertebral endplates. The pattern may be Wire Electro-Discharge Machined, cut by laser, chemically etched, or formed by other suitable means.
FIG. 34A shows an embodiment of a non-axisymmetric expander 153 having a superior edge 166 and an inferior edge 168 . The expander 153 can form a frame of barrier 12 . This embodiment comprises dissecting surfaces or ends 160 , radial elements or fingers 162 and a central strut 164 . The circular shape of the dissecting ends 160 aids in dissecting through the nucleus pulposus 20 and/or along or between an inner surface of the anulus fibrosis 10 . The distance between the left-most and right-most points on the dissecting ends is the expansion means length 170 . This length 170 preferably lies along the inner perimeter of the posterior anulus following implantation. The expander length 170 can be as short as about 3 mm and as long as the entire interior perimeter of the anulus fibrosis. The superior-inferior height of these dissecting ends 160 is preferably similar to or larger than the posterior disc height.
This embodiment employs a multitude of fingers 162 to aid in holding a flexible sealer or membrane against the superior and inferior vertebral endplates. The distance between the superior-most point of the superior finger and the inferior-most point on the inferior finger is the expansion means height 172 . This height 172 is preferably greater than the disc height at the inner surface of the posterior anulus. The greater height 172 of the expander 153 allows the fingers 162 to deflect along the superior and inferior vertebral endplates, enhancing the seal of the barrier means 12 against egress of material from within the disc 15 .
The spacing between the fingers 162 along the expander length 170 can be tailored to provide a desired stiffness of the expansion means 153 . Greater spacing between any two neighboring fingers 162 can further be employed to insure that the fingers 170 do not touch if the expansion means 153 is required to take a bend along its length. The central strut 164 can connect the fingers and dissecting ends and preferably lies along the inner surface of the anulus 10 when seated within the disc 15 . Various embodiments may employ struts 164 of greater or lesser heights and thicknesses to vary the stiffness of the overall expansion means 153 along its length 170 and height 172 .
FIG. 35 depicts an alternative embodiment to the expander 153 of FIG. 34 . Openings or slots 174 can be included along the central strut 164 . These slots 174 promote bending of the expander 153 and fingers 162 along a central line 176 connecting the centers of the dissecting ends 160 . Such central flexibility has been found to aid against superior or inferior migration of the barrier means or barrier 12 when the barrier 12 has not been secured to surrounding tissues.
FIGS. 34B and 34C depict different perspective views of a preferred embodiment of the expander/frame 153 within an intervertebral disc 15 . Expander 53 is in its expanded condition and lies along and/or within the posterior wall 21 and extends around the lateral walls 23 of the anulus fibrosis 10 . The superior 166 and inferior 168 facing fingers 162 of expander 153 extend along the vertebral endplates (not shown) and/or the cartilage overlying the endplates. The frame 153 can take on a 3-D concave shape in this preferred position with the concavity generally directed toward the interior of the intervertebral disc and specifically a region occupied by the nucleus pulposus 20 .
The bending stiffness of expander 153 can resist migration of the implant from this preferred position within the disc 15 . The principle behind this stiffness-based stability is to place the regions of expander 153 with the greatest flexibility in the regions of the disc 153 with the greatest mobility or curvature. These flexible regions of expander 153 are surrounded by significantly stiffer regions. Hence, in order for the implant to migrate, a relatively stiff region of the expander must move into a relatively curved or mobile region of the disc.
For example, in order for expander 153 of FIG. 34B to move around the inner circumference of anulus fibrosis 10 (i.e. from the posterior wall 21 onto the lateral 23 and/or anterior 27 wall), the stiff central region of expander 153 spanning the posterior wall 21 would have to bend around the acute curves of the posterior lateral corners of anulus 10 . The stiffer this section of expander 153 is, the higher the forces necessary to force it around these corners and the less likely it is to migrate in this direction. This principle was also used in this embodiment to resist migration of fingers 162 away from the vertebral endplates: The slots 174 cut along the length of expander 153 create a central flexibility that encourages expander 153 to bend along an axis running through these slots as the posterior disc height increases and decreased during flexion and extension. In order for the fingers 162 to migrate away from the endplate, this central flexible region must move away from the posterior anulus 21 and toward an endplate. This motion is resisted by the greater stiffness of expander 153 in the areas directly inferior and superior to this central flexible region.
The expander 153 is preferably covered by a membrane that acts to further restrict the movement of materials through the frame and toward the outer periphery of the anulus fibrosis.
FIG. 36 depicts an embodiment of the expander 153 of FIG. 33A with an enlarged central strut 164 and a plurality of slots 174 . This central strut 164 can have a uniform stiffness against superior-inferior 166 and 168 bending as shown in this embodiment. The strut 164 can alternatively have a varying stiffness along its height 178 to either promote or resist bending at a given location along the inner surface of the anulus 10 .
FIGS. 37A-C depict a further embodiment of the frame or expander 153 . This embodiment employs a central lattice 180 consisting of multiple, fine interconnected struts 182 . Such a lattice 180 can provide a structure that minimizes bulging of the sealing means 51 under intradiscal pressures. The orientation and location of these struts 182 have been designed to give the barrier 12 a bend-axis along the central area of the expander height 172 . The struts 182 support inferior 168 and superior 166 fingers 162 similar to previously described embodiments. However, these fingers 162 can have varying dimensions and stiffness along the length of the barrier 12 . Such fingers 162 can be useful for helping the sealer 51 conform to uneven endplate geometries. FIG. 37B illustrates the curved cross section 184 of the expander 153 of FIG. 37A . This curve 184 can be an arc segment of a circle as shown. Alternatively, the cross section can be an ellipsoid segment or have a multitude of arc segments of different radii and centers. FIG. 37C is a perspective view showing the three dimensional shape of the expander 153 of FIGS. 37A and 37B .
The embodiment of the frame 153 as shown in FIGS. 37A-C , can also be employed without the use of a covering membrane. The nucleus pulposus of many patients with low back pain or disc herniation can degenerate to a state in which the material properties of the nucleus cause it to behave much more like a solid than a gel. As humans age, the water content of the nucleus declines from roughly 88% to less than 75%. As this occurs, there is an increase in the cross linking of collagen within the disc resulting in a greater solidity of the nucleus. When the pore size or the largest open area of any given gap in the lattice depicted in FIGS. 37A , 37 B, and 37 C is between 0.05 mm 2 (7.75×10 −5 in 2 ) and 0.75 mm 2 (1.16×10 −3 in 2 ), the nucleus pulposus is unable to extrude through the lattice at pressures generated within the disc (between 250 KPa and 1.8 MPa). The preferred pore size has been found to be approximately 0.15 mm 2 (2.33×10 −4 in 2 ). This pore size can be used with any of the disclosed embodiments of the expander or any other expander that falls within the scope of the present invention to prevent movement of nucleus toward the outer periphery of the disc without the need for an additional membrane. The membrane thickness is preferably in a range of 0.025 mm to 2.5 mm.
FIG. 38 depicts an expander 153 similar to that of FIG. 37A without fingers. The expander 153 includes a central lattice 180 consisting of multiple struts 182 .
FIGS. 39 through 41 depict another embodiment of the expander 153 of the present invention. These tubular expanders can be used in the barrier 12 embodiment depicted in FIG. 31A . The sealer 51 can cover the expander 153 as shown in FIG. 31A . Alternatively, the sealer 51 can cover the interior surface of the expander or an arc segment of the tube along its length on either the interior or exterior surface.
FIG. 39 depicts an embodiment of a tubular expander 154 . The superior 166 and inferior surfaces 168 of the tubular expander 154 can deploy against the superior and inferior vertebral endplates, respectively. The distance 186 between the superior 166 and inferior 168 surfaces of the expander 154 are preferably equal to or greater than the posterior disc height at the inner surface of the anulus 10 . This embodiment has an anulus face 188 and nucleus face 190 as shown in FIGS. 39B , 39 C and 39 D. The anulus face 188 can be covered by the sealer 51 from the superior 166 to inferior 168 surface of the expander 154 . This face 188 lies against the inner surface of the anulus 10 in its deployed position and can prevent egress of materials from within the disc 15 . The primary purpose of the nucleus face 190 is to prevent migration of the expander 154 within the disc 15 . The struts 192 that form the nucleus face 190 can project anteriorly into the nucleus 20 when the barrier 12 is positioned across the posterior wall of the anulus 10 . This anterior projection can resist rotation of the tubular expansion means 154 about its long axis. By interacting with the nucleus 20 , the struts 192 can further prevent migration around the circumference of the disc 15 .
The struts 192 can be spaced to provide nuclear gaps 194 . These gaps 194 can encourage the flow of nucleus pulposus 20 into the interior of the expander 154 . This flow can insure full expansion of the barrier 12 within the disc 15 during deployment.
The embodiments of FIGS. 39 , 40 and 41 vary by their cross-sectional shape. FIG. 39 has a circular cross section 196 as seen in FIG. 39C . If the superior-inferior height 186 of the expander 154 is greater than that of the disc 15 , this circular cross section 196 can deform into an oval when deployed, as the endplates of the vertebrae compress the expander 154 . The embodiment of the expander 154 shown in FIG. 40 is preformed into an oval shape 198 shown in FIG. 40C . Compression by the endplates can exaggerate the unstrained oval 198 . This oval 198 can provide greater stability against rotation about a long axis of the expander 154 . The embodiment of FIGS. 41B , 41 C and 41 D depict an ‘egg-shaped’ cross section 202 , as shown in FIG. 41C , that can allow congruity between the curvature of the expander 154 and the inner wall of posterior anulus 10 . Any of a variety of alternate cross sectional shapes can be employed to obtain a desired fit or expansion force without deviating from the spirit of the present invention.
FIGS. 40E , 40 F, and 40 I depict the expander 154 of FIGS. 40A-D having a sealing means 51 covering the exterior surface of the anulus face 188 . This sealing means 51 can be held against the endplates and the inner surface of the posterior anulus by the expander 154 in its deployed state.
FIGS. 40G and 40H depict the expander 154 of FIG. 40B with a sealer 51 covering the interior surface of the anulus face 188 . This position of the sealer 51 can allow the expander 154 to contact both the vertebral endplates and inner surface of the posterior anulus. This can promote ingrowth of tissue into the expander 154 from outside the disc 15 . Combinations of sealer 51 that cover all or part of the expander 154 can also be employed without deviating from the scope of the present invention. The expander 154 can also have a small pore size thereby allowing retention of a material such as a nucleus pulposus, for example, without the need for a sealer as a covering.
FIGS. 42A-D depict cross sections of a preferred embodiment of sealing means 51 and enlarging means 53 . Sealing means 51 has internal cavity 17 and opening 8 leading from its outer surface into internal cavity 17 . Enlarger 53 can be inserted through opening 8 and into internal cavity 17 .
FIGS. 43A and 43B depict an alternative configuration of enlarger 53 . Fixation region 4 extends through opening 8 in sealing means 51 . Fixation region 4 has a through-hole that can facilitate fixation of enlarger 53 to tissues surrounding defect 16 .
FIGS. 44A and 44B depict an alternative shape of the barrier. In this embodiment, sealing means 51 , enlarger 53 , or both have a curvature with radius R. This curvature can be used in any embodiment of the present invention and may aid in conforming to the curved inner circumference of anulus fibrosis 10 .
FIG. 45 is a section of a device used to affix sealing means 51 to tissues surrounding a defect. In this figure, sealing means 51 would be positioned across interior aspect 50 of defect 16 . The distal end of device 110 ′ would be inserted through defect 16 and opening 8 into the interior cavity 17 . On the right side of this figure, fixation dart 25 has been passed from device 110 ′, through a wall of sealing means 51 and into tissues surrounding sealing means 51 . On the right side of the figure, fixation dart 25 is about to be passed through a wall of sealing means 51 by advancing pusher 111 relative to device 110 ′ in the direction of the arrow.
FIG. 46 depicts the use of thermal device 200 to heat sealing means 51 and adhere it to tissues surrounding a defect. In this figure, sealing means 51 would be positioned across the interior aspect 36 of a defect 16 . The distal end of thermal device 200 would be inserted through the defect and opening 8 into interior cavity 17 . In this embodiment, thermal device 200 employs at its distal end resistive heating element 210 connected to a voltage source by wires 220 . Covering 230 is a non-stick surface such as Teflon tubing that ensures the ability to remove device 200 from interior cavity 17 . In this embodiment, device 200 would be used to heat first one half, and then the other half of sealing means 51 .
FIG. 47 depicts an expandable thermal element, such as a balloon, that can be used to adhere sealing means 51 to tissues surrounding a defect. As in FIG. 18 , the distal end of device 130 can be inserted through the defect and opening 8 into interior cavity 17 , with balloon 150 ′ on the distal end device 130 in a collapsed state. Balloon 150 ′ is then inflated to expanded state 150 , expanding sealing means 51 . Expanded balloon 150 can heat sealing means 51 and surrounding tissues by inflating it with a heated fluid or by employing RF electrodes. In this embodiment, device 130 can be used to expand and heat first one half, then the other half of sealing means 51 .
FIG. 48 depicts an alternative embodiment to device 130 . This device employs an elongated, flexible balloon 150 ′ that can be inserted into and completely fill internal cavity 17 of sealing means 51 prior to inflation to an expanded state 150 . Using this embodiment, inflation and heating of sealing means 51 can be performed in one step.
FIGS. 49A through 49G illustrate a method of implanting an intradiscal implant. An intradiscal implant system consists of an intradiscal implant 400 , a delivery device or cannula 402 , an advancer 404 and at least one control filament 406 . The intradiscal implant 400 is loaded into the delivery cannula 402 which has a proximal end 408 and a distal end 410 . FIG. 49A illustrates the distal end 410 advanced into the disc 15 through an annulotomy 416 . This annulotomy 416 can be through any portion of the anulus 10 , but is preferably at a site proximate to a desired, final implant location. The implant 400 is then pushed into the disc 15 through the distal end 410 of the cannula 402 in a direction that is generally away from the desired, final implant location as shown in FIG. 49B . Once the implant 400 is completely outside of the delivery cannula 402 and within the disc 15 , the implant 400 can be pulled into the desired implant location by pulling on the control filament 406 as shown in FIG. 49C . The control filament 406 can be secured to the implant 400 at any location on or within the implant 400 , but is preferably secured at least at a site 414 or sites on a distal portion 412 of the implant 400 , i.e. that portion that first exits the delivery cannula 402 when advanced into the disc 15 . These site or sites 414 are generally furthest from the desired, final implant location once the implant has been fully expelled from the interior of the delivery cannula 402 .
Pulling on the control filament 406 causes the implant 400 to move toward the annulotomy 416 . The distal end 410 of the delivery cannula 402 can be used to direct the proximal end 420 of the implant 400 (that portion of the implant 400 that is last to be expelled from the delivery cannula 402 ) away from the annulotomy 416 and toward an inner aspect of the anulus 10 nearest the desired implant location. Alternately, the advancer 404 can be used to position the proximal end of the implant toward an inner aspect of the anulus 20 near the implant location, as shown in FIG. 49E . Further pulling on the control filament 406 causes the proximal end 426 of the implant 400 to dissect along the inner aspect of the anulus 20 until the attachment site 414 or sites of the guide filament 406 to the implant 400 has been pulled to the inner aspect of the annulotomy 416 , as shown in FIG. 49D . In this way, the implant 400 will extend at least from the annulotomy 416 and along the inner aspect of the anulus 10 in the desired implant location, illustrated in FIG. 49F .
The implant 400 can be any of the following: nucleus replacement device, nucleus augmentation device, anulus augmentation device, anulus replacement device, the barrier of the present invention or any of its components, drug carrier device, carrier device seeded with living cells, or a device that stimulates or supports fusion of the surrounding vertebra. The implant 400 can be a membrane which prevents the flow of a material from within the anulus fibrosis of an intervertebral disc through a defect in the disc. The material within the anulus fibrosis can be, for example, a nucleus pulposus or a prosthetic augmentation device, such as hydrogel. The membrane can be a sealer. The implant 400 can be wholly or partially rigid or wholly or partially flexible. It can have a solid portion or portions that contain a fluid material. It can comprise a single or multitude of materials. These materials can include metals, polymers, gels and can be in solid or woven form. The implant 400 can either resist or promote tissue ingrowth, whether fibrous or bony.
The cannula 402 can be any tubular device capable of advancing the implant 400 at least partially through the anulus 10 . It can be made of any suitable biocompatible material including various known metals and polymers. It can be wholly or partially rigid or flexible. It can be circular, oval, polygonal, or irregular in cross section. It must have an opening at least at its distal end 410 , but can have other openings in various locations along its length.
The advancer 404 can be rigid or flexible, and have one of a variety of cross sectional shapes either like or unlike the delivery cannula 402 . It may be a solid or even a column of incompressible fluid, so long as it is stiff enough to advance the implant 400 into the disc 15 . The advancer 404 can be contained entirely within the cannula 402 or can extend through a wall or end of the cannula to facilitate manipulation.
Advancement of the implant 400 can be assisted by various levers, gears, screws and other secondary assist devices to minimize the force required by the surgeon to advance the implant 400 . These secondary devices can further give the user greater control over the rate and extent of advancement into the disc 15 .
The guide filament 406 may be a string, rod, plate, or other elongate object that can be secured to and move with the implant 400 as it is advanced into the disc 15 . It can be constructed from any of a variety of metals or polymers or combination thereof and can be flexible or rigid along all or part of its length. It can be secured to a secondary object 418 or device at its end opposite that which is secured to the implant 400 . This secondary device 418 can include the advancer 404 or other object or device that assists the user in manipulating the filament. The filament 406 can be releasably secured to the implant 400 , as shown in FIG. 49G or permanently affixed. The filament 406 can be looped around or through the implant. Such a loop can either be cut or have one end pulled until the other end of the loop releases the implant 400 . It may be bonded to the implant 400 using adhesive, welding, or a secondary securing means such as a screw, staple, dart, etc. The filament 406 can further be an elongate extension of the implant material itself. If not removed following placement of the implant, the filament 406 can be used to secure the implant 400 to surrounding tissues such as the neighboring anulus 10 , vertebral endplates, or vertebral bodies either directly or through the use of a dart, screw, staple, or other suitable anchor.
Multiple guide filaments can be secured to the implant 400 at various locations. In one preferred embodiment, a first or distal 422 and a second or proximal 424 guide filament are secured to an elongate implant 400 at or near its distal 412 and proximal 420 ends at attachment sites 426 and 428 , respectively. These ends 412 and 420 correspond to the first and last portions of the implant 400 , respectively, to be expelled from the delivery cannula 402 when advanced into the disc 15 . This double guide filament system allows the implant 400 to be positioned in the same manner described above in the single filament technique, and illustrated in FIGS. 50A-C . However, following completion of this first technique, the user may advance the proximal end 420 of the device 400 across the annulotomy 416 by pulling on the second guide filament 424 , shown in FIG. 50D . This allows the user to controllably cover the annulotomy 416 . This has numerous advantages in various implantation procedures. This step may reduce the risk of herniation of either nucleus pulposus 20 or the implant itself. It may aid in sealing the disc, as well as preserving disc pressure and the natural function of the disc. It may encourage ingrowth of fibrous tissue from outside the disc into the implant. It may further allow the distal end of the implant to rest against anulus further from the defect created by the annulotomy. Finally, this technique allows both ends of an elongate implant to be secured to the disc or vertebral tissues.
Both the first 422 and second 424 guide filaments can be simultaneously tensioned, as shown in FIG. 50E , to ensure proper positioning of the implant 400 within the anulus 10 . Once the implant 400 is placed across the annulotomy, the first 422 and second 424 guide filaments can be removed from the input 400 , as shown in FIG. 50F . Additional control filaments and securing sites may further assist implantation and/or fixation of the intradiscal implants.
In another embodiment of the present invention, as illustrated in FIGS. 51A-C , an implant guide 430 may be employed to aid directing the implant 400 through the annulotomy 416 , through the nucleus pulposus 10 , and/or along the inner aspect of the anulus 10 . This implant guide 430 can aid in the procedure by dissecting through tissue, adding stiffness to the implant construct, reducing trauma to the anulus or other tissues that can be caused by a stiff or abrasive implant, providing 3-D control of the implants orientation during implantation, expanding an expandable implant, or temporarily imparting a shape to the implant that is beneficial during implantation. The implant guide 430 can be affixed to either the advancer 404 or the implant 406 themselves. In a preferred embodiment shown in FIGS. 52A and 52B , the implant guide 430 is secured to the implant 400 by the first 424 and second 426 guide filaments of the first 426 and the second 428 attachment sites, respectively. The guide filaments 424 and 426 may pass through or around the implant guide 430 . In this embodiment, the implant guide 430 may be a thin, flat sheet of biocompatible metal with holes passing through its surface proximate to the site or sites 426 and 428 at which the guide filaments 422 and 424 are secured to the implant 400 . These holes allow passage of the securing filament 422 and 424 through the implant guide 430 . Such an elongated sheet may run along the implant 400 and extend beyond its distal end 412 . The distal end of the implant guide 430 may be shaped to help dissect through the nucleus 10 and deflect off of the anulus 10 as the implant 400 is advanced into the disc 15 . When used with multiple guide filaments, such an implant guide 430 can be used to control rotational stability of the implant 400 . It may also be used to retract the implant 400 from the disc 15 should this become necessary. The implant guide 430 may also extend beyond the proximal tip 420 of the implant 400 to aid in dissecting across or through the anulus 10 proximate to the desired implantation site.
The implant guide 430 is releasable from the implant 400 following or during implantation. This release may be coordinated with the release of the guide filaments 422 and 424 . The implant guide 430 may further be able to slide along the guide filaments 422 and 424 while these filaments are secured to the implant 400 .
Various embodiments of the barrier 12 or implant 400 can be secured to tissues within the intervertebral disc 15 or surrounding vertebrae. It can be advantageous to secure the barrier means 12 in a limited number of sites while still insuring that larger surfaces of the barrier 12 or implant juxtapose the tissue to which the barrier 12 is secured. This is particularly advantageous in forming a sealing engagement with surrounding tissues.
FIGS. 53-57 illustrate barriers 12 having stiffening elements 300 . The barrier 12 can incorporate stiffening elements 300 that run along a length of the implant required to be in sealing engagement. These stiffening elements 300 can be one of a variety of shapes including, but not limited to, plates 302 , rods 304 , or coils. These elements are preferably stiffer than the surrounding barrier 12 and can impart their stiffness to the surrounding barrier. These stiffening elements 300 can be located within an interior cavity formed by the barrier. They can further be imbedded in or secured to the barrier 12 .
Each stiffening element can aid in securing segments of the barrier 12 to surrounding tissues. The stiffening elements can have parts 307 , including through-holes, notches, or other indentations for example, to facilitate fixation of the stiffening element 300 to surrounding tissues by any of a variety of fixation devices 306 . These fixation devices 306 can include screws, darts, dowels, or other suitable means capable of holding the barrier 12 to surrounding tissue. The fixation devices 306 can be connected either directly to the stiffening element 300 or indirectly using an intervening length of suture, cable, or other filament for example. The fixation device 306 can further be secured to the barrier 12 near the stiffening element 300 without direct contact with the stiffening element 300 .
The fixation device 306 can be secured to or near the stiffening element 300 at opposing ends of the length of the barrier 12 required to be in sealing engagement with surrounding tissues. Alternatively, one or a multitude of fixation devices 306 can be secured to or near the stiffening element 300 at a readily accessible location that may not be at these ends. In any barrier 12 embodiment with an interior cavity 17 and an opening 8 leading thereto, the fixation sites may be proximal to the opening 8 to allow passage of the fixation device 306 and various instruments that may be required for their implantation.
FIGS. 53A and 53B illustrate one embodiment of a barrier 12 incorporating the use of a stiffening element 300 . The barrier 12 can be a plate and screw barrier 320 . In this embodiment, the stiffening element 300 consists of two fixation plates, superior 310 and inferior 312 , an example of which is illustrated in FIGS. 54A and 54B with two parts 308 passing through each plate. The parts 308 are located proximal to an opening 8 leading into an interior cavity 17 of the barrier 12 . These parts 8 allow passage of a fixation device 306 such as a bone screw. These screws can be used to secure the barrier means 12 to a superior 50 and inferior 50 ′ vertebra. As the screws are tightened against the vertebral endplate, the fixation plates 310 , 312 compress the intervening sealing means against the endplate along the superior and inferior surfaces of the barrier 12 . This can aid in creating a sealing engagement with the vertebral endplates and prevent egress of materials from within the disc 15 . As illustrated in FIGS. 53A and 53B , only the superior screws have been placed in the superior plate 310 , creating a sealing engagement with the superior vertebra.
FIGS. 55A and 55B illustrate another embodiment of a barrier 12 having stiffening elements 300 . The barrier 12 can be an anchor and rod barrier 322 . In this embodiment, the stiffening elements 300 consist of two fixation rods 304 , an example of which is shown in FIGS. 56A and 56B , imbedded within the barrier 12 . The rods 304 can include a superior rod 314 and an inferior rod 316 . Sutures 318 can be passed around these rods 314 and 316 and through the barrier means 10 . These sutures 318 can in turn, be secured to a bone anchor or other suitable fixation device 306 to draw the barrier 12 into sealing engagement with the superior and inferior vertebral endplates in a manner similar to that described above. The opening 8 and interior cavity 17 of the barrier 12 are not required elements of the barrier 12 .
FIG. 57 illustrates the anchor and rod barrier 322 , described above, with fixation devices 306 placed at opposing ends of each fixation rod 316 and 318 . The suture 18 on the left side of the superior rod 318 has yet to be tied.
Various methods may be employed to decrease the forces necessary to maneuver the barrier 12 into a position along or within the lamellae of the anulus fibrosis 10 . FIGS. 58A , 58 B, 59 A and 59 B depict two preferred methods of clearing a path for the barrier 12 .
FIGS. 58A and 58B depict one such method and an associated dissector device 454 . In these figures, the assumed desired position of the implant is along the posterior anulus 452 . In order to clear a path for the implant, a hairpin dissector 454 can be passed along the intended implantation site of the implant. The hairpin dissector 454 can have a hairpin dissector component 460 having a free end 458 . The dissector can also have an advancer 464 to position the dissector component 460 within the disc 15 . The dissector 454 can be inserted through cannula 456 into an opening 462 in the anulus 10 along an access path directed anteriorly or anterior-medially. Once a free-end 458 of the dissector component 460 is within the disc 15 , the free-end 458 moves slightly causing the hairpin to open, such that the dissector component 460 resists returning into the cannula 456 . This opening 462 can be caused by pre-forming the dissector to the opened state. The hairpin dissector component 460 can then be pulled posteriorly, causing the dissector component 460 to open, further driving the free-end 458 along the posterior anulus 458 . This motion clears a path for the insertion of any of the implants disclosed in the present invention. The body of dissector component 460 is preferably formed from an elongated sheet of metal. Suitable metals include various spring steels or nickel titanium alloys. It can alternatively be formed from wires or rods.
FIGS. 59A and 59B depict another method and associated dissector device 466 suitable for clearing a path for implant insertion. The dissector device 466 is shown in cross section and consists of a dissector component 468 , an outer cannula 470 and an advancer or inner push rod 472 . A curved passage or slot 474 is formed into an intradiscal tip 476 of outer cannula 470 . This passage or slot 474 acts to deflect the tip of dissector component 468 in a path that is roughly parallel to the lamellae of the anulus fibrosis 10 as the dissector component 468 is advanced into the disc 15 by the advancer. The dissector component 468 is preferably formed from a superelastic nickel titanium alloy, but can be constructed of any material with suitable rigidity and strain characteristics to allow such deflection without significant plastic deformation. The dissector component 468 can be formed from an elongated sheet, rods, wires or the like. It can be used to dissect between the anulus 10 and nucleus 20 , or to dissect between layers of the anulus 10 .
FIGS. 60A-C depict an alternate dissector component 480 of FIGS. 59A and 59B . Only the intradiscal tip 476 of device 460 and regions proximal thereto are shown in these figures. A push-rod 472 similar to that shown in FIG. 59A can be employed to advance dissector 480 into the disc 15 . Dissector 480 can include an elongated sheet 482 with superiorly and inferiorly extending blades (or “wings”) 484 and 486 , respectively. This sheet 482 is preferably formed from a metal with a large elastic strain range such as spring steel or nickel titanium alloy. The sheet 482 can have a proximal end 488 and a distal end 490 . The distal end 490 can have a flat portion which can be flexible. A step portion 494 can be located between the distal end 490 and the proximal end 488 . The proximal end 488 can have a curved shape. The proximal end can also include blades 484 and 486 .
In the undeployed state depicted in FIGS. 60A and 60B , wings 484 and 486 are collapsed within outer cannula 470 while elongated sheet 482 is captured within deflecting passage or slot 474 . As the dissector component 480 is advanced into a disc 15 , passage or slot 478 directs the dissector component 480 in a direction roughly parallel to the posterior anulus (90 degrees to the central axis of sleeve 470 in this case) in a manner similar to that described for the embodiment in FIGS. 59A and 59B . Wings 484 and 486 open as they exit the end of sleeve 470 and expand toward the vertebral endplates. Further advancement of dissector component 480 allows the expanded wings 484 and 486 to dissect through any connections of nucleus 20 or anulus 10 to the endplates that may present an obstruction to subsequent passage of the implants of the present invention. When used to aid in the insertion of a barrier, the dimensions of dissector component 480 should approximate those of the barrier such that the minimal amount of tissue is disturbed while reducing the forces necessary to position the barrier in the desired location.
FIGS. 61A-61D illustrate a method of implanting a disc implant. A disc implant 552 is inserted into a delivery device 550 . The delivery device 550 has a proximal end 556 and a distal end 558 . The distal end 558 of the delivery device 550 is inserted into an annulotomy illustrated in FIG. 61A . The annulotomy is preferably located at a site within the anulus 10 that is proximate to a desired, final implant 552 location. The implant 400 is then deployed by being inserted into the disc 15 through the distal end 558 of the delivery device 550 . Preferably the implant is forced away from the final implant location, as shown in FIG. 61B . An implant guide 560 can be used to position the implant 400 . Before, during or after deployment of the implant 400 , an augmentation material 7 can be injected into the disc 15 . Injection of augmentation after deployment is illustrated in FIG. 61C . The augmentation material 7 can include a hydrogel or collagen, for example. In one embodiment, the delivery device 550 is removed from the disc 15 and a separate tube is inserted into the annulotomy to inject the flowable augmentation material 7 . Alternately, the distal end 558 of the delivery device 550 can remain within the annulotomy and the fluid augmentation material 554 injected through the delivery device 550 . Next, the delivery device 550 is removed from the annulotomy and the intradiscal implant 400 is positioned over the annulotomy in the final implant location, as shown in FIG. 61D . The implant 400 can be positioned using control filaments described above.
Certain embodiments, as shown in FIGS. 62-66 , depict anulus and nuclear augmentation devices which are capable of working in concert to restore the natural biomechanics of the disc. A disc environment with a degenerated or lesioned anulus cannot generally support the load transmission from either the native nucleus or from prosthetic augmentation. In many cases, nuclear augmentation materials 7 bulge through the anulus defects, extrude from the disc, or apply pathologically high load to damaged regions of the anulus. Accordingly, in one aspect of the current invention, damaged areas of the anulus are protected by shunting the load from the nucleus 20 or augmentation materials 7 to healthier portions of the anulus 10 or endplates. With the barrier-type anulus augmentation 12 in place, as embodied in various aspects of the present invention, nuclear augmentation materials 7 or devices can conform to healthy regions of the anulus 10 while the barrier 12 shields weaker regions of the anulus 10 . Indeed, the anulus augmentation devices 12 of several embodiments of the present invention are particularly advantageous because they enable the use of certain nuclear augmentation materials and devices 7 that may otherwise be undesirable in a disc with an injured anulus.
FIG. 62 is a cross-sectional transverse view of an anulus barrier device 12 implanted within a disc 15 along the inner surface of a lamella 16 . Implanted conformable nuclear augmentation 7 is also shown in contact with the barrier 12 . The barrier device 12 is juxtapositioned to the innermost lamella of the anulus. Conformable nuclear augmentation material 7 is inserted into the cavity which is closed by the barrier 12 , in an amount sufficient to fill the disc space in an unloaded supine position. As shown, in one embodiment, fluid nuclear augmentation 554 , such as hyaluronic acid, is used.
Fluid nuclear augmentation 554 is particularly well-suited for use in various aspects of the current invention because it can be delivered with minimal invasiveness and because it is able to flow into and fill minute voids of the intervertebral disc space. Fluid nuclear augmentation 554 is also uniquely suited for maintaining a pressurized environment that evenly transfers the force exerted by the endplates to the anulus augmentation device and/or the anulus. However, fluid nuclear augmentation materials 554 used alone may perform poorly in discs 15 with a degenerated anulus because the material can flow back out through anulus defects 8 and pose a risk to surrounding structures. This limitation is overcome by several embodiments of the current invention because the barrier 12 shunts the pressure caused by the fluid augmentation 554 away from the damaged anulus region 8 and toward healthier regions, thus restoring function to the disc 15 and reducing risk of the extrusion of nuclear augmentation materials 7 and fluid augmentation material 554 .
Exemplary fluid nuclear augmentation materials 554 include, but are not limited to, various pharmaceuticals (steroids, antibiotics, tissue necrosis factor alpha or its antagonists, analgesics); growth factors, genes or gene vectors in solution; biologic materials (hyaluronic acid, non-crosslinked collagen, fibrin, liquid fat or oils); synthetic polymers (polyethylene glycol, liquid silicones, synthetic oils); and saline. One skilled in the art will understand that any one of these materials may be used alone or that a combination of two or more of these materials may be used together to form the nuclear augmentation material.
Any of a variety of additional additives such as thickening agents, carriers, polymerization initiators or inhibitors may also be included, depending upon the desired infusion and long-term performance characteristics. In general, “fluid” is used herein to include any material which is sufficiently flowable at least during the infusion process, to be infused through an infusion lumen in the delivery device into the disc space. The augmentation material 554 may remain “fluid” after the infusion step, or may polymerize, cure, or otherwise harden to a less flowable or nonflowable state.
Additional additives and components of the nucleus augmentation material are recited below. In general, the nature of the material 554 may remain constant during the deployment and post-deployment stages or may change, from a first infusion state to a second, subsequent implanted state. For example, any of a variety of materials may desirably be infused using a carrier such as a solvent or fluid medium with a dispersion therein. The solvent or liquid carrier may be absorbed by the body or otherwise dissipate from the disc space post-implantation, leaving the nucleus augmentation material 554 behind. For example, any of a variety of the powders identified below may be carried using a fluid carrier. In addition, hydrogels or other materials may be implanted or deployed while in solution, with the solvent dissipating post-deployment to leave the hydrogel or other media behind. In this type of application, the disc space may be filled under higher than ultimately desired pressure, taking into account the absorption of a carrier volume. Additional specific materials and considerations are disclosed in greater detail below.
FIG. 63 is a cross-sectional transverse view of anulus barrier device 12 implanted within a disc 15 along an inner surface of a lamella 16 . Implanted nuclear augmentation 7 comprised of a hydrophilic flexible solid is also shown. Nuclear augmentation materials include, but are not limited to, liquids, gels, solids, gases or combinations thereof. Nuclear augmentation devices 7 may be formed from one or more materials, which are present in one or more phases. FIG. 63 shows a cylindrical flexible solid form of nuclear augmentation 7 . Preferably, this flexible solid is composed of a hydrogel, including, but not limited to, acrylonitrile, acrylic acid, polyacrylimide, acrylimide, acrylimidine, polyacrylonitrile, polyvinylalcohol, and the like.
FIG. 63 depicts nuclear augmentation 7 using a solid or gel composition. If required, these materials can be designed to be secured to surrounding tissues by mechanical means, such as glues, screws, and anchors, or by biological means, such as glues and in growth. Solid but deformable augmentation materials 7 may also be designed to resist axial compression by the endplates rather than flowing circumferentially outward toward the anulus. In this way, less force is directed at the anulus 10 . Solid nuclear augmentation 7 can also be sized substantially larger than the annulotomy 416 or defect 8 to decrease the risk of extrusion. The use of solid materials or devices 7 alone is subject to certain limitations. The delivery of solid materials 7 may require a large access hole 417 in the anulus 10 , thereby decreasing the integrity of the disc 15 and creating a significant risk for extrusion of either the augmentation material 7 or of natural nucleus 20 remaining within the disc 15 . Solid materials or devices 7 can also overload the endplates causing endplate subsidence or apply point loads to the anulus 10 from corners or edges that may cause pain or further deterioration of the anulus 10 . Several embodiments of the present invention overcome the limitations of solid materials and are particularly well-suited for use with liquid augmentation materials 7 . The barrier device 12 of various embodiments of this invention effectively closes the access hole 417 and can be adapted to partially encapsulate the augmented nucleus, thus mitigating the risks posed by solid materials.
Solid or gel nuclear augmentation materials 7 used in various embodiments of the current invention include single piece or multiple pieces. The solid materials 7 may be cube-like, spheroid, disc-like, ellipsoid, rhombohedral, cylindrical, or amorphous in shape. These materials 7 may be in woven or non-woven form. Other forms of solids including minute particles or even powder can be considered when used in combination with the barrier device. Candidate materials 7 include, but are not limited to: metals, such as titanium, stainless steels, nitinol, cobalt chrome; resorbable or non-resorbing synthetic polymers, such as polyurethane, polyester, PEEK, PET, FEP, PTFE, ePTFE, Teflon, PMMA, nylon, carbon fiber, Delrin, polyvinyl alcohol gels, polyglycolic acid, polyethylene glycol; silicon gel or rubber, vulcanized rubber or other elastomer; gas filled vesicles, biologic materials such as morselized or block bone, hydroxy apetite, cross-linked collagen, muscle tissue, fat, cellulose, keratin, cartilage, protein polymers, transplanted or bioengineered nucleus pulposus or anulus fibrosus; or various pharmacologically active agents in solid form. The solid or gel augmentation materials 7 may be rigid, wholly or partially flexible, elastic or viscoelastic in nature. The augmentation device or material 7 may be hydrophilic or hydrophobic. Hydrophilic materials, mimicking the physiology of the nucleus, may be delivered into the disc in a hydrated or dehydrated state. Biologic materials may be autologous, allograft, zenograft, or bioengineered.
In various embodiments of the present invention, the solid or gel nuclear augmentation material 7 , as depicted in FIG. 63 , are impregnated or coated with various compounds. Preferably, a biologically active compound is used. In one embodiment, one or more drug carriers are used to impregnate or coat the nuclear augmentation material 7 . Genetic vectors, naked genes or other therapeutic agents to renew growth, reduce pain, aid healing, and reduce infection may be delivered in this manner. Tissue in-growth, either fibrous (from the anulus) or bony (from the endplates), within or around the augmentation material can be either encouraged or discouraged depending on the augmentation used. Tissue in-growth may be beneficial for fixation and can be encouraged via porosity or surface chemistry. Surface in-growth or other methods of fixation of the augmentation material 7 can be encouraged on a single surface or aspect so as to not interfere with the normal range of motion of the spinal unit. In this way, the material is stabilized and safely contained within the anulus 10 without resulting in complete fixation which might cause fusion and prohibit disc function.
FIG. 64 is a cross-sectional transverse view of anulus barrier device 12 implanted within a disc 15 along an inner surface of a lamella 16 . Several types of implanted nuclear augmentation 7 , including a solid cube, a composite cylindrical solid 555 , and a free flowing liquid 554 are shown. The use of multiple types of nuclear augmentation with the barrier 12 is depicted in FIG. 64 . The barrier device 12 is shown in combination with fluid nuclear augmentation 554 , solid nuclear augmentation 7 , in the form of a cube, and a cross-linked collagen sponge composite 555 soaked in a growth factor. In several embodiments of the present invention, a multiphase augmentation system, as shown in FIG. 64 , is used. A combination of solids and liquids is used in a preferred embodiment. Nuclear augmentation 7 comprising solids and liquids 554 can be designed to create primary and secondary levels of flexibility within an intervertebral disc space. In use, the spine will flex easily at first as the intervertebral disc pressure increases and the liquids flows radially, loading the anulus. Then, as the disc height decreases and the endplates begin to contact the solid or gelatinous augmentation material, flexibility will decrease. This combination can also prevent damage to the anulus 10 under excessive loading as the solid augmentation 7 can be designed to resist further compression such that the fluid pressure on the anulus is limited. In a preferred embodiment, use of multiphase augmentation allows for the combination of fluid medications or biologically active substances with solid or gelatinous carriers. One example of such a preferable combination is a cross-linked collagen sponge 555 soaked in a growth factor or combination of growth factors in liquid suspension.
In one aspect of the invention, the nuclear augmentation material or device 7 , 554 constructed therefrom is phase changing, i.e. from liquid to solid, solid to liquid, or liquid to gel. In situ polymerizing nuclear augmentation materials are well-known in the art and are described in U.S. Pat. No. 6,187,048, herein incorporated by reference. Phase changing augmentation preferably changes from a liquid to a solid or gel. Such materials may change phases in response to contact with air, increases or decreases in temperature, contact with biologic liquids or by the mixture of separate reactive constituents. These materials are advantageous because they can be delivered through a small hole in the anulus or down a tube or cannula placed percutaneously into the disc. Once the materials have solidified or gelled, they can exhibit the previously described advantages of a solid augmentation material. In a preferred embodiment, the barrier device is used to seal and pressurize a phase changing material to aid in its delivery by forcing it into the voids of the disc space while minimizing the risk of extrusion of the material while it is a fluid. In this situation, the barrier or anulus augmentation device 12 may be permanently implanted or used only temporarily until the desired phase change has occurred.
Another aspect of the present invention includes an anulus augmentation device 12 that exploits the characteristics of nucleus augmentation devices or materials to improve its own performance. Augmenting the nucleus 20 pressurizes the intervertebral disc environment which can serve to fix or stabilize an anulus repair device in place. The nucleus 20 can be pressurized by inserting into the disc 15 an adequate amount of augmentation material 7 , 554 . In use, the pressurized disc tissue and augmentation material 7 , 554 applies force on the inwardly facing surface of the anulus augmentation device 12 . This pressure may be exploited by the design of the anulus prosthesis or barrier 12 to prevent it from dislodging or moving from its intended position. One exemplary method is to design the inwardly facing surface of the anulus prosthesis 12 to expand upon the application of pressure. As the anulus prosthesis 12 expands, it becomes less likely to be expelled from the disc. The prosthesis 12 may be formed with a concavity facing inward to promote such expansion.
In several embodiments, the anulus augmentation device 12 itself functions as nuclear augmentation 7 . In a preferred embodiment, the barrier 12 frame is encapsulated in ePTFE. This construct typically displaces a volume of 0.6 cubic centimeters, although thicker coatings of ePTFE or like materials may be used to increase this volume to 3 cubic centimeters. Also, the anulus augmentation device may be designed with differentially thickened regions along its area.
FIG. 65 depicts a sagittal cross-sectional view of the barrier device connected to an inflatable nuclear augmentation device 455 . The barrier device 12 is shown connected via hollow delivery and support tube 425 to an nuclear augmentation sack 455 suitable for containing fluid material 554 . The tube 425 has a delivery port or valve 450 that extends through the barrier device and can be accessed from the access hole 417 after the barrier device 12 and augmentation sack 455 has been delivered. This nuclear and anulus augmentation combination is particularly advantageous because of the ease of deliverability, since the sack 455 and the barrier 12 are readily compressed. The connection of the barrier 12 and the augmentation sack 455 also serves to stabilize the combination and prevent its extrusion from the disc 15 . The nuclear augmentation 7 may be secured to the anulus augmentation prosthesis 12 to create a resistance to migration of the overall construct. Such attachment may also be performed to improve or direct the transfer of load from the nuclear prosthesis 7 through the anulus prosthesis 12 to the disc tissues. The barrier 12 and augmentation 7 can be attached prior to, during, or after delivery of the barrier 12 into the disc 15 . They may be secured to each other by an adhesive or by a flexible filament such as suture. Alternatively, the barrier 12 may have a surface facing the augmentation material 7 that bonds to the augmentation material 7 though a chemical reaction. This surface may additionally allow for a mechanical linkage to a surface of the augmentation material 7 . This linkage could be achieved through a porous attachment surface of the barrier 12 that allows the inflow of a fluid augmentation material 7 that hardens or gels after implantation.
Alternatively, the anulus augmentation device 12 and nuclear augmentation material 7 may be fabricated as a single device with a barrier 12 region and a nuclear augmentation region 7 . As an example, the barrier 12 may form at least a portion of the surface of an augmentation sack 455 or balloon. The sack 455 may be filled with suitable augmentation materials 7 once the barrier has been positioned along a weakened inner surface of the anulus 10 .
The sequence of inserting the barrier 12 and nuclear augmentation 7 in the disc can be varied according to the nuclear augmentation 7 used or requirements of the surgical procedure. For example, the nuclear augmentation 7 can be inserted first and then sealed in place by the barrier device 12 . Alternatively, the disc 15 can be partially filled, then sealed with the barrier device 12 , and then supplied with additional material 7 . In a preferred embodiment, the barrier device 12 is inserted into the disc 15 followed by the addition of nuclear augmentation material 7 through or around the barrier 12 . This allows for active pressurization. A disc 15 with a severely degenerated anulus can also be effectively treated in this manner.
In an alternative embodiment, the nuclear augmentation material 7 is delivered through a cannula inserted through an access hole 417 in the disc 15 formed pathologically, e.g. an anular defect 8 , or iatrogenically, e.g. an anuulotomy 416 that is distinct from the access hole 417 that was used to implant the barrier 12 . Also, the same or different surgical approach including transpsoas, presacral, transsacral, tranpedicular, translaminar, or anteriorly through the abdomen, may be used. Access hole 417 can be located anywhere along the anulus surface or even through the vertebral endplates.
In alternative embodiments, the anulus augmentation device 12 includes features that facilitate the introduction of augmentation materials 554 following placement. The augmentation delivery cannula may simply be forcibly driven into an access hole 417 proximal to the barrier 12 at a slight angle so that the edge of the barrier 12 deforms and allows passage into the disc space. Alternatively, a small, flexible or rigid curved delivery needle or tube may be inserted through an access hole 417 over (in the direction of the superior endplate) or under (in the direction of the inferior endplate) the barrier 12 or around an edge of the barrier 12 contiguous with the anulus 15 .
In several embodiments, ports or valves are installed in the barrier 12 device that permit the flow of augmentation material into, but not out of, the disc space. One-way valves 450 or even flaps of material held shut by the intervertebral pressure may be used. A collapsible tubular valve may be fashioned along a length of the barrier. In one embodiment, multiple valves or ports 450 are present along the device 12 to facilitate alignment with the access hole 417 and delivery of augmentation material. Flow channels within or on the barrier 12 to direct the delivery of the material 554 (e.g. to the ends of the barrier) can be machined, formed into or attached to the barrier 12 along its length. Alternatively, small delivery apertures (e.g. caused by a needle) can be sealed with a small amount of adhesive or sutured shut.
FIG. 66 is sagittal cross-sectional view of a functional spine unit containing the barrier device unit 12 connected to a wedge-shaped nuclear augmentation 7 device. FIG. 66 illustrates that the geometry of the nuclear augmentation 7 can be adapted to improve the function of the barrier. By presenting nuclear augmentation 7 with a wedge-shaped or hemicircular profile towards the interior of the intervertebral disc space, and attaching it in the middle of the barrier device 12 between the flexible finger-like edges of the barrier device, the force exerted by the pressurized environment is focused in the direction of the edges of the barrier device sealing them against the endplates. Accordingly, this wedge-shaped feature improves the function of the device 12 . One skilled in the art will understand that the nuclear augmentation material 7 may also be designed with various features that improve its interaction with the barrier, such as exhibiting different flexibility or viscosity throughout its volume. For example, in certain applications, it may be preferable for the augmentation 7 to be either stiff at the interface with the barrier 12 and supple towards the center of the disc, or vice versa. The augmentation 7 can also serve to rotationally stabilize the barrier 12 . In this embodiment, the augmentation is coupled to the inward facing surface of the barrier and extends outward and medially into the disc forming a lever arm and appearing as “T-shaped” unit. The augmentation device 7 of this embodiment can extend from the middle of the disc 15 to the opposite wall of the anulus.
One skilled in the art will appreciate that any of the above procedures involving nuclear augmentation and/or anulus augmentation may be performed with or without the removal of any or all of the autologous nucleus. Further, the nuclear augmentation materials and/or the anulus augmentation device may be designed to be safely and efficiently removed from the intervertebral disc in the event they no longer be required.
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.
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FIELD OF THE INVENTION
[0001] The present invention relates to improvements in polysaccharide emulsifying agents and emulsions made from these emulsifiers.
BACKGROUND OF THE INVENTION
[0002] Emulsifying agents for oil in water as well as water in oil emulsions find numerous applications in a wide array of industries. The subject invention is based upon the recognition that an appropriate blend of several natural polysaccharide gums effectively will act as emulsifiers suitable for providing a variety of natural emulsion products.
[0003] Traditional emulsifiers are surfactants, i.e. surface-active agents, which have polar and non-polar regions. An emulsifying agent is effective because its polar region has an affinity for water whereas the non-polar region of the molecule has an affinity for the oil.
[0004] A mixture or dispersion of the surfactant, water, and oil will form small droplets known as micelles when subjected to high energy such as homogenization or other high speed shearing forces.
[0005] In oil in water types of emulsions (OIW), these micelles are essentially oil droplets suspended in water. The emulsifier forms a shell around the oil droplet and is aligned in such a manner that the polar end of the molecule faces the water and the non-polar end of the molecule faces the oil droplet. In other formulations, water in oil emulsions (WIO) are provided.
[0006] The use of emulsifiers or surfactants above a critical micelle concentration (CMC) reduces the energy required to form these coated droplets and reduces the tendency of these droplets to re-orient into two separate phases.
[0007] Although many different emulsifying agents have been heretofore available in the art, it will be seen that improved combinations of natural agents and natural emulsification products made therewith can now be provided in accordance with the subject disclosure. Furthermore, the subject natural emulsifier may also function effectively without the necessity of heating the formulations so long as the emulsion phases are both liquid.
SUMMARY OF THE INVENTION
[0008] A primary advantage of the subject formulations is the recognition that an appropriate mixture and application of natural polysaccharide gums can act as an effective and successful emulsifier. Such natural polysaccharide gum emulsifying agents are suitable for both oil in water as well as water in oil emulsions.
[0009] The subject natural emulsifying agents contain a pectin-type polysaccharide and at least one other different polysaccharide. In one particular embodiment, a mixture of polysaccharides including pectin, xanthan gum, and sodium alginate are combined in the manner specified below and thereafter used as a natural emulsifier for a variety of oil and water products. In embodiments where the oil, water and any conventional additives are also considered “natural”, the entire resulting emulsion is also considered a natural product.
[0010] The emulsifying blends of polysaccharides may be dispersed in oil (mineral or vegetable, such as corn, olive, canola, etc) and then added to water. The polysaccharide emulsifying agents thereupon swell to provide a polymeric matrix capable of entrapping the oil molecules as a clathrate. A clathrate produced in this manner is stable to stress such as elevated temperatures. Microscopic evaluation indicates an emulsion having true micellular structure.
[0011] The pectin-type polysaccharide is a polysaccharides comprised of α-(1-4)-linked D-galacturonic acid chains, typically of β-D-mannuronic and a-L-guluronic acids, attached with 1-4 linkages and β-D-glucose backbone. The 1-4 linkages commonly refer to the covalent bonds along the sugar chain polymerization backbone.
[0012] The subject natural emulsifiers contain pectin and at least one other polysaccharide. Some preferred formulations combine pectin with xanthan gum and sodium alginate, however, these further polysaccharides may be substituted by others. The following are also suitable polysaccharides: cellulose, hemi-cellulose, arabinoxylan, chitin, beta-glucans, glycosaminoglycans, agar, carageenan, alginates, and galactomannan, etc.
[0013] Generally, the polysaccharides are stabilized by the addition of small amounts of multivalent cations such as calcium, magnesium, and other alkaline earth salts. The multivalent cations serve to lock the tertiary structure of the polymer network, thereby stabilizing the micellular structure of the emulsion as well.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0014] The natural emulsifying agents utilized in formulations of the subject disclosure are comprised of a combination of natural polysaccharide gums such as pectin and at least another polysaccharide. Formulations of the subject natural emulsifier will preferably comprise 50-70% pectin and about 30-50% by weight of one or more additional natural polysaccharides and any optional stabilizer. More preferred formulations of the subject natural emulsifier will comprise about 50-70% pectin,10-20% by weight xanthan gum, 15-25% sodium alginate and 3-6% calcium carbonate.
[0015] Polysaccharides are polymeric carbohydrate structures, formed of repeating units (either mono- or di-saccharides) joined together by glycosidic bonds. These structures are often linear, but may contain various degrees of branching. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure, these macromolecules can have distinct properties from their monosaccharide building blocks. They may be amorphous or even insoluble in water. When all the monosaccharides in a polysaccharide are the same type the polysaccharide is called a homopolysaccharide, but when more than one type of monosaccharide is present they are called heteropolysaccharides. Examples include storage polysaccharides such as starch and glycogen, and structural polysaccharides such as cellulose and chitin. Polysaccharides have a general formula of C x (H2O) y where x is usually a large number between 200 and 2500. Considering that the repeating units in the polymer backbone are often six-carbon monosaccharides, the general formula can also be represented as (C 6 H 10 O5)n where 40≦n≦3000.
[0016] The subject natural emulsifiers all contain pectin which is the common name for the polymers of galacturonic acid. In its natural state, the polymer is partially esterified (up to 80%) with methanol. Calcium and magnesium compounds, such as peptides are added to stabilize the three dimensional structure of the matrix as well as enhance the emulsifier properties of the system.
[0017] The typical structure of pectin is a linear chain of α-(1-4)-linked D-galacturonic acid that forms the pectin-backbone, a homogalacturonan. Peptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond.
[0018] As stated, a further different polysaccharide is combined with the pectin in the subject formulation. A preferred second polysaccharide is xanthan gum which is a polysaccharide used as a food additive and rheology modifier. It is produced by fermentation of glucose or sucrose by the Xanthomonas campestris bacterium. In cosmetics, xanthan gum is used to prepare water gels, usually in conjunction with bentonite clays. It is not considered an emulsifier but it is also used in oil-in-water emulsions to help stabilize the oil droplets against coalescence. It is known to have some skin hydrating properties.
[0019] Another polysaccharide which can be used in combination with pectin in the subject formulations is an alginate such as sodium alginate. The compound sodium alginate is the sodium salt of alginic acid. Its empirical chemical formula is NaC 6 H 7 O 6 . It is form as a gum when extracted from the cell walls of brown algae and is used by the food industry to increase viscosity and has uses as an emulsifier. In the most preferred formulations the pectin is combined with both of the xanthan and alginate components.
[0020] As mentioned earlier, the subject emulsifying agents are blends of polysaccharides which may be dispersed in oil and then added to water. The natural polysaccharide emulsifying agents thereupon swell to provide a polymeric matrix capable of entrapping the oil molecules as a clathrate.
[0021] In a preferred embodiment of the subject formulation, the polysaccharides comprise: α-(1-4)-linked D-galacturonic acid chains of β-D-mannuronic and a-L-guluronic acids attached with 1-4 linkages and β-D-glucose backbone.
[0022] In other embodiments, the following are also suitable polysaccharides: cellulose, hemi-cellulose, arabinoxylan, chitin, beta-glucans, glycosaminoglycans, agar, carageenan, alginates, and galactomannan, etc.
[0023] In still further embodiments, it is preferred to stabilize the polysaccharides by the addition of small amounts of multivalent cations such as calcium, magnesium, aluminum and other alkaline earth salts. The multivalent cations serve to lock the tertiary structure of the polymer network, thereby stabilizing the micellular structure of the emulsion as well.
[0024] In general, an emulsifying amount of the natural polysaccharide emulsifying agents will typically be about 1-10 parts by weight and preferably about 2-5 parts by weight corresponding to 100 parts by weight of an oil and water mixture. Conventional methods of emulsion preparation typically involve heating of the aqueous and non-aqueous phases, followed by mixing and homogenization during the subsequent cool down stage.
[0025] The polysaccharides employed in the subject natural polysaccharide emulsifying formulations are commercially available from a number of sources and are specified by quality and purity suitable for the intended applications. In the examples below, cosmetic or food grade materials were employed.
[0026] In the following examples, a series of natural polysaccharide emulsifying agent blends were prepared by mixing the polysaccharide gum powders at the indicated ratios, where parts given are by weight. Formulations A and E did not contain calcium carbonate.
[0000]
TABLE 1
Examples A-H
Parts Given By Weight
Material
A
B
C
D
E
F
G
H
Xanthan Gum
10
20
10
20
20
20
20
20
Pectin
60
60
60
60
60
60
60
60
Sodium
20
20
20
20
20
20
20
20
Alginate
Calcium
0
3.5
4.5
5.5
0
3.5
4.5
5.5
Carbonate
[0027] Emulsion products were prepared by mixing 2.5 grams of each of the above emulsifying agent formulations with 30 parts by weight of canola oil and 67.5 parts by weight of water. The formulations were thereafter mixed with a high speed propeller blade to provide emulsion products. The pH was adjusted and stabilized using citric acid and sodium citrate. Other suitable buffering and pH adjustments additives include those weak acids and their respective salts which are of quality and purity applicable to cosmetic and personal care products.
[0028] Preservation of the emulsion products may be accomplished using conventional preservatives, such as paraben esters and phenoxyethanol, added in conventional amounts to prevent spoiling.
[0029] Samples Formula A and E produced emulsions which are markedly unstable as noted by separation of the oil and water phases.
[0030] Sample Formula B and F showed relatively better emulsion stability.
[0031] Sample Formula C, D, G and H provided the most stable emulsions, each surviving one-month at 45 degrees C. without destruction of the emulsion.
[0032] Emulsion products made as described above had a creamy consistency that applied well to skin. The rheology was such that it had a long playtime, without the stickiness or tackiness associated with polymer-stabilized emulsions.
[0033] The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein.
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BACKGROUND OF THE INVENTION
This invention relates generally to improvements in transportable seating devices. More specifically, it relates to improvements in seating devices that may also function as canes or walking aids.
A device known to the applicant that may serve as both a cane or walking aid and provide a surface for sitting when desired is the "English shooting stick". This device consists of a shaft having a pair of handles hinged at its upper end. A strip of canvas is attached to the handles, and when the handles are moved outwardly from the shaft, the canvas is stretched between them to provide a seat.
While the English shooting stick has served its purpose for many years, it is believed that it can be improved upon by the invention disclosed herein.
Therefore, it is an object of this invention to provide a transportable seating device which is relatively simple in construction having essentially only one moving part.
It is another object of this invention to provide a novel transportable seating device that is relatively economical to manufacture.
A further object of this invention is to provide a novel transportable seating device which is formed in such a way that it is durable, having no parts made of canvas or other fabrics subject to the wear usually attendant by the use of such material.
A still further object of this invention is to provide a novel transportable seating device which is relatively compact.
BRIEF SUMMARY OF THE INVENTION
The foregoing and other objects are achieved in one embodiment of the invention by the provision of a cane or shaft, a seat supporting arm mounted in the shaft and rotatable from a position essentially parallel to the shaft to a position approaching the perpendicular to the shaft and a seat mounted on the free end of the arm.
BRIEF DESCRIPTION OF THE DRAWING
The invention itself is set forth in claims appended hereto and forming a part of this specification, while an understanding of an embodiment thereof may be had by reference to the detailed description taken in conjunction with the drawing in which:
FIG. 1 is a front view of an embodiment of the invention showing the seating device in a first or folded position;
FIG. 2 is a side view of the embodiment of FIG. 1;
FIG. 3 is a partial side view of the embodiment of FIG. 1 showing the seating device in its second or opened position;
FIG. 4 is a view along the line 4--4 of FIG. 1; and
FIG. 5 is a view similar to FIG. 1 illustrating an alternative embodiment of the invention.
DETAILED DESCRIPTION
In the embodiment of the invention illustrated in the drawing, a cane or shaft 2 is provided at its upper end with a knob or handle 4 which can be used for grasping, or as will be described, for supporting a part of the body when the device is in use as a seat. A plastic or rubber tip 6 is provided on the bottom of the shaft to provide a high friction surface for contact with a floor or other surface to minimize slippage when the device is used either as a walking aid or a seat. Alternatively, a pointed end for penetrating the ground may be provided.
An arm or brace 8 is rotatably mounted in the shaft 2 at a distance from the top such that when the arm is rotated to provide a seat the person using the device is seated comfortably above a floor or other surface. For example, if the shaft 2 is 30" long then the seat should perhaps be 20" off the floor. Obviously these suggested dimensions may be changed by a designer.
The arm 8 includes a first portion 10 angled upwardly to and engaging rotatably in the shaft 2. As seen in FIG. 2, the portion 10 extends outwardly from the shaft and is integral with a second portion 12 which extends generally vertical or parallel with the shaft. A seat 14 is attached to the second portion 12 by any suitable means. In the embodiment illustrated, the seat is shown as a round disc like device but it may be shaped in a number of different ways as desired by a designer.
As may be seen in FIG. 4 the first portion 10 of the arm is mounted in a recess 16 in an enlarged part 18 of the shaft 2. A cylindrical sleeve 20 is fitted into the recess and encompasses the portion 10 to function as a bearing. An opening 22 is provided in the sleeve 20 to permit a ball detent 24 to engage in a groove 26 formed in the portion 10 near its inner end. The groove 26 extends over approximately 180° of the periphery of the first position 10 so that as the portion 10 is rotated the ball detent 24 rides in the groove 26 but limits the rotation of that portion to about 180° as determined by the extent of the groove. Depressions 28 may be formed at opposite ends of the groove into which the ball detent 24 may be pressed to further limit rotation of the arm 8 and therefore the seat 14.
The ball detent 24 is urged into the groove 26 or one of the depressions 28 by a coil spring 30. The coil spring 30 is held in a container 32 having an opening 34 through which a portion of the surface of the ball detent 24 extends to engage in the depressions 28 and groove 26. The container 32 in turn is fixed in a recess 36 in the enlarged portion 18 by any suitable means, such as a friction fit or an adhesive, so that the coil spring at its bottom rests on a relatively fixed surface, the interior of the container, to urge the ball detent onwardly. For esthetic purposes the recess 36 may be closed by a plug 38 with its outer surface conforming to the shape of the portion 18.
This embodiment of the invention may be used as a cane or walking aid with the seat 14 in the position shown in FIGS. 1 and 2, that is, substantially parallel to the longitudinal axis of the shaft 2. When it is desired to use the invention as a seat, the seat 14 and second portion 12 and first portion 10 of the arm are rotated within the sleeve 20. As seen in FIG. 2 this may be out of the plane of the drawing. At the beginning of this rotation the ball detent 24 will be forced out of a depression 28 and ride in the groove 26 so that rotation is permitted until that detent engages in the depression 28 at the opposite end of the groove 26. Because the groove extends over about 180° of the periphery of the portion 10 the arm 8 will be rotated about the longitudinal axis 40 of the portion 10 until the portion 12 and seat 14 are in the position shown in FIG. 4, that is, in a plane substantially perpendicular to the longitudinal axis of the shaft 2. In this position the seat provides a horizontal surface on which a person may sit.
When the arm has been so rotated a person sitting on the seat 14 may rest his arm on the knob 4 and tilt the shaft 2 slightly from a perpendicular to a supporting surface so that the shaft with the individuals' legs engaging the supporting surface forms a kind of tripod providing support.
FIG. 5 illustrates an alternative embodiment of the invention, particularly with respect to the means which can be used to retain the arm 8 in the shaft 2. In this embodiment of the invention, those elements which are identical have been given the same reference numeral.
In FIG. 5 the portion 10 of the arm 8 extends into the opening or recess 16 in the shaft 2. The arm is rotatably mounted within a cylindrical liner 42 which may be formed of a metallic material and mounted within the recess 16. A groove 44 is formed adjacent one end of the portion 10 and an O-ring 46, formed from plastic or rubber, is positioned in the groove 44 and, bearing against the liner 42, adds increased friction so as to hold the portion 10 in any position to which it has been rotated.
To retain the arm 8 in the recess 16, a plug 48 having a tooth or serrated periphery 50 is mounted in the shaft 2 and is provided with an upper portion 52 having an enlarged head 54. Cooperating with the plug 48 is a plug 56 held in a recess in the bottom of the portion 10 by means of teeth or serrations 58. The plug 56 has an opening in its bottom generally conforming to the shape of the head 54 but dimensioned to permit rotation of the arm portion 10 about the plug 48. As may be seen in the drawing, the teeth on the plugs 48 and 56 are formed in opposite directions so as to resist their removal once inserted into their respective openings. This embodiment of the invention reduces the number of parts required to assemble the device.
Obviously, there may be numerous variations in design and dimensions. For instance, an enlarged portion 18 need not be provided but rather the shaft 2 may be thickened throughout its length and a diameter big enough to accommodate the portion 10 and the mechanism which retains it and permits its rotation. Likewise, various materials such as plastic, wood, or metal in various combinations thereof may be used.
It is intended by the claims appended hereto to cover all variations and modifications which come within their scope.
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BACKGROUND OF THE INVENTION
[0001] Microemulsions have been recently thoroughly studied as carriers of medicaments. Pharmaceutical compositions based on microemulsions have been proposed for example for the oral, parenteral, trans-mucosal, aerosol and topical administration.
[0002] For instance, EP 387647 discloses microemulsions for the transdermal, nasal or rectal drug delivery particularly of dihydroergotamine mesylate.
[0003] Parenteral compositions of diclofenac in microemulsion form are disclosed in WO 95/03121.
[0004] Water-oil-water microemulsions of antigenic peptides are disclosed in U.S. Pat. No. 6,117,432.
[0005] The use of tocopherols as emulsion vehicle for poorly soluble drugs is disclosed in WO 00/71163.
[0006] JP 10330287 disclose a water in oil in water emulsion wherein the inner phase comprises insulin and gelatins whereas the oil phases comprise lecithins, tocopherols, glycerides, a surfactant and docosahexaenoic acid. The disclosed composition, which is not in form of microemulsion, addresses the problem of insulin absorption through the colon and rectum.
[0007] WO 99/27918 discloses water/oil/water microemulsions for delivering drugs through the brain blood barrier.
[0008] WO 03/013421 and WO 03/51334 disclose double microemulsions incorporated onto a solid support particularly suited for the oral administration in form of capsules and tablets.
[0009] None of the prior art documents however addresses neither the problem of the metabolic degradation of the drug at the site of action by inhibiting enzymes or that of the usually low permeation of the drug through the membranes and mucosae. A further factor negatively affecting the absorption of a given drug through tissues is due to the so called drug-efflux phenomenon, determined by specific enzymes located in some mucosae and which actively oppose the absorption of the drug through cells and tissues.
DESCRIPTION OF THE INVENTION
[0010] It has now been surprisingly found that the prior art drawbacks cab be effectively overcome by including into the external phases of double microemulsions suitable enzymes and/or permeation enhancers.
[0011] The invention provides therefore water/oil/water or oil/water/oil double microemulsions as carriers of drugs having different solubility characteristics, said microemulsions being characterized in that they comprise agents improving the bioavailability of the drug, either by inhibiting enzymes responsible for the metabolic degradation of the drug at the site of action, by enhancing the permeation of the drug through the membranes and mucosae and/or by inhibiting enzymes responsible for the drug-efflux phenomenon.
[0012] The invention also provides pharmaceutical compositions comprising said double microemulsions as carriers of medicaments to be administered oral, topical, transdermal, nasal, pulmonary, transmucosal, vaginal, ocular, rectal application.
[0013] Both scarcely water-soluble/hydrophobic drugs and highly polar, water-soluble drugs may be advantageously formulated according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides pharmaceutical compositions comprising oil/water/oil (O1/W2/O3) or a water/oil/water (W1/O2/W3) double microemulsions wherein the external phases (W2 and O3 for O1/W2/O3, O2 and W3 for W1/O2/W3) contain mucosal/physiological environment enzymes-inhibitors and/or P-gp inhibitors and/or absorption permeation enhancers.
[0015] Examples of permeation enhancers contained in the external phases O2 and W3 of W1/O2/W3 double microemulsion or to external phases W2 and O3 of O1/W2/O3 double microemulsion include non-ionic surfactants such as polyoxyalkylene fatty ethers (BRIJ®), (TWEEN® 20, TWEEN® 80, etc.); ionic surfactants such as sodium dodecylsulfate; bile salts (e.g., sodium glycholate, sodium taurocholate, sodium deoxycholate, etc.); fatty acids like oleic acid, palmitoleic acid, linoleic acid, sodium oleate, sorbitan trioleate, polyoxyethylene sorbitan trioleate, etc; sodium salicylate, sodium caprate, diethylmaleate, laurylmaltopyranoside, etc.
[0016] Examples of metabolic degradation enzymes inhibitors contained in the external phase O2 and W3 of W1/O2/W3 double microemulsion or to the external phases W2 and O3 of O1/W2/O3 double microemulsion are CYP3A inhibitors, protease inhibitors like aprotinin, chymostatin, bacitracin, benzamidine, phosphoramidon, leupeptin, bestatin, leupeptin, cystatin, amastatin, pepstatin, potato carboxypeptidase, soybean trypsin inhibitor, diisopropylfluorophosphate, EDTA.
[0017] Examples of drug-efflux P-glycoprotein enzymes inhibitors contained in the external phase O2 and W3 of W1/O2/W3 double microemulsion or in the external phases of W2 and O3 of O1/W2/O3 double microemulsion are flavonoids contained in fruit juices such as Naringenin, Isoquercetin, Quercetin, Vitamin E TPGS (Tocopheryl Glycolsuccinate).
[0018] The microemulsions of the invention may contain both a permeation enhancing agent and an enzyme inhibitor.
[0019] Preferred drugs which may be advantageously formulated in the double microemulsion O1/W2/O3 of the invention are scarcely water-soluble/hydrophobic drugs, with very low polarity and consequent poor solubility in the biological aqueous fluids such as gastro-intestinal content, pulmonary fluids or buccal fluids.
[0020] Examples of these drugs are anesthetics, anti-asthma agents, antidepressants, anti-diabetics, anti-epileptics, anti-fungals, anti-gout, anti-neoplastics, anti-obesity agents, anti-protozoals, anti-virals, anti-psychotics, calcium regulating agents, cardiovascular agents, corticosteroids, diuretics, dopaminergic agents, gastrointestinal agents, hormones (peptide and non-peptide), immunosuppressants, lipid regulating agents, phytoestrogens, prostaglandins, relaxants and stimulants, vitamins/nutritionals and xanthines.
[0021] Said therapeutic categories include well known compounds such as paclitaxel, docetaxel, etoposide, teniposide, fludarabine, doxorubicin, daunomycin, mitoxanthrone, emodin, 5-fluorouracil, camptothecin, retinoic acids, ubidecarenone, verapamil, cyclosporine, tacrolimus, statins such as lovastatin, atorvastatin, simvastatin, piroxicam, nimesulide, naproxen, ibuprofen, indomethacin, phenyloin, fentanyl, desmopressin, angiotensin I, II and III, enkephalins and their analogs, ACTH, antiinflammatory peptides I, II, III, bradykinin, calcitonin, Interferon, cholecystikinin (CCK) fragments, luteinizing hormone releasing hormone (LHRH), neurokinins (e.g. neurokinin A), somatostatin, substance P, thyroid releasing hormone (TRH), vasopressin, fibrinogen receptor antagonists growth hormone releasing peptides (GHRP), insulin, LH-RH releasers and inhibitors, immunosuppressive anti-TNF alpha-monoclonal antibodies (e.g. Rituximab, Trastuzumab, Infliximab, Gemtuzumab, Alemtuzumab, Ibritumomab, Tositumomab-Iodine 131, Cetuximab, Bevacizumab) endothelins, atrial natriuretic factor, gastrin, MSH modulators, cytokines, renin inhibitors, HIV protease inhibitors, fluconazole, itraconazole, nifedipine, carbamazepine, fluoxetine, griseofulvin, raloxifene, paroxetine, glimepiride, anagrelide, modafinil, losartan, valsartan, cabergoline, replaginide, glipizide, benzodiazepines, clofibrate, chlorpheniramine, digoxin, digitoxin, ergotamine tartate, estradiol, fenofibrate, hydrochlorothiazide, hydrocortisone, medrogeston, oxyphenbutazone, prednisolone, prednisone, polythiazide, progesterone, spironolactone, tolbutamide, 10,11-dihydro-5H-dibenzo[a,d]cyclo-heptene-5-carboxamide, 5H-dibenzo[a,d]cycloheptene-5-carboxamide. In the case of the double microemulsion W1/O2/W3, the preferred drugs are very water-soluble, highly polar, in some case with ionic charges and/or high molecular weight, with consequent poor permeability of biological barriers such as gastro-intestinal or pulmonary or buccal mucosa.
[0022] Examples of these drugs are antibiotics, polypeptides, proteins (insulin, erythropoietin, CSF), polynucleotides, acellular vaccines, bisphosphonates (alendronate, ibandronate, clodronate, zoledronate, pamidronate, risedronate, etidronate etc.), enalapril, acyclovir, enfuvirtide, polyphenols, bioflavones, hydrosoluble vitamins, choline, carnitine, carnosine and related peptides, platinum complexes, glycosamineglycans such as heparins or fraction thereof, hyaluronic acid, dermatans, glucosamine.
[0023] The oil used for the internal/external phases of the double microemulsions of the invention can be natural, synthetic or semisynthetic. Examples of natural oils include of olive, sunflower, safflower, peanut, corn, soybean, maize, coconut, sesame oils.
[0024] Examples of synthetic or semisynthetic oils are esters of short, medium or long chain fatty acids as isopropyl miristate, isopropylpalmitate, ethyl laurate, isopropyl caprilate, isopropyl caprinate, isopropyl laurate, isopropyl stearate, ethyl oleate, oleyl oleate or long chain alcohols or polyols such as hexadecylic alcohol, oleic alcohol, lauric alcohol, cetyl stearylic alcohol, benzyl alcohol, decanoic acid, butanoic acid, silicon oils, mono-, di- and tri-glycerides mixtures or poly-ethoxylated derivatives thereof, polyhydroxyethyl triglycerides, polyhydroxy triglycerides, capricocaprilic triglycerides.
[0025] The surfactants can be of natural or synthetic origin; examples of surfactants include sorbitan laurate, sorbitan palmitate, sorbitan stearate (Span 20®, Span 40®, Span 60® respectively), polysorbates such as polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate (Tween 60®, Tween 40®, Tween 20®, Tween 80®), polyoxyethylene ethers of fatty acids, e.g. polyoxyethylene 2 cetyl ether, polyoxyethylene 20 cetyl ether (Brij 52®, Brij 58®) and polyoxyethylene hydrogenated castor oil 40 (HCO-40®). Polyvinyl alcohol may also be used as amphiphylic surfactant.
[0026] Combinations of surfactants with different chemical characteristics can also be used.
[0027] The cosurfactants can either be synthetic or natural. Examples of synthetic cosurfactants include short chain alcohols such as ethanol, isopropanol, n-butanol, ethanediol, 1,2-propanediol, 1,3-propanediol, 1,3-butane diol, 1,4-butane diol, glycerine, polyethylene glycols (e.g. PEG 400, PEG 600) butyric acid, valerianic acid, capronic acid, benzyl acid, decanoic acid, lauric acid, lauryl alcohol.
[0028] Examples of natural cosurfactants include lecithins and phospholipids.
[0029] The external water (w/o/w) phase of the double microemulsions of the invention (W1/O/W3) consists of water as such or buffered at different pH's and ionic strengths, of mixtures of water and polyethylenglycols, polyol glycerides, propylene glycol, tetra glycol, ethoxy glycol, mixtures of water and polyvinylpyrrolidone, polyacrylic acids and derivatives, polymethacrylic acids and derivatives, alginic acids and derivatives, polyvinylalcohol, chitosan and derivatives, xanthan and derivatives, guar gum, arabic gum, dextran, cellulose and derivatives, starch and derivatives.
[0030] The internal aqueous phase of the double microemulsions of the invention (W2 for O1/W2/O3) consists of water as such or buffered at different pH's and ionic strengths or of mixtures of water and polyethyleneglycols, polyglycol glycerides, propylene glycol, tetra glycol, ethoxy glycol.
[0031] The double microemulsions (O1/W2/O3 or W1/O2/W3) of the invention have the following preferred compositions by weight percentage:
[0032] a) double microemulsion O1/W2/O3:
[0033] a1) oil (O1, internal phase) from 1.0% to 5.0%.
[0034] a2) water or aqueous solution (W2) from 3.0% to 10%.
[0035] a3) oil (03, external phase) from 60% to 90%
[0036] a4) metabolic enzymes-inhibitor, P-gp-inhibitor, absorption enhancer from 0.05% to 10.0%.
[0037] a5) drug from 0.01% to 15%.
[0038] a6) surfactant from 2.0% to 20%.
[0039] a7) cosurfactant from 0% to 5.0%.
[0040] b) double microemulsion W1/O2/W3:
[0041] b1) water or aqueous solution (W1, internal phase) from 1.0% to 5.0%.
[0042] b2) oil (O2 external phase) from 6.0% to 15%.
[0043] b3) water or aqueous solution (W3, external phase) from 60% to 90%.
[0044] b4) metabolic enzymes inhibitor, P-gp-inhibitor, absorption enhancer from 0.05% to 10.0%.
[0045] b5) drug from 0.01% to 15%.
[0046] b6) surfactant from 2.0% to 20%.
[0047] b7) cosurfactant from 0% to 5.0%.
[0048] The compositions of the invention can be prepared by a process comprising:
a. solubilization of the mucosal/physiological environment enzymes-inhibitor, P-gp-inhibitor, absorption permeation enhancer in the external phase/phases of the double microemulsion of choice (W2 and O3 for O1/W2/O3, O2 and W3 for W1/O2/W3); b. solubilization of the drug in the internal phase of the double microemulsion of choice (O1 of the O1/W2/O3 in the case of hydrophobic, scarcely water soluble drug; W1 of the W1/O2/W3 in the case of water soluble, poorly permeable drugs); c. addition of the oil or water drug solution of stage b) to the water or oil solution of stage a); d. addition of surfactant/cosurfactant to the mixture of stage c and agitation with the formation of the O1/W2 or W1/O2 microemulsion; e. addition of the microemulsion O1/W2 or W1/O2 of stage d) to the oil (O3) phase or water (W3) phase containing surfactant/cosurfactant and agitation with the formation of the double microemulsion O1/W2/O3 or W1/O2/W3 with mucosal/physiological environment. enzymes-inhibitors and/or P-gp-inhibitors and/or absorption permeation enhancers in the W2 and O3 of the O1/W2/O3 or O2 and W3 of the W1/O2/W3 double microemulsion.
[0054] Possible variations to this process can be introduced in relation to specific experimental conditions.
[0055] For example, in some cases, the mucosal/physiological environment enzymes-inhibitor/P-gp-inhibitor/absorption enhancer cannot be completely solubilized in the oil or water external phase of choice: in this case the substance will be dispersed in the suitable external phase.
[0056] It is also possible that the drug is dispersed in the internal phase of choice when it is not completely soluble in the internal oil or water phase of choice.
[0057] If desired, a viscosity-increasing substance can be added to the second external phase of the double microemulsions (W3 for the W1/O2/W3, O3 for the O1/W2/O3) such as polymers such as hydroxypropylcellulose, chitosan, polyvinylpyrrolidone, polymethylmethacrylate.
[0058] Said viscosity-increasing substances can also be added to the other phases of the double microemulsions.
[0059] In some cases, these viscosity-increasing polymers may also have bioadhesive properties so to increase residence-time in the biological environment of action (e.g., stomach, eye sac, mouth cavity, etc.) or to guarantee more intimate contact with the biological barrier to be overcome, e.g., gastro-intestinal tract mucosa, pulmonary tissues, etc.
[0060] The compositions according to the invention may be formulated with the addition of conventional excipients as dosage forms for oral, topical, transdermal, nasal, pulmonary, transmucosal, vaginal, ocular, rectal application.
[0061] The compositions according to the invention may also be formulated in dosage forms after the addition of said compositions onto solid adsorbent particles.
[0062] The compositions of the present invention present unexpected improved properties both in terms of biopharmaceutical properties (particle size of droplets in the nanometers range with consequent extremely high surface area, high solubility of hydrophobic drugs in the oil components, higher diffusion tendency through hydrophobic membranes of very polar drugs) and in terms of a much lower metabolic degradation or P-glycoprotein efflux effects with consequent much higher biological membranes/barriers permeation tendency.
[0063] The invention is disclosed in more detail in the following some examples.
Example 1
a) w/o Formulation
[0064] A w/o microemulsion was prepared by mixing using a paddle mixer at the speed of 250 rpm at 25° C. for 1 h an aqueous phase containing erythropoietin dissolved (300 μg/g) to an oily phase Lauroglycol FCC®:Labrasol® (1:1) containing chymostatin (200 μg/g) and the surfactant Tween 20® (1.04 g).
[0000]
Erythropoietin
0.00061
g
Water
2.03
g
Polyetyhlene glycol monoester
6.01
g
of lauric acid (Lauroglycol FCC ®)
Mixture of mono-, di- and
6.01
g
triglycerides and mono-
and di-fatty esters of
polyethylene glycol (Labrasol ®)
Chymostatin
0.0024
g
Polyoxyethylene (20) sorbitan
1.04
g
monolaurate (Tween 20 ®)
b) w/o/w Formulation
[0065] The microemulsion a) w/o was added to an aqueous phase (75.45 g) under paddle stirring at the speed of 300 rpm for 0.75 h, Tween 20® was then added (4.04 g) under paddle stirring at the speed of 280 rpm for 0.5 h to obtain a double microemulsion w/o/w. The composition of the resulting w/o/w double microemulsion was the following:
Example 1
w/o/w Composition
[0066]
[0000]
Erythropoietin
0.00061
g
Polyetyhlene glycol monoester
6.01
g
of lauric acid (Lauroglycol FCC ®)
Mixture of mono-di and
6.01
g
triglycerides and mono
and di-fatty esters of
polyethylene glycol (Labrasol ®)
Chymostatin
0.0024
g
Polyoxyethylene (20) sorbitan
5.08
g
monolaurate (Tween 20 ®)
Water
77.48
g
Example 2
a) w/o Formulation
[0067] A w/o microemulsion was prepared by mixing using a paddle mixer at the speed of 240 rpm at 25° C. an aqueous phase containing sodium alendronate dissolved (0.5 g/g) with an oily phase containing Akoline®:Labrasol®:TaurumDeoxycholate in ratio 1:1:0.09, and the surfactant Tween 80® (0.653 g).
[0000]
Sodium Alendronate
0.492
g
Water
0.984
g
Monoglycerides of caprylic/capric
1.88
g
acids (Akoline ®).
Mixture of mono-di and triglycerides
1.88
g
and mono and di-fatty esters of
polyethylene glycol (Labrasol ®)
Taurum Deoxycholate
0.168
g
Polyoxyethylene (20) sorbitan
0.653
g
monooleate (Tween 80 ®)
b) w/o/w Formulation
[0068] The microemulsion a) w/o was added to an aqueous phase (33.39 g) under paddle stirring at the speed of 300 rpm for 0.5 h, Tween 80® was then added (2.50 g) under paddle stirring at the speed of 280 rpm for 0.75 h to obtain a double microemulsion w/o/w. The composition of the resulting w/o/w double microemulsion was the following:
Example 2
w/o/w Composition
[0069]
[0000]
Sodium Alendronate
0.492
g
Monoglycerides of caprylic/capric
1.88
g
acids (Akoline ®)
Mixture of mono-di and triglycerides
1.88
g
and mono and di-fatty esters of
polyethylene glycol (Labrasol ®)
Taurum Deoxycholate
0.168
g
Polyoxyethylene (20) sorbitan
3.153
g
monooleate (Tween 80 ®)
Water
33.39
g
Example 3
a) w/o Formulation
[0070] A w/o microemulsion was prepared by mixing using a paddle mixer at the speed of 220 rpm at 25 C an aqueous phase containing somatostatin dissolved (0.4 g/g), to an oily phase, Labrafac CC®:Egg Lecithin (1:0.005), containing CYP3A inhibitor as hesperidin (100 μg/g), and the surfactant Span 40® (2.04 g).
[0000]
Somatostatin
0.82
g
Water
2.05
g
Hesperidin
0.0008
g
Sorbitan palmtate (Span 40 ®)
2.04
g
Triglycerides of caprylic/capric acids (Labrafac CC ®)
8.00
g
Egg lecithin
0.04
g
b) w/o/w Formulation
[0071] The microemulsion a) w/o was added to an aqueous phase (72.78 g) under paddle stirring at the speed of 310 rpm for 0.5 h, Span 40® was then added (5.03 g) under paddle stirring at the speed of 280 rpm for 0.5 h to obtain a double microemulsion w/o/w. The composition of the resulting w/o/w double microemulsion was the following:
Example 3
w/o/w Composition
[0072]
[0000]
Somatostatin
0.82
g
Triglycerides of caprylic/capric acids (Labrafac CC ®)
8.00
g
Hesperidin
0.0008
g
Sorbitan palmitate (Span 40 ®)
7.07
g
Egg Lecithin
0.04
g
Water
74.83
g
Example 4
a) o/w Microemulsion Formulation
[0073] A o/w microemulsion was prepared by mixing using a paddle mixer at the speed of 220 rpm for 0.5 h at 25° C. an oily phase (Akoline®:Transcutol HP®7:3) containing simvastatin dissolved (0.34 g/g), to a water phase, the surfactant Tween 80® was subsequently added with a mixing rate of 250 rpm for 0.5 h; the composition of the resulting microemulsion was:
[0000]
Simvastatin
0.366 g
Monoglycerides of caprylic/capric acids(Akoline ®)
0.754 g
Diethylene glycol monoethyl ether (Transcutol HP ®)
0.323 g
Polyoxyethylene (20) sorbitan monooleate (Tween 80 ®)
0.303 g
Water
3.230 g
b) o/w/o Double Microemulsion
[0074] The o/w microemulsion a) was added under stirring (300 rpm) for 0.75 h to a an oily phase (Akoline®), the surfactant Tween 80® (3.01 g) was added under paddle stirring at speed of 270 rpm for 0.5 h, obtaining a double microemulsion containing simvastatin.
[0000]
Simvastatin
0.367 g
Monoglycerides of caprylic/capric acids (Akoline ®)
23.804 g
Diethylene glycol monoethyl ether (Transcutol HP ®)
0.323 g
Polyoxyethylene (20) sorbitan monooleate (Tween 80 ®)
3.313 g
Water
3.230 g
Example 5
a) o/w Microemulsion Formulation
[0075] A o/w microemulsion was prepared by mixing using a paddle mixer at the speed of 220 rpm for 0.75 h at 25° C. an oily phase (Lauroglycol FCC®) containing quercetin (0.05 g/g) and dissolved Itraconazole (0.44 g/g) to a water phase, the surfactant Tween 80® was subsequently added with a mixing rate of 250 rpm for 0.5 h; the composition of the resulting microemulsion was:
[0000]
Itraconazole
1.35 g
PolyethyleneGlycolmonoester of
3.05 g
lauric acid (Lauroglycol FCC ®)
Quercetin
0.15 g
Polyoxyethylene (20) Sorbitan
2.05 g
Monooleate (Tween 80 ®)
Water
6.05 g
b) o/w/o Double Microemulsion
[0076] The o/w microemulsion a) was added under stirring (300 rpm) for 0.5 h to an oily phase (Lauroglycol®:Quercetin) (55.90), the surfactant Tween 80® (4.01 g) was added under paddle stirring at speed of 270 rpm for 0.75 h, obtaining a double microemulsion containing itraconazole.
[0000]
Itraconazole
1.35 g
PolyethyleneGlycolmonoester of
53.10 g
lauric acid (Lauroglycol FCC ®)
Quercetin
2.80 g
Polyoxyethylene (20) Sorbitan
6.06 g
Monooleate (Tween 80 ®)
Water
6.05 g
Example 6
a) o/w Microemulsion Formulation
[0077] A o/w microemulsion was prepared by mixing using a paddle mixer at the speed of 280 rpm for 0.50 h at 25° C. an oily phase (Plurol oleique CC497®) containing Quercetin (0.02 g/g) and dissolved danazole (0.40 g/g) to a water phase, the surfactant Tween 80® was subsequently added with a mixing rate of 240 rpm for 0.5 h; the composition of the resulting microemulsion was:
[0000]
Danazol
0.408
g
Polyglyceril-6 dioleate (Plurol oleique ® CC497)
1.02
g
Quercetin
0.0204
g
Polyoxyethylene (20) sorbitan monooleate (Tween 80 ®)
0.700
g
Water
5.022
g
b) o/w/o Double Microemulsion
[0078] The o/w microemulsion a) was added under stirring (300 rpm) for 0.5 h to a an oily phase (Plurol oleique CC497®) (26.96 g), the surfactant Tween 80® (2.02 g) was added under paddle stirring at speed of 280 rpm for 0.50 h, obtaining a double microemulsion containing itraconazole
[0000]
Danazol
0.408
g
Polyglyceril-6 dioleate (Plurol oleique ® CC497)
27.980
g
Quercetin
0.0204
g
Polyoxyethylene (20) sorbitan monooleate (Tween 80 ®)
2.720
g
Water
5.022
g
[0079] Characterization Tests
[0080] The double microemulsions of the invention were characterized by the following methods.
[0081] Size Determination of the Droplets of Double Microemulsions of the Invention
[0082] The size of the droplets of the double microemulsions prepared as shown in the examples 1-6 was determined by Laser Light Scattering (Coulter Counter, Mod. N4 Plus); data are reported in Table 1.
[0000]
TABLE 1
Droplets size of the double microemulsions of the
invention
Sample
Droplets Size
Example 1
1 85 nm
Example 2
230 nm
Example 3
120 nm
Example 4
285 nm
Example 5
210 nm
Example 6
6 305 nm
[0083] Solubilization Kinetics of the Double Microemulsions of the Invention
[0084] The “in vitro” solubilization kinetics was determined in buffer solution (pH 7.4, 37° C.); sample of the double microemulsion under testing is dispersed in tubes filled with 50 ml of buffer solution and placed over a thermostated shaking plate; at predetermined time intervals samples of the solution were filtered and then ultra-centrifuged; drug concentration was determined by HPLC, data are reported in Table 2.
[0000]
TABLE 2
Solubilization kinetics of the double microemulsions of the
invention
Drug concentration (ug/ml)
Sample
0.5 hr
1 hr
3 hr
8 hr
24 hr
Example 5 (Itraconazole)
5
11
16
20
25
Itraconazole pure dispersion
0.05
0.1
0.3
0.5
1.5
Example 6 (Danazol)
25
58
72
85
94
Danazol pure dispersion
0.2
0.5
1.0
1.5
2.0
[0085] “In Vivo” Permeation Test
[0086] The permeation test was carried out on anasthetized Wistar rats; the intestinal tract was isolated and incannulated starting form the Treitz ligament (entrance cannula) to a point at 20-30 cm of distance (exit cannula); the experimental double microemulsion under analysis was dispersed in a pH 7.4, 37° C. buffer solution and then perfused; the drug concentration remaining in the perfusion liquid was analyzed by HPLC at predetermined time intervals; apparent permeability (Pa) values are derived from the decrease over time of drug concentration in the perfusion liquid (dC/dt=Pa. Cin-Cfin). Data relative to alendronate in double microemulsion of invention are reported in Table 3.
[0000]
TABLE 3
Apparent permeability of Alendronate Sodium
Sample
Pa, Apparent Permeability (cm/sec)
Alendronate solution
0.15 × 10 − 4
Alendronate in double micro-
14.5 × 10 − 4
emulsion of Example 1
| 1a
|
FIELD OF THE INVENTION
[0001] The present invention relates to a pharmaceutical composition for topical administration suitable for the prophylaxis and treatment of herpes virus infections. The pharmaceutical composition comprises the compound 2,3-dimethyl-6-(N,N-dimethylaminoethyl)-6H-indolo-(2,3-b)quinoxaline (herein below also referred to as B-220) or a pharmaceutically acceptable to salt thereof, optionally in combination with at least one additional therapeutically active, ingredient suitable for topical administration, e.g. selected from antiviral agents, antibiotics, analgesics, anaesthetic agents, antiphlogistic agents, and anti-inflammatory agents.
BACKGROUND OF THE INVENTION
[0002] Herpes virus infections in humans can be caused by different human and animal herpes viruses, the most common being herpes simplex virus and varicella-zoster virus.
[0003] Following a primary infection with herpes simplex or varicella-zoster virus, the virus establishes latency in the sensory nerve cells for the rest of the patient's life and subsequently repeated virus reactivation can occur. Following a reactivation in the nerve cell the virus is transported through the nerves to the skin and then a lesion will develop Immediately upon an outbreak of virus replication inflammation will follow. The inflammation contributes to the symptoms associated with herpes virus recurrence, including redness, swelling, itching and pain as well as lesions.
[0004] Herpes simplex viruses may be grouped into two serotypes, HSV type 1 (HSV-1) and type 2 (HSV-2), the clinical manifestations of which range from benign self-limiting orofacial and genital infections to potentially life threatening conditions such as encephalitis and generalized neonatal infections. Oral-facial HSV infections are primarily caused by HSV-1, which becomes latent after a primary infection e.g. in childhood. After reactivation a recurrent oral-facial HSV infection develops, more commonly known as a cold sore. About half of the patients experience early symptoms, e.g. pain, burning or itching at the site of the subsequent lesions. The condition is generally rapidly self-limiting and the healing time of a typical episode is about 10 days from the initial symptoms. Viral replication in the lip is initiated early and maximum virus load is attained 24 hours after the onset of the reactivation. The virus concentration is then dramatically reduced and typically virus cannot be isolated 70-80 hours after the onset.
[0005] The clinical presentation of genital HSV infections is similar to the oral-facial infections with some important exceptions. Genital HSV infections are most often caused by HSV-2 and following the primary infection the virus will latently infect sensory or autonomic ganglions. Reactivation will produce the local recurrent lesions on or near the genitals that are to characteristic of the herpes infection.
[0006] A primary infection with varicella-zoster virus (VZV) causes chicken-pox. Like HSV, VZV becomes latent following the primary infection and can be activated as herpes zoster later on in life. Zoster usually results in skin rash and intensive acute pain. In 30% of the patients, the pain can be prolonged and continue for weeks or months after the rash has cleared up, or may even be permanent.
[0007] HSV and VZV may, in addition to mucous or cutaneous manifestations, also cause keratitis in the eyes. This condition is also recurrent and may cause blindness.
[0008] There are a number of antiviral agents which are active against the human herpes viruses. However, so far clinical success in the treatment of recurrent herpes virus infections has been only limited and there still exists no cure for herpes.
[0009] Various antivirals are used with varying success, e.g.: acyclovir (aciclovir), valacyclovir (valacyclovir), famciclovir, and penciclovir. For example, a cream formulation of acyclovir for topical application is sold by Ranbaxy under the generic name Zovirax.
[0010] WO96/024355 describes a combination formulation for topical administration comprising a topically acceptable antiviral agent, e.g. acyclovir, and an antiinflammatory glucocorticoid, e.g. hydrocortisone. A composition within the scope of said patent application, useful for the topical treatment of recurrent herpes labialis (cold sores) is commercially available as Xerclear™ (Xerese™ in the USA). Said composition contains 5% acyclovir and 1% hydrocortisone in a cream formulation.
[0011] There however still remains a need for effective drugs and methods of treatment for primary as well as recurrent herpes infections.
[0012] B-220 was disclosed for the first time in the PCT application published as WO87/04436, which showed the antiviral effect of a number of indoloquinoxalines against herpes simplex virus of both type 1 and 2. The antiviral effect was shown by injecting the test substance in mice receiving also an intracerebral injection of the virus.
[0013] The antiviral activity of B-220 against human cytomegalovirus has also been mentioned in the PCT application published as WO07/084073, where B-220 is used as a reference compound in a modified plaque assay.
SUMMARY OF THE INVENTION
[0014] It has now been found that primary and recurrent herpes virus infections can be surprisingly effectively treated by topical administration of B-220.
[0015] The invention therefore relates to a pharmaceutical composition for topical administration comprising 2,3-dimethyl-6-(N,N-dimethylaminoethyl)-6H-indolo-(2,3-b)quinoxaline (B-220) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
[0016] The composition of the invention is useful for topical administration to a mammal subject suffering from a primary or recurrent herpes virus infection, especially of oral-facial type.
[0017] In one embodiment, the pharmaceutical composition of the invention additionally comprises at least one additional therapeutically active ingredient suitable for topical administration.
[0018] According to one aspect, the invention relates to B-220 or a pharmaceutically acceptable salt thereof for use in the treatment of herpes virus infections of the skin or mucous membranes in a mammal subject by topical administration of a therapeutically effective dose thereof to the skin and/or mucous membrane of the mammal subject.
[0019] In one embodiment, the invention relates to B-220 or a pharmaceutically acceptable salt thereof is used in combination with at least one additional pharmaceutically active ingredient suitable for topical administration.
[0020] According to another aspect, the invention relates to a method of prophylactic and/or curative treatment of herpes virus infections of the skin or mucous membranes in a mammal subject comprising topical administration of a therapeutically effective dose of B-220 or a pharmaceutically acceptable salt thereof.
[0021] In one embodiment, the method also comprises topical administration, in combination or in sequence, of at least one additional pharmaceutically active ingredient suitable for topical administration, e.g. selected from antiviral agents, antibiotics, anaesthetic agents, analgesic agents, antiphlogistic agents, and anti-inflammatory agents.
DETAILED DESCRIPTION OF THE INVENTION
[0022] B-220, i.e. 2,3-dimethyl-6-(N,N-dimethylaminoethyl)-6H-indolo-(2,3-b)quinoxaline, has the structural formula
[0000]
[0023] and may be prepared e.g. as described in WO87/04436, the contents of which is incorporated herein by reference.
[0024] Pharmaceutically acceptable salts of B-220 may be formed using any organic or inorganic, pharmaceutically acceptable acid, such as are well-known to the person of ordinary skill in the art. Pharmaceutically acceptable acid addition salts according to the invention are salts that are safe and effective for topical use in mammals and that possess the desired biological activity, e.g. hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, or p-toluenesulfonate salts.
[0025] The pharmaceutical composition of the invention comprises B-220 and at least one pharmaceutically acceptable excipient. In one embodiment of the invention, the pharmaceutical composition comprises B-220 or a pharmaceutically acceptable salt thereof in a pharmaceutical carrier suitable for topical delivery of the active ingredient.
[0026] In one embodiment, the pharmaceutical composition comprises B-220 or a pharmaceutically acceptable salt thereof and an additional therapeutically active ingredient, suitable for topical administration, e.g. selected from antiviral agents, antibiotics, anaesthetic agents, analgesic agents, antiphlogistic agents and anti-inflammatory agents.
[0027] In one embodiment, the additional therapeutically active ingredient comprises or is an antiviral agent. The antiviral agents suitable for the purposes of the present invention are topically acceptable antiviral compounds, which in addition to being specific inhibitors of herpes virus multiplication also are active after topical administration and in addition are pharmaceutically acceptable for topical administration. This means that the toxicity of the antivirals must be sufficiently low to allow for a continuous contact with the human body and in particular with the skin and mucous membranes. Examples of antiviral agents are substances within the group comprising compounds acting on viral DNA polymerase, such as nucleoside analogues after phosphorylation to their triphosphate forms; phosphonoformic and phosphonoacetic acids and their analogues; and other antiviral compounds having a different mechanism of action. As examples of antiviral agents which can be used in the combination of the invention can be mentioned acyclovir (ACV), ACV-phosphonate, brivudine (bromovinyldeoxyuridine, BVDU), carbocyclic BVDU, buciclovir, CDG (carbocyclic 2′-deoxyguanosine), cidofovir (HPMPC, GS504), cyclic HPMPC, desciclovir, edoxudine, famciclovir, ganciclovir (GCV), GCV-phosphonate, genivir (DIP-253), H2G (9-[4-hydroxy-2-(hydroxy-methyl)butyl]-guanine), HPMPA, lobucavir (bishydroxymethylcyclobutylguanine, BHCG), netivudine (zonavir, B W882C87), penciclovir, PMEA (9-(2-phosphonylmethoxy-ethyl)adenine), PMEDAP, sorivudine (brovavir, BV-araU), valacyclovir, 2242 (2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine), HOE 602, HOE 961; BPFA (batyl-PFA), PAA (phosphonoacetate), PFA (phosphonoformate); arildone, amantadine, BILD 1263, civamide (capsaicin), CRT, ISIS 2922, peptide T, tromantadine, virend, 1-docosanol (lidakol) and 348U87 (2-acetylpyridine-5-[2-chloro-anihno-thiocarbonyl]-thiocarbono-hydrazone).
[0028] Preferred antiviral agents are those with specific antiviral activity such as herpes specific nucleoside analogues which are preferentially phosphorylated in virus-infected cells and have very low or non-existent incorporation into cellular DNA as well as other compounds with specific antiviral activity. Acyclovir, for instance, has a selectivity ratio for the inhibitory activity against HSV-1 in vitro of about 2000. Among said preferred substances can in addition to acyclovir be mentioned brivudine, cidofovir, desciclovir, famciclovir, ganciclovir, to HOE 961, lobucavir, netivudine, penciclovir, PMEA, sorivudine, valacyclovir, 2242, BPFA, PFA, PAA.
[0029] A suitable antiphlogistic agent, i.e. an agent capable of reducing inflammation, pain and/or fever, e.g. may be a non-steroidal anti-inflammatory drug (NSAID), such as diclofenac (IUPAC name 2-(2,6-dichloranilino)phenylacetic acid), or ibuprofen, (IUPAC name (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid), or a pharmaceutically acceptable salt thereof, e.g. a sodium, potassium or diethylamine salt thereof.
[0030] A suitable anaesthetic agent e.g. may be lidocaine (IUPAC name 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide).
[0031] A suitable antiinflammatory agent e.g. may be adenosine (IUPAC name: (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol.
[0032] The antiinflammatory agent also may be selected from antiinflammatory glucocorticoids. A suitable glucocorticoid can be either naturally occurring or synthetic and can be selected from any of the Group I-ID glucocorticoids, according to a classification system for topical glucocorticoids used in the Nordic countries, corresponding to less potent, low or moderately potent glucocorticoids. Examples of glucocorticosteroids are alclometasone, amicinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasone, clocortolone, cloprednol, cortison, desonide, desoximethasone, dexamethasone, diflorosane, diflucortolone, difluprednate, fludrocortisone, fludroxycortid, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluprednidene, fluticasone, halcinonide, halobetasol, halometasone, hydrocortisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednicarbate, prednisone, prednylidene, rofleponide, tipredane and triamcinolone and their esters, salts and solvates, that is hydrates, where applicable.
[0033] Some preferred glucocorticoids are hydrocortisone, alclometasone, desonide, fluprednidene, flumethasone, hydrocortisone butyrate, clobetasone, triamcinolone acetonide, betamethasone, budesonide, desoximethasone, diflorosane, fluocinolone, fluocortolone, fluticasone, methylprednisolone aceponate, mometasone and rofleponide; in particular hydrocortisone, budesonide and fluticasone.
[0034] A suitable antibiotic e.g. may be selected from clindomycin, erythromycin, mupirocin, bacitracin, polymyxin and neomycin.
[0035] The carrier of the pharmaceutical composition should be stable and pharmaceutically acceptable and suitable for topical application. It should also enable incorporation of sufficient amounts of B-220 or of the pharmaceutically acceptable salt thereof, and optionally additional active ingredient(s). In addition to conventional ingredients in creams, lotions, gels or ointments, aerosolizable liquids, and foams, compositions based on phospholipids, including sphingolipids can be advantageous. In a cream or ointment formulation the carrier may be white petrolatum.
[0036] A liquid carrier may include water, alcohols or glycols or water-alcohol/glycol blends, in which effective amounts of the active ingredient(s) according to the invention can be dissolved or dispersed, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and antimicrobial agents can be added to optimize the properties for a given use. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, creams etc., for application directly to the skin and/or mucous membrane of the user.
[0037] A pharmaceutical composition of the invention can be used for the prophylaxis and/or treatment of herpes virus infections in mammals including man. In a preferred embodiment the composition is used for the treatment of primary or recurrent herpes virus infections. The treatment of infection should take place during the virus replication, preferably from the first appearance of redness/lesion or prodromal symptoms and for a period of 3-4 days at least. The formulation may be repeatedly applied, e.g. up to every two hours, during the whole episode until healing.
[0038] Prophylactic treatment may be performed in patients having regularly recurrent disease. In this case the formulation is applied to the area where a recurrence is expected before the appearance of the first symptoms. The compositions of the invention can be used to treat all types of herpes virus that replicate in the skin or the mucous membrane, e.g. HSV-1, HSV-2 and VZV.
[0039] The pharmaceutical compositions for topical administration according to the present invention are preferably creams, lotions, gels, sprays, foams, ointments or drops. The pharmaceutical compositions can be incorporated into plasters or patches to be applied to the skin of a patient to be treated for herpes infections or into pens or sticks for application to the skin or mucous membranes.
[0040] Liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
[0041] Topical administration refers in this context to dermal or mucosal administration to the skin or mucous membrane.
[0042] The person of ordinary skill in the art will be well able to select suitable excipients in view of the selected formulation and form of administration, referring to e.g. handbooks such as Remington: The Science and Practice of Pharmacy 21st Edition. Philadelphia, Pa. Lippincott Williams & Wilkins. 2005.
[0043] In embodiments where a glucocorticoid is included in the pharmaceutical composition of the invention, care must be taken to define the optimal dose of the respective components, due to the herpes virus-stimulating effects of glucocorticoids. Too high a dose of the glucocorticoid might stimulate virus multiplication to an extent that can not be inhibited by the antiviral agent. With too low a dose the desired reduction of the symptoms of inflammation might not be achieved.
[0044] A pharmaceutical composition according to the present invention should contain a therapeutically effective amount of B-220. For example, the relative amount of B-220 in a pharmaceutical composition according to the present invention can be within the range of 0.1-10% (w/w), preferably 0.5-5% (w/w), e.g. about 1% (w/w).
[0045] In embodiments where an additional therapeutically active ingredient, such as any of the above-mentioned agents, is present in the composition, its concentration can be e.g. within the range of 0.005-5% (w/w), or within the range of 0.01-2% (w/w) or 0.25-1% (w/w).
[0046] In still another aspect, the present invention refers to a method of prophylactic and/or curative treatment of herpes virus infections of the skin or mucous membranes in a mammal subject, e.g. a human, comprising topical administration, in combination or in sequence, of a therapeutically effective dose of B-220 or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient as mentioned herein above.
EXAMPLE
[0047] B-220 (1 part) was mixed with white petrolatum (99 parts) in a homogenizer to provide a preparation in the form of an ointment, free of other components. This ointment is stable for more than 24 months and accordingly no stabilizers or conditioners had to be added. Variants of this preparation, e.g. containing a higher percentage of B-220, such as 2.5% (w/w) may be prepared in the same way.
Biological tests
[0048] An ointment containing 1% by weight B-220 in white petrolatum was administered topically to 10 volunteers suffering from recurrent herpes labialis. The administration was performed repeatedly every day by applying a thin layer of the ointment to affected areas. All test subjects reported that pain surprisingly disappeared or was substantially alleviated within 1-2 days and redness disappeared or were substantially reduced within 2-4 days.
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CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application claims the benefit of U.S. provisional application Ser. No. 62/149,895, filed Apr. 20, 2015, which is hereby incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to adjustable fitness handwear.
BACKGROUND
[0003] Typical gloves and mittens provide insulation and weather-resistant properties for the wearer, but do not facilitate shared warmth of the palm, fingers, and thumb encased by the glove or mitten. Heat produced by these body parts is lost to the fabric touching the various parts of the hand. Additionally, gloves and mittens do not allow access to the bare hand and typically must be entirely removed in order to have full use of the exposed hand. In some cases, excess clothing is worn at the start of cold weather activity to maintain a comfortable body temperature before the body is fully warmed up, but the excess clothing (such as gloves or mittens) later becomes unnecessary as the wearer's body produces extra heat during fitness activities. Thus, when an athlete's body temperature increases due to fitness activities, the excess clothing that provided comfort at the beginning of the activities can become unnecessary and may increase the risk of overheating and dehydration. The athlete then may wish to remove the clothing and set it down while risking its loss, or may hold onto the removed clothing during the remaining fitness activities, which can be uncomfortable.
SUMMARY OF THE INVENTION
[0004] The present invention provides a cold-weather outdoors handwear article that is particularly suited for fitness activities. Specifically, the handwear article is openable to facilitate regulating the temperature and comfort of a wearer's hand and wrist during fitness activities. Furthermore, the handwear article can be folded back over the hand and thus retained on the wearer's wrist during running or other fitness activities to facilitate cooling and use of the hands, to prevent loss of the article, and may be used to clear sweat from the wearer's brow or forehead. Optionally, the article also includes pockets to store personal items such as keys, credit cards, or hand warmers during running or other fitness activities.
[0005] The handwear article has at least three configurations, and optionally four or five configurations, for regulating heat and comfort of the wearer's hand, depending on the outdoor conditions and level of fitness activity. Notably, it is envisioned that the handwear article does not have separate or divided chambers for individual digits (fingers or the thumb). Instead, the article has one inner chamber shaped to hold the wearer's hand in a loose fist or fist-like shape, and has overlapping fabric layers on a palm side that allow the wearer to quickly gain practically full use of the wearer's uncovered hand. This may be accomplished without using the wearer's other hand to pull back the article. In a first configuration, the handwear article encloses the wearer's hand, and allows the hand to be in a relaxed or loose fist to conserve heat and warm the wearer's fingers and thumb with their palm.
[0006] The first configuration further allows the wearer to keep their hand in a common and natural curled finger position as for running. In a second configuration the wearer's fingers exit through the palm side opening, optionally remaining in a relaxed or loose fist position, allowing increased airflow and heat escape. In a third configuration the wearer's fingers and thumb exit through an opening of the handwear article, such as by using only the hand that is wearing the handwear, such that the wearer gains practically full use of their hand. In a fourth configuration, the article is pulled or folded back on itself at a palm side to further expose the wearer's hand so that the wearer has substantially unobstructed use of their hand and their wrist. In a fifth configuration, the article is further pulled back to fully expose the wearer's hand and wrist.
[0007] According to one form of the present invention, the handwear article includes a back panel and a palm panel that cooperate to define a chamber. The chamber receives a wearer's hand in a fist-like shape and encloses the hand without any portions of the handwear article interspaced between the fingers. The palm panel defines an opening that is open to the chamber. The handwear article is reconfigurable or repositionable from a configuration that completely encloses the wearer's hand in the chamber, to another configuration in which the wearer pulls the handwear article proximally (i.e. toward the elbow), such that it lies inside out against the wearer's forearm.
[0008] In one aspect, the opening defined in the palm panel is positioned adjacent to the wearer's fingers to allow the hand to open the opening and extend from the chamber using only the fingers of the hand that is wearing the handwear.
[0009] In another aspect, the handwear article also includes one or more pockets that are accessible next to the opening in the palm panel. Optionally, the palm panel forms at least part of one of the pockets.
[0010] According to another form of the present invention, a handwear article is made up of a set of panels including a back panel, a proximal palm panel, and a distal palm panel that cooperate to define an internal chamber. The back panel has a proximal end portion, a distal end portion, and opposing sides that extends between the proximal and distal end portions. Likewise, the proximal palm panel and the distal palm panel each have a respective proximal end portion, a distal end portion, and opposing sides. The opposing sides of the proximal palm panel are coupled to respective opposing sides of the back panel, and the distal end portion of the proximal palm panel terminates between the proximal and distal end portions of the back panel. The distal palm panel has a proximal end portion, a distal end portion, and opposing sides. The distal end portion of the distal palm panel is coupled to the distal end portion of the back panel. The proximal end portion of the distal palm panel overlaps and terminates proximally of the distal end portion of the proximal palm panel.
[0011] In one aspect, the back panel, the proximal palm panel, and the distal palm panel define the chamber, which receives the wearer's hand in a fist-like shape through an opening. The opening is formed in a palm side of the chamber between the proximal end portion of the distal palm panel and the distal end portion of the proximal palm panel.
[0012] Thus, the handwear article provides insulation and weather resistance when disposed fully around the wearer's hand, permitting the hand to be held in a relaxed or loose fist-like shape with the fingers curled to conserve heat with the palm, and without excessive material extending loosely a significant distance beyond the knuckles, for comfort at least at the start of fitness activities in cold weather. The handwear article has a slot or opening formed between overlapping palm-side panels, which allows the wearer to work the fingers of the hand that is wearing the article out through the opening to expose at least the fingertips, and to optionally expose more of the fingers or most of the hand, as desired. This may be done to enhance the wearer's ability to grip objects or cool the hand, for example. The handwear article can be drawn further back to expose more of the wearer's hand as desired, to provide even further increased cooling and less obstructed or completely unobstructed use of the hand.
[0013] These and other objects, advantages, purposes and features of this invention will become apparent upon review of the following specification in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a palm or inner side view of a right-hand handwear article according to the present invention;
[0015] FIG. 2 is a back-of-hand or outer side view of the handwear article of FIG. 1 ;
[0016] FIG. 3 is a back-of-hand or outer side view of the handwear article with the wearer's right hand inserted therein;
[0017] FIG. 4 is a palm or inner side view of the handwear article, shown with fingers working out from a fist position through an opening;
[0018] FIG. 5 is a side view of the hand in the handwear article, shown with fingers free of the handwear article and having at least limited use;
[0019] FIG. 6 is a back-of-hand or outer side view of the hand in the handwear article in the configuration of FIG. 5 ;
[0020] FIG. 7 is a palm or inner side view of the hand in the handwear article in the configuration of FIG. 5 ;
[0021] FIG. 8 is a fingertip or end view of the hand in the handwear article in the configuration of FIG. 5 ;
[0022] FIG. 9 is a back-of-hand or outer side view of the hand in the handwear article, in which an outer flap is folded back over itself and inside-out or partially retracted, such that the fingers are generally free of the handwear article;
[0023] FIG. 10 is a side view of the hand in the handwear article in the configuration of FIG. 9 ;
[0024] FIG. 11 is a fingertip or end view of the hand in handwear article in the configuration of FIG. 9 ;
[0025] FIG. 12 is a side view of the hand in the handwear article with the outer flap fully retracted over itself and cuffed;
[0026] FIG. 13 is a bottom view of the hand in the handwear article in the configuration of FIG. 12 ; and
[0027] FIG. 14 is a cross-sectional view of the handwear article of FIG. 3 with the hand in a fist-like shape.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0028] Referring now to the drawings and illustrated embodiments depicted therein, particularly FIGS. 1-3 , an openable handwear article 10 is provided for a hand H of a wearer ( FIGS. 4-8 and 11-14 ), such as for use outdoors in a cold and/or wet environment. The handwear article 10 is particularly suited for running and other outdoor athletic activities to regulate the temperature and comfort of the wearer's hand H and wrist. The handwear article 10 can be retained on the wearer's wrist during running or other fitness activities to prevent loss, to store personal items, to cool the hands, or to clear sweat from the wearer's brow or forehead, and to facilitate replacing the article 10 on the wearer's hand H. Optionally, the handwear article 10 may include one or more storage pockets or pouches to store personal items such as keys, credit cards, or handwarmers, as will be described below in more detail.
[0029] In a first or substantially fully closed configuration, handwear article 10 allows the wearer to have their hand H in a loose fist or fist-like shape ( FIGS. 3 and 14 ) to conserve heat and warm their fingers and thumb with their palm. The first configuration further allows the wearer to keep their hand H in a common and natural curled or loose fist-like position such as may be desired for running. The handwear article 10 allows the wearer's digits (fingers and thumb) to work out from an opening 12 of the handwear article 10 to expose the fingertips in a second configuration ( FIGS. 1 and 4 ), such that the wearer gains cooling to the interior of the handwear 10 and, optionally, may have limited use of the uncovered fingertips. In a third configuration the fingers are fully nearly fully exposed for full dexterity ( FIGS. 5-8 ), allowing practically full use of their hand H in the third configuration. A fourth configuration ( FIG. 9-11 ) allows the wearer to gain further use of their hand H and their wrist. A fifth configuration ( FIG. 12-13 ) is achieved by drawing a portion of the handwear article 10 further back over the wrist to provide uninhibited motion and use of the wrist and hand H.
[0030] As illustrated in FIGS. 1, 2, 4, and 14 , the handwear article 10 is assembled from a back panel 14 and a two-piece palm panel 16 that cooperate to define a hand chamber 18 . The back panel 14 has a proximal end portion 20 , a distal end portion 22 , and opposing sides 24 , 26 that extend between the proximal end portion 20 and distal end portion 22 . The two-piece palm panel 16 is made up of a proximal palm panel 28 and a distal palm panel 30 . A proximal portion of the distal palm panel 30 overlaps a distal portion of the proximal palm panel 28 to define the opening 12 , such as shown in FIGS. 1 and 2 . Each of the panels 14 , 16 are sewn together at opposing sides 24 , 26 and thereby cooperate to define the hand chamber 18 . The back panel 14 and two-piece palm panel 16 may be sewn together, or can be mechanically joined in any suitable manner, such as with adhesive or other suitable bonding material or process.
[0031] The chamber 18 ( FIG. 14 ) is formed by joining the back panel 14 and two-piece palm panel 16 to receive the wearer's hand H in the fist-like shape to conserve heat and warm the wearer's fingers, thumb, and palm. Chamber 18 encloses the wearer's hand H without any portions of the handwear article 10 interspaced between any fingers or thumb of the wearer's hand H. As shown in FIGS. 9, 10, 12, and 13 , the back panel 14 has an inner portion or surface 32 and an outer portion or surface 34 , and the two-piece palm panel 16 has an inner portion or surface 36 and an outer portion or surface 38 . In at least one configuration, such as the first configuration of FIG. 14 , the inner portions 32 , 36 are interior surfaces that cooperate to define the chamber 18 and the outer portions 34 , 38 are outer surfaces exposed to the environment. Thus, the chamber 18 is formed as a single cavity that is shaped to fit the wearer's hand H in a loose fist, which allows the wearer to keep their hand H in a common and natural position for running, for example.
[0032] Back panel 14 and the two-piece palm panel 16 cooperate to substantially form the fist-like shape of chamber 18 . For example, and with reference to FIGS. 1-3 , distal end portion 22 of the back panel 14 and a distal end portion 40 of the two-piece palm panel 16 are wider than respective proximal end portions 20 , 42 of the back panel 14 and the two-piece palm panel 16 . Each proximal end portion 20 , 42 couples to a wrist panel 44 that is configured to encircle at least a portion of the wearer's wrist.
[0033] The proximal palm panel 28 is generally adjacent to the wearer's palm and has the proximal end portion 42 , a distal end portion 46 and opposing sides 48 , 50 ( FIG. 7 ). The opposing sides 48 , 50 of the proximal palm panel 28 are coupled to respective opposing sides 24 , 26 of the back panel 14 . The distal end portion 46 of the proximal palm panel 28 terminates between a proximal end portion 52 of the distal palm panel 30 and the distal end portion 40 of the distal palm panel 30 . Thus, the proximal end portion 52 of distal palm panel 30 overlies or overlaps distal end portion 46 of proximal palm panel 28 to form opening 12 when the handwear article 10 is in the first configuration of FIGS. 1-4 and 14 .
[0034] The distal palm panel 30 is generally adjacent to the wearer's fingers, and in addition to proximal end portion 52 and distal end portion 40 , the distal palm panel 30 has opposing sides 54 , 56 . The opposing sides 54 , 56 of the distal palm panel 30 are coupled to respective opposing sides 24 , 26 of the back panel 14 . The distal end portion 40 of the distal palm panel 30 is coupled to a distal end portion 22 of the back panel 14 . In addition, the proximal end portion 52 of distal palm panel 30 overlaps the distal end portion 46 of the proximal palm panel 28 .
[0035] The fist-like shape of the handwear article 10 is further defined by a substantially asymmetric perimeter 58 ( FIG. 2 ). A seam is formed along the perimeter 58 where opposing sides 54 , 56 of the distal palm panel 30 are coupled to respective opposing sides 24 , 26 of the back panel 14 . The seam has an outboard portion 60 that is substantially in line with an outboard edge 62 of the wrist panel 44 . The seam further has an inboard portion 64 that forms an arcuate shape about the distal end portions 22 , 40 of the back panel 14 and the two-piece palm panel 16 that is opposite the outboard portion 60 . Therefore, the handwear article 10 has a substantially asymmetric shape along a centerline 68 of the wrist panel 44 , such as shown in FIG. 1 .
[0036] The opening 12 allows the wearer's fingers to cool when there is less need to conserve heat. For example, the wearer may have less need to conserve heat while running or during another fitness activity, or while indoors or in a heated area. Specifically, the opening 12 allows the wearer to work their fingers, thumb, and wrist out of the article 10 to cool, such as shown in FIGS. 4-12 . In addition, the opening 12 allows the wearer to fully use their hand H. The opening 12 is generally formed as a slot between the proximal end portion 52 of the distal palm panel 30 and the distal end portion 46 of the proximal palm panel 28 . In the illustrated embodiment, opening 12 extends substantially across the entire width of handwear 10 . Thus, the opening 12 is defined in the two-piece palm panel 16 and is configured to permit the wearer's hand H to reach through the opening 12 (see FIGS. 4-13 ) from the chamber 18 of the handwear article 10 . The opening 12 is generally positioned adjacent to the wearer's fingers to allow the wearer's hand H to extend out of the chamber 18 through the opening 12 using only the fingers or thumb of the wearer's hand H.
[0037] Each inner portion 32 , 36 and outer portion 34 , 38 is generally composed of a fabric such as cotton, wool, fleece, or the like. It is generally desirable that the inner portions 32 , 36 of article 10 are soft and have insulating and/or moisture-wicking properties. It is also generally desirable that the outer portions 34 , 38 have water- or wind-resistant properties, thus the outer portions 34 , 38 may be composed of wool, polyester, nylon, or other fabrics. It will be appreciated that each portion 32 , 34 , 36 , 38 can be composed of different materials to have different uses for different intended purposes, such as for cold or wet conditions.
[0038] In the illustrated embodiment, and as best shown in FIG. 14 , the inner portion 32 of back panel 14 cooperates with a distal pocket panel 70 to form a distal pocket 76 , and the inner portion 36 of the two-piece palm panel 16 cooperates with a proximal pocket panel 72 to form a proximal pocket 74 . The wearer may access the distal pocket 76 via a distal pocket opening 78 and may access the proximal pocket 74 via a proximal pocket opening 80 . The pockets 74 , 76 are accessible when the handwear article 10 is in any of the first through fifth configurations, by opening the respective pocket openings 80 , 78 with the user's fingers of hand H that is in the article 10 , or with the user's other hand. The distal pocket 76 is formed by the distal palm panel 30 and the distal pocket panel 70 , which cooperate to form the distal pocket opening 78 adjacent to the opening 12 and the palm of the hand H when in the first configuration. The proximal pocket 74 is formed by the proximal palm panel 28 and the proximal pocket panel 72 , which cooperate to form the proximal pocket opening 80 adjacent to the end of opening 12 that is in the handwear interior (i.e., at chamber 18 ) and near the fingers when in the first and second configurations, and along the palm of the hand H when in the third and fourth configurations.
[0039] Each pocket 74 , 76 is sewn at the perimeter 58 of the handwear article 10 and may be sewn at least partially inboard from seams 60 , 64 . However, each of the openings 78 , 80 is sufficiently wide to allow the wearer to store and remove personal items from the pockets 74 , 76 . Thus, the proximal pocket opening 80 is formed at the distal end portion 46 of the proximal palm panel 28 , and the distal pocket opening 78 is formed at the proximal end portion 20 of the distal palm panel 30 . In the illustrated embodiment, the distal pocket 76 has a flap 82 to cover or partially block the distal pocket opening 78 to prevent personal items from unintentionally exiting the distal pocket 76 . One would understand that the proximal pocket 74 could also have a flap to cover or partially block the proximal pocket opening 80 . Thus, the distal pocket 76 has a similar shape and perimeter as the distal palm panel 30 , and the proximal pocket 74 has a similar shape and perimeter as the proximal palm panel 28 .
[0040] As noted above, the handwear article 10 is capable of assuming multiple configurations that provide differing and selectable amounts of exposure of the wearer's hand H for cooling and use of the hand. Each configuration allows the wearer to have their hand H in the fist-like shape, which is commonly a natural position for running and other fitness activities. In the first configuration ( FIGS. 1-3 and 14 ), the handwear article 10 receives the wearer's hand H in the fist-like shape to enclose the hand H. Specifically, the chamber 18 of the handwear article 10 receives the wearer's hand H through the wrist panel 44 , and the wrist panel 44 at least partially encircles the wearer's wrist. The distal palm panel 30 conceals the proximal pocket opening 80 and the flap 82 . However, the distal pocket 76 and the proximal pocket 74 are still accessible to the wearer's other hand through opening 12 , or by the wearer's fingers on hand H within the chamber 18 . Thus, in the first configuration the wearer's hand H is received in the single chamber 18 , without any panel or portion of the handwear article 10 located between the wearer's fingers and thumb.
[0041] In a second configuration, illustrated in FIG. 4 , the wearer's hand H begins in the fist-like shape of the first configuration, from which the wearer's fingers or thumb extend from the chamber 18 through the opening 12 . Optionally, it may be possible for the wearer to use only the fingers of the hand H that is wearing the article 10 to expose portions of the wearer's hand H through the opening 12 , without need for grasping the handwear article 10 with the other hand. In the second configuration of FIG. 4 , the proximal pocket opening 80 is open to the environment, but the flap 82 is still concealed by the distal palm panel 30 . However, the distal pocket 76 and the proximal pocket 74 are accessible to the wearer's other hand through opening 12 , or by manipulating the wearer's fingers on hand H within the chamber 18 . Thus, the second configuration allows the wearer to increase ventilation of hand H to regulate temperature while still wearing the handwear article 10 .
[0042] To achieve the third configuration, illustrated in FIG. 5-8 , the wearer's hand H begins in the fist-like shape of the first configuration and the fingers are worked at least partially out through the opening 12 as in the second configuration, from which the wearer's fingers and then palm extend outwardly from the chamber 18 and through the opening 12 , which is generally adjacent to the fingers. Optionally, it may be possible for the wearer to use only the fingers of the hand H wearing the article 10 to more fully expose the wearer's hand H through the opening 12 , without need for grasping the handwear article 10 with another hand. Thus, the third configuration allows the wearer to gain practically full use of their partially-exposed or mostly-exposed hand H while still wearing the handwear article 10 about the wrist, the back of the hand, and the heel of the palm.
[0043] Furthermore, the third configuration allows the wearer to increase ventilation and conserve less heat when desired, such as while running or during other fitness activities. As noted above the third configuration still covers the wrist and a substantial portion of the wearer's hand H, and may cover at least a heel portion of the wearer's palm that is proximal to the wearer's wrist ( FIGS. 5-8 ). In the third configuration, the proximal pocket opening 80 is open to the environment, but the flap 82 is concealed by the distal palm panel 30 as in the first and second configurations. The distal pocket 76 and the proximal pocket 74 are still accessible to the wearer's other hand through opening 12 , or by the wearer's fingers of hand H within the chamber 18 . Thus, the third configuration encloses a portion of the wearer's hand H and wrist to conserve some heat, allow use of the hand H, and retain the handwear article 10 on the wrist during running or other fitness activities.
[0044] To achieve the fourth configuration ( FIGS. 9-11 ) from the third configuration, the proximal end portion 52 of distal palm panel 30 is pulled distally from the wearer's hand H, typically using the wearer's other hand (not shown) to grasp the back panel 14 and the distal palm panel 30 . The proximal end portion 52 is folded back over itself and onto the distal end portion 22 of the back panel 14 and toward the wearer's wrist, which essentially turns the handwear article 10 partially inside-out. Therefore, the fourth configuration is generally less obtrusive to the wearer's hand H and wrist movement than the second and third configurations. Compared to the third configuration, the fourth configuration also conserves less heat and allows for greater ventilation while retaining the handwear article 10 on the wearer during running or other fitness activities.
[0045] It will be appreciated that the fourth configuration substantially exposes at least the inner portion 32 of the back panel 14 to the outside environment. In the fourth configuration of FIGS. 9-11 , the distal pocket opening 78 and the flap 82 , which conceals the distal pocket opening 78 , are open or at least more exposed to the environment. Specifically, in the fourth configuration the flap 82 and the distal pocket opening 78 are positioned on the back of the wearer's hand H adjacent to the back panel. The proximal pocket 74 and the proximal pocket opening 80 are still accessible to the wearer's other hand or, to a limited extent, by the wearer's fingers on hand H within the proximal portion of the chamber 18 that is still defined between the proximal palm panel 28 and back panel
[0046] To achieve a fifth configuration ( FIGS. 12 and 13 ), the article 10 begins in the fourth configuration and the wearer further pulls the handwear article 10 in the proximal direction (i.e., towards the elbow) to turn the handwear article 10 substantially inside-out, with the distal end portion 22 of the back panel 14 , the distal end portion 40 of the distal palm panel 30 , and the distal end portion 46 of the proximal palm panel 28 all facing rearwardly or proximally (i.e., toward the wearer's elbow) with their interior surfaces 32 , 36 exposed to the outside environment. The handwear article 10 is pulled further from the wearer's hand H to cover only the wearer's wrist and lay against the wearer's forearm, such that the article 10 lies flat against the wearer's forearm. Thus, the fifth configuration also conserves less heat than the first, second, third, and fourth configurations while retaining the handwear article 10 to the wearer during running or other fitness activities. In the fifth configuration of FIGS. 12 and 13 , the proximal pocket opening 80 is open to the environment and generally lies against the inside of the wearer's forearm. In the fifth configuration the wearer stores and removes personal items from the proximal pocket 74 with the wearer's other hand. The distal pocket opening 78 and flap 82 are concealed by the back panel 14 , adjacent to the back side or outside of the wearer's wrist.
[0047] The wearer may return article 10 to the first configuration from any of the second through fifth configurations by generally reversing the steps noted above. For example, to return the article to the fourth configuration from the fifth configuration the wearer pulls the handwear article 10 in the distal direction (i.e., towards the fingers) to turn the handwear article 10 partially inside-in so the distal end portion 40 of the distal palm panel 30 , the distal end portion 22 of the back panel 14 , and the distal end portion 46 of the proximal palm panel 28 all facing rearwardly or proximally (i.e., toward the wearer's elbow) all face forwardly or distally (i.e., toward the fingers). To return the article to the third configuration from the fourth configuration, the wearer pulls the proximal end portion 52 of distal palm panel 30 distally around the fingers to unfold the proximal end portion 52 from over back panel 14 . To return the article to the second configuration from the third configuration the wearer's hand H generally forms the fist-like shape and the wearer's other hand pulls the article 10 so at least the palm of hand H is generally within the chamber 18 . To return the article to the first configuration from the second configuration the wearer generally retracts the fingers of hand H through the opening 12 into the chamber 18 so that the opening 12 closes. It will be appreciated that returning handwear article 10 from the fifth configuration to the first configuration can generally be accomplished in two steps, where the first step involves pulling the distal ends 22 , 40 of back panel 14 and the distal palm panel 30 forwardly (distally) from the fifth configuration to the third configuration, and the second step involves pulling the proximal end portion 52 of the distal palm panel 30 forwardly (distally) over and around the fingers while curling and retracting the fingers into chamber 18 and pulling the proximal end portion 52 rearwardly (proximally) to overlap the distal end portion 46 of proximal palm panel 28 in a relatively smooth and substantially continuous motion.
[0048] Accordingly, it will be appreciated that the handwear article 10 is particularly suited for running and other outdoor fitness activities to regulate the temperature and comfort of a wearer's hand H and wrist such as in cold or wet environments, and may also be used to store personal items. Furthermore, even when the handwear article 10 is removed from the wearer's hand H, it can be retained along the wearer's wrist and/or forearm during running or other fitness activities, or can be partially retracted to expose varying amounts of the wearer's hand to adjust for comfort, as desired.
[0049] Changes and modifications in the specifically described embodiments can be carried out without departing from the principles of the present invention which is intended to be limited only by the scope of the appended claims, as interpreted according to the principles of patent law including the doctrine of equivalents.
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PRIORITY CLAIM
[0001] This application is a Continuation Application of International Patent Application No. PCT/CH01/00104, filed on Feb. 16, 2001, which claims priority to German Application No. DE 100 09 814.2, filed on Mar. 1, 2000, both of which are hereby incorporated by reference.
BACKGROUND
[0002] The invention relates to an injector cap for an ampoule support. In particular, the invention relates to the field of so-called injection “pens”, i.e., pen-like injectors or injection devices such as are used for hypodermally administrating medicines, for example for administering insulin for diabetics. The application claims the priority of German patent application No. 100 09 814, filed on Mar. 1, 2000 with the German Patent and Trademark Office.
[0003] Basically, injection pens comprise an ampoule support on which a cannula support comprising a cannula is arranged on a facing side. A cap is fastened over the cannula or needle, said cap in its basic state completely hiding the cannula or needle. From this position, the cap can be retracted in the direction of the ampoule support, wherein the cannula emerges from a hole formed on the front facing side of the cap. It is therefore possible to place the pen on the skin, press on it such that the cap slides backwards against a spring force, administer the injection and remove the pen again, wherein the spring force ensures that the cap is returned to its initial position and the needle is hidden again. In this way, a user can administer the injection without ever even seeing the needle, which is particularly advantageous when patients who have phobias or aversions to needles are reliant on such treatments. Moreover, the cap protects the cannula from contamination.
[0004] A “pen” is known from U.S. Pat. No. 5,609,577 in which the cap can only be retracted once a holding mechanism is twisted up against a spring force. A disadvantage of the pen disclosed in the '577 patent and other conventional injectors is that the cannula can easily be exposed again after the injector has been used. This creates the danger that a cannula which is no longer sterile is used a second time and so causes inflection. Furthermore, such an exposed cannula can cause injury and transmit diseases, which in the age of Aids can be life-threatening.
SUMMARY
[0005] It is therefore the object of the present invention to provide an injector cap which does not exhibit the above disadvantages. In particular, the intention is to simply but reliably prevent the possibility of the cannula of an injector provided with the cap being used or exposed again after having been used once.
[0006] This object is addressed in accordance with the present invention by providing an injector cap for an ampoule support, said cap comprising a sliding sleeve slidably mounted on said ampoule support, wherein the sliding sleeve is pressed by a pre-tensioning means into a first position in which it covers a cannula, and wherein the sliding sleeve can be slid against the pretensioning into a second position in which the cannula emerges from the front facing end of the sliding sleeve, wherein a blocking means is provided which non-detachably blocks the sliding sleeve against sliding further when it has been returned from the second position to the first position. The invention further relates to an injector comprising an ampoule support of an injector cap in accordance with the invention.
[0007] In one embodiment, the present invention comprises an injector cap comprising a sleeve and a lock, wherein the sleeve is mounted slidably on a portion of an injection device, e.g., on an ampoule support, is forced by a pre-tensioning means into a first position in which it covers a cannula carried by the injection device, and can be slid against the pre-tensioning means into a second position in which the cannula emerges from the end of the sleeve, and wherein the lock non-releaseably locks the sleeve against sliding when it has been returned from the second position to the first position.
[0008] An advantage of the injector cap in accordance with the invention is that an injector equipped with said cap cannot be used again once it has been used once. Furthermore, it is not possible to expose again a cannula which has already been used once, such that the danger of injury and thus also the danger of infection are practically completely removed.
[0009] In one embodiment, the blocking means comprises locking means, by means of which the sliding sleeve is locked relative to a fixed part of the ampoule support, once it has returned to the first position. In particular, the blocking means can comprise a locking ring which is slidably mounted in the sliding sleeve and locks in behind a locking protrusion of a cannula support fastened to the ampoule support, when the sliding sleeve is slid into the second position.
[0010] In an embodiment of the latter variant, the locking ring comprises locking clips arranged circumferentially and converging inwards, which lock in behind the locking protrusion.
[0011] There exists the possibility of additionally providing spacer clips which the sliding sleeve pushes against, once the sliding sleeve has returned to the first position, and preferably via elastic stays on the sliding sleeve.
[0012] In accordance with an embodiment of the latter variant, the sliding sleeve comprises a stopper for the spacer clips of the locking ring which, when the sliding sleeve is transferred from the first position to the second position, slides the locking ring over the cannula support until the locking clips lock in behind the locking protrusion of the cannula support.
[0013] The invention further relates to an injector comprising an ampoule support and an injector cap designed in accordance with one or more of the embodiments described above. In one embodiment in this respect, the injector cap or cannula support is attached to the ampoule support via a thread means. If these components are screwed on, there no longer exists the danger of the injector cap latching via the blocking mechanism even when it is attached to the ampoule support for the first time, thus preventing its use.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] [0014]FIG. 1 is a perspective representation of a cut-away injector cap in accordance with the invention, in its initial state on the ampoule support;
[0015] [0015]FIG. 2 is a longitudinal section of the arrangement shown in FIG. 1, in its initial state;
[0016] [0016]FIG. 3 is a longitudinal section through the injector arrangement in accordance with the invention, comprising the injector cap in its fully retracted state (second position); and
[0017] [0017]FIG. 4 depicts an injector arrangement in accordance with the invention, in a longitudinal section, according to its use in accordance with the regulations, the injector cap being retracted into its initial state and blocked against sliding further.
DETAILED DESCRIPTION
[0018] The design of an injector cap in accordance with the invention and attaching it to an ampoule support will now be illustrated first, with reference to FIG. 1.
[0019] In the figures, the ampoule support is indicated by the reference numeral 5 . A cannula support 3 is placed at its front facing end, said cannula support in turn keeping the cannula 6 protruding towards the front both at its facing side and centrally. The cannula support 3 comprises a locking protrusion 9 , running in a circle, at the front end of its circular cylindrical section, said locking protrusion forming a heel at its end facing the ampoule support 5 , and tapering towards the other side.
[0020] The components described above are those which are fixed in their positions.
[0021] The cut-away sliding sleeve 1 is shown in FIGS. 1 and 2, mounted slidably and like a cap. As with the components described herein below, this sleeve 1 is one of the movable components of the injector cap.
[0022] In the initial state shown in FIGS. 1 and 2, the injector is ready to administer an injection. To this end, the sliding sleeve 1 is situated in a first position in which its facing side exhibits its greatest distance from the ampoule support 5 . In this state, the cannula 6 is completely hidden within the sliding sleeve 1 . The sliding sleeve 1 is held in the position in which it is shown in FIGS. 1 and 2 by a spring 4 between the facing end of the cannula support 3 and inner attachment (not shown) at the facing end of the sliding sleeve 1 . A circular opening 7 is provided on the front facing wall of the sliding sleeve 1 , to provide the cannula 6 with a way of emerging.
[0023] A locking ring, indicated at 11 , is mounted slidably in a guide on the inside of the sliding sleeve 1 . In the initial state shown in FIGS. 1 and 2, the locking ring 11 comprises inner locking clips 8 , arranged circumferentially and forwards and converging inwards, as well as two spacer clips 2 likewise extending forwards and further outwards. The locking ring 11 abuts the stopper 12 of the sliding sleeve 1 via its spacer clips 2 , i.e., via its front facing edge. The stopper 12 forms the front end of the guide for the locking ring 11 , said guide being worked out of the inside of the sliding sleeve 1 over a particular length.
[0024] In this area, the sliding sleeve 1 also comprises two opposing stays 10 , exposed from the surrounding material, which at their free end form a heel protruding obliquely inwards. The stays 10 can be elastically deformed in the radial direction.
[0025] Proceeding from the state shown in FIGS. 1 and 2, it can be shown by way of the representations in FIGS. 3 and 4 how the injector cap in accordance with the present invention functions.
[0026] If a dose of medicine is to be administered by means of the injector, then said injector is placed on the skin of a patient at the front facing side of the sliding sleeve 1 .
[0027] The ampoule support 5 is then slid forwards, such that the sliding sleeve 1 slides backwards relative to the ampoule support 5 and against the force of the spring 4 , until the cannula support 3 abuts the inner attachment at its front facing end, said attachment surrounding the opening 7 and being enclosed by the spring 4 . This state is shown in FIG. 3.
[0028] Activating the device as described above does not affect the position of the locking ring 11 comprising the clips 8 and clips 2 relative to the sliding sleeve 1 , i.e., the spacer clips 2 are still pressing against the stopper 12 . What does change, however, is the position of the locking ring 11 relative to the cannula support 3 ; the cannula support 3 is slid, together with the ampoule support 5 , forwards into the locking ring 11 , through the locking clips 8 . As they pass through the locking protrusion 9 , this first pushes the locking clips 8 outwards, somewhat elastically, and they then latch in behind the locking protrusion 9 , fixing the locking ring 11 with respect to the cannula support 3 .
[0029] In this state, the cannula 6 has traveled far out of the opening 7 , and the injection can be administered.
[0030] After the injection has been administered, the spring 4 causes the sliding sleeve 1 to be slid back away from the cannula support 3 , as depicted in FIG. 4.
[0031] Since, as shown in FIG. 3 and already mentioned above, the locking ring 11 is then fixed behind the locking protrusion 9 on the cannula support 3 by the locking clips 8 , it also remains fixed when the sliding sleeve 1 is brought forward again, i.e., the sliding sleeve 1 moves forward again without slaving the locking ring 11 . As the sliding sleeve 1 thus moves forward, the stays 10 then slide along the outer circumference of the spacer clips 2 and are briefly, elastically pressed outwards as the rear heel passes over the spacer clips 2 , before they latch back inwards beyond the front end of the spacer clips 2 with their rear facing end. After this latching back, the stays 10 are in the position shown in FIG. 4, i.e., they abut the front area of the spacer clips 2 with their facing side. This locks or prevents the sliding sleeve 1 from sliding back again relative to the cannula support 3 or the ampoule support 5 .
[0032] In the state depicted in FIG. 4, once the medicine dose has been administered once, the sliding sleeve 1 is therefore blocked against sliding further and again completely covers the cannula 6 against the environment. In this way, using the injector again is positively prevented. The possibility of injury or infection from the needle is likewise prevented.
[0033] The locking and/or blocking means of an injector cap in accordance with the invention are all substantially situated in the interior of the cap or have their functional parts facing the interior, such that repeated use—which in accordance with health care standards and regulations is not supposed to happen—can only be achieved by extensively manipulating it, which would probably lead to the injector or injector cap being destroyed.
[0034] In the foregoing description embodiments of the invention have been presented for the purpose of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Obvious modifications or variations are possible in light of the above teachings. The embodiment was chosen and described to provide the best illustration of the principals of the invention and its practical application, and to enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth they are fairly, legally, and equitably entitled.
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RELATED APPLICATIONS
This claims the benefit of U.S. Provisional Application Ser. No. 60/571,148 filed May 14, 2004 entitled “Scope Dock.”
BACKGROUND
1. Technical Field
This disclosure relates to a medical device for docking an endoscope.
2. Background Information
Modern, non-invasive surgical procedures often require the use of an endoscope. Endoscopes are thin, tube-like devices used to visualize human anatomies such as the gastrointestinal tract. During endoscopic procedures, a physician manually grips a proximal end of the endoscope. Additionally, in the course of most endoscopic procedures, physicians manipulate and maneuver the endoscope in a variety of ways to rotate, adjust, or torque the endoscope.
At some stage in an endoscopic procedure, a physician may need to release the endoscope, for example, to perform an ancillary procedure or write notes. To do this, the physician carefully hands the endoscope to a nurse or places the scope in a stationary docking station. Docking stations are stands for receiving and holding an endoscope. Docking stations are typically affixed to a stationary point, such as a ceiling, wall, or floor. Other docking stations can be part of or affixed to a chair, a bed, or a table.
Both handing the endoscope to a nurse and docking the endoscope in a traditional docking station present significant drawbacks. First, whether the physician hands the endoscope to a nurse or docks it in a traditional docking station, the physician is disconnected from the patient during the procedure—even though the endoscope is still engaged in the patient's body. That is, the physician loses direct control of the endoscope. Second, presently available docking stations have very limited functionality. As a result, conventional docking stations are only suited for stationary hanging or gripping an endoscope that is not in use.
BRIEF SUMMARY
Accordingly, it is an object of the present invention to provide a medical device having features that resolve or improve upon one or more of the above-described drawbacks.
The invention is defined by the following claims, and nothing in this section should be taken as a limitation on those claims.
One aspect of the present invention provides a scope dock including a harness and a main body. The harness allows the scope dock to be attached to an operator, and the main body may include a scope holder which receives a scope. The harness may be a shoulder harness, midsection harness, or any other type of harness. The scope holder may hold the scope directly or through the use of other devices situated on the scope or the scope holder.
This invention also provides a method for using a scope dock. The method comprises a step of attaching a scope dock to an operator and a step of docking a scope in the scope dock. A catheter may be inserted into the scope as another step or another medical procedure may be performed.
Other embodiments are disclosed, and each can be used alone or in combination with another.
BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 illustrates a perspective view of a scope dock having a hub.
FIG. 2 illustrates a perspective view of a scope in a retracted position.
FIG. 3 illustrates a side view of an endoscope situated in a scope dock.
FIG. 4 illustrates a flow-chart of exemplary steps for using a scope dock.
FIG. 5 illustrates a perspective view of a scope dock having an integral device hub.
FIG. 6 illustrates a front view of a user wearing a scope dock configured with a chest support and a waist support.
FIG. 7 illustrates a front view of a user wearing a scope dock configured with a chest support.
FIG. 8 illustrates a front view of a user wearing a scope dock configured with a neck support.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described with reference to the drawings in which like elements are referred to by like numerals. The relationship and functioning of the various elements of this invention are better understood by the following detailed description. However, the embodiments of this invention as described below are by way of example only, and the invention is not limited to the embodiments illustrated in the drawings. It should also be understood that the drawings are not to scale and in certain instances details have been omitted, which are not necessary for an understanding of the present invention, such as conventional details of fabrication and assembly.
Turning now to FIG. 1 , that figure discloses a scope dock 100 and a hub 102 . The scope dock 100 includes a harness 103 comprising a belt 104 , a waist adjustment 108 to adjust the length of the belt, and a belt buckle 110 to allow the belt to be buckled and unbuckled in order to put on and take off the scope dock 100 . The belt 104 is connected to a main body 106 . The main body broadens into a central portion 112 which includes a scope holder 114 and a scope pivot 116 . The scope pivot 116 is allowed to pivot by the scope holder 114 . The scope holder 114 may optionally maintain the scope pivot 116 at various pivot positions from the vertical, such as at 0°, 15°, and 30° from the vertical. The central portion also includes a release button 118 which releases the scope holder from an inactive position, where it is flush with the central portion, to an active position, where it is approximately perpendicular to the central portion. When the scope holder is in the active position, it may be locked into place, such that the scope holder may not be unlocked or moved until the release button is again pressed.
A scope bearing sleeve 120 slides onto a scope 122 , such as an endoscope. The scope bearing sleeve is optionally in a friction fit relationship with the scope, which may hold the two together in such a way that they do not move. At the same time, the scope bearing sleeve and the scope pivot are arranged such that the scope bearing sleeve is able to rotate coaxially within the scope pivot. The exemplary scope pivot shown here includes a chamfered out portion that allows the scope bearing sleeve to sit in the scope pivot. Additionally, at least one optional device hub 124 may be clipped onto the scope bearing sleeve, and the device hub may have a device clip 126 on its end. The device clip 126 may clip onto a variety of medical devices, such as catheters or other devices used with the scope.
Furthermore, the main body in this exemplary embodiment may comprise a semi-rigid over-molding, which is rubberized. Such a material may allow the main body to comfortably flow around the mid-section of the doctor while he is wearing the scope dock. Though a semi-rigid material is shown here, any variety of flexible or rigid or semi-rigid materials may be used to manufacture the main body of the scope dock.
Additionally, the belt 104 may be made of nylon braid or any suitable material, such as rubber, leather, plastic, natural or synthetic threads, or any other material that may be used to make a belt. The waist adjustment may be a single clip—or any other suitable clip or device—that allows the belt to be lengthened or shortened depending on the size of the mid-section of a doctor and the desired level of tightness about the doctor. Though the exemplary waist adjustment shown in FIG. 1 is separate of the belt buckle, it may also be integral with the belt buckle. The belt buckle shown in FIG. 1 is a parachute type belt buckle having two finger grips that may be pressed together to unbuckle the belt. Even though a parachute type belt buckle is shown here, any type of clip arrangement, belt buckle, hook and loop fastener, or other suitable device may be used to secure the belt. Moreover, though the exemplary scope dock of FIG. 1 uses a belt as a harness to secure the scope dock, a wide variety of harnesses may be used to secure the scope dock to the doctor, such as shoulder harnesses, neck harnesses, leg harnesses, or other types of harnesses.
Next, the scope bearing sleeve may be made of a hardened plastic, but the sleeve may be made of metal, rubber, a harder or softer plastic, or any other suitable material. Alternatively, the scope bearing sleeve may be disposable after one use or reusable for any number of uses. The scope bearing sleeve may also be integral with the scope or included with the scope at the time of scope purchase. Similarly, the device hub is made of a hardened plastic or any suitable material. The device hub may be disposable after one use or reusable for a number of procedures or a period of time. The device hub, as well, may be rotatable about the scope bearing sleeve, and the hub and sleeve may share a frictional or other type of fit. If a frictional fit is used, the fit may be such that the device hub and the scope bearing sleeve are stably maintained by the fit in a particular position relative to one another. At the same time, the frictional fit may optionally allow the hub and sleeve to be moved relative to one another by the application of a certain amount of force, such as a light or medium pressing of the hub by the doctor or nurse. Further, the clip of the device hub may itself be coaxially rotated, depending upon the needs of the doctor. This coaxial rotation is an optional feature of the device hub. The exemplary scope bearing sleeve of FIG. 1 is—but is not necessarily—cut to fit around the access port of the scope, and this may increases the stability of the fit such that the scope bearing sleeve not rotate in relation to the scope while in use. Optionally, the scope bearing sleeves may be different based upon the brand and type of scope used in order to fit the respective scope.
Turning now to FIG. 2 , that figure discloses a scope dock 200 similar to the one shown in FIG. 1 . The scope dock 200 has a scope holder 202 in an inactive retracted position. When a scope (not shown) is not needed at a particular time during a procedure or before a procedure, the doctor may remove the scope from the scope holder, and he may retract the scope holder. The scope holder maintains a scope pivot, in a similar way as the scope holder 114 maintains scope pivot 116 of FIG. 1 .
Because of its low profile, the exemplary scope dock 200 need not be removed when not in active use. In fact, the scope dock 200 itself may assist a doctor in bearing the weight of a lead apron (not shown), which the doctor may wear during a medical procedure. As noted earlier, in order to activate the scope holder 202 , a doctor or his assistant may press the release button 204 to allow the scope holder 202 to rotate to a locked position approximately perpendicular to a main body of the scope dock 200 .
Turning now to FIG. 3 , that figure discloses a side view of scope dock 300 , which is similar to the scope docks 100 , 200 shown in FIGS. 1 and 2 . The scope dock 300 includes a harness 301 , comprising a belt 302 , a buckle 303 , and a waist adjustment 304 , connected to a main body 306 . Extending from the main body 306 is a scope holder 308 which maintains a scope pivot 310 . The scope pivot 310 is shown at a 15° rotation from the vertical, and a scope and scope bearing sleeve are seated in the scope pivot. The scope bearing sleeve also has a device hub attached to it. In the exemplary embodiment of FIG. 3 , the scope pivot may be adjusted to a 0°, 15°, or 30° rotation from the vertical. Similar to the example in FIG. 1 , the scope bearing sleeve may rotate within the scope pivot, and the device hub may rotate about the scope bearing sleeve.
Turning now to FIG. 4 , that figure discloses an exemplary method 400 of performing a medical procedure using a scope dock similar to the ones disclosed in FIGS. 1-3 . Though the method 400 steps are shown in an order for the sake of the present example, some of them are optional, and many of them may be performed in a different order than that presented in this example. In a procedure that may involve the use of radioactive substances, a doctor may wear a lead apron or other protective clothing over standard hospital clothing. Often, this clothing extends across the region of the body upon which the scope dock will be situated, and so, the protective clothing may be in place prior to performing method 400 .
In step 402 , the scope dock is situated on the doctor. The scope dock can be fastened around the doctor's midsection ( FIGS. 1-3 ), placing a shoulder harness over his head and onto his shoulders, placing a neck harness around his neck, or situating the scope dock in any other way on the doctor. Then, in step 404 , the scope dock is secured to the doctor by buckling a belt buckle, fastening a Velcro hook and loop fastener, or securing the scope dock in any other way. In some instances, the steps 402 , 404 of situating and securing may be performed as one action or the step 402 of situating may also provide the securing onto the doctor—such as in the case of a shoulder harness that may have adjustment devices but no additional securing devices.
Step 406 comprises situating a scope bearing sleeve onto the scope. This particular step 406 is optional, depending on the scope dock in use, and may be performed at a variety of times—before the doctor even arrives in the procedure room, before the procedure has begun, just prior to use of the scope, or any appropriate time. Situating a device hub onto the scope bearing sleeve is step 408 . This step 408 is also optional, and in an alternate embodiment, the device hub may be situated onto the main body of the scope dock or onto the scope itself. This step 408 may also be performed at a any appropriate time before or during a procedure, and any number of device hubs may be situated, depending on the needs of the doctor.
The exemplary method 400 shows an optional feature of the scope dock system in step 410 . In this exemplary step 410 , a doctor performs a first procedure with the scope, after the step 402 of situating the scope dock on the doctor and before the step 414 of situating the scope in the scope dock. Though shown in this sequence for the sake of example, these steps may be performed in any order and in a variety of ways. This first procedure may be any kind of procedure, such as inserting the scope into the patient's mouth or performing a test on the scope itself.
Then, the doctor or nurse releases a scope holder on the scope dock to an active position in step 412 . This step 412 of releasing may involve the pressing of a release button—as shown on the exemplary scope docks of FIGS. 1 and 2 —manipulating the scope holder to an active position manually, or some other releasing. The releasing of step 412 is optional, as some scope docks may not have a releasing functionality, or the releasing may be performed at a different time before or during a procedure. Next, in step 414 , the doctor or nurse may situate the scope and scope bearing sleeve into the scope pivot of the scope holder by moving the scope laterally through the open portion of the scope holder and then lowering the scope and scope bearing sleeve into the scope pivot of the scope holder. The optional scope pivot featured in FIGS. 1-3 may allow coaxial rotation of the scope while situated in the scope dock, and the scope pivot may allow for the scope to be situated at different angles in relation to the scope dock or the vertical plane. As noted above in FIGS. 1-3 , the various features of the scope pivot are optional, as is the scope pivot itself. In some exemplary scope docks, the scope holder itself may hold the scope without using a scope pivot, and in some exemplary scope docks, the scope may be situated on the scope dock without using a specific scope holder portion.
In exemplary step 416 , the doctor performs a second procedure with the scope situated on the scope dock. This second procedure may be any kind of procedure, such as a inserting a catheter or wire guide into an access port of the scope, viewing the inside of the patient on a monitor, performing a cannulation using a catheter, shooting fluoroscopy inside a patient, writing a note on the condition of the patient, or any other procedure.
In step 418 , the doctor or nurse removes the scope from the scope dock. In the exemplary scope dock of FIGS. 1-3 , this may involve removing the scope bearing sleeve from the scope pivot. As noted earlier, this step 418 may be performed at a variety of times and in a variety of ways during a scope procedure. After the scope is removed from the scope dock, the scope holder may be released to the inactive position in step 420 . In the exemplary FIGS. 1-3 , this may involve pressing the release button to release the scope holder and then manually pressing the scope holder down until it is in an inactive position. Even so, the scope holder may be implemented in a variety of ways, such as being fixed in position; automatically moving from active to inactive position at the press of a button; released by using a lever, switch, or other mechanism; or in some other way.
Finally, in step 422 , the scope dock is removed from the doctor. This may involve unbuckling a belt buckle, removing a harness, or other way of releasing the scope dock. The scope dock of exemplary FIGS. 1-3 may be unbuckled by either the doctor or nurse and set aside for sanitization and the next procedure. Additionally, in step 424 , the scope bearing sleeve may be removed from the scope. After removal, the scope bearing sleeve may be thrown away, if it is a disposable sleeve, or set aside for sanitization and the next procedure, if it is a reusable sleeve. As noted above, some scope docks do not work in conjunction with a scope bearing sleeve, and therefore, in these instances, step 424 and other steps involving the sleeve would be unnecessary.
In use, a doctor may buckle the scope dock around himself prior to a procedure. Then, the scope bearing sleeve may be slid onto the scope and brought into a friction fit with it. At the appropriate point in the procedure, the scope bearing sleeve and the scope may be seated in the scope bearing hub of the scope dock. In this way, the doctor is able to have an extra free hand to write notes, to grab on to a catheter, or to perform another desired portion of the medical procedure. During a procedure, the doctor may insert a catheter into the endoscope, and after this, he may wish to dock the handle of the catheter into the device clip of the device hub. In this way, he does not need to support the other end of the catheter or worry about where the other end of the catheter is, as it would be immediately in front of him at a convenient position for hand activation. Additionally, the doctor may rotate the device hub and the device clip in order to position a handle or other end of a catheter in whatever position he desires. While in the device hub, the catheter handle may be manipulated without having to maintain the entire end of the catheter independently.
Turning now to FIG. 5 , that figure discloses an exemplary embodiment of a scope dock 500 . The scope dock 500 includes a harness 501 comprising a belt 502 , a belt buckle 504 , and waist adjustment 506 . The belt 502 is attached to a main body 508 which has a scope receiving hub 510 . A scope bearing sleeve 512 is seated in the scope receiving hub 510 , and a device hub 514 is integral with the scope bearing sleeve 512 . The scope bearing sleeve 512 is friction fit around a scope 516 , preferably prior to commencing a medical procedure involving the scope 516 . In this embodiment, the device hub 514 is rotatable within the scope bearing sleeve 512 , and the device hub 514 has an independently rotatable device clip 518 at its end. The device clip 518 is able to receive a variety of devices and is shown here attached to the wrapping portion of a catheter 520 . The catheter 520 has a handle and multiple ports. The handle may be actuated and the ports accessed while the catheter 520 is situated in the device clip 518 .
Turning now to FIG. 6 , that figure discloses an exemplary embodiment of a scope dock 600 . The scope dock 600 includes a harness 602 having midsection straps 604 , 606 , shoulder straps 608 , 610 , a shoulder support 612 , and a back plate 614 . The midsection straps 604 , 606 connect to a main body 616 by clips (not shown), which may be released by pressing clip release buttons 618 , 620 , respectively. The operator or his assistant may adjust the straps at the shoulder support 612 , belt buckles 616 , 618 , or back plate 614 . A scope bearing hub 622 receives the scope 624 . The scope 624 and the scope bearing hub 622 may share a friction fit, as well. The scope bearing hub 622 shown here is a removable ball seated in a socket joint. The scope bearing hub 622 has opposing finger rests 624 , 626 that may be squeezed together to release the scope bearing hub 622 from the socket joint and, thereby, from the main body 616 . This allows simple removal of the scope bearing hub 622 from main body 616 .
FIG. 7 illustrates an exemplary embodiment of scope dock 700 , which is configured as a chest support. Scope dock 700 includes a harness having chest straps 708 and 710 that are integral to a main body 716 . The main body is provided with a docking mechanism as described above regarding the previous embodiments. That is, the main body is outfitted with a scope receiving hub as detailed in any of the above-described embodiments. The scope receiving hub allows a physician to dock or release the endoscope as needed. As illustrated in FIG. 7 , the scope dock 700 includes a widened portion 721 . Widened portion 721 is adapted to distribute the weight of the endoscope about the chest of a physician. Widened portion 721 further provides a stable platform for the physician. Of course, scope dock 700 can alternatively be provided with without a widened portion 721 .
FIG. 8 illustrates an exemplary embodiment of scope dock 800 , which is configured as a neck support. Scope dock 800 is similar to the scope dock shown in FIG. 7 . Scope dock 800 , however, is adapted to be worn about a physician's neck, rather than the shoulders. For comfort, scope dock 800 can be provided with neck pads 810 and 808 . Neck pads 810 and 808 can be formed from a wide variety of widely available cushion materials, such as high density foam. Scope dock 800 further includes a Y-shaped main body 816 having a scope receiving hub as detailed in any of the previously described embodiments. Main body 816 can be formed of a lightweight, durable material, for example, plastic or carbon fiber.
It is to be understood that changes and modifications to the embodiments described above will be apparent to those skilled in the art, and are contemplated. Such changes include varying the configuration of the disclosed harnesses. Alternative harnesses could include strapless harness variations. For example, it will become apparent to one of ordinary skill that a protective garment, a jacket, or a vest could be used as a harness for a scope dock. Indeed, a scope dock could be provided integrally with a protective lead vest. It is therefore intended that the foregoing detailed description be regarded as illustrative rather than limiting, and that it be understood that it is the following claims, including all equivalents, that are intended to define the spirit and scope of this invention.
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FIELD OF THE INVENTION
The present invention relates to a method and apparatus for averting trespass of geese and other waterfowl on property, particularly property adjacent to bodies of water.
BACKGROUND OF THE INVENTION
Lawns, walkways, picnic areas, and other properties adjacent to ponds, lakes and rivers are often frequented by waterfowl, with the drawback that these birds typically leave excrement throughout their wanderings over these properties. In recent decades, large numbers of Canadian geese have acclimated to human activity, and have exploded in number within urban centers, as well as suburban and rural lakes. Business properties and housing projects often include ponds and other waterways within open green spaces. These ponds naturally draw waterfowl, especially the aforementioned Canadian geese. Neighboring lawns provide particularly attractive feeding areas for these geese. A common sight at many such locations is a string of geese walking onto a lawn from the water's edge, to feed on the grass. These flocks of geese will even cross busy roadways to reach such attractive feeding areas. Golf courses are also plagued with geese populations for the same reasons.
Because of the ubiquitous droppings of waterfowl on these lawns, particularly those of geese, affected property owners cannot fully enjoy their properties. Lakeside homeowners, golfers, noontime walkers in business campuses, people on a picnic at a park with a pond—all must watch their steps.
Some methods have been put forth in an effort to control the problem of goose trespass and goose droppings. Stuffed effigies of swans, hawks and eagles have been mounted on poles, buildings and tree limbs to scare away waterfowl. These have some effect on smaller fowl such as ducks, but little or no effect on larger fowl such as geese. Some golf courses and industrial campuses have employed trained border collies, which discourage Canadian geese habitation due to their movements, which resemble the movements of predatory foxes in the wild. Homeowners on lakefront properties cannot reasonably go to such an extreme to deter trespass of Canadian geese. Crisscrossing lines of colored or reflective fibers have been strung over small ponds. These crisscrossing lines have been relatively effective on deterring flocks of waterfowl from landing on the ponds. These lines are unsightly, however, and are practical for use only on small bodies of water. They are totally unacceptable on ponds and lakes large enough to invite recreation with boats, canoes, and other personal water craft. Similarly, arrays of reflective streamers or lines loaded with reflective tinsel have been erected on water frontage properties to visually repel waterfowl. A large number of such streamers, erected by property owners in a localized area around a lake or pond, becomes in itself a visual blight. A further problem of such streamers is that they interfere commonly with ordinary activities on the affected properties, including recreation, lawn mowing, and so forth. A recent device has even been developed for private lakefront lawns, wherein an intruder is detected by an electric eye and bombarded with a jet of water. Such a device, unfortunately, cannot adequately distinguish between a goose, a child, or a pet dog.
A continuing need exists for a method and means to deter unwanted,trespass by waterfowl, especially geese, on selected areas that would normally be inhabited by such waterfowl, wherein the means of deterrence is not visually a blight in itself.
It is an object of this invention therefore to provide an improved method and means of deterring waterfowl trespass on selected property.
It is a further object of this invention to deter waterfowl trespass on selected properties in a manner that does not create in itself a visual blight.
It is a further object of the invention to provide a method and means of waterfowl deterrence that is inexpensive, easily installed, and easily taken down, providing little interference to ordinary activities on the properties to be protected thereby.
These and other objects of the invention are fulfilled by means of the invention disclosed hereinbelow.
SUMMARY OF THE INVENTION
A method and means to deter trespass of waterfowl, particularly geese, onto a real estate property, particularly a property bordering onto a body of water, has been discovered and is herein disclosed. The barrier disclosed herein is surprisingly simple in its structure, yet surprisingly effective also in meeting the objects mentioned above. The barrier or fence, in its simplest embodiment, includes a first and a second line, both lines being suspended above and generally parallel to a surface of a property and defining a boundary on this surface, the first line being suspended at about 3 to 10 inches above the surface, the second line being suspended at about 8 to 30 inches above the surface and juxtaposed above the first line, a separation of at least about 5 inches being interposed between the first and second lines. The lines are conveniently suspended by means of posts, and the lines are conveniently made of plastic monofilament, such as fishing line. Though occupying only a fraction of a percent of air space along a desired boundary, these lines provide thereby an effective barrier to a goose walking.
A preferred embodiment of the goose fence is a retractable fence having a pair of lines, both lines being suspended above and generally parallel to a surface of a property and defining a boundary on this surface, a first line being suspended at about 3 to 10 inches above the surface, a second line being suspended at about 8 to 30 inches above the surface and juxtaposed above the first line, a separation of at least about 5 inches being interposed between the first and second lines, the first and second lines being fed from at least one rotatable spool mounted on a starting post, the lines traversing to an ending post, a means being provided for rewinding the lines onto a rotatable spool on the starting post, and a means for holding such lines in a taut arrangement providing thereby an effective barrier to a goose walking. The first and second lines are preferably connected end-to-end to form a single overall line, the latter being fed from a single spool. A plurality of intermediate posts are advantageously provided for suspending the lines along a boundary between the starting post and the ending post. The lines are suspended on the intermediate posts by means of loops, slots, wire pigtails, or orifices located in or on said intermediate posts. The posts are set in receptacles located in the surface of the property, the posts being reversibly removable from said receptacles, particularly when the line is retracted and rewound onto the spool. Such a retractable fence, when erected, provides thereby an effective barrier to a goose walking, is easily removable when the owner or user of the property desires unfettered access to the full property, and is easily re-erected, admirably meeting the various objects of the invention. Use of this invention effectively provides a method of deterring goose trespass upon the property.
DESCRIPTION OF FIGURES
FIG. 1 is a schematic diagram of a simplified goose barrier.
FIG. 2 is a schematic diagram of a retractable goose barrier including a line dispenser.
FIG. 3 is a schematic diagram illustrating a means for erecting a post of a retractable barrier.
DESCRIPTION OF THE INVENTION
In its simplest form, the invention may be seen in FIG. 1 as a waterfowl barrier fence, wherein two lines 10 , 11 are suspended in air above the ground surface of a real estate property, these two lines defining a boundary on the surface that fences off a portion of the real estate property from trespass by geese on foot. These two lines are preferentially arranged so that they are not only generally parallel with the surface, and are also generally parallel with each other, one line being suspended above the other line. Where the surface of the boundary undulates or follows a non-level slope, the lines may not be exactly parallel with the boundary surface. Nevertheless, optimally they will be suspended so as to follow generally the contour of the boundary surface, this being understood and included in the meaning of the term “generally parallel.” More than two lines may be employed within the scope of the invention, but it has been found that two lines are generally sufficient for attainment of the purposes of the invention. Additionally, the two lines may be connected end-to-end to form a single overall line; otherwise stated, a single line may be continuously strung so as to include two portions of the single line equivalent to two lines suspended in accord with the description provided immediately above.
The two lines 10 , 11 are suspended by means of a plurality of above-ground members or posts 12 , preferably two or more stakes generally arranged vertically, with means for attachment of the lines to the above-ground members. These members may be metal rods, wooden stakes, rock or concrete formations, plastic or fiberglass articles, stems or trunks of growing bushes and trees, or any other suitable above-ground member desirable to the owner or user of the property. Combinations of such above-ground members may be used. For purposes of simplifying claim language, these various above-ground members are herein collectively defined as “posts.” The posts 12 are preferably rigid and resistant to outdoor weathering. Metallic stakes are particularly preferably for use as the posts for suspending the lines.
The path of the two lines may follow a straight line, or alternatively may follow a curved, zig-zag, or box-shaped paths. Such pathways are generally to be defined by the property owner or user with due regard to fencing off a desired plot of ground from trespass by geese. For example, a property abutting a body of water frequented by waterfowl is often preferentially protected by means of a fence as herein described, following a boundary facing the body of water, and with turns from this main boundary into flanks at either or both ends, the flank segments of the fence being sufficiently long to inhibit trespass of waterfowl simply by walking around the end of an otherwise straight fence.
The lines 10 , 11 may consist of cotton string, glass fiber, metal wire, plastic filament, or other suitable materials similar in shape and function. Plastic filament is generally preferable. Suitable plastics include, for instance, polyethylene, polypropylene, polyester, nylon or polyvinylidene fluoride. Particularly advantageous are monofilament plastic lines commonly available as fishing lines. Such lines are conveniently obtained, already wound on spools, from suppliers of fishing tackle.
The two lines are preferably suspended in a height range of about 3 inches to about 30 inches above the property surface, more preferably about 5 inches to 20 inches. The first line is preferably suspended at a height of about 3 to 10 inches above the surface of the property along the boundary, more preferably 6 to 8 inches high, and the second line at a height of about 8 to 30 inches above the surface along the same boundary, more preferably 12 to 20 inches high, with a minimum of about 5 inches separation between the first and second lines, more preferably a separation of about 8 to 12 inches between them.
As a general guide, the optimum height of the first line is believed to be at or moderately above the knee joint of a targeted waterfowl. The optimum height of the second line is believed to be below the normal eye level of the waterfowl but at or moderately above the height of the back of the waterfowl. Thus, the waterfowl must simultaneously stoop to step underneath the upper line, while raising itself to step over the first line. In that the size of waterfowl may vary considerably from bird to bird, the heights of the two lines may be varied for best effect. For geese, especially the commonly encountered species known as Canadian geese, it has been found that the first line is optimally suspended at a height of about 7 inches, and the second line is optimally suspended at a height of about 17 inches. A third, and even a fourth, line may be added to the fence in the case of particularly pesky waterfowl, but these added lines are not believed to be necessary in all but the most unusual circumstances.
While the invention is described in terms of first and second lines, the terms “first” and “second” do not have a chronological meaning attached. Either of these lines in a fence row may be set up prior to the other. And, where the first and second lines are sections of one continuous line strung along a first and second path, either path may be set up prior to the other path chronologically.
A preferred embodiment of the invention is shown in FIG. 2 wherein a line dispenser 20 is positioned on a starting post 21 , and a line 22 a is fed from the line dispenser 20 to an ending post 24 , following a path generally parallel to the surface of the ground between the starting post and the ending post, the line being suspended therein at a desired or selected height range. Optimally, the line is further continued from the ending post back to the starting post, but at a height range different than the initial path height, therein providing the second line 22 b of the fence. The path of the line or lines may be generally varied and controlled by additional posts 23 interposed along the path. Such posts 23 may be interposed so as to cause the line to follow a path generally conforming to the contour of the ground surface underneath the line pathway, or to follow a desired boundary which need not be straight but may delineate a curve, a bend, a corner turn, or even a zig-zag. The defined pathway may include, for example, a connection to a dock extending from a waterfront property out into a body of water.
The line dispenser 20 depicted in FIG. 2 advantageously includes a spool of a line, such as a monofilament fishing line, the spool being rotatable within a housing attachable to the starting post. The dispenser preferably includes a means for rotating the spool so as to rewind the line when desired. The dispenser preferably also includes a means for fixing the position of the spool so that the line cannot play out beyond what is desired. This latter feature advantageously allows a user of the goose barrier to fix and hold the line is a reasonably taut condition as it is suspended in its pathway between the starting post and the ending post. These three features may all be found in a fishing reel. It is desirable in the context of this invention, however, to locate the spool of line inside of a cover, such that the spool of line is protected from environmental attack by sunlight, precipitation, falling leaves, assault by rodents and other animals, and so forth. Thus, while attachment of a fishing reel to a post suffices as an element of the invention being described herein, the preferred embodiment of the invention will preferably incorporate a protective enclosure for a spool of a line as a feature of the dispenser. The protective enclosure will preferably include a cavity for accepting a spool of line, a crank means for engaging the spool so as to turn it or alternately to prevent it from turning further, an opening or conduit for communication of the line from the spool to space outside the protective enclosure, and a means for attachment of the protective enclosure to the starting post. It will be evident to one of ordinary skill in the art of dispensers that several ways may be found for accomplishing these attributes.
The line 22 a being fed from the dispenser 20 may be passed along a series of posts 23 on its way to the ending post 24 , and may be returned from the ending post 24 through a series of posts 23 to a termination at the starting post 21 . Attachment to each of these posts may be by any number of means. However, it is preferable to provide a means of attachment 25 whereby the line may be easily attached and also easily withdrawn. Such means of attachment 25 may include, for example, a slot, a loop, a hook, or an orifice in the post. Particularly advantageous is a line guide patterned after a wire hose clamp, wherein the ends of the hose clamp are formed into loops for accepting and guiding the line, the clamp being made of spring steel so that it can be easily moved up or down a post to a desired height. The line preferably will have a loop 26 or similar means of engagement at its end, whereby the line may be facilely attached to a protuberance 27 (such as the head of a screw) on a post at the termination of the line pathway. The loop 26 or other means of engagement on the end of the line will preferably be of small size, such that upon rewinding of the line onto the spool, the end of the line will easily pass through the attachment points 25 on each of the posts without snagging or jamming. In a variation of the invention where the line terminates on a post from which the line is also dispensed, the end of the line may advantageously be durably affixed to this post, and yet be part of a retractable fence. This is further elaborated below.
It is a desired feature of the invention that the goose barrier be easily set up and easily taken down. The user of the property will likely desired unfettered access to the ground surface under the goose barrier for purposes of mowing the grass or otherwise grooming the surface. Also, when full recreational use of the property is intended, the fence may constitute a nuisance at such a time. Facile removal and set up of the fence may be accomplished when the line is easily retractable and the posts are easily removed. Means to make the line easily retractable have been presented immediately above. The posts themselves are conveniently removed from the boundary if they are removably set into receptacles inserted into the ground. FIG. 3 illustrates a simple means of erecting a post 30 , wherein a receptacle 31 is installed into the ground, and an opening in the receptacle receives a post 30 upon which the line or lines 32 , 33 are to be attached. When the posts are easily removable and the line extends from a dispenser on the starting post to termination on the self same post, its end being durably affixed to the starting post or otherwise modified so as not to be able to slip back through the wire guides (such as attachment of a washer to the end of the line), the starting post may be picked up and the line retracted onto the reel while the post is walked or otherwise moved along the boundary of the protected property. Wherever an intervening post is encountered, it may be easily picked up as well and carried alongside the starting post, while the line continues to be retracted. Thus, an entire row of posts may be easily removed, with the line remaining in a pathway threaded through the full set of the posts, wherein the line may be wound snugly through the set of posts, actually helping to hold the set of posts adjacent one another, e.g., in a bundle, together for easy handling and storage.
Thus, by means of the designs and features illustrated in the above description, a property user or owner may conveniently prohibit trespass by geese and other waterfowl on the property by erecting a goose barrier fence that is easily put up, and also easily retracted and taken down. In a location fronting on a body of water, this fence is especially useful in deterring trespass by geese and other waterfowl afoot, these fowl not willing to cross through even this simplest of fences and become separated from their body of water by the fence. The fence can be also very non-obtrusive to property owners and users, in that a line consisting of a transparent plastic monofilament may be chosen such that a goose most definitely perceives the line when approaching the fence, but the owner or property user does not perceive the line from a distance, and is not visually repulsed by such an unobtrusive fence. In a situation wherein the owner or property user wants increased visibility of the fence, flags may be affixed to either line, both lines, or to any point on the line wherein a single overall line is strung through a set of posts. The flags may consist of any of a number of materials such as cloth, plastic, or metal, including metallic foil and colored string as examples. Optionally, such flags may be loosely attached onto the line so as to allow sliding contact of the line during retraction of the fence. Alternatively, the flags may be easily disengaged from the line. Any number of means for hanging or affixing flags to a line will be evident an owner or user of the fence.
The above description has provided details for a goose barrier, both in its most simplified form and in its most preferred embodiment as presently contemplated. The scope and breadth of the invention are not limited by the features specifically delineated in the above description, however, but are to be judged by the claims that follow.
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TECHNICAL
[0001] The present invention relates to a composition containing an inducer of SIRT1 (silent mating type information regulation 2 homolog) expression for preventing or treating a sepsis or septic shock.
BACKGROUND ART
[0002] Bacterial infections and other strong stimuli may initiate an immune reaction which may cause a systemic inflammation or a systemic inflammatory response system (SIRS). A serious SIRS causes serious fever, hypotoxemia, trachypnea, tachycardia, endothelium inflammation, myocardial dysfunction, mental disorder, blood vessel collapse, and eventually a multiple organ failure syndrome (MODS) which accompanies an organ injury, e.g., an acute respiratory distress syndrome, coagulation disorder, heart failure, renal failure, shock and/or coma.
[0003] A sepsis is defined as a situation in which an infection has been confirmed or is doubted along with systemic inflammatory response. A sever sepsis is defined as a case an which a sepsis is accompanied by an organ dysfunction (low blood pressure, hypoxia, oliguria, metabolic acidosis, thrombocytopenia, consciousness disorder). A septic shock is defined as a case in which blood pressure is not normalized even if infusion therapy is used or medicine for enhancing blood pressure is used. The sepsis may progress to a severe sepsis and finally a clinical step of a septic shock. The clinical sepsis is defined in a broad sense as a state in which the invasion by the microorganism agent is related with the clinical symbols of the infection. The clinical symbols of the sepsis are (1) Body temperature >38° C. or <36° C.; (2) Heart rate >90 times per minute; (3) Respiratory rate >20 times per minute or PaCO 2 <32 mmHg; (4) The number of white corpuscles >12000/cu mm, <4,000/cu mm or >10% immature (band) form; (5) organ dysfunction or high blood pressure, but the present invention is not limited to these examples.
[0004] If an infection occurs, the macrophage of the infection region is activated so as to secrete TNF-α and IL-1, thereby the amount of discharge of the plasma protein into the organs increases, the movement of phagocytes and lymphocytes to the organs increases, and the attachment of the blood platelets on the walls of the blood vessels increases. In this way, the local blood vessels are closed, and the pathogenic organisms are concentrated on the infected region. Particularly, in the sepsis, the systemic infection occurs, and the serious blood vessel closure induced by TNF-α is accompanied. Further, the systemic discharge of TNF-α causes the loss of the volume of the blood plasma due to the blood vessel enlargement and the increase of the permeability of the blood vessel, thereby causing a shock. In the septic shock, TNF-α further stimulates blood coagulation, thereby causing generation of blood clots and mass consumption of blood coagulation protein in small blood vessels. Since the blood coagulation ability of a patient is lost, important organs such as kidney, liver, heart, and lung are damaged by the dysfunction of the normal vessels. It has been reported that the mortalities of the severe sepsis and the septic shock reach 25 to 30% and 40 to 70%, respectively.
[0005] In many cases of the sepsis, the pathogenic organism. is E. coli , but gram negative bacteria such as Klebsiella - Enterobact - Serratia group and Pseudomonas may also cause such a state. Gram-positive microorganisms such as Staphlococcus , systemic viruses and Fungus may also cause the sepsis.
[0006] Urogenital vessel, gastrointestinal vessel and respiratory tract are most commonly infected regions which cause the sepsis. In addition, other sepsis-related infection regions are a or burn region, a pelvic infection region and a catheter infection region within a vein, etc.
[0007] The sepsis mostly frequently occurs in a hospitalized patient suffering from a basal disease or symptom sensitive to the invasion of the hematocele, or a burn, wound or surgical patient. Factors of making a person sensitive to the invasion of the hematocele are a weakened immune system, for example, an immune system of an infant or an elderly person, and a symbol, or disease which increases a local sensitivity to infection, for example, a weakened circulation, diabetes, uremia and AIDS. Finally, a subject having a tendency of a weakened immune response which may occur due to the existence of various allelic genes of IL-1 gene also has a greater possibility of an outbreak of the sepsis (U.S. Pat. No. 6,251,598).
[0008] It is understood that the sepsis is generated as a result of complicated reciprocal action between bacteria causing infection and the immune, inflammation and coagulation system of the host. Both the response level of the host and the features of the bacteria causing infection significantly affect the convalescence of the sepsis. Organ failure observed in the sepsis occurs when the response to the bacteria causing the infection of the host is inappropriate, and if the response is excessively increased, the organ of the host itself may be damaged. Based on this concept, antagonists to TNF-α, IL-1β, IL-6, which are proinflammatory cytokines that perform a leading role in the inflammation response to the host, has been used in an attempt to cure the sepsis, but most of the attempts have failed, and injection of activated protein C and treatment of glucocorticoid are now being used in an attempt to cure the sepsis, but many limits are being indicated. Hence, there is a need for a new treatment for preventing or treating the sepsis and the septic shock.
[0009] SIRT1 (silent mating type information regulation 2 homolog; sirtuin 1) is known as an enzyme for regulating the function of the protein by deacetylating the lysine residue of various proteins, which depends on NAD+ (Ageing Res, Vol. 1, pages 313-326, (2002)), and is most similar to Sir2 of the yeast having (NAD+)-dependent class III histone deacetyl activity. In particularly, SIRT1 cuts the acetyl group attached on the transcription factor such as Nuclear factor-kB and p53 (Cancer Res, Vol. 64, pages 7513-7525, (2004); Cell, Vol. 107, pages 149-159, (2001); Trends Endocrinol Metab, Vol. 17, pages 186-191, (2006)). Further, SIRT1 participates in reconfiguration of chromatin related with the inhibition of gene expression, DNA damage response, life extension related with restricted diet, etc. (Chen et al., Science 310, 1641, 2005). That is, SIRT1 reconfigures chromatin through histone deacetylation as in Sir2 of: the yeast, inhibits expression of gene, and induces deacetylation of various transcription factors related with cell growth, stress reaction and internal secretion regulation, etc. as well as histone protein. Further, according to a recent study, there has been a report of a technology which applies the SIRT1 to diabetes, obesity, nervous degenerative diseases or aging related diseases, etc. by increasing the deacetylation of the SIRT1.
[0010] Likewise, there is a report on pharmacological effects that the SIRT1 may be applicable to various diseases by increasing the deacetylation activity, but there is no study on pharmacological effects for preventing or treating the sepsis or septic shock. Hence, there is a need for a new treatment for preventing or treating the sepsis or septic shock.
DISCLOSURE
Technical Problem
[0011] The inventors of the present invention have been developing a new treatment of A sepsis or a septic shock, and have found that SIRT1 expression inducer may significantly reduce the mortality by the sepsis by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines.
[0012] Hence, an object of the present invention devised to solve the problem lies in providing a composition containing an inducer of SIRT1 (silent mating type information regulation 2 homolog) expression for preventing or treating sepsis or septic shock.
Technical Solution
[0013] The present invention provides a composition containing an inducer of SIRT1 (silent mating type information regulation 2 homolog) expression for preventing or treating sepsis or septic shock.
[0014] Further, the present invention, provides a composition containing an inducer of SIRT1 (silent mating type information regulation 2 homolog) expression for preventing or improving sepsis or septic shock.
Advantageous Effects
[0015] According to the present invention, SIRT1 expression inducer may significantly reduce the mortality by the sepsis by reducing pro-inflammatory cytokines and increasing anti inflammatory cytokines, and thus may be utilized in preventing or treating a sepsis or a septic shock.
DESCRIPTION OF DRAWINGS
[0016] FIG. 1 shows a result of analysis of SIRT protein expression western blot after W treatment of LPS and interferon beta and (B) treatment of IFN-β blocking antibody (a-INF β) and LPS to a macrophage originated from the marrow of a mouse.
[0017] FIG. 2 shows of a result of analysis the amount of pro-inflammatory cytokines and anti-inflammatory cytokines secreted after inducing overexpression of SIRT1 using adenovirus-SIRT1 and interferon beta to the macrophage originated from the mouse marrow and processing LPS ((*, P<0.05; * *, P<0.01 (Student test)).
[0018] FIG. 3 shows the survival rate of the mouse after injecting LPS after pre-treatment of adenovirus-SIRT1 or interferon beta to the mouse.
[0019] FIG. 4 shows t survival rate of the mouse after processing LPS after injecting Adenovirus-Dominant-negative SIRT1 and interferon beta to the mouse.
[0020] FIG. 5 shows the survival rate of the mouse after causing a sepsis by cecal ligation and Puncture (CLP) operation after treatment of adenovirus-SIRT1 or interferon beta to the mouse.
BEST MODE
[0021] The present invention provides a composition containing an inducer of SIRT1 (silent mating type information regulation 2 homolog) expression for preventing or treating sepsis or septic shock.
[0022] The composition includes a pharmaceutical composition and food composition.
[0023] Hereinafter, the present invention will be described in detail.
[0024] According to the present invention, SIRT1 expression inducer may significantly reduce the mortality by the sepsis by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines, and thus may be utilized in preventing or treating a sepsis or a septic shock.
[0025] The SRT expression inducing material may include at least one selected from a group composed of an interferon beta, cyclic guanosine monophosphate (cGMP), adiponectin, pyruvate, and 2-deoxyglucose, but the present invention is not limited thereto.
[0026] The interferon beta may include one of two isoforms, i.e., interferon beta 1a (KFN-β1a) and interferon beta 1b (IFN-β1. Interferon beta 1a is produced from Chinese hamster ovary (CHO) containing human interferon beta genes, is composed of 166 amino acid residues, and is glycosylated protein having a size of 25 kD. Interferon beta 1b is protein composed of 165 amino acid residues produced from E. coli, does not have sugar, and does not have amino acid no. 1 methionine residue. Further, no. 17 cysteine residue has been substituted by serine. It is known that interferon beta la and interferon beta 1b may be used to treat multiple sclerosis, but it is not known that they are used to prevent or treat a sepsis or a septic shock.
[0027] The prevention or treatment of the sepsis or the septic shock means reducing, improving or removing clinical symbols related with the sepsis and the state related to the multi-organ failure syndrome, for example, fever, hypotoxemia, trachypnea, tachycardia, endothelium inflammation, myocardial dysfunction, mental disorder, blood vessel collapse, and eventually an organ injury, e.g., an acute respiratory distress syndrome, coagulation disorder, heart failure, renal failure, shock and/or coma.
[0028] The composition of the present invention may contain one of known valid elements having the effects of preventing or treating a sepsis or septic shock along with SIRT1 expression inducing materials.
[0029] The pharmaceutical composition of the present invention may include at least one of pharmaceutically allowable carriers for injection in addition to the above disclosed valid elements. Some examples of a carrier, an excipient, and a diluent are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, aerythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, propylhydroxybenzoate, talc, magnesium stearate, and mineral. The pharmaceutical composition of the present invention may be prepared using a generally used a filler, an extender, a binder, a wetting agent, a disintegrant, a diluent such as a surfactant, or an excipient.
[0030] Solid content for oral dosage includes a tablet, pill, powder, granule, capsule, etc., and the solid content is prepared mixing the above valid element with at least one of the excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Further, a lubricant such as magnesium stearate and talc may also be used in addition to a simple explant.
[0031] Liquid substances for oral dosage may mean a suspension, liquid, oil, syrup, etc., and may include various expients such as a wetting agent, a sweetener, an aromatic, and a preservative.
[0032] Substances for parenteral dosage include sterilized aqueous solution, suspension, non-aqueous solvent, oil, lyophiliztion materials, and suppository. Plant oil such as propylene glycol, polyethylene glycol, and olive oil, and injectable ester such as ethylolate may be used as suspend and non-aqueous solvent. Witepsol, macrogol, twin 61, cacao butter, Laurin, glycerinated gelatin, etc.
[0033] Pharmaceutical composition of the present invention may be injected in various ways according to a purposed method. For example, the composition may be injected by oral dosage, rectum, vein, muscle, hypodermic injection, intradural injection within the womb, or cerebrovascular injection,
[0034] The valid amount of injection of the pharmaceutical composition of the present invention may be different depending on the patient's state, weight, level of disease, type of composition, injection path, and period, but may also be appropriately selected by those skilled in the art. The daily amount of injection of the SIRT1 expression inducin material is preferably between 5000 and 50000 IU/kg, the amount may be injected once a day or the amount may be divided into several parts to be injected several times a day, but the injection method of the present invention is not limited to this example.
[0035] Further, the pharmaceutical composition of the present. invention may be used along with an anti-inflammatory agent, antipyretic anodyne, blood coagulation inhibitor, antibiotic, bactericide, anti-allergy agent, etc.
[0036] The food composition of the present invention may additionally include a carrier allowable as food. For example, when the food composition is a drink, there is no restriction in the liquid except the fact that SIRT1 expression inducing material should be contained as an essential element, and several flavoring agents or natural carbohydrate, etc. may be contained as in common drinks. At this time, some examples of natural carbohydrate are monosaccharide such as glucose and fructose, disaccharide such as maltose and sucrose, polysaccharide such as dextrin and cyclodextrin, and sugar alcohol such as xylitol, sorbitol, and erythritol, etc. Further, some examples of the flavoring agent are natural flavoring agents such as thaumatin, stevia extracts, and glycyrrhizin, and synthetic flavoring agents such as saccharin and aspartame.
[0037] In addition to the above drinks, the food composition of the present invention may contain various medicines for promoting nutrition, vitamins, minerals, synthetic flavoring agents, natural flavoring agents, coloring agents, enhancers, pectic acids, salt thereof, alginic acids, salt thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, cerin, alcohol, carbonation reagents used in soda, etc.
[0038] The food composition may be provided as various foods, candy, chocolate, gum, tea, vitamin complex, various health supplements, etc., and may be provided in the form of powder, granules, pills, capsules or drinks.
[0039] The valid amount of the SIRT1 expression inducing material contained in the food composition may be set according to the valid amount of the pharmaceutical composition, but when the food composition is taken in for a long period for the purpose of health or hygiene, or for the purpose of health adjustment, the valid amount may be less than the above amount.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0040] Hereinafter, exemplary embodiments of the present invention will be described in detail. However, the exemplary embodiments below merely illustrate the present invention, and the present invention is not limited to the embodiments.
Exemplary Embodiment 1
Measuring Amount of SIRT1 Expression After Treatment of LPS and Interferon to Macrophage Originated from Mouse Marrow
[0041] Femur and tibia marrow cells of C57BL/6 mouse have been differentiated in culture solution containing M-CSF(10 ng/ml), and then have been used as mouse macrophage. LPS (0, 100, 500, 1000 ng/ml) and interferon beta (0, 100, 200, 500 units/ml) have been injected to the macrophage by concentrations, and the SIRT1 expression amount has been compared by western blot. Further, the SIRT1 protein expression amount when LPS has been injected along with IFN-β blocking antibody has been measured.
[0042] The result is shown in FIG. 1 .
[0043] As illustrated in FIG. 1 , when LPS has been injected to the macrophage originated from the mouse marrow by 100 ng/ml, the SIRT protein expression has increased most, and when 500 ng/ml and 1000 ng/ml of LPS has been used, the SIRT1 protein expression has rather decreased. Further, when interferon beta has been used by concentrations, the SIRT1 expression has most significantly increased when 100 units/ml has been used.
[0044] Further, the SIRT1 expression increased by LPS decreased again by injecting TFN-β blocking antibody together. Hence, it can be known that the secretion of the SIRT1, which has been increased by LPS, is performed through the interferon beta, and through which the interferon beta induces the expression of SIRT1 (B).
Exemplary Embodiment 2
Influence of Adenovirus-SIRT1 and Interferon Beta on the Amount of Secretion of Pro-Inflammatory and Anti-Inflammatory Cytokines
[0045] After infecting the macrophage with the adenovirus-SIRT1 by 10,000 MOI (multiplicity of infection), LPS 100 ng/ml has been injected for 24 hours. Further, LPS 100 ng/ml has been used along with interferon beta 100 units/ml for 24 hours, and then the amount of secretion of pro-inflammatory and anti-inflammatory cytokines of the cell culture medium has been measured by Elisa. The experiment has been performed three times, and the result has been expressed by the average±standard deviation.
[0046] The result is shown in FIG. 2 .
[0047] As shown in FIG. 2 , with respect to the amount of the pro-inflammatory cytokines, which has been increased by the LPS treatment, IL-6 has been decreased by 40% and 54%, respectively, and TNF-α has been decreased by 22% and 29%, respectively, by the pre-treatment of adenovirus-SIRT1 and interferon beta. Further, it has been found that MOP-1, which is another pro-inflammatory cytokine, which is increased by the LPS treatment, has, slightly decreases by the adenovirus-SIRT1 and interferon beta. In contrast, it has been found that the amount of the IL-10, which is the anti-inflammatory cytokine, has increased by 2.8 times and 4.7 times, respectively. Hence, it is understood that the treatment by the Interferon beta, which is the cytokine that promotes the expression of SIRT1, may inhibit the excessive inflammatory response by the LPS.
[0048] 1
Exemplary Embodiment 3
Analysis of Survival Rate of Mouse After Injecting LPS after Pre-Treatment of SIRT1 or Interferon Beta to Mouse
[0049] Adenovirus-LacZ, which is control gene delivery system, and adenovirus-SIRT1, which is the SIRT1 gene delivery system, are injected into the mouse tail vein by 3×10 8 pfu (plaque forming unit), and LPS 15-20 mg/kg after 48 hours. Then the survival rate of the mouse has been observed for 10 days.
[0050] Further, interferon beta 1000 units or the same amount of salt solution per 20 g of the mouse weight is injected into the mouse tail vein, and LPS 15-20 mg/kg has been injected after 30 minutes. Then the survival rate of the mouse has been observed for 10 days.
[0051] The result is shown in FIG. 3 .
[0052] As shown in FIG. 3 , When the LPS is injected to the mouse which has been pre-injected with the adenovirus-SIRT1, the survival rate of the mouse after 10 days is and thus the survival rate has been significantly higher than the survival rate 20% of the control group, ane mouse, to which the adenovirus-LacZ has been injected. Further, the survival rate of the mouse, into which the LPS has been injected after the injection of the interferon beta, was 70%, which was significantly higher than the survival rate 30% of the control group, the mouse, into which the salt solution has been injected. The result shows a significant difference even by the Kaplan-Meier survival statistical analysis (p<0.05). Hence, the interferon beta, which is a substance that induces the SIRT1 expression, significantly reduces the mortality of the mouse by the LPS treatment by inhibiting the excessive inflammatory response by LPS.
[0053] 1
Exemplary Embodiment 4
Analysis of Survival Rate of Mouse at the Time of Treatment of Adenovirus-Dominant-Negative SIRT1
[0054] Adenovirus-Dominant-negative SIRT1, which the gene delivery system for blocking the function of the intrinsic SIRT1, (Adenovirus for inducing mutant protein that has changed histidine no. 355 into tyrosine), is injected into the mouse tail vein by 3×10 3 pfu, and after 48 hours, interferon beta 1000 units per 20 g of the mouse weight is injected into the mouse tail vein. After 30 minutes, LPS 15˜20 mg/kg is injected, and the survival rate of the mouse is observed for 10 days.
[0055] The result is shown in FIG. 4 ,
[0056] As shown in FIG. 4 , in the case in which Adenovirus-Dominant-negative SIRT1 is pre-injected for 48 hours, interferon beta is injected and then LPS is infected into the mouse, the survival rate 50% has been observed after 10 days. This is a result similar to the survival rate 50% of the control group, the mouse into which the salt solution has been injected, and through which the interferon beta, which is the material for inducing the SIRT1 expression, significantly reduces the mortality of the mouse by LPS.
Exemplary Embodiment 5
Analysis of Survival Rate According to SIRT1 and Interferon Beta Treatment in a Mouse Sepsis Model
[0057] In a mouse sepsis model, which is induced through cecal ligation and Puncture (CLP) surgery, the following experiment has been performed to check the survival rate changed according to the injection of SIRT1 and interferon beta.
[0058] Adenovirus-LacZ or adenovirus-SIRT1 has been injected into the mouse tail vein 3×10 8 pfu. After 24 hours, the anesthetic is injected into the abdominal cavity, and the sepsis has been caused through CLP. That is, after the center of the abdomen of the mouse is cut, the appendix is exposed to the outside so that the end of the ileocecal valve is ligated by the silk suture, two holes are made using a needle, and then a certain amount of fecal materials are discharged. The appendix as well as fecal materials has been inserted again into the abdomen, then the abdomen has been stitched, and then a physiological salt solution has been injected through a hypodermic injection. After two hours of SLP operation, interferon beta 1000 units or the same amount of salt solution per 20 g of the mouse weight have been injected into the mouse tail vein.
[0059] The result is shown in FIG. 5 .
[0060] As shown in FIG. 5 , the sepsis is induced to the mouse into which the adenovirus-SIRT1 has been injected in advance, and the survival rate of the mouse after 10 days was 60%. This is a significantly high survival rate of 0% of the control group, mouse into which the adenovirus-LacZ has been injected in advance.
[0061] Further, in the case of the experimental group in which interferon beta has been injected into the sepsis-induced mouse, the survival rate was 76, but in the case of the control group, the mouse into which the salt solution has been injected, the survival rate was 0%. The result shows a significant difference even by Kaplan-Meier survival statistical analysis (p<0.05).
[0062] Hence, the interferon beta, which induces the expression of SIRT1, significantly reduces the mortality of the mouse due to the sepsis, and thus may be utilized in preventing or treating the sepsis or septic shock.
[0063] Substances for a composition of the present invention are illustrated below.
SUBSTANCE EXAMPLE 1
Pharmacological Substance
[0064] 1. Preparation of Powder
[0065] 2 g of SIRT1 expression inducing material
[0066] 1 g of lactose
[0067] The above materials are mixed and are then filled in an airtight container so as to make powder.
[0068] 2. Preparation of a pill
[0069] 100 mg of SIRT1 expression inducing material
[0070] 100 mg of corn starch
[0071] 100 mg lactose
[0072] 2 mg of stearic acid magnesium
[0073] After mixing the above materials, pills are manufactured according to a general pill manufacturing method.
[0074] 3. Preparation of capsules
[0075] 100 mg of SIRT1 expression inducing material
[0076] 100 mg of corn starch
[0077] 100 mg lactose
[0078] 2 mg of stearic acid magnesium
[0079] After mixing the above materials, capsules are prepared in gelatin capsules according to a general capsule manufacturing method.
SUBSTANCE EXAMPLE 2
Preparation of Food
[0080] The foods containing SIRT1 expression inducing materials of the present invention have been made as follows.
[0081] 1. Preparation of spice for cocking
[0082] Spice for cooking for health improvement has been made as 20 to 95 weight % of SIRT1expression inducing materials.
[0083] 2. Preparation of tomato ketchup and sauce
[0084] 0.2 to 1.0 weight % of SIRT1 expression inducing materials has been added to tomato ketchup or sauce so as to make tomato ketchup or sauce for health improvement.
[0085] 3. Preparation of wheat flour food
[0086] 0.5 to 5.0 weight % of SIR9 expression inducing materials are added to wheat flour, and bread, cake, cookies, crackers and noodles are made using the mixture so as to prepare food for health improvement.
[0087] 4. Preparation of soup and gravies
[0088] 0.1 to 5.0 weight % of SIRT1 expression inducing materials are added to soups and gravies so as to prepare meat processed food, soups of noodles, and gravies for health improvement.
[0089] 5. Preparation of ground beef
[0090] 10 weight % of SIRT expression. inducing materials is added to the ground beef so as to prepare the ground beef for health improvement.
[0091] 6. Preparation of diary products
[0092] 5 to 10 weight % of SIRT1 expression. inducing materials is added to milk, and various diary products such as butter and ice cream are made using the milk.
SUBSTANCE EXAMPLE 3
Preparation of Drinks
[0093] 1. Preparation of Soda
[0094] 10 to 15% of SIRT expression inducing materials, 5 to 10% of sugar, 0.05 to 0.3% of citric acid, 0.005 to 0.02% of caramel, 0.1 to 1% of vitamin C and 70 to 80% of refined water are mixed to make syrup. The syrup is sterilized for 20 to 180 seconds at 85˜98° C., and the syrup is mixed with the cooling water at the ratio of 1:4, then 0.5 to 0.82% of carbonic acid gas is injected so as to prepare soda containing SIRT1 expression inducing materials.
[0095] 2. Preparation of Healthy Drinks
[0096] SIRT1 expression inducing materials (solid content 2.5%, 97.16%), jujube extract (65 brix, 2.67), fruit and vegetable extract (solid content 70%, 0.12%), vitamin C (0.02%), calcium pantothenate (0.02), licorice extract (solid content 65%, 0.01%) are mixed, then the mixture is sterilized for a few seconds, and then the mixture is packed. in a small container such as a glass bottle and a plastic bottle so as to make a health drink,
[0097] 3. Preparation of Vegetable Juice
[0098] 0.5 g of SIRT1 expression inducing materials is added to 1.00 ml of tomato or carrot juice so as to snake a vegetable juice for health improvement.
[0099] 4. Preparation of Fruit Juice
[0100] 0.1 g of SIRT1 expression inducing materials is added to 1,000 ml of apple or grape juice so as to make a fruit juice for health improvement.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. patent application Ser. No. 11/838,492 filed Aug. 14, 2007 now U.S. Pat. No. 7,871,094, all of which is incorporated herein in its entirety by this reference thereto.
FIELD OF THE INVENTION
This invention relates to wheelchairs. More particularly, the invention relates to a modular wheelchair assembly that is configurable to different tilt configurations and to features thereof.
BACKGROUND OF THE INVENTION
The designs of most wheelchairs are optimized to accommodate a particular level of disability. Persons with low disability tend to use relatively inexpensive wheelchairs that have no seat tilt or a fixed seat tilt and a footrest assembly that easily accommodates self-propulsion using the occupant's feet.
Persons with moderate disability may prefer a wheelchair that allows for optional self-propulsion but that can be tilted to offer a range of seating angles. Tilting the seat provides pressure relief to the occupant, reduces discomfort associated with sitting for long periods of time, and provides passive correction for deformities. The ability to self propel using the feet may be preserved despite various tilt angles by providing the axis of rotation near the front of the seat such that the distance from the knees to the ground remains relatively constant. A disadvantage of such a configuration is the force required in order to move the weight of the occupant about the axis of rotation. This is sometimes compensated for by a pneumatic assist mechanism extending between the base of the chair and the seat frame as described in commonly owned U.S. Pat. No. 6,447,064.
High disability individuals typically require a wheelchair with deeper tilt angles to improve trunk stability and head control. Some such wheelchairs also use mechanical actuators to accommodate the significant force sometimes required to move the weight of the occupant through deep tilt angles. It is also known in the prior art to minimize the effort required to tilt the occupant by providing a pivot point as close as possible to his center of gravity. U.S. Pat. No. 7,007,965 provides an example of such a system.
While various tilt configurations may be suited to particular types or levels of disability, many individuals suffer from disabilities that progress over time. Over the course of such a disability, the occupant may graduate through 3-4 different types of wheelchairs, each having different attributes. For example, a no-tilt or fixed tilt wheelchair may be used at the early onset of disability, a self-propellable tilting wheelchair can be used when the disability becomes moderate, and a deep tilt wheelchair can be used in the later stages of disability.
The present invention addresses the need for a reconfigurable modular wheelchair that is capable of being selectively configured in a fixed tilt configuration, a dynamic tilt-in-space configuration with the axis of rotation near the occupant's knees, or a dynamic tilt-in-space configuration with the axis of rotation near the occupant's center of gravity, as required to accommodate the evolving needs of the occupant.
SUMMARY OF THE INVENTION
The wheelchair according to the invention comprises a base frame, a seat frame, and interchangeable interface components adapted to assemble the base frame and seat frame to one another according to either a fixed tilt configuration, a dynamic tilt-in-space configuration with the axis of rotation near the front of the seat, or a dynamic tilt-in-space configuration with the axis of rotation near the center of gravity of the occupant.
In a first configuration, the wheelchair comprises a base frame assembly pivotally connected to a seat frame assembly about cooperating pivot elements at a pivot point located near the knees of the occupant. A support assembly extends between a base crossbar assembly and a seat crossbar assembly. The support assembly comprises a bracket removably attached to one of such crossbar assemblies, and an interface element attached between the brace and the other one of such crossbar assemblies. The interface element includes a plurality of attachment points arrayed to share a constant radius in relation to the pivot point. The selection of the attachment point allows the base frame and the seat frame assemblies to be assembled at a variety of fixed tilt angles to thereby provide adjustable static positioning for the user requiring minimal support and correction.
In a second configuration, the wheelchair again provides a pivot point near the knees of the occupant through cooperating pivot elements on the base frame and seat frame assemblies. A support assembly extending between the base crossbar assembly and the seat crossbar assembly comprises a bracket and a bias mechanism such as a gas strut to enable the occupant to be lifted from a low tilt angle more easily than would be the case without the mechanism. In one aspect, the pneumatic mechanism includes a bell crank arrangement to converts the longitudinal force from the gas strut to an upward force to lift the seat frame and to modulate the degree of resistance provided at different tilt angles as the centre of gravity of the occupant moves forward or backward and to translate.
In a third configuration, the chair may be tilted about an axis that approximately coincides with the centre of gravity of the occupant. The tilting is provided by suspending the seat frame from an axis of rotation supported on the base frame. This configuration has the advantage of making it very easy to tilt the wheelchair and obviates the need for pneumatic mechanisms or actuators.
The invention is also directed to a drive wheel system wherein the wheel lock assembly and the anti-tip assembly are connected to the axle mounting plate such that the change of drive wheel position on the base frame does not require consequent adjustment of the lock and anti-tip assemblies.
In yet a further aspect, the invention is directed to a telescoping crossbar assembly comprising an outer sleeve having a base with a non-straight cross-section, a hollow inner shaft having a base with a cross-section conforming to said non-straight cross-section, and a pair of aligned fastener holes in said outer sleeve, one of said fastener holes having a larger diameter than the other.
In yet a further aspect, the invention is directed to a mounting assembly for securing fasteners to an elongated hollow member such as a side tube of a wheelchair. The hollow member has a plurality of fastener apertures extending longitudinally of the hollow member. An elongated insertion member is adapted to be longitudinally inserted and retained in the hollow member. A plurality of nuts are retained in several seats provided along the length of the insertion member such that when it is inserted and retained in the hollow member with the nuts aligned to the fastener apertures, fasteners inserted into the apertures will engage the nuts and be retained without the need to traverse the opposing wall of the hollow member.
In a further aspect, the wheelchair has a seat frame assembly comprising opposed seat rails and at least one seat crossbar assembly extending between them. A base frame assembly comprises opposed base rails and at least one base crossbar assembly extending between the base rails. A forward portion of the seat frame assembly and a forward portion of the base frame assembly is adapted to receive opposed removable pivot assemblies to pivot the seat frame assembly in relation to the base frame assembly. The seat and base crossbar assemblies are adapted to removably receive a support assembly extending between them. A forward portion of each of the seat rails is adapted to selectively attach a pivot member thereto and a rearward portion of each of the base rails is adapted to receive a removable pivot arm thereon enabling reconfiguration of the wheelchair between a pivot point near the user's knees and a center of gravity pivot point.
In another aspect, a fixed tilt wheelchair comprises a seat frame assembly and a base frame assembly. A first pivot element is removably attached to a forward portion of the seat frame assembly. A second pivot element is removably attached to a forward portion of the base frame assembly and the first and second removable pivot elements, when installed, cooperate to define a pivot point between them. A removable support assembly is connected between the seat frame assembly and the base frame assembly, the support assembly being configurable to define any one of a plurality of predetermined relative pivot angles between the seat frame and base frame assemblies.
Another aspect of the invention relates to a mounting assembly for an elongated hollow member. An elongated hollow member has a plurality of fastener apertures extending transversely of the hollow member. An elongated insertion member is adapted to be longitudinally inserted and retained in the elongated hollow member, the insertion member having a plurality of seats for retaining nuts therein. A plurality of nuts are seated in the seats and the insertion member is inserted into the hollow member to align said nuts with the fastener apertures.
In another aspect a dynamically tiltable wheelchair comprises a seat frame assembly, a base frame assembly, a first pivot element removably attached to a forward portion of the seat frame assembly and a second pivot element removably attached to a forward portion of the base frame assembly. The first and second removable pivot elements, when installed, cooperate to define a pivot point between them, said first and second pivot elements being operatively secured to one another. A removable support assembly is connected between the seat frame assembly and the base frame assembly, the support assembly comprising bias means between the seat frame assembly and the base frame assembly.
In another aspect the bias means comprises an extendible element one end of which is pivotally secured to a bell crank, and said bell crank is retained in operative relationship to said base frame assembly.
In another aspect, a dynamically tiltable wheelchair comprises a seat frame assembly having opposed seat rails and a base frame assembly having opposed base rails. A pivot arm is removably secured to a rearward portion of each of the base rails, said pivot arm extending upwards above said seat frame assembly. A hanger member is removably secured to a rearward portion of each of the seat rails and extends upwardly. The pivot arm and the hanger member cooperate to define a pivot point near the expected center of gravity of a wheelchair occupant for pivoting the seat frame assembly in relation to the base frame assembly.
In a method aspect of the invention, the wheelchair may be reconfigured from a fixed tilt configuration to a dynamically tiltable configuration. By removing from the fixed tilt configuration an element that renders a removable support assembly configurable to any one of a plurality of predetermined relative pivot angles between the seat frame and the base frame. A biasing mechanism is also installed that provides a mechanical advantage in tilting the seat frame in relation to the base frame.
In another method aspect, the wheelchair is reconfigurable from a first dynamically tillable configuration where the pivot axis is near the front of the wheelchair to a second dynamically tiltable configuration where the tilt axis is near the expected center of gravity of an occupant. The first dynamically tiltable configuration comprises a seat frame, a base frame, a removable forward pivot assembly pivotally attaching the forward portion of the seat frame to the forward portion of the base frame and a removable support assembly connected between the seat frame and the base frame, the support assembly comprising a biasing mechanism that provides a mechanical advantage in tilting the seat frame in relation to the base frame. The reconfiguration is accomplished by disengaging the forward pivot assembly and installing a center of gravity pivot assembly comprising a pivot point near the expected center of gravity of a seated occupant.
In another aspect, the invention comprises a kit for a reconfigurable wheelchair system comprising a seat frame assembly, a base frame assembly and a plurality of alternative support assemblies for supporting the seat frame assembly on the base frame assembly.
In an aspect of the invention relating to the crossbar assembly, there is provided a telescoping crossbar assembly for rigidly extending between structural elements at selectable degrees of extension comprising a hollow outer tube, an inner tube slidably receivable in the outer tube, the inner tube and the outer tube having generally corresponding cross-sectional shapes. A plurality of fasteners extend through the outer tube and the inner tube, each of the fasteners having a body portion and a head portion larger than the body portion, and wherein the head portion bears on the inner tube through an aperture in the outer tube.
In yet another aspect, the invention is a drive wheel assembly for a wheelchair comprising a mounting element adapted to be adjustably secured to a component of a base frame in one of a plurality of alternative positions. A wheel mountable on the mounting element and a rod having a wheel lock assembly mounted thereon is attached to the mounting element. Adjustment of the mounting element in relation to the base frame maintains the position of the wheel lock assembly in relation to the wheel without requiring separate adjustment thereof.
In a further aspect of the invention, there is provided a crossbar mounting system for the crossbar between opposed rails. The crossbar has a substantially hollow tube having opposed apertures therein and the rail has at least one aperture extending therethrough. An insert is adapted to be inserted through said opposed apertures, said insert having at least one aperture adapted to receive a fastener extending through said aperture and said rail for securing said crossbar to the rail.
The foregoing was intended as a broad summary only and of only some of the aspects of the invention. It was not intended to define the limits or requirements of the invention. Other aspects of the invention will be appreciated by reference to the detailed description of the preferred embodiment and to the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
The preferred embodiment of the invention will be described by reference to the drawings thereof in which:
FIG. 1 is a front perspective view of the TF configuration of the wheelchair of the preferred embodiment;
FIG. 2 a is a side elevation of the TF configuration at a neutral (horizontal) tilt angle;
FIG. 2 b is a side elevation of the TF configuration at a different tilt angle than in FIG. 2 a;
FIG. 3 is a bottom rear perspective view of the TF configuration;
FIG. 4 is a front perspective view of the T20 configuration;
FIG. 5 a is a side elevation of the T20 configuration at a neutral (horizontal) tilt angle;
FIG. 5 b is a side elevation of the T20 configuration at a different tilt angle than in FIG. 5 a;
FIG. 6 is a front perspective view of the T50 configuration;
FIG. 7 a is a side elevation of the T50 configuration at a neutral (horizontal) tilt angle;
FIG. 7 b is a side elevation of the T50 configuration at a different tilt angle than in FIG. 7 a;
FIG. 8 is a perspective view of the base frame, seat frame, support and pivot assemblies of the TF configuration;
FIG. 8 a is a perspective view of the base frame assembly of the TF configuration, with the interface mount secured to the rear base crossbar assembly;
FIG. 9 is a perspective view of the base frame, seat frame, support and pivot assemblies of the T20 configuration;
FIG. 9 a is a partially sectioned side view of the support assembly of the T20 configuration;
FIG. 10 is a perspective view of the base frame, seat frame, support and pivot assemblies of the T50 configuration;
FIG. 10 a is a top perspective view of the base frame assembly of the T50 configuration, including the pivot arms mounted thereon;
FIG. 10 b is a partially sectioned, top perspective view of the support (lock) assembly for the T50 configuration;
FIG. 11 is a perspective view of a pivot support;
FIG. 12 is a side elevation of a pivot support;
FIG. 13 is a perspective view of a bracket used in the T20 and T50 configurations;
FIG. 14 is an exploded view showing the crossbar assembly and the mounting of the crossbar on a rail;
FIG. 15 is a bottom perspective view of the seat frame, pivot and support assemblies for the T50 configuration, using transit tie-down brackets;
FIG. 16 is an exploded view of the pivot assembly in relation to the base and seat frame assemblies in the T50 configuration;
FIG. 17 is a cross-sectional view of the crossbar assembly according to the preferred embodiment;
FIG. 18 is a partially sectioned view of the inner tube of the crossbar assembly;
FIG. 19 is a perspective view of a transit tie-down bracket;
FIG. 20 is side and end elevations of the transit tie-down bracket;
FIG. 21 is a side elevation of a rear crossbar mount;
FIG. 22 is a partially exploded view of rear base rail mounting system;
FIG. 23 is an exploded view of the rear (drive) wheel mounting assembly;
FIG. 24 is a partially sectioned view of the rear wheel mounting assembly;
FIG. 25 is a partially sectioned view of the rear wheel mounting assembly, including the wheel lock assembly;
FIG. 26 is an exploded view of back cane mounting assembly for the TF and T20 configuration; and,
FIG. 27 is a side elevation of a pivot hanger bracket.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIGS. 1 , 2 a , 2 b and 3 illustrate the preferred embodiment of the fixed tilt configuration of the wheelchair according to the invention, which in this disclosure will be referred to as the “TF” configuration. In TF configuration, the wheelchair is set at one of several possible angles of tilt about a pivot axis 10 near the knees of the occupant. FIGS. 2 a and 2 b illustrate two alternative fixed tilt angles for the TF configuration.
FIGS. 4 , 5 a and 5 b illustrate the preferred embodiment of the dynamic tilt-in-space configuration of the wheelchair, in which the axis of rotation 12 is provided near the front of the seat frame assembly 14 . The preferred embodiment of this configuration is designed to ensure that the front of the occupant's knees move upward only a very small amount as the chair undergoes a full range of tilt of up to 20 degrees. In this disclosure, this configuration will be referred to as the “T20” configuration. FIGS. 5 a and 5 b illustrate two different degrees of tilt for the T20 configuration.
FIGS. 6 , 7 a and 7 b illustrate the preferred embodiment of the dynamic tilt-in-space configuration of the wheelchair, in which the axis of rotation 16 is provided near the center of gravity of the occupant. The preferred embodiment of this configuration is designed for tilt angles of up to 50 degrees. In this disclosure, that configuration will be referred to as the “T50” configuration. FIGS. 7 a and 7 b illustrate two different degrees of tilt for the T50 configuration
Each of the TF, T20 and T50 configurations is built around a set of sub-assemblies that is common to each of the configurations, and that are adapted to receive interchangeable components to modify the wheelchair to the desired configuration.
The principal sub-assemblies that are modified to effect a change in the configuration of the wheelchair are the support assemblies for providing load-bearing support between the base frame assembly and the seat frame assembly (or to lock the seat frame against pivoting), and the pivot assemblies that provide a pivot connection between the base frame assembly to the seat frame assembly. FIGS. 8 , 9 and 10 illustrate the base frame and seat frame assemblies for the TF, T20 and T50 configurations respectively, including their associated support and pivot assemblies.
TF Configuration
Referring to FIG. 8 , a seat frame consists of an assembly 18 comprising a left and right seat rails 20 , 22 joined by front and rear seat crossbar assemblies 24 , 26 . A base frame consists of an assembly 28 comprising left and right base rails 30 , 32 joined by front and rear base crossbar assemblies 34 , 36 . In the TF configuration, seat frame assembly 18 is set in pivoted relation to the base frame assembly 28 about opposed pivot points (only pivot point 38 is visible in FIG. 8 ) located near the front of the left and right seat rails 20 , 22 . The pivot points are located between 1⅝ and 6⅝ inches from the forward edge of a seat pan that is secured, as intended, to the seat crossbar assemblies 24 , 26 . to The pivot assembly in the TF configuration generally comprises two pivot elements that cooperate to define pivot point 38 between them: pivot supports 40 and pivot hanger brackets 42 .
The support assembly 44 for the TF configuration is attached between the front and rear seat crossbar assemblies 24 , 26 and the rear base crossbar assembly 36 . Support assembly 44 comprises brace bracket 46 and an interface mount element 48 . Different degrees of relative tilt between the seat frame and base frame are achieved by connecting the lower end of brace bracket 46 to one of several attachment points 50 on interface mount 48 that is in turn removably attached to the inner tube 52 of the rear base crossbar assembly 36 . The attachment points comprise apertures 50 arrayed at different angular positions along an arc of constant radius in relation to the pivot points 38 . Inner tube 52 of the rear base crossbar assembly 36 includes a centrally located aperture 54 to receive a removable fastener 56 for attachment of the interface mount 48 thereto. A better view of the interface mount 48 is provided in FIG. 8 a.
Referring to the pivot assembly, the pivot support 40 is illustrated in detail in FIGS. 11 and 12 . Pivot support 40 consists of a seating block one surface 58 of which is shaped to conform to the inside of a seat rail, and further including a downwardly extending tab 60 having an pivot pin hole 62 therethrough to receive a pivot pin. Seating block 40 includes two spaced apertures 64 , 66 for receiving fasteners 68 , 70 that are used to secure the front seat crossbar assembly 24 to the rail as will be discussed in more detail below.
The pivot hanger bracket 42 (shown in detail in FIG. 27 ) similarly includes a pivot pin hole to receive a pivot pin at pivot point 38 . Pivot hanger bracket 42 also has a base 72 through which extend two apertures for receiving fasteners 74 , 76 used to attach the lower end of the bracket to the front base crossbar assembly 26 . The pivot hanger bracket 42 is preferably provided with an oblong aperture 78 in the body thereof so as to be used as a transit tie-down bracket for optional use in securing the wheelchair to tie-down stations in vehicles. The pivot hanger bracket 42 has a portion thereof that is shaped to mate with a seat provided in a partial sleeve 80 that is welded to the front portion of each rail.
T20 Configuration
FIG. 9 illustrates the base frame, seat frame, support and pivot assemblies for the T20 configuration. As in the case of the TF configuration, the seat frame assembly 82 and the base frame assembly 84 are connected at pivot points 86 by means of pivot supports 88 mounted to the left and right seat rails 94 , 96 and pivot hanger brackets 98 , 100 mounted to the left and right base rails 102 , 104 . The pivot supports and pivot hanger brackets of the TF and T20 configurations are identical.
The T20 configuration uses a different support assembly than does the TF configuration. The T20 support assembly 106 comprises a bracket 108 (slightly different from the TF bracket 46 ) attached to the front and rear seat crossbar assemblies and to the rear base crossbar assembly by means of a bell crank 110 pivotally mounted to the inner tube 112 of the rear base crossbar assembly. The bell crank serves to modulate the degree of resistance provided at different tilt angles and to accommodate the change in spatial relationship between the bracket and the base frame as the seat frame is tilted.
Referring to FIGS. 9 , 9 a and 13 , bracket 108 has spaced shoulders 114 , 116 . The front 118 of the bracket includes a bridge 120 extending between the shoulders 114 , 116 . Bridge 118 has a fastener aperture for attachment of one end of a gas strut.
A gas strut 120 is mounted between the shoulders of the bracket. One end of gas strut 120 is secured to bridge 118 by means of a shoulder bolt while the other end is attached to another shoulder bolt 122 extending through the medial portion of the bell crank 110 . A trigger 124 is provided to control the gas strut. Because the gas strut is connected to the center of the bell crank, a pivoting of the base frame 84 in relation to the seat frame 82 will also cause a translation of the lower end of the bell crank in relation to the vertical plane. Such translation is accommodated by connecting the lower end of the bell crank to a slide 126 mounted on a guide tang 128 that is attached to the inner tube 112 of the rear base crossbar assembly by means of a fastener threaded through a suitable aperture in the inner tube 112 .
T50 Configuration
FIG. 10 illustrates the base frame, seat frame, support (lock) and pivot assemblies for the T50 configuration. In the T50 configuration, the forward pivot point that was a feature of the TF and T20 configurations is not present and the pivot hanger brackets are not used in the T50 configuration. The pivot supports on the seat rails may be replaced by transit tie-down brackets 132 (see FIG. 15 ) according to whether the wheelchair is intended to be attachable to tie-downs on public and private transit vehicles. The transit tie-down brackets also double as crossbar mounting elements. The pivot hanger brackets that would normally be seated in partial sleeve 80 on the base rails are replaced by filler blocks 134 .
The pivot assembly for the T50 configuration comprises a pivot arm 136 extending up from each of left and right base rails 138 , 140 to a height 142 above the seat pan. In the preferred embodiment, apart from being secured to the rails, each pivot arm is also braced by attachment to the rear base crossbar assembly 144 . The seat frame assembly is supported about pivot pins 146 at the upper end of the pivot arms by means of opposed pivot hanger plates 148 that are attached to the left and right seat rails 150 , 152 and that are pivotally suspended from the pivot pins 146 .
The pivot arm 148 comprises a base 154 having a surface conforming to the rear of the base rail (see FIG. 15 ). Apertures 156 are provided in the base 154 to enable the base to be secured by fasteners to selected apertures 158 in a longitudinal recess 160 formed in the rear portion of the base rails. Vertically spaced apertures 162 are adapted to secure the pivot arm 136 to the rear base crossbar assembly 144 . In the preferred embodiment, the pivot arm 148 extends generally upward to a forwardly extending elbow 164 to avoid interfering with the hardware used to secure the seat frame, then upwards to the pivot point 142 .
Pivot pin 146 extends through the pivot arm 136 and through the pivot aperture of the pivot hanger plate 148 .
The height of the pivot point 142 is selected by reference to the expected center of gravity of the occupant, as calculated using publicly available anatomical data. In the preferred embodiment, the height of this point is about 6.75 inches (171.4 mm) above the seat pan. Such height has been selected by accounting for a typical seat cushion of about 2″ in thickness and an anatomically typical occupant.
The precise location in the horizontal plane of the center of gravity of a occupant tends to vary more than does its location in the vertical plane. The invention accommodates such variation by providing means to adjust the horizontal position of the back rest and of the seat pan in the fore and aft directions. This allows the occupant or installer to optimize the coincidence of the pivot point 142 at the top of the pivot arm with the center of gravity of the occupant. A matrix of apertures 166 (see FIG. 6 ) is provided along the edge of the seat pan 168 allowing the seat pan to be located at different fore and aft positions in relation to the seat frame assembly. The pivot arm 136 is also adapted to be set at various horizontal positions on the base rails, for example to change the wheel base load distribution and to clear interference of the front rigging and front casters.
Referring to FIG. 16 , the pivot hanger plate 148 has a broad base 170 that tapers to a pivot aperture 172 in the top of the plate forming a generally triangular shape that can also serve as a guard to prevent the occupant's clothing from coming into contact with the rear wheel. The base 170 of the pivot hanger plate includes a bottom portion 174 that conform to the top surface of the rail 176 , and a downwardly extending flange 178 shaped to abut the outside of the rail. The flange 178 includes a plurality of apertures 180 the rearmost five of which are used to receive fasteners for releasably securing the back cane mounting to the pivot hanger plate 148 and the rail 178 . Two of the apertures are to receive fasteners extending through the hanger plate 148 , the rail 176 , the transit tie-down bracket 184 (for tansit-ready chairs only) and a threaded insert 186 (see FIG. 14 ) extending laterally through the sleeve tube 188 of the rear crossbar assembly. A tab 190 extends downward from the center of the flange and is securable to the transit tie-down bracket by means of a fastener.
A plurality of cane mounting apertures are provided at the rear of the pivot hanger plate including three sets of apertures 192 arranged in diverging arcs. The apertures are used to mount a back cane at various angles and positions in relation to both the rail 176 and the pivot hanger plate 148 .
Referring again to FIG. 10 , the preferred embodiment, the support assembly for the T50 configuration comprises the same bracket as in the T20 configuration, as well as an extendible lock rod 193 attached between the rear ends 194 of the shoulders of the bracket. The rear end of the lock rod is pivotally attached to a rod mount 196 attached to the inner tube 198 of the base crossbar assembly. A trigger 200 is provided to selectively lock the rod against retraction or extension to prevent rocking of the seat frame about the pivot points.
Crossbar Assemblies
In order to provide adjustability in the width of the wheelchair, each of the seat and base crossbar assemblies are telescope assemblies in which an inner tube 202 is received within opposed sleeve tubes 188 as may appreciated by reference to FIGS. 14 and 17 . The inner and sleeve tubes have generally corresponding cross-sectional shapes and dimensions to facilitate the telescoping function.
Inner tube 202 is hollow save for a series of ribs 189 extending along the central longitudinal axis of the tube. A series of apertures 204 adapted to receive fasteners 206 are located between the ribs. The ribs provide rigidity against deformation when the inner and sleeve tubes are brought into engagement with one another by means of head screws 206 extending through selected ones of the apertures 208 and corresponding apertures in the sleeve tube.
A feature of the invention is the means by which the crossbar assemblies may be secured in a given telescoped position with a high degree of rigidity. Rather than the head of a fastener bearing on one side of the sleeve tube and a nut bearing on its opposite side, the invention provides apertures 208 in the top wall 210 of the sleeve tube 188 that are larger than the aligned apertures in the bottom wall (not visible) of the sleeve tube and that are sufficiently large that the head of the fastener bears directly on the top wall 212 of the inner tube 202 . This allows the inner tube 202 to bear against the inner bottom surface 214 of the sleeve tube thereby providing a great deal of friction against relative displacement.
In addition, the inner tube shape and dimensions are selected to accommodate a small degree of elastic deformation of the inner tube to further lock the inner tube against the sleeve tube when the positioning fasteners are tightened. In the preferred embodiment, this is accomplished by providing non-flat mating bottom walls 216 , 218 of the inner and sleeve tubes respectively such that any deformation of the inner tube will result in several points and angles of contact between them. In the preferred embodiment such non-flat portions comprises opposed, spaced protuberances 220 , 222 .
In order to accommodate the elastic deformation of the inner tube, a small dimensional gap 224 or tolerance is provided between the inner and sleeve tube contact surfaces. It will be appreciated that the extent of the gap is selected according to the elastic range of the inner tube but it should not be so large as to allow plastic deformation to occur. The telescoping joint mechanism ensures that the joint stays tight even with continuous variations in loading (fatigue). Plastic deformation of the inner tube would compromise the joint integrity and allow the joint to become loose over time.
Crossbar Mounting
Referring to FIG. 14 , each seat crossbar assembly is secured to each rail by a mounting element 130 that interfaces between the rail 226 and the sleeve tube 188 of the crossbar assembly and by fasteners 228 that extend through the rail and the mounting element 130 to engage an insert 186 seated laterally through the sleeve tube.
The front seat crossbar mounting elements for all configurations are the pivot supports 40 . One side of each mounting element conforms to the inside of a rail 226 , and the opposite side is shaped to engage the outer end of the sleeve tube 188 . Two apertures 230 are provided in the mounting element and are spaced to correspond to the spacing of two mounting holes 232 in the rail so that fasteners 228 may be received through the rail and through the mounting element. The fasteners engage insert 186 that extends laterally through the hollow inside of the sleeve tube.
The mounting elements for the rear seat crossbar assemblies for all configurations consist of either a simple mounting element 130 as in FIG. 14 or a transit tie-down bracket 132 , best illustrated in FIGS. 19 and 20 that conform on one side to the inside of the rail and are configured on the other side to engage the end of the crossbar assembly.
In the case of the base crossbar assemblies, securement to the rails is by means of components that conform to a part of the rail and that include a seat to receive and secure the end of the crossbar assembly by means of fasteners. In the case of the TF and T20 configurations, the front base crossbar assembly is seated in and against partial sleeve 80 and the rear base crossbar assembly is seated in and against rear crossbar mount 81 . Rear crossbar mount 81 is shaped to conform to the outside and top of the rear portion of the rail, including recess 160 . Rear crossbar mount 81 also has a flat surface 83 for receiving and securing the end of the crossbar o assembly, as seen in FIG. 21 . The rear base crossbar assembly is oriented such that its transverse breadth lies in the vertical plane. This allows attachment of the interface mount 48 , the slider assembly 126 , 128 or the mechlok rod mount 196 (as the case may be) to be attached to the inner tube by a fastener through an aperture traversing the width of the inner tube.
In the case of the T50 configuration, the front base crossbar assembly is seated against a seat in a forward crossbar mount 80 that conforms to part of the front of the base rail and that has a seat adapted to receive and secure the end of the crossbar assembly.
The rear base crossbar assembly of the T50 configuration is seated in a seat provided on the inside of the base of the pivot arm 136 and is secured by two screws 162 .
Base Rail Mounting System
The invention provides adjustability of the wheel base as well as the location of the pivot point in the horizontal plane for the T50 configuration by a longitudinal recess 160 journaled in the rear portion of each base rail 233 . Referring to FIG. 22 , a plurality of aligned apertures 234 along the interior of the recess receive fasteners 236 that are used to secure the rear (drive) wheel axle mounting plate 238 , crossbar mounts or the base of the pivot arms as the case may be. The relative front to back position of those components can be adjusted by selecting the appropriate apertures. The edges of the channel include grooves 240 adapted to receive clip-on masking caps 242 (see for example FIG. 5 a ) to provide an aesthetic cover for those portions of the channel that are not otherwise covered by one of the foregoing components.
A mounting assembly is provided for securing the fasteners within the hollow interior of the rail. An elongated rod 244 is adapted to be longitudinally inserted and retained in the hollow rail 233 . A plurality of nuts 246 are retained in several spaced seats 248 provided along the length of the rod such that when it is inserted and retained in the rail with the nuts aligned to the fastener apertures 234 , fasteners 236 inserted into the apertures will engage the nuts and be retained without the need to traverse the opposing wall of the rail. This arrangement also avoids potential problems that might arise from securing the fasteners directly to the rail itself. As the rail and the fasteners may be of different materials, the potential for reaction between them is reduced by the invention.
The forward ends of the rails terminate in a caster clamp for retaining a standard caster assembly. The forward ends of the seat rails terminate in a front rigging hanger with an insertion tube adapted to telescope a selected depth into the front end of the rail and a vertically oriented sleeve adapted to receive a standard footrest assembly.
Drive/Wheel Assembly
The rear (drive) wheel assembly is illustrated in FIGS. 23 , 24 and 25 . The wheel assembly includes an axle mounting plate 250 secured to the base rail 252 and means to mount each of the wheel, the wheel lock assembly and the anti-tip assembly directly onto the axle mount. This allows the position of the wheel on the frame to be adjusted by changing the location of the axle mounting plate, rather than needing to separately adjust an anti-tip assembly 254 , an axle mounting plate and a wheel lock assembly 256 .
The axle mounting plate 250 has a base 258 with an inner dimension corresponding to the outer shape of the rail including the recess, and an extension 260 having a plurality of aligned vertical positioning apertures 262 for receiving a rear wheel axle receiver 264 in any one of several vertical positions: The axle mounting plate 250 is secured to the rail 252 by fasteners 266 extending through apertures in the base of the axle mounting plate and through apertures provided in the recess 160 .
The axle receiver 264 is inserted through a selected one of the vertically aligned apertures 262 according to the preferred ground clearance for the base frame of the wheelchair. A wheel lock tube 268 is secured between the rear wheel 270 and the axle mounting plate 250 by means of a mounting piece 272 that is adapted to provide a secure mating seat 274 for the side of the axle mount. A clearance aperture 276 through the mounting piece 272 provides a passageway for the axle receiver. The end of the axle receiver is threaded so as to receive a nut 278 used to tighten the wheel lock tube (through the mounting piece) to the axle mount. The axle 280 is inserted through the nut and the mounting piece 272 and into the hollow interior of axle receiver 264 . The end of axle 280 includes retainers 282 that project out of the end of axle receiver to hold the axle therein.
Retainers 282 are biased and may be manually depressed to allow the axle to be disengaged from the axle receiver. Upon doing so, removal of the nut is all that is required in order to remove the axle receiver 264 and mounting piece 272 so as to be able to reposition the axle receiver into a different vertical positioning aperture 262 .
The invention provides a simple means of repositioning the height of the rear wheel 270 in relation to the base frame with a minimum of tools and effort. In addition, since the anti-tip assembly 254 and the wheel lock assembly 256 are both mounted on the wheel lock tube 268 which in turn is mounted to the axle mounting plate, it is possible to adjust the horizontal position of the rear wheel on the base rail by repositioning the axle mount without the need to separately readjust the anti-tip assembly or the wheel lock assembly.
Back Cane Mounting
A back cane assembly illustrated in FIG. 26 . The assembly 284 is adapted to be mounted in various angular and fore and aft positions by providing a back plate 286 having plurality of suitable apertures to accommodate different orientations and positions of the cane 290 . Back plate 286 is secured to the inside of the seat rail 294 by means of two fasteners 296 on the inside of the back cane. A number of fore and aft positions can be selected using a plurality of apertures 298 provided on the rail. The cane is then secured to the back plate by a pivot fastener 300 and by a second fastener 302 inserted through one of several apertures 288 provided in an arc about the pivot fastener 300 , thereby enabling the cane to be mounted at different angles in relation to the rail.
In the TF and T20 configurations, a second back plate 302 is provided on the outside of the rail and all fasteners extend through both the inside and outside back plates. In the case of the T50 configuration, the outside back plate 302 is omitted but the pivot hanger plate 148 is provided with corresponding apertures and fulfills the same function as the outside back plate does in the TF and T20 configurations.
Converting from TF to T20 or T50
Reconfiguring a wheelchair from the TF fixed tilt configuration to a dynamically tiltable configuration (i.e. to either the T20 or the T50) is generally accomplished as follows.
The TF configuration comprises a support assembly (brace bracket 46 and interface mount element 48 ) connected between the seat frame assembly 18 and the base frame assembly 28 . The interface mount element 48 is configurable by the selection of different attachment points 50 to define any one of a plurality of predetermined relative pivot angles between the seat frame and the base frame. The interface mount element 48 is first removed by removing fasteners 56 and 57 . A bias mechanism is then installed to provide a mechanical advantage in tilting the seat frame in relation to the base frame, thereby providing a dynamically tiltable wheelchair. In the case of the T20, the bias mechanism is the assembly consisting of gas strut 120 , bell crank 110 and slide 126 . One end of gas strut 120 is secured to bell crank 110 . The other end of the gas strut is secured to the seat frame, or more particularly to a bracket 108 that is associated with the seat frame. Bell crank 110 is secured (through slide 126 and guide tang 128 ) to the same attachment point that received fastener 56 in the TF configuration. In the case of the T50m the bias mechanism is a mech lok.
Converting from T20 to T50
The conversion to the T20 to the T50 configuration involves both a change of the pivot assembly and of the support assembly.
In the T20, the pivot assembly consists of cooperating pivot elements, namely pivot supports 88 and pivot hanger brackets 98 , 100 , each of which is removably attached to the chair by fasteners 68 , 70 or fasteners 74 , 76 . The pivot assembly of the T20 is removed by disengaging fasteners 68 , 70 , 74 and 76 . A new centre of gravity pivot assembly is installed by mounting pivot arms 136 on the base rails and mounting pivot hanger plates 148 to the seat rails, and pivotally connecting the pivot arms to the hanger plates by pivot pins 146 . The pivot arm is secured to the base rails by inserting fasteners in to apertures that extend to the pivot arm and in to the base rails. The hanger plates are mounted by securing fasteners to the plate and into apertures in the seat rails. If desired, a transit tie down bracket can be installed where the pivot hanger brackets would normally be attached in the T20 configuration.
The preferred embodiment of the invention has been described in some detail. However, those skilled in the art will appreciate that various modifications to the constructional details of the embodiment may be practiced without departing from the spirit and scope of the invention, which scope is properly defined by the claims that follow. The following claims are nonetheless to be considered part of the disclosure herein.
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CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of application Ser. No. 959,808, filed Nov. 13, 1978, now abandoned.
BACKGROUND OF THE INVENTION
Canine herpesvirus (CHV) is an important cause of the deaths of neonatal pups; however, the disease caused by this virus is inapparent in older animals; Carmichael, J. Am. Vet. Med. Assoc. 156: 1714-1721 (1970); Carmichael et al, Am. J. Vet. Res., 26: 802-814 (1965). The dog is the only known host, and viral growth occurs exclusively in cells of canine origin; Carmichael et al, Proc. Soc. Exp. Biol. Med., 120: 644-650 (1966). Growth of CHV is markedly restricted by the temperature of incubation, the optimal range being 35° to 37° C.; Aurelian, Am. J. Vet. Res., 30: 1945-1952 (1968); Carmichael et al, J. Am. Vet. Med. Assoc., 120: 664-668 (1970). Plaque characteristics of several field isolates grown at optimal temperatures in primary dog kidney cell (DKC) cultures have appeared consistent in size and character (Pryde et al, Vet. Rec., 79: 660-661 (1966); Spertzel et al, Proc. Soc. Exp. Biol. Med., 120: 651-655 ( 1965)), with the unique exception of the BR strain isolated in England from the genital tract of dogs in vesicular lesions; Poste, Arch. Gesamte Virusforsch., 36: 147-157 (1972). The BR strain of CHV was unusual in that it caused plaques on DKC monolayers consisting principally of polykaryocytes. Unfortunately, it was apparently not preserved in a viable state.
The recognition of natural plaque mutants of several animal viruses has facilitated the exploration of viral genetics; in some instances plaque characteristics also have been associated with differences in strain virulence and have been exploited for vaccine; Darlington et al, The Herpesviruses (Kaplan, ed.) Academic Press Inc., New York, 1973, pages 93-132; Takemoto, Prog. Med. Virol., 8: 314-348 (1966). Herpesvirus plaque morphology has been used as a biological marker for genetic studies (Arlington et al and Takemoto, supra), as well as for discriminating closely related strains; Cho, Avian Dis., 20: 324-331 (1976); Lancz, Arch. Gesamte Virusforsch.; 46: 31-43 (1974); Monk et al, Arch. Gesamte Virusforsch.; 37: 308-315 (1972). Plaque characteristics of Marek's disease herpesvirus (MDHV) in natural host cells also have proved useful in the preliminary assessment of strain virulence; Biggs et al Oncogenesis and Herpeviruses (Biggs et al ed.), WHO International Agency for Research on Cancer, Lyon (1972) Pages 88-94; Cho, Avian Dis., 20: 324-331 (1976).
Herpesvirus virulence has been associated with a variety of other in vitro properties, including the type of cytopathology, viral growth characteristics at difference temperatures, antigenic differences, host cell range, resistance to 5-iododeoxyuridine, and plaque characteristics in alien host cells; Cho, supra; Darlington, supra; Koment et al, Intervirology, 5: 10-20 (1975); Pryde, supra; Tokumaru, Proc. Soc. Exp. Biol. Med., 96: 55-58 (1957). Herpesvirus homines (HVH) types have been studied extensively. With this virus, differences in plaque morphology have permitted the clear discrimination between strains; Monk et al, supra; Roizman, Virology; 15: 75-79 (1961). An HVH-1 strain that produced small plaques in rabbit kidney cells also was found to be less virulent for rabbits and mice than the wild-type (large plaque) virus; Rapp et al, Proc. Soc. Exp. Biol. Med., 166: 361-365 (1964).
BRIEF DESCRIPTION OF THE INVENTION
It has now been proven that canine herpesvirus passaged in a canine herpesvirus growth supporting tissue culture at suboptimal temperatures produces a small plaque variant (an mP strain), which lacks pathogenicity for newborn pups, but which when employed as a vaccine for canines imparts resistance against virulent canine herpesvirus strains.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the relative plaque morphology of CHV strains the left hand photo being the MP (wild-type) with the right hand photo being the mP (variant) at the same scale.
FIG. 2 is a graphic representation of the growth of MP and mP strains of CHV at 30° C. and 35° C.
FIG. 3 is a graphic representative of the inactivation kinetics of MP and mP strains of CHV at 38° C.
FIG. 4 is a graphic representation of the growth of MP and mP strains of CHV at 30° C. and 37° C. in canine spleen cells.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that canine herpesvirus passaged in a canine herpesvirus growth supporting tissue culture at suboptimal temperatures process a small plaque variant which lacks pathogenicity yet imparts resistance to virulent CHV, when employed as a vaccine in bitches or new born pups.
Analysis of the plaque characteristics of 14 CHV strains isolated at various times and from different geographical areas reveals an overall mean plaque size of 1.50±0.09 mm at 35° C. Plaques produced by the different field strains did not differ significantly in size (P<0.01).
TABLE 1.__________________________________________________________________________History and mean plaque size of different CHV strains in DKC monolayercultures after 5 days of growth at 30° and 35° under a 1%methylcelluloseoverlay medium Plaque size (mm)Strain Geographical source(yr) Tissue source.sup.a DKC cultures 30° C. 35° C.__________________________________________________________________________F-205 New York ('61) Lung 2 0.6 ± 0.05 1.50 ± 0.12F-205-MP New York ('61) Lung 312 0.6 ± 0.09 1.50 ± 0.15F-205-mP New York ('61) Lung --.sup.b 0.65 ± 0.03 0.75 ± 0.04G 4/66 Georgia ('66) Spleen 3 0.57 ± 0.07 1.56 ± 0.05M 4/66 Maryland ('66) Kidney 2 0.62 ± 0.05 1.48 ± 0.04O 3/66 Ontario ('66) Urine ? 0.58 ± 0.07 1.50 ± 0.08S 4/63 Washington, D. C. ('63) TC ? 0.60 ± 0.10 1.52 ± 0.22K 9/67 Kentucky ('67) Kidney 3 ND.sup.c 1.46 ± 0.07N.J. 2/68 New Jersey ('68) Kidney 2 ND 1.52 ± 0.10N.Y. 6/69 New York ('69) Vagina 4 0.48 ± 0.12 1.50 ± 0.06SL/18 Maryland ('65) Spleen 2 ND 1.49 ± 0.10M 9/68 Maine ('68) Kidney 2 ND 1.54 ± 0.08F 8/73 New Yori ('73) Lung 2 0.56 ± 0.07 1.45 ± 0.12B 10/73 Massachusetts ('73) Kidney 3 0.62 ± 0.03 1.46 ± 0.10N.J. 2/74 New Jersey ('74) Kidney 3 ND 1.52 ± 0.10PR/1 Missouri ('67) TC 4 ND 1.49 ± 0.22__________________________________________________________________________ .sup.a Samples were neonatal pup tissues received for diagnosis or infected DKC cultures. The exceptions were strains 0 3/66 and N.Y. 6/69, which were isolated from mature female dogs. TC indicates canine kidney cell cultures. .sup.b See text for natural history of mP variant of strain F205. .sup.c ND, Not done.
When the wild (MP) strains of canine herpesvirus are tissue culture passaged at optimal temperatures neither a reduction in virulence for newborn pups nor the emergence of plaque variants is observed.
However, when the MP strains are tissue culture passaged in a canine herpesvirus growth supporting medium at suboptimal growth sustaining temperatures, i.e. <33° C., preferably between about 28° C. and about 33° C., there appears in a very few passages, i.e. usually less than ten and frequently 2 or 3, a substantial number of small plaques which contain a canine herpevirus small plaque (mP) variant which lacks pathogenicity for newborn pups, but which serves as a vaccine to impart resistance to dogs against virulent MP canine herpesvirus strains.
The small plaque (mP) variant can be cloned and is temperature and tissue culture passage stable. The mP variant has a plaque size at 35° C. less than about 0.7 times the diameter of the MP strain from which it is derived. For example, in contrast to the wild type MP virus, (Table 1 supra) the mP variant (e.g. strain F-205) produced plaques at 35° C. that were approximately one-half the size of the wild-type (MP) virus plaques (FIG. 1). Similar consistency in plaque size and character was observed at the 30° C. growth temperature. At the lower temperature, however, plaques produced by the MP virus were approximately 60% the diameter observed at 35° C. Plaques formed by the mP virus at 30° C. were 86% the size produced at 35° C. Plaques formed under a methylcellulose medium did not differ significantly from those produced when agarose was used in the overlay medium.
The above observations are based upon the following examples with the F-205 strain of CHV, found fully virulent for newborn pups after 312 passages in DKC cultures incubated at 35° C. gave rise to plaques of the MP type. This type was characteristic of 12 additional CHV field strains that had been passaged fewer than four times in DKC cultures. However, after fewer than 20 additional passages at low temperature (30° C.), a stable mP variant of strain F-205 was the principal viral type. Since cloned mP virus retained the small plaque characteristic after more than 60 passages at 30° C., the mP marker appears to represent a stable biological property inherent to the genome of the variant virus.
EXAMPLE
Virus strains and cell cultures
The characteristics of CHV (strain F-205) and methods for its cultivation and assay have been previously described; Carmichael et al, Am. J. Vet. Res., 26: 802-814 (1965); Carmichael et al, Proc. Soc. Biol. Med., 120: 644-650 (1966). Additional isolates (See Table 1, supra) were recovered from tissue specimens submitted to the James A. Baker Institute for Animal Health, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York, for viral culture or, in some instances, were obtained from other investigators.
Standard plaque medium for cloning was double-strength Eagle minimal essential medium (MEM; BBL), supplemented with 10% fetal bovine serum (FBS) and 0.5% lactalbumin hydrolysate (LAH) mixed with an equal volume of 2% agarose (Sea Plaque).
For plaque size determinations and viral assays, monolayer DKC cultures in 60-mm plastic plates were inoculated with 0.2 ml amounts of serial 10-fold dilutions of virus and absorbed for 1.5 h. at room temperature. After the absorption period, 5-ml amounts of MEM, supplemented with 5% FBS and 0.5% LAH that contained 1% methylcellulose (Hotchin, Nature (London ), 175: 352 (1955)) were added to each plate, and cultures then were incubated in a humidified 5% CO 2 atmosphere at 30° or 35° C. After 5 days of incubation, the viscous medium was decanted, and plates were fixed for 10 min. with 10% neutral formalin, rinsed in tap water, and then stained with 1% aqueous crystal violet solution. Plaque size was measured with a calibrated ocular micrometer. At least 100 plaques were measured for each strain studied.
Cultures of canine spleen cells were prepared by rapidly stirring, at room temperature, minced tissue in MEM without added trypsin. After 2 h., the suspensions were filtered through six layers of sterile gauze and diluted in growth medium (MEM supplemented with 10% FBS and LAH) to contain approximately 10 6 cells/ml. Cultures were prepared in 25-cm 2 plastic flasks, using 5-ml amounts per flask. After 24 h., cultures were shaken, and the adherent cells, which were more than 90% mononuclear, were used for viral growth studies.
Natural History of mP Variant
In an attempt to select strains of reduced virulence, CHV (strain F-205) was rapidly transferred (2-day intervals), for a total of 312 passages, using terminal dilutions at approximately each 10th passage. Each 10th DKC passage was harvested and stored frozen at -70° C. in a stabilizing menstruum for later tests of pathogenicity in newborn pups and for the study of certain biological properties, as noted later. After 312 passages at 35° C., neither a reduction in virulence for newborn pups nor the emergence of plaque variants was observed.
The 312th DKC passage virus, which caused fatal infections and was uniform with regard to plaque characterstics under a 1% methylcellulose overlay, was then rapidly transferred at 30° C. After approximately 20 passages at 30° C., subtle changes in the cytopathic effects (CPE) were observed in tube cultures, and the principal plaque type measured approximately one-half the diameter (0.75 mm) of the parental strain. After plaque purification, using an agarose overlay medium, a typical mP clone was selected for further passage and study. It was designated CHV-mP to distinguish it from the macroplaque (MP) parental virus. The mP variant has retained its unique plaque characteristics after 66 passages in DKC cultures incubated at 30° C.
Heat Inactivation
Freshly harvested 24-h . cultures of the mP and MP strains were rapidly frozen and thawed three times. Cell debris was removed by centrifugation at 600×g for 10 min. at 4° C., and clarified virus in MEM containing 10% FBS was placed in a water bath at 38° C. Aliquots were removed at intervals for infectivity titrations. Virus survival was plotted versus time.
Immunodiffusion
Antigens for immunodiffusion tests were prepared from mP and MP virus grown in 75-cm 2 plastic flasks. When cultures had evidence of extensive CPE, the adherent cells were scraped off the flask with a rubber policeman. After centrifugation at 600×g, the fluid portions were discarded and the cell portions were taken up in one-tenth the original volume in distilled water, frozen and thawed three times, and then clarified by low-speed centrifugation. The supernatant portions then were placed in cellophane dialysis tubing and dialyzed for 24 h. at pH 10.3 (glycine-NaOH buffer) to dissociate viral subunits. After overnight dialysis against 0.15 M phosphate-buffered saline, pH 7.2, the antigen preparation was stored frozen at -70° C. Tests were performed on 2.5- by 7.5- cm plastic immunodiffusion slides, using 0.6% agarose in phosphate-buffered saline. An eight-well pattern was used to compare all permutations of mP or MP antigens with the respective hyperimmune antisera that had been prepared in specific-pathogen-free beagles.
Tests for Virulence
A total of 21 specific-pathogen-free beagle pups (four litters) from the Institute's disease-free colony were used. All animals were obtained from bitches without detectable CHV-neutralizing antibody. Serum neutralization methods have been described previously; Carmichael, J. Am. Vet. Med. Assoc., 156: 1714-1721 (1970. Thirteen neonatal pups (two litters) were given intraperitoneal or oral-nasal inoculations within the first 48 h. of birth, since pups rapidly develop resistance to generalized, usually fatal, infections after that time; Carmichael et al, J. Infect. Dis., 120: 669-678 (1970).
To examine effects of immunosuppression on the pathogenicity of the mP variant, eight 2-week-old pups were divided into four groups, each consisting of two pups. In one group, each pup was inoculated with 0.5 ml of goat anti-dog thymoctye serum (ATS) at the time of infection with mP virus and again on post-inoculation days 2 and 4. Another group of two pups was given mP virus but no ATS. The thid group was inoculated with CHV-MP, and the fourth received CHV-MP plus ATS. Viral doses were 10 5 .2 50% tissue culture infective doses (TClD 50 ) (CHV-mP) or 10 4 .8 TCID 50 (CHV-MP). The ATS, prepared in our laboratory, had a canine lymphocyte cytotoxicity titer of 1.320. After two injections (0.5 ml/kg), there was a marked (>80%) diminution in the normal responses of canine peripheral blood lymphocytes to phytohemagglutinin, severe thymic atrophy, and profound alteration in the course of CHV infection in normally resistant 2-week-old pups.
While primary dog kidney cell (DICC) cultures are the cultures of choice, the growth supporting medium employed as the tissue culture for virus passage is not unduly critical. Any tissue culture medium can be employed which supports canine herpesvirus growth. A number of such media are known in the art.
Based upon the above and similar experimental work the following observations are made:
Growth characteristics of the MP and mP strains in DKC cultures incubated at 30° and 35° C.
Growth of the mP strain in DKC cultures at 35° C. was not restricted (FIG. 2). When viral inputs were approximately equal, the titers of inputs were approximately equal, the titers of CHV-mP, after 24 h. of growth, were at least 0.8 log 10 greater than those of the MP strain. CPE of the two strains were similar, but not identical. Cells infected with the mP variant generally were more swollen and refractile than those infected with MP virus, and they tended to clump around the edges of a plaque. Cells infected with the MP strain were uniformly rounded, and they detached readily from the growth surface. Syncytia were not observed with either virus. A consistent feature of the mP variant was the late appearance of CPE in relation to the production of infectious virus.
Both strains grew more slowly at 30° C.; however, growth of the MP virus was somewhat more restricted at this temperature. An additional difference between the MP virus and the mP variant was the amount of infectious virus released (Table 2). The MP virus was significantly more cell associated throughout the growth period than was the mP variant.
TABLE 2.______________________________________Cell-associated virus released MP and mP canineherpesvirus grown at 35° C. Virus Titer.sup.a Virus ReleaseIncubation CHV-MP.sup.b CHV-mP (%)time (h) Cells Fluid Cells Fluid MP mP______________________________________12 4.8 1.8 3.2 1.5 0.1 1.918 5.5 2.5 4.8 3.0 0.1 1.624 5.5 2.8 5.2 3.5 0.2 1.9______________________________________ .sup.a Log.sub.10 TCID.sub.50 /0.2ml. .sup.b Viral inputs were 10.sup.6.3 (MP) and 10.sup.5.8 (mP) per flask culture.
Inactivation at 38° C.
Results (FIG. 3) suggested that the MP strain is somewhat more heat labile than the MP virus; however, the differences were slight.
Antigenic comparisons
Antisera raised in dogs against the MP field strain (F-205) neutralized the homologous virus and the mP variant to the same extent in plaque reduction and kinetic neutralization tests. Immunodiffusion analysis also failed to reveal antigenic differences, for two precipitin lines of identify were observed between the mP and MP viral antigens and the respective antisera.
Growth and mP and Mp strains in splenic macrophage cultures at 30° and 37° C.
Splenic macrophage cultures maintained at 30° C. continued to release small amounts of infectious virus (˜10 plaque-forming units/0.2 ml) throughout the 70-h. incubation period; however, there was scant growth of either virus (FIG. 4). Growth of the mP virus was restricted to a greater extent than that of the MP strain in macrophage cultures incubated at 37° C. At 37° C. the mP virus persisted intracellularly without decrease in titer for 24 h., but infectious virus then declined. Extracellular virus was not detected. By 60 h. postinfection, the mP virus no longer could be detected; however, cell-associated MP virus still was present (3×10 3 plaque-forming units/0.2 ml) after 70 h. of incubation. At this time, cell cultures were <90% viable as judged by trypan blue exclusion tests.
Virulence of the MP and mP strains for newborn pups
The response of pups to inoculations with MP and mP virus are summarized in Table 3. The MP strain produced generalized and fatal infections in all pups, regardless of the route of inoculation. High viral titers were found in all tissues examined. In contrast, the mP variant was markedly reduced in virulence, for none of the pups had signs of illness. Nevertheless, mP virus was recovered from the nasopharynx of all pups for 4 to 6 days after inoculation. Although small amounts of virus were recovered from kidney, spleen, and lung tissues of one pup (I-660) euthanized 6 days after intraperitoneal inoculation and from the liver of an additional pup (I-661), there were no macroscopic lesions. Virus was not recovered from the other three pups that were infected with mP virus and then euthanized 6 or 8 days later. Pups that were allowed to survive did not have signs of illness, and they all developed CHV-neutralizing antibody by post-inoculation week 3.
TABLE 3.__________________________________________________________________________Tests for virulence of MP and mP variant CHV in newborn pups Viral isolation (log.sub.10 TCID.sub.50 /0.2 g of tissue) Macro- Naso-Plaque Viral dose Inoculation Survival scopic le- pharynx Cerebel-Pup No.Type (TCID.sub.50) route.sup.a or death.sup.b sions.sup.c (days) Kidney Spleen Liver lum Lung__________________________________________________________________________I-658MP 10.sup.4.8 i.p. D(5) Severe +(2-5) 4.5 3.5 4.5 2.5 3.5I-659MP 10.sup.4.8 O/N D(6) Severe +(2-6) 4.5 3.0 4.0 2.5 3.5I-660mP 10.sup.5.2 i.p. E(6) None +(3-5) 1.0 2.5 <1 <1 2.5I-661mP 10.sup.5.2 O/N E(6) None +(2-6) <1 <1 1.0 <1 <1I-662mP 10.sup.5.2 i.p. E(6) None +(3-5) <1 <1 <1 <1 <1II-644MP 10.sup.4.5 i.p. D(6) Severe +(2-6) 5.0 3.5 3.5 2.5 4.5II-645MP 10.sup.4.5 O/N D(8) Severe +(2-6) 5.5 4.5 4.0 3.0 5.0II-646mP 10.sup.5.0 i.p. E(6) None +(2-6) <1 <1 <1 <1 <1II-647mP 10.sup.5.0 i.p. S.sup.d --.sup.e +(2-4) -- -- -- -- --II-648mP 10.sup.5.0 i.p. S -- +(2-5) -- -- -- -- --II-649mP 10.sup.5.0 O/N E(8) None +(2-4) <1 <1 <1 <1 <1II-650mP 10.sup.5.0 O/N S -- +(2-5) -- -- -- -- --II-651mP 10.sup.5.0 O/N S -- +(2-4) -- -- -- -- --__________________________________________________________________________
Effects of ATS
CHV growth was greatly restricted in the 2-week-old pups given the Mp or mP virus (groups 1 and 2; Table 4); however, the pups that received ATS at the time of inoculation with MP virus (group 4) dies by the 6th post-inoculation day. Pups that were inoculated with mP virus and then treated with ATS did not have signs of illness; however, at necropsy, their thymus glands were approximately one-third the weight of the thymuses from the non-treated animals. None of the pups that received mP virus had prominent macroscopic lesions, although occasional small areas of focal necrosis, but no hemorrhages, were observed microscopically in the lung and liver of one pup (no. 4). The lesions were similar to those seen in 2-week-old pups that were given MP virus but not ATS. In contrast, the pups (no. 7 and 8) given MP virus and ATS had high viral titers in several organs. Remarkably high titers were found in the brain.
Microscopic lesions in the inoculated 2-week-old pups that were given the MP virus but no ATS were disseminated small foci of interstitial pneumonitis, necrosis of occasional hepatocytes, and minute areas of renal hemorrhage and focal interstitial necrosis, with minimal inflammatory changes. Contrasting with these modest lesions were the prominent changes observed in the MP-inoculated pups treated with ATS (group 4). They consisted of interstitial pneumonitis, with alveolar necrosis and hemorrhages, necrotic foci throughout the liver, and multiple foci of necrosis and hemorrhages in the renal cortices, with both tubular and glomerular destruction. Central nervous system changes consisted of disseminated focal enephalitis, necrosis of neuronal and astroglial cells with mononuclear cell infiltrations, and segmental leptomeningitis. Other lesions typical of CHV infection of neonatal puppies also were observed in these animals; Carmichael, J. Am. Vet. Med. Assoc., 156: 1714-1721 (1970); Carmichael et al., Am. J. Vet. Res., 26: 802-814 (1965); Pryde, supra.
TABLE 4.__________________________________________________________________________Response of 2-week-old pups to CHV (MP or mP) and effects of ATS Macro- Viral isolation (log.sub.10 TCID.sub.50 /0.2g) Plaque type in- scopic le- Nasol- oculated (pup sions at ne- Thymus wt pharynx Cerebel-Group no.) Illness cropsy.sup.a (g) (days) Kidney Spleen Liver Lung lum__________________________________________________________________________1 CHV-mP (1) None None 1.8 +(2-7) <1 <1 <1 <1 <1 (2) None None 2.0 +(2-5) <1 <1 <1 1.2 <12 CHV-mP (3) None None 0.7 +(2-8) <1 1.0 <1 1.0 <1 + ATS (4) None None 0.5 +(2-8) <1 0.8 1.0 1.5 <13 CHV-MP (5) None Mild 1.9 +(2-8) 1.0 <1 1.0 2.5 <1 (6) None Mild 1.8 +(2-8) 0.8 <1 <1 2.0 <14 CHV-MP (7) Died.sup.b Severe 0.5 +(2-4) 3.5 <1 2.5 4.5 3.5 + ATS (8) Died Severe 0.6 +(2-6) 4.0 3.5 2.0 5.5 2.5__________________________________________________________________________ .sup.a See text for lesion descriptions .sup.b Pups no. 7 and 8 dies on postinfection days 4 and 6, respectively. Surviving pups were euthanized at day 8.
The above studies demonstrate that the mP virus had additional biological properties that distinguished it from the parental MP virus. Notwithstanding the subtle, but nevertheless distinct, differences between the MP and mP strains in the character of cytopathology, the times of onset of CPE, the rates and amounts of virus produced at 30° and 35° C., viral persistence in canine spleen monocyte cultures, and, of lesser significance, the rates of inactivation at 38° C., there were distinct differences in their virulence for pups.
The MP (wild-type) virus was highly virulent for newborn pups and for 2-week-old animals that had received ATS at the time of infection. The mP variant, however, was clearly an attenuated strain. Although the mP variant persisted for several (4 to 6) days in the nasopharynx, it rarely was recovered from other tissue sites favored by the MP virus, and then only in small amounts.
Association between small plaque size and reduced virulence has been reported for plaque variants or mutants of other herpesviruses [Darlington R. W. et al. "Replication-biological aspects", in The herpesvirues (Kaplan ed.) Academic Press Inc., New York (1973), pp 93-132; Rapp, F., et al., Proc. Soc. Exp. Biol. Med., 116: 361-365 (1964)], the most noteworthy being MDHV [Biggs et al., "Biological properties of a number of Marek's disease virus isolates", in Oncogenesis and herpesviruses (Biggs et al., ed.) WHO International Agency for Research on Cancer, Lyon (1972) pp 88-94; Cho, Avian Dis., 20: 324-331 (1976); Darlington et al. supra]. The mP-CHV, however, did not behave as an attenuated host range, temperature-sensitive mutant, as described for the large- and small- plaque mutants of HVH-2; Darlington et al, supra; Korment et al, supra. It did not regularly engender the formation of syncytia, as described for the CHV-BR strain, Poste, supra, or occur as a naturally attenuated plaque variant, as described for field isolates of MDHV, but it originated after less than 20 passages in DKC cultures incubated at 30° C. after prolonged culture (312 passages) at 35° C. Unfortunately, the precise passage at which the mP variant emerged could not be determined, but it was the dominant type after 20 passages at 30° C.
Unlike the antigenic change (loss of the "A antigen") that has been associated with the attenuation of MDHV after prolonged passage in chicken renal cell cultures, Purchase et al., Infect. Immun., 3: 295-303 (1971), antigenic markers specific for the attenuated CHV-mP strain were not detected.
Immunological tests
The following three examples demonstrate the efficacy of the mP canine herpesvirus strain in imparting resistance to wild-type virulent canine herpesvirus. Because signs of illness are absent in dogs older than one week of age, (Carmichael et al, J. Am. Vet. Med. Assoc. 156: 1714-1721 (1970) vaccine trials were designed so as to demonstrate efficacy based upon relative duration of viral shed (equivalent to viral growth in host) following challenge inoculation with virulent (mP) virus.
Littermate SPF Beagle dogs each were inoculated intramuscularly (1 M) or oral/nasally (O/N) with 10 5 .2-5.8 tissue culture infective doses (TCD 50 ) of mP CHV. Blood samples were taken prior to vaccination and before challenge-inoculation with virulent (MP, macroplaque) CHV (strain F-205), and thereafter at intervals. Nasal-pharyngeal swab samples were collected for a period of 2 weeks after both vaccination and challenge-inoculation for viral isolations. Results (serologic responses, signs of illness, virus shedding) were recorded for vaccinated and unvaccinated (control) animals that received challenge inoculations at the same time as the vaccinates.
EXAMPLE
The first of three groups of pups was vaccinated at four months of age and challenge-inoculated three months later (D800 through 802). Control animals were D803-804. See Table 5. Vaccine virus given IM did not spread to unit-contact controls over a period of three months. Neither vaccinated animals nor controls had signs of illness post-vaccination or post-challenge. This was considered to be a normal response since immunity to this virus must be based on the relative restriction of viral shedding of vaccinates and controls.
TABLE 5.______________________________________Intramuscular vaccination at 4 months of age (CHV mP) Post-vac. Pre-chall. Post-chall. virus shed SN antibody virus shedDog (days) (3 mo. p.v.) (days) Conclusion______________________________________VaccinatesD800 0 1:16 2(MP) ImmuneD801 0 1:4 0 ImmuneD802 0 1:4 0 immuneControls NotD803 -- <1:2 8(MP) immune NotD804 -- <1:2 11(MP) immune______________________________________
EXAMPLE
The second group was vaccinated oral/nasally at three days of age and challenge-inoculated one month later, with appropriate controls (D612-617 vaccinated; D618-619 controls). See Table 6.
The mP (attenuated) virus was shed from 1-7 days after O/N inoculation, in contrast to the MP virus that is commonly shed in copious amounts for approximately 14 days (8-17 days in more than 30 dogs studied). Low antibody titers were generated that did not completely exclude the MP challenge virus. However, there was evidence of an anamnestic response (results of 8-day serology) in vaccinated dogs, with accelerated rejection of the challenge MP virus, as compared with controls. An immune response with reduction in viral shed is clearly evident. No signs of illness were observed in vaccinated or control dogs. Although not an object of this trial, it may be concluded further (confirming published reports from this laboratory, Infection and Immunity 20:108-114, April 1978) that mP is avirulent for neonatal pups.
TABLE 6.__________________________________________________________________________Oral-nasal vaccination at 3 days of age (SPF beagles) Post-vacc. Pre-chall. Post-chall. AntibodyDog virus shed antibody(SN) virus shed(days) 8 day post-chall. Conclusion__________________________________________________________________________VaccinatesD612 1-5(days)mP* 1:8 1-7 (MP) 1:32 ImmuneD614 1-7 mP 1:4 2-7 (MP) 1:16 ImmuneD615 1-7 mP 1:4 2-8 (MP) 1:12 ImmuneD616 1-4 mP 1:8 2-3 (MP) 1:16 ImmuneD617 1-4 mP 1:8 2-5 (MP) 1:16 ImmuneControls(non-contact)D618 -- <1:2 1-12 1:4 Not immuneD619 -- <1:2 1-16 1:8 Not immune__________________________________________________________________________ *mP = attenuated virus MP = virulent virus
EXAMPLE
The third group (D54-57) was vaccinated intramuscularly at 2 months of age. Animals were challenge-inoculated one month later. 2-months later all dogs received corticosteroid (dexamethasone, 1 mg/day for 5 days), a drug shown to cause recrudescence of persistent CHV. Swab samples were collected during and following steroid treatment for a total period of 12 days. Virus recovered following steroid treatment was analyzed for plaque type (MP=virulent, mP=vaccine strain). See Table 7.
Viral shed did not occur following initial vaccination (IM route), and there was no spread of virus to in-unit contacts. Following challenge viral shed was again reduced. Relative amounts of virus recovered (generally less than 10 TCD 50 ) was significantly less in vaccinates than controls (100 to 10,000 TCD 50 ). All vaccinates developed low SN antibody titers. Within 8 days following challenge, titers did not change, indicating minimal immune response to challenge virus, i.e. limited viral growth. Following corticosteroid drug treatment (dexamethasone), there was no recrudescence of the vaccine virus. MP virus (virulent) was recovered, however, from the control dogs that had received challenge inoculums 2 months previous to drug treatment, and which had been negative to viral isolation attempts (3×weekly) during the period following initial viral shedding and steroid treatment.
TABLE 7.__________________________________________________________________________Host-response to MP and persistence of virus as revealed byviral recrudescence following steroid treatment Post-vacc. Pre-chall. Post-chall. Viral re-excretion virus shed SN anti- virus shed following steroidDog (days) body titer (days) Immune treatment (2 mo. post-chall.)__________________________________________________________________________Vaccinates54 0 1:16 1-5 Yes Neg.55 0 1:8 1-4 Yes Neg.56 0 1:8 2-7 Yes Neg.57 0 1:6 2-4 Yes Neg.Controls58 -- <1:2 1-16 No Pos. (3-9 day; MP virus)59 -- <1:2 1-14 No Pos. (5-10 day; MP virus)__________________________________________________________________________
The microplaque (mP) variant of CHV (strain F-205) is available from the James A. Baker Institute for Animal Health, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, upon request.
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RELATED APPLICATIONS
This Patent application is a continuation in part of Provisional Patent Application U.S. Ser. No. 60/033,231, filed on Dec. 5, 1996, which is hereby incorporated by reference.
FIELD OF INVENTION
The present invention relates to human genes which encode a specialized group of proteins which function to promote the growth, differentiation, and denucleation of immature erythrocytes (red blood cells) and erythroid leukemic cells.
BACKGROUND OF INVENTION
During erythropoiesis, red blood cells are matured in fetal liver or adult bone marrow through the proliferation and differentiation of committed progenitor cells, which are the erythroid burst forming unit and the erythroid-colony forming unit. These progenitor cells are dependent upon lineage-specific growth factors for their proliferation and differentiation. In contrast, primitive pluripotent hematopoietic stem cells, which are generally quiescent and are triggered to proliferate only when a need is expressed in the periphery, respond to a combination of multiple hematopoietic growth factors. Recently, several factors have been identified that appear to be involved in the triggering of cell division in the quiescent hematopoietic progenitor cells and in the differentiation of committed progenitor cells. It has been demonstrated that burst promoting factor (BPF), colony stimulating factor (CSF), and interleukin-3 (IL-3) have a dependent-effect upon the proliferation and differentiation of pluripotent stem cells and progenitor cells. Additional studies have also determined that erythropoietin (EPO) is the sole factor involved in the late stages of erythroid differentiation prior to the stage of basophilic erythroblast. However, the role of these factors in the regulation of the final differentiation stages, beyond basophilic eythroblast, are still uncertain.
Numerous types of cells express cell-surface proteins known as "integrins" which are recognized by extracellular proteins such as fibronectin, collagen, osteoprotein, fibrinogen, vitronectin, thrombospondin, and Von Willebrand factor (VWF), which function in the attachment of these cells to their surroundings. Integrins, which act as receptors for several of these aforementioned extracellular proteins, have been identified with human platelet glycoprotein--which functions to mediate VWF-dependent adhesion of platelets to exposed vascular endothelium.
Another common group of adhesion-promoting molecules are referred to generically as "cellular adhesion molecules" (CAMs) which are glycosylated proteins belonging to the immunoglobulin super-family. The classified CAMs include: neuronal cellular adhesion molecule (NCAM); myelin-associated glycoprotein (MAG); intercellular adhesion molecule (ICAM); lymphocyte function-associated antigen-3 (LFA-3); the T-cell subset cell-surface marker CD-4; the major glycoprotein of peripheral myelin (Po); carcinoembryonic antigen (CEA); and platelet-endothelial cell adhesion molecule 1 (PECAM-1). See e.g., Williams, D. F. & Barclay, T., 6 Ann. Rev. Immunol. 381 (1988).
Of particular interest in the instant invention, is platelet-endothelial cell adhesion molecule 1 (PECAM-1). These cellular adhesion molecules typically are comprised of 711 amino acids and possess a molecular weight of 130 kd. PECAM-1 has been demonstrated to be expressed on platelets, circulating monocytes, and at the intercellular junctions of resting endothelial cells. See e.g., Ashman & Aylett, 38 Tissue Antigen 208 (1991). PECAM-1's are important mediators of platelet-platelet, platelet-leukocyte, and platelet-endothelial cell interactions in the process of platelet aggregation. In addition, these molecules may also be involved in the development of atherosclerotic plaque and thrombi from vascular trauma (e.g., from angioplasty), as well as in leukocyte-endothelial cell interactions in inflammation and transendothelial cell migration.
DESCRIPTION OF THE FIGURES
The present invention may be better-understood and its advantages appreciated by those individuals skilled in the relevant art by referring to the accompanying figures wherein:
FIG. 1 Illustrates a flow-chart of the various experimental methodologies utilized in these series of experiments.
FIG. 2A--Illustrates the morphological characteristics of murine erythroid leukemia (MEL) cells co-cultured with fetal rat liver extract by use of Wright stain. 2B--Illustrates benzidine reaction measurements for -globin.
FIG. 3 Illustrates the influence, as determined by an MTT microcolormetric assay, of varying concentration of fetal rat liver extract on the growth and differentiation of murine erythroid leukemia (MEL) cells in vitro.
FIG. 4 FIG. 4A illustrates the percentage of murine erythroid leukemia, as determined by a differential cell count (FIGS. 4B-4D), of (MEL) cells following a 7-day co-culture with various electrophoretically-separated protein bands from fetal rat liver extract.
FIG. 5 Illustrates the inhibitory effect, as determined by a differential cell count, of selected monoclonal antibodies specific for fetal rat liver extract co-cultured with murine erythroid leukemia (MEL) cells.
FIG. 6 FIG. 6A--Illustrates in histogram form the inhibitory effect, as determined by MTT microcolormetric assay, of the #15 and #59 monoclonal antibodies (specific for the 94 kD EDDF protein) directed against fetal liver extract on murine erythroid leukemia (MEL) cells. 6B--Illustrates in histogram form the inhibitory effect, as determined by MTT microcolormetric assay, of the B7 and A12 monoclonal antibodies (specific for the 17 kD EDDF protein) directed against fetal liver extract on murine erythroid leukemia (MEL) cells.
FIG. 7 Illustrates in histogram form the inhibitory effect, as determined by MTT microcolormetric assay, of monoclonal antibodies directed against individual PhastGel strips containing electrophoretically-separated fetal rat liver extract proteins co-cultured with murine erythroid leukemia (MEL) cells.
FIG. 8 8A--DNA sequence of the large, 2721 bp EDDF1 EcoRl-generated cDNA fragment, SEQ ID NO: 1 derived from the human bone marrow cDNA library. 8B--depicts the DNA sequence of the smaller, 650 bp EcoRl-generated cDNA fragment, SEQ ID NO: 2. 8C--depicts the DNA sequence of the 288 bp EcoRl-generated, translatable hrEDDF1, SEQ ID NO: 3. By standard convention the DNA sequence is shown in the 5' to 3' orientation.
FIG. 9 depicts the amino acid sequence, SEQ ID NO:4, encoded by the 288 bp. EcoRl-generated, translatable hrEDDF1. By standard convention the amino acid sequence is shown from the --NH 2 to --COOH terminus.
SUMMARY OF THE INVENTION
The present invention is directed to a family of erythroid differentiation and denucleation factors (EDDFs) including EDDF1 (17 kDa) and EDDF2 (94 kDa), which have been shown to possess diagnostic and therapeutic applicability in mammals.
The present invention is also directed to a novel genomic DNA sequence which encodes human EDDF1, a vector which contains this novel DNA sequence, an expression system and associated transformed host which contains the novel DNA sequence, and which is also capable of expressing the novel recombinant human EDDF1 protein.
DETAILED DESCRIPTION OF THE INVENTION
The present invention utilizes a methodology named "Protein Band-Fishing by Cells" (see Chau, R. M. W., et al., Muscle Neuronotrophic Factors Specific for Anterior Horn Motoneurons of Rat Spinal Cord. In: Recent Advances in Cellular and Molecular Biology, Vol. 5, Peeters Press, Leuven, Belgium, pp. 89-94 (1992)) in an attempt to identify various erythroid differentiation and denucleation factors (EDDFs).
The novel methodology of "Protein Band-Fishing by Cells" was applied to identify the erythroid differentiation and denucleation factor (EDDF) activities in fetal rat liver extract on the growth and differentiation of murine erythroid leukemia (MEL) cells in vitro. See Chan, S. S. W., et al., Erythroid Differentiation and Denucleation Factors from Fetal Rat Liver: Monoclonal Antibodies Preparation for Clone Screening from Human Bone Marrow cDNA Library, (Abstract), 6th International Congress on Cell Biology (1996); Chau, R. M. W. et al., Effects of the Rat Fetal Liver Extract on the Proliferation and Differentiation of Murine Erythroid Leukemia Cells, (Abstract), 6th International Congress on Cell Biology (1996), whose disclosures are incorporated herein by reference. As the fetal liver has been shown to be one of the progenitors of fetal blood stem cells (which contain factors for erythroid differentiation) prior to the development of the bone marrow, fetal liver extract, obtained from embryonic-15-day Sprague Dawley rat fetus, was used as the source of EDDF in an attempt to identify and isolate specific EDDF(s) in vitro. Proteins present in the fetal rat liver extract were electrophoretically-separated in native form utilizing the PHASTGEL electrophoresis system (LKB Pharmacia).
After isolation of protein bands, monoclonal antibodies were made to the proteins and screened for their ability to inhibit the differentiation and denucleation activities of the isolated proteins. These antibodies were then used to immunoselect clones containing genes coding for the desired functions.
The inserts from the selected clones were isolated and their DNA was sequenced. Some sequences were subdloned to obtain the most efficient clones of the EDDF genes. The subdlones were tested for expression of proteins with the appropriate biological activity. The amino acid sequence of the protein was then determined. It was discovered that there was homology between the isolated EDDF protein and one exon of an unrelated cell adhesion protein, PECAM. However, the subcloned sequence which expressed this EDDF is somewhat shorter than the PECAM sequence disclosed.
A flow-chart of the various methodologies utilized in the following series of experiments is illustrated in FIG. 1.
EXAMPLE 1
Co-Culture of Murine Erythroid Leukemia Cells with Fetal Rat Liver Extract
Murine erythroid leukemia (MEL) cells were co-cultured with fetal rat liver extract (FRLE) at a concentration of 0.4 mg/ml. FIG. 2A depicts the morphological characteristics of the MEL cells co-cultured with the FRLE and illustrates a basophilic staining of the MEL cell cytoplasm after day 4. Generally, it was found that the nuclei of the MEL cells became smaller, more compact, and more intensely stained as a function of their total time in culture. The total number of MEL cells without a nucleus (reticulocytes) gradually increased from 5.4% on day 2 to 56% on day 7.
FIG. 2B, panel b illustrates the results of measurement of benzidine (a substrate for the peroxidase activity B-globin). Measurable enzymatic reaction (as shown by the accumulation of dark-greenish granules in the cytoplasm) was only found in the cytoplasm of MEL cells co-cultured with FRLE.
Similarly, MEL cells were co-cultured with FRLE at concentrations of 0.1, 0.2, and 0.4 mg/ml. 1.8% dimethyl sulfoxide (DMSO), a differentiation inducer, was utilized as a negative control for cell growth, whereas DMEM medium was utilized as a positive control. The determination of MEL cell viability and the influence of the FRLE on MEL cell growth was performed utilizing both MTT microassay wherein the optical density of the cell culture was determined at 570-630 nm and morphological measurement via inverted phase microscopy (Zeiss Axiophot Inverted Microscope, West Germany). MTT is a tetrazolium derivative [3-(4,5-dimethylthiazol-2-yl)-2,5-dipheny tetrazolium bromide] which can be converted by viable cells to form a formazan product which can subsequently be measured with an ELISA colorimeter.
The results of the MTT colormetric assays, illustrated in FIG. 3, demonstrated that greater concentrations of FRLE caused increased inhibition of MEL cell growth. For example, with a 0.2 mg/ml FRLE concentration, a 5.5-fold inhibition of MEL cell growth was observed on day 3 when compared with the negative control (cells cultured with DMEM medium alone). It was found that the higher the concentration of FRLE, the greater the inhibition of MEL cell growth in culture.
EXAMPLE 2
Isolation of EDDFs by the "Protein Band-Fishing by Cells" Methodology
The erythroid differentiation and denucleation factor (EDDF) in fetal rat liver extract (FRLE) was isolated utilizing the proprietary "Protein Band-Fishing by Cells" methodology as initially reported in Chau, R. M. W., et al., Muscle Neuronotrophic Factors Specific for Anterior Horn Motoneurons of Rat Spinal Cord. In: Recent Advances in Cellular and Molecular Biology, Vol. 5, Peeters Press, Leuven, Belgium, pp. 89-94 (1992). Additionally, this methodology allowed for the determination of the effect of EDDF on the growth and differentiation of murine erythroid leukemia (MEL) cells in vitro. See Chan, S. S. W., et al., Erythroid Differentiation and Denucleation Factors from Fetal Rat Liver: Monoclonal Antibodies Preparation for Clone Screening from Human Bone Marrow cDNA Library, (Abstract), 6th International Congress on Cell Biology (1996); Chau, R. M. W. et al., Effects of the Rat Fetal Liver Extract on the Proliferation and Differentiation of Murine Erythroid Leukemia Cells, (Abstract), 6th International Congress on Cell Biology (1996).
Erythroid differentiation and denucleation factors are generally found in minute quantities in vivo this can potentially cause tremendous difficulties in their isolation utilizing traditional biochemical methodologies. In view of this fact, a novel technique designated "Protein Band-Fishing by Cells" was developed in which viable MEL cells were co-cultured with an electrophoretic gel containing the separated proteins from fetal rat liver extract (FRLE). This methodology thus allowed the MEL cells to "fish-out" those fetal rat liver extract proteins which exhibited biological activity specific for those erythroid leukemic cells (i.e., differentiation and denucleation of MEL cells into reticulocytes or mature erythrocytes).
For electrophoretic protein separation, the livers from embryonic 15 day-old Sprague Dawley rats fetuses were aseptically dissected into small sections and washed 3-times in Ca +2 /Mg +2 -free Hank's medium. The hepatic tissue was then homogenized in 10 mM Tris-HCl (pH 7.2). A cell lysate was obtained by centrifugation at 3,000 r.p.m. for 10 minutes, and the supernatant was filtered utilizing a 0.2 μm Millipore filter membrane (Millipore Corp., Waltham, Mass.).
The filtered, fetal rat liver extract (FRLE, 10-20 μl of a 1 mg/ml solution) was then applied to a pre-cast 20% native PHASTGEL® (50×40×0.45 mm, Pharmacia LKB Biotech AB, Upsala, Sweden) for separation by the PhastSystem gel electrophoresis (Pharmacia LKB Biotech AB, Upsala, Sweden). The electrophoretic conditions utilized were those suggested by the computer program of Olsson, I., et al., Computer Program for Optimizing Electrophoretic Protein Separation, 9 Electrophoresis 16 (1988). Following electrophoretic separation, 2×10 4 MEL cells were seeded onto the surface of the protein-containing PHASTGEL® and cultured for 7 days, thus allowing for differentiation and denucleation. After the 7 day incubation period, the PHASTGEL™/MEL cell culture was fixed in 0.4% paraformaldehyde in Phosphate-buffered saline (PBS) for approximately 2 hours, stained using a silver stain-based methodology, and the degree of differentiation and denucleation was determined using inverted-phase microscopy (Zeiss Axiophot Inverted Microscope, West Germany).
The results, as illustrated in FIG. 4A, demonstrated that at the PHASTGEL® regions which contained protein bands with apparent molecular weights of 17 kDa (EDDF1) and 94 kDa (EDDF2) there were increased numbers of differentiated and denucleated reticulocytes and mature red blood cells found to be present. In order to verify the presence of EDDF activities in these two bands, the PHASTGEL® was cut into 50 strips from top to bottom and each strip was co-cultured with MEL cells. The results, as illustrated in FIG. 4D, revealed that 60-70% of the MEL cells in the cultures containing the 17 kDa protein band (EDDF1) were differentiated and denucleated into reticulocytes and mature RBCs, as compared to 20% in the control cultures with no MAbs present. Similarly, FIG. 4C, revealed that 70% of the MEL cells in the cultures containing the 94 kDa protein band (EDDF2) were differentiated and denucleated into reticulocytes and mature RBCs. In contrast, FIG. 4B ˜80% of the MEL cells in cultures with control gel strips (no EDDF) were found to be proerythroblasts and basophilic erythroblasts.
EXAMPLE 3
Production of Anti-EDDF Monoclonal Antibodies
In order to confirm the specific EDDF activity of the 17 kDa and 94 kDa proteins, the two bands were excised from the PHASTGEL® and the proteins contained therein were used as antigen in the immunization of BALB/c mice for subsequent preparation of anti-EDDF monoclonal antibodies (MAbs). The 17 kDa and 94 kDa protein bands were excised from a PhastSystem gel (1×30 mm gel containing 100 ng trophic factor) and utilized as antigens in the immunization of separate groups of Balb/c mice. Specifically, the EDDF-containing PHASTGEL® sections were excised and finely minced. The PHASTGEL® pieces were then mixed with an equal volume of complete Freund's adjuvant and directly injected intraperitoneally into the Balb/c mice. A total of 3 antigen immunizations were performed, with intraperitoneal injections of EDDF1-containing and EDDF2-containing PHASTGEL® in physiological saline on the 7th and 21st day following the initial immunization. The spleens of the Balb/c mice were harvested and allowed to fuse with either NS-1 or SP2/0 myeloma cells.
The resultant hybridomas were then screened utilizing MTT microassays and microscopic examination. From each hybridoma, two clones were selected as a function of their ability to inhibit, in MEL cell cultures, the differentiation and denucleation activities of EDDFs present in the extract and/or of the 17 kDa and 94 kDa proteins in the PHASTGEL® strips. The two MAbs specific for the 94 kD protein were designated MAb #15 and #59; whereas the 17 kDa MAbs were designated B7 or A12.
The results, illustrated in FIG. 5, demonstrated that approximately 70-74% of the MEL cells remained undifferentiated in the cultures with the EDDF and the specific MAb, as compared to ˜20% in the control cultures with no MAb. FIG. 6A, panel a illustrates the results obtained by MTT microassay of cell culture O.D. of the MEL cells incubated with FRLE and the anti-94 kDa MAbs #15 and #59. Similarly, FIG. 6B, illustrates the results obtained by MTT microassay of cell culture O.D. of the MEL cells incubated with FRLE and the anti-17 kDa MAbs B7 and A12.
Additionally, an experiment was performed in which a PHASTGEL®, containing electrophoretically-separated FRLE proteins, was cut into 50 strips (1 mm/strip, with the orientation of the strip going from the top-to-bottom of the gel). The individual gel strips were co-cultured with 2×10 4 MEL cells with the two anti-17 kDa MAbs (B 7 and A12) in a 96-well culture plate for 7 days. The results of this assay are illustrated in histogram form in FIG. 7. These results suggested that clones had been selected which expressed fusion proteins with EDDF-like activities that possessed the ability to induce the differentiation and denucleation of 60% of the MEL cells. In addition, this aforementioned induction was inhibited by their specific "blocking" monoclonal antibodies.
EXAMPLE 4
Immunselection of Recombinant 17 kDa and 94 kDa Human EDDF Proteins
The selected EDDF-blocking monoclonal antibodies (EDDF-Mabs) were next utilized to immunoselect clones of human EDDF from a human bone marrow cDNA library (produced by Clonetech Co., Palo Alto, Calif.). The immunoscreening procedure utilized was a modification of that described in Young, R. A., and Davis, R. W., Efficient Isolation of Genes Using Antibody Probes, 80 Proc. Nat'l Acad. Sci USA 1194 (1983), whose disclosure is incorporated herein by reference. The aforementioned modification consisted of using ammonium nickel sulfate as an enhancing agent to increase 100-fold the sensitivity of the peroxidase-avidin-biotin complex reaction utilizing diamino-benzidine as the substrate. A maximum of 4 nitrocellulose membrane "replicas" were made from each colony plate for immunoscreening and only the most intensely-stained clones were selected in the immunoscreening procedure. The selected clones were then allowed to express the recombinant proteins which were subsequently assayed to determine their potential EDDF-specific biological activity in vitro. It should be noted that only the clones with the highest EDDF-specific biological activity in the MEL cell cultures were selected for further analysis.
A total of four EDDF-specific monoclonal antibodies were selected. The two MAbs specific for the 94 kDa protein (#15 and #59) and the two 17 kDa-specific MAbs (B7 and A12) were utilized as immunoprobes in the screening of positive expression clones from a selected human bone marrow cDNA library. In brief, the precipitation procedure for the cDNA library involved the isolation of mRNAs from cells of the human bone marrow library, followed by reverse transcription to synthesize the EDDF cDNAs. The selected, EDDF-specific cDNAs were ligated into a gt-11 phage vector and subsequently transformed in an E. coli strain Y1090 host bacteria. The cDNA insert of the gt-11 clone would then be sub-cloned into an in vitro expression vector system for protein expression.
(a) Preparation and Purification of 17 kD EDDF1/gt-11 Phage
A cDNA was synthesized from a 17 kDa EDDF1 mRNA selected from the human bone marrow library. The EDDF1 cDNA was ligated into a gt-11 phage and the resulting recombinant gt-11 clone was designated Lambda.17 kDa.EDDF1 (or EDDF1-A12).
Purified Lambda.17 kDa.EDDF1 was obtained by the following methodology: 10 plaque-forming units (pfu) of EDDF/gt-11 phage was inoculated into a 500 ml overnight culture of E. coli stain Y1090 until complete lysis of the bacteria was observed. The Lambda phage were recovered and purified by centrifugation and enzymatic treatment with RNase and DNase in an NaCl/PEG 8000 solution, followed by high speed CsCl density gradient centrifugation to collect the purified phage at a final gradient density of approximately 1.5 gm CsCl/ml.
Isolation and purification of the Lambda.17 kDa.EDDF1 DNA was facilitated by initial digestion of the Lambda phage (1 ml) in EDTA, SDS, and proteinase K, followed by repeated extractions with phenol, phenol/chloroform, and chloroform. The EDDP1 DNA was then ethanol precipitated with 95% ethanol and collected by centrifugation. Following repeated washes in 70% ethanol, the resultant Lambda.17 kDa.EDDF1 DNA pellet was redissolved in Tris-EDTA buffer.
(b) Recovery of the 17 kDa EDDF1 cDNA Insert from Lambda.17 kDa.EDDF1
10 g of Lambda.17 kDa.EDDF1 DNA was digested overnight with EcoRl and electrophoresed. The results of the EcoRl digestion demonstrated the presence of three discreet DNA fragments: (1) 0.65 kbp fragment designated as the EDDF1; (2) a 2.06 kbp fragment designated as the large DNA fragment; and (3) a 46 kbp fragment designated as the Lambda phage DNA. Three discreet DNA fragments were observed due to the presence of an internal EcoRl restriction site within the Lambda.17 kDa.EDDF1 cDNA insert located at the position of base pair 2066.
Following electrophoresis, the 0.65 kbp EDDF1 DNA fragment was visualized utilizing U.V. light, excised from the agarose gel, and recovered via standard techniques. The recovered EDDF1 cDNA was then prepared for High Protein Expression by recombination with the pGEX-1 Lambda T EcoRl/BAP vector.
EXAMPLE 5
DNA Sequencing of Lambda.17 kDa.EDDF1
Lambda.17 kDa.EDDF1 was sequenced utilizing 5' and 3' Lambda phage sequencing primers and TAQ® polymerase (Pharmacia Biotech) in an automated DNA sequencing apparatus (ABI). This sequencing methodology provided extremely accurate and reproducible results with respect to the DNA sequencing of the Lambda phage "hosting" the EcoRl-generated fragments. The DNA sequencing indicated that the large EDDF1 fragment consisted of 2721 bp, SEQ ID NO:1 whereas the smaller DNA fragment was found to consist of 656 bp, SEQ ID NO:2. Moreover, only 288 bp, SEQ ID NO:3 of the aforementioned 656 bp, SEQ ID NO:2 sequence was subsequently shown (by computer-based intron/exon analysis) to be translated into the human, recombinant EDDF1 (hrEDDF1) protein.
FIG. 8A depicts the DNA sequence of the large, 2721 bp EDDF1 EcoRl-generated cDNA, SEQ ID NO:1 fragment derived from the human bone marrow cDNA library. FIG. 8B depicts the DNA sequence of the smaller, 656 bp EcoRl-generated cDNA fragment, SEQ ID NO:2. FIG. 8C depicts the DNA sequence of the 288 bp EcoRl-generated, translatable hrEDDF1, SEQ ID NO:3. By standard convention the DNA sequence is shown in the 5' to 3' orientation.
EXAMPLE 6
Sub-Cloning of the 17 kDa EDDF1 EcoRl-Generated Fragments
The EcoRl-generated, 288 bp EDDF1 DNA fragment (see FIG. 8C and SEQ ID NO. 3) was sub-cloned into the pGEX-1 Lambda T EcoRl/BAP High Protein Expression vector (hereinafter pGEX). The pGEX vector was selected due to the following factors: (1) it possessed a high efficiency transcriptional promotor at its 5'-terminus and a 3'-terminus poly(A) tail; and (2) it provided an easy methodology for the purification of the two EDDF recombinant proteins via affinity column chromatography-based purification of the glutathione-S-transferase (GST)-containing EDDF1 fusion proteins.
a. Transformation of Recombinant Plasmid
The pGEX vector was digested with EcoRl. The digested pGEX vector was then incubated overnight with the EcoRl-generated, 288 bp EDDF1 DNA fragments (hereinafter EDDF1-288, SEQ ID NO:3) in the presence of T4 DNA ligase. Following ligation, competent E. coli strain DH5 bacteria were transformed with the recombinant vector and transferred onto Luria broth (LB) agar plates containing 100 g/ml ampicillin for overnight incubation. Due to the fact that the pGEX vector contained a gene which conferred ampicillin resistance to the transformed bacteria, the use of ampicillin screening allowed the exclusive selection of transformed bacterial colonies, as only those bacteria containing the recombinant vector would be viable in its presence.
b. Identification and Isolation of the EDDF1-288 Transformants
The transformed bacterial colonies were individually selected, inoculated into a small volume of LB medium containing 100 g/ml ampicillin, and incubated for approximately 3 hours. Following incubation, the transformed bacteria were collected via centrifuigation for subsequent isolation of the recombinant vector DNA by the alkaline lysis "mini prep" technique as described in Maniatis, T., Fritsch, E. F., and Sambrook, J., Molecular Cloning, 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. pp. 134-136 (1986). With this technique, the collected bacteria were lysed by the addition of a Tris-EDTA/NaOH/SDS solution with vigorous vortexing. After centrifugation to collect contaminating cellular debris, the recombinant vector DNA-containing supernatant was aspirated, extracted with phenol and chloroform, and precipitated with 95% ethanol. The mixture was centrifuged to collect the precipitated DNA and the nucleic acid pellet was dissolved in Tris-EDTA buffer.
The collected recombinant vector DNA was then digested with EcoRl to release the EDDF1-288, SEQ ID NO:3 insert from the 4.9 Kbp pGEX vector. The digested DNA was subjected to agarose gel electrophoresis and the individual DNA bands were identified via U.V. light visualization.
"Positive" bacterial colonies (i.e., those which contained the EDDF1-288, SEQ ID NO:3 insert) were selected and inoculated into LB medium for large scale plasmid purification via alkaline lysis and PEG precipitation. The purified recombinant vector DNA was then transfected into an E. coli strain BL-21 host bacterium to facilitate high levels of expression of human recombinant EDDF1-288 (hrEDDF1-288) protein, SEQ ID NO:4.
EXAMPLE 7
Expression and Amplification of Recombinant Human EDDF Proteins
The pGEX-EDDF1-288 recombinant molecule was transfected into E. coil stain BL-21 competent bacteria in 50 ml of LB medium. IPTG was utilized to induce high levels of expression of the human recombinant EDDF1-228 (hrEDDF1-288) protein, SEQ ID NO:4. Collected bacteria were lysed, frozen, and thawed a total of 4-times using liquid nitrogen, sonicated, and centrifuged. The supernatant, containing the hrEDDF1-288 fusion protein, SEQ ID NO:4 was then passed through an anti-GST affinity chromatography column containing anti-GST monoclonal antibodies (Pharmacia). The use of this type of affinity chromatography allowed purification of the GST-hrEDDF1-288 fusion protein which was bound to the matrix through the GST moiety. Following a high salt wash, the GST-hrEDDF1-288 fusion protein was eluted. The proteolytic enzyme thrombin was utilized to cleave the linkage between the hrEDDF1-288 protein, SEQ ID NO:4 and the GST moiety and the purified hrEDDF1-288 protein, SEQ ID NO:4 was collected for subsequent in vivo and in vitro assays.
EXAMPLE 8
Determination of In Vitro Biological Activity of the hrEDDF1-288 Protein
The MEL cell line was utilized to determine the biological activity (i.e., the differentiation and denucleation activity) of the hrEDDF1-288 protein in vitro. The MEL cells were co-cultured with the hrEDDF1-288 protein, SEQ ID NO:4 for 3 days in DMEM medium supplemented with 15% FCS. After 3 days of co-culture, an MTT microassay was performed to determine the degree of inhibition of MEL cell proliferation by the hrEDDF1-288 protein, SEQ ID NO:4. After 6 days of co-culture, a differential cell count assay was performed to determine the degree of differentiation and denucleation of the MEL cells into mature erythrocytes.
EXAMPLE 9
Amino Acid Sequence of the hrEDDF1-288 Protein
FIG. 9 depicts the amino acid sequence of the hrEDDF1-288 protein, SEQ ID NO:4 translated from the 288 bp hrEDDF1-288 DNA fragment, SEQ ID NO:3. Subsequent analysis following both nucleic acid and amino acid sequencing indicated that hrEDDF1-288 protein, SEQ ID NO:4 possessed almost complete homology with human platelet-endothelial cell adhesion molecule-1 (PECAM-1). Specifically, the hrEDDF1-288 protein, SEQ ID NO:4 was homologous to that which was found in exon 8 of the PECAM-1 molecule. See Newman, P. J., U.S. Pat. No. 5,264,554; Newman, P. J. et al., PCT Publication WO 96/01271. Although there is sequence homology between these two molecules, the in vivo and in vitro biological functions are completely diverse in that EDDF1 functions in the differentiation and denucleation of erythrocytes and PECAM-1 is involved in cellular adhesion processes.
While embodiments and applications of the present invention have been described in some detail by way of illustration and example for purposes of clarity and understanding, it would be apparent to those individuals whom are skilled within the relevant art that many additional modifications would be possible without departing from the inventive concepts contained herein. The invention, therefore, is not to be restricted in any manner except in the spirit of the appended claims.
__________________________________________________________________________# SEQUENCE LISTING- (1) GENERAL INFORMATION:- (iii) NUMBER OF SEQUENCES: 4- (2) INFORMATION FOR SEQ ID NO:1:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 2721 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: DNA (genomic)- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:- CTAATGGTGT GAGGCATACA AAAAAGAAGA CATATTCTTT GTTTCAATGC TG - #TGGTAAGA 60- AACACAAGCT CTCCTAATGA AAATGATGGA CAAACATCTG AATCATACTA CC - #AATAAGCA 120- TAGAAAAAAT GTTGGGGGTC ATGTTTGGTT GTCACGTGAA CTATATCCTT AC - #AGTGATGG 180- TGATAGTAAT TTAGGGTATG CCAGACTTCA TCTAGCTTAA GTGGGTAAAC AT - #TGTGAAAA 240- AGCTGGGCTA GGTGCCAGGG CTTGAGAATG GGTGGCCAGA GAAGGCTGAA GA - #TGGCTGAA 300- CATCTCCAGC AAACACATGA GCCAAAAGGT CCCATGGGGC ACTTCAAAAG AC - #TGTGCGCA 360- GCCAGGTGCG GTGGCTCACG CCTATAATCC CAGCACTTTG GGAGACCGAA TG - #GGGTGGAT 420- CACTTGAGCC CAGAGGTTTG TGACTAGCTT GGCCAACATG GCAAAACCCC GT - #CTCTACTA 480- AAAATACAAA AATTAGCCCA GCGTGGTGGT GGGTGTCCTG TAGCCCCAGC TA - #CTCAGGTG 540- GCTGAGGTGG TAGAATCACT TGAATCCAGG AGGCAGAGGT TGCAGTGAGC CA - #AGATCGTG 600- CCACTGCACT CCAGCCTGGG TGACAGAGTG AGACTCTATC TCCACAAAAA AA - #AAAAAAAA 660- AAAAAAAATT AAAGGACTGT GGCCAAATCA GATGGCTGGA AACAAAGGCT GG - #AGTTTGGG 720- AATGGAGAAT CACCGGATAT GAGCTGAAAA AGTGGCTGAG CCTAAGCGTG AC - #AGGTGTCA 780- GGTGCCAGTC TCAGGAGTAG GCAAGTGTCC TGCATGCAGT GAAAAGCCAG AA - #GATGGAAG 840- GAAGAACAGG ATGCAAATGA GTTCTCGGAA CGATCCACCT GGTGGCTGGG TC - #AGGGAGCA 900- GGCATGGTGA CTTCAGACCT CATGGTACGT TAGAGGCTAA TGTGAAGCCC AT - #GTGAAGCT 960- GTTGGTTTAA ACTGGGTCGA TATCAGTGGC ACACATTTAC TGACCATGTG TC - #CAGCCCTG1020- TGTGAAGTAC TGTAGTAAAT TGCTCCAATG GAAACTCACA ATAACCACAG AA - #GGCCAGTA1080- ACAGCATTGT CGTTATTTTA TCATGACGCA ACTGAGGCTT AGGGCAGACA GC - #TGGTGGGT1140- GGTGGGACTG GGATTTGAGC CCACTGGTGT CCCAGGCCCG GAGCTTGGCT TC - #TTCCATTG1200- TCTTACCACA GCCTGCACTC ACAGGAGAGT GACCTATAAG TTACAATACC AT - #CTGCTGAC1260- CATCTGCTCT CACACTAGAA GGAAAGTCTA CTTGGGGAGA CAATTTAGGA TC - #CGAATTTT1320- GGTAGTTGAG GATGGAGCTA GGAAAAGCGG ATACAGGAGG TAGCCAAGTT CT - #GCTTGGAC1380- CTGCAGGGAG TGAGGCTGGC CGGGCTCCAG GTGGAAATCC CCAGGTGAAA AG - #GGAGACTT1440- GGAGGTCAGG AAAGTAACCT GGACTGGAGC CATAGGTTTA GGTGTCAGTG GC - #TCAGAGAC1500- AGAAGCTCAG CGTGTAGGTG AAATCACCCA GGAGGAGAAT GGGGATGGAA AA - #CTGAGGAT1560- TGAATTTTGC AAAATGTTCA TACTTCCGGG GAAAACAAAG AATAACCAGT GA - #ATAAGAAA1620- GGGGTGCCAG GTAAGAAGGG AAGAGAATCA GAGTCATGAG GAACCCCAGA AC - #CCCAGAAA1680- AAGCTGAGTT CCACGTAAGA CCTGGGCAAC AGTGAAGTAT GGAGAGCCCA AG - #ATTGGGAG1740- CGTGGAGGAA GAGCATCCAC CACTGAATTT AATCAGCCCC GGACTCAGGG AC - #GTTGGTTG1800- GGGAATCAAG TGACCTTCCC AGTTTCTTCA AAACTTGAGA GAGAGTGCAG TG - #TCACAAGA1860- TTGTGACTAC AAAAGAGTGC AGTCAGATTT CAGGGGTAAC AAGAAAGTGT GA - #AATAAGGG1920- AGTCAAAGCA TAAAGGAAAA AGGAGAAAAA ATGGCCGATA GCTAGAGAAG GC - #GTGGGTCA1980- AGATTGTCTG TGGCCTGGCA TGGTGGCTTA TGCCTGTAAT CCCAGCATTT TG - #GAAGGCCG2040- AGGTGGGCAA ATCACCTGAG GTCAGGAATT CAAGACCAGC CTGGCCAACA GG - #GCAAAACC2100- CCGTCTCTAA AACAACAACA ACAACAAAAA AATCCAAAAA GTTAGCTGGG CC - #TGGTGGGC2160- GCACCTGTCA TTCCAGCTAC TCGGGAGGCT GAGGCAGGAG ATTTGCTTGA AC - #CCAGGAGG2220- CACACGTTGC GGTAAGCTGA GATTATACCA CTGCACTCCA GCCTGGGTGA TA - #AGAGCGGG2280- ACTCTGTCTC AGAGGAAAAA AAAAAAAGTT GAGCAGTGGC TGTCTCATGT TC - #CTCTTCCT2340- CTGCCCTTCT TTGCTCAGTG TGAATCCTTT TCCTGCTTTT CAGCCCCGGT GG - #ATGAGGTC2400- CAGATTTCTA TCCTGTCAAG TAAGGTGGTG GAGTCTGGAG AGGACATTGT GC - #TGCAATGT2460- GCTGTGAATG AAGGATCTGG TCCCATCACC TATAAGTTTT ACAGAGAAAA AG - #AGGGCAAA2520- CCCTTCTATC AAATGACCTC AAATGCCACC CAGGCATTTT GGACCAAGCA GA - #AGGCTAAC2580- AAGGAACAGG AGGGAGAGTA TTACTGCACA GCCTTCAACA GAGCCAACCA CG - #CCTCCAGT2640- GTCCCCAGAA GCAAAATACT GACAGTCAGA GGTGAGTCAG GGTCTCCATA GC - #AAGCTGTG2700# 2721AA G- (2) INFORMATION FOR SEQ ID NO:2:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 656 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: DNA (genomic)- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:- GAATTCAAGA CCAGCCTGGC CAACAGGGCA AAACCCCGTC TCTAAAACAA CA - #ACAACAAC 60- AAAAAAATCC AAAAAGTTAG CTGGGCCTGG TGGGCGCACC TGTCATTCCA GC - #TACTCGGG 120- AGGCTGAGGC AGGAGATTTG CTTGAACCCA GGAGGCACAC GTTGCGGTAA GC - #TGAGATTA 180- TACCACTGCA CTCCAGCCTG GGTGATAAGA GCGGGACTCT GTCTCAGAGG AA - #AAAAAAAA 240- AAGTTGAGCA GTGGCTGTCT CATGTTCCTC TTCCTCTGCC CTTCTTTGCT CA - #GTGTGAAT 300- CCTTTTCCTG CTTTTCAGCC CCGGTGGATG AGGTCCAGAT TTCTATCCTG TC - #AAGTAAGG 360- TGGTGGAGTC TGGAGAGGAC ATTGTGCTGC AATGTGCTGT GAATGAAGGA TC - #TGGTCCCA 420- TCACCTATAA GTTTTACAGA GAAAAAGAGG GCAAACCCTT CTATCAAATG AC - #CTCAAATG 480- CCACCCAGGC ATTTTGGACC AAGCAGAAGG CTAACAAGGA ACAGGAGGGA GA - #GTATTACT 540- GCACAGCCTT CAACAGAGCC AACCACGCCT CCAGTGTCCC CAGAAGCAAA AT - #ACTGACAG 600- TCAGAGGTGA GTCAGGGTCT CCATAGCAAG CTGTGCTGTG GGCCCCCAAG GG - #CAAG 656- (2) INFORMATION FOR SEQ ID NO:3:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 288 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: DNA (genomic)- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:- GCCCCGGTGG ATGAGGTCCA GATTTCTATC CTGTCAAGTA AGGTGGTGGA GT - #CTGGAGAG 60- GACATTGTGC TGCAATGTGC TGTGAATGAA GGATCTGGTC CCATCACCTA TA - #AGTTTTAC 120- AGAGAAAAAG AGGGCAAACC CTTCTATCAA ATGACCTCAA ATGCCACCCA GG - #CATTTTGG 180- ACCAAGCAGA AGGCTAACAA GGAACAGGAG GGAGAGTATT ACTGCACAGC CT - #TCAACAGA 240# 288GTGT CCCCAGAAGC AAAATACTGA CAGTCAGA- (2) INFORMATION FOR SEQ ID NO:4:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 96 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: protein- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:- Ala Pro Val Asp Glu Val Gln Ile Ser Ile Le - #u Ser Ser Lys Val Val# 15- Glu Ser Gly Glu Asp Ile Val Leu Gln Cys Al - #a Val Asn Glu Gly Ser# 30- Gly Pro Ile Thr Tyr Lys Phe Tyr Arg Glu Ly - #s Glu Gly Lys Pro Phe# 45- Tyr Gln Met Thr Ser Asn Ala Thr Gln Ala Ph - #e Trp Thr Lys Gln Lys# 60- Ala Asn Lys Glu Gln Glu Gly Glu Tyr Tyr Cy - #s Thr Ala Phe Asn Arg#80- Ala Asn His Ala Ser Ser Val Pro Arg Ser Ly - #s Ile Leu Thr Val Arg# 95__________________________________________________________________________
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CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to U.S. Provisional Patent Application 61/788,657, filed on Mar. 15, 2013, the disclosure of which is incorporated herein by reference in its entirety for any purpose whatsoever.
BACKGROUND
1. Field
The present application relates to a travel carrying case for liquid based products used in personal care.
2. Description of Related Art
In August 2006, the Transportation Security Administration (hereinafter TSA) enacted the “311” rules that stipulate any liquids passing through security checkpoints must be only for personal use, and must be placed in containers of 3.4 ounce or less, and all containers must fit into a 1 quart (QT) bag. The TSA 311 rule=3 ounces (oz.) liquid, 1 QT plastic baggie, per 1 person.
The TSA's focus has been, and will continue to remain, squarely on managing liquid carry-ons to find explosive weapons, such as those that are carried in ordinary skin cream jars and in liquids containers. For this reason, it is not expected that the TSA will loosen the restrictions on the liquid 311 rules in the near future. In addition, large consumer brands in the personal product space spend millions on developing and enhancing brand loyalty to their products, but they rarely manufacture their products in small convenient travel sizes.
Current inexpensively made travel tubes are hard to fill, difficult to clean, and usually not meant to store liquid products contents over long periods. If the traveler has liquid product left over in the container after the trip, the unused lotion may have to be discarded, thus wasting valuable and expensive skin-care products. Additionally, these travel bottles and tubes may not be watertight sealed and may leak into travel bags. Moreover, other travel tubes and bottles containers currently available are sometimes made from unidentified types of plastics (unless there is a recycling symbol on the bottom) and are made, look and feel inexpensive and are usually not dishwasher safe. The present application provides improvements over the state of the art as described herein.
SUMMARY OF THE DISCLOSED EMBODIMENTS
Advantages of the present disclosure will be set forth in and become apparent from the description that follows. Additional advantages of the disclosure will be realized and attained by the methods and systems particularly pointed out in the written description and claims hereof, as well as from the appended drawings.
The present disclosure relates to a travel kit which includes a carrying case having a bottom portion and a top portion. The top portion connects to the bottom portion via a suitable fastener. The kit includes a plurality of containers for the carrying and storage of liquid and similar substances. The containers include a lid with a locking mechanism. The case includes a plurality of securing connectors attached to the interior wall of the top portion of the carrying case which corresponds to the shape of the plurality of containers and receives the plurality of containers. The case includes a plurality of raised edges attached to the interior bottom wall of the bottom portion of the carrying case. The plurality of raised edges correspond to the shape of the plurality of containers and receives the plurality of containers. The kit includes an instrument for transferring liquid or similar substances into the plurality of containers which is secured to the interior of the carrying case.
The present disclosure relates to a container for holding liquids which includes an upper portion with a top lid with an interior perimeter fitted gasket and a bottom portion with a hollow interior compartment for receiving liquids and similar substances. The bottom portion includes a perimeter for receiving the interior fitted gasket. The container includes a fastening means affixed to the external wall of the bottom portion and a hinge attached to the bottom portion and top lid. The upper portion of the container is sealed to the bottom portion through the interior fitted gasket and further secured by the fastener.
In some implementations, the present application's liquid carrying travel case meets the burden placed on airline travelers by allowing a traveler to pass through TSA security screening checkpoints and travel on the airplane with multiple containers of 3 ounces (oz.) or less of personal liquids, such as shampoo, hair conditioners, skin creams, liquid cosmetics, etc. in compliance with the TSA 311 rules.
The liquid carrying case of the present application benefits a more affluent traveler that is more conscious of and concerned with their appearance, health and status. Such a traveler typically uses more expensive personal liquid products, yet still is cost conscious and unlikely to purchase expensive skin creams when traveling to avoid the TSA rules or checking bags. The target market consumer would rather have some way to bring these expensive products with them in small quantities.
The liquid carrying case is not limited to air travel. The liquid traveling case is used in many other traveling situations where personal liquids (i.e. skin and hair liquid products) may be carried for personal consumption in watertight containers.
Illustrative embodiments of the liquid carrying case includes plastic Tritan® material (a type of branded engineering polymer co-polyester plastic from Eastman Chemical Company (Kingsport, Tenn.)) containers which are waterclear, highly durable, chemical and heat resistant while being dishwasher safe, food-grade and BPA-free. The liquid container design is open at the top and the containers are durable and sturdy enough to allow a user to efficiently and completely wash it out using nothing more than ordinary dishwasher detergent. Containers will be very easy to clean by hand or placed into a dishwasher.
If the containers are used for air travel, the cargo hold of any airplane is pressurized but very often unevenly temperature controlled. The cargo hold of the airplane and the airport tarmac in a colder location, could drop to or below freezing and if travel bags are left in those cold environments long enough, the bag's liquid contents could freeze as well, and through liquid freezing and the subsequent container expansion, would present a leaking hazard when the frozen liquids thaw out. The liquid carrying case of the present application solves this problem because the container design has a well built into the bottom of the container and at the top lid to accommodate a liquid freezing inside without breaking the gasket seal.
It is to be understood that the foregoing general description and the following detailed description are exemplary and are intended to provide further explanation of the disclosed embodiments. The accompanying drawings, which are incorporated in and constitute part of this specification, are included to illustrate and provide a further understanding of the disclosed methods and systems. Together with the description, the drawings serve to explain principles of the disclosure.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a perspective view of an exemplary carrying case and locking mechanism.
FIG. 2 is a perspective view of the carrying case with containers and spatula.
FIG. 3 is an alternative perspective view of the carrying case with top lid showing the bumpers and mirror.
FIG. 4 is a perspective view of the bottom lid of the carrying case showing the securing ridges.
FIG. 5 is a perspective view of an individual container in a closed position.
FIG. 6 is a perspective view of an individual container in an open position.
FIG. 7 is a perspective view of the large and small individual containers.
FIG. 8 is a perspective cross sectional view of the individual container.
FIG. 9 is a perspective view of the spatula.
FIG. 10 is the perspective views of the internal gasket of the individual container.
DETAILED DESCRIPTION
As shown in FIG. 1 , an illustrative liquid carrying case to of the present application is a personal liquid carrying case designed to be a luxury travel goods product primarily targeted to female travelers. The purpose of the liquid carrying case is to allow a traveler to pass through TSA security screening checkpoints and travel on the airplane with 3 ounces (oz.) or less of personal liquids, such as shampoo, hair conditioners, skin creams, liquid cosmetics, etc. in compliance with the TSA 311 rules. The liquid travel case usage is not limited to airline travel and the case is used for other types of travel by car or elsewhere to carry hair and skin liquid products.
The liquid carrying case to includes an external shell case top lid 11 and shell case bottom lid 12 with a sliding latch 13 located on the bottom lid 12 . The illustrated case 10 is rectangular and measures approximately 6 inches width by 8 inches length and 1.7″ inches in height (6 W×8″ L×1.7″ H), but it will be appreciated that these dimensions are non-limiting examples. The internal surface of the top lid has an illustrative logo in raised embossing. In another embodiment, the carrying case can include a variety of shapes and sizes. In another embodiment, the case can be closed by a spring loaded sliding latches, pull up latches, buttons, levers or snaps.
An example of a complete travel kit can be equipped with a mirror 21 affixed to the top lid 11 (as shown in FIG. 2 ), seven rubber bumpers 15 on the inside top lid 11 that secure the liquid containers, a separate spatula (as shown in FIG. 2 and in FIG. 9 ) that is used to transfer liquid products to the liquid containers, a protective nylon pouch cover (not shown) and an accompanying sheet of clear, white or colored adhesive labels for the containers (not shown).
As shown in FIG. 2 , the carrying case can be fitted with seven internal containers—3 large (2 oz.) containers 22 , 23 , 24 and 4 (1 oz) small containers 25 , 26 , 27 that are shaped into hexagons. In another embodiment, the case can include other transferring instruments, such as a spoon or a plastic or wooden instrument. In another embodiment, the case can include more or less containers of varying sizes and shapes.
The seven liquid containers are positioned on the bottom lid in a horizontal array in two rows, including a top row and a bottom row. The 3 large containers are positioned in the top row and the 4 small containers are positioned in the bottom row. The seven liquid containers do not touch each other due to hexagonal raised edges 44 ( FIG. 4 ). The hexagonal raised edges will be described in greater detail below.
In some embodiments, the top lid includes a first interlocking ridge 28 , and the bottom lid includes a second interlocking ridge 29 , wherein the first interlocking ridge and second interlocking ridge engage when the carrying case is in a closed position adding stability and preventing unwanted movement between the top and bottom lid. Sliding latch 13 is designed to lock into a locking portion 16 located on the first interlocking ridge. The locking portion is located in the same lateral position on the carrying case as the sliding latch. The sliding latch slides from left to right engaging the locking portion to lock the case as well known in the art.
Still referring to FIG. 2 , the seven rubber bumpers are positioned on the inner section of the top lid 11 bordering the top and bottom surfaces of mirror 21 . The seven rubber bumpers are designed to secure the seven internal containers in place. The mirror is made from an acrylic material and is positioned in the center of the inner section of the top lid. A top lip 17 and bottom lip 18 help position the mirror on the inner section of the top lid. The seven rubber bumpers have a height profile that is greater than the height profile of the mirror such that, when the carrying case is in a closed position, the bumpers are compressed against the internal containers preventing the containers from contacting and damaging the mirror.
The liquid products are placed into the liquid containers and not within the outer external case. As shown in FIG. 3 , the top lid 31 of the external case 30 has a mirror attached 32 , and seven (e.g., rubber) bumpers 15 to hold the containers in place and a spatula 91 (as shown in FIG. 2 ) that is secured inside the case. In another embodiment, the outer case can be made from either a co-polyester plastic or ABS. The bottom lid of the case 35 can have radius bumps (not shown) for feet to keep the case from sitting directly on a table. The bumps can have an average diameter of ¼″, for example, or any other suitable dimension. In another embodiment, indented discs can be added to the outer case hinge to allow for the top lid to be adjusted into a plurality (2, 3, 4 . . . ) different position. In another embodiment, the outer case can contain a spring for the latch so that when the top lid is closed against the bottom lid, the spring loaded latch seals the top lid to the bottom lid. In another embodiment, the thickness of the top lid of the individual container can be increased by 0.030″ so it does not warp under pressure. This will enhance the container top lid's stability when closed.
In another embodiment, the sides of the outer case, where the top and bottom lids meet, can be longer to further stabilize the case when sealed. In a further embodiment, the carrying case can be imprinted with designs utilizing a hydrographic printing process. The designs are preferably disposed only on the outside of the case.
In another embodiment, the outer case can be square or box shaped and has less curvature in the front. In this embodiment, a flatter (instead of curved front design) outer case design is equipped with a pull-up spring loaded clasp instead of a sliding latch. The pull-up clasp can be attached to prongs on the bottom lid. In another embodiment, the clasp can be metal and may be adorned with decorations. In another embodiment, the bottom lid of the container can include a secondary insert affixed to the interior bottom of the case that would have hexagonal holes corresponding to the size of the liquid containers and designed to hold the liquid containers. This insert can replace the rubber bumpers in the lid to secure the containers during transit.
As shown in FIG. 4 , the spatula holder 42 can be on the bottom lid and have two sets (4 in total) of prongs protruding from the bottom with ridges to secure the spatula. The spatula can snap into the prong ridges flat horizontally on the bottom of the case. In another embodiment, the prong ridges can be on the top lid such that the spatula is held vertically instead of flat horizontally. In another embodiment, the spatula can slide into the ridge prongs vertically. Yet in another embodiment, the prong ridges can be on the top lid such that the spatula is held horizontally by the prong ridges.
Illustrated are two sizes of internal containers large (2 oz.) and small (1 oz.), wherein both are shaped into a hexagonal external shape. The carrying case can be configured to accommodate different sizes and shapes of containers. In such cases, the corresponding bumpers on the inside of the top portion of the case can be designed to receive and secure the various shaped and sized containers. The case can be equipped with 3 large containers each measuring approximately 2.6″ width by 1.5″ height with a 2 fluid ounce capacity and 4 small containers each measuring approximately 1.9″ width by 1.5″ height with a 1 fluid ounce capacity.
As shown in FIG. 4 , each container can be secured on the bottom of the outer case by placing the container into a hexagonal raised edge 44 that lines the interior of the case's bottom and follow the hexagonal shape of each of the containers. Each individual container can be removable from the raised edges in the bottom of the external shell case. In another embodiment, the hexagonal ridges may contain vertical guides on each side of the ridge of about ⅜ or ½″ tall that guide the liquid containers into the hexagonal pocket. These vertical guides protrude out from each side of the hexagonal pockets.
The hexagonal raised edges work in conjunction with the rubber bumpers ( FIG. 3 ) to secure the internal containers in place when the top lid is closed. It shall be understood, that the internal containers are not attached to the bottom lid, however they are secured in place by the combination of the rubber bumpers and hexagonal raised edges.
FIG. 5 shows perspective views of illustrative individual closed containers. FIG. 6 shows perspective views of the individual containers in an opened position. FIG. 7 shows the perspective views in relation to the differences in size between the large container and the small container. Each internal container is preferably sealable and watertight when closed to prevent the personal liquids from leaking out during travel. The lid on each container can be fitted with a hexagonal gasket to ensure watertight sealing. FIG. 8 shows the gasket locking mechanism of the containers. FIG. 10 shows a front and side perspective view of the gasket. The gasket may be made from silicone, polyurethane, or polyethylene, for example. The containers are preferably made out of a food-grade, free of bisphenolA (BPA), high clarity, highly durable, and dishwasher-safe type of plastic called Tritan® (a branded type of copolyester) made by Eastman Chemical Company. In another embodiment, the gasket may be larger on the outside and larger on the inside.
The hinge/latch design of the internal containers is a useful design that prevents the containers from popping open unexpectedly during transit and requires a secondary manual motion in order to open the lid. As shown in FIG. 6 , the hinge 61 is raised and there are reinforcing support ridges 62 that extend to the container body 60 that reinforce the hinge. In another embodiment, the indent on the liquid container latch lever is convex instead of concave so it is easier to open.
As shown in FIG. 6 , In a preferred embodiment, the liquid containers are sealed and secured with a flexible external latch lever 63 that extends down the front of the container body 60 . When the latch lever 63 is sealed it catches into a latch shelf 65 which is a molded undercut built into the container top lid 64 . The external latch lever 63 on each container body 60 is a separate plastic strip extending the length of the front of the container. In order to open the containers, the top front external latch lever 63 is pressed inwards, which releases it from the undercut latch shelf 65 built into the top lid 64 . The top lid 64 is manually pulled up to open the container. When the container is sealed, the latch lever 63 is secured to the top lid 64 by the molded undercut latch shelf 65 .
A particularly inventive feature of the present invention is that the latch level is positioned on the outer surface of the container body, allowing the container top lid to remain in an uncompressed state when opening and closing the top lid. In previous container configurations, a top lid would have to be compressed to open the container, which may affect the seal of the container over time. The present invention's configuration avoids potential stress that might affect the life the container and particularly the seal, allowing the container to provide a watertight seal throughout the useable life of the container.
The design of the container's lids are preferred for preventing the lids from being jostled open when the liquid carrying case is inserted into a checked travel bag. The hinge/latch design also prevents the lid from being accidently popped open if liquid contents freeze inside the container when placed into the airplane's cargo hold or left on the tarmac in a cold temperature environment during airplane transfers.
In another embodiment, the latch can be extended lower down the container by a small distance (e.g., ¼″). In another embodiment, a small bead (e.g., ⅙″) can be located around the container lid on rim of the lid. The bead can be to assist a traveler in prying the container lid open. In another embodiment, the ridge surrounding the container is not included on the front of the container but the ridge is included on all other sides around the perimeter of the container.
As described above, FIG. 8 shows a cross sectional view of an individual container. The container 80 includes a latch shelf (a), latch lever (b), internal gasket (c), hinge (d), container top lid (e), container body (f), and inside ridge (g). As described above the latch lever fits into the latch shelf to secure the container top lid to the container body. The hinge connects the top lid and the container body and further controls the opening and closing of the top lid. The internal gasket fits along the inside of the container top lid, and is held in place by the inside ridge by tension force. The inside ridge protrudes perpendicularly from the inside surface of the container top lid, and is positioned approximately 3 mm from container body. Further, the internal gasket is an inverted “L” shape providing two sealing locations, specifically positioned vertically along the inside wall of the container body and the inside ridge, and positioned horizontally flat against the inside surface of the container top lid and a top surface (h) of the container body. When the container top lid is in a closed position (as illustrated), the internal gasket seals the container by means of a compression force of the container top lid against the top surface of the container body, and from the inside surface of the inside ridge against the inside wall of the container body. The internal gasket further comprises a first protruding finger (i; FIG. 10 ) and a second protruding finger (j; FIG. 10 ). The first and second protruding fingers provide additional sealing by gripping the inside wall of the container body. The internal gasket and protruding fingers are further shown and illustrated in FIG. 10 .
As mentioned previously a well 82 is built into the bottom of the container to accommodate changes in pressure and allows bottom surface 81 to expand should liquids freeze in the container.
Still referring to FIG. 8 , the container top lid is attached to the container body by hinge (d). The hinge is constructed from two portions, the first portion is attached to the container top lid and the second portion is attached to the container body. The first and second portions are secured together via a pin 61 b extending through the first and second portions of the hinge. The latch level positioned in the front of the container adds pressure and works in conjunction with the force of the hinge to seal the container via the latch shelf and internal gasket.
The cargo hold of any airplane is pressurized but may have uneven temperature control unless there are animals, plants or other temperature sensitive cargo on board. The cargo hold of the airplane, and certainly the airport tarmac in a colder location, can drop far below the freezing point of water, and if travel bags are left in those environments long enough, the bag's liquid contents can freeze as well. The present disclosed embodiments are preferably configured to withstand the pressure changes that occur in a passenger cabin when an airplane takes off and lands.
An airplane will typically normalize its pressure at 8000 ft. (10.9 psia) when ascending into the air. To simulate those conditions, exemplary containers made in accordance with the teachings herein underwent testing in a polycarbonate tank with a vacuum transducer in order to simulate the change in pressure from sea level at 14.7 psia to 8000 ft 10.9 psia that is a pressure decrease of 3.8 psi (7.74 Hg), 1 inch of Mercury (Hg)=0.4911541 psia. The containers were filled about ⅔ full of water and then placed upside down on absorbent paper in the vacuum chamber. The pressure was then decreased inside the chamber to −8 Hg for 30 seconds. The test revealed that no water escaped the container nor did water visually appear on the absorbent paper.
The front external latch lever configuration of the containers has been designed to withstand the expansion pressure caused by freezing liquids. Water is known to expand by about 9% upon freezing and since many personal liquids—particularly shampoos and hair conditioners have a high content percentage of water, they can freeze as well given cold enough temperatures. The external front latch lever configuration prevents the accidental opening of the lid during travels and also adds extra protection against the containers opening when liquids freeze inside.
As a secondary precaution, the containers can also be designed with space for expansion at their bottom and top lids in case the liquids inside may freeze and expand. In the event the liquids do freeze inside the containers, since the external front clasp latch requires a manual effort to open, the lid cannot just pop open as long as the container is not overfilled. It is recommended that containers should be filled no more than the bottom lip of the container's lid.
The liquid carrying case is intended to carry personal liquids onto an airplane but is also used for travel anywhere personal liquids need to be taken, for example in a car or to the gym. The illustrated configuration of three large containers and four small containers can be particularly advantageous, based on the types of personal liquids and amounts of each liquid a traveler used during a trip. For example, the three large containers can hold liquids required in larger amounts like shampoo, conditioner and sunscreen lotions. The four small containers can hold liquids used in smaller amounts like liquid cosmetic foundation, and a variety of different skin creams like day cream, night cream, eye creams, etc.
Since each container fluid volume capacity is fairly small, the liquid carrying case product is designed for a frequent traveler who may want to carry a variety of personal liquids in small amounts for short trips. The liquid carrying case is used for both the personal and business traveler.
All types of travelers, including those who travel for personal purposes as well as business, may also want to use the liquid carrying case if they have at some point in their past travels, had a lot of personal products confiscated at the TSA security checkpoints for non-compliance with the TSA 311 rules.
Another benefit of the containers is that, in some embodiments, they can be made from a specially designed plastic called Tritan® plastic, which is a copolyester resin and not a polycarbonate (which contains BPA). The Tritan® plastic does not contain BPA and therefore will not leach BPA (a harmful chemical) into the skin or hair liquid products. The liquid containers can be made from an FDA food-grade rated version of Tritan® copolyester plastic resin. Since this chemical leaching will not occur, and the plastic used is food-grade, the internal compartment containers can also be used for long-term storage of any unused liquid products—i.e. skincare lotions-remaining at the end of trip. Thus, expensive skin creams and the like will not be wasted by having to discard them when the trip is over.
The liquid carrying case is useful for the frequent traveler who is a loyal consumer of commercial skin-care lotions and creams, shaving creams, makeup and other liquid personal products. Large consumer brands in the personal product space spend millions of dollars on developing and enhancing brand loyalty to their products, but they rarely manufacture their products in small convenient travel sizes. Many of the commercially available brand skin care product sizes are over 3 oz., or if they are under 3 oz, the jar is often large and bulky and won't fit into a 1 QT size plastic bag as required by the TSA. Because of the size constraints for traveler's favorite products, many business airline travelers are forced to place their favorite skin creams into checked suitcases that otherwise may be more conveniently carried onto the plane.
Alternatively, for the frequent airline travelers who cannot or will not check their bags, they usually won't be able to use their favorite liquid products. These travelers are forced to buy other skin care products, often of inferior quality, or travel sized skin-care products available at pharmacies for their carry-on bags. Applicant intends that the product shall be sold and marketed under the name Airsafe Carryon™.
Various other components may be included and called upon for providing for aspects of the teachings herein. For example, additional materials, combinations of materials and/or omission of materials may be used to provide for added embodiments that are within the scope of the teachings herein. In the present application a variety of variables are described, including but not limited to components and conditions. It is to be understood that any combination of any of these variables can define an embodiment of the disclosure. Other combinations of articles, components, conditions, and/or methods can also be specifically selected from among variables listed herein to define other embodiments, as would be apparent to those of ordinary skill in the art.
When introducing elements of the present disclosure or the embodiment(s) thereof, the articles “a,” “an,” and “the” are intended to mean that there are one or more of the elements. Similarly, the adjective “another,” when used to introduce an element, is intended to mean one or more elements. The terms “including” and “having” are intended to be inclusive such that there may be additional elements other than the listed elements.
While the disclosure refers to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the disclosure. In addition, many modifications will be appreciated by those skilled in the art to adapt a particular instrument, situation or material to the teachings of the disclosure without departing from the spirit thereof. Therefore, it is intended that the disclosure not be limited to the particular embodiments disclosed.
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BACKGROUND OF THE INVENTION
[0001] 1) Field of the Invention
[0002] The present invention relates to optical-based pulse oximetry. It concerns, more particularly, a pulse oximetry device for monitoring the oxygen saturation (the so called SpO2) of the haemoglobin in arterial blood.
[0003] One very interesting application of the invention is the help of subjects requiring continuous SpO2 monitoring, such as, for example, persons suffering from sleep disturbances, neonates, persons having aerospace and aviation activities, alpinists, high altitude sportsmen.
[0004] 2) Description of Related Art
[0005] Since the early works of T. Aoyagi, the principles of pulse oximetry have been established (J. G. Webster, Design of Pulse Oximeters, Institute of Physics Publishing, 1997).1]. Two contrasting wavelength lights (e.g. λ r =660 nm and λ ir =940 nm) are injected in a tissue and a reflected or transmitted part of the photons is further recuperated at the skin surface. The changes in light absorption occurred through the pulsated vascular bed are analysed by means of the Beer-Lambert law. According to this law, the intensity l of light recuperated at the skin surface can be characterized by the expression I=I 0 e α λ d , where I 0 denotes the baseline intensity of light and e α λ d models the vascular bed absorption which depends on the absorption index α λ at the wavelength λ and the vascular bed thickness d.
[0006] Due to cardiac activity, the thickness of the vascular bed continuously evolves (d=d 0 +Δd(t)) and so does I=I(t). By identifying a characteristic cardiac pattern in both I r and I ir , an estimation of the ratio α r /α ir can be obtained. Hence, the relative content of oxygenated haemoglobin in the arterial tree is derived by means of an empirically calculated calibration look-up table.
[0007] Classical pulse oximeters, one example of which is described in the above-mentioned publication, require the cardiac pattern to be continuously identified and tracked. The apparition of the cardiac activity in the optical intensity is detected by a photo-plethysmograph. The amount of absorbed light correlates with the pulsation of arterial blood, and thus, to the cardiac activity.
[0008] In the state-of-the-art, two types of SpO2 probes are currently used, namely reflectance and transmission probes. Both methods are based on the placement of two light sources (LED) and a light detector (photodiode) on the skin surface.
[0009] In transmission probes, the optical elements are located on opposite sides of a body part. This configuration assures an easy detection of pulsatile patterns but limits considerably the areas of the body where it can be used: finger-tip, ear-lobes and toe.
[0010] In reflectance probes, both optical elements are placed at the same plane of a body surface. The recuperated light is, in this case, backscattered in the body and collected at the skin surface. This configuration virtually allows locating the SpO2 probe at any body placement but creates a severe limitation on its ambulatory use. The probe design must eliminate the possibility of direct light passing from the optical source to the photo-detector (cross-talk or optical shunt). Up-to-date, this limitation has been solved either by glue-fixing the probe to the skin or by means of vacuum techniques. An alternative approach is to further separate the optical components. Hence, the probability of cross-talk is considerably reduced. However, due to the enlarged light-path, a drastic decrease of the received light power is obtained and the detection of pulsatile light becomes troublesome. Some manufacturers have proposed the use of the ECG as an additional recording to overcome such limitations.
[0011] The WO 95/12349 publication discloses a pulse oximetry device comprising first, second and third light sources, for placement on the skin surface, light detectors located at a relatively short distance from the first light source and at relatively long distance from the second and third light, and computing means performing a statistical analysis of the noise contributions of the output signals of the long and short distance light detectors for deriving more accurate oximetry measurements.
[0012] A disadvantage of this method is that it requires that the light intensities measured at the long and short distances depict enough quality to be used in the computation. Two possibly wrong indications may, therefore, if they are combined, lead to a completely wrong oximetry measurement.
SUMMARY OF THE INVENTION
[0013] It is an object of this invention to provide a device for monitoring arterial oxygen saturation that does not suffer from the above mentioned disadvantages.
[0014] It is another object of this invention to provide a device for monitoring arterial oxygen saturation that extends the use of reflectance optical-probes to any body location by reducing fixation constrains. Even more, the method overcomes the requirement of an auxiliary ECG recording and restricts the probe to an optical-only-sensor.
[0015] These objects are attained according to the invention by providing an optical based pulse oximetry device comprising:
first, second and third light emitting means, for placement on the skin surface of a body part of a person to inject light in a tissue of said part, the wavelengths of the light emitted by said second and third means being different from each other, first light detecting means for collecting, at the skin surface, light from said first emitting means having travelled through said tissue, second and third light detecting means for collecting, at the skin surface, respectively light from said second and third emitting means having travelled through said tissue, said first detecting means being located at a shorter distance from said first emitting means than the distance separating said second and third detecting means from said second and third emitting means, and delivering shorter distance output signals representative of the cardiac activity of the person, said second and third detecting means being located at a longer distance from said second and third emitting means than the distance separating said first detecting means from said first emitting means, and delivering longer distance output signals, first computing means for denoising said longer distance output signals by using said shorter distance output signals, and second computing means for deriving oximetry measurements from said denoised longer distance output signals.
[0023] In other words, the device of the invention derives an oximetry measurement from only the long distance signals, able to provide a more accurate indication than the short distance signals, which are simply used, as synchronisation (triggering) signals, to denoise the long distance signals. The risk resulting from a possibly double wrong source of information for the final computation is therefore eliminated. This approach is not rendered obvious by the teaching of the already cited WO 95/12349 publication.
[0024] According to a first preferred embodiment of the invention, said first computing means is programmed to detect the temporal positions of every maximum of the output signals of said short distance light detecting means, then to perform, from the sequence of the detected maximum positions, a triggered averaging of the output signals of said long distance light detecting means.
[0025] According to a second preferred embodiment of the invention, said first computing means is programmed to estimate a representation of the spectral distribution of the output signals of said short distance light detecting means, then to perform, from said estimated representation, the restoring of the output signals of said long distance light detecting means.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Other features and objects of the present invention will become more apparent by reference to the following description taken in conjunction with the attached drawings, in which:
[0027] FIGS. 1 and 4 are block diagrams of two preferred embodiments of an optical based pulse oximetry device according to this invention; and
[0028] FIGS. 2 and 3 show two examples of placement of the light emitting means and the light detecting means at the skin surface.
DETAILED DESCRIPTION OF THE INVENTION
[0029] When performing reflectance pulse oximetry, two main reasons justify the increase of the physical separation between optical parts (LEDs and photo-diode).
1. In any pulse oximetry probe, the relative pulse amplitude is a good indicator of the quality of the probe placement. This quality factor, usually depicted as Perfusion Index (PI), is also interpreted as a quantification of the width of the vascular bed traversed by a light beam. It was demonstrated (Y. Mendelson, Noninvasive Pulse Oximetry Utilizing Skin Reflectance Photoplethysmography, IEEE Transactions on Biomedical Engineering, Vol 35, No 10, 1988) that, given a reflectance probe, the PI is linearly increasing with the increase of the physical separation between the optical parts. 2. The probability of direct-light being short-cut from the light sources to the light detector by scattering in the outer part of the skin or/and successive reflection in the probe-skin interface is reduced when both optical elements are dispersed. Due to the reduced light short-cut, probe design can be simplified (no glue fixing is required anymore).
[0032] However, by increasing the distance between the optical parts, the absolute intensity of received light at the light detector is exponentially decreased and, thus, the quantification of the pulsatile signal becomes problematic, compromising the feasibility of successfully identifying cardiac activity.
[0033] In the state-of-the-art reflectance probes, the facts here exposed have imposed a trade-off between:
Increasing the physical separation of optical elements, thus reducing cross-talk and increasing the Perfusion Index (PI). Assuring enough light intensity at the photo-detector.
[0036] This trade-off has historically forced transmittance probes to include severe fixing mechanism such as glue or vacuum approaches, as described in the already mentioned J. G. Webster publication or by V. Konig (Reflectance Pulse Oximetry—Principles and Obstetric Application in the Zurich System, Journal of Clinical Monitoring and Computing 14:403-412, 1998).
[0037] The following table summarizes the advantages and disadvantages of near and far-field photo-plethysmography:
[0000]
Received
Perfusion
Cross-
Separation
Light Intensity
Index (PI)
talk
Utility
Near
Excellent
Poor
Likely
Easy detection of
cardiac activity
Far
Poor
Excellent
Unlikely
Reliable pulse
oximetry
estimations
[0038] The present invention merges the advantages of both near and far field photo-plethysmography in a single method. As shown in FIG. 1 , the invention consists in combining far and near photo-plethysmographs so that:
a near-field photo-plethysmograph allows the continuous tracking/detection of cardiac activity; a far-field photo-plethysmograph performs pulse oximetry measurements on the basis of estimated cardiac activity information.
[0041] According to the invention, a near-field reflectance photo-plethysmograph and a far-field reflectance photo-plethysmograph are merged in a unique device comprising:
for the near-field function, a first light source 10 , which can be a LED emitting in the infra-red range at 940 nm, a first light detector 11 , such as a photo-diode, located to receive light from the source, and a first analog-to-digital converter (ADC) 12 connected at the output of the light detector; for the far-field function, a second light source 13 , such as a LED, emitting in the infra-red range at 940 nm, a second light detector 14 , such as a photo-diode, located to receive light from source 13 , a second analog-to-digital converter (ADC) 15 connected at the output light detector 14 , a third light source 16 , such as a LED, emitting in the red range at 660 nm, a third light detector 17 , such as a photo-diode, located to receive light from source 16 , and a third analog-to-digital converter (ADC) 18 connected at the output of light detector 17 ; a microprocessor 19 connected at the outputs of analog-to-digital converters 12 , 15 and 18 ; and a display device 20 connected at the output of microprocessor 19 .
[0046] The above-mentioned wavelength values of 660 and 940 nm are just given as examples. More generally, these wavelengths must be in the visible infra-red region, i.e comprised between 400 and 2000 nm, and be different from each other.
[0047] As shown in FIG. 2 , light sources 10 - 13 - 16 and light detectors 11 - 14 - 17 are positioned at the surface of the skin S of a body part. The light detectors are at the same location. Near-field light source 10 is at a shorter distance from the detectors than far-field light sources 13 - 16 , located at the same place.
[0048] Typically, the separation between the near-field light source and the light detectors is between 4 and 10 mm, whereas the separation between the far-field light sources and the light detectors is between 10 and 50 mm.
[0049] FIG. 2 shows that the light collected by the detectors has travelled in tissue T longer and deeper for the far-field beam F than for the near-field beam N.
[0050] The above described structure is a simplified presentation of the device of the invention. Needless to mention that a single light detector and a single analog-to-digital converter can also be used in association with time-sharing control means adapted to apply to microprocessor 19 data corresponding respectively to the three light sources 10 , 13 and 16 .
[0051] According to the present invention, the light sources and the light detectors can be arranged at the skin surface in many different configurations, the only rule to respect being:
to collect a light beam having travelled over a short distance in the body, and to collect two light beams of different wavelengths in the visible infra-red region having travelled over a longer distance in the body.
[0054] Thus, for example, the three light sources can be located at the same place, with a near-field detector at short distance and far-field detectors at longer distance.
[0055] Another example is to have a plurality of light sources distributed around far-field detectors, with a near-field detector located at a shorter distance from one of the sources.
[0056] FIG. 3 shows, as a further example (with the same reference letters as FIG. 2 ), that the device of the invention can be arranged around the finger of a person. In that case, light sources 10 - 13 - 16 are located at the same place, near-field detector 11 is near the sources and far-field detectors 14 - 17 stand opposite to the light sources.
[0057] Microprocessor 19 has the following two functions:
[0058] Stage 21
Due to the increased distance between light sources 13 - 16 and far light detectors 14 - 17 , the digital signals provided by far-field analog-to-digital converters 15 and 18 are noise polluted and render very difficult a reliable identification of the cardiac activity. But the reduced distance separating light source 10 and near light detector 11 assures enough received light intensity and provides a much better identification of the cardiac activity. In stage 21 , the near-field signals are used, therefore, to base the pulse oximetry measurements on an improved far-field information.
[0060] Stage 22
The signals provided by stage 21 are finally used for conventional pulse oximetry calculations.
[0062] As shown in FIG. 1 , the digital output of near-field ADC 12 is first applied to a band-pass filter 23 , such as a Chebyshev filter Type 1, 3 rd order, having a band-pass of 0.5 to 3.5 Hz. Knowing that the useful portion of the signal corresponds to the normal, around 1 Hz, cardiac frequency of a person, this filter eliminates the portions of the signal which are outside the 0.5-3.5 Hz range.
[0063] Similarly, the digital outputs of infra-red far-field ADC 15 and of red far-field ADC 18 are first applied respectively to band-pass filters 24 and 25 , identical to band-pass filter 23 .
[0064] In addition, the digital outputs of infra-red far-field ADC 15 and of red far-field ADC 18 are applied respectively to identical low-pass filters 26 and 27 , such as Butterworth filters, 2 nd order, which have the function to eliminate the portion of the received signals above 0.2 Hz. The remaining portion of the signals are taken respectively as the DC-infra-red (DC ired ) and the DC-red (DC red ) components of the far-field signals.
[0065] The operation shown in 28 is the detection of the temporal position of every maximum of the signal delivered by band-pass filter 23 . The sequence of the maximum position is then used to perform, respectively in 29 and 30 , a triggered averaging of the infra-red and red far-field signals produced by band-pass filters 24 and 25 . The triggered averaging is performed in a similar way to that described in the already mentioned publication of J. G. Webster. The triggered averaged signals resulting from operations 29 and 30 are taken respectively as the AC-infra-red (AC ired ) and the AC-red (AC red ) components of the far-field signals.
[0066] Finally, in stage 22 , the DC ired , DC red , AC ired and AC red signals are used to perform classical pulse oximetry calculations 31 , as described by J. G. Webster. The results of the calculations are displayed by device 20 connected at the output of microprocessor 19 .
[0067] Reference is made, now, to FIG. 4 which presents another method for obtaining pulse oximetry measurements from the signals delivered by band-pass filters 23 , 24 and 25 and by low-pass filters 26 and 27 . The elements common to the device of FIG. 1 are designated by the same references
[0068] As shown in FIG. 4 , the near-field signals produced by band-pass filter 23 are used, in 32 , to estimate a a-priori representation of the spectral distribution of the cardiac activity, as disclosed, for example, in the publication of D. G. Manolakis, Statistical and Adaptive Signal Processing, McGraw-Hill Higher Education, 2000.
[0069] Then, the estimated representation of the spectral distribution of the cardiac activity is used, respectively in 33 and 34 , to denoise and/or restore the corrupted infra-red and red far-field signals produced by band-pass filters 24 and 25 . The technique used is described, for example, in the already mentioned publication of D. G. Manolakis. The restored signals resulting from operations 33 and 34 are taken respectively as the AC-infra-red (AC ired ) and the AC-red (AC red ) components of the far-field signals. They are finally used to perform the classical pulse oximetry calculations 31 .
[0070] The present invention can be used in many optical-based pulse oximetry applications. For example, a probe carrying the light sources and the light detectors can be placed:
in a head band, the frontal bone acting as reflectance surface; in a mask, the maxillary bone acting as reflectance surface; in a chest-belt, the manubrium acting as reflectance surface; around a finger; around the leg or arm of a neonate; as a ear-phone.
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CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. §119(e)(1) to provisional application Ser. No. 60/449,451 filed Feb. 24, 2003 by the inventors named herein, the entire subject matter of which provisional application is incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention relates to an umbrella for a pet, such as a dog, and particularly relates to a combined pet leash and umbrella which in an open position of the umbrella canopy overlies the pet to protect the pet from inclement weather conditions while also serving as a leash for the pet in both umbrella canopy opened and closed positions.
While umbrellas have been conventionally provided individuals to protect them from inclement weather conditions, animals likewise require protection from inclement conditions, e.g. when they are being walked. Obviously the protection afforded by the protective envelope or spread of a conventional umbrella useful to protect individuals from inclement weather conditions is insufficient to protect the pet from such conditions. The pet obviously would walk beyond the envelope of protection afforded by the individual's umbrella.
Umbrellas for pets are per se not new and a number of umbrella type devices have been adapted to protect pets from inclement weather conditions. For example, U.S. Pat. Nos. 5,546,970 and 5,918,611 disclose umbrellas for pets which are secured to conventional pet harnesses and the pet collars. These umbrellas are independent of any leash for the pet whereby the individual may retain control of the pet. Also the movement of the pet relative to the harness, collar and/or umbrella as can be discerned from those patents may cause the umbrella to be skewed from its intended protective position overlying the pet to a partially unprotecting position. See also U.S. design patents D324,117; D324,943; and D325,296. It will be appreciated therefore that there is a need for an umbrella to protect a pet from inclement weather conditions and which umbrella is under control of the individual walking the pet as well as enabling the pet to be under control of the individual via the umbrella and a leash in both umbrella opened and closed positions.
BRIEF SUMMARY OF THE INVENTION
In accordance with a preferred aspect of the present invention, there is provided an umbrella having a shaft with a handle at one end and a coupling at an opposite end for securing a leash to the umbrella whereby the umbrella/leash combination are used to secure and control the pet. The canopy of the umbrella is carried by the shaft and is secured to a sleeve slidable along the shaft between canopy opened and canopy closed positions. In the canopy open position, the canopy has an upper generally convex surface facing the handle and a generally concave lower surface facing the coupling and the pet. The canopy in the open position is angularly related to the axis of the umbrella shaft whereby the canopy is generally horizontal in use while the shaft is inclined in use and toward the individual holding the umbrella/leash combination. Ribs interconnect the sleeve and margins of the canopy and a plurality of struts interconnect between the umbrella shaft and the ribs to support the canopy. While a circular canopy using ribs of equal length and struts of unequal length, an oval canopy in plan is preferred. In that embodiment both ribs of unequal length and struts of unequal length are employed. Thus the major axis of the oval shaped canopy extends in the same direction as the shaft maintaining the angular relation between the canopy and the shaft.
In a preferred aspect of the present invention, there is provided a combined pet leash and umbrella comprising a shaft having a handle at one end and a leash coupled to said shaft adjacent an opposite end thereof. A canopy is carried by said shaft and secured thereto by a sleeve slidable along the shaft between a canopy opened position and a canopy closed position, the canopy in the opened position having a generally convex surface facing the handle. A plurality of ribs are pivotally coupled at one end to the sleeve and to the canopy at opposite ends thereof adjacent margins of the canopy to support the canopy in the opened position. A plurality of struts is pivotally connected at one end to said shaft and pivotally connected at opposite ends to the ribs, the struts supporting the ribs in the canopy opened position. A detent is co-operable between the shaft and the hub for releasably maintaining the canopy in the opened position.
In a further aspect of the present inventions, there is provided an umbrella for a pet comprising a shaft having a handle at one end and a coupling adjacent an opposite end of the shaft enabling attachment of a pet leash. A canopy is carried by the shaft and secured thereto by a sleeve slidable along the shaft between a canopy opened position and a canopy closed position, the canopy in the opened position having a generally convex surface facing the handle and a generally concave lower surface facing the coupling. A plurality of ribs is pivotally coupled at opposite ends to the sleeve and the canopy, respectively. A plurality of struts is pivotally connected at opposite ends to the shaft and the ribs, respectively, and supporting the ribs and the canopy in the canopy opened position. A detent co-operable between the shaft and the sleeve for releasably maintaining the canopy in the opened position.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic illustration of a combined leash and umbrella for a pet constructed in accordance with the preferred embodiment of the present invention;
FIG. 2 is a view similar to FIG. 1 illustrating the umbrella in an open position protecting the pet from inclement weather conditions;
FIG. 3 is a schematic illustration showing the opening and closing mechanism of the umbrella/leash with the canopy in the open position;
FIG. 3 a is a fragmentary view illustrating a different type of handle for the umbrella/leash combination;
FIG. 4 is a schematic illustration similar to FIG. 3 illustrating the umbrella in a canopy closed position;
FIG. 5 is a perspective view of the umbrella/leash combination in an open position; and
FIG. 6 is a schematic top plan view of a further embodiment hereof illustrating a circular umbrella.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to the drawings, particularly to FIGS. 1 and 2 , there is illustrated an umbrella/leash combination generally designated 10 with an umbrella canopy in closed and opened positions, respectively. The umbrella is mounted on a shaft 12 having a handle 14 at one end and a coupling 16 at its opposite end for connecting the umbrella with one end of a leash 18 . It will be appreciated that leash 18 may be releasably secured to a collar 20 on the pet, in this instance a pet dog is illustrated.
In FIG. 2 the umbrella/leash combination is illustrated with the umbrella canopy 22 in an opened position overlying the pet. While the canopy in the opened position may be circular (as discussed hereafter), preferably the canopy is in a generally oval configuration in plan with the major axis of the oval configured canopy extending in a vertical plane also containing the shaft 12 and handle 14 . From a review of FIGS. 1 and 2 it will be appreciated that the canopy 22 is supported by a plurality of ribs or spokes 24 which in turn are supported by a plurality of struts 25 . Canopy 22 is also preferably formed of a clear plastic see-through material, preferably vinyl, although other materials including opaque materials can be used.
Referring now to FIGS. 3 and 4 , the shaft 12 mounts a sleeve 26 slidable axially along the shaft 12 between detented canopy opened and closed positions illustrated in FIGS. 3 and 4 , respectively. As illustrated in FIG. 3 , the sleeve 26 is detented in the canopy opened position by a spring biased tab 28 carried by the shaft 12 . Tab 28 is receivable in an opening or slot, not shown, through the sleeve 26 when the sleeve 26 is advanced to the canopy opened position. Another spring biased tab 30 is carried on the shaft 12 at a location adjacent the handle 14 and, in cooperation with sleeve 26 , similarly serves to detent the sleeve 26 in the canopy closed position as illustrated in FIG. 4 . The ribs 24 are pivotally mounted at proximal ends to sleeve 26 . The opposite distal ends of ribs 24 are secured to margins of the canopy 22 . Any suitable connection between the distal ends of the ribs 24 and the canopy 22 may be utilized and is well known in the art. As illustrated in FIGS. 3 and 4 , the sleeve 26 has an annular recess 27 angled relative to shaft 12 . Proximal ends of the ribs 22 are pivotally mounted to sleeve 26 in the annular recess 27 and slots are formed in the lower portion of the sleeve 26 to accommodate the pivoting movement of the ribs 22 when the umbrella is moved between canopy opened and canopy closed positions. While six ribs and six struts are illustrated in this preferred embodiment, it will be appreciated that a fewer or greater number of ribs and struts may be utilized to support the canopy.
Similarly, a hub 34 is mounted on shaft 12 at a location along the shaft 12 remote from the handle and on the opposite side of the sleeve 26 from the handle 14 . Hub 34 is preferably fixed to the shaft but may be movable relative thereto. The hub 34 includes an annular recess 36 in which proximal ends of the struts 25 are pivotally mounted to the hub 34 . Upper edge margins of the hub 34 have slots for receiving the struts 25 in the canopy closed position illustrated in FIG. 4 . The opposite ends of struts 25 are of course pivotally connected to the ribs 22 intermediate opposite ends of the ribs. It will be appreciated that planes P 1 and P 2 passing through the annular recesses 27 and 36 of the movable sleeve 26 and hub 34 , respectively, lie in parallel planes. Also it will be appreciated that the major axis of the oval shaped canopy lies in a vertical plane generally also including the shaft 12 and normal to planes ρ 1 and ρ 2 . Thus the shaft 12 and the planes P 1 and P 2 passing through sleeve 26 and hub 34 in the recesses 27 and 36 form an included angle α in the vertical plane containing the major axis of the canopy 22 . The angle α preferably lies in a range of about 30°-60°. It will also be appreciated that the minor axis of the oval shaped canopy extends perpendicular to the major axis and passes perpendicularly through the vertical plane containing the shaft 12 and the major axis of the oval shaped canopy. The handle 14 and coupling 16 for the leash lie on respective opposite sides of the minor axis.
Also, as illustrated in FIG. 3 a , the handle 14 may comprise a straight handle 14 a as compared with the arcuate handle 14 illustrated in FIG. 3 . Additionally, the sleeve 26 may have a non-circular interior opening complementary to the shaft, or maybe be slidably detented to the shaft to prevent the canopy from twisting relative to the shaft.
From a review of the drawing figures, it will be appreciated that the ribs 24 defining the generally oval shaped canopy are symmetrical about the major axis. Ribs 24 along opposite sides of the canopy are, however, different in length as compared to the ribs 24 extending along the major axis of the oval shaped canopy. Likewise, the struts 25 are symmetrical about the major axis. Struts 25 along the opposite sides of the canopy are, however, different in length as compared with the struts parallel to the major axis. Further, as illustrated in FIG. 3 , the strut 25 a between hub 34 and the rib 24 forwardly of the minor axis is shorter than the strut 25 b extending between hub 34 and the rearwardly extending rib 24 on the opposite side of the minor axis. Thus, the struts paralleling the major axis of the oval shaped canopy 22 and on opposite sides of the minor axis are unequal in length relative to one another.
In use, the leash 18 is attached to the pet collar 20 and also to the distal end of the umbrella i.e., to the coupling 16 . Any suitable connection may be used. In the canopy closed position, the shaft 12 serves as part of the leash for the pet. To open the umbrella during inclement weather conditions, detent 30 is depressed enabling the sleeve 26 to be manually displaced along shaft 12 in a direction away from the handle 14 and toward the coupling 16 . Upon the sleeve 26 obtaining a position along the shaft in registration with tab 28 , the tab is biased outwardly into the slot formed on the sleeve 26 to maintain the sleeve in position along the shaft with the canopy extended in the canopy opened position as illustrated in FIG. 3 . It will be appreciated that the different lengths of the ribs 24 and the struts 26 enable the canopy 22 to open into a generally oval configuration in plan. Additionally, it will be appreciated that in the canopy opened position, a vertical plane passing through the major axis also contains the shaft 12 . The included angle between the shaft 12 and the planes P 1 and P 2 preferably lies in a range of approximately 35°-60°. Thus the canopy extends forwardly from the individual holding the handle 14 , lies in a generally horizontal position and extends lengthwise from the individual. When it is desired to close the canopy 22 , the tab 28 is depressed releasing the sleeve 26 for manual sliding movement in a direction toward the handle where it is once again detented by the tab 30 in the canopy closed position.
Referring now to FIG. 6 , there is illustrated a further embodiment of the combined umbrella/leash hereof with a canopy having a generally circular configuration. In this form, the shaft 12 a connects to the movable sleeve 26 a at the apex of the circular canopy 22 a . The shaft 12 a extends below the canopy to a fixed hub similarly as in the previous embodiment to which the struts are pivotally connected. In this form, the ribs 24 a supporting the canopy 22 a are of equal length while the struts supporting the canopy are of unequal length. This enables the circular canopy to lie in a generally horizontal orientation when in the canopy opened position with the shaft 12 a being inclined relative to the canopy.
While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
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FIELD OF THE INVENTION
[0001] The present invention relates generally to multitube catheter assemblies, and more particularly to multitube catheter assemblies having distal split independent free floating tip ends, stepped tip end or tapered tip end for positioning within an area to be catheterized
[0002] The lumens of the multitube catheter are full circular where they extend all through the distal end, the catheter main stem and the proximal end of the extension part.
[0003] The presented multitube catheter are to be used in any medical field where an access to the central venous system is required like haemodialysis, haemofiltration, plasma exchange, chemotherapy infusion . . . ect.
BACKGROUND OF THE INVENTION
(A) Technical Background
[0004] [Catheters for the introduction or removal of fluids may be located in various venous locations and cavities throughout the body for the introduction or removal of fluids. Such catheterization may be performed by using a single catheter having multiple lumens. A typical example of a multiple lumen catheter is a dual lumen catheter in which one lumen introduces fluids and one lumen removes fluids. Catheterization may also be performed by using separate, single lumen catheters inserted through two different incisions into an area to be catheterized. Procedures are also known as described for inserting two wholly independent single lumen catheters into a vessel through a single insertion site. (Such multiple catheter assemblies are known traded as Tesio catheters U.S. Pat. No. 5,776,111)
[0005] Generally, to insert any catheter in a blood vessel, the vessel is identified by aspiration with a long hollow needle in accordance with the Seldinger technique. When blood enters a syringe attached to the needle, indicating that the vessel has been found, a thin guide wire is then introduced, typically through a syringe needle or other introducer device, into the interior of the vessel. The introducer device is then removed leaving the guide wire within the vessel. The guide wire projects beyond the surface of the skin.
[0006] At this point, several options are available to a physician for catheter placement. The simplest is to pass a catheter into the vessel directly over the guide wire. The guide wire is then removed leaving the catheter in position within the vessel. However, this technique is only possible in cases where the catheter is of a relatively small diameter, made of a stiff material and not significantly larger than the guide wire, for example, for insertion of small diameter dual lumen catheters. If the catheter to be inserted is significantly larger than the guide wire, a dilator device is first passed over the guide wire to enlarge the hole. The catheter is then passed over the guide wire, and the guide wire and dilator are removed.
[0007] In the case of an individual, soft single-lumen catheter typically used in multiple catheter assemblies, a physician may use an introducer sheath. For Haemodialysis as example, each catheter may be inserted in two separate veins, such as the femoral vein. Alternatively, each catheter may be inserted in two different locations of the same vein, such as the internal jugular vein as noted above. The introducer sheath is simply a large, stiff thin-walled tube, which serves as a temporary conduit for the permanent catheter which is being placed. Tear away sheaths are also available which split apart for easier removal. The introducer sheath is positioned by placing a dilator device inside of the introducer and passing both the dilator and the introducer together into the vessel over a guide wire. The guide wire, left in the vessel after insertion as described above and the dilator are then removed, leaving the thin-walled introducer sheath in place. The catheter is placed through the introducer sheath. Each of the catheters in the assembly is typically subcutaneously secured within the patient's body by a cuff located in a subcutaneous tunnel, or by otherwise externally affixing the catheter to the body.
[0008] The Single lumen catheter may also be inserted, as noted above, through a single insertion point using a sheath into the vessel. The catheter, once inserted in the vessel, is then tunneled separately through the patient in two subcutaneous tunnels for securement of the external, proximal portions of the catheter.
[0009] The double catheter assembly, while comfortable for the patient, due to its soft durometer, and very effective for Haemodialysis, typically requires multiple procedures and incisions for insertion and/or for tunneling, which increase the attendant risks of the catheterization procedure. Further, in the case of side-by-side placement of two catheter tubes through a single insertion site in a vessel, while minimizing the number of procedures, can present a potential for leakage between the catheter tubes at the point where the catheter tubes pass into the vessel.
[0010] However, catheters like Tesio catheter assemblies provide catheters which are capable of independent movement within the vessel. Such catheters present several advantages over one catheter with multiple lumen. Because the individual tubes of a Tesio double catheter assembly are independently movable at their fluid outlets, it is possible to provide fluid intake and/or return flow around the entire circumference of the distal ends of the catheter tubes. In addition, if one tube becomes blocked, or otherwise requires replacement, it can be removed independently of the other tube. Further, the softer durometer of such catheters, which are typically made of a silicone or a similar material, reduces the risk of vessel wall damage. The 360.degree. circumferential flow provides a more stable tube within the vessel, which is less likely to be suctioned against the vessel wall due to a pressure differential, as occasionally occurs in the use of some side-by-side multi-lumen catheters.
[0011] U.S. Pat. No. 5,718,692, issued to Schon, et al., (“the Schon catheter”) describes a self-retaining double catheter system in which each catheter can be subcutaneously secured without the use of fabric tissue ingrowth cuffs or external suturing as a result of the placement of a retaining sleeve surrounding both individual catheters in a multiple catheter assembly to hold the catheters together at the location of the sleeve. The individual catheters are permanently linked in one portion by a hub for self-anchoring under the skin, as an alternative to requiring a fabric stabilizing cuff, such that such cuffs are optional. The distal ends are longitudinally prespaced by an appropriate distance to avoid recirculation. While this device requires only one incision, it requires two subcutaneous tunnels in order to facilitate the self-retaining feature. This catheter provides independently movable distal ends within the vessel and 360.degree circumferential flow in the manner of a standard Tesio. Further, since the retaining sleeve is located outside the vessel when in place to provide the self-retaining feature, at the point of entry into the vessel, the catheters are side-by-side in the manner of a standard Tesio catheter, and there still remains the potential risk of blood leakage between the catheters at the vessel site.
[0012] The idea of using splitable catheter rose in 1983 U.S. Pat. No. 4,411,654 issued to Boarini et al, by using longitudinal lumens or grooves are placed 180 degrees apart into the wall of the catheter during extrusion to provide lines of weakness from the proximal end to the distal end of the catheter.
[0013] U.S. Pat. No. 5,180,372 issued to Vegoe, et al. describe an improved placement catheter of the type having a longitudinal line of weakness whereby the catheter may be split longitudinally. The improved catheter is made with radiation cross-linked tubing to provide better splittability.
[0014] U.S. Pat. No. 5,947,953 issued to Ash et al. (2001) (“the split Ash catheter”) discloses a splittable multiple catheter assembly that has a hub and at least two fully independent catheter tubes which are initially releasably joined together, for example, by a breakable membrane. A single subcutaneous tunnel may be used in inserting the catheter, and the catheter tubes are at least partially separated by splitting the catheter tubes prior to insertion into a vessel. As a result, the portions of the catheter within the vessel are capable of independently moving and having 360.degree. circumferential flow from the distal portion of each tube. The catheter may be secured using standard securement means such as suturing, ingrowth or other available securement devices.
[0015] U.S. Pat. No. 20,030,153,898 issued to Schon et al (2003) (“the Schoncath”) discloses a multilumen catheter assembly, which includes a unitary portion and at least two distal end tubes extending distally from the unitary portion. The unitary portion includes an exterior having a generally round or oval shape in cross section and includes at least two distal end tubes of generally circular (or other) cross sectional shape extending longitudinally therethrough. The catheter assembly may be made by extruding a unitary tube having internal longitudinally extending lumens (of circular or other shape), then splitting the tube on its distal end portion to form distal end tubes. The tubes are then ground and polished, the finished tubes retaining in combination the generally oval cross sectional shape of the unitary extrusion, or the finished tubes can each be finished to a circular, or other, cross sectional shape, or the finished tubes could include a combination of cross sectional shapes over its longitudinal length.
[0016] U.S. Pat. No. 6,524,302 which issued to Kelley (February, 2003), describes A multi-lumen catheter and method of manufacturing such a multi-lumen catheter having a plurality of individual catheter tubes. Each catheter tube has an outer surface, an inner surface and a lumen. The catheter tubes can be made of different thermoplastic materials. A mandrel is first inserted into the lumen of each catheter tube to provide support. The catheter tubes are then juxtaposed to each other in an arrangement. Importantly, the outer surface of one catheter tube is in contact with the outer surface of at least one other catheter tube in the arrangement. The arrangement of catheter tubes is then held in a sleeve and is advanced through the sleeve, and through a heating cylinder to fuse the outer surfaces of the catheter tubes. A cooling means is placed in the lumen of each catheter tube to prevent the inner surface of each catheter tube from melting.
[0017] There is a need in the art for a multiple catheter assembly and a need for making such a catheter assembly which can provide the advantages of the above-mentioned multi-lumen catheters with respect to easy insertion through a single tunneling procedure and which can prevent the potential risk of leakage at the site of vessel entry, but which can still provide the advantage of multiple catheter assemblies with respect to independent movement within a vessel and good flow properties.
(B) Manufacturing Background
[0018] The SchonCath (U.S. Pat. No. 20,030,153,898) invention includes methods for making the multilumen catheter. The method includes forming a unitary catheter tube having a proximal portion, a distal portion, and a distal end portion terminating in a distal end tip. The unitary catheter tube may be formed using any suitable heat molding process, including injection molding, expansion/compression molding, and extrusion. The unitary catheter tube is formed by extrusion through a die to form internal lumens, the lumens are substantially the same and substantially identical in size and configuration. The unitary catheter tube, with internal longitudinally extending lumens, may also be formed by injection molding the tube around metal rods which have the shape of the internal lumens. The unitary catheter tube is then split longitudinally along the distal portion of the tube using a sharp edge such as a hot knife or razor blade for a pre-determined distance, depending upon the particular size desired for the catheter. The tube is preferably split as evenly as possible between the two lumens along an internal septum. Splitting the unitary catheter tube forms a first distal end tube and a second distal end tube The second distal end tube can then cut to size relative to the first distal end tube, if it is desired that one distal end tube be greater in length than the other. Separate lengths for the distal end tubes helps avoid recirculation of fluids entering and leaving the tubes within the area to be catheterized. After the unitary catheter tube and the distal end tubes are formed, the exterior surface of the unitary catheter tube and the exterior surfaces of the distal end tubes are then ground and polished to a smooth surface. Radio frequency (RF) tipping can be used to provide the smooth surface. Radio frequency (RF) tipping uses RF energy to re-heat an outer surface until there is some melting and then to polish the surface. Further, the unitary catheter tube and the distal end tubes could undergo radio frequency (RF) tipping on a mandrel, so that the tubes may be re-shaped to have a generally circular transverse cross section both in the interior passageways (lumens) and on the exterior surfaces, if desired. Once the surfaces are shaped and smoothed, holes can then be formed in the distal end tubes, if desired, using techniques well known in the art. The number, size, shape, and spacing of the holes are as individually preferred, but some general and specific aspects have been described above. Portions of the split catheter can then be releasably attached, if desired, by bonding portions of exterior surfaces of the distal end tubes with a weak adhesive. As an alternative to splitting the unitary catheter tube, after forming that tube, individual distal end tubes, which may be previously extruded or heat molded, may be fused onto the unitary catheter tube. The distal end tubes are formed such that they each have a respective longitudinal passageway (lumen) extending longitudinally therethrough, and may also be formed to include a plurality of holes either prior to attachment to the distal end of the unitary catheter tube. Each formed distal end tube is then attached to the distal end of the unitary catheter tube by a suitable heat molding process, or by another form of attachment, such as adhesive, ultrasonic welding or other methods known in the art, such that the first passageway in the first distal end tube is in fluid communication with the first lumen of the unitary catheter tube and the second passageway in the second distal end tube is in fluid communication with the second lumen in the unitary catheter tube. In one aspect of the invention, heat fusing is used to attach the distal end tubes, and the fusing may be carried out using heat applied to the unitary catheter tube and to the distal end tubing lengths in a female cavity mold to create a smooth fused portion where the tube and end tube lengths meet. Extension tubes may be provided either by extruding or molding the extension tubes initially when forming the unitary catheter tube using techniques similar to those used to form the distal end tubes as described above. However, it is preferred to attach the extension tubes to a proximal end of the unitary catheter tube using a hub. A hub is then molded around the proximal end of the unitary tube and the distal end of the proximally extending catheter tubes. Preferably, to maintain the unitary catheter and extension tubes in place, the hub mold either has cavities to receive the tubes, or metal rods inserted through the extension tubes and lumens within the formed unitary catheter portion, to retain the shape of the lumens and hold the tubes in place. A plurality of holes may also be provided to the distal end portions of the catheter tubes.
[0019] The Split Ash catheter (U.S. Pat. No. 6,190,349) invention, the multiple catheter assembly includes extrusion of a first catheter has an outer surface defining a first lumen. The second catheter has an outer surface defining a second lumen extend through the full length of their respective catheters. Te lumens each have a generally semi-circular cross section. Accordingly, the first catheter has an outer surface defined by a rounded wall portion and a generally flat side surface, and the second catheter also has an outer surface defined by a rounded wall portion and a generally flat side surface, as viewed in cross section. The flat side surfaces face each other. The generally flat side surfaces do not touch each other, but are very close. Also, the lumens and respective rounded wall portions and generally flat side surfaces are identical to each other so that the cannulating portion of the catheter assembly has a generally circular cross section. The catheter assembly includes a splitable membrane which extends longitudinally between and joins the opposite generally flat side surfaces of the first and second catheters. It is preferred that the membrane extends between the central line of the flat side surfaces for dimensional stability. However, the membrane could extend between edges of the side surfaces or between other regions of the flat side surfaces or rounded wall portions. The membrane performs multiple functions. First, the membrane joins the first and second catheters so that the catheters can be easily manipulated, particularly along the section of the catheters where the membrane is unbroken. If the membrane is completely intact, the catheters can be manipulated as a single catheter. Second, the membrane allows the first and second catheters to be at least partially longitudinally split apart from each other without damaging the outer surfaces of either of the first or second catheters thereby allowing independent movement of the split end regions in the vessel or other area to be catheterized. The membrane is constructed to split easily when the first and second catheters are forcibly separated from each other. The membrane has a cross-sectional width at its thinnest portion is a very small fraction of the outer diameter of the catheter assembly to facilitate easy tearing. The membrane is constructed of a material which will tear before the forces exerted on the outer surfaces of either of the first or second catheters reach a level sufficient to cause damage thereto. However, the membrane material should be sufficiently strong to resist tearing during normal handling of the assembly. The membrane has a cross-sectional length which is also a small fraction of the outer diameter of catheter assembly. The cross-sectional length also defines the distance between the generally flat side surfaces. The cross-sectional distance is preferably small to maintain an overall generally circular cross section for the un-separated section of the catheter assembly and to facilitate handling of the un-separated section of the catheter assembly in the cannulation portion. The cannulation portion is joined to the extension tube portion by a hub.
[0020] Kelly catheter (U.S. Pat. No. 6,524,302) and method for manufacturing can't control the surface or the size of the end result fused tube as the cross-section of the multi-lumen catheter has an outer periphery with at least three distinct lobes, with each distinct lobe corresponding to one of said fused tubes and not round outer surface area. Also an additional lumen is created from the outer surfaces of the three fused catheter tubes.
SUMMARY OF THE INVENTION
[0021] The present invention relates generally to multitube catheter assemblies includes two or more tube fused together to form one catheter tube shaft. Each tube has at least one lumen extending longitudinally through the catheter from its distal end to its proximal end. The tubes are fused together by use of heat & pressure.
[0022] The multitube catheter assemblies has distal split independent free floating tip ends, stepped tip end or tapered tip end for positioning within an area to be catheterized.
[0023] The lumens of the multitube catheter are full circular where they extend all through the distal end, the catheter main stem and the proximal end of the extension part. The presented multitube catheter are to be used in any medical field where an access to the central venous system is required like haemodialysis, haemofiltration, plasma exchange, chemotherapy infusion . . . ect.
[0024] The way of fusion and the degree of heat and pressure applied, can allow the catheter tubes to be releasable joined and can longitudinally split from each other. The tubes are fused together by use of heat sensitive tube slides over the tubes while metallic mandrels are passed through each tube lumen to protect the lumens during fusion. The heat sensible tube will generate pressure once heat is applied. Continual heating will melt/re-shape the catheter tubes inside the heat sensitive tube. After cooling the heat sensitive tube is to be removed around the catheter tube. The metallic mandrels then pulled back. The tubes, forming the one catheter tube are separated at each end. The end result is a multitube tube catheter has a distal splited end.
[0025] In one aspect of the present invention, the assembly includes fusion between first tube and shorter second tube together to form one catheter tube. Each tube has at least one lumen extending longitudinally through the catheter. The way of fusion and the degree of heat and pressure applied, allow the catheter tubes to be un-releasable joined. The tubes are fused together by use of heat sensitive tube slides over the tubes while metallic mandrels are passed through each tube lumen to protect the lumens during fusion. The heat sensible tube will generate pressure once heat is applied. Continual heating will melt/re-shape the catheter tubes inside the heat sensitive tube. After cooling the heat sensitive tube is to be removed around the catheter tube. The metallic mandrels then pulled back. The end result is a multitube tube catheter has a distal stepped end.
[0026] In another aspect of the present invention, the assembly includes fusion between two or more tube fused together to form one catheter tube shaft. Each tube has at least one lumen extending longitudinally through the catheter from its distal end to its proximal end. The way of fusion and the degree of heat and pressure applied, allow the catheter tubes to be un-releasable joined. The tubes are fused together by use of heat sensitive tube slides over the tubes while metallic mandrels are passed through each tube lumen to protect the lumens during fusion. The heat sensible tube will generate pressure once heat is applied. Continual heating will melt/re-shape the catheter tubes inside the heat sensitive tube. After cooling the heat sensitive tube is to be removed around the catheter tube. The metallic mandrels then pulled back. The distal end of fused united tube is tapered tipped. The end result is a multitube tube catheter has a distal tapered tip end.
[0027] In another aspect of the present invention, the catheter tube stem, the distal end tubes, and the lumens, can also have a different shape or configuration at different points along a respective longitudinal length of each.
[0028] In another aspect of the present invention, Through using the art of heat shrink tube, the outer wall of the catheter stem tube, the outer wall of the distal end tubes, and the lumens, can have various shapes in cross section, such as but not limited to a circular, semi-circular, or oval shape.
[0029] In another aspect of the present invention, the first and the second distal end tubes are possibly having an outer wall with half-circular cross section, that can be re-formed to a circular wall by using the same principle of the current invention by applying a heat shrink tube over each of the distal tube.
[0030] The present invention also provides a method for making a multitube catheter assembly, by fusing two or more tubes together by use of heat sensitive tube slides over the tubes while metallic mandrels are passed through each tube lumen to protect the lumens during fusion. The heat sensitive tube will generate pressure once heat is applied. Continual heating will melt/re-shape the catheter tubes inside the heat sensitive tube while the letter will not be affected due to its high melting temperature. After cooling the heat shrink tube is removed around the fused catheter tubes, the metallic mandrels pulled back and the tubes, forming the one catheter tube.
[0031] In another aspect of the invention a method for making a multitube catheter assembly, by fusing two or more tubes together by use of a elastic tube stretched & slides over the tubes while metallic mandrels are passed through each tube lumen to protect the lumens during fusion. The elastic tube will compress the catheter tubes. Continual heating will melt/re-shape the catheter tubes inside the silicon tube while the letter will not be affected due to its high temperature resistance. The elastic tube will compress over the melted catheter tubes. After cooling the elastic tube is slide back the fused catheter tubes, the metallic mandrels pulled back and the tubes, forming the one catheter tube. The elastic tube can be silicon, rubber or equivalents material.
[0032] In another aspect of the invention, a cuff or similar device is applied to the catheter stem. The absence of a connector or a hub between catheter shaft and extension line allows the catheter to be tunneled in both direction i.e. placing and positioning of catheter tip inside the vessel then tunnel the subcutaneous part OR tunnel the subcutaneous part then advance the catheter tip in the vessel. Catheter luer end is to be provided separately (to be assembled after tunneling) or pre-attached to the extension lines.
[0033] In another aspect of the invention, the absence of a connector or a hub between catheter shaft and extension line allows the catheter to be advanced and positioned to any desirable length then fixed with any fixation devices.
[0034] In another aspect of the invention, the multitube catheter assembly extension legs (lines) may end in a fixed or removable luer end.
BRIEF DESCRIPTION OF THE DRAWINGS & PICTURES
[0035] The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate the presently preferred embodiments of the invention, and, together with the general description given above and the detailed description given below, serve to explain the features of the invention in the drawings:
[0036] FIG. 1 is a top plan view of a catheter assembly according to the first embodiment of the present invention.
[0037] FIG. 2 is a top plan view of a catheter assembly according to the second embodiment of the present invention.
[0038] FIG. 3 is a top plan view of a catheter assembly according to the third embodiment of the present invention.
[0039] FIG. 4 is an enlarged view of catheter tube cross sectional changes during different steps of the fusion process.
DETAILED DESCRIPTION OF THE INVENTION
[0040] In describing the embodiments of the invention illustrated in the drawings, specific terminology will be used for the sake of clarity. However, the invention is not intended to be limited to the specific terms so selected, it being understood that each specific term includes all technical equivalents operating in similar manner to accomplish similar purpose. It is understood that the drawings are not drawn exactly to scale. In the drawings, similar reference numbers are used for designating similar elements throughout the several figures.
[0041] The following describes particular embodiments of the invention. However, it should be understood, based on this disclosure, that the invention is not limited to the embodiments detailed herein. Generally, the following disclosure refers to dual or triple lumen catheter assemblies, although catheter assemblies having more lumens and/or distal end tubes are within the scope of the invention. Further, the methods described below for making the catheter assemblies of the present invention are also applicable to making catheter assemblies having more than two lumens and/or distal end tubes. It is only for reasons of convenience that the following description refers to two or three lumen embodiments of the present invention.
[0042] The multitube catheter assemblies of the present invention are inserted into an area of a body of a patient to be catheterized for removing and introducing fluids to the body. The catheter assemblies of the present invention are secured to a fixed location in or on the patient body, such as a subcutaneous area, before the catheter assembly is properly inserted and positioned in the area to be catheterized. This method is particularly preferred for long term catheterization. Alternatively, in short term catheterization, the catheter assemblies of the present invention may be secured to an external surface of the body before or after the catheter assembly is properly inserted and positioned in the area to be catheterized.
[0043] The multitube catheter assemblies of the present invention can be adapted for use in various applications in which bodily fluids, medicaments, or other solutions are introduced into and removed from the body, such as perfusion, infusion, plasmapheresis, hemodialysis, chemotherapy, and the like. The catheter assemblies of the present invention are particularly suitable for chronic hemodialysis and apheresis. The area to be catheterized is preferably a blood vessel, such as an internal jugular vein, but may be any suitable area within the body. Other areas in which the catheter assemblies may be used include other blood vessels, including the femoral and subclavian veins, any cavity, and other areas of the body including intra-abdominal, sub-diaphragmatic and sub hepatic areas. It is understood that the above-referenced areas are exemplary, and that the catheter assemblies of the present invention may be used to remove or introduce fluids to various areas to be catheterized.
[0044] The embodiments of the present invention shown in the figures are particularly useful for intake, or removal, of blood to be purified from a blood vessel, such as the internal jugular vein, and introduction of purified blood into the same vessel. The blood can be purified by any suitable hemodialysis apparatus attached in communication with lumens of the disclosed catheter assemblies. The catheter assemblies of the present invention may also be used to introduce medication or other fluids, including glucose or saline solutions, into the body.
[0045] For purposes of describing the embodiments of the present invention shown in the figures, the catheter assemblies will be described with respect to an application of hemodialysis and or as channeling to the venous system. However, it is understood that the catheter assemblies of the present invention can be configured and adapted, by increasing or decreasing a size (diameter or length) and/or number of distal end tubes and/or lumens in the respective catheter assembly, so that the catheter assembly can be beneficially used for other medical applications in which fluids are introduced into and/or removed from the body.
A First Embodiment
[0046] FIG. 1 illustrates one embodiment of the present invention, where a catheter assembly has at least two lumens. The illustration of two lumens is exemplary, and the scope of the invention encompasses catheters having more than two lumens.
[0047] The catheter assembly includes first tube T 1 which has a proximal end 101 and a distal end 103 . The catheter assembly includes second tube T 2 which has a proximal end 104 and a distal end 106 . The fist tube T 1 and the second tube T 2 united (fused) at catheter shaft TC as a result of fusion of a portion 104 of first tube T 1 and the 105 of second tube T 2 .
[0048] The catheter assembly can be provided (manufactured) so that the first distal end tube D 1 and the second distal end tube D 2 are splitable (releasable attached) or separate at their respective distal ends. Splitable is defined as releasable attached, meaning the first and the second distal end tubes D 1 and D 2 are fused, or otherwise attached, so that only minor force is necessary to pull apart, or split, along the imaginary line 118 .
[0049] The First tube T 1 and second tube T 2 are split at the end of the catheter tube fused part TC at the point 108 and form free floating distal parts D 1 & D 2 .
[0050] The multilumen catheter assembly includes a first lumen 112 and a second lumen 113 extending longitudinally therethrough as illustrated at C 1 .
[0051] The first lumen 112 is continuous with and through the floating distal part D 1 , the catheter shaft TC and first extension tube E 1 . The second lumen 113 is continuous with and through the floating distal part D 2 , the catheter shaft TC and first extension tube E 2 . The first and the second extension tubes E 1 and E 2 lead to a proximal end of the catheter assembly, through which the materials entering and or exiting the patient enter and/or exit the catheter assembly. The words “proximal” and “distal” refer to directions away from and closer to, respectively, the inserted end of the catheter assembly.
[0052] The exterior of the catheter shaft TC is smooth, rounded without ridges or grooves.
[0053] As shown in the cross-section C 1 of the catheter shaft TC, the outer surface of the catheter shaft TC is generally rounded in shape (outer configuration), C 1 illustrating in cross-section a generally round shaped outer wall, with the first and the second lumens 112 , 113 having a circular cross-section. Catheter shaft TC can have various shapes, such as but not limited to circular, semi-circular or oval. Also lumen cross section can have various shapes, such as but not limited to circular, semi-circular or oval
[0054] A cuff 114 may and may not be located at a point along the catheter shaft TC. Cuffs are known in the art and provide a surface onto which internal tissue may adhere to stabilize the catheter assembly within the patient.
[0055] In the above mentioned embodiments, it is noted that the proximal ends 101 , 104 may occur at different locations in various catheters. It is within the scope of the present invention to incorporate, in the dimensional aspects of length disclosed above, all locations where the proximal ends 101 , 104 could be said to occur in catheters known in the art, disclosed herein, or to be developed.
[0056] The smooth generally round exterior surface of the catheter shaft TC passes through and remains positioned at a vessel wall insertion site during insertion of the catheter assembly into a patient. A vessel wall seals quite well around the smooth, round exterior surface of the catheter shaft TC, as shown in cross-section C 1 . Since the exterior of the catheter shaft TC provides a good seal at the insertion site, the risk of blood loss around the catheter assembly at the insertion site is minimized.
[0057] The first and the second distal end tubes D 1 , D 2 extend distally from the catheter shaft TC at the split point 108 . The first and the second distal end tubes D 1 , D 2 have outer surfaces continuous with the outer wall of the unitary catheter shaft TC, and are capable of independent movement when split from one another.
[0058] The first and the second distal end tubes D 1 , D 2 are defined by circular outer walls. The first and the second lumens 112 , 113 are circular.
[0059] The first and the second lumens 112 , 113 are always circular since circular cross sections are most conducive to fluid flow properties. However, other shapes such as D-shaped passageways and/or lumens, oval, triangular, square, elliptical, kidney-bean shaped passageways and/or lumens, or other configurations are also within the scope of the invention. Further, while the catheter tubes T 1 , T 2 , the distal end tubes D 1 , D 2 , the lumens 112 , 113 and the proximal end tubes E 1 , E 2 are preferably identical in cross section, it is within the scope of the invention to vary the size, shape and/or configuration such that smaller distal end tubes and/or lumens, or varying types of lumens and distal end tubes may be used for other applications, such as an addition of a third, smaller lumen and corresponding distal end tube for introduction of medication.
[0060] In addition to an L 1 & L 2 distal end opening, the first and the second distal end tubes D 1 , D 2 may or may not have a plurality of side holes 109 , 110 extending through exterior surfaces of the distal end tubes D 1 , D 2 to the first and the second lumens 112 , 113 . The side holes 109 , 110 provide additional or alternative flow paths. The side holes 109 , 110 can be arranged circumferentially and helically around the distal end tubes D 1 , D 2 to provide optimal flow properties, and to avoid suctioning of the distal tubes against an area to be catheterized, such as a vessel wall. The side holes 109 , 110 can be of various shape, but are typically circular or oval, or of some combination thereof and may also vary in number between the shorter and longer of the distal end tubes D 1 , D 2 .
A Second Embodiment
[0061] FIG. 2 illustrates another embodiment of the present invention, where a catheter assembly has at least two lumens. The illustration of two lumens is exemplary, and the scope of the invention encompasses catheters having more than two lumens.
[0062] The catheter assembly includes first tube T 1 which has a proximal end 101 and a distal end 103 . The catheter assembly includes a shorter second tube T 2 which has a proximal end 104 and a distal end 106 . The fist tube T 1 and the second tube T 2 united (fused) at catheter shaft TC as a result of fusion of a portion 104 of first tube T 1 and the 105 of second tube T 2 .
[0063] The catheter assembly can be provided (manufactured) so that the first distal end tube D 1 is extending distally beyond the second tube distal end 106 .
[0064] The multilumen catheter assembly includes a first lumen 112 and a second lumen 113 extending longitudinally therethrough as illustrated at C 1 .
[0065] The first lumen 112 is continuous with and through the first tube T 1 from the distal end 103 of the floating distal part D 1 , the catheter shaft TC and first extension tube E 1 . The second lumen 113 is continuous with and through the second tube T 2 from the distal end 106 of the second tube T 2 , the catheter shaft TC and first extension tube E 2 . The first and the second extension tubes E 1 and E 2 lead to a proximal end of the catheter assembly, through which the materials entering and or exiting the patient enter and/or exit the catheter assembly. The words “proximal” and “distal” refer to directions away from and closer to, respectively, the inserted end of the catheter assembly.
[0066] The exterior of the catheter shaft TC includes a smooth, rounded without ridges or grooves.
[0067] As shown in the cross-section C 1 of the catheter shaft TC, the outer surface of the catheter shaft TC is generally rounded in shape (outer configuration), C 1 illustrating in cross-section a generally round shaped outer wall, with the first and the second lumens 112 , 113 having a circular cross-section. Catheter shaft TC can have various shapes, such as but not limited to circular, semi-circular or oval. Also lumen cross section can have various shapes, such as but not limited to circular, semi-circular or oval.
[0068] A cuff 114 may or may not be located at a point along the catheter shaft TC. Cuffs are known in the art and provide a surface onto which internal tissue may adhere to stabilize the catheter assembly within the patient.
[0069] In the above mentioned embodiments, it is noted that the proximal ends 101 , 104 may occur at different locations in various catheters. It is within the scope of the present invention to incorporate, in the dimensional aspects of length disclosed above, all locations where the proximal ends 101 , 104 could be said to occur in catheters known in the art, disclosed herein, or to be developed.
[0070] The smooth generally round exterior surface of the catheter shaft TC passes through and remains positioned at a vessel wall insertion site during insertion of the catheter assembly into a patient. A vessel wall seals quite well around the smooth, round exterior surface of the catheter shaft TC, as shown in cross-section C 1 . Since the exterior of the catheter shaft TC provides a good seal at the insertion site, the risk of blood loss around the catheter assembly at the insertion site is minimized.
[0071] The distal end tubes D 1 extend distally from the catheter shaft TC at the point 108 . The distal end tubes D 1 has outer surfaces continuous with the outer wall of the unitary catheter shaft TC, and are capable of independent movement.
[0072] The first distal end tubes D 1 is defined by circular outer wall. The first and the second lumens 112 , 113 are circular.
[0073] The first and the second lumens 112 , 113 are always circular since circular cross sections are most conducive to fluid flow properties. However, other shapes such as D-shaped passageways and/or lumens, oval, triangular, square, elliptical, kidney-bean shaped passageways and/or lumens, or other configurations are also within the scope of the invention. Further, while the catheter tubes T 1 , T 2 , the distal end tube D 1 , the lumens 112 , 113 and the proximal end tubes E 1 , E 2 are preferably identical in cross section, it is within the scope of the invention to vary the size, shape and/or configuration such that smaller distal end tubes and/or lumens, or varying types of lumens and distal end tubes may be used for other applications, such as an addition of a third, smaller lumen and corresponding distal end tube for introduction of medication.
[0074] The assembly according to the second embodiment, in addition to an L 1 & L 2 distal end opening, may or may not include a plurality of side holes 109 extending through exterior surfaces of the distal end tubes D 1 , to the first lumen 112 . A second set of side holes 110 extending through exterior surfaces of the distal end of tube 105 , to the second lumen 113 . The side holes 109 , 110 provide additional or alternative flow paths. The side holes 109 , 110 can be of various shape, but are typically circular or oval, or of some combination.
A third Embodiment
[0075] FIG. 3 illustrates another embodiment of the present invention, where a catheter assembly has at least two lumens. The illustration of two lumens is exemplary, and the scope of the invention encompasses catheters having more than two lumens.
[0076] The catheter assembly includes first tube T 1 which has a proximal end 101 and a distal end 103 . The catheter assembly includes a second tube T 2 which has a proximal end 104 and a distal end 106 . The fist tube T 1 and the second tube T 2 united (fused) at catheter shaft TC as a result of fusion of a portion 104 of first tube T 1 and the 105 of second tube T 2 .
[0077] The catheter assembly can be provided (manufactured) so that the first tube T 1 and the second tube T 2 is fused along a portion extending from the point 107 to the end of both tube 103 , 106 so as to have a common distal end.
[0078] The assembly according to the third embodiment includes tipping of the distal end of the catheter shaft TC to form a distal catheter tip 120 .
[0079] The multilumen catheter assembly includes a first lumen 112 and a second lumen 113 extending longitudinally therethrough as illustrated at C 1 .
[0080] The first and second lumen 112 , 113 are continuous with and through the first and second tube T 1 , T 2 from the distal end 103 , 106 , the catheter shaft TC and first and second extension tube E 1 , E 2 . The first and the second extension tubes E 1 and E 2 lead to a proximal end of the catheter assembly, through which the materials entering and or exiting the patient enter and/or exit the catheter assembly. The words “proximal” and “distal” refer to directions away from and closer to, respectively, the inserted end of the catheter assembly.
[0081] The exterior of the catheter shaft TC includes a smooth, rounded without ridges or grooves.
[0082] As shown in the cross-section C 1 of the catheter shaft TC, the outer surface of the catheter shaft TC is generally rounded in shape (outer configuration), C 1 illustrating in cross-section a generally round shaped outer wall, with the first and the second lumens 112 , 113 having a circular cross-section. Catheter shaft TC can have various shapes, such as but not limited to circular, semi-circular or oval. Also lumen cross section can have various shapes, such as but not limited to circular, semi-circular or oval
[0083] In the above mentioned embodiments, it is noted that the proximal ends 101 , 104 may occur at different locations in various catheters. It is within the scope of the present invention to incorporate, in the dimensional aspects of length disclosed above, all locations where the proximal ends 101 , 104 could be said to occur in catheters known in the art, disclosed herein, or to be developed.
[0084] The smooth generally round exterior surface of the catheter shaft TC passes through and remains positioned at a vessel wall insertion site during insertion of the catheter assembly into a patient. A vessel wall seals quite well around the smooth, round exterior surface of the catheter shaft TC, as shown in cross-section C 1 . Since the exterior of the catheter shaft TC provides a good seal at the insertion site, the risk of blood loss around the catheter assembly at the insertion site is minimized.
[0085] The first and the second lumens 112 , 113 are always circular since circular cross sections are most conducive to fluid flow properties. However, other shapes such as D-shaped passageways and/or lumens, oval, triangular, square, elliptical, kidney-bean shaped passageways and/or lumens, or other configurations are also within the scope of the invention. Further, while the catheter tubes T 1 , T 2 , the lumens 112 , 113 and the proximal end tubes E 1 , E 2 are preferably identical in cross section, it is within the scope of the invention to vary the size, shape and/or configuration such that smaller distal end tubes and/or lumens, or varying types of lumens and distal end tubes may be used for other applications, such as an addition of a third, smaller lumen and corresponding distal end tube for introduction of medication.
[0086] A plurality of side holes 109 , 110 extending through exterior surfaces of tubes 102 , 105 , to the first and second lumens 112 , 113 . The side holes 109 , 110 provide additional or alternative flow paths. The side holes 109 , 110 can be of various shape, but are typically circular or oval, or of some combination.
[0087] A cuff 114 may or may not be located at a point along the catheter shaft TC. Cuffs are known in the art and provide a surface onto which internal tissue may adhere to stabilize the catheter assembly within the patient.
[0088] The catheter assembly according to the various embodiments may be secured to patient skin by a fixation device.
[0089] The catheter assembly according to the various embodiments may incorporate a hub secured or over molded over point 107 .
[0090] The present invention further includes methods for making the multilumen catheter assemblies described above.
[0091] The fusion parameter settings allow the catheter tube either to be releasable joined to allow longitudinally split from each other or non releasable joined.
[0092] The present invention also provides a method for making a multitube catheter assembly, by fusing two or more tubes together by use of heat sensitive tube slides over the tubes while metallic mandrels are passed through each tube lumen to protect the lumens during fusion. The heat sensitive tube will generate pressure once heat is applied. Continual heating will melt/re-shape the catheter tubes inside the heat sensitive tube while the letter will not be affected due to its high melting temperature. After cooling the heat shrink tube is removed around the fused catheter tubes, the metallic mandrels pulled back and the tubes, forming the one catheter tube.
[0093] At FIG. 4 illustrate the catheter tube T 1 , T 2 cross sectional changes during the fusion process. According to C 5 , the first tube T 1 and the second tube T 2 has a general round outer surface and circular lumen 112 , 113 and a wall 115 , 116 . C 4 illustrates the presence of the heat sensitive tube 117 slides over the first and second tube T 1 , T 2 . The heat sensitive tube 117 contract and generates pressure once heat is applied. Continual heating will melt/re-shape the catheter tubes T 1 , T 2 inside the heat sensitive tube 117 while the letter will not be affected due to its high melting temperature. At C 3 , continual heating melt the wall 115 , 116 of the first and second tube T 1 , T 2 . At C 2 , The wall 115 , 116 fuse together forming one wall 111 defining the catheter tube TC around the catheter lumen 112 , 113 . Catheter lumens 112 , 113 are protected during fusion process by the presence of a round mandrel with definite size inside each of them. At C 1 , after cooling, the heat sensitive tube 117 is removed around the formed TC. The metallic mandrels are to be pulled back the catheter shaft tube TC is formed with the wall 111 around the catheter lumens 112 , 113 .
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FIELD OF THE INVENTION
The present invention relates to the treatment of Lymes disease and associated debilitating conditions using photoactivateable compounds such as psoralens and activating electromagnetic radiation to engender a therapeutic immune response.
BACKGROUND OF THE INVENTION
Lymes disease is caused by a tick-borne spirochete. Early symptoms of Lymes disease which appear in weeks to months following initial infection include meningitis, facial palsy and migratory muscular-skeletal pain. Later appearing symptoms which can occur months to years after initial infection include chronic arthritis, encephalopathy, polyneuropathopy and leukoencephalitis. The usual therapy for Lymes disease is a 10-20 day course of antibiotics which must be implemented during the early stages of infection in order to have any appreciable expectation of success. However, even with early intervention, in a small percentage of patients the antibiotic therapy will be ineffective. This is particularly so if the spirochete has spread to the patient's nervous system.
Untreated patients, patients who did not receive antibiotic therapy early enough, or the small percentage of patients who did receive antibiotic therapy but nevertheless failed to respond, will generally experience the symptoms noted above as well as disturbances of memory, mood or sleep, axonal polyneuropathy with paresthesias or spinal pain. Typically, patients, particularly initially untreated patients, may also experience large knee effusions. The foregoing conditions associated with Lymes disease generally cannot be alleviated by late intervention with antibiotics.
Fortunately, it has now been discovered that untreated symptomatic patients as well as patients who received antibiotic therapy for Lymes disease but failed to respond, can be effectively treated using the photopheresis methods described below.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention a method has been found for treating patients who are afflicted with Lymes disease and associated debilitating conditions using a photoactive compound that binds to nucleic acid upon activation by exposure to electromagnetic radiation of a prescribed spectrum, such as ultraviolet light. Psoralen compounds are particularly preferred for this purpose, especially the compound 8-methoxypsoralen--in which case UVA radiation is preferred for activating said compound.
In accordance with the invention, a photoactive compound such as 8-methoxypsoralen is administered to the patient's blood, or some fraction thereof, in vitro or in vivo using conventional administration routes. A portion of the patient's blood is then treated (preferably, extracorporeally) using photopheresis, which comprises subjecting the blood to electromagnetic radiation in such wavelengths suitable for activating the photoactive compound, such as ultraviolet light, preferably long wavelength ultraviolet light in the wavelength range of 320 to 400 nm, commonly called UVA light. The treated blood, or a fraction thereof, is returned to the patient (in the case of extracorporeal photopheresis) or remains in the patient (following in vivo photopheresis).
DETAILED DESCRIPTION OF THE INVENTION
While it is not intended that the scope of the present invention be limited by any specific theory of operation, it is believed that infections, particularly those which are not controlled by the normal immunological response of a patient, can be treated using a photopheresis treatment according to the invention. The herein described treatment is also believed by the inventors to (i) restore the ability of a treated patient's immune system to combat other infections, and (ii) restore the immune system's anamnestic response to previous infections.
In accordance with the photopheresis methods of the invention, treated infected cells as well as killed and/or attenuated pathogen, peptides, native sub-units of the pathogen itself (which are released upon cell break-up and/or shed into the blood) and/or pathogenic noninfectious pathogens may be used.
Mutation of the pathogen does not shield it from attenuation/inactivation during photopheresis and consequent generation of an immune response to the mutant forms of the pathogen. Thus, the treatment methods according to the invention provide a dynamic autogenous vaccine against infection.
The invention methods are also useful in the treatment of patients having an abnormally low white blood cell count.
According to the claimeds methods, a photoactive compound is first administered to the blood of an infected patient. The photoactive compound may be administered in vivo (e.g., orally or intravenously) or may be administered in vitro to a portion of the patient's blood which has been removed from the patient by employing conventional blood withdrawal techniques.
In accordance with the present invention, the photoactive compound selected should preferably be one that binds to the cell membrane of the pathogen and/or infected cells (e.g., by binding to a receptor and/or a nucleic acid fragment on the cell membrane) and/or to a nucleic acid in the cell nucleus or cell cytoplasm upon activation by exposure to electromagnetic radiation of a prescribed spectrum, such as ultraviolet light, for the purpose of inactivating and/or attenuating the pathogen and permitting the so treated pathogen and/or infected cells to be presented to the immune system of the patient. Psoralen compounds are particularly preferred for this purpose, especially the compound 8-methoxypsoralen--in which case UVA radiation is preferred for activating said compound.
Next, the portion of the patient's blood to which the photoactive compound has been administered is treated by subjecting the portion of the blood to photopheresis using said electromagnetic radiation--for example, ultraviolet light. The photopheresis step is preferably carried out in vitro using an extracorporeal photopheresis apparatus.
The photopheresis step in accordance with the present invention may also be carried out in vivo (PUVA).
A presently preferred extracorporeal photopheresis apparatus for use in the methods according to the invention is currently manufactured by Therakos, Inc., Westchester, Pa. under the name UVAR. A description of the Therakos UVAR photopheresis apparatus may be found in U.S. Pat. No. 4,683,889, granted to R. L. Edelson on Aug. 14, 1987, the contents of which are hereby incorporated by reference in their entirety.
The exposure of blood to ultraviolet light in a photopheresis apparatus is within the ability of persons having ordinary skill in the art.
When the photopheresis step is carried out in vitro, at least a fraction of the treated blood, or the treated free isolated virus, is returned to the patient following the photopheresis treatment. Preferably, the treatment method described hereinabove is repeated at an interval of about once per week to about once every four weeks. Most preferably, the treatment methods described herein are administered on two successive days and repeated approximately once per month (i.e., the patient preferably receives two treatments every month).
In view of the disclosure contained herein, those persons who are skilled in the art will be able to adjust the treatment parameters--i.e., dosage of the photoactive compound and electromagnetic radiation, periodicity of treatment (e.g., monthly, weekly, etc.) and the number of treatments administered in each period (e.g., twice per month on two successive days)--depending on the condition of the patient and the patient's response to the treatment.
Preferred photoactive compounds for use in accordance with the present invention are compounds known as psoralens (or furocoumarins) which are described in U.S. Pat. No. 4,321,919 the disclosure of which is incorporated herein by reference in their entirety.
The preferred photoactive compounds for use in accordance with the present invention include the following"
psoralen;
8-methoxypsoralen;
4,5'8-trimethylpsoralen;
5-methoxypsoralen;
4-methylpsoralen;
4,4-dimethylpsoralen;
4-5'-dimethylpsoralen; and
4',8-methoxypsoralen
The most particularly preferred photoactive compound for use in accordance with the invention is 8-methoxypsoralen.
The determination of an effective dosage is within the ability of persons having ordinary skill in the art.
The photoactive compound, when administered to the patient's blood in vivo is preferably administered orally, but also can be administered intravenously and/or by other conventional administration routes.
The preferred dosage of the photoactive compound is in the range of about 0.3 to about 0.7 mg/kg of body weight although larger or smaller doses may be employed. When the photoactive compound is administered in vitro to only a portion of the patient's blood or fraction thereof, it is within the ability of those skilled in the art to calculate a dosage which is equivalent to said range based upon the volume of treated blood or fraction thereof.
When administered orally, the photoactive compound should preferably be administered at least about one hour prior to the photopheresis treatment. The timing of administration may be adjusted up or down as needed depending on the bioavailability of the photoactive compound, its expected half-life, etc. If administered intravenously, the times would generally be shorter.
The photopheresis treatment in the treatment methods according to the invention is preferably carried out using long wavelength ultraviolet light (UVA) at a wavelength within the range of 320 to 400 nm. The exposure to ultraviolet light during the photopheresis treatment preferably has a duration of about three to four hours, although shorter or longer treatment periods may be used if desired.
Whatever the spectrum of electromagnetic radiation, the exposure of infected cells and/or pathogen thereto, following administration of the photoactive compound, should be of sufficient intensity/duration to effectively inactivate and/or attenuate the pathogen. The selection of an appropriate wavelength for photopheresis as well as the exposure, depending upon the photoactive compound being employed and the conditions of treatment (e.g., in vivo exposure or in vitro exposure), is within the ability of those skilled in the art in view of the present disclosure.
When the photoactive compound is 8-methoxypsoralen, it is preferred in accordance with the invention to utilize an exposure to UVA radiation of about 2 Joules/meter 2 based upon the surface area of the pathogen and infected cells undergoing treatment.
When the photopheresis treatment according to the invention is carried out in vivo, careful attention should be paid to controlling the maximum radiant exposure so as to avoid unnecessary injury to the patient. Methods for calculating maximum radiant exposure to ultraviolet light are known in the art and, therefore, shall not be described herein.
WORKING EXAMPLE
A male patient, roughly 47 years of age, having Lymes disease and arthritis (diagnosis based upon positive Lymes titer, severe arthritis and effusion of the right knee) and who failed to respond to multiple courses of antibiotic therapy, was treated in the following manner:
The patient received treatment employing an 8-MOP dosage of 0.6 mg/kg (two treatments on successive days) initially repeated every four weeks. After three to four courses of the treatment in accordance with the invention, the patient enjoyed a general sense of well-being and, in particular, his joint pain completely subsided so that he was able to exercise as normal. The patient was maintained on the foregoing course of therapy for ten months at which point the frequency of treatment was extended to one 2-day treatment every six weeks. This course of therapy was continued for four months at which point the frequency of treatment was extended to one 2-day treatment every eight weeks. It was found that expansion of the treatment frequency in this manner did not cause the patient to regress. The patient is now being treated every three months on two successive days.
Thus, it was found that the photopheresis treatment employed in this patient was able to relieve all of his debilitating symptoms which were consistent with an advanced state of Lymes infection while conventional antibiotic therapy was completely ineffective.
While the foregoing description has been provided to illustrate the present invention, the inventors intend the scope of their invention to be limited solely by the scope of the following claims.
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BACKGROUND OF THE INVENTION
This invention pertains in general to a sanitizer for bathroom articles, and more particularly to a device for housing and sanitizing bathroom articles such as toothbrushes, including the effective draining of drainage fluid from the interior of the sanitizer under the force of gravity.
The existence of a specialized cabinet having a particular germicidal lamp or similar device contained therein for sterilizing bathroom articles placed within the cabinet is a well known concept. The following list of U.S. patents all relate to the subject of sterilizing bathroom articles.
______________________________________U.S. Pat. No. Inventor(s) Issue Date______________________________________3,955,922 Moulthrop May, 19763,820,251 Abernathy June, 19743,776,694 Leittl December, 19733,353,905 Ellis November, 19673,309,159 LeSueur et al March, 19672,592,131 Farrar April, 19522,579,242 Pask December, 19512,554,156 Rosenthal May, 19512,424,036 Jackel July, 19472,356,505 Christensen August, 1944______________________________________
Bathroom articles such as toothbrushes or hair brushes frequently have fluids (e.g., water, saliva, etc.) contained therein after their use which must be drained therefrom to obtain proper sterilization and sanitization. Retained water offers fertile breeding ground for unwanted bacteria and other germs. Ultimately, the deadly Legionnaire's Disease outbreak of Philadelphia, Pa. in the 1970's was traced to such breeding in the stagnate portions of a hotel's water system.
The U.S. patents listed above fall into three categories with respect to drainage of such drainage fluid. The first category includes those that literally make no provision for drainage of the subject fluid, or there is no defined housing from which drainage is necessary. A second category includes devices which have some sort of drainage function, but which is carried out rather ineffectively (i.e., there is no rigorous method to drain all fluids), or in partial dependence upon ventilation. In some instances, constituting a third category, auxiliary means which require a power input are provided to assist with the removal of drainage fluid. For example, in Moulthrop, an electric motor drives a fan to provide forced ventilation over toothbrushes to provide evaporation of drainage fluid. In Abernathy, an electrically powered heating means is used to literally dry the toothbrushes within the housing.
The present invention discloses a device which effectively permits drainage of fluid from toothbrush articles while they are being sanitized within a housing without the necessity of an auxiliary power input.
OBJECTS AND SUMMARY OF THE INVENTION
One object of the present invention is to provide a device which effectively sterilizes a plurality of bathroom articles, such as toothbrushes. A further object of this invention includes effective drainage of drainage fluid from the bathroom articles.
To accomplish these and numerous other objects, a closeable housing is provided having therein a germicidal lamp and a storage rack for holding toothbrushes or similar bathroom articles within the housing. A drainage diaphragm fitted within a bottom portion of the housing is shaped so as to force drainage fluid which precipates from the bathroom articles to a peripheral portion of the housing. Drainage holes may be associated with this peripheral portion of the housing to permit passage of the drainage fluid from the housing as directed thereto by the drainage diaphragm.
The housing of the present invention may be cylindrical in shape with a domed top and a relatively flat bottom. The domed top may be partially transparent so as to permit light from the germicidal lamp to also function as a nightlight. The cylindrical housing may have a curved, hinged door to permit access to the interior of the housing, where toothbrushes or the like may be mounted on a revolving plate having spring clips about its periphery. This revolving plate may also have holes therein to permit drainage of fluid from the bathroom articles downward under the force of gravity towards the drainage diaphragm.
The drainage diaphragm is curved downward (i.e., concave in the direction of gravity) to permit the force of gravity to direct precipitating drainage fluid towards the periphery of the housing. Drainage holes lining the periphery of the housing immediately above the plane formed by the intersection of the housing and the diaphragm permits this precipitated and directed drainage fluid to be removed from the interior of the housing.
The drainage diaphragm also serves to seal off an even lower portion of the housing from the drainage fluid. This function permits installation of adjunct self-contained electrical appliances within the housing. These appliances may include electrical devices such as a radio or an electric clock. Knobs and control elements of such electrical appliances may be protruded through this base portion of the housing. Further, feet may be mounted on the bottom of the housing itself to permit sound from a speaker formed in the bottom of the housing to be emitted in conjunction with operation of an adjunct installed radio, etc.
The particular spring clips of the revolving plate of this invention may be used in conjunction with custom toothbrushes which have registration elements emerging from the normally smooth handles thereof to permit the head of such toothbrushes to be held in predetermined relationship with the revolving plate. This function permits the bristles of the toothbrushes to be isolated from surfaces foreign to the bristle mount itself.
The present invention also includes a second embodiment wherein the adjunct electrical devices housed beneath the concave diaphragm include a rechargeable battery for powering the germicidal lamp. The base of such an embodiment is further adapted to be mated with a rechargeable base unit for recharging the rechargeable battery. The resulting sanitizing device is a portable apparatus capable of performing the sanitizing, nightlight and drainage features of the present invention.
The present invention also further encompasses the inclusion of mounting means on the housing bodies of the various present embodiments to permit selective mounting of those bodies on a surface, such as a bathroom or kitchen wall.
The foregoing summary of the invention offers but an incomplete listing of some of the more important features and aspects of the present invention. A more complete understanding and appreciation of the features of this invention may be understood by studying the accompanying figures and the following disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
Concepts and features of the presently preferred embodiments of this invention may be better understood with reference to the following figures, in which:
FIG. 1 is a front elevation of a preferred embodiment;
FIG. 2 is a side elevation of FIG. 1;
FIG. 3 is a longitudinal section through the center of FIG. 1;
FIGS. 4 through 6 are cross-sections taken at various levels in other figures as indicated;
FIG. 7 is a base plan of the FIG. 1 preferred embodiment;
FIG. 8 is an elevational view with parts thereof in section of a second embodiment of a device in accordance with the present invention which constitutes a portable (i.e., rechargeable battery-powered) version thereof;
FIG. 9 illustrates a custom toothbrush having a registration element for use with either the FIG. 1 or FIG. 8 embodiment; and
FIG. 10 illustrates a perspective view of mounting means for use with the FIG. 1 or FIG. 8 embodiment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to FIG. 1, a front elevation of a presently preferred embodiment of a sanitizer for bathroom articles in accordance with the present invention is illustrated. A cylindrical housing is defined by cover 10. This cover may be comprised of a frosted plexiglas material, or of other suitable material. The cylindrical housing 10 has an upper portion 12 which may be transparent plastic to permit light from a germicidal lamp contained within the housing to pass from the housing, thereby accomplishing a nightlight function. A door 14 permits selective closing and opening of the housing 10 to permit placement and retrieval of bathroom articles. Door 14 has hinges 16 and 18 and doorknob 20, which function in a conventional manner.
Reference character 22 points to a dotted line representation of a drainage diaphragm contained within the housing 10. In accordance with the present invention, drainage fluid associated with the bathroom articles stored within the housing 10 precipitates onto the drainage diaphragm 22 by the force of gravity. Since the diaphragm 22 is concave-shaped in the direction of gravity and blocks all possible downward paths of the fluid, all such precipitated drainage fluid is directed toward the periphery of the housing 10. At such peripheral portions of the housing 10 are located a plurality of drainage holes 24 to permit drainage of this fluid from within the housing. The drainage diaphragm 22 and plurality of drainage holes 24 constitute a drainage means for venting by the force of gravity drainage fluid from the interior of the housing through a peripheral base portion of the housing 10.
In accordance with the present invention, the drainage diaphragm 22 seals off all portions within the housing below the diaphragm from drainage fluid. Therefore, adjunct self-contained electrical devices may be safely incorporated into this further base portion of the housing 10 beneath the diaphragm 22. For example, 26 is a face plate or display for a radio device, with knobs 28 and 30 operating the same. Reference character 32 refers to a display for a digital or electronic clock. Switch 34 may control the germicidal lamp contained within the housing 10, discussed further below. Reference characters 36 illustrate rubber cushion pads which may be placed on the bottom of housing 10 to provide non-skid footing for the sanitizer and to permit sound to emerge from a speaker mounted in the bottom of housing 10. This is discussed further below.
Although various physical dimensions may be applied to the embodiment of FIG. 1 in accordance with the present invention, this exemplary embodiment is drawn roughly to scale for a six inch diameter thereof, with a total height of twelve inches from the lowermost tip of rubber cushion pads 36 to the uppermost tip of transparent dome 12.
Referring now to FIG. 2, a side elevation of the FIG. 1 embodiment is illustrated. Throughout this application, like reference numerals among figures refer to the same or analogous elements thereof. Hence, reference character 12 again refers to the transparent dome top of housing 10. Diaphragm 22 is again shown in dotted line since it is contained within housing 10, and the drainage holes 24 are shown to continue around the total periphery of the housing 10. Control knobs 28 and 30, and display segments 26 and 32 are associated with an adjunct radio and electric clock, as in FIG. 1. Rubber feet 36 are all of identical size and shape, but only appear of different sizes due to the changing perspective thereof brought on by rotation of the figure. Base plan FIG. 7, discussed below, clearly shows that rubber cushion feet 36 are identical with respect to each other. Reference characters 138 and 142 refer to a mounting means for the present invention, discussed further below with regard to FIG. 10.
FIG. 3 is a longitudinal section of the embodiment shown in FIGS. 1 and 2 along the center thereof. Section markers for FIGS. 4-6 refer to the sections represented by FIGS. 4 through 6, respectively.
Reference character 100 refers to an upright post mounted within the housing 10, which is threaded at both of its ends so as to be fixedly mounted within the housing. The upright post 100 in turn serves as an element for mounting the germicidal lamp 102 and revolving plate 104. In this embodiment, the germicidal lamp 102 comprises a circular fluorescent ultraviolet light, but other known germicidal lamps are freely substitutable with this element. Details of the mounting of germicidal lamp 102 on upright post 100 is shown and discussed further below.
The bottom end of upright post 100 deadends into the upper surface of diaphragm 22. Tube 106 surrounds upright post 100 between the upper surface of diaphragm 22 and the lower surface of revolving plate 104. The revolving plate 104 may be fixed to the upper end of tube 106, and ball bearings may be employed between upright post 100 and tube 106 so as to provide free circular movement for revolving plate 104 around an axis defined by post 100.
Spring clips 108 are mounted around the periphery of revolving plate 104 so as to receive and hold inserted bathroom articles. Holes 124 are drainage passages, discussed further below with regard to FIG. 5. By way of example only, the spring clip holders 108 of FIG. 3 have contained therein toothbrushes. Toothbrush 110 is a conventional style toothbrush which is locked into place by the spring force which is inherent in the spring clip 108. Toothbrush 112 is a toothbrush modified in accordance with the present invention so as to have registration elements 114 protruding from the handle thereof so as to ensure that the bristles of toothbrush 112 remain out of contact with the spring clip 108. Such contact could occur if the toothbrush 112 were to slide downward under the force of gravity towards spring clip 108 until the brushes of toothbrush 112 actually touched spring clip 108. Inasmuch as one of the chief functions and objects of the present invention is to sanitize bathroom articles, the registration element 114 of toothbrush 112 furthers this purpose by physically isolating the bristles of toothbrush 112 from foreign surfaces other than the actual mounting portion of toothbrush 112.
Cavity 116 may house the workings of an electric radio which uses window 26 as a display. Control knobs 28 and 30 are again illustrated to show their cooperation with cavity 116. Cavity 118 may be used for housing the functional elements of an electric clock, etc., which utilizes window 32 as a display therefor.
Reference character 120 refers to a retractable AC power cord (shown further, below) which may be used to provide power from a conventional AC power source to the various electrical devices of an apparatus in accordance with the present invention, including the germicidal lamp 102, a radio contained within cavity 116 and an electric clock contained in cavity 118.
The revolving plate 104, peripheral spring clips 108 and tube 106 with its ball bearings may constitute storing means for storing bathroom articles (such as toothbrushes) within the housing 10. While the longitudinal sectional view apparently shows only two such peripheral spring clips 108, different numbers of such peripheral spring clips may be used in accordance with the present invention. Hence, different numbers of bathroom articles such as toothbrushes or a mix of different articles may be stored within an apparatus in accordance with the present invention. As discussed further below, FIG. 5 discloses an embodiment having six such peripheral spring clips 108, while FIG. 8 discloses an embodiment having only two such peripheral spring clips 108.
Referring now to FIGS. 4 through 6, three respective cross-sections as indicated in FIG. 3 are disclosed. The sectional lines of FIGS. 4 through 6 illustrate the longitudinal section orientation of FIG. 3.
FIG. 4 illustrates a sectional line of FIG. 3 as indicated, looking upward therefrom. Upright post 100 is shown as a small circular part in the center of the cross-section. The germicidal lamp 102 is shown as a concentric circular element surrounding the shaft 100. As stated before, this particular preferred embodiment illustrates the germicidal lamp as being a circular fluorescent tube emitting light in the ultraviolet range, but other suitable equivalents are permitted. Cross member 122 supports the germicidal lamp 102.
FIG. 5 illustrates the indicated cross-section in FIG. 3, also looking upward. Revolving plate 104 is shown as a circular plate having drainage passages 124 therein. These drainage passages permit drainage fluids to flow from toothbrushes mounted in peripheral spring clips 108 (shown as six in number in this embodiment) downward to diaphragm 22. Under the force of gravity, diaphragm 22 then directs the precipitated drainage fluid towards the periphery of housing 10, as discussed above. Rotating plate 104 is concentric with the upright mounting shaft 100. In FIG. 5, shown at the periphery of housing 10 is the doorknob 20 of door 14.
FIG. 6 illustrates a cross-section taken along the indicated line of FIG. 3, which looks downward therefrom. Cavities 116 and 188 are shown as they are located within the housing 10. Control knob 28 associated with cavity 116 is illustrated, but control knob 30 which appears directly below knob 28 is not illustrated since it is blocked from view. Shaft 100 is again centrally located in the cross-section. Retractable AC power cord 120 winds around in a circular fashion within housing 10 as shown.
FIG. 7 illustrates a base plan of the housing 10 of FIG. 1 (i.e., looking at only the bottom of the housing). As discussed above, cushion pads 36 are all identical in nature and located symmetrically around the center of housing 10. Also shown in FIG. 7 is one exemplary embodiment of audio holes 126 formed in the bottom of the housing 10 to permit sound from a speaker contained therein to emerge to a listener. Any suitable pattern may be used, as is true for the configuration of cushion pads 36, and the FIG. 7 illustration is exemplary only and not intended to be limitive of the present invention. Also shown are control knob 30, door knob 20 and power cord 120.
FIG. 8 illustrates a second preferred embodiment of the present invention which is "portable" in that it has a rechargeable battery contained within the base of housing 10 beneath the diaphragm 22. The base of housing 10 is adapted to mate with a rechargeable base unit 128 for recharging the enclosed battery. Details of such a battery recharging system are well known and need not be repeated here. That portion of the sanitizer above base portion 128 may then be detached and taken along as a portable unit for traveling with the user. The physical dimensions of the FIG. 8 embodiment may typically be smaller than that of the FIG. 1 embodiment, and hence the revolving plate 104 may be limited in size so as to support or house only two toothbrushes 110 and 112, or other similar bathroom articles. As before, germicidal lamp 102 sanitizes the bathroom articles placed in the peripheral clips of revolving plate 104, which revolves around upright shaft 100. Drainage diaphragm 22 and peripheral drainage holes 24 function as before to vent by the force of gravity any drainage fluid from within the housing 10.
FIG. 9 discloses an exemplary embodiment of the toothbrush 112 usable with the embodiments of FIGS. 1 and 8, having registration elements 114 to suitably hold the bristles of toothbrush 112 a predefined distance separate from the peripheral spring clamps 108 of revolving plate 104. This particular embodiment shown in FIG. 9 also includes an enlarged handle portion 130 for easier manipulation of the toothbrush, and an elongated tip (rubberized) 132 for easy removal of large food particles from between teeth. The toothbrush of FIG. 9 is part of and furthers the objects of the present invention in that it utilizes its registration element feature to further the sanitization effects of the FIG. 1 and FIG. 8 apparatuses. As discussed before, elements 114 serve to register (or separate) the bristles of toothbrush 112 from any foreign surfaces (i.e. surfaces other than the mounting portions of toothbrush 112 for the bristles).
FIG. 10 illustrates a perspective view of a mounting means for the present invention. Element 134 defines a wall bracket which is suitably attached by elements (e.g., a plurality of screws 136) to a desired surface, such as a bathroom or kitchen wall. Wall bracket 134 has a semi-circular extension piece 138 which is integrally attached thereto and extends therefrom. Extension piece 138 has contained therein various select holes 140 for variably mounting a suction cup 142 or similar device therein. The holes 140 (shown as 5 in the exemplary embodiment of FIG. 10, but which may be other in number) are threaded to receive a threaded base portion of suction cup 142. Other methods of mounting, such as a bayonet mount, are possible in place of the screw mount. The suction cup 142 may be formed of rubber, with the threaded base portion thereof being hardened rubber. The suction cup 142 is then attached to a desired portion of housing 10, and its threaded end associated with a desired one of holes 140. The wall bracket 134 is affixed to the desired surface with elements 136, and the result is selective and desired fixation of a sanitizer in accordance with the present invention to a suitable surface.
Many further modifications and variations of the present invention are possible within the skill of one of ordinary skill in the art. For example, the germicidal lamp 102 may be any other known germicidal lamp other than an ultraviolet fluorescent circular tube. Also, any of the materials used in producing the present apparatus may be appropriately plastic, rubber, metal, etc. in accordance with particular design and aesthetic needs. Also, housing 10 need not be strictly limited to a cylindrical shape, but might be other shapes such as rectangular or triangular, with the diaphragm 22 suitably adapted to have its outer peripheral portion lie flush with the inner walls of the particular housing. Peripheral holes 24 may then be suitably located around the periphery of the particular shape of the housing so as to drain off precipitated drainage fluid directed thereto by the diaphragm 22. Other adjunct electrical devices such as transceivers, calculators or televisions may be included in the base portion of the housing 10 beneath the protective diaphragm 22. All such modifications and variations which would occur to one of ordinary skill in the art are intended to be included within the scope of the present invention, which is further defined by the appended claims.
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RELATED APPLICATIONS
This is a continuation of application Ser. No. 09/159,731 filed Sep. 24, 1998, which is hereby incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the field of agricultural planters. More particularly, the invention is concerned with a twin row planter including planting units arranged in pairs. Each pair is configured and positioned for planting two rows of seeds less than about ten inches apart to produce two rows of crops in order to increase the yield of the plot. With this spacing, the rows in each pair are close enough to simulate a single row enabling the use of a conventional cultivator, sprayer or harvesting machine.
2. Description of the Prior Art
Conventional planters include a plurality of evenly spaced planting units connected to a tool bar. The planters are usually on centers of 30, 36 38 or 40 inches which is the spacing required for conventional harvesting machines. It is known that rows planted more closely together can result in a higher yield for a given plot of land, but conventional cultivators, sprayers and harvesting machines cannot handle these closely spaced rows. As a result, crop yield is lost and land use is less efficient.
SUMMARY OF THE INVENTION
The present invention solves the prior art problems mentioned above and provides a distinct advance in the state of the art. More particularly, the planter hereof enables the planting of more closely spaced rows in order to increase crop yield in a manner allowing harvesting by conventional harvesting machines.
The preferred planter includes a plurality of planting units mounted to a tool bar with the planting units arranged in pairs. The pairs of planting units are arranged on standard centers such as thirty or thirty-six inches, for example, but the planting units of each pair are positioned and configured so that the respective rows planted by each pair of planting units are spaced apart less than about ten inches. With this spacing, each set of two rows of resulting crops are close enough to simulate a single row thereby enabling the use of a conventional harvesting machine. Other preferred aspects of the present invention are disclosed herein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plan view of the preferred planter in accordance with the present invention;
FIG. 2 is a plan view of a pair of planting units of FIG. 1 shown mounted to the tool bar;
FIG. 3 is a side elevational view in partial section taken along line 3 — 3 of FIG. 2;
FIG. 4 is a side elevational view in partial section taken along line 4 — 4 of FIG. 2; and
FIG. 5 is a plan view in partial section taken along line 5 — 5 of FIG. 3 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The drawing figures illustrate preferred planter 10 in accordance with the present invention. Referring to FIG. 1, planter 10 includes tool bar 12 , drive wheels 14 and 16 coupled with and supporting tool bar 12 , drive mechanism 18 and a plurality of planting units 20 a, 20 b, 22 a, 22 b, 24 a, 24 b, 26 a and 26 b arranged in pairs 20 , 22 , 24 , 26 . Tool bar 12 , drive wheels 14 , 16 and drive mechanism 18 are conventional components such as those available on the MONOSEM planter available from ATI, Inc. of Lenexa, Kans. Pairs 20 - 26 are substantially identical except for their relative positions along tool bar 12 .
Referring to pair 20 , planting unit 20 a includes a furrow opener including a pair of opener discs 28 seed hopper 30 , metering assembly 32 , a depth gauge wheel assembly including inboard depth gauge wheel 34 and outboard depth gauge wheel 36 , and a furrow closer including closer wheels 38 . In the usual manner, the planting unit 20 a further includes a seed tube 39 that extends downwardly from the metering assembly 32 and between the discs 28 so that the lower outlet end 40 is received in the furrow (see FIGS. 3 and 5 ). In this regard, the seed tube 39 serves to deposit seed metered by the assembly 32 into the furrow. As best viewed in FIG. 5, inboard depth gauge wheel 34 is narrower than outboard wheel 36 by about half the width thereof. Except for this difference, planting unit 20 a is otherwise conventional such as the MONOSEM planting unit available from ATI, Inc.
Mounting structure 42 includes spacer 44 having extender 46 and cross bar 48 . U-bolts 50 couple extender 46 with tool bar 12 and U-bolts 52 couple mounting face 54 of planter 20 a with cross bar 48 . Spacer 44 is configured to space planting unit 20 a about six inches from tool bar 12 . This places planting unit 20 a in a staggered relationship relative to planting unit 20 b with portions thereof overlapping as best viewed in FIGS. 1, 2 and 5 .
Referring to FIG. 3, drive mechanism 18 includes conventional drive shaft 56 . Mounting structure 42 includes power transfer assembly 58 for transferring mechanical power from drive shaft 56 to planting unit 20 a to operate metering assembly 32 , needed because of the spacing from tool bar 12 . Power transfer assembly 58 includes drive sprocket 60 coupled with drive shaft 56 , driven sprocket 62 coupled with power shaft 63 of planting unit 20 a, chain 64 intercoupling sprockets 60 , 62 and idler sprocket 66 engaged with chain 64 to maintain the tension thereof.
Planting unit 20 b includes mounting face 68 mounted to tool bar 12 with no spacer therebetween. Unit 20 b is otherwise the same as planting unit 20 a except for the orientation of seed hopper 72 . Referring to FIG. 2, seed hopper 72 is turned on its mounting (compared to hopper 30 of unit 20 a ) so that it extends substantially to one side of the centerline of planting unit 20 b. Planting unit 20 b also includes a narrow inboard depth gauge wheel 74 and outboard depth gauge wheel 76 .
Referring to FIGS. 1, 2 and 5 , planting units 20 a,b are positioned on centers of about nine inches in the preferred embodiment. With this arrangement, units 20 a,b plant twin rows of seeds 78 and 80 also spaced apart about nine inches as are the resulting rows of crops. This is critical because conventional harvesters cannot adequately handle a crop row with a width greater than ten inches. With a spacing of less than about ten inches, the crops from rows 78 , 80 simulate a single row to a conventional harvesting machine. The planting units in the other pairs 22 - 26 are also on nine inch centers, but the pairs themselves are spaced as needed for the harvesting machine that will be used to harvest the crop. In the preferred embodiment, pairs 20 - 26 are spaced at 30 inches but spacings of 36 , 38 and 40 inches are also common.
As best viewed in FIG. 2, the orientation of seed hopper 72 to the right of the centerline of planting unit 20 b enables the close spacing between units 20 a and 20 b. This close spacing is further enabled by the narrow width of inboard depth gauge wheels 34 and 74 as shown in FIG. 5 and by the staggered relationship between units 20 a and 20 b. As further illustrated by FIG. 5, and the other drawing figures, planting units 20 a,b also overlap. In this relationship, the forward portion of inboard depth gauge wheel 34 is adjacent the rearward portion of inboard depth gauge wheel 74 . In this relationship, wheels 34 and 74 move in opposite directions where they overlap as planter 10 moves along the ground. This prevents dirt clods, rocks and crop residue from lodging between wheels 34 and 74 , which might otherwise be a problem if units 20 a,b were not staggered.
In the use of planter 10 , metering assemblies 32 of each planting unit 20 a - 26 b are adjusted as needed for the desired seed spacing. Also, the metering assemblies and mounting structures are adjusted, as needed, so that the seeds planted in each row pair are also staggered as illustrated in FIG. 5 . This maximizes the spacing between the seeds in the twin rows for maximum yield.
For a conventional planter, the normal seed spacing might be 8 seeds per foot. With the present invention, the metering assemblies can be adjusted so that each places about 6 seeds per foot, for example. For the double row planted by each pair of planting units, this results in 12 seeds per foot, which is a 50% increase in the amount of seed planted. It has been found that this can result in a yield increase of about 25% which substantially offsets the additional cost of seed and increases the overall profit on a given plot.
As those skilled in the art will appreciate, the present invention encompasses many variations in the preferred embodiment described herein. Having described this embodiment, the following is claimed as new and desired to be secured by Letters Patent:
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BACKGROUND OF THE INVENTION
(1) Field of the Invention:
This invention relates to a blood pressure measurement apparatus and method in which a waveform discrimination method is used in the recognition of Korotkoff sounds in the measurement of blood pressure by auscultation.
(2) Description of the Prior Art:
In the detection of Korotkoff sounds according to the prior art, the most widespread approach is a discrimination method using a filter and comparator. This is referred to as the filter comparator method. Another approach used much less widely is a discrimination method, namely a pattern recognition method, which is based on the waveform of the Korotkoff sounds.
It is known that the spectral distribution of Korotkoff sounds generally has a frequency component different from body movement and external noise. The filter comparator method utilizes this fact and measures blood pressure by filtering a signal detected by a microphone attached to a pressure cuff fastened to a patient's arm, reducing the amplitude of frequency components other than the frequency component of the Korotkoff sounds, then comparing the frequency component of the Korotkoff sounds with a preset threshold value by means of a voltage comparator, and discriminating this frequency component based on its magnitude.
However, the frequency component of Korotkoff sounds not only varies from one patient to another but also differs for one and the same patient depending upon such measurement conditions as the time at which measurement is made and cuff pressure. Moreover, since the frequency band of interest is fairly wide, ranging from several tens of Hertz to 200-300 Hz, it is very difficult to extract solely the Korotkoff sound component by removing the sound of the patient's pulse and noise.
When the frequency component of the Korotkoff sounds is small in comparison with the sound of the patient's pulse, it is difficult to distinguish between the pulse sound and the Korotkoff sounds. Furthermore, since the discrimination is made based on a voltage level, measurement precision is readily influenced by any disparity in the amplitude of the Korotkoff sounds.
The aforementioned pattern recognition method in which discrimination is made based on the waveform of the Korotkoff sounds has recently been put into partial practical use.
In general, the waveform of a Korotkoff sound is as shown in FIG. 2(A). The waveform is subjected to an A-D conversion so as to make it easier to process the sound data detected by a pick up, with the digital signal resulting from the conversion being stored in means such as a memory. This is referred to as pattern detection processing. Next, maximum and minimum values are calculated from the stored signal values. For example, characteristic points are successively detected, as shown at C1, C2, C3, C4 in FIG. 3(A), four of such points being the minimum number necessary. This is referred to as a characteristic point plotting step. After the characteristic points have been detected, the general position of each characteristic point is verified and a decision is rendered as to whether the waveform is indeed indicative of a Korotkoff sound. This step is referred to as a discrimination processing step. Thus, recognition processing is divided into three process blocks.
If a characteristic point is not detected in the characteristic point plotting processing step, the pattern detection processing step is returned to for further signal read in. If a decision is rendered in the discrimination step to the effect that the waveform is not that of a Korotkoff sound, processing is executed for detecting further characteristic points or for reading in a new signal.
The relationship among the pattern recognition processing blocks is illustrated in FIG. 6.
A problem encountered in the pattern recognition approach is that in the actual measurement data obtained from a living body, a fine ripple shown in FIG. 7 tends to be produced in the vicinity of the maximum and minimum points of the Korotkoff sound signal owing to the influence an A-D conversion error.
Accordingly, with the method of detecting maximum and minimum values one by one while traversing the signal waveform in regular order and then treating each such value as a characteristic point, there is very large amount of feedback from the discrimination processing and, hence, the method requires a considerable period of time for execution. In addition, there is strong possibility that characteristic points will be detected erroneously.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a blood pressure measurement apparatus and method adapted to detect a maximum value or minimum value of an extreme point capable of being traversed by a Korotkoff sound signal constituent within a predetermined time region in which detected characteristic points of detected blood vessel information serve as a reference, perform a Korotkoff sound recognition by comparing characteristic points, and recognize Korotkoff sounds accurately without the influence of a ripple component produced in the vicinity of the extreme values of the Korotkoff sounds.
Another object of the present invention is to provide a blood pressure measurement apparatus and method in which a Korotkoff sound recognition is performed with detected characteristic points serving as a reference, whereby extreme value points having the greatest certainty of being detected in a Korotkoff signal waveform can be treated as reference characteristic points.
According to the present invention, the foregoing objects are attained by providing a blood pressure measurement apparatus comprising: blood vessel information detecting means for detecting a signal waveform of a sound or vibration produced by a blood vessel; holding means for holding the signal waveform detected by the blood vessel information detecting means; maximum point detecting means for detecting a maximum point (C3) of the waveform held by the holding means; first C-point detecting means for detecting a minimum value point (C2) within a predetermined time region (t 1 ) the final instant of which is the maximum point (C3) detected by the maximum point detecting means; first discriminating means for discriminating whether a level difference between the minimum value point (C2) detected by the first C-point detecting means and the maximum point (C3) falls within a predetermined range; second C-point detecting means for detecting a maximum value point (C1) within a predetermined time region (t 2 ) the final instant of which is the detected minimum value point (C2), this being performed when the first discriminating means discriminates that the level difference falls within the predetermined range; second discriminating means for discriminating whether a level difference between the maximum value point (C1) detected by the second C-point detecting means and the minimum value point (C2) falls within a predetermined range; third C-point detecting means for detecting a minimum value point (C4) within a predetermined time region (t 3 ) the starting instant of which is the maximum point (C3), this being performed when the second discriminating means discriminates that the level difference falls within the predetermined range; third discriminating means for discriminating whether a level difference between the minimum value point (C4) detected by the third C-point detecting means and the maximum point (C3) falls within a predetermined range; and a control unit for starting at least the three C-point detecting means and three discriminating means, advancing control successively when the respective conditions are realized, and recognizing a Korotkoff sound in the signal waveform when the third discriminating means discriminates that the level difference between the minimum value point (C4) and maximum point (C3) falls within the predetermined range.
According to a preferred embodiment of the present invention, the control unit includes control means for restarting control from detection of the maximum point (C3) when the discrimination condition for any of the level discriminating means fails to be satisfied, and the blood vessel sound detecting means includes setting means for setting a threshold value of a detection signal in accordance with the magnitude of a Korotkoff sound recognized immediately before.
Further, the control unit includes holding means for holding the signal waveform at every predetermined time.
The foregoing objects may also be attained by providing a blood pressure measurement apparatus comprising: blood vessel information detecting means for detecting a signal waveform of a sound or vibration produced by a blood vessel; holding means for holding the signal waveform detected by the blood vessel information detecting means; minimum point detecting means for detecting a minimum point (C3) of the waveform held by the holding means; first C-point detecting means for detecting a maximum value point (C2) within a predetermined time region (t 1 ) the final instant of which is the minimum point (C3) detected by the minimum point detecting means; first discriminating means for discriminating whether a level difference between the maximum value point (C2) detected by the first C-point detecting means and the minimum point (C3) falls within a predetermined range; second C-point detecting means for detecting a minimum value point (C1) within a predetermined time region (t 2 ) the final instant of which is the detected maximum value point (C2), this being performed when the first discriminating means discriminates that the level difference falls within the predetermined range; second discriminating means for discriminating whether a level difference between the minimum value point (C1) detected by the second C-point detecting means and the maximum value point (C2) falls within a predetermined range; third C-point detecting means for detecting a maximum value point (C4) within a predetermined time region (t 3 ) the starting instant of which is the minimum point (C3), this being performed when the second discriminating means discriminates that the level difference falls within the predetermined range; third discriminating means for discriminating whether a level difference between the maximum value point (C4) detected by the third C-point detecting means and the minimum point (C3) falls within a predetermined range; and a control unit for starting at least the three C-point detecting means and three discriminating means, advancing control successively when the respective conditions are realized, and recognizing a Korotkoff sound in the signal waveform when the third discriminating means discriminates that the level difference between the maximum value point (C4) and minimum point (C3) falls within the predetermined range.
The control unit includes control means for restarting control from detection of the minimum point (C3) when the discrimination condition for any of the level discriminating means fails to be satisfied.
The blood vessel sound detecting means includes setting means for setting a threshold value of a detection signal in accordance with the magnitude of a Korotkoff sound recognized immediately before.
The apparatus further includes inverting means for inverting, with respect to a reference level, a signal waveform held by detection of the minimum point by the minimum point detecting means, wherein a value of an output inverted by the inverting means is used as a reference for maximum/minimum value detection and level discrimination performed by at least the three C-point detecting means and three discriminating means.
The control unit includes holding means for holding the signal waveform at every predetermined time.
Further, according to the present invention, there is provided a blood pressure measurement method which comprises: a blood vessel information detecting step for detecting a signal waveform of a sound or vibration produced by a blood vessel; a holding step for holding the signal waveform detected at the blood vessel information detecting step; a maximum point detecting step for detecting a maximum point (C3) of the waveform held at the holding step; a first C-point detecting step for detecting a minimum value point (C2) within a predetermined time region (t 1 ) the final instant of which is the maximum point (C3) detected at the maximum point detecting step; a first discriminating step for discriminating whether a level difference between the minimum value point (C2) detected at the first C-point detecting step and the maximum point (C3) falls within a predetermined range; second C-point detecting means for detecting a maximum value point (C1) within a predetermined time region (t 2 ) the final instant of which is the detected minimum value point (C2), this being performed when it is discriminated at the first discriminating step that the level difference falls within the predetermined range; a second discriminating step for discriminating whether a level difference between the maximum value point (C1) detected at the second C-point detecting step and the minimum value point (C2) falls within a predetermined range; third C-point detecting step for detecting a minimum value point (C4) within a predetermined time region (t 3 ) the starting instant of which is the maximum point (C3), this being performed when it is discriminated at the second discriminating step that the level difference falls within the predetermined range; a third discriminating step for discriminating whether a level difference between the minimum value point (C4) detected at the third C-point detecting step and the maximum point (C3) falls within a predetermined range; and a step of starting at least the three C-point detecting steps and three discriminating steps, advancing control successively when the respective conditions are realized, and recognizing a Korotkoff sound in the signal waveform when it is discriminated at the third discriminating step that the level difference between the minimum value point (C4) and maximum point (C3) falls within the predetermined range.
The present invention further provides a blood pressure measurement method which comprises: a blood vessel information detecting step for detecting a signal waveform of a sound or vibration produced by a blood vessel; a holding step for holding the signal waveform detected at the blood vessel information detecting step; a minimum point detecting step for detecting a minimum point (C3) of the waveform held at the holding step; a first C-point detecting step for detecting a maximum value point (C2) within a predetermined time region (t 1 ) the final instant of which is the minimum point (C3) detected at the minimum point detecting step; a first discriminating step for discriminating whether a level difference between the maximum value point (C2) detected at the first C-point detecting step and the minimum point (C3) falls within a predetermined range; second C-point detecting means for detecting a minimum value point (C1) within a predetermined time region (t 2 ) the final instant of which is the detected maximum value point (C2), this being performed when it is discriminated at the first discriminating step that the level difference falls within the predetermined range; a second discriminating step for discriminating whether a level difference between the minimum value point (C1) detected at the second C-point detecting step and the maximum value point (C2) falls within a predetermined range; a third C-point detecting step for detecting a maximum value point (C4) within a predetermined time region (t 3 ) the starting instant of which is the minimum point (C3), this being performed when it is discriminated at the second discriminating step that the level difference falls within the predetermined range; a third discriminating step for discriminating whether a level difference between the maximum value point (C4) detected at the third C-point detecting step and the minimum point (C3) falls within a predetermined range; and a step of starting at least the three C-point detecting steps and three discriminating steps, advancing control successively when the respective conditions are realized, and recognizing a Korotkoff sound in the signal waveform when it is discriminated at the third discriminating step that the level difference between the maximum value point (C4) and minimum point (C3) falls within the predetermined range.
Other features and advantages of the present invention will be apparent from the following description taken in conjunction with the accompanying drawings, in which like reference characters designate the same or similar parts throughout the figures thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram illustrating the basic construction of a Korotkoff sound recognition apparatus embodying the present invention;
FIGS. 2(A) and 2(B) are views showing typical patterns of Korotkoff sounds;
FIGS. 3(A) and 3(B) are views showing characteristic portions of a Korotkoff sound waveform;
FIG. 4(A) and 4(B) is a flowchart illustrating processing extending from detection of each characteristic point of a Korotkoff sound to recognition of a Korotkoff sound according to an embodiment of the present invention;
FIGS. 5(A) to 5(O) are views illustrating the recognition states of each characteristic point of a Korotkoff sound waveform when the processing indicated by the flowchart of FIG. 4 is executed;
FIG. 6 is a block diagram illustrating a conventional Korotkoff sound discrimination method based on waveform configuration; and
FIG. 7 is a view showing a Korotkoff signal waveform in which a small ripple is produced in the vicinity of extreme values.
DESCRIPTION OF THE PREFERRED EMBODIMENT
An embodiment of the present invention will now be described in detail with reference to the drawings.
FIG. 1 is a block diagram illustrating the basic construction of an embodiment of the present invention. The arrangement includes a microphone 1 for picking up Korotkoff sounds (hereafter referred to as "K-sounds") and for producing an analog output signal indicative thereof. The input analog signal between range of 0.3 V and 2.0 V is converted into a 8 bit digital signal every 4 milliseconds (ms) by an analog-digital (A/D) converter 2 before being applied to an arithmetic circuit 3. The latter serves as recognition means and is adapted to recognize a K-sound by processing a series of sound data signals obtained in digital form from the A/D converter 2. The arithmetic circuit 3 comprises a one-chip CPU having a RAM and a ROM and is so illustrated that the various functions implemented by executing a program stored in the ROM are shown in block form. The present invention is capable of implementing these functions efficiently with the limited memory and limited processing time given the CPU. Numeral 4 denotes a display unit for displaying the fact that a K-sound has been recognized, for displaying other information as well.
The arithmetic circuit 3 includes a data read-in unit 5 for reading the digital output signal from the A/D converter 2 into the arithmetic circuit 3, a threshold value setting unit 6 which compares the newly read digital signal data from the data read-in unit 5 and the threshold value determined based upon the most recent K-sound. The arithmetic circuit 3 further includes a time generator for generating time information, and a memory (RAM) 9 for storing a digital data as well as the time information prevailing at the instant of detection. The threshold value which is to be held in the threshold value setting unit 6 is calculated from the most recent K-sound in a K-sound recognition unit 15 in accordance with the following equation,
|C3-P.sub.o |·β1, (1)
where
C3: the characteristic point of the detected K-sound
P o : reference level
β1: one-third (1/3)
If the newly read digital signal is larger than the most recent threshold value, the sign bit is set to "1". This sign bit is included in the output 106. If, on the contrary, the new data is smaller than the threshold value, the sign bit is set to "0". After completion of this operation, the digital data signal containing the sign bit is delivered to the memory 9 as digital signal data 106. The sign bit is referred to by a C3 detector 10 in order to determine whether to produce a signal on line 113 or not.
Before continuing with the description of the functional blocks of the apparatus shown in FIG. 1, let us discuss typical patterns of the K-sounds which are to be recognized by the apparatus.
FIG. 2(A) is a typical pattern of a K-sound waveform recognized by the apparatus of the illustrated embodiment, and FIG. 2(B) illustrates the pattern when the signal level is inverted. As it is possible that the input waveform may represent two opposite waveforms, drawings illustrating the respective waveforms, for example, FIGS. 2(A) and 2(B), are provided in this application. The characteristic points of the K-sound waveform are the four points C 1 -C 4 shown in FIGS. 3(A), (B). In order to help understanding of the present invention, level differences dP1 to dP3 and time regions T 1 to T 3 are labeled in FIG. 3A. They will be referred to in the following discussion. In the illustrated embodiment, a K-sound is recognized on the basis of the relationship among these four points.
In FIGS. 3(A), (B), the point C3 is defined as the point where the signal level attains an absolute extreme value, i.e., the highest peak or lowest valley, and is a portion which has great significance for the purpose of K-sound recognition, described below. Specifically, once the characteristic point C3 has been found, the characteristic points C1, C2, C4 are each obtained by a prescribed analytical method which starts from the point C3.
Each of the functional blocks described below constitutes means for recognizing the abovementioned K-sound waveform patterns both reliably and efficiently.
Returning to FIG. 1, numeral 10 is the C3 detector for detecting a relative (local) extreme value, i.e., a maximum value or minimum value in the digital signal data read out of the memory 9. Numeral 11 designates a level inverter which, for the purpose of K-sound recognition, inverts the level of the signal waveform data, which is read out of the memory 9, whenever necessary. A characteristic point detector 12 performs a predetermined calculation with regard to the signal waveform data read out of the memory 9 and time data to check for the presence of a waveform located at each of the characteristic points C1, C2, C4. The characteristic point detector 12 comprises a time region setting unit 13 for generating prescribed time region data, and a K-sound discriminator 14 for discriminating whether sound data of a signal level forming a characteristic is present within the time region, and is adapted to detect each characteristic point in accordance with a predetermined calculation procedure, described below, when a signal indicating that the C3 point has been detected is received from the C3 detector 10. The output of the K-sound discriminator 14 is applied to a K-sound recognition unit 15, which examines the positional relationship among a collection of characteristic points found by the characteristic point detector 12, in order to recognize a K-sound.
The operation of the present embodiment comprising the foregoing elements will now be described.
The output of the microphone 1 is an analog electric signal 101 indicative of a K-sound picked up by the microphone. The signal 101 is converted into a digital signal 102 at every 4 ms sampling instant by the A/D converter 2. The digital signal 102 at the output of the A/D converter 2 is read into the arithmetic circuit 3 by the data read-in unit 5 and is applied to the threshold value setting unit 6 as a series of digital signal data 103 in a time series. The threshold value setting unit 6 sets a threshold value in dependence upon a signal 117 from the K-sound recognition unit 15 indicative of the magnitude of a K-sound which appeared last in accordance with equation 1. By setting the threshold value to |C3-P o |·β1, the unit 6 reduces the influence of noise contained in the waveform data 103.
In order to suitably deal with a signal pattern input of any amplitude whatsoever at the start of measurement, no threshold value is set when measurement starts. After measurement starts, however, a threshold value is set upon predicting, from the magnitude of an immediately preceding K-sound, the smallest magnitude capable of being traversed by the next K-sound. More specifically, in a case where a K-sound has already appeared in the course of measurement, the threshold value setting unit 6 sets a threshold value in dynamic fashion in dependence upon the signal 117 from the K-sound discriminator 15 indicative of the magnitude of the threshold |C3-P o |·β1, thereby making it possible to detect the C3 point accurately and rapidly.
Accordingly, the threshold value setting unit 6 in the apparatus of the illustrated embodiment is different in nature from threshold value setting means in the conventional comparator method, in which a threshold value is set that is fixed with respect to the amplitude of the K-sound. The threshold value setting unit 6 delivers the digital signal data 106 to the memory 9 each 4 ms interval and also delivers timing signal 105 to the time generator 8 each sampling instant at the A/D converter 2.
The time generator 8 is a unit which cyclically counts timing information that increases every millisecond, by way of example. When the timing signal 105 is received from the threshold value setting unit 6, the time generator 8 successively counts up a write-in address 120 of the memory 9 so that the digital signal data 106 from the threshold value setting unit 6 and prevailing clocked time information 107 are written into the memory in accordance with the counted up address. Thus, the digital signal value data 106 and the time information 107 prevailing at the moment of detection are stored in the memory 9.
The time generator 8 also outputs a read-out address 120 of the memory 9 at a predetermined time interval and produces a read enable signal 121 when a read-out becomes possible.
The digital signal data 106 stored in memory 9 is read by the C3 detector 10 and characteristic point detector 12 in accordance with the read enable signal 121, whereby K-sound recognition processing is performed. In order that the memory 9 can be read from any address when K-sound recognition processing is executed, the characteristic point detector 12 provides the time generator 8 with an address designating signal 122 for designating a read-out address from which a read-out is to be started.
The K-sound recognition processing will now be described with reference to the flowchart of FIGS. 4(A) and 4(B).
In accordance with the read enable signal 121 from the time generator 8, the C3 detector 10 reads sound data 108 out of the memory 9 in accordance with the successively stored time series, examines these data in regular order and executes processing for detecting the C3 point in the signal pattern shown in FIG. 3(A) or FIG. 3(B).
In the first step S90 of the flowchart shown in FIGS. 4(A) and (B), an inversion flag 10a internally of the C3 detector 10 is set to "0". When the inversion flag 10a is "0", an inversion indicating signal 109 is reset; when the flag 10a is "1", the inversion designating flag 109 is set. When the inversion indicating signal 109 is in the reset state, the level inverter 11 delivers read-out data 110 from memory 9 directly to the characteristic point detector 12 as output data 111. When the inversion indicating signal 109 is in the set state, the level inverter 11 inverts the read-out data from the memory 9 and delivers the result to the characteristic point detector 12 as the output data 111.
Initially, the inversion flag 10a is set to "0" and the inversion designating signal 109 is reset. Consequently, the read-out data from memory 9 is applied as such to the characteristic point detector 12.
Next, at a step S9l, the C3 detector 10, in accordance with the read enable signal 121, reads the digital signal data 106 from the threshold value setting unit 6 stored successively in memory 9 via, the A/D converter 2 out of the memory in the same order in which it was stored and compares this with digital signal data 106 read out immediately before. The time generator 8 exercises read-out control separate from the write-in of the digital signal data 106. The reading of data from the memory 9 can be performed immediately by writing in the digital signal data 106 by means of the threshold value setting unit 6. Extreme value detection processing is executed from step S92 onward and is performed by a level comparison of digital signals at three consecutive points in the sound data 108.
Thus, at the step S92, digital signals at three consecutive points are compared to determine whether a valley point has been detected, that is, to check whether the level difference between adjacent ones of the points changes from a decreasing value to an increasing value. If a valley point is detected and this valley point is given a sign bit "1", that is the newly obtained digital signal data is determined by the C3 detector 10 to be larger than the current threshold value, this point is treated as being the characteristic point C3 and the program proceeds from the step S92 to a step S94, at which the inversion flag 10a is set to "1" and the inversion indicating signal 109 is delivered to the level inverter 11. The program then proceeds to a step S95.
When the inversion indicating signal 109 is delivered to the level inverter 11, K-sound detection is performed. To this end, the level of each item of waveform data 110 corresponding to the characteristic points C 1 -C 4 in FIG. 3(B) and read out of the memory 9 is inverted with regard to a base line [level P o shown in FIGS. 5(D), (E)] that will turn these levels into the signal pattern shown in FIG. 3(A). The inverted levels are delivered to the characteristic point detector 12.
If a valley point is not detected at the step S92, the program proceeds to a step S93, at which it is determined whether a peak C3 has been detected, that is, whether the level difference between adjacent ones of the three consecutive points changes from an increasing value to a decreasing value. If a peak is detected, this peak is determined as to whether the peak is exceeding the threshold value with referring to the sign bit included in the digital signal data 106. If the peak is exceeding the threshold value, the peak is treated as being the characteristic point C3 and the program proceeds to a step S95. If a peak is not detected at the step S93, the program returns to the step S9l, the next item of digital signal data is read and processing for detecting a characteristic point C3 is performed again.
If a peak point is detected at the step S93, the inversion flag 10a remains at "0" and the program proceeds to the step S95. This step calls for a characteristic point detection signal 113 to be sent from the C-point detector 10 to the characteristic point detector 12 to indicate that the detected point is a characteristic point. The program then proceeds to a step S104.
If a K-sound is recognized, what is detected first is the peak point. An example of the state in which the initial peak is detected is illustrated in FIG. 5(A).
In response to the characteristic point detection signal 113 from the C3 detector 10 indicating that the C3 point has been detected, the characteristic point detector 12 initiates detection of each characteristic point of the digital signal data constituting a K-sound. This being performed by processing from step S104 onward.
When the characteristic point detection signal 113 is received, the characteristic point detection circuit 12 produces the address designating signal 122 so that data stored in the memory 9 prior to detection of the characteristic point are read out of the memory sequentially in the same order that the data were stored. These data are stored in a RAM. In other words, each item of data from C1 to C3 is stored every 4 ms sampling period in the RAM at the instant C3 is detected.
The step S104 calls for the time region setting unit 13 to set a predetermined time region t 1 the final instant of which is the position of C3. The unit 13 produces a time region signal 114 indicative of this time region and applies the signal to the K-sound discriminator 14. The setting of this time region can be accomplished by storing in a ROM a predetermined value in accordance with the figures given in below. The set time region t 1 is illustrated in FIG. 5(B). According to the embodiment of the present invention, each time region t 1 , t 2 and t 3 have the values t 1 =10, t 2 =15 and t 3 =15 [×4 ms]. And these time region data have been stored previously in the ROM which is constituting the time region setting unit 13.
Next, the program proceeds to a step S105, at which the K-sound discriminator 14 reads digital signal data within the time region t 1 set by the time region setting unit 13 and stored in the RAM, detects a minimum value within the read data and treats this value as C2 [FIG. 5(C)]. The minimum level point is detected by comparing the levels of two points in the output data 111 from the level inverter 11. Next, a step S106 calls for a decision as to whether the level difference (dP2) between C2 and C3 falls within a predetermined range. The upper and lower limits of this range are stored beforehand in the ROM in accordance with the below table. According to the embodiment of the present invention, each level difference dP1, dP2 and dP3 is given as follows.
______________________________________ lower limit upper limit______________________________________dP2 15 --dP1 dP2 × α1 dP2 × α2dP3 dP1 × α3 dP2 × α4______________________________________
In the above table, the unit is 0.7 V/256 and also, the level differences illustrated in FIG. 3A, dP1, dP2 and dP3, are given below.
dP1: voltage difference between C1 and C2
dP2: voltage difference between C3 and C2
dP3: voltage difference between C3 and C4
In FIG. 5(C), the level difference is not within the predetermined range, so that the program returns to the step S90 for detection of the next characteristic point.
A valley point shown in FIG. 5(D) is detected by subsequent C3 detection processing. The program proceeds from the step S92 to the step S94, the inversion flag 10a is set and, in the data read out of the memory 9 and stored in the RAM, the input signal level is level-converted from P to 2P o -P (where P o is a reference level) by the level inverter 11, thereby giving the waveform shown in FIG. 5(E). Thus, the signal waveform is apparently inverted. Next, the minimum point C2 is detected within the set time region t 1 through the steps S104, S105 [FIG. 5(F)]. The decision step S106 now finds that the point C2 lies within the predetermined limits, so that the program proceeds from this step to a step S107, where the time region setting unit 13 sets a predetermined time region t 2 the final instant whereof is the position of C2. A signal 114 indicative of this time region is delivered to the K-sound discriminator 14. The set time region t 2 is shown in FIG. 5(G).
Next, the program proceeds to a step S108, at which the point (value) of a maximum level is detected within the time region t 2 and treated as C1. The detection of the maximum level is performed by comparing the level between two points. This is followed by a step S109, at which it is determined whether the level difference dP1 between C1 and C2 lies with a predetermined range. In FIG. 5(H), detection of C1, C2, C3 is judged to be improper and the program returns to the step S90.
The characteristic point detected next is C3 shown in FIG. 5(I) and no inversion is made of the read waveform by the level inverter 11. At the step S104, the time region t 1 is set as shown in FIG. 5(J), the characteristic point C2 shown in FIG. 5(K) is detected at the step S105, the time region t 2 having the characteristic point C2 as its final instant is set at the step S107, as shown in FIG. 5(L), and the maximum value C1 is detected within the time region t 2 shown in FIG. 5(M) at the step S108. This is followed by the level decision step S109, at which it is judged that detection of C1, C2, C3 is proper.
The program then proceeds to a step S110, at which the time region setting unit 13 sets a time region t 3 the final instant of which is the position of C3, as shown in FIG. 5(N). Next, at a step S111, a digital signal data 103 within the time region t 3 is read out of the memory 9, the point of a minimum level is detected and the point is treated as being C4. This is shown in FIG. 5(O). This is followed by a step S112, at which it is determined whether the level difference dP3 between C3 and C4 falls within a predetermined range.
If the level difference does not fall within the predetermined range, the program returns to the step S90. If the level difference does fall within the predetermined range, the signal is recognized to be a K-sound at a step S113.
Since the present method is a very simple method of detecting the characteristic points C1, C2, C3, C4, it is suited to real-time processing performed by a one-chip CPU. Furthermore, since the maximum value of a peak or the minimum value of a valley is detected within each predetermined time period, the influence of noise (FIG. 7) produced in the vicinity of extreme values of the K-sound waveform is almost nil.
When the K-sound discriminator 14 successively detects the positions C3, C2, C1 and C4, an output 115 is produced so as to inform the K-sound recognition unit 15 that the digital signal data should be treated as a K-sound. When the K-sound is recognized by the unit 15, the unit performs a computation adapting equation 1 to obtain and to deliver the new threshold value to the threshold value setting unit 6 in order to renew the current threshold value. The recognized K-sound is delivered from the K-sound recognition unit 15 to the display unit via line 116.
In the illustrated embodiment, an example has been described in which characteristic points are detected upon inverting peaks and valleys of the signal waveform as reference characteristic points whenever necessary. However, it is permissible to execute processing without making the inversion or to treat a reference characteristic point solely as the waveform peak. In such case, the inversion flag and level inverter 11 can be deleted.
ADVANTAGES OF THE INVENTION
According to the present invention as described above, the characteristics of a K-sound waveform are investigated directly. As a result, it is unnecessary to place a restriction upon the frequency band characteristic of a filter or to set a threshold value fixed with respect to the amplitude of a K-sound, as in the prior art. Moreover, measurement precision is not readily influenced by the frequency component constituting the K-sound or by the effect of a disparity in the amplitude of the K-sound.
Further, according to the present invention, the maximum value or minimum value capable of being traversed by a K-sound signal constituent is detected within each set time region, unlike the conventional method in which maximum and minima are detected one by one while traversing the waveform in regular order. Accordingly, the detection of candidates for characteristic points can be readily performed by a very short program and measurement precision is not influenced by fine ripple produced in the vicinity of extreme values of a K-sound waveform, particularly ripple due to a conversion error which readily occurs after the A/D conversion.
According to the present invention, a plurality of signal patterns indicative of K-sounds can be recognized efficiently on a real-time basis in the limited memory and processing time given a one-chip CPU by using simple software programmed in such a manner that typical patterns of K-sound waveforms are recognized. By adopting an arrangement in which level inverting means is provided, a plurality of patterns can be recognized by a short program.
As many apparently widely different embodiments of the present invention can be made without departing from the spirit and scope thereof, it is to be understood that the invention is not limited to the specific embodiments thereof except as defined in the appended claims.
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BACKGROUND OF THE INVENTION
This invention relates to a non-invasive field kit to permit self-determination the relative level of a chemical agent in the urine of a person, particularly a person involved in a health program. In particular, the invention relates to a means to self-test urine using a disposable, indicator test strip having an impregnated reagent area for estimating the amount of urea nitrogen in the urine for determination of the nitrogen balance of a person in a dietary and physical exercise program.
It has been recently recognized that the rate at which an individual absorbs and excretes nitrogen is a good indicator of the individual's nutritional health. Particularly when an individual is involved in a program requiring both dietary control and physical activity, the nitrogen "balance" is considered to be critical in determining whether the individual will have a net physiological gain or loss from a particular physical session.
Nitrogen balance is a term used to define whether an individual is experiencing a net gain or loss in nitrogen, in the form of protein, as a result of his food intake and activity level. Useable nitrogen is added to the body through consumption of protein. Nitrogen is eliminated from the body through various pathways such as urine, feces, perspiration, menstruation and respiration. Other particular situational phenomena can add to normal losses, such as calorie reduction, injury, stress, heavy physical training, profuse sweating and abnormally low quality or quantity of protein intake. As heavy physical training is one known method of substantially altering the body's requirement for nitrogen in the form of dietary amino acids, it is desirable that anyone involved in strenuous athletic activity or in physical training, be conscious of his metabolic rate, and be particularly conscious of the assimilation, utilization and elimination of nitrogen compounds.
Unlike plants which can assimilate nitrogen from fertilizers and in certain cases directly from the air itself, a human is totally dependent upon protein for the daily requirements of nitrogen. The various amino acids that form the intake proteins are utilized for the resulting synthesis of body proteins. Synthesized proteins find their way into the formation of virtually all of the body's tissues, including most prominently muscle tissue, but also in hair, organs and to one degree or another almost in every other particle of the human body. When there is an equilibrium nitrogen balance, the proteins taken in by an appropriate diet replace those proteins that are metabolized or discarded on a daily basis. Dietary protein, therefore, s a critical factor in maintaining a nitrogen balance. Utilization of body protein during the process of athletic training, particularly strenuous activities such as weight training, can also affect the protein balance. Exercise leads to enhanced metabolization of both protein and available carbohydrates.
Clinical methods of determining the urea content and hence nitrogen content of whole blood and plasma have been developed. Furthermore, a reagent strip test method for estimating urea content of whole blood simplifies the test procedure and provides a useful screening test for uremia. The reagent strip test, however, requires at least one or two drops of blood and is therefore an inconvenient method for regular and repetitive testing, particularly for self-testing under less than antiseptic conditions.
Reagent strips such as pH indicators are a known means of providing a convenient method to approximate the acidity or alkalinity of a solution. The urea content of bodily fluids can be detected by reacting the urea with urease which catalyzes the hydrolysis of urea to carbon dioxide and ammonium hydroxide. The ammonium hydroxide quantitatively increases the pH of the solution and this increased pH is measured by color change of a pH sensitive indicator, such as bromthymol blue.
Although past invasive systems are inappropriate for the purposes proposed, this invention devises a means for adapting and utilizing the reagent strip screening test for monitoring nitrogen turnover and approximate balance, enabling a user to adjust his diet and exercise program according to quantitative results of convenient, self-administered urine tests. The urine tests are compared to a personal baseline developed by following a test regimen whereby the user is able to determine whether he or she is in a state of protein surplus or deficiency.
SUMMARY OF THE INVENTION
This invention relates to a system for determining the nitrogen turnover and status of a user who is involved in a health program where diet, exercise or both are monitored and adjusted for optimizing physical development. Since urea is predominantly discharged from the body through urine, testing the urea content of urine provides a non-invasive manner of determining the relative level of urea nitrogen in the system. Fluctuations in the urea content under controlled conditions can provide a quantitative method of determining the effect of emphasized factors in diet and training. By use of a simple quantitative test indicator, a training athlete or dieter can tailor his dietary and exercise program to maximize the body's protein utilization and minimize those situations where excess training or dieting may be deleterious to bodily development. The non-invasive indicator system of this invention comprises a kit including a plastic stick having a reagent zone on which is included a reactant such as urease, and a pH indicator such as bromthymol blue. By the use of color chart blocks representing a range of urea nitrogen concentrations, the user's urine nitrogen content can be personally determined by comparing the altered color of the reagent zone of an exposed test strip to the color chart. The indicator system can be adapted to include additional reagent zones for determining other nutritional status, such as vitamin, hormone or metabolite states, by appropriate reactants and color indicator means.
Although, a single sampling for nitrogen level will not provide sufficient basis for determining the nitrogen balance of the tested user, repetitive sampling under controlled conditions can establish a general personal level from which deviations can be detected that are indicative of changes in diet or training variables such as intensity, frequency and duration. As the test method is non-invasive, and can be accomplished in a simple procedure during normal urination with a discardable implement, repetitive sampling is a minimal burden. The system, while primarily used for human use is adaptable for use with animals, particularly those involved in strenuous training programs such as race horses, greyhounds and sled dogs.
Clinical methods of determining nitrogen balance require complex and exact determination of nitrogen intake and nitrogen discharge. Nitrogen intake is almost exclusively a factor of dietary intake of useable protein. Nitrogen loss is primarily in the form of eliminated urea. Urea is measured in excreted urine, feces and perspiration. Other nitrogen losses, such protein discard as hair loss during shaving, blood loss during menstruation and other nitrogen losses must be carefully measured. The nitrogen balance is determined by comparing the nitrogen intake with the nitrogen loss over a defined period of time. In a similar manner, the relative nitrogen balance can be determined by detecting the level of nitrogen excreted in the urine. While the level of nitrogen loss for various pathways may vary according to individuals, the quantitative measurement of the nitrogen level in the urine can provide an approximate indicator as to the current state of the individual when compared with a personal baseline developed by controlled measurements over a period of time. Urea content of the urine measured during relatively nascent periods of exercise with normal dietary habits can establish a preliminary baseline. Variations in exercise and diet, including dietary supplements, can assist in establishing a reliable personal baseline. Once the baseline is determined, deviations from the baseline as a result of defined activities can be detected to determine whether the individual is in a positive state (anabolic), a negative state (catabolic), or a state of equilibrium. The degree of deviation from the baseline as a result of defined activities can provide a clear indication of the state of approximate nitrogen balance, that is, a balance, or, the level of imbalance. As the user becomes more practiced, the baseline can be confidently adjusted to more accurately reflect the actual state of equilibrium. Fewer tests are subsequently required to detect deviations and determine physical state.
In order that the indicator system be practical for use in athletic training, it must be non-invasive and convenient to perform. The use of a wetable and discardable indicator stick having a reagent thereon that can be passed through a urine stream during normal urination for immediate visual detection and subsequent discard incorporates these features. When coupled with a convenient comparison chart and procedure for determining the user's baseline, the nitrogen balance test kit provides a quantitative means for determining the effect of diet and exercise in a diet, health or fitness program. As additional factors in nutritional health become quantifiable by self-administered urine tests, other reagent zones can be added to the test strip to determine nutritional states, for example vitamin or hormone levels.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a test stick.
FIG. 2 is a plan view of a color code card.
FIG. 3 is a plan view of a test record pad.
FIG. 4 is a plan view of a diet record pad.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The non-invasive indicator system of this invention is directed at determining the relative level of approximate nitrogen turnover and balance of an individual, particularly an individual engaged in a dietary or exercise program and most specifically in a health and fitness program with attention to both diet and exercise. The indicator system comprises a simple field test method for athletic training programs where both exercise and dietary regimens are deliberately regulated to maximize the positive effect of the training program. The indicator system is designed for human use, but is adaptable to animal use, particularly for training programs involving speed or endurance.
While a number of factors directly influence the nitrogen balance, predominant factors are the quantity and quality of amino acids consumed in the form of dietary protein and the intensity, duration and frequency of the physical training regimen. Intense physical exercise can result in a hypermetabolic state that elevates an individual's energy requirements to three times as high as a basal state. This can result in a catabolic or protein deficient state in which the body responds by utilizing its own amino acid supply resulting in fatigue and muscle cannibalization.
While elaborate quantitative tests can be performed to precisely determine the nitrogen balance of an individual, the procedure requires the exact cataloging of the amino acid intake including the type of protein and its utilization factor, that is, the measure of the effectiveness in which the body can utilize that particular type of protein. Nitrogen loss, through the various pathways previously enumerated, must also be quantified. Intake and loss must then be compared to determine the surplus or deficiency during the period measurements are performed.
This invention provides a personal system for an individual to establish his own baseline level of approximate nitrogen turnover and balance and to determine the state of his nitrogen balance by a simple, non-invasive test.
As shown in FIG. 1, an indicator stick or detection wand, designated generally by the reference numeral 10 is fabricated from a plastic strip 12 with a reagent area or zone 14 at one end of the strip having a chemical reagent 16 thereon that reacts with urine to indicate the level of nitrogen in the specimen of urine tested. The reactive ingredients of the reagent are urease and bromthymol blue under a permeable membrane. The urease reacts with the urea in the urine to hydrolyze the urea to carbon dioxide and ammonium hydroxide. The liberated ammonium hydroxide increases the pH of the specimen and the shift in alkalinity is indicated by the change in hue of the bromthymol blue. To achieve the range desired, the reagent zone is impregnated with 3.2 I.U. of urease and 33 mcg. bromthymol blue. A non-reactive yellow dye is added to the reagent to provide a convenient color scale change from yellow through green to dark blue-green for comparison with a color block grid.
As shown in FIG. 2 a convenient wallet-size card 18 includes a series of color blocks 20 forming a color block grid 22 having hue variations that are calibrated in range steps of 50, 287.5, 525, 762.5 and 1000 to indicate milligram quantities of urea nitrogen per decaliter of urine sample.
The color block chart is calibrated to define the current level of nitrogen in the urine sample. By careful repetition of a recommended test procedure, a reasonable accuracy can be established in measuring the level of nitrogen in the urine specimen.
In order for the user to have a comparative means to determine whether the tested level of urea nitrogen conforms to an anabolic or catabolic state, the user must establish a baseline representing the balanced state. To establish a personal baseline, the user records a series of tests performed under relatively constant programs of moderate exercise and preferably normal diet. During the period of establishing the baseline, there should be no overall weight gain or weight loss. As an example, to establish a baseline level of approximate nitrogen balance, a period of at least three days is used for testing. The trainee's urine is tested upon waking (within 30 minutes of waking and before breakfast); before lunch; before moderate exercise (zero to 30 minutes prior); after exercise (one to two hours and before eating); and prior to bedtime (zero to 30 minutes).
The same testing procedure is utilized for each test. The indicator stick 10 is wet at the reagent zone by a urine stream or with a least two drops of urine. The reagent zone is wiped clean with a tissue after 15 seconds of contact. At the end of 60 seconds the color of the reagent area is compared with the color blocks 20 of the reference grid 22 on the chart card 18 and the quantitative level of urine nitrogen read.
To conveniently record each result of the tests, a graph pad 24 having sheets 25 with a reference grid 26 for plotting the test results during the baseline test procedure. After three days of testing, a fourth chart can be constructed using the average of each of the five daily periods. This chart will provide a convenient reference to the normal fluctuations that occur during the day.
To convert the nitrogen level tests to a general protein balance baseline, the average five periods are again in turn averaged to provide a single value signifying the baseline balance point for future reference. This can be provided on a stick-on conversion strip 28 as shown in FIG. 2. The stick-on conversion strip has a center balance arrow 29 that aligns with the appropriate nitrogen level in the color block grid 22 representing the averaged value. The conversion strip 28 is divided into plus and minus segments having values designating the approximate excess or deficiency of protein in grams per day.
To determine the effects of physical training alterations, the diet should be held relatively constant for five consecutive days while training changes occur. Diet is recorded and listed for nitrogen content on the diet record pad 34 shown in FIG. 4. The diet record pad 34 has sheets 36 with a graph format for recording grams of dietary protein over a five day test period. Fluctuations in nitrogen excretion, relative to nitrogen intake, reflect effects of physical training. Similarly, to determine the effect of dietary alterations, hold the physical training constant for five consecutive days while diet changes take place. Diet is recorded and listed for nitrogen content. Fluctuations in nitrogen excretion, relative to nitrogen intake, reflect effects of the diet. Preferably, for such determinations, the test procedure for determining the baseline, that is the Phase I procedure, should be utilized. In Phase 2, the test procedure can be reduced to three period during the day: waking (within 30 minutes of waking and before breakfast); before an exercise workout (zero to 30 minutes prior); and after the workout (one to two hours and before a snack). If desired, these can similarly be recorded on the record pad 24. Adjustments can be made in the position of the nitrogen balance conversion sticker 28 as more information is compiled. The conversion sticker has a "sticky-back" that permits the strip to be repeatedly repositioned.
Finally, after the trainee has determined a reliably personal baseline, the trainee can engage in a Phase 3 maintenance program where the urine is tested only before workout (zero to 30 minutes prior); and after workout (one to two hours and before a snack).
The use of the system to self-test the urine to determine nitrogen content and establish the trainee's status on an anabolic/catabolic spectrum provides a quantitative basis for modifying the trainee's dietary and workout programs to maximize the utilization of intake protein and minimize the dangers of a catabolic state from excess intense training. The athlete is provided with a means for determining whether his diet is a proper balance of protein and carbohydrates, whether the athlete is wasting intake protein by overconsumption of protein and whether the desired anabolic level is being maintained.
Because of the availability of protein supplements with an accurately determined useable protein content, variations in diet using such supplements can assist in determining a reliable baseline, and can be used to quantitatively adjust protein intake to accommodate variations in the trainee's physical exercise program. Similarly, the availability of other nutritional supplements of quantified content suggest use of a similar urine test strip test to determine excess or deficiency in other nutritional substances detectable in the urine. The auxiliary test utilizes a secondary reagent zone 32 with a reagent that reacts to the nutritional substance or product of the nutritional substance in the urine.
Although the term trainee is used herein, it is to be understood that this term includes animals, as well as humans, and dieters as well as athletes.
While, in the foregoing, embodiments of the present invention have been set forth in considerable detail for the purposes of making a complete disclosure of the invention, it may be apparent to those of skill in the art that numerous changes may be made in such detail without departing from the spirit and principles of the invention.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to a bracelet that radiates anion and far infrared rays, those use of which purifies blood, activates body cells, increases immunity, stabilizes nerves, enhances respiratory and internal organs, reduces fatigue, assists in maintaining health and promoting the activation of body cells.
2. General Background and State of the Art
As health issues get more attention, a substantial number of health-related products are being released in the market such as for example a product that cures shoulder problems by facilitating the blood circulation with magnetic energy or far infrared rays.
As another example, Japanese Patent Publication SHO 10-295830 discloses an adhesive, for adjusting bodily ions, installed in between a metal with a positive charge on the one side and a negative charge on the other side. This adhesive is claimed to generate ions effectively, provide electric stimulus to the spots on the body suitable for acupuncture by the effect of minus ions and local fine current; to transfer to the autonomic nerve through neurons; to promote the body function of the sympathetic nerve or parasympathetic nerve, and to increase the blood flow by enlarging the capillary vessels of the diseased or ailing body part.
However, this adhesive has the drawback that it is hard to get an effective potential difference between the positive and negative electric potential, and the ion generation function is not sufficient. In addition, the effect is limited to the spot where it is applied, and if wider treatment on an area is needed, a larger sized adhesive is required, making the movement of the body difficult.
Accordingly, to allow the body to move freely yet maintain ion generation devices in contact with the skin, various accessories are being developed such as bracelets, necklaces, and rings in order to enhance health by supplying ions to the surface of the body.
Korean Patent Publication No. 96-28107 reveals a bracelet on which a magnet is installed to control biorhythm by balancing anion and cation that flows in the human body. Likewise, Korean Utility Model Publication No. 95-24281 discloses a ceramic bracelet radiating far infrared rays where the ceramic is installed on the back side of the bracelet. But magnets or ceramics that radiate infrared rays often became detached from the bracelet, and the effect on the body was not satisfactory.
INVENTION SUMMARY
The objective of the present invention is to address the limitations of the previous products, and provide an elegant, comfortable, and cure-effective bracelet that radiates anion and far infrared rays, by radiating far infrared rays and anion to the human body.
The embodiment of the bracelet that irradiates anion and far infrared rays, according to the invention, comprises a metal core with an anion-radiating material layer and a gold plate layer sequentially coated on the metal core configured in a “C” shape main part and a connecting arm and clasp whose ends are linked to both ends of the main part by hinge pins so that the bracelet can be engaged or disengaged with a magnet attached to the clasp of the connecting arm.
About 60 to 70% of the human body is composed of bodily fluid containing electrolytes and non-electrolytes. Electrolytes are composed of the balanced cations and anions, and if this balance is lost, human body is vulnerable to various illnesses.
It is known that such difference in the distribution of ions enclosing human cells is significantly related to the nerve cells, and has significant influence on the recovery of health or deterioration of disease.
These cations and anions exist by using cellular walls as barriers, the cellular wall permeability differing in accordance with the amount of positive, negative, and dipolar electric potentials. Ions move around the human body according to a certain rule, influenced by the strength or distribution of energy in the inside and outside environment.
Other systems, methods, features and advantages of the invention will be or will become apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be included within this description, be within the scope of the invention, and be protected by the accompanying claims.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention can be better understood with reference to the following figures. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. Moreover, in the figures, like reference numerals designate corresponding parts throughout the different views.
FIG. 1 is a perspective view illustrating the whole appearance of the bracelet that radiates anion and far infrared rays;
FIG. 2 is a perspective view illustrating how to use the bracelet that radiates anion and far infrared rays;
FIG. 3 is a schematic cross-sectional view along the line A—A of FIG. 1 ;
FIG. 4 a is a schematic enlarged cross-section illustrating the closed connector of the bracelet that radiates anion and far infrared rays;
FIG. 4 b is a schematic enlarged cross-section illustrating the unlocked connector of the bracelet that radiates anion and far infrared rays;
FIG. 5 is a perspective view illustrating the disassembled bracelet that radiates anion and far infrared rays;
FIG. 6 is a schematic cross section illustrating the material used for the bracelet that radiates anion and far infrared rays;
FIG. 7 is a graph illustrating the comparison between radiation strength of a black body (A) and far infrared rays of the bracelet (B) that radiates anion and far infrared rays.
FIG. 8 is a graph illustrating emissivity of the far infrared rays of the bracelet that radiates anion and far infrared rays.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following is the description of the preferred embodiment, where the attached figures will be also explained.
FIG. 1 is a perspective view illustrating the whole appearance of the bracelet that radiates anion and far infrared rays.
The bracelet ( 100 ), in accordance with the present invention that radiates anion and far infrared rays, is composed of “C” shaped main part ( 10 ) and a connecting arm ( 20 ).
The main part ( 10 ) of the bracelet ( 100 ), in accordance with the present invention, is designed to radiate anion and far infrared rays. The main part ( 10 ) is C-shaped, and is connected to a connecting arm ( 20 ) with a clasp ( 21 ) with one end connected to hinge pin ( 25 ) so that the connecting arm ( 20 ) can rotate the main part ( 10 ) about an axle or pin ( 25 ). The other end of the main part ( 10 ) has a pin ( 26 ) connected to a clasp ( 30 ) which couples to clasp ( 21 ) to allow the bracelet ( 100 ), in accordance with the present invention, to be opened and closed.
The connecting arm ( 20 ) has the clasp ( 21 ) as shown in FIGS. 4 a , 4 b , 5 . The clasp ( 21 ) defines a space ( 35 ) where magnet ( 33 ) is installed in a fixing part that holds the magnet ( 33 ).
It is desirable to have a projection ( 36 ) around the magnet ( 33 ) so that when the magnet ( 33 ) couples with the magnet ( 33 ′) of the clasp ( 30 ) the projection ( 36 ) mates with the space ( 35 ) of the connector ( 30 ), and can be afixed easily. The magnets ( 33 , 33 ′) are held in place by fixing parts ( 34 ). Alternatively, one of the magnets ( 33 , 33 ′) could be a ferromagnetic material.
The magnets ( 33 , 33 ′) installed in the clasps ( 30 , 21 ) not only hold the connecting arm ( 20 ) in place but they also help circulate the blood due to the influence of the magnetic field when wearing the bracelet ( 100 ) in accordance with the present invention which also radiates anion and far infrared rays.
When using the bracelet ( 100 ) as shown in FIG. 2 , a user pulls up the connecting arm ( 20 ) to disengage the magnet ( 33 ) of the clasp ( 30 ), and open the bracelet, by separating the magnet ( 33 ) installed in the end of connecting arm ( 20 ) from the magnet ( 33 ′) of the clasp ( 21 ).
FIG. 6 is a schematic cross-section illustrating the material used for the bracelet ( 100 ) that radiates anion and far infrared rays.
The bracelet ( 100 ) in accordance with the present invention is shown in the cross-sectional view of FIG. 6 as including an anion radiating material layer ( 12 ) coated on the surface of a metal core ( 14 ), and a gold (or silver) plate layer ( 16 ) applied over the whole surface of the anion radiating material layer ( 12 ). The metal core ( 14 ) can be any appropriate metal such as upper, brass, iron, tin or alternatively it may alternatively be a polymeric material.
The anion radiating material layer ( 12 ) formed on the surface of the metal core ( 14 ) is for generating anion, and comprises a rare-earth metal such Lanthanum, Cerium and their mixtures. In order to enhance the radiation effect of the anion and far infrared rays, it is desirable to use mineral extracted from volcanic ashes.
Rare-earth metals include Scandium, Yttrium, and the Lanthanides series, i.e., the elements with numbers 57 through 71 . The Lanthanum Group includes 14 elements starting from Cerium. The six elements from Lanthanum to Samarium are called the Cerium group, those from Europium to Lutetium also belong to the rare earth elements, however, Promethium is a radioisotope, and no stable isotope exists. There are less odd-numbered elements than even-numbered ones, and generally rare-earth metals are silvery-white or gray. Further, these metals oxidize slowly when exposed to air, and melt in acid and hot water, but not in alkali. These metals are very similar chemically, and usually positively trivalent compounds are made, but +4 valent for Cerium, Praseodymium, and positively divalent for Ytterbium, Europium, and Samarium. Similar to alkali metal and alkali earth metal, rare-earth metals have strong positive charge, and their hydroxides are basic.
FIG. 7 is a graph illustrating the comparison between radiation strength of black body (A) and far infrared rays of the bracelet (B) that radiates anion and far infrared rays.
The bracelet, in accordance with the present invention, that radiates anion and far infrared rays can be designed by making one axle longer of the connecting arm ( 20 , 21 ) than the other one, and the same result can be obtained.
In order to understand better the bracelet, in accordance with the present invention the following non-limiting examples are illustrated.
EXAMPLE 1
A molded bracelet, ( 100 ), that irradiates anion and far infrared rays was made by using for the core ( 14 ) a metal, a ceramic or a polymeric material.
An anion radiating material layer ( 12 ) that irradiates significant amounts of anion is formed on the core ( 14 ) by coating anion radiating material made of minerals extracted from rare-earth metal, volcanic ashes on the surface of the core ( 14 ).
Next, a gold plate layer ( 16 ) was formed by coating gold film on the whole surface of the anion radiating material layer ( 12 ). In this manner, a metal material was prepared that can be used for making a bracelet that irradiates anion and far infrared rays in accordance with the present invention.
By using the core ( 14 ), a C-shape main part ( 10 ) was formed, and connecting arm ( 20 ) was installed which can rotate where both ends of the main part ( 10 ) have pins to act as axles, with one end of the connector ( 20 ) combined an end of the main part ( 10 ) by the hinge pin ( 25 ).
The connecting arm ( 20 ) is formed longer than the clasp ( 21 ) so that the bracelet ( 100 ) in accordance with the present invention that irradiates anion and far infrared rays can be opened/closed more easily.
A clasp ( 30 ) is formed at the end of the connector ( 20 ) opposite the end connected to the main part ( 10 ). The clasp ( 30 includes a magnet ( 33 ) installed so that the clasp ( 30 ) can be connected to make clasp 21 which may also include a magnet 33 ′.
The clasp ( 30 ) is composed of part ( 35 ) containing the magnet ( 33 ) and a fixing part ( 34 ) that holds the magnet ( 33 ), and a projection ( 36 ) installed around the magnet ( 33 ) so that the magnet ( 33 ) cannot be detached from the clasp ( 30 ) because it is firmly stuck to the fixing part ( 34 ).
EXAMPLE 2
A test for a necklace made in the same manner that the bracelet was made, in accordance with the Example 1 of the present invention, that irradiates anion and far infrared rays, was requested of the Application & Evaluation Center of Far Infrared Rays, Korea Institute of Construction Materials for measuring the amount of anion irradiation, irradiation strength and emissivity of far infrared rays.
The amount of anion radiated from the bracelet in accordance with the present invention that radiates anion and far infrared rays was measured as follows.
By using the device measuring charged particles, the test was done under the condition of 23/° C., humidity of 58%, and the number of anions in atmosphere was 21/cc. The number of anions irradiated from the article tested was measured and the number was calculated per unit volume, which is as follows:
Item
Sample Name
Anion (ION/cc)
Necklace
23
The far infrared rays irradiated from the bracelet in accordance with the Example 1 of the present invention that irradiates anion and far infrared rays was measured compared to Black Body at 40/° C., by using FT-IR Spectrometer, and the result is as follows.
Emissivity (5˜20 μm)
Irradiation Energy (W/m 2 )
0.437
1.76 × 10 2
As shown in FIG. 7 , the energy of 1.76×10 2 W/m 2 irradiated from the bracelet in accordance with the present invention that irradiates anion and far infrared rays, after comparing the irradiation strength of the bracelet at a wavelength between 5 and 20 μm to the Black Body at 40/° C.
As shown in FIG. 8 , the emissivity of the bracelet in accordance with the present invention that irradiates anion and far infrared rays is 0.437, i.e., 44% at a wavelength between 8 and 14 μm, and even at higher wavelength, nearly similar emissivity was maintained.
The bracelet, in accordance with the present invention, that irradiates anion and far infrared rays was allowed to be worn by 50 patients with either the problem of blood circulation such as stitching in the shoulder or whole body or the problem of suffering from neuralgia in the wrist was targeted.
The result was that all the patients wearing the bracelet felt the aches steadily decrease and, after about 15 days, the aches nearly disappeared.
As described above, the bracelet that irradiates anion and far infrared rays, in accordance with the present invention, has an elegant appearance due to its gold plate and can be used as a bracelet as an accessory, and it does not give any inconvenience to the human body since it is attached to the body.
The bracelet in accordance with the present invention can irradiate anion and far infrared rays more effectively through static electricity occurred at the friction between bracelet and skin as well as sunlight, and by regulating cellular ion balance, the electric charge inside and outside the skin gets normal, and controls complex biorhythm such as promoting blood circulation and metabolism, besides activates body cells, lowers blood pressure to increase regenerate tissues, suppressing aging phenomena.
While various embodiments of the invention have been described, it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of this invention. Accordingly, the invention is not to be restricted except in light of the attached claims and their equivalents.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to an apparatus for improving the swing of a player utilizing a sports bat, club or racquet, and is a continuation in part application of my co-pending U.S. patent application Ser. No. 09/740,769 filed Dec. 19, 2000, and is incorporated herein by reference, in its entirety.
[0003] 2. Prior Art
[0004] The attainment of success in any sport requires concentration, muscle development and “follow-through”, particularly in those sports utilizing a bat, club, or a racquet. “Follow-through” may be defined as completing the swing of that bat, club or racquet through an arc from an initial start position, then around and into the strike zone, and thereafter maintaining that swing until the player's arm has been fully extended. The necessity for such follow-through is often a requirement for directing the ball or puck in the direction in which the player has intended and for providing the power to drive the ball or puck with maximum force. Such follow-through, though, is a difficult lesson to learn and to remember. Muscle memory would ensure that such follow through would take place if the player could in fact develop such a muscle memory capability.
[0005] The sports of baseball, golf, tennis, and hockey all require an arcuate and full swing of a bat, club, or racquet. Other body motion other than movement of the arm is also required. It is thus significant to instill in the player, a muscle memory so that such follow through becomes automatic.
[0006] There exists no arrangement or apparatus to instill upon the player, the reminder that the follow-through be undertaken each time, except for a coach or personal trainer who must otherwise be present during practice or playing and remind that player each time a swing is undertaken.
[0007] It is an object of the present invention to provide an apparatus which will provide a sport player with the follow-through skills necessary which are not taught by the prior art.
[0008] It is a further object of the present invention to provide a sport skill training device which does not require assistance to operate.
[0009] It is still yet a further object of the present invention to provide a realistic sports swing training apparatus which is adaptable to a number of sports so that its use may be appreciated by a number of different players.
[0010] It is a still yet further object of the present invention to provide a sport training apparatus which is stepwise adaptable to the improving skill level of the particular player or user of that apparatus.
[0011] It is a further object of the present invention to provide a bat or racket swing training apparatus which is adaptable for attachment to existing sports equipment such as basketball hoops with minimal effort and equipment.
[0012] It is a further object of the present invention which is rotatably adaptable for left or right handed players.
[0013] It is yet a further object of the present invention to provide a swing trainer which is heightwise variable for different height players.
BRIEF SUMMARY OF THE INVENTION
[0014] The present invention comprises an improved, movably supported swing trainer apparatus for instructing a player of baseball, tennis, hockey or golf, in the lessons of “following through” with the swing of their bat, racquet, club or stick.
[0015] The swing trainer apparatus of the present invention comprises a vertically supported hanger assembly comprised of a housing, a plurality of downwardly extending flexible, spaced-apart swing resistant straps supported within that housing. The housing has an upper portion defined as a hanger assembly with an elongated, bendable spring, extending vertically therefrom. The bendable spring has an upper end which is attached to a vertically adjustable hanger post. The hanger post is adjustably lockable within a generally cylindrically shaped post-bearing housing. The post bearing housing is arranged on the distal end of a support arm. The support arm has a proximal end which is fixedly attached to an enclosure bearing. The enclosure bearing is a generally cylindrically shaped housing which is vertically adjustable on a main support post.
[0016] The main support post may be telescopable, and is vertically adjustable itself into a post housing arranged about the lowermost end of the support post. The post housing is a generally cylindrically shaped member having a lower end which is fixedly attached to a support post base. The support post is heightwise adjustable with respect to the post housing, through a plurality of spaced apart openings which receive a lower adjustment bolt therethrough. The lower adjustment bolt rides on the upper edge of the post housing to permit the vertical adjustment of the support post with respect to the post housing. A support post is swingable with respect to the lower post housing, to permit the entire assembly to be rotated about the vertical axis of the support post.
[0017] The main support post preferably also has a plurality of vertically spaced apart adjustment openings near its uppermost end. An upper adjustment bolt is arranged through the enclosure bearing to engage successively any one of the spaced apart adjustment openings in the upper end of the support post, to permit the support arm to be vertically raised or lowered with respect to that main support post.
[0018] The frame of the hanger assembly as aforementioned supports a plurality of generally horizontally arranged strap support rods and vertically disposed swing resistant straps arranged thereon. That frame assembly may have a peripheral shape which defines in one embodiment wherein a “home plate” shape is configured as its “footprint” so as to provide a player or user of this apparatus, with a realistic and proper geometric and spacial swing area in which a baseball would likely travel for that player to swing at.
[0019] The plurality of vertically disposed swing resistant straps have a foremost strap or straps which may present a target thereon. Such a target in one preferred embodiment, may be the representation of a baseball. Such a target representation may of course be adjusted vertically depending upon the height of the player being instructed.
[0020] The hanger post in the post bearing on the distal end of the support arm may be rotated about its vertical axis 180 degrees so as to provide that target to an alternatively handed player that is a left handed player or a right handed player.
[0021] When a player being instructed to follow-through with his or her swing, the bat or sports racquet will swing through the swing resistant straps thus providing the muscle tone and memory, to encourage such a follow through for proper playing of the sport. The vertically disposed bendable spring arranged between the upper side of the hanger assembly and the lower portion of the hanger post will yield and may twist somewhat so as to not provide too much resistance and injure the player during long practice sessions.
[0022] The swing resistant straps are hung in a parallel array on a plurality of removable parallel strap support rods. Initial practice with this apparatus, may consist of only utilizing several parallel support rods with the swing resistant straps thereon. Each of the swing resistant straps may be held in an overlapping relationship to the strap support rods and held in that position by a fastener, such as a rivet. Those flexible straps may be changed, and may be slidably adjustable on those support rods in the support rod axial direction of those as desired by the player being trained.
[0023] A further embodiment of the present invention may consist of the hanger post and hanger assembly being vertically supported on an attachment bracket arrangement. The attachment bracket arrangement is comprised of an upper hoop bracket connector and a lower hoop bracket connector. The upper hoop bracket connector and the lower hoop bracket connector mate about the ring of a basketball hoop, so as to provide the swing trainer assembly to be utilized on an existing piece of sports equipment, such as a basketball hoop with its typical backboard and basketball hoop support post supporting that assembly.
[0024] The attachment bracket arrangement or bracket connector in this embodiment comprises a lower post bearing in the lower hoop bracket connector, and an upper post bearing for receipt of the upper portion of the hanger post therethrough. A receiving opening extends through the lower post bearing so as to permit an adjustment bolt to be received through the adjustment hole and into the receiving openings in the upper end of the hanger post. This permits the hanger post to be vertically adjustable with respect to the connector bracket arrangement attached to the basketball hoop. The lower hoop bracket connector and the upper hoop bracket connector may each have a plurality of radially directed arms which are in vertical alignment with one another on either side of the basketball hoop. Each radially directed arm may have an opening therethrough for receipt of a connector bolt. The arms each have a flange or lip on their radially outer or distalmost end to engage the outer periphery of the basketball hoop to lock that connector arrangement therearound. The connector bolts secure the upper hoop bracket connector to the lower hoop bracket connector both connectors thus being securedly fixed to the basketball hoop.
[0025] Thus, such a hanger assembly may vertically support a plurality of swing resistant straps from an existing sports apparatus such as a basketball hoop, while providing the same vertical adjustment with respect to those swing resistant straps and also providing the bendable spring arranged between the lower portion of the hanger post and the upperpost portion of the hanger assembly to permit the yielding of that assembly as a bat or racquet is pushed through the swing resistant straps.
[0026] The invention thus comprises a swing trainer apparatus for the teaching of a sport player the proper follow-through of a swing to hit a ball or puck. The said swing trainer apparatus comprises a movable hanger assembly supporting a plurality of swing resistant straps; a support arrangement for adjustably supporting the hanger assembly, to permit the swing resistant straps to be moved for different sport players. The movable hanger may comprise a frame for supporting the straps in a vertical array. The support arrangement may comprise a hanger post attached to the hanger assembly. The hanger post may be is vertically adjustable. The hanger post may be rotatably adjustable about a vertical axis. The hanger post may be supported on an elongated support arm. The support arm may be supported on a main support post. The support arm may be rotatable about a vertical axis of the main support post. The support arm may be vertically adjustable with respect to the main post, by an adjustment bold disposed therebetween. The straps may be supported in a rectilinear configuration to define a baseball game “homeplate” shape for a player to swing a bat towards. The support arrangement may be connected to an attachment bracket for securement to a basketball hoop. The attachment bracket may comprise an upper hoop bracket connector and a lower hoop bracket connector. The upper hoop bracket connector and the lower hoop bracket connector are securable to the upper and lower sides of a basketball hoop ring. The upper hoop bracket connector and the lower hoop bracket connector have an arrangement of radial arms extending from an upper and a lower post housing respectively. The arms may have an outer end with a flange thereon to engage an outer edge of the basketball hoop ring. The upper hoop bracket connector and the lower hoop bracket connector are secured together on the ring by a plurality of bolts. At least one of the straps may have a swing target arranged thereon. The support assembly may include an elongated twistable and bendable spring therewith. The spring is preferably arranged between a hanger post and a hanger assembly to permit a player from being injured while swinging a bat or stick into the straps.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] The objects and advantages of the present invention will become more apparent when viewed in conjunction with the following drawings in which:
[0028] [0028]FIG. 1 is a perspective view of a swing trainer apparatus constructed according to the principles of the present invention;
[0029] [0029]FIG. 2 is a perspective of the hanger assembly and the swing resistant straps in an enlarged viewing thereof, similar to that shown in FIG. 1;
[0030] [0030]FIG. 3 is a perspective view of a portion of a swing resistant strap and its strap support rod arranged therewith; and
[0031] [0031]FIG. 4 is an exploded view of a further embodiment of the present invention wherein the hanger assembly and swing resistant strap arrangement may be fixedly and adjustably attached to an existing sports apparatus such as a basketball hoop assembly.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0032] Referring now to the drawings in detail and particularly to FIG. 1, there is shown the present invention which comprises a movably supported swing trainer apparatus 10 for instructing a player of baseball, tennis, hockey or golf, in the lessons of “following through” with the swing of their bat, racquet, club or stick.
[0033] The swing trainer apparatus 10 of the present invention comprises a vertically supported hanger assembly 12 comprised of a housing 14 , a plurality of downwardly extending flexible, spaced-apart swing resistant straps 16 supported within that housing 14 . The housing 14 has an upper portion defined as a hanger assembly 18 with an elongated, bendable and twistable coil spring 20 extending vertically therefrom. The bendable spring 20 has an upper end which is attached to a vertically adjustable hanger post 22 , as shown in FIGS. 1 and. 3 . The hanger post 22 is adjustably lockable within a generally cylindrically shaped post-bearing housing 24 , shown in FIG. 1. The post-bearing housing 22 is arranged on the distal end of a support arm 26 . The support arm 26 has a proximal end which is fixedly attached to an enclosure bearing 28 . The enclosure bearing 28 is a generally cylindrically shaped housing which is vertically adjustable on a main support post 30 , as represented in FIG. 1.
[0034] The main support post 30 may be telescopable, and is vertically and rotatably adjustable itself into a post housing 32 arranged about the lowermost end of the support post 30 . The post housing 32 is preferably a generally cylindrically shaped member having a lower end 34 which is fixedly attached to a support post base 36 , which base 36 may be movably supported on wheels, not shown for clarity. The support post 32 is heightwise adjustable with respect to the post housing 34 through a plurality of longitudinally spaced apart openings 38 which receive a lower adjustment bolt 40 therethrough. The lower adjustment bolt 40 slidably rides on the upper edge 42 of the post housing 32 , as shown in FIG. 1, to permit the vertical (and rotational) adjustment of the support post 30 with respect to the post housing 32 , as represented by the arrows “H” and “R” respectively. The support post 30 is thus swingable with respect to the lower post housing 32 , to permit the entire assembly to be rotated about the vertical axis “V” of the support post 30 .
[0035] The main support post 30 preferably also has a plurality of vertically spaced apart adjustment openings 42 near its uppermost end, as shown in FIG. 1. An upper adjustment bolt 44 is arranged through the enclosure bearing 28 to engage successively any one of the spaced apart adjustment openings 42 in the upper end of the support post 30 , to permit the support arm 26 to be vertically raised or lowered with respect to that main support post 30 .
[0036] The frame 14 of the hanger assembly 12 as aforementioned, supports a plurality of generally horizontally arranged strap support rods 50 and vertically disposed swing resistant straps 16 arranged thereon, as may be seen in FIGS. 1, 2 and 3 . That frame assembly 12 may have a peripheral shape or contour which defines in one preferred embodiment as shown in FIG. 1, wherein a “home plate” shape is configured as its “footprint” 52 , so as to provide a player or user of this apparatus 10 with a realistic and proper geometric and spacial swing area in which a baseball would likely travel for that player to swing.
[0037] The plurality of vertically disposed swing resistant straps 16 have a foremost strap 54 or straps which may present a target 56 thereon. Such a target in one preferred embodiment, as represented in FIGS. 1 and 2, may be the representation of a baseball 58 . Such a target representation may of course be adjusted vertically depending upon the height of the player being instructed.
[0038] The hanger post 22 in the post bearing 24 on the distal end of the support arm 26 may be rotated about its vertical axis 180 degrees, as represented by arrows “A”, so as to provide that target to an alternatively handed player that is a left handed player or a right handed player.
[0039] When a player being instructed to follow-through with his or her swing, the bat or sports racquet will swing through the swing resistant straps thus providing the muscle tone and memory, to encourage such a follow through for proper playing of the sport. The vertically disposed bendable and twistable coil spring 28 arranged between the upper side of the hanger assembly 18 and the lower portion of the hanger post 22 will yield and may twist somewhat so as to not provide too much resistance and injure the player during long practice sessions.
[0040] The swing resistant straps 16 are hung in a parallel array on a plurality of removable parallel strap support rods 50 as represented best in FIG. 2. Initial practice with this apparatus, may consist of only utilizing several parallel support rods 50 with the swing resistant straps 16 thereon. Each of the swing resistant straps 16 may be held in an overlapping relationship to the strap support rods 50 and held in that position by a fastener, such as a rivet 60 , as shown in FIG. 3. Those flexible straps 16 may be changed, and may be slidably adjustable on those support rods 50 in the support rod's 50 axial direction of those as desired by the player being trained.
[0041] A further embodiment of the present invention may consist of the hanger post and hanger assembly 12 being vertically supported on an attachment bracket arrangement 70 , as shown in FIG. 4. The attachment bracket arrangement 70 is comprised of an upper hoop bracket connector 72 and a lower hoop bracket connector 74 . The upper hoop bracket connector 72 and the lower hoop bracket connector 74 mate about the ring 76 of a basketball hoop 78 , so as to provide the swing trainer assembly to be utilized on an existing piece of sports equipment, such as a basketball hoop with its typical backboard and basketball hoop support post 80 supporting that assembly 12 .
[0042] The attachment bracket arrangement or bracket connector 70 in this embodiment comprises a lower post bearing 82 in the lower hoop bracket connector 74 , and an upper post bearing 84 for vertical and rotatable adjustable receipt of the upper portion 86 of the hanger post 12 therethrough. A receiving opening 88 extends through the lower post bearing 82 so as to permit an adjustment bolt 90 to be received through the adjustment hole 88 and into the receiving openings 92 in the upper end of the hanger post 12 . This permits the hanger post 12 to be vertically adjustable with respect to the connector bracket arrangement 70 attached to the basketball hoop 78 . The lower hoop bracket connector 74 and the upper hoop bracket connector 72 may each have a plurality of radially directed arms 94 which are in vertical alignment with one another on either side of the basketball hoop ring 76 . Each radially directed arm 94 may have an opening 96 therethrough for receipt of a connector bolt 98 . The arms 94 each have a flange or lip 100 on their radially outer or distalmost end to engage the outer periphery of the basketball hoop ring 76 to lock that connector arrangement therearound. The connector bolts 98 secure the upper hoop bracket connector 72 to the lower hoop bracket connector 74 , both connectors 72 and 74 thus being securedly fixed to the ring 76 of the basketball hoop 78 .
[0043] Thus, such a hanger assembly may vertically support a plurality of swing resistant straps from an existing sports apparatus such as a basketball hoop, while providing the same vertical adjustment with respect to those swing resistant straps and also providing the bendable spring arranged between the lower portion of the hanger post and the upperpost portion of the hanger assembly to permit the yielding of that assembly as a bat or racquet is pushed through the swing resistant straps.
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CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application claims priority to German Utility Model Application No. 20 2004 001 504.8, filed Feb. 2, 2004, the entire content of which is expressly incorporated herein by reference thereto.
FIELD OF THE INVENTION
[0002] The present invention relates to a device for manipulating bone and, in particular, a device for clamping bone fixation elements, which are attached to bone, for manipulating fragments of a fractured bone.
BACKGROUND OF THE INVENTION
[0003] Bone fractures, especially fractures of the proximal femoral shaft, have proven difficult to manipulate in preparation for internal fixation. For example, when proximal shaft fractures of the femur occur, the distal end of the proximal fragment rotates anterior (flexion) and lateral (abduction) creating difficulty in accessing the piriformis fossa and/or the desired entry point for intramedullary nailing or in performing other methods of internal fixation.
[0004] Several devices for aligning fractured bones are described in the prior art. For example, WO 02/096294 discloses a device for aligning bones. The device includes an elongated shaft which connects a handle, located at a proximal end of the device, to a bone grappling claw, located at a distal end of the device. The shaft and handle define a channel which may receive a compression rod. The claw is positioned around the bone and the rod is moved in the channel towards the claw thereby positioning the bone between the rod and the claw. The positioning of the claw around the bone may necessitate the detachment of the soft tissue surrounding the bone.
[0005] There remains a need for a device which can be used to manipulate a bone without the need to detach soft tissue surrounding the bone.
SUMMARY OF THE INVENTION
[0006] The device of the present invention may include a hollow body defining a cavity, a longitudinal axis, a front end, a rear end, a clamping body which may be moved axially within the cavity, and a clamping device which may be operably associated with the clamping body. The clamping device may be connected to the clamping body by a connecting member (e.g., a rod or bar) and may be used to move the clamping body axially within the cavity and along the longitudinal axis of the hollow body.
[0007] A free end of at least one bone fixation element (e.g., Kirschner wires, bone pins, screws) may be inserted into the cavity of the hollow body, the other end of the at least one bone fixation element may be inserted into bone. The cavity may have a wall and may comprise a conical segment and a cylindrical segment. A first end of the conical segment may be positioned proximate the front end of the cavity and a second end of the conical segment may be positioned within the hollow body. The cylindrical segment may be positioned adjacent the second end of the conical segment. The conical segment may taper from the first end to the second end such that a first dimension at the first end of the conical segment may be greater than a second dimension at the second end of the conical segment. The second dimension may be the same as the diameter of the cylindrical segment. In another embodiment, the cavity may comprise only a conical segment.
[0008] The clamping device may include a screw connection having a sleeve which may be rotated to move the clamping body axially within the cavity. Additionally, the clamping device may also include a mechanism having a lever for locking the clamping body in a fixed position in the cavity of the hollow body. Using the clamping device, an operator may move the clamping body out of the cavity so that the fixation element(s) may be inserted between an external surface of the clamping body and the wall of the cavity. The clamping device may also be used to move the clamping body into the cavity to wedge the fixation element(s) between the external surface of the clamping body and the wall of the cavity.
[0009] In one embodiment, the lever may have a loosened or unlocked position and a tightened or locked position. The sleeve of the screw connection may include external threads which may engage internal threads formed in a borehole in the hollow body. With the lever in the loosened position, the sleeve may be rotated in a first direction, drawing the sleeve into the hollow body thereby causing the clamping body to move out of the cavity of the hollow body so that a free end of a fixation element, which may have another end positioned in a bone fragment, may be inserted into the cavity between the clamping body and the cavity wall. The sleeve may then be rotated in a second direction, drawing the sleeve out of the hollow body and causing the clamping body to move into the cavity of the hollow body. The clamping body may include grooves for receiving the fixation element(s). As the clamping body moves further into the cavity, the fixation element(s) may be wedged between the clamping body and the wall of the cavity. Thereafter, the lever may be moved to the tightened position, thereby locking the clamping body within the cavity and fixing the fixation element(s) with respect to the device of the present invention. An operator may use the device to manipulate the fixation element(s)s and, thus, manipulate bone.
[0010] Some advantages achieved by the present invention include:
only small incisions in the body may be necessary and detachment of the soft tissue surrounding the bones may be unnecessary; fixation elements may be attached to the bone such that the fixation elements may not penetrate into the medullary space or pass through the bone and, therefore, a medullary pin may be introduced into the medullary space of the bone without removing the device of the present invention, and the fixation elements may be disposed in the bone so that a bone plate may be placed on the surface of the bone without removing the device of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The present invention may be better understood by reference to the following drawings, wherein like reference numerals represent like elements. The drawings are merely exemplary to illustrate certain features that may be used singularly or in combination with other features and the present invention should not be limited to the embodiments shown.
[0015] FIG. 1 is a cross-sectional view of an embodiment of the device of the present invention; and
[0016] FIG. 2 is another cross-sectional view of an embodiment of the device of the present invention engaging fixation elements inserted into bone.
DETAILED DESCRIPTION
[0017] As shown in FIG. 1 , the device 10 of the present invention includes a hollow body 1 having a longitudinal axis 2 , a clamping body 6 which may be moved axially and fixed in a cavity 5 of the hollow body 1 , and a clamping device 16 which may be disposed at a rear end 3 of the hollow body 1 . It should, however, be understood that those of ordinary skill in the art will recognize many modifications and substitutions which may be made to various elements of the present invention.
[0018] The clamping body 6 may be moved between a first position, for example, as shown in FIG. 1 , and a second position, for example, as shown in FIG. 2 . In the first position, there may be a first distance A between the clamping body 6 and the wall 7 of the cavity 5 . The first distance A may sized and configured for introducing one or more bone fixation elements (e.g., Kirschner wires 8 ) into a front end 4 of the hollow body 1 , past the clamping body 6 and into the cavity 5 between the clamping body 6 and the wall 7 of the cavity 5 . Distance A may be between about 3.0 mm and about 6.0 mm. In the second position, there may be a second distance “a” between the clamping body 6 and the wall 7 of the cavity 5 . Preferably, distance “a” is less than distance A so that a fixation element may be wedged between the clamping body 6 and the wall 7 of the cavity 5 . Distance “a” may be between about 1.0 mm and about 3.0 mm. In one preferred embodiment, the ratio of distance “a” to distance A (a: A) may be between about 0.1 and about 0.9.
[0019] As shown in FIG. 1 , the cavity 5 may include two separate segments. For example, the cavity 5 may include a conical segment 12 at the front end 4 of the hollow body 1 and a hollow cylindrical segment 11 which may adjoin the conical segment 12 . Alternatively, the cavity 5 may include only a single conical segment 12 . It will be appreciated, however, by one skilled in the art that other shapes may be used to form the cavity 5 .
[0020] The cylindrical segment 11 and the conical segment 12 may have axes which may be coaxial with each other and with the longitudinal axis 2 . Moreover, the conical segment 12 may have a first end proximate the front end 4 of the hollow body 1 and a second end located within the hollow body 1 and proximate the cylindrical segment 11 . The first end of the conical segment 12 may have a first dimension and the second end of the conical segment 12 may have a second dimension. The conical segment 12 may expand towards the front end 4 of the hollow body 1 such that the first dimension may be greater than the second dimension. The angle α of the conical segment 12 may be between about 5° and about 35° and the wall 7 of the conical segment 12 of the cavity 5 may extend along at least a longitudinal section X of the cavity 5 . It will be appreciated by one skilled in the art that the minimum internal diameter D of the conical segment 12 may correspond to the internal diameter of the hollow cylindrical segment 11 .
[0021] The clamping body 6 may move within the cavity 5 and may have a maximum external diameter d, which may be larger than the minimum internal diameter D of the conical segment 12 . The clamping body 6 may be positioned within the hollow body 1 so that the clamping body 6 may be centered in the device 10 and may be used to clamp fixation elements simultaneously. Fixation elements of different sizes may be used with the device 10 . For example, Kirschner wires 8 having diameters ranging, for example, from about 1.0 mm to about 3.5 mm, may be used with the device 10 .
[0022] To clamp Kirshner wires 8 in the device 10 , the clamping body 6 may be moved towards the rear end 3 of the hollow body 1 such that the Kirschner wires 8 may be clamped in the gap between the wall 7 of the conical segment 12 and an external surface 9 of the clamping body 6 . By moving the clamping body 6 towards the rear end 3 of the hollow body 1 , the gap between the wall 7 of the conical segment 12 and the external surface 9 of the clamping body 6 may be decreased. Moreover, the external surface 9 of the clamping body 6 may include grooves 13 , which may be distributed uniformly on the periphery of the surface 9 and extend on meridians. Such a configuration may enable fixation elements, such as Kirschner wires 8 , to be captured positively in the grooves 13 and guided laterally. In this way, an increased torque may be transferred about the longitudinal axis 2 .
[0023] To simplify the introduction of the fixation elements into the gap between the wall 7 of the cavity 5 and the external surface 9 of the clamping body 6 , the clamping body 6 may be spherically convex in shape on an axial section 14 , which may be directed towards the rear end 3 of the hollow body 1 , and conical in shape on an axial section 15 , which may be directed towards the front end 4 of the hollow body 1 . This configuration may produce small contact zone(s) between the fixation elements and the clamping body 6 and may result in larger clamping forces being exerted on the fixation elements.
[0024] A clamping device 16 may be used to move the clamping body 6 with respect to the hollow body 1 and to axially fix the clamping body 6 during the clamping of the fixation elements. The clamping device 16 may be connected to a connecting member, for example, rod 21 which, in turn, may be operably attached to the clamping body 6 so that movement of the clamping device 16 may result in corresponding movement of the clamping body 6 . The clamping body 6 may be attached to the front end 22 of the rod 21 . The rod 21 may be guided in a central borehole 18 passing coaxially through the hollow body 1 . The clamping body 6 may be connected with the rod 21 such that the clamping body 6 may be moved axially along the longitudinal axis 2 and may be centered within the cavity 5 . This may enable fixation elements of different diameters to be clamped between the clamping body 6 and the wall 7 of the cavity 5 .
[0025] In one embodiment, the device 10 may incorporate a mechanism 19 or a screw connection 20 to move the clamping body 6 with respect to the hollow body 1 . In other embodiments, the device 10 may incorporate both the mechanism 19 and the screw connection 20 to move the clamping body 6 within the cavity 5 .
[0026] The mechanism 19 may be located at the rear end 23 of the rod 21 and the screw connection 20 may be located at the rear end 3 of the hollow body 1 . The mechanism 19 may include a clamping lever 25 with a contact surface 26 . The contact surface 26 may be, for example, cylindrical in shape and may be eccentric with respect to an axis of rotation 24 . The clamping lever 25 may swivel about the axis of rotation 24 , which may be orthogonal to the longitudinal axis 2 . For example, the clamping lever 25 may be rotated between a first position, as shown in FIG. 1 , and a second position, as shown in FIG. 2 . Moreover, the construction of the mechanism 19 may enable an operator to assert a large clamping force on a fixation element. The mechanism 19 may also function as a safeguard preventing the clamping device 16 from loosening unintentionally and, thereby, releasing the fixation elements.
[0027] The screw connection 20 may have an axis which may be coaxial with the longitudinal axis 2 . Rotating the screw connection 20 may cause the clamping body 6 to move towards the rear end 3 of the hollow body 1 in an axial direction along the longitudinal axis 2 . The screw connection 20 may be rotated until the external surface 9 of the clamping body 6 contacts the fixation elements and causes the fixation elements to be pressed against the wall 7 of the cavity 5 . Rotating the screw connection 20 in the opposite direction may cause the clamping body 6 to move towards the front end 4 of the hollow body 1 .
[0028] The axially adjustable screw connection 20 may include a sleeve 30 having an external threaded portion 28 for engaging an internal threaded portion 27 formed in an enlarged portion of the borehole 18 at the rear end 3 of the hollow body 1 . The external threaded portion 28 may engage the internal threaded portion 27 such that when the sleeve 30 is rotated in a first direction, the clamping body 6 may move out of the cavity 5 (away from the rear end 3 ), and when the sleeve is rotated in a second direction, the clamping body 6 may move into the cavity 5 (towards the rear end 3 ). The rod 21 may pass through the sleeve 30 and may be dimensioned to extend between the clamping body 6 and the clamping lever 25 such that the contact surface 26 of the clamping lever 25 may rest on the outer end surface 31 of the sleeve 30 .
[0029] In use, a first end of a pair of fixation elements (e.g., Kirschner wires 8 ) may be inserted (e.g., drilled, hammered, etc.) by a surgeon into a bone 17 . Alternatively, as appreciated by one skilled in the art, any number of fixation elements may be inserted into bone 17 . In an embodiment wherein the device 10 includes both a mechanism 19 and a screw connection 20 , the clamp lever 25 may be rotated into the position shown in FIG. 2 (i.e., the loosened or unlocked position). The clamping body 6 may be moved axially out of the cavity 5 to a certain extent by rotating the sleeve 30 in the first direction until the clamping body 6 is in a first position. In the first position, a second end of the fixation element(s) (i.e., the end of the fixation element(s) which has not been inserted into bone) may be introduced into the gap between the clamping body 6 and the wall 7 of the cavity 5 . Thereafter, the sleeve 30 may be rotated in the second direction until the clamping body 6 is moved into the second position so that the external surface 9 of the clamping body 6 contacts the second end of the fixation element(s) and causes the fixation element(s) to be pressed against the wall 7 of the cavity 5 . The lever 25 may then be rotated into the position shown in FIG. 1 (i.e., the tightened or locked position) to tension the lever 25 and assert an additional upward force on the clamping body 6 , which may move the clamping body 6 further into the cavity 5 . In this way, the fixation element(s) may be fixed firmly in the gap between the clamping body 6 and the wall 7 of the cavity 5 .
[0030] While the foregoing description and drawings represent the preferred embodiments of the present invention, it will be understood that various additions, modifications and substitutions may be made therein without departing from the spirit and scope of the present invention as defined in the accompanying claims. In particular, it will be clear to those skilled in the art that the present invention may be embodied in other specific forms, structures, arrangements, proportions, and with other elements, materials, and components, without departing from the spirit or essential characteristics thereof. One skilled in the art will appreciate that the invention may be used with many modifications of structure, arrangement, proportions, materials, and components and otherwise, used in the practice of the invention, which are particularly adapted to specific environments and operative requirements without departing from the principles of the present invention. The presently disclosed embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and not limited to the foregoing description.
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FIELD OF THE INVENTION
[0001] The present invention pertains generally to ophthalmic laser surgery procedures. More particularly, the present invention pertains to laser surgical procedures which are performed to reshape or restructure the cornea of an eye by using photoablation techniques to remove stromal tissue. The present invention is particularly, but not exclusively, useful as a method and system for creating a flap in the cornea of an eye that can be moved or lifted to expose stromal tissue for photoablation.
BACKGROUND OF THE INVENTION
[0002] Within the past number of years, the so-called LASIK procedure has been used successfully to correct vision difficulties for a significantly large number of patients. In overview, a LASIK procedure is used to reshape or restructure the cornea of an eye in order to change its refractive properties. The object is to thereby minimize optical aberrations and to improve a patient's vision by altering the corneal shape.
[0003] As is well known to those skilled in the art, a LASIK procedure involves the removal of stromal tissue by photoablation. For a typical LASIK procedure, this photoablation is accomplished using an “excimer” laser. Excimer lasers, however, are most effective when they are used to superficially photoablate tissue. Accordingly, when using an excimer laser for the photoablation of tissue, it is necessary to somehow expose the target tissue that is to be photoablated. In the case of a LASIK procedure, it has been the practice to mechanically access the target tissue. Heretofore, this has involved the creation of a corneal flap which can be moved, or lifted, to expose the target tissue. The “excimer” laser is then used to photoablate the exposed stromal tissue. After the photoablation of tissue is accomplished, as desired the flap can be repositioned over the stroma. A major benefit of this so-called “Flap and Zap” procedure is that trauma to the epithelial layer at the anterior surface of the cornea is minimized. Trauma to the stroma under the epithelial layer, however, may still be significant.
[0004] A general knowledge of the anatomy of the cornea of an eye is helpful for appreciating the problems that must be confronted whenever a corneal flap is created. More specifically, the cornea comprises various layers of tissue which are structurally distinct. In order, going in a posterior direction from outside the eye toward the inside of the eye, the various layers in a cornea are: an epithelial layer, Bowman's membrane, the stroma, Decimet's membrane, and an endothelial layer. Of these various structures, the stroma is the most extensive and is generally around four hundred microns thick.
[0005] In detail, the stroma of the eye is comprised of around two hundred identifiable and distinguishable layers of lamella. Each of these layers of lamella in the stroma is generally dome-shaped, like the cornea itself, and they each extend across a circular area having a diameter of approximately six millimeters. Unlike the layer that a particular lamella is in, each lamella extends through a shorter distance of only about one tenth to one and one half millimeters. Thus, each layer includes several lamellae. Importantly, each lamella includes many fibrils which, within the lamella, are substantially parallel to each other. The fibrils in one lamella, however, are not generally parallel to the fibrils in other lamellae. This is so between lamellae in the same layer, as well as between lamellae in different layers. Finally, it is to be noted that, in a direction perpendicular to the layer, the individual lamella are only about two microns thick.
[0006] Within the general structure described above, there are at least three important factors concerning the stroma that are of interest insofar as the creation of a corneal flap is concerned. The first of these factors is structural, and it is of interest here because there is a significant anisotropy in the stroma. Specifically, the strength of tissue within a lamella is approximately fifty times the strength that is provided by the adhesive tissue that holds the layers of lamella together. Thus, much less energy is required to separate one layer of lamella from another layer (i.e. peel them apart), than would be required to cut through a lamella. The second factor is somewhat related to the first, and involves the stromal tissue response to photoablation. Specifically, for a given energy level in a photoablative laser beam, the bubble that is created by photoablation in the stronger lamella tissue will be noticeably smaller than a bubble created between layers of lamellae. The third factor is optical, and it is of interest here because there is a change in the refractive index of the stroma between successive layers of lamellae. This is due to differences in the orientations of fibrils in the respective lamella. When consideration is given to using a laser beam for the purpose of creating a corneal flap in a LASIK procedure, these factors can be significant.
[0007] In light of the above, it is an object of the present invention to provide a method for using a laser beam to separate lamella in the stroma of an eye which minimizes the heating of the stromal tissue. Another object of the present invention is to provide a method for using a laser beam to separate lamellae in the stroma of an eye that can be accomplished quickly in order to minimize the time a patient must fixate. Still another object of the present invention is to provide a method for separating lamellae in the stroma that avoids excessive trauma to the stromal tissue in the cornea. Yet another object of the present invention is to provide a method for separating lamellae in the stroma that is easy to perform and is comparatively cost effective.
SUMMARY OF THE PREFERRED EMBODIMENTS
[0008] In accordance with the present invention, a method for separating lamellae in the stroma of an eye requires focusing a laser beam between layers of the lamellae and photoablating tissue at the interface between these layers. This involves first locating a start point in the stroma. Preferably, this start point will be at a distance into the stroma that is approximately one hundred and eighty microns from the anterior surface of the cornea. As contemplated by the present invention, the anterior surface of the cornea can be identified using a wavefront sensor.
[0009] Once the start point is located, tissue at the start point is photoablated to create a bubble. The size of this bubble is then measured and compared with a reference to determine whether the bubble was created within a lamella or between layers of lamellae. If the bubble is created inside a lamella, subsequent bubbles can be created at different points in the stroma until the resultant bubble size indicates that photoablation is occurring between layers of lamellae. An ellipsometer is then used to detect a birefringent condition in the stroma between these layers of lamellae. Specifically, this birefringent condition will result from a change in the orientation of fibrils in the respective lamella, and will be indicative of the interface between layers of lamellae in the stroma. Further, it happens that from layer to layer of lamellae there will be a birefringent change that is manifested as a change in phase of about one half degree. Recall, the thickness of the lamellae is around two microns. The importance of all this is that the detection of a birefringent change will indicate a change from one layer of lamellae to another. Thus, it can be used to establish and maintain a focal depth in the stroma.
[0010] The photoablation of tissue along the interface between layers of lamellae in the stroma begins by focusing the laser beam to a focal point at the established focal depth in the stroma. Initially, the laser beam is set to operate at an energy level that is slightly above the threshold for photoablation of stromal tissue (i.e. above approximately one and one half microjoules for a ten micron diameter spot size). For example, the initial energy level that can be used for the laser beam may be around five microjoules for a ten micron diameter spot. In any event, whenever the laser beam is activated, there will be a photoablative response from the tissue that results from the particular energy level that is being used. Importantly, this photoablative response will vary according to the energy level of the laser beam, as well as the nature of the tissue that is being photoablated.
[0011] As intended for the present invention, the photoablative response is measured as the diameter of the gas bubble that is created in the stromal tissue during photoablation. This photoablative response is then compared with the reference value mentioned above to determine whether the initial energy level is sufficient for further operation. For the purposes of the present invention, this reference value is chosen to correspond to a hypothetical gas bubble in the stroma that, as a result of photoablation, would have a diameter of approximately fifteen microns. Depending on the difference between the photoablative response and the reference value, the energy level of the laser beam will either be held constant, or it will be changed. For the present invention, the change in energy level will be between a relatively low energy level (e.g. approximately five microjoules per ten micron diameter spot size) and a relatively high energy level (e.g. approximately fifteen microjoules per ten micron diameter spot size).
[0012] A condition wherein the photoablative response is greater than the reference value is indicative that the photoablation of tissue is occurring in the weaker tissue that is located at the interface between layers of lamella, rather than inside the lamella. Accordingly, further photoablation is accomplished by maintaining the initial energy level of the laser beam at the relatively lower energy level, and moving its focal point at the focal depth between the layers of lamellae. As this is being done, the ellipsometer can be used periodically to ensure the photoablation is being done at the same interface between lamellae. This continues as long as this condition persists. On the other hand, when the photoablative response becomes less than the reference value, the indication is that the focal point is no longer located between layers of lamellae. Thus, the energy level needs to be increased to a higher energy level. Also, the focal point needs to be moved until the photoablative response is substantially greater than the reference value. At this point, i.e. when the photoablative response becomes substantially greater than the reference value, the indication is that the focal point is again between layers of lamella. The energy level of the laser beam is then returned to its former lower value. Also, if desired, the focal depth can be verified by the ellipsometer and adjusted as necessary.
[0013] In the operation of the present invention, the energy level of the laser beam is altered in the above manner to follow the interface between lamella, and it is guided to create a flap from the corneal tissue. Specifically, the focal spot of the laser beam is moved within a boundary that can be generally defined by a first edge and a second edge. More specifically, to create the flap, the first edge should be a substantially straight line between a first point and a second point. The second edge can then be a curved line between the first point and the second point with the curved line having a radius of curvature around the optical axis of the eye of about four and one half millimeters. Further, this curved line should be centered approximately on the optical axis of the eye and extend through an arc of about two hundred and seventy degrees.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The novel features of this invention, as well as the invention itself, both as to its structure and its operation, will be best understood from the accompanying drawings, taken in conjunction with the accompanying description, in which similar reference characters refer to similar parts, and in which:
[0015] [0015]FIG. 1 is a schematic diagram, in a closed-loop feedback control format, showing the operative components of an apparatus that is useful for performing the methods of the present invention;
[0016] [0016]FIG. 2 is a logic flow chart of the sequential steps to be accomplished in accordance with the methods of the present invention;
[0017] [0017]FIG. 3 is a cross sectional view of the cornea of an eye;
[0018] [0018]FIG. 4 is a cross sectional view of layers of lamella in the cornea of an eye; and
[0019] [0019]FIG. 5 is a plan view of the cornea of an eye.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0020] Referring initially to FIG. 1, an apparatus for use in performing the methods of the present invention is shown schematically in a control loop format and is generally designated 10 . As shown, the apparatus 10 includes a laser source 12 which, preferably, is capable of generating a continuous train of ultra-short pulses, with each pulse having a pulse duration of approximately one pico-second. Specifically, it is necessary that each pulse have an energy level that is above the threshold necessary for the photoablation of stromal tissue (i.e. above approximately one and one half microjoules per ten micron diameter spot size). The apparatus 10 also includes an ellipsometer 14 that is capable of determining the birefringent properties within stromal tissue. For the purposes of the present invention, an ellipsometer of the type disclosed and claimed in U.S. Pat. No. 5,822,035, which issued to Bille for an invention entitled “Ellipsometer.” Further, FIG. 1 shows that the apparatus 10 includes a wavefront sensor 16 , such as a Hartmann-Shack sensor, which is capable of modeling a wavefront. Additionally, the apparatus 10 includes guidance optics 18 that are capable of steering and focusing a laser beam onto predetermined focal points. A power unit 20 is also provided. In combination, these components cooperate with each other to generate a laser beam 22 that is directed to a focal point in the cornea 24 of an eye 26 with a predetermined energy level. Control over this operation, to include the location of the focal point and its energy level, is made possible by using the ellipsometer 14 and the wavefront sensor 16 to monitor reflected light 28 as it is reflected from the cornea 24 .
[0021] Referring now to FIG. 2, it will be seen that in the operation of apparatus 10 , the performance of the methods of the present invention begins by establishing a start point (action block 30 ). In FIG. 3 it will be seen that this start point 32 is established in the stroma 34 of cornea 24 . Specifically, the start point 32 is established at a distance 36 that is measured from the anterior surface 38 of the cornea 24 in a direction that is substantially perpendicular to the anterior surface 38 . As intended for the apparatus 10 , the exact location of the anterior surface 38 can be determined using the wavefront sensor 16 , and the distance 36 can then be arbitrarily chosen to be around about one hundred and eighty microns from the anterior surface 38 .
[0022] Once a start point 32 has been established in the stroma 34 , action block 40 in FIG. 2 indicates that the next step in the methods of the present invention is to photoablate tissue at the start point 32 to create a response (i.e. a bubble in the stromal tissue). As indicated by inquiry block 41 , this response is then compared with a reference (e.g. 15 μm). If the response is less than the reference, action block 43 indicates the focal point should be moved from the start point 32 through a distance 42 (FIG. 4). This distance 42 will preferably be taken in an anterior direction (indicated by the arrow 44 in FIG. 4) and will, most likely, be less than two microns. It will be appreciated, however, that in some cases this distance 42 may be taken in a posterior direction (indicated by arrow 46 in FIG. 4). In either case, as this movement from the start point 32 is being accomplished, the inquiry block 41 in FIG. 2 indicates that when the response becomes greater than the reference, reflected light 28 from cornea 24 can be monitored by the ellipsometer 14 to determine a birefringent reference (action block 48 ). It happens that this birefringent reference can be determined due to a variation in the orientation of tissue in the stroma 34 and will, perhaps, be best understood by reference to FIG. 4.
[0023] In FIG. 4, a portion of the stroma 34 in the cornea 24 of the eye 26 is shown to include a plurality of lamellae 50 , of which the lamellae 50 a , 50 b and 50 c are only exemplary. Dimensionally, each of the lamellae 50 in the stroma 34 have a depth 52 that is approximately two microns, and a width 54 that is between approximately one tenth and one and one half millimeters. Thus, the lamellae 50 each have a very thin disk shape. Anatomically, the lamella 50 lie on top of each other in layers that extend across the cornea 24 through a distance 56 that is approximately nine millimeters. As shown in FIG. 4, the individual lamella 50 overlap to some extent and are somewhat randomly arranged. Nevertheless, they create many interface layers that, in general, are substantially parallel to each other and extend all the way across the cornea 24 . The interface layer 58 shown in FIG. 4 is only exemplary of the many interface layers in the cornea 24 .
[0024] For the purposes of the present invention, an interface layer 58 is important in two aspects. First, the birefringent properties of stromal tissue in the lamella 50 change at the interface layer 58 . Recall, from the disclosure above, this change in birefringent properties is due to changes in the orientation of fibrils (not shown) in the lamella 50 . Second, the stromal tissue along the interface layer 58 is weaker than stromal tissue inside the lamella 50 . Accordingly, the stromal tissue along the interface layer 58 can be effectively photoablated at lower energy levels.
[0025] It happens that whenever stromal tissue is photoablated, a bubble is formed in the stroma 34 . For a given type of tissue, the size of the bubble that is formed will be a function of the energy level in the laser beam 22 . In this case, the higher the energy level, the larger the bubble. Further, for a given energy level, the size of the bubble that is formed will be a function of the type of tissue. In this case, with the same energy level, the stronger tissue will yield a smaller bubble and the weaker tissue will yield a larger bubble. With this in mind, consider the bubbles 60 and 62 shown (not to scale) in FIG. 4 that would be formed using a same energy level in the laser beam 22 . The larger bubble 60 is shown generally in weaker tissue at the interface layer 58 between the lamella 50 a and 50 b. On the other hand, the smaller bubble 62 is shown in stronger tissue inside the lamella 50 b. Fortunately, as used for the present invention, the respective sizes of the bubbles 60 and 62 will serve as photoablative responses that can be measured by the wavefront sensor 16 using relatively well known wavefront techniques. Accordingly, the photoablative response of a bubble 60 or bubble 62 can be compared with a reference value, and the energy level of the laser beam 22 can be altered as desired.
[0026] Returning now to FIG. 2, and in light of the above discussion with reference to FIG. 4, it will be appreciated that the combined functions of inquiry block 41 and action block 48 is to find the interface layer 58 . This is accomplished whenever the ellipsometer 14 detects a birefringent change. It will happen that this birefringent change will be on the order of plus or minus one half degree. Importantly, finding the interface layer 58 will fix a focal depth for the laser beam 22 that will be a combination of the distances 36 and 42 . The apparatus 10 can then begin to photoablate stromal tissue (action block 64 ).
[0027] Action block 64 in FIG. 2 indicates that, at least initially, the apparatus 10 will photoablate stromal tissue at a relatively low energy level, e.g. approximately five microjoules per ten micron spot size. As indicated above, if photoablation begins at this energy level in the interface layer 58 as intended, a relatively large bubble 60 will result. In any event, as indicated by the inquiry block 66 , the resultant bubble (photoablative response) will be compared with a reference value to determine whether photoablation at this energy level should continue (inquiry block 66 ). For the present invention, the reference value will correspond to a hypothetical bubble in stromal tissue (not shown) which would have a diameter of approximately fifteen microns. If the resultant bubble in the stroma 34 has a photoablative response that is greater than the reference value, it is indicative of the fact that weaker tissue in the interface layer 58 is being photoablated. In this case, the inquiry block 67 may be selectively used to determine whether the birefringent reference has changed. Such a change would be on the order of one half a degree and would indicate that another interface 58 ′ was being photoaltered. If so, action block 68 indicates the birefringent reference can be reset to reestablish on the desired interface 58 . In either case, the action block 70 in FIG. 2 indicates that the guidance optics 18 should continue to scan the laser beam 22 through the interface layer 58 . As this is being done, the interaction of blocks 64 , 66 , 67 and 68 in FIG. 2 indicate that a photoablative response is continuously being monitored by the wavefront sensor 16 .
[0028] Whenever the photoablative response falls below the reference value, such as would happen when photoablation is occurring within a lamella 50 (e.g. bubble 62 ), action block 72 indicates that the energy level in the laser beam 22 should be increased to a higher energy level. Again, the photoablative response is monitored by the wavefront sensor 16 . Due to the higher energy level being used, when the laser beam 22 is next focused onto the interface layer 58 , the photoablative response will most likely be much greater than the reference value. In any event, inquiry block 74 and action block 75 indicates that the laser beam 22 will continue to move and photoablate tissue until the photoablative response is considerably greater than the reference value. When this happens, depending on the desires of the operator, the methods of the present invention indicate that the laser beam 22 can continue operation at the relatively lower energy level (action block 64 ). In either case, blocks 66 , 67 , 68 and 70 indicate that the photoablation of stromal tissue will continue until the procedure is ended. Specifically, the procedure is ended when an interface layer 58 having a predetermined dimension has been created.
[0029] It is the purpose of the present invention to create a flap of corneal tissue that can be lifted easily from the eye to expose stromal tissue under the flap to further surgical photoablation. Accordingly, the present invention is directed toward the photoablation of weaker tissue along an interface layer 58 between lamella 50 and to, thereby, use less laser energy. The extent of this photoablation will be best appreciated with reference to FIG. 5. In FIG. 5, a substantially straight edge 76 is shown between a point 78 and a point 80 . Also, a substantially curved edge 82 is shown connecting the point 78 to the point 80 . More specifically, the curved edge 82 is generally centered on the optical axis 84 of the eye 26 and has a radius of curvature 86 that defines the edge 82 . As shown, the curved edge 82 will extend through approximately two hundred and seventy degrees. Effectively the desired corneal flap will be created between the straight edge 76 and the curved edge 82 . Consequently, by photoablating tissue between the anterior surface 38 of the cornea 24 and the curved edge 82 , a flap of corneal tissue can be lifted from the interface layer 58 to expose stromal tissue under the flap for further photoablation.
[0030] While the particular Method for Separating Lamellae as herein shown and disclosed in detail is fully capable of obtaining the objects and providing the advantages herein before stated, it is to be understood that it is merely illustrative of the presently preferred embodiments of the invention and that no limitations are intended to the details of construction or design herein shown other than as described in the appended claims.
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BACKGROUND OF THE INVENTION
[0001] The present invention relates to baseball and softball bats. More particularly, the present invention relates to a bat having a vibration damping, flexible structure between the grip and the head of the bat.
[0002] Baseball and softball are very popular sports in the United States, Mexico, Cuba, Japan and elsewhere. Due to the competitive nature of the sports, players are constantly seeking ways of improving their performance. An important aspect of baseball and softball is the ability to effectively hit the ball. Aluminum (metal) bats are allowed in baseball amateur play from Little League to College levels. Metal bats are also typically used in slow and fast pitch softball. Such bats are advantageous over wood bats in that they do not break and splinter like wood bats and thus can be repeatedly used with consequent cost savings. Metal bats also have a larger optimal hitting area or power zone (commonly referred to as the “sweet spot”) than wood bats. Furthermore, the ball comes off a metal bat faster than a wood bat resulting in longer hits.
[0003] However, metal bats have certain disadvantages. Metal bats vibrate upon impact and may send painful vibrations into the hands and arms of the batter if the ball is not hit within the power zone of the bat. Metal bats, particularly aluminum bats, may also dent or otherwise deform due to forceful impacts with the ball. Metal bats also emit an undesirable high-pitched metallic sound, as opposed to the traditional sound heard when a wood bat contacts the ball.
[0004] Various attempts have been made to overcome the problems associated with metal bats. Some attempts have been to coat or wrap the exterior of the metal bat with materials such as carbon reinforcing fibers to enhance batting performance. These externally wrapped bats have been found to be aesthetically unpleasant and lacking in significant improvement. Other attempts have been made to insert internal layers or compartments within the metal bat to improve performance. Such designs include utilizing multiple-layered graphite inserts to provide durability and flexibility to the bat, tubular coiled spring steel inserts to improve the spring-board effect when the ball contacts the bat, and pressurized air chambers within the bat. While providing benefits, these designs also have drawbacks. Some designs are very expensive to manufacture and are prone to structural failure. The composite sheaths break down over time and the bats are subject to premature longitudinal cracks in the barrel of the bat. In many of the newly designed metal bats, the reinforcement is focused around the optimal hitting area or center of the hitting area of the bat and do not run the length of the barrel of the bat.
[0005] Accordingly, there is a need for a bat which enhances the performance of the bat and overcomes the disadvantages previously experienced with metal bats. The present invention fulfills these needs and provides other related advantages.
SUMMARY OF THE INVENTION
[0006] The present invention resides in a vibration damping baseball bat that includes a barrel portion, a handle portion, and interconnects the barrel portion and the handle portion in an aligned and spaced-apart relation. The mechanism by which the barrel and handle portions are interconnected dampens vibrations created when a ball contacts the bat and provides limited pivotal movement of the barrel portion relative to the handle portion.
[0007] The bat includes a first elastomeric washer disposed between the interconnecting mechanism and the barrel portion, and a second elastomeric washer disposed between the interconnecting mechanism and the handle portion.
[0008] The interconnecting mechanism forms a tapered portion of the bat and includes an intermediate tapered section having first and second engaging members connected to, respectively, the barrel portion and the handle portion. In this manner, the first elastomeric washer is disposed between the tapered section and the barrel portion and the second elastomeric washer is disposed between the tapered section and the handle portion.
[0009] The interconnecting mechanism includes a plug positioned within the barrel portion to receive the first engaging member. This barrel plug is sized and shaped to abuttingly engage the barrel portion when receiving the first engaging member. The barrel plug expands to wedge against the barrel portion as the plug receives the first engaging member. Threads within the barrel plug engage threads of the first engaging member, causing the plug to spread.
[0010] Likewise, the interconnecting mechanism includes a plug positioned within the handle portion to receive the second engaging member. This handle plug is sized and shaped to abuttingly engage the handle portion when receiving the second engaging member. The handle plug expands to wedge against the handle portion as the plug receives the second engaging member. Threads within the handle plug engage threads of the second engaging member, causing the plug to spread.
[0011] The tapered section is comprised of an elastomeric material to dampen vibrations created when a ball contacts the bat.
[0012] The barrel and handle portions each include a tapered first end having an aperture. The barrel and handle plugs are each tapered and disposed within their respective portions of the bat near the aperture of that portion. Each plug abuttingly engages, respectively, the tapered first end of its respective portion when receiving the interconnecting mechanism.
[0013] The interconnecting mechanism includes a mechanism for adjusting weight distribution of the bat. This adjustment mechanism includes a sleeve extending between the handle and barrel portions and a threaded rod received within the sleeve. A pair of threaded washers engage ends of the threaded rod that extend past the sleeve such that movement of at least one washer along the threaded rod adjusts weight distribution of the bat.
[0014] Other features and advantages of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The accompanying drawings illustrate the invention. In such drawings:
[0016] FIG. 1 is a perspective view of a bat embodying the present invention;
[0017] FIG. 2 is a cross-sectional elevation view of the bat of FIG. 1 showing the handle, barrel and mechanism for interconnecting the barrel and handle;
[0018] FIG. 3 is a perspective view of the interconnecting mechanism of FIG. 2 with the bat shown in phantom; and
[0019] FIG. 4 is an exploded perspective view of the handle, barrel and interconnecting mechanism;
[0020] FIGS. 5-7 are cross-sectional elevation views showing the assembly of the bat by connecting the handle and the barrel using the interconnecting mechanism;
[0021] FIG. 8 is a cross-sectional elevation view of another bat embodying the present invention that shows the handle, barrel and mechanism for interconnecting the barrel and handle;
[0022] FIG. 9 is a perspective view of the interconnecting mechanism of FIG. 8 with the bat shown in phantom;
[0023] FIG. 10 is a partially exploded perspective view of the interconnecting mechanism of FIG. 9 ;
[0024] FIG. 11 is an exploded perspective view of the handle, barrel and interconnecting mechanism of the bat of FIG. 8 ;
[0025] FIGS. 12 and 13 are cross-sectional elevation views showing the assembly of the bat of FIG. 8 by connecting the handle and the barrel using the interconnecting mechanism; and
[0026] FIG. 14 is a flow chart illustrating the steps taken in manufacturing the bat of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0027] As shown in FIGS. 1-13 for purposes of illustration, the present invention is concerned with a bat 20 for use in baseball or softball, having an elongate hollow handle shell portion 22 , an elongate hollow barrel shell portion 24 and an intermediate cylindrically tapered section 26 interconnecting the handle portion 22 and the barrel portion 24 . A knob 28 may be welded or otherwise securely attached to the end of the handle portion 22 . The knob 28 may be made of various materials including, without limitation, aluminum, polyurethane, polycarbonate, a composite material or the like. Also, the handle portion 22 is typically wrapped with a grip 30 comprised of rubber, polyurethane, leather or the like, for comfort. The construction of the intermediate tapered section 26 dampens vibrations created when a ball contacts the bat 20 and provides limited pivotal movement of the barrel portion 24 relative to the handle portion 22 .
[0028] The handle and barrel portions 22 , 24 may be made of various materials including, without limitation, wood, a lightweight yet durable metal (e.g., aluminum, titanium, magnesium, or an alloy thereof, a composite material (e.g., fiberglass, carbon fibers, or a combination of glass and carbon fibers) or the like. Preferably, the handle and barrel portions 22 , 24 are comprised of a 6000 or 7000 series aluminum alloy in which zinc is the major alloying element coupled with a smaller percentage of magnesium, resulting in a heat-treatable alloy of very high strength. The handle and barrel portions 22 , 24 are finished to a mechanical strength of T6 Temper.
[0029] The handle and barrel portions 22 , 24 each include a tapered first end 32 , 34 having an aperture 36 , 38 . The intermediate tapered section 26 includes a central tapered connector 40 having generally cylindrical first and second engaging members 42 , 44 and a central cylindrically tapered section 46 disposed therebetween. The tapered connector 40 is hollow and includes a central cavity 43 within the central section 46 and the engaging members 42 , 44 . The diameters of the engaging members 42 , 44 may be the same, or the diameter of one of the engaging members 42 , 44 may be larger than the diameter of the other of the engaging members 44 , 42 .
[0030] A plug 48 positioned within the barrel portion 24 receives the first engaging member 42 . This barrel plug 48 is sized and shaped to abuttingly engage the barrel portion 24 when receiving the first engaging member 42 . The barrel plug 48 expands to wedge against an interior wall 50 of the barrel portion 24 as the plug 48 receives the first engaging member 42 . Likewise, a plug 52 positioned within the handle portion 22 receives the second engaging member 44 . This handle plug 52 is sized and shaped to abuttingly engage the handle portion 22 when receiving the second engaging member 44 . The handle plug 52 expands to wedge against an interior wall 54 of the handle portion 22 as the plug 52 receives the second engaging member 44 .
[0031] The barrel and handle plugs 48 , 52 are disposed within the interior of their respective portions 24 , 22 of the bat 20 near the aperture 38 , 36 of that portion 24 , 22 . The end 32 , 34 of each portion 22 , 24 is curled or turned inwardly to create, respectively, an interior shoulder 56 , 58 about the aperture 36 , 38 . Each plug 52 , 48 abuttingly engages, respectively, the shoulder 56 , 58 and interior wall 54 , 50 of the portion 22 , 24 when the plug 52 , 48 receives its respective engaging member 44 , 42 of the connector 40 .
[0032] A generally continuous taper is formed on the exterior surface of the intermediate tapered section 26 by the tapered end 34 of the barrel portion 24 , a first tapered cylindrical elastomeric washer 60 disposed between a shoulder 62 of the central section 46 and an exterior shoulder 64 of the tapered first end 34 of the barrel portion 24 , the central section 46 of the tapered connector 40 , a second tapered cylindrical elastomeric washer 66 disposed between another shoulder 68 of the central section 46 and an exterior shoulder 70 of the tapered first end 32 of the handle portion 22 , and the tapered end 32 of the handle portion 22 . The components of the intermediate tapered section 26 tightly fit together to isolate vibrations which insulates the handle portion 22 from vibrations generated in the barrel portion 24 when a ball strikes the barrel portion 24 . The length of the intermediate tapered section 26 will be varied based on the size and type of bat (e.g., adult baseball bat, youth baseball bat, softball bat or the like). A high strength bonding glue (not shown) may be applied to all joins to secure all the connections.
[0033] The tapered connector 40 is comprised of a material to dampen vibrations created when a ball contacts the bat; isolating shock transmission from the barrel portion 24 to a hand of a batter gripping the handle portion 22 when a ball is in contact with the bat 20 . This material comes in various forms including, without limitation, an elastomeric material (e.g., solid rubber, high performance rubber foam, silicone or similar materials), polyurethane, polycarbonate, or a composite material (e.g., fiberglass, carbon fibers, or a combination of glass and carbon fibers). The plugs 48 , 52 and washers 60 , 66 may be made of the same materials as the connector 40 .
[0034] An end 80 of the barrel portion 24 is typically open and directed inward for acceptance and retention of an end plug 82 . The end plug 82 is typically comprised of urethane, polyurethane, Zytel or the like. The end plug 82 has a circumferential groove 84 which accepts the inwardly directed annular lip 86 of the barrel portion 24 .
[0035] As can be seen from FIGS. 1-7 , in one embodiment of the present invention, each engaging member 42 , 44 is generally cylindrical and includes exterior threads 72 , 74 for engaging, respectively, the plugs 48 , 52 of the barrel and handle portions 24 , 22 .
[0036] The barrel plug 48 is cylindrical tapered with a threaded bore 73 opening on an angled end 75 . The angle of the end 75 matches the angle of the interior shoulders 58 of the first end 34 of the barrel portion 24 ; the angle of the end 75 being between zero and forty-five degrees. The angle of the exterior shoulder 64 of the barrel portion 24 matches the angle of the exterior shoulder 62 of the central section 46 ; the angle of the exterior shoulder 62 being between zero and forty-five degrees. The washer 60 disposed between the shoulder 62 of the central section 46 and the exterior shoulder 64 of the first end 34 of the barrel portion 24 is compressed and bends to match this angle as the tapered connector 40 is connected to the barrel portion 24 .
[0037] The handle plug 52 includes a cylindrical threaded bore 77 opening on an angled end 79 . The angle of the end 79 matches the angle of the interior shoulder 56 of the first end 32 of the handle portion 22 ; the angle of the end 79 being between zero and forty-five degrees. The angle of the exterior shoulder 70 of the handle portion 22 matches the angle of the exterior shoulder 68 of the central section 46 ; the angle of the exterior shoulder 68 being between zero and forty-five degrees. The washer 66 disposed between the shoulder 68 of the central section 46 and the exterior shoulder 70 of the tapered first end 32 of the handle portion 22 is compressed and bends to match this angle as the tapered connector 40 is connected to the handle portion 22 .
[0038] Interior threads 76 , 78 within bores 73 , 77 of the plugs 48 , 52 engage, respectively, the exterior threads 72 , 74 of its engaging member 42 , 44 . As the engaging members 42 , 44 are threadedly received within the respective plug 48 , 52 , the plug 48 , 52 begins to spread until the plug 48 , 52 abuts against the interior walls 50 , 54 and shoulders 58 , 56 . In the alternative, sides of the plugs 48 , 52 may be comprised of a number of fingers (not shown) that spread to abut against the interior walls 50 , 54 and shoulders 58 , 56 as the engaging members 42 , 44 are received within the respective plug 48 , 52 .
[0039] The bat 20 may be assembled in a number of ways. In one particular way, the barrel plug 48 is inserted through the open end 80 of the barrel portion 24 and positioned adjacent the aperture 38 . The diameter of the plug 48 is larger than the diameter of the aperture 38 so the plug 48 will not go through the aperture 38 . The handle plug 52 is inserted through the aperture 36 of the handle portion 22 . The diameter of the plug 52 is the same or smaller than the diameter of the aperture 36 but larger than the diameter of the handle portion 22 past the tapered end 32 so the plug 52 will not go through the handle portion 22 towards the knob 28 .
[0040] The first washer 60 is positioned around the first engaging member 42 and disposed between the shoulder 62 of the central section 46 and the exterior shoulder 64 of the tapered first end 34 of the barrel portion 24 . The second washer 66 is positioned around the second engaging member 44 and disposed between the shoulder 68 of the central section 46 and the exterior shoulder 70 of the tapered first end 32 of the handle portion 22 . The engaging members 42 , 44 are threadedly engaged to their respective plugs 48 , 52 until the barrel and handle portions 24 , 22 are tightly connected together by the tapered connector 40 . The end plug 82 is then secured to the end 80 of the barrel portion 24 .
[0041] In another embodiment of the present invention, as seen in FIGS. 8-13 , each engaging member 42 , 44 is generally cylindrical and of constant diameter from where the engaging member 42 , 44 is adjacent the central section 46 to about half its length when the engaging member 42 , 44 tapers outwardly for the rest of its length.
[0042] The barrel plug 48 is cylindrically tapered with a smooth-walled tapered bore 88 opening on an angled end 90 . The angle of the end 90 matches the angle of the interior shoulders 58 of the first end 34 of the barrel-portion 24 ; the angle of the end 90 being between zero and forty-five degrees. The angle of the exterior shoulder 64 of the barrel portion 24 matches the angle of the exterior shoulder 62 of the central section 46 ; the angle of the exterior shoulder 62 being between zero and forty-five degrees. The washer 60 disposed between the shoulder 62 of the central section 46 and the exterior shoulder 64 of the first end 34 of the barrel portion 24 is compressed and bends to match this angle as the tapered connector 40 is connected to the barrel portion 24 .
[0043] The handle plug 52 is cylindrically tapered with a smooth-walled tapered bore 92 opening on an angled end 94 . The angle of the end 94 matches the angle of the interior shoulder 56 of the first end 32 of the handle portion 22 ; the angle of the end 94 being between zero and forty-five degrees. The angle of the exterior shoulder 70 of the handle portion 22 matches the angle of the exterior shoulder 68 of the central section 46 ; the angle of the exterior shoulder 68 being between zero and forty-five degrees. The washer 66 disposed between the shoulder 68 of the central section 46 and the exterior shoulder 70 of the tapered first end 32 of the handle portion 22 is compressed and bends to match this angle as the tapered connector 40 is connected to the handle portion 22 .
[0044] Interior cylindrically tapered mounds 96 , 98 within bores 88 , 92 of the plugs 48 , 52 engage, respectively, cylindrically tapered receptacles 100 , 102 of its engaging member 42 , 44 . When the engaging member 42 , 44 is fully received within the bore 88 , 92 of the respective plug 48 , 52 , an end 104 , 106 of the receptacle 100 , 102 abuts against an end 108 , 110 of mound 96 , 98 . In the alternative, sides of the plugs 48 , 52 may be comprised of a number of fingers (not shown) that spread to abut against the interior walls 50 , 54 and shoulders 58 , 56 as the engaging members 42 , 44 are received within the respective plug 48 , 52 .
[0045] The tapered connector 40 and plugs 48 , 52 are held together by press-fit engagement as well as by a mechanism for adjusting weight distribution 112 of the bat 20 . This adjustment mechanism 112 includes a sleeve 114 extending between the handle and barrel portions 22 , 24 through a central bore 116 in the tapered connector 40 that has openings 118 , 120 in the receptacles 100 , 102 of the engaging members 42 , 44 . Each plug 48 , 52 also includes a central bore 122 , 124 through which the sleeve 114 extends. Exterior ends 126 , 128 of the sleeve 114 are threaded. Each plug 48 , 52 includes a shallow hexagonal recess 130 , 132 for receiving a threaded hexagonal washer 134 , 136 that engages a respective threaded end 126 , 128 of the sleeve 114 . The engagement of the washers 134 , 136 and sleeve 114 help connect the tapered connector 40 and plugs 48 , 52 together.
[0046] A rod 138 with threaded ends 140 , 142 is received within and extends past the ends 126 , 128 of the sleeve 114 . Interior portions 150 , 152 of the ends 126 , 128 of the sleeve 114 are threaded to engage the threads of the threaded ends 140 , 142 of the rod 138 and hold the rod 138 in position relative to the sleeve 114 until otherwise adjusted by a user. In the alternative, the entire exterior surface of the rod 138 may be threaded. In another alternative, the entire interior surface of the sleeve 114 may be threaded. A pair of threaded washers 144 , 146 engage the threaded ends 140 , 142 of the rod 138 that extend past the sleeve 114 such that movement of at least one washer 144 , 146 along the threads of the rod 138 adjusts the weight distribution of the bat 20 . In a further alternative, the interior surface of the sleeve 114 may be smooth bored so as to allow the rod 138 to slidably move within the sleeve 114 , the rod 138 being held in place by the washers 144 , 146 on the ends 140 , 142 of the rod 138 . The washers 144 , 146 may be the same weight or different weights. In this manner, centripetal acceleration would cause the rod 138 to slide within the sleeve 114 when the bat 20 is swung by a user, as well as causing mass of the bat 20 to shift between the handle and barrel portions 22 , 24 .
[0047] The bat 20 may be assembled in a number of ways. In one particular way, the barrel plug 48 is inserted through the open end 80 of the barrel portion 24 and positioned adjacent the aperture 38 . The diameter of the plug 48 is larger than the diameter of the aperture 38 so the plug 48 will not go through the aperture 38 . The washer 134 is threadedly engaged to the sleeve 114 and the sleeve 114 inserted into the plug bore 122 until the washer 134 is fully received within the recess 130 . The washer 144 is threadedly engaged to the rod 138 and the rod 138 inserted into the sleeve 114 . The first washer 60 is positioned around the first engaging member 42 and disposed between the shoulder 62 of the central section 46 and the exterior shoulder 64 of the tapered first end 34 of the barrel portion 24 .
[0048] The sleeve 114 (and the rod 138 within and extending beyond the sleeve 114 ) pass through the central bore 116 and openings 118 , 120 of the tapered connector 40 when the first engaging member 42 is received within the plug 48 .
[0049] The tapered handle plug 52 is inserted one of the open ends of the handle portion 22 with the sides of the tapered plug 52 being compressed as necessary to position the plug 52 within the handle portion 22 . The taper of the plug 52 , once positioned, prevents the plug 52 from going through the handle portion 22 towards the knob 28 or through the aperture 36 of the handle end 32 . Once the plug 52 is in position, the second washer 66 is positioned around the second engaging member 44 and disposed between the shoulder 68 of the central section 46 and the exterior shoulder 70 of the tapered first end 32 of the handle portion 22 . The second engaging member 44 is then received within the plug 52 with the sleeve 114 (and the rod 138 within and extending beyond the sleeve 114 ) passing through the bore 124 of the plug 52 . The washers 136 , 146 are then connected, respectively, to the sleeve 114 and rod 138 with the barrel and handle portions 24 , 22 being connected together thereby. The end plug 82 is then secured to the end 80 of the barrel portion 24 .
[0050] The interconnection of the handle portion 22 and the barrel portion 24 improves and amplifies the spring-board effect when the ball contacts the bat 20 by allowing the bat 20 to bend along the intermediate section 28 upon impact and then springing back to its original shape. The intermediate section 26 also reduces vibrations in that the components of the intermediate section 26 deflects, absorb and isolate vibrations traveling along the length of the barrel portion 24 towards the handle portion 22 , thus reducing the vibration created when a ball contacts the bat 20 . The width and depth of the intermediate section 26 can be varied to obtain the ultimate performance of the bat, depending on the design of the bat. The diameters and thicknesses of the handle portion 22 , barrel portion 24 and intermediate section 26 can be varied to alter the characteristics and performance of the bat 20 .
[0051] The knob 28 includes a bore 148 that allows an Allen wrench to be inserted into the handle portion 22 to engage and adjust the position of the rod 138 within the sleeve 114 .
[0052] An example of one particular method of manufacturing the bat 20 of the present invention will now be described. It is to be understood that the following method may be altered in some respects while still creating a bat 20 having the desired characteristics. Also, certain dimensions, materials, temperatures, etc. may be altered depending upon the size, weight and intended use of the resulting bat 20 . Accordingly, a softball bat having a length of 34 inches and weighting 28 ounces will be described by way of example in connection with the manufacturing method.
[0053] Metal tubes, such as aluminum alloy tubes, are provided at predetermined lengths and weights prior to manufacturing. For purposes of the following example, aluminum alloy tubes are provided for the handle and barrel portions 22 , 24 .
[0054] With reference to FIG. 14 , the metal tubes are first thermally treated ( 36 ). This is often referred to in the art as an annealing process. The thermal treatment softens the metal by removing the stress resulting from cold working. This process is to be repeated after a certain amount of cold work has been performed on the metal tubes. Before each cold forming process, the temperature of an anneal oven is set at 410° C. The aluminum tubes are heated in the oven at this temperature for approximately three hours. The oven temperature is then decreased by 20° C. per hour, after the three hour soak time, until the temperature of the tubes has reached 20° C. The aluminum tubes are then heated at a temperature of 230° C. for two hours, at which point the oven temperature is reset to 140° C. The tubes are removed from the oven when the temperature of the oven has reached 140° C.
[0055] The tubes are then cleaned ( 38 ). During the annealing process, an oxidation scale develops on the surface of the aluminum tubes. An acid cleaning process is required to remove the oxidation scale. The tubes are soaked in a sulfuric acid solution for approximately thirty minutes to remove the oxidation scale each time the tubes are annealed.
[0056] The tubes are then formed into handle and barrel portions 22 , 24 of desired thickness, contour and length ( 40 ). This wall forming process is a cold working process. It is performed to obtain a wall of a desired thickness. Several cold forming passes may have to be performed depending upon several factors including metal type and the type of bat 20 desired. In the instant example, the tubes forming the aluminum handle and barrel portions 22 , 24 are subject to the cold working process on the outside diameter and the wall thickness simultaneously to obtain a wall thickness of 0.055 inches with a tolerance of ±0.003 inches.
[0057] The portions 22 , 24 are then cleaned ( 42 ). A degreasing process is required to remove all lubricants and residue substances out of the aluminum portions 22 , 24 . This is performed using an ultrasonic method with a detergent agent before and after the aluminum tube is annealed.
[0058] The portions 22 , 24 are then cut, trimmed and swaged to a desired length and contour ( 44 ). A thin end of each aluminum portion 22 , 24 is trimmed to a predetermined length. It is important to have the thin ends of the aluminum portions 22 , 24 squarely trimmed to avoid folding problems when the tubes are swaged by a rotary taper swager. The aluminum portions 22 , 24 are swaged with a rotary swaging machine to obtain the desired contour shape and wall thickness. In the instant example, the required wall thickness after swaging is generally 0.055 inches with a tolerance of ±0.002 inches for the barrel portion 24 . The required wall thickness for the handle portion 22 is generally 0.085 inches with a tolerance of ±0.002 inches. The rotary swaging machine also contours the tapered ends 32 , 34 of the handle 22 and barrel 24 portions.
[0059] The tapered connector 40 , plugs 48 , 52 , and washers 60 , 66 may be formed using conventional methods which may vary according to whether a bat 20 of FIGS. 1-7 or a bat 20 of FIGS. 8-13 is desired. The tapered connector 40 is shaped to obtain a desired contoured shape.
[0060] If necessary, after shaping, the handle and barrel portions 22 , 24 are cut to the desired length. In the instant example, the total required length of the bat 20 is 34.5 inches and the weight is 17 ounces. From the end of the barrel portion 24 to an index is 19.5 inches, and from the index to the end of the handle portion 22 is 15 inches.
[0061] The handle and barrel portions 22 , 24 are then thermally treated, quenched and aged ( 46 ). It is commonly known in the art to expose metal or alloys to a heating and cooling treatment to obtain desired conditions, properties and an increase in strength. The handle and barrel portions 22 , 24 are heat treated to obtain the highest tensile and yield strengths. The required temperature and time for the solution heat treatment is twenty-seven minutes at a temperature of 480° C. After the handle and barrel portions 22 , 24 are heat treated, they are quenched immediately with either air or water. Quenching is a controlled rapid cooling of a metal from an elevated temperature by contact with a liquid, gas or solid. Precipitation from solid solution results in a change in properties of the alloy, usually occurring rapidly at elevated temperatures. The handle and barrel portions 22 , 24 are aged in an oven for twelve hours at 135° C.
[0062] The handle and barrel portions 22 , 24 are then cleaned again ( 48 ). Due to the treatments in step 510 , the handle and barrel portions 22 , 24 oxidize. This oxidation is removed by an anodizing process. The handle and barrel portions 22 , 24 are anodized for five minutes. To eliminate all possible contaminations, the surface of the handle and barrel portions 22 , 24 are then thoroughly cleaned with methyl ethyl ketone.
[0063] At this point, the handle and barrel portions 22 , 24 are assembled as outlined above, with respect to FIGS. 1-7 and FIGS. 8-13 .
[0064] Thereafter, approximately a 0.50 inch portion of the open barreled end 80 is rolled inward at a 90° angle to accommodate the end plug 82 . If necessary, the protruded portion of the rolled portion is machined to achieve an opening of 1.25 inches in diameter for installing the end plug 82 .
[0065] The bat 20 is then polished and decorated ( 52 ). Any appropriate methods of polishing and decoration, as are well known in the art, can be applied. In the preferred embodiment, the outer surfaces of the handle and barrel portions 22 , 24 are exposed to sodium hydroxide to strip an anodize coating created during the manufacturing process as well as to prepare the outer surface for anodic coating process. Typically, the concentration of the sodium hydroxide is fifty grams per liter. The outer surface of the handle and barrel portions 22 , 24 are mechanically polished to obtain a mirror finish. The external surface of the handle and barrel portions 22 , 24 are then anodized. In the alternative, the external surface of the handle and barrel portions 22 , 24 may be painted, chromed, powder-coated, or covered by some other method of decorative coating. The outer surface of the handle and barrel portions 22 , 24 may be decorated with a graphic by using various methods such as silkscreening, heat transferring, or pad stamping.
[0066] The bat 20 is completed by attaching the knob 28 , typically by welding a knob comprised of 5000 series or 6000 series aluminum alloy to an open end of the handle portion 22 opposite the tapered end 32 . The grip 30 and the end plug 82 are also installed to finish the bat 20 ( 54 ).
[0067] In the alternative, the above described method of manufacturing the bat 20 may be varied. For example, physical characteristics of the bat 20 , such as the length, wall thickness or diameter may be increased or decreased.
[0068] Although constructed from affordable medium to high strength, light weight, and commercially available materials, the bat 20 of the present invention offers the performance and advantages of expensive and high strength materials. The bat 20 provides improved dent resistance. The bat 20 also dampens the vibrations created when traditional metal bats hit the ball that would otherwise sting the hitter's hand when a bat contacts a ball. Premature longitudinal cracking of the barrel portion 24 , caused in traditional bats with thin wall thicknesses and high stress conditions, is avoided in the present invention.
[0069] The above-described embodiments of the present invention are illustrative only and not limiting. It will thus be apparent to those skilled in the art that various changes and modifications may be made without departing from this invention in its broader aspects. Therefore, the appended claims encompass all such changes and modifications as falling within the true spirit and scope of this invention.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is based on U.S. Provisional Patent Application Ser. No. 60/714,987 titled, “Combination Basting Brush, Spoon, and Spatula,” filed Sep. 8 2005.
FIELD OF THE INVENTION
[0002] The present invention relates to cooking utensils.
BACKGROUND OF THE INVENTION
[0003] When cooking meats or other food items, a condiment such as barbeque sauce, ketchup or marinate is often applied to enhance flavor. Some chefs prefer to spread the condiment over the food item for even distribution to obtain a more consistent flavor. Present practice is to use a small brush to achieve such spreading. Current basting brushes on the market perform like traditional paint brushes when basting. These simply spread sauces over food with a flimsy bristle. These bristles are too soft and do not allow for any real control in “scooping-out” the sauce (from a jar or bowl), applying it, and/or scraping the jar or bowl sides clean to eliminate waist.
[0004] In addition, over time the bristles of these brushes often become contaminated with food and grease residues which decompose and harden. Microbial organisms which thrive on the food and grease residues may be inadvertently transferred to fresh meats and other foods during further use of the basting brush, and therefore pose a potentially significant health risk. Because the organic food residues tend to be concealed in nooks and crannies of the basting brush, inaccessible to typical washing procedures, the brush is rendered essentially uncleanable and therefore unusable. After a short period of time, these residue-clogged basting brushes become aesthetically and hygienically unappealing for continued use, and are discarded even though the handle portions of the brushes remain useful and their disposal is economically wasteful. Thus, what is needed is a device that would enhance the hygiene and appeal of reusing the brush, and therefore alleviate the waste of brush handles.
[0005] Still further, when cooking meats and similar food items, a user often intermittently applies marinades, sauces, and similar condiments to enhance the flavor of the meat and to prevent the meat from drying out. A spoon is typically used to do so. Once the sauce is applied, it is often desirable to evenly distribute the sauce over the exterior surface of the meat to assure that the entirety of the meat is evenly coated. Accordingly, a user must maintain a brush or similar utensil nearby.
[0006] Once the spoon and the brush are initially used, they must be continuously held which is inconvenient; alternatively, it must be placed on a support surface which can promote unsanitary conditions as the spoon and the brush are often placed on a countertop after use, which transfers a small amount of condiment to the countertop, giving rise to a breeding area for bacteria. What would be desirable is a device for applying condiments to foods without risk of contacting the applicator to a countertop or other surface upon which bacteria can survive. It would further be desirable to provide a device that would enhance the hygiene and appeal of reusing the brush, and therefore alleviate the waste of brush handles.
SUMMARY OF THE INVENTION
[0007] A device in accordance with the principals of the present applies condiments to foods without risk of contacting the applicator to a countertop or other surfaces upon which bacteria can survive. A device in accordance with the principals of the present enhances the hygiene and appeal of reusing the brush, and therefore alleviate the waste of brush handles. In accordance with the principles of the present invention, a combination basting brush, spoon, and spatula is provided that combines the functionality of a basting brush, spoon, and spatula in one device. The combination basting brush, spoon, and spatula comprising a handle portion and a combined concave spoon portion, spatula edge portion, and bristle portion. The present invention enables a user to perform multiple tasks in a more efficient manner.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is perspective view of a combination basting brush, spoon, and spatula in accordance with the principles of the present invention.
[0009] FIG. 2 is an overhead view of a combination basting brush, spoon, and spatula in accordance with the principles of the present invention.
[0010] FIG. 3 is elevated side-view of a combination basting brush, spoon, and spatula in accordance with the principles of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Referring to FIG. 1 , a perspective view of a combination basting brush, spoon, and spatula in accordance with the principles of the present invention is seen. The combination basting brush, spoon, and spatula of the present invention is a unique 3-in-1 cooking utensil combining the functionalities of a spoon, spatula, and basting brush into one device. The spoon aspect allows users to scoop large portions of basting sauce. The spatula aspect allows users to scrap the sides of a vessel clean without wasting any sauce and the basting bristles allow for efficient basting capabilities.
[0012] The device 10 integrally comprises a handle portion 12 , a concave spoon portion 14 , a spatula edge portion 16 , and a bristle portion 18 . The handle portion 12 may be constructed from a variety of materials. The handle portion 12 can be in an ergonomic shape and can be made of a soft material that provides good grip and comfort when used for long periods and when hands are wet. In one embodiment, the handle portion 12 can comprise a one piece molded silicon with the concave spoon portion 14 , spatula edge portion 16 , and bristle portion 18 . Alternatively, the handle portion 12 can comprise alternative materials like metal or wood that is internally secured to the concave spoon portion 14 , spatula edge portion 16 , and bristle portion 18 . In this embodiment, the handle portion 12 can be provided as separable to enable separate cleaning. In this embodiment, a soft grip can be added to the handle portion 12 .
[0013] The size of the device 10 can vary depending on whether it is intended for use as a grilling utensil or stove top product. The handle portion 12 should be lengthy enough to reach across the grills area and ensure a safe working distance from hot grill. In one embodiment, the end of the handle portion 12 can include a notch or aperture for hanging.
[0014] The bristles portion 18 of the present invention comprises a plurality of bristles. The bristles of a device in accordance with the present invention are flexible but are made of higher durometer silicon offering a stiffer action. The use of such “stiffer” but flexible bristles allow users to baste with more control. The bristles should be firm and wide which provide basting capabilities allowing liquids and sauces to be applied to surfaces of food, including difficult to reach cavities and crevices. In one embodiment, the bristles can have a durometer of around 60 shore to provide suitable rigidity. In various embodiments, the bristles can comprise a single layer, a double layer, a triple layer or other numbers of layers of bristle ends. In one embodiment, 17 bristles can be provided although the invention is not limited to any particular number. In one embodiment the length of the bristles will be about 0.8 inches or less, which has been found to give the user the desired controlled flex necessary to apply sauces, although again the invention is not limited to any bristle length.
[0015] The concave spoon portion 14 of the present invention can be preferably integrally formed with the bristle portion 18 . The concave spoon portion 14 enables the user to “scooping-out” sauce from a jar or bowl or the like. The concave spoon portion 14 of the present invention comprises a sufficiently deep well to capture a sufficient amount of fluids, making the device 10 more productive in transferring sauces. The sauces then cascade down to the bristles for generous basting capabilities. In one embodiment, the depth of the scoop can be sized for a controlled measure. The concave spoon portion coupled with the bristles further provides the ability to apply more sauce in a controlled manner, in each application.
[0016] The spatula edge portion 16 of the present invention can preferably be integrally formed with the concave spoon portion 14 and the bristle portion 18 . The spatula edge portion 16 can be comprised about the concave spoon portion 14 , with the two sides 16 coming to a thinner/sharper edge to act as a spatula blade. The spatula edge portion 16 acts as a spatula blade, which provides an edge that enhances a scraping “squeegee” like action enabling the user to scraping the sides of a jar or bowl or the like to eliminate waste. In one embodiment, the device 10 can be provided with a plurality of spatula blades. In a further embodiment, the plurality of spatula blades can comprise one blade being more flexible relative to the other blade, thus providing the user with a choice of which to use.
[0017] The spatula edge portion 16 , concave spoon portion 14 , and the bristle portion 18 of the present invention can preferably be made of “high-temperature” silicon which can have heat resistance up to about 650 F/350 C degrees. The use of such materials further results in a non-stick design. The present invention can be offered in small, medium, and large sizes to accommodate a user's preference. The present invention could also be used for additional applications such as for example applying frosting on cake, etc.
[0018] Thus, a combination basting brush, spoon, and spatula in accordance with the principles of the present invention is easy to clean, dishwasher safe, difficult to stain, virtually unlimited color offerings with the silicon material, and silicon will not scratch cookware, high-end stoves, etc.
[0019] It should be understood that various changes and modifications to the preferred embodiments described herein would be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims.
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FIELD OF THE INVENTION
[0001] The present invention relates to water-dispersible nanoparticles. More specifically, the present invention relates to water-dispersible nanoparticles which are excellent in dispersion stability and contain a blood circulation promoter.
BACKGROUND ART
[0002] Extensive applications of fine particle materials have been expected for biotechnology. In particular, the application of nanoparticle materials generated based on the advancement of nanotechnology to food, cosmetics, pharmaceutical products and the like has been actively discussed. In this regard, the results of many studies have been reported.
[0003] For instance, regarding cosmetics, more obvious skin-improving effects have been required in recent years. Manufactures have been attempting to improve the functionality and usability of their own products and to differentiate their own products from competitive products by applying a variety of new technologies such as nanotechnology. In general, the stratum corneum serves as a barrier for the skin. Thus, medicines are unlikely to permeate therethrough into the skin. In order to obtain sufficient skin-improving effects, it is essential to improve the skin permeability of active ingredients. In addition, it is difficult to formulate many active ingredients due to poor preservation stability or tendency to result in skin irritancy, although they are highly effective to the skin. In order to solve the above problems, a variety of fine particle materials have been under development for the improvement of transdermal absorption and preservation stability, reduction of skin irritancy, and the like. Recently, a variety of fine particle materials such as ultrafine emulsions and liposomes have been studied (e.g., Mitsuhiro Nishida, Fragrance Journal, Nov. 17, (2005)).
[0004] Hitherto, it has been usual to add oil-based components to water-based cosmetics. However, since oil-based components are water-insoluble or weakly water-soluble, it has been common to mix an oil-based component, which is a so-called emulsified product, into an aqueous medium with the use of a certain emulsifying means. Light scattering of emulsified products depends on particle size. Thus, in some cases, emulsified products and foods or cosmetics containing emulsified products have cloudy appearances, which is not preferable. Therefore, it has been desired to miniaturize the particle size of an emulsified product to such an extent that the light scattering intensity becomes very low. In addition, emulsified products are generally in a metastable state. In such state, the particle size increases during storage and long-term storage results in separation, which are seriously problematic. In the cases of beverages, adherence of an aggregate of oil droplets to container walls and neck ring formation with such an aggregate are examples of oil droplet separation phenomenon observed in emulsified products.
[0005] As described above, many fine particle materials used for foods or cosmetics are related to emulsified products. Meanwhile, in recent years, polymer micelles have been gaining attention in the fields of pharmaceutical products and cosmetics (e.g., JP Patent Publication (Kokai) No. 2002-308728 A). Polymer micelles are characterized by large drug contents, high water solubility, high structural stability, non-accumulative properties, functional separation properties, and the like. Studies have been conducted on inclusion of a drug into a micelle structure of an amphiphilic polymer for administration into the blood, and the resulting product has been under clinical trials (e.g., Y. Mizumura et al., Jap. J. Cancer Res., 93, 1237 (2002)).
[0006] In the cases of emulsified products, surfactant-induced electrostatic interactions are used, and this always causes stability problems, such as a droplet separation phenomenon. On the other hand, polymer micelles are structurally formed with covalent bonds, which is advantageous in terms of stability. Further, if miniaturization (nanoparticle formation) of polymer micelles can be achieved, sufficient transparency is obtained upon water dispersion. However, as compared with generally used synthetic surfactants, biodegradable polymers, and particularly, natural polymers such as proteins, are highly safe for use. Therefore, nanoparticles made of biodegradable polymers have been awaited.
[0007] Meanwhile, blood circulation promoters are widely added as skin-roughness-preventive, skin dietary supplement, or hair-growing/increasing components, to products such as cosmetics, including lotions, creams, and emulsions, quasi-drugs, and externally applied pharmaceutical products. They are categorized as synthetic substances, plant extracts, vitamins, sugars, or the like. However, such extracts are extracted from organic solvents such as ethanol and 1,3-butylene glycol. Thus, it has been known that it is not always possible to keep such extracts in a stable state when adding them to water dispersions. In addition, it has been known that products other than extracts are also very weakly water-soluble. Addition of such components can be achieved by controlling the contents of organic solvents from 20% to less than 100% or by emulsifying such components with surfactants, for example. However, it has been known that such organic solvents cause excessive skin degreasing, and that surfactants and the like induce skin irritation or allergy.
SUMMARY OF THE INVENTION
[0008] It is an object of the present invention to solve the above problems of the conventional techniques. Specifically, it is an object of the present invention to provide a nanoparticle which comprises a blood circulation promoter and a biodegradable polymer, which is safe and excellent in terms of dispersion stability and has high transparency and good absorbability due to its small particle size.
[0009] As a result of intensive studies to achieve the above object, the present inventors have found that a water-dispersible nanoparticle can be prepared by mixing a blood circulation promoter with a biodegradable polymer. The present invention has been completed based on the above findings.
[0010] The present invention provides a water-dispersible nanoparticle which comprises a blood circulation promoter and a biodegradable polymer.
[0011] Preferably, the content of the blood circulation promoter is 0.1% to 100% by weight with respect to the weight of the biodegradable polymer.
[0012] Preferably, the average particle size is 10 to 1000 nm.
[0013] Preferably, the blood circulation promoter is an ionic substance or a fat-soluble substance.
[0014] Preferably, the blood circulation promoter is a cosmetic component, a functional-food component, a quasi-drug component, or a pharmaceutical product component.
[0015] Preferably, the blood circulation promoter is at least one blood circulation promoter selected from the group consisting of a tocophenol derivative, a nicotinic acid derivative, cephalanthin, finasteride, minoxidil, and a Swertia japonica extract.
[0016] Preferably, the biodegradable polymer is a protein.
[0017] Preferably, the protein is at least one protein selected from the group consisting of collagen, gelatin, acid-treated gelatin, albumin, ovalbumin, casein, sodium casein, transferrin, globulin, fibroin, fibrin, laminin, fibronectin, and vitronectin.
[0018] Preferably, the protein is subjected to crosslinking treatment during and/or after nanoparticle formation.
[0019] Preferably, a transglutaminase is used for the crosslinking treatment.
[0020] The present invention further provides a casein nanoparticle which is prepared by the following steps (a) to (c):
(a) mixing casein with a basic aqueous medium at a pH of from 8 to less than 11; (b) adding at least one blood circulation promoter to the solution obtained in step (a); and (c) injecting the solution obtained in step (b) into an acidic aqueous medium at a pH of 3.5 to 7.5.
[0024] The present invention further provides a casein nanoparticle which is prepared by the following steps (a) to (c):
(a) mixing casein with a basic aqueous medium at a pH of from 8 to less than 11; (b) adding at least one blood circulation promoter to the solution obtained in step (a); and (c) lowering the pH of the solution obtained in step (b) to a pH value that is pH 1 or more away from the isoelectric point, while stirring the solution.
[0028] The present invention further provides a drug delivery agent which comprises the nanoparticle of the present invention as mentioned above.
[0029] Preferably, the drug delivery agent of the present invention is used as a transdermally absorbable agent, a topical therapeutic agent, an oral therapeutic agent, an intradermal parenteral injection, a subcutaneous parenteral injection, an intramuscular parenteral injection, an intravenous parenteral injection, a cosmetic, a quasi-drug, a functional food, or a supplement.
[0030] The particle of the present invention which contains a blood circulation promoter is a nanoparticle, and thus it has good absorbability and high transparency. The nanoparticle of the present invention is a nanoparticle comprising a biodegradable polymer such as a protein, and thus the structure thereof is highly stable. In addition, the particle can be produced without using a chemical crosslinking agent or synthetic surfactant, and thus it is highly safe. Further, dispersion of nanoparticles containing a hydrophobic blood circulation promoter can be achieved. Thus, there is no need to add a large volume of ethanol, and therefore skin irritation caused by ethanol can be reduced.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] The embodiments of the present invention will be described in detail below.
[0032] The water-dispersible nanoparticle of the present invention is characterized in that it comprises a blood circulation promoter and a biodegradable polymer.
[0033] Specific examples of a blood circulation promoter that can be used in the present invention are described below, but they are not particularly limited thereto as long as blood circulation promoting effects can be exhibited. The term “blood circulation promotion” refers to effects of increasing the blood flow resulting from effects of, for example, blood vessel dilation induced by relaxation, enhancement and stimulation of capillary vessels, and temperature increase. Preferably, the blood circulation promoter used in the present invention is an ionic substance or fat-soluble substance. In addition, examples of the blood circulation promoter that can be used in the present invention include synthetic substances, plant extracts, vitamins, and sugars.
[0034] Examples of synthetic substances include minoxidil which is known to have effects of anti-hypertensive agents; finasteride which is known to have effects of anti-prostatic hypertrophy agents; and carpronium chloride which is known to have effects as a drug for alopecia areatas.
[0035] Examples of plant extracts include Swertia japonica extracts obtained from rhizomes and stolons of plants belonging to the family Gentianaceae, carrot extracts obtained from rhizomes and stolons of plants belonging to the family Araliaceae, Sophora angustifolia extracts obtained from rhizomes and stolons of plants belonging to the family Leguminosae, peppermint extracts obtained from peppermint leaves and the like, cepharanthine, which is an alkaloid of a plant belonging to the family Menispermaceae, cayenne pepper tinctures obtained from cayenne pepper, ginger tinctures obtained from ginger, and garlic extracts extracted from garlic.
[0036] Preferably, vitamins are vitamin B, vitamin E, and derivatives thereof. Examples of vitamin E and derivatives thereof include tocopherol, tocopherol acetate, and nicotinic acid tocopherol, which are preferably naturally occurring α-tocopherols. In addition, examples of vitamin B and derivatives thereof include nicotinic acid, nicotinic acid amide, and nicotinic acid benzyl, which are widely existing hydrophilic and hydrophobic substances.
[0037] Preferably, sugars are mucopolysaccharides. Specific examples thereof include heparin, which has a blood-coagulation-inhibiting action.
[0038] Preferably, the blood circulation promoter used in the present invention is a tocophenol derivative, a nicotinic acid derivative, cephalanthin, finasteride, minoxidil, or a Swertia japonica extract.
[0039] According to the present invention, a component used as the above blood circulation promoter can be selected from the group consisting of cosmetic components, quasi-drug components, functional-food components, and pharmaceutical product components. The blood circulation promoter used in the present invention may be used alone or in combinations of two or more.
[0040] According to the present invention, a blood circulation promoter may be added during, before or after the formation of nanoparticle of the biodegradable polymer.
[0041] The nanoparticle of the present invention preferably contains the blood circulation promoter in an amount of 0.1% to 100% by weight with respect to the weight of the biodegradable polymer, and more preferably contains the blood circulation promoter in an amount of 0.1% to 50% by weight with respect to the weight of the biodegradable polymer.
[0042] The average particle size of the nanoparticle of the present invention is generally 1 to 1000 nm, preferably 10 to 1000 nm, more preferably 10 to 500 nm, and particularly preferably 15 to 400 nm.
[0043] The biodegradable polymer used in the present invention may be a protein or a biodegradable synthetic polymer.
[0044] The type of the biodegradable polymer is not particularly limited. However, a protein having a lysine residue and a glutamine residue is preferable. In addition, such protein having a molecular weight of approximately 10,000 to 1,000,000 is preferably used. The origin of the protein is not particularly limited. However, a human-derived protein, is preferably used. Specific examples of a protein that can be used include at least one selected from the group consisting of collagen, gelatin, acid-treated gelatin, albumin, ovalbumin, casein, sodium casein, transferrin, globulin, fibroin, fibrin, laminin, fibronectin, and vitronectin. However, the compound used in the present invention is not limited to the aforementioned compounds. In addition, the origin of the protein is not particularly limited. Thus, bovine, swine, and fish, as well as recombinant protein of any thereof, can be used. Examples of recombinant gelatin that can be used include, but are not limited to, gelatins described in EP1014176 A2 and U.S. Pat. No. 6,992,172. Among them, casein, acid-treated gelatin, collagen, or albumin is preferable. Further, casein or acid-treated gelatin is most preferable. When casein is used in the present invention, the origin of the casein is not particularly limited. Casein may be milk-derived or bean-derived. Any of α-casein, β-casein, γ-casein, and κ-casein, as well as a mixture thereof, can be used. Caseins may be used alone or in combinations of two or more.
[0045] Proteins used in the present invention may be used alone or in combinations of two or more. Examples of the biodegradable synthetic polymer include polylactic acid, and poly(lactic-co-glycolic acid) (PLGA).
[0046] According to the present invention, a protein can be subjected to crosslinking treatment during and/or after nanoparticle formation. For the crosslinking treatment, an enzyme can be used. Any enzyme may be used without particular limitation as long as it has been known to have an action of causing protein crosslinking. Among such enzymes, transglutaminase is preferable.
[0047] Transglutaminase may be derived from a mammal or a microorganism. A recombinant transglutaminase can be used. Specific examples thereof include the Activa series by Ajinomoto Co., Inc., commercially available mammalian-derived transglutaminase serving as a reagent, such as guinea pig liver-derived transglutaminase, goat-derived transglutaminase, rabbit-derived transglutaminase, or human-derived recombinant transglutaminase produced by, for example, Oriental Yeast Co., Ltd., Upstate USA Inc., and Biodesign International.
[0048] The amount of an enzyme used for the crosslinking treatment in the present invention can be adequately determined depending upon protein type. In general, an enzyme can be added in a weight that is 0.1% to 100% and preferably approximately 1% to 50% of the protein weight.
[0049] The duration for an enzymatic crosslinking reaction can be adequately determined depending upon protein type and nanoparticle size. However, in general, the reaction can be carried out for 1 to 72 hours, and preferably 2 to 24 hours.
[0050] The temperature for an enzymatic crosslinking reaction can be adequately determined depending upon protein type and nanoparticle size. In general, the reaction can be carried out at 0° C. to 80° C. and preferably at 25° C. to 60° C.
[0051] Enzymes used in the present invention may be used alone or in combinations of two or more.
[0052] Nanoparticles of the present invention can be prepared in accordance with Patent Document: JP Patent Publication (Kokai) No. 6-79168 A (1994); or C. Coester, Journal Microcapsulation, 2000, vol. 17, pp. 187-193, provided that an enzyme is preferably used instead of glutaraldehyde for a crosslinking method.
[0053] In addition, according to the present invention, the enzymatic crosslinking treatment is preferably carried out in an organic solvent. The organic solvent used herein is preferably an aqueous organic solvent such as ethanol, isopropanol, acetone, or THF.
[0054] It is also possible to add at least one component selected from the group consisting of lipids (e.g., phospholipid), anionic polysaccharides, cationic polysaccharides, anionic proteins, cationic proteins, and cyclodextrin to the water-dispersible nanoparticle of the present invention. The amounts of lipid (e.g. phospholipid), anionic polysaccharide, cationic polysaccharide, anionic protein, cationic protein, and cyclodextrin to be added are not particularly limited. However, they can be added usually in a weight that is 0.1% to 100% of the protein weight. In the case of the drug delivery agent of the present invention, it is possible to adjust the release rate by changing the ratio of the above components to the protein.
[0055] Specific examples of phospholipids that can be used in the present invention include, but are not limited to, the following compounds: phosphatidylcholine (lecithin), phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol, and sphingomyelin.
[0056] Anionic polysaccharides that can be used in the present invention are polysaccharides having an acidic polar group such as a carboxyl group, a sulfate group, or a phosphate group. Specific examples thereof include, but are not limited to, the following compounds: chondroitin sulfate, dextran sulfate, carboxymethyl cellulose, carboxymethyl dextran, alginic acid, pectin, carrageenan, fucoidan, agaropectin, porphyran, karaya gum, gellan gum, xanthan gum, and hyaluronic acids.
[0057] Cationic polysaccharides that can be used in the present invention are polysaccharides having a basic polar group such as an amino group. Examples thereof include, but are not limited to, the following compounds: polysaccharides such as chitin or chitosan, which comprise, as a monosaccharide unit, glucosamine or galactosamine.
[0058] Anionic proteins that can be used in the present invention are proteins and lipoproteins having a more basic isoelectric point than the physiological pH. Specific examples thereof include, but are not limited to, the following compounds: polyglutamic acid, polyaspartic acid, lysozyme, cytochrome C, ribonuclease, trypsinogen, chymotrypsinogen, and α-chymotrypsin.
[0059] Cationic proteins that can be used in the present invention are proteins and lipoproteins having a more acidic isoelectric point than the physiological pH. Specific examples thereof include, but are not limited to, the following compounds: polylysine, polyarginine, histone, protamine, and ovalbumin.
[0060] According to the present invention, it is possible to use casein nanoparticles prepared by the following steps (a) to (c):
(a) mixing casein with a basic aqueous medium at a pH of from 8 to less than 11; (b) adding at least one blood circulation promoter to the solution obtained in step (a); and (c) injecting the solution obtained in step (b) into an acidic aqueous medium at a pH of 3.5 to 7.5.
[0064] Further, according to the present invention, it is possible to use casein nanoparticles prepared by the following steps (a) to (c):
(a) mixing casein with a basic aqueous medium at a pH of from 8 to less than 11; (b) adding at least one blood circulation promoter to the solution obtained in step (a); and (c) lowering the pH of the solution obtained in step (b) to a pH value that is pH 1 or more away from the isoelectric point, while stirring the solution.
[0068] According to the present invention, it is possible to prepare casein nanoparticles of desired sizes. Also, with the use of interaction between a hydrophobic blood circulation promoter and a casein hydrophobic domain, it is possible for casein nanoparticles to contain the blood circulation promoter. In addition, it was found that such particles remain stable in an aqueous solution.
[0069] Further, it was found that a particle mixture of casein and ionic polysaccharide or another ionic protein contains an ionic blood circulation promoter.
[0070] The method for preparing casein nanoparticles of the present invention involves a method wherein casein is mixed with a basic aqueous medium solution and the solution is injected into another acidic aqueous medium, and a method wherein casein is mixed with a basic aqueous medium solution and the pH of the solution is lowered during stirring, for example.
[0071] The method wherein casein is mixed with a basic aqueous medium solution and the solution is injected into another acidic aqueous medium is preferably carried out using a syringe for convenience. However, there is no particular limitation as long as the injection rate, solubility, temperature, and stirring conditions are satisfied. Injection can be carried out usually at an injection rate of 1 mL/min to 100 mL/min. The temperature of the basic aqueous medium can be adequately determined. In general, the temperature is 0° C. to 80° C. and preferably 25° C. to 70° C. The temperature of an acidic aqueous medium can be adequately determined. In general, the temperature can be 0° C. to 80° C. and preferably 25° C. to 60° C. The stirring rate can be adequately determined. However, in general, the stirring rate can be 100 rpm to 3000 rpm and preferably 200 rpm to 2000 rpm.
[0072] In the method wherein casein is mixed with a basic aqueous medium solution and the pH of the medium is lowered during stirring, it is preferable to add acid dropwise for convenience. However, there is no particular limitation as long as solubility, temperature, and stirring conditions are satisfied. The temperature of a basic aqueous medium can be adequately determined. However, in general, the temperature can be 0° C. to 80° C. and preferably 25° C. to 70° C. The stirring rate can be adequately determined. However, in general, the stirring rate can be 100 rpm to 3000 rpm and preferably 200 rpm to 2000 rpm.
[0073] The aqueous medium that can be used for the present invention is an aqueous solution or a buffer comprising an organic acid or base or an inorganic acid or base.
[0074] Specific examples thereof include, but are not limited to, aqueous solutions comprising: organic acids such as citric acid, ascorbic acid, gluconic acid, carboxylic acid, tartaric acid, succinic acid, acetic acid, phthalic acid, trifluoroacetic acid, morpholinoethanesulfonic acid, and 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid; organic bases such as tris (hydroxymethyl), aminomethane, and ammonia; inorganic acids such as hydrochloric acid, perchloric acid, and carbonic acid; and inorganic bases such as sodium phosphate, potassium phosphate, calcium hydroxide, sodium hydroxide, potassium hydroxide, and magnesium hydroxide.
[0075] The concentration of an aqueous medium used in the present invention is preferably approximately 10 mM to 1 M, and more preferably approximately 20 mM to 200 mM.
[0076] The pH of a basic aqueous medium used in the present invention is preferably 8 or more and less than 11, and more preferably 10 to 11. When the pH is excessively high, there is concern regarding hydrolysis or risks in handling. Thus, the pH is preferably in the above range.
[0077] According to the present invention, the temperature at which casein is mixed with a basic aqueous medium at pH of 8 or more and less than 11 is preferably 0° C. to 90° C., more preferably 10° C. to 80° C., and further preferably 20° C. to 70° C.
[0078] The pH of an acidic aqueous medium used in the present invention is preferably 3.5 to 7.5 and more preferably 5 to 6. If the pH is beyond the aforementioned range, there is a tendency where the particle size becomes large.
[0079] The nanoparticle of the present invention comprises a blood circulation promoter. When the blood circulation promoter is an active component, the nanoparticle of the present invention which comprises such an active component can be administered to the affected part for use. Specifically, the nanoparticle of the present invention is useful as a drug delivery agent.
[0080] Preferably, the nanoparticle of the present invention is administered via transdermal or transmucosal absorption, or injection into blood vessel, body cavity or lympho tissue. More preferably, the nanoparticle of the present invention is administered via transdermal or transmucosal absorption.
[0081] In the present invention, the usage of the drug delivery agent is not particularly limited. For example, the drug delivery agent is used as transdermally absorbable agent, a topical therapeutic agent, an oral therapeutic agent, an intradermal parenteral injection, a subcutaneous parenteral injection, an intramuscular parenteral injection, an intravenous parenteral injection, a cosmetic, a quasi-drug, a functional food, or a supplement.
[0082] In the present invention, the drug delivery agent may comprise an additive. The type of such additive is not particularly limited. Examples of such additive include a moisturizer, a softener, an antiinflammatory agent, a percutaneous absorption promoter, soothing agents, preservatives, antioxidants, coloring agents, thickeners, aroma chemicals, and pH adjusters.
[0083] Specific examples of the moisturizer that can be used in the present invention include, but are not limited to, agar, diglycerin, distearyldimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, hexylene glycol, coix seed extract, vaserine, urea, hyaluronic acid, ceramide, Lipidure, isoflavone, amino acid, collagen, mucopolysaccharide, fucoidan, lactoferrin, sorbitol, chitin, chitosan, malic acid, glucuronic acid, Placenta extract, Seaweed extract, Moutan cortex extract, Hydrangeae dulcis folium extract, hypericum extract, coleus extract, Euonymus japonica, safflower extract, Rosa rugosa flower extract, Polyporus Sclerotium extract, hawthorn extract, rosemary extract, duku extract, chamomile extract, lamium album extract, Litchi Chinensis extract, Achillea Millefolium extract, aloe extract, marronnier extract, Thujopsis dolabrata extract, Fucus extract, Osmoin extract, oat extract, Tuberosa polysaccharide, Cordyceps Sinensis extract, barley extract, orange extract, Rehmannia root extract, zanthoxylum fruit extract, and coix seed extract.
[0084] Specific examples of the softener that can be used in the present invention include, but are not limited to, glycerin, mineral oil, and emollient ingredients (e.g. isopropyl isostearate, polyglyceryl isostearate, isotridecyl isononanoate, octyl isononanoate, oleic acid, glyceryl oleate, cacao butter, cholesterol, mixed fatty acid triglyceride, dioctyl succinate, sucrose acetate stearate, cyclopentanesiloxane, sucrose distearate, octyl palmitate, octyl hydroxystearate, arachidyl behenate, sucrose polybehenate, polymethylsilsesquioxane, myristyl alcohol, cetyl myristate, myristyl myristate, and hexyl laurate).
[0085] Examples of an antiinflammatory agent used in the present invention may include a compound which is selected from azulene, guaiazulene, diphenhydramine hydrochloride, hydrocortisone acetate, prednisolone, glycyrrhizinic acid, glycyrrhetinic acid, mefenamic acid, phenylbutazone, indometacin, ibuprofen and ketoprofen, and its derivative and its salt; and a plant extract which is selected from Scutellariae Radix extract, Artemisia capillaris Thunb. Extract, Platycodon grandiflorum extract, Armeniacae Semen extract, Common gardenia extract, Sasa veitchii extract, Gentiana lutea extract, Comfrey extract, white birch extract, Malva extract, Persicae Semen extract, peach blade extract, and loquat blade extract; proteins; polysaccharides; and animal extracts, but are not limited thereto.
[0086] Specific examples of the percutaneous absorption promoter that can be used in the present invention include, but are not limited to, ethanol, isopropyl myristate, citric acid, squalane, oleic acid, menthol, N-methyl-2-pyrrolidone, diethyl adipate, diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, isopropyl palmitate, isopropyl oleate, octyldodecyl oleate, isostearyl alcohol, 2-octyldodecanol, urea, vegetable oil, and animal oil.
[0087] Specific examples of soothing agents that can be used in the present invention include, but are not limited to, the following compounds: benzyl alcohol, procaine hydrochloride, xylocaine hydrochloride, and chlorobutanol.
[0088] Specific examples of preservatives that can be used in the present invention include, but are not limited to, the following compounds: benzoic acid, sodium benzoate, paraben, ethylparaben, methylparaben, propylparaben, butylparaben, potassium sorbate, sodium sorbate, sorbic acid, sodium dehydroacetate, hydrogen peroxide, formic acid, ethyl formate, sodium hypochlorite, propionic acid, sodium propionate, calcium propionate, pectin degradation products, polylysine, phenol, isopropylmethyl phenol, orthophenylphenol, phenoxyethanol, resorcin, thymol, thiram, and tea tree oil.
[0089] Specific examples of antioxidants that can be used in the present invention include, but are not limited to, the following compounds: vitamin A, retinoic acid, retinol, retinol acetate, retinol palmitate, retinyl acetate, retinyl palmitate, tocopheryl retinoate, vitamin C and derivatives thereof, kinetin, β-carotene, astaxanthin, lutein, lycopene, tretinoin, vitamin E, α-lipoic acid, coenzyme Q10, polyphenol, SOD, and phytic acid.
[0090] Specific examples of coloring agents that can be used in the present invention include, but are not limited to, the following compounds: krill pigment, orange dye, cacao dye, kaoline, carmines, ultramarine blue, cochineal dye, chrome oxide, iron oxide, titanium dioxide, tar dye, and chlorophyll.
[0091] Specific examples of thickeners that can be used in the present invention include, but are not limited to, the following compounds: quince seed, carrageenan, gum arabic, karaya gum, xanthan gum, gellan gum, tamarind gum, locust bean gum, gum traganth, pectin, starch, cyclodextrin, methylcellulose, ethylcellulose, carboxymethylcellulose, sodium alginate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, and sodium polyacrylate.
[0092] Specific examples of aroma chemicals that can be used in the present invention include, but are not limited to, the following compounds: musk, acacia oil, anise oil, ylang ylang oil, cinnamon oil, jasmine oil, sweet orange oil, spearmint oil, geranium oil, thyme oil, neroli oil, mentha oil, hinoki (Japanese cypress) oil, fennel oil, peppermint oil, bergamot oil, lime oil, lavender oil, lemon oil, lemongrass oil, rose oil, rosewood oil, anisaldehyde, geraniol, citral, civetone, muscone, limonene, and vanillin.
[0093] Specific examples of pH adjusters that can be used in the present invention include, but are not limited to, the following compounds: sodium citrate, sodium acetate, sodium hydroxide, potassium hydroxide, phosphoric acid, and succinic acid.
[0094] The dose of the nanoparticle of the present invention can be adequately determined depending upon type and amount of active ingredient and upon user weight and condition, for example. The dose for single administration is generally approximately 10 μg to 100 mg/kg, and preferably 20 μg to 50 mg/kg. In case of via transdermal or transmucosal administration, the nanoparticle can be administered in an amount of approximately 1 μg to 50 mg/cm, and preferably 2.5 μg to 10 mg/cm.
[0095] The present invention is hereafter described in greater detail with reference to the following examples, although the technical scope of the present invention is not limited thereto.
EXAMPLES
Example 1
[0096] Milk-derived casein Na (10 mg; Wako Pure Chemical Industries, Ltd.) was mixed with 50 mM phosphate buffer (pH 9)(1 mL). Tocopherol acetate (0.75 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.1 mL). The tocopherol acetate solution was added dropwise to the casein solution during stirring. The resulting liquid mixture (1 ml) was injected into 200 mM phosphate buffer water (pH 5) (10 mL) with the use of a microsyringe at an external temperature of 40° C. during stirring at 800 rpm. Thus, a water dispersion of casein nanoparticles containing tocopherol acetate was obtained. The particle size of the obtained casein particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 18.0 nm.
Example 2
[0097] Nanoparticles were prepared as in Example 1, except that tocopherol acetate (3.75 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.1 mL). The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 19.2 nm.
Example 3
[0098] Nanoparticles were prepared as in Example 1, except that tocopherol nicotinate (0.5 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.1 mL). The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 19.2 nm.
Example 4
[0099] Nanoparticles were prepared as in Example 1, except that tocopherol nicotinate (2.5 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.1 mL). The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 20.5 nm.
Example 5
[0100] Nanoparticles were prepared as in Example 1, except that tocopherol (0.75 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.1 mL). The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 18.8 nm.
Example 6
[0101] Nanoparticles were prepared as in Example 1, except that tocopherol (3.75 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.1 mL). The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 20.3 nm.
Example 7
[0102] Nanoparticles were prepared as in Example 1, except that nicotinic-acid amide (0.85 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.2 mL). The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 20.0 nm.
Example 8
[0103] Nanoparticles were prepared as in Example 1, except that benzyl nicotinate (1.1 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.1 mL). The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 17.5 nm.
Example 9
[0104] Nanoparticles were prepared as in Example 1, except that cephalanthin (0.85 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.3 mL). The average particle size of the obtained particles was measured with a light scattering photometer (Microtrack, Nikkiso, Co., Ltd.), and was found to be 22 nm.
Example 10
[0105] Nanoparticles were prepared as in Example 1, except that finasteride (0.85 mg; LKT Laboratories Inc.) was dissolved in ethanol (0.3 mL). The average particle size of the obtained particles was measured with a light scattering photometer (Microtrack, Nikkiso, Co., Ltd.), and was found to be 29 nm.
Example 11
[0106] Nanoparticles were prepared as in Example 1, except that minoxidil (1 mg; LKT Laboratories Inc.) was dissolved in ethanol (0.02 mL). The average particle size of the obtained particles was measured with a light scattering photometer (Microtrack, Nikkiso, Co., Ltd.), and was found to be 23.4 nm.
Example 12
[0107] Nanoparticles were prepared as in Example 1, except that Swertia japonica extract (1.05 ml; Maruzen Pharmaceuticals Co., Ltd.; Swertia japonica extract liquid) was added dropwise. The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 26.3 nm.
Example 13
[0108] Nanoparticles were prepared as in Example 1, except that benzyl nicotinate (1.1 mg; Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol (0.1 mL) and chili pepper tincture (0.01 ml; Maruzen Pharmaceuticals Co., Ltd.) was added dropwise. The particle size of the obtained particles was measured with a “Zetasizer Nano” (Sysmex), and the volume average particle size was determined. It was found to be 27.3 nm.
Example 14
[0109] Nanoparticles were prepared as in Example 1, except that collagen (Nitta Gelatin Inc.), gelatin, acid-treated gelatin, or albumin was used in place of casein. As a result, similar nanoparticles were obtained.
Test Example 1
[0110] Water dispersions of casein nanoparticles for Examples 8 and 13 and water dispersions obtained by removing casein from those used in Examples 8 and 13 for Comparative Examples (referred to as Comparative Example 8A and Comparative Example 13A, respectively) were prepared and allowed to stand at 4° C. for 16 hour. Precipitation was exclusively observed in the water dispersions for Comparative Examples 8A and 13A, while on the other hand, no precipitation was observed in the water dispersions for Examples 8 and 13. The results indicate that the nanoparticles of the present invention are excellent in terms of stability.
Test Example 2
[0111] Dorsal hair of C3H mice at the trichogenous or dormant phase were cut with a hair clipper. On the next day, the mice were shaved with a shaver. The water dispersions of protein nanoparticles containing a blood circulation promoter which were prepared in Examples 8 and 9 were separately applied to all shaved areas once daily. The degree of ability to cause phase transition to the growth phase in mouse dorsal hair follicles was examined. As a result, hair growth effects were promoted and activity of causing hair cycle transition from the dormant phase to the growth phase was observed, as compared with the cases of ethanol solutions containing a blood circulation promoter alone (at the same concentrations) used in Examples 8 and 9. Therefore, it has been revealed that the water dispersions of the present invention cause no excessive skin degreasing or skin irritation caused by an ethanol solution, and exhibit hair growth effects derived from blood circulation promoting effects to a greater extent than the case of using ethanol solution.
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This application is a continuation of U.S. patent application Ser. No. 12/247,698 filed Oct. 8, 2008, now U.S. Pat. No. 8,434,616.
BACKGROUND OF THE INVENTION
A world-wide health care problem and need is the disposal of used syringes; this is a continuing health threat to the public. Of great concern, of course, are AIDS and other serious infectious diseases such as hepatitis. And, needles can become contaminated when used to treat various conditions such as allergies, infertility, arthritis, migraines, HIV, growth hormones among others.
Health care regulations have mandated the safe disposal of used syringes. A number of approaches, procedures and apparatus have been proposed for the storage of used syringes and the subsequent disposal thereof.
After a needle has been used either by or on a patient, then the syringe needle is contaminated from contact with the blood of the patient. If the user is HIV positive or a carrier of hepatitis or other blood born pathogen, then an accidental needle stick by the contaminated needle could spread the disease.
In hospitals and clinics the health care industry uses special containers dedicated for the disposal of needles and other invasive devices. Such containers are frequently referred to as “sharps” containers. The sharps containers with used syringes/needles therein are then disposed by industrial waste collectors and are usually either burned, disintegrated or buried, depending upon local health care regulations.
There is an additional dimension to the problem; that is the uses of syringes in private homes. For example, home syringe users are frequently diabetics who require frequent doses of insulin to regulate their glucose level. The practice of disposing and safe storage of used syringe syringes in private homes is far less organized than in hospitals and clinics. Home disposing techniques are varied and frequently home invented, using discarded or empty containers found around the home; such arrangements are high risk for accidental spreading of disease. There is currently no standard disposal practice for insulin users.
Medical delivery pens have become widely used in place of, or in addition to, medical syringes, e.g., by diabetics, who frequently inject themselves several times a day with accurately measured, adjustable, pre-selected amounts of insulin or other medication. Medical delivery pens include a reservoir of medication and a distal end adapted to be attached, usually by thread means, to a pen needle assembly. As is well known (see, for example, FIG. 1 of U.S. Pat. No. 5,545,145), a pen needle assembly has, within an outer, generally cylindrical shield, a generally cylindrical housing within which is mounted an axially extending hollow needle, (i) the proximal end of which punctures a seal in the distal end of the medical delivery pen to allow the flow there-through of medication when the delivery pen is screwed into the proximal end of the pen needle cylindrical housing, and (ii) the distal end of which is for insertion into tissue of the person requiring the medication. The pen needle assemblies typically also include a removable thin sterile seal covering the proximal (large diameter) end of the outer shield and a removable tube-like shield covering the distal portion of the hollow needle. The pen needle assembly is then factory sterilized. The user of a pen needle assembly removes the seal from the outer shield, screws the pen into the proximal end of the pen needle housing, removes the outer and tube-like shields, sets the medical delivery pen for the desired dose of medication, and then inserts the distal end of the pen needle into the target tissue following which the medical delivery pen is actuated to deliver the desired dose of medication through the hollow needle into said tissue.
Many diabetics routinely administer medication to themselves several times a day by injection of a pre-selected quantity of insulin (or substitute medication) in liquid form; the correct amount of medication can be determined from prior professional medical instruction or by use of convenient portable blood analysis kits which are small, compact and provide rapid indicators of the user's blood sugar level. Some of the typical several daily injections are often done away from the diabetic's residence which has made the use of the portable, convenient medical delivery pens widespread. The aforesaid testing kits and the medical delivery pens are relatively small in size and can easily fit within a woman's purse or equivalent. A typical scenario for a diabetic at a restaurant for a meal is to first use the blood sugar testing kit to obtain an indicator of his or her blood sugar level. This information then facilitates programming or adjusting the medical delivery pen to deliver the desired quantity of medication. Then the pen with an attached pen needle (a pen needle assembly without the outer cylindrical and tube shields) is used to inject the tissue and dispense the medication. These steps require a relatively short length of time and can be done with minimum loss of privacy. Some people requiring multiple daily medicine injections use both medical syringes and medical delivery pens with pen needles.
Medical delivery pens are also widely used by doctors, nurses and other professionals in their duties. Many individuals will request that an injection be done with a pen needle rather than a syringe. The aforementioned professionals are especially mindful of possible dangers from a needle stick and the possible unwanted “sticks” that occur in the professional world.
The user, both individual and professional, of a pen needle assembly should, after the first use of a pen needle, carefully detach the used pen needle from the medical delivery pen and safely dispose said pen needle into a safe sharps container. The approved disposal procedure is insertion of the distal end of the needle into the tube-like shield (sometimes omitted) and thence the shielded needle and pen needle cylindrical housing into the outer cylindrical shield, unscrewing of the medical delivery pen from the proximal end of the pen needle cylindrical housing, and careful placement of the used pen needle assembly into a safe sharps container. Further, in the “perfect” world, the user of a medical syringe would safely dispose the used syringe into a safe sharps container.
Unfortunately, the recommended safe disposal procedures are not always followed. Used and potentially dangerous syringes, pen needles or pen needle assemblies are routinely left in unsafe places where third parties may unwittingly be “stuck” with possible dire consequences. Examples of such unsafe places are purses, the pockets on the back of aircraft seats, private and public wastebaskets, garbage receptacles, dumpsters and empty milk or other unsafe containers.
Further, the above described pen needle assembly or pen needle disposal procedure requires that the user or associate handle or hold the pen needle while the pen is unscrewed therefrom; this creates the possibility of a potentially dangerous “stick.” Also, if the user or associate tries to insert the pen needle into the outer shield to form a pen needle assembly, then additional handling is again required with the possibility of a “stick”.
Similar disposal considerations apply to the more traditional syringe needles which may have associated syringe needle covers.
SUMMARY OF THE DISCLOSURE
The present disclosure relates to space efficient systems for distributing, storing, and dispensing a number of medical or laboratory sharps with subsequent safe disposal of the used sharps. Concern about inadvertent transmission of disease through accidental sticks makes it highly desirable to ensure that each used sharps is properly disposed of in an approved sharps container, preferably provided with the sharps at the point of purchase. At the same time, as transportation costs rise, it becomes increasingly desirable to avoid shipping the empty space associated with a sharps disposal container. Each of the embodiments of the system disclosed herein for the efficient distribution and storage of new and used sharps comprises a first container sized to contain and safely dispose of a number of medical or laboratory sharps and a second associated container sized to contain and dispense a similar number of medical or laboratory sharps, wherein the system has a first configuration having a first volume substantially equal to the volume of a first container and a second configuration equal in volume to the sum of the volumes of the first container and a second container having a volume sufficient to contain the number of medical or laboratory sharps.
The system provides an efficient lower volume during shipping and initial storage than would otherwise be obtained when shipping the two containers, yet still provides convenient dispensing of unused sharps and disposal of used sharps in the use location. In a first embodiment, system comprises a first outer container having at least one repositionable wall portion, said repositionable wall portion having a first position and a second position, wherein when the repositionable wall portion is in the first position, the first outer container defines an opening large enough to permit the removal of a quantity of sharps, said sharps selected from pen needles, hypodermic needles, and syringes with attached hypodermic needles, from the first outer container, further wherein when the repositionable wall portion is in the second position, said opening is closed. The first outer container also defines a first aperture which comprises an associated one-way mechanism for conveying a used sharp from the exterior of the first outer container to the interior of the first outer container, wherein said sharp is selected from pen needles, hypodermic needles, and syringes with attached hypodermic needles otherwise known as unibody syringes. The repositionable wall portion and the first outer container cooperatively define a nonreversible locking mechanism for securing said repositionable wall to the first outer container when the repositionable wall is in the second position thereby forming a complete enclosure. The system also comprises a second, inner container sized to fit within the first outer container and to be removed from the first outer container through the opening, wherein said second, inner container contains the quantity of sharps and further comprises a dispensing mechanism for unused sharps.
In a second embodiment, system comprises a first container having at least one repositionable wall portion, said repositionable wall portion having a first position and a second position, wherein when the repositionable wall portion is in the first position, the first container defines an opening large enough to permit the removal of a quantity of sharps, said sharps selected from pen needles, hypodermic needles, and syringes with attached hypodermic needles, from the first container, further wherein when the repositionable wall portion is in the second position, said opening is closed. The first container also defining a first aperture which comprises an associated one-way mechanism for conveying a used sharp from the exterior of the first container to the interior of the first container, wherein said sharp is selected from pen needles, hypodermic needles, and syringes with attached hypodermic needles. The repositionable wall portion and the first container cooperatively define a nonreversible locking mechanism for securing said repositionable wall to the first container when the repositionable wall is in the second position thereby forming a complete enclosure. The system further comprises a second container, having a collapsed distribution configuration and an expanded storage configuration sized to hold the quantity of sharps which are contained within the first container. System embodiments provide a container for the included unused sharps which may be bundled with the sharps disposal container without incurring the penalties associated with shipping, storing, and stocking within the supply chain at least one empty container.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a perspective view of an embodiment of the system.
FIG. 2 is a perspective view of the system of FIG. 1 with the second container partially removed.
FIG. 3 is a perspective view of the system of FIG. 1 with the second container completely removed.
FIG. 4 is a perspective view of an embodiment of the system.
FIG. 4A is a perspective view of the system of FIG. 4 with the second container detached and expanded.
FIG. 4B is a perspective view of an embodiment of the invention.
While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The following description should be read with reference to the drawings wherein like reference numerals indicate like elements throughout the several views. The drawings, which are not necessarily to scale, are not intended to limit the scope of the claimed invention.
All numbers are herein assumed to be modified by the term “about.” The recitation of numerical ranges by endpoints includes all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).
As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include the plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
Although the systems described herein may be readily adapted to distribute and dispense any of a variety of unused sharps and to dispose of them safely after use, it will be convenient to describe certain aspects of the several containers of the system as they relate to specific types of sharp. It will be understood that one of ordinary skill in the art would be capable of modifying the description herein to adapt each of the systems for use with other sharps including, among others, pen needles, pen needle assemblies, hypodermic needles, unibody syringes having integral hypodermic needles, and the like. It will be further understood that the system may be readily adapted to dispense and/or receive more than one type of sharp should that be desired.
Referring now to the drawings, FIG. 1 illustrates a system 10 comprising a first outer container 20 having a repositionable wall portion 24 . When repositionable wall portion 24 is in a first position, generally associated with shipping and storage, an opening is exposed in container 20 , said opening being sufficiently large to allow the removal of an inner container 40 sized to contain a quantity of sharps and to include a dispensing mechanism 22 for unused sharps. The repositionable wall portion 24 and the first outer container 20 cooperatively defining nonreversible locking fasteners 26 , 28 for securing said repositionable wall portion 24 to the first outer container 20 when the repositionable wall is in the second position thereby forming a complete enclosure. In the illustrated embodiment, the outer container 20 includes an aperture including a rotary mechanism 30 which may convey used syringe 50 into outer container 20 . It will be readily appreciated that other mechanisms 30 may be employed for this purpose. FIG. 1 further includes a second inner container 40 sized to contain a quantity of unused sharps, in this embodiment syringes 30 , and to include a dispensing mechanism for unused sharps, here represented by dispensing door 22 .
In FIG. 2 , the inner container 40 of system 10 has been partially removed from outer container 20 by sliding over repositionable wall portion 24 which has been pivoted to an open position. It will be appreciated that repositionable wall portion 24 may be completely detached in some embodiments and tethered, hinged, or otherwise pivotably attached to outer container 20 in other embodiments. Continuing to FIG. 3 , the system 10 is now configured for use with inner dispensing container 40 completely removed from outer container 20 and with repositionable wall portion 24 in place and locked to outer container 20 by means of nonreversible locking fasteners 26 , 28 . In this configuration of system 10 , unused sharps may be removed from inner container 40 through door 22 , used, and subsequently returned to the interior of outer container 20 through rotary mechanism 30 for safe disposal.
As illustrated in FIG. 4 , second container 40 may be supplied as a component of system 10 in the form of a folded container distributed as a component of the system 10 . As depicted in FIG. 4 , second container 40 is initially secured to the outside of first container 20 by band 60 which holds the components 20 , 40 of system 10 together during shipping while the unused sharps (not shown) are contained within first container 20 . Although second container 40 has been illustrated in the form of an exterior folded container in FIG. 4 , it will be readily appreciated that folded container 40 could have been initially stored within first container 20 (see FIG. 4B ) along with a number of unused sharps. Following distribution of system 10 , the user removes removable wall portion 25 , including mechanism 30 which will be used to convey used sharp 50 , a pen needle assembly in this embodiment, into first container 20 , from first container 20 providing access to unused sharps stored therein.
Folded container 40 is then detached from first container 20 , or removed from the interior of container 20 in other embodiments (see FIG. 4B ), and expanded to provide the unused sharps container 40 of FIG. 4A . The unused sharps 50 are then placed within the expanded container 40 from which they may be dispensed as needed. If desired, an optional dispensing component of container 40 which is not readily collapsed, such as a drawer, may also be removed from the interior of container 20 and installed in container 40 prior to transferring the sharps. Replacement of removable wall portion 25 with engagement of nonreversible locking mechanisms (not shown) completes the deployment of the components of the system 10 . In use, unused sharps 50 will be dispensed from expanded container 40 , optionally through a dispensing aperture or mechanism analogous to door 22 of FIG. 1 . They will subsequently be used and returned to the interior of first container 20 through mechanism 30 , here depicted as a pivoting chute. Once the supply of unused sharps has been exhausted, container 40 may again be collapsed for space efficient disposal.
In some embodiments, when the repositionable wall portion is secured to the first outer container by the nonreversible locking mechanism, the complete enclosure is sealed at the perimeter of the repositionable wall portion with respect to liquid leakage from the complete enclosure. In other embodiments, a material capable of absorbing and storing fluid associated with the container is positioned within the first container. In such embodiments, the material capable of absorbing and storing fluid may be selected from organic or inorganic absorbing materials. Any of the known of fluid absorbing materials and forms may be used providing they have sufficient capacity to hold liquids which may incidentally be introduced into the container along with the pen needles, syringe needles, or other sharps to be stored. The following group of absorbing materials is intended to be illustrative and non-limiting. Powders of desiccants such as silica gel, calcium sulfate, calcium chloride, montmorillonite clay, and molecular sieves or organic materials such as polyacrylic acid, polymethacrylic acid, polyacrylamide, and polyalkylene oxide may be provided alone or in layered constructions with a liquid permeable sheet. The polymers may conveniently be provided as nonwoven pads or as powders. In addition to homopolymers such as those listed, the fluid absorbing material may be copolymers and/or optionally may be crosslinked.
The absorbent material may be associated with one or more of the floor and/or walls of the internal storage space. In certain embodiments, the fluid absorbent material within the container has a fluid capacity of at least 0.02 gram for each pen needle, syringe needle or unibody syringe to be stored. In other embodiments, the fluid absorbent material within the container has a fluid capacity of at least 0.05 gram or even at least 0.01 gram for each sharp to be stored. In yet other embodiments, the available fluid capacity per pen needle or syringe needle may be reduced based upon assumptions regarding the rate of evaporation of fluids from the container and the rate at which additional pen needles, syringe needles, or unibody syringes are to be added to the container so long as sufficient capacity is present to absorb the fluid associated with each new sharp deposited.
In some embodiments, when the repositionable wall portion is in the first position, it is pivotably attached to the first outer container along one edge of the repositionable wall portion. In other embodiments, when the repositionable wall portion is in the first position, it is detached from the first outer container. During distribution and storage prior to use, it may be desirable to provide a covering material for the opening in the first container before the repositionable wall portion is secured over the opening following removal of the sharps and second container, if present. In some embodiments, the opening in the outer container is covered by a shrink wrap film. The shrink wrap film may also encompass the repositionable wall portion to create a unitary package for shipping the system. The shrink wrap may also encompass the second container.
In other embodiments, the first container may be contained within a further container which also covers the opening in the first container. In such embodiments, the further container may be, for example, a cardboard box suitable for shipping the system. The further container may also contain the repositionable wall portion and the second container during distribution and storage prior to use. In yet other embodiments, the first container may be contained within the second container during distribution.
In some embodiments, the one-way mechanism which conveys a used sharp into the first container may be functional in two or more orientations of the first container. That is, the one-way mechanism may be accessible and functional in two or more orientations of the first container which differ in that the container rests on different faces in the two orientations. For example, in a first orientation, the container may rest upon a small face such that its greatest dimension is substantially vertical, while in the second orientation the greatest dimension may be substantially horizontal. It will be understood that some containers may be substantially equal in all dimensions and still have orientations which differ with respect to which face of the container forms the base and also with respect to the orientation of the aperture associated with one-way mechanism. In some embodiments, the one-way mechanism is configured to accept and facilitate the removal of a hypodermic needle from one of an associated syringe and an injection pen. In some of those embodiments the removed hypodermic needle may be conveyed directly into the second compartment following removal. The one-way mechanism may have any of the configurations known in the art at the time that the device is designed. For example, the one-way mechanism may be a rotating mechanism, a pivoting mechanism, a sliding mechanism, or a largely passive flexing mechanism such as a diaphragm.
In some embodiments, the portion of the first container which receives sharps such as pen needles, pen needle assemblies, syringe needles, syringe needle covers, and combinations thereof provides a visual contrast to the surrounding portions of the housing to aid visually impaired users in properly orienting and inserting the pen needles, pen needle assemblies, syringe needles, syringe needle covers, and combinations thereof. The visual distinctive feature may be provided in the form of color contrast and/or patterning relative to the surrounding housing. Preferably, the color associated with the receiving region or a patterned portion thereof will be red. In some embodiments, the means for receiving pen needles includes a combination of protrusions and recesses which engage the pen needle to prevent rotation thereof as a pen is rotated relative to the pen needle within the said means. This engagement facilitates one hand removal of a pen needle from a medical delivery pen, thereby minimizing the risk of accidental sticks.
In some embodiments, the means for receiving pen needles, pen needle assemblies, syringe needles, syringe needle covers, and combinations thereof includes a means for rotating the receiving means relative to the housing. In certain embodiments, the rotation will be about an axis generally perpendicular to an axis associated with the pen needle, pen needle assembly, syringe needle, syringe needle cover, or combinations thereof which are to be conveyed into the interior storage space. In other embodiments, the rotation will be about an axis which is generally parallel to an axis associated with the pen needle, pen needle assembly, syringe needle, syringe needle cover, or combinations thereof which are to be conveyed into the interior storage space. The means for rotating the receiving means may be either manual or automated as by a spring drive or electric motor.
In some embodiments, the means for receiving pen needles, pen needle assemblies, syringe needles, syringe needle covers, and combinations thereof includes an ejector assembly having an ejector axis and wherein the means for receiving pen needles, pen needle assemblies, syringe needles, syringe needle covers, and combinations thereof is operatively coupled to the means for rotating said receiving means relative to the housing. In those embodiments, rotation of the receiving means may convey the pen needles, pen needle assemblies, syringe needles, syringe needle covers, and combinations thereof within the internal storage space whereupon the ejector assembly ejects the pen needle, pen needle assembly, syringe needle, syringe needle cover, or combinations thereof from the receiving means into the internal storage space.
In some embodiments, the container includes one or more guards which prevent pen needles, pen needle assemblies, syringe needles, syringe needle covers, or combinations thereof within the internal storage space from re-entering the means for receiving and ejecting pen needles, pen needle assemblies, syringe needles, syringe needle covers, and combinations thereof. This is desirable to prevent accidental or intentional removal of sharps from the internal storage space, particularly when the container is inverted or otherwise placed in an orientation other than that normally employed for disposing of sharps. Absent such guards, sharps might accidentally be released during transport. In certain embodiments, the one or more guards are structures within the internal storage space which prevent access to the receiving means in positions other than those associated with receiving or ejecting pen needles, pen needle assemblies, and combinations thereof.
In those embodiments in which the second container includes a dispensing mechanism, the mechanism may be configured to facilitate removal of a single unused sharp or it may be configured to facilitate removal of multiple sharps. For example, the sharps may be removed in individual containers such as pen needle assemblies, covered hypodermic needles, covered unibody syringes, or the like. Alternatively, the sharps may be removed as prepackaged multiple sharps, for example, a package of two pen needle assemblies. In some embodiments, the sharps may be presented at the aperture in the form of a continuous strip of packaged sharps from which the user may selectably remove one or more sharps as desired. The mechanisms may include doors, drawers, and the like. In other embodiments, the unused sharps may be associated with a roll, reel, stack, serpentine ribbon, or the like which may convey the sharps sequentially to the dispensing mechanism.
Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the scope and principles of this invention, and it should be understood that this invention is not to be unduly limited to the illustrative embodiments set forth hereinabove. All publications and patents are herein incorporated by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to electrical defibrillation, and relates more specifically to particular types of implantable electrodes and methods of implanting them with a minimal amount of surgery.
It is well known in the field of cardiology that certain types of cardiac arrhythmias known as ventricular tachycardia and fibrillation can be effectively treated by the application of electrical shocks to the heart to defibrillate the fibrillating tissues. Such defibrillation may be achieved by the application by medical personnel of electrical paddles to the chest of the patient or directly to the heart tissue, if the chest is open during surgery.
More recent improvements have led to the development of implantable defibrillators which automatically monitor the heart for arrhythmia and initiate defibrillation when arrhythmia occurs. Such devices typically incorporate electrodes which are located either next to the heart or on an intravascular catheter, or both. Because the electrodes are closer to the heart tissue, implanted defibrillators require less electrical energy to stimulate the heart than external electrodes.
However, major surgery is generally necessary to implant present defibrillator lead systems, such as a median sternotomy or lateral thoracotomy. These procedures can be very traumatic to the patient, and may have adverse side effects such as surgical complications, morbidity or mortality. Because of these risks, only those persons whose condition is so dire that the potential benefits outweigh the risks are suitable candidates for such surgery, thus excluding many patients who might otherwise benefit from the surgery.
2. Description of the Relevant Art
There have been various attempts to solve these problems, such as that of Heilman, U.S. Pat. No. 4,291,707, and Heilman, U.S. Pat. No. 4,270,549, which respectively show an electrode and the method of implanting it. Heilman teaches the use of rectangular paddle electrodes measuring 4 cm. by 6 cm. Two such electrodes are used, requiring in the illustrated embodiments two incisions, one in the abdominal wall and one in the interior thoracic region. Alternatively, one paddle electrode may be inserted through an incision and another intravascular electrode inserted into the superior vena cava. This still requires two separate intrusions into the body, however. Heilman does briefly mention the possibility of inserting both electrodes through a single incision; however, even in this case, that incision must be a long median sternotomy or thoracotomy, such as that commonly performed for an open heart procedure such as a coronary artery bypass, in order to allow passage of the paddles.
Another attempted solution involves the use of bipolar electrodes, i.e. a single assembly that contains both electrodes, so that only that single assembly need be put in contact with the heart tissue. Such electrodes are shown in Ackerman, U.S. Pat. No. Re. 27,569, and Alferness, U.S. Pat. No. 4,355,642. However, it is believed that better results are obtained by locating the electrodes on opposite sides of the heart, either side to side or front to back.
Other types of electrodes, some of which may be used transvenously, are shown in Williamson, U.S. Pat. No. 3,749,101, Kallok et al., U.S. Pat. No. 4,355,646, and Moore, U.S. Pat. No. 4,567,900.
SUMMARY OF THE INVENTION
In accordance with the illustrated preferred embodiment, the present invention provides for passing a first catheter through the pericardial sac and into the intrapericardial space such that it terminates in a position proximate to the heart; inserting a first electrode into the intrapericardial space by sliding it through said first catheter such that the distal end of said first electrode is extended beyond the distal end of said first catheter and is located proximate to the heart; passing a second catheter through the pericardial sac and into the intrapericardial space such that it terminates in a position proximate to the heart; and inserting a second electrode into the intrapericardial space by sliding it through said second catheter such that the distal end of said second electrode is extended beyond the distal end of said second catheter and is located proximate to the heart.
In the preferred embodiment, both catheters and electrodes are inserted in a single incision in the upper abdominal wall, resulting in less trauma to the patient than in procedures requiring two incisions. A fluoroscope may be used to view the heart and assist in placing the electrodes.
The proximate ends of the catheter are attached to the pericardium or the surrounding connective tissue so that the catheters, and thus the electrodes, are held in a nearly fixed position. This prevents the electrodes from migrating as mentioned above, and may be accomplished by use of a "button" which is sutured to the pericardium or surrounding tissue, and which contains in its center a metal ring which may be crimped on the catheter once the correct position has been attained.
In an alternative embodiment, the catheters may be used only to insert the electrodes and then removed, leaving the electrodes in place. In this case, it is preferable to attach the electrodes to the heart tissue or surrounding tissue to prevent migration.
In the preferred embodiment, each electrode is preconfigured such that the distal end assumes a specified configuration, such as a spiral, upon exiting from the distal end of the respective catheter, allowing a cylindrical electrode to approximate the function of a paddle-type electrode. However, other shapes might also be used. The conductive portion of the electrode may be a spiral of metal foil or wire on a non-conductive, generally cylindrical stem, or a wire element contained in the stem and exposed in short cylindrical sections or in a channel along one side of the stem. Applicants have a co-pending application entitled Implantable Defibrillation Electrode on electrodes that may be used with this invention.
The features and advantages described in the specification are not all inclusive, and particularly, many additional features and advantages will be apparent to one of ordinary skill in the art in view of the drawings, specification and claims hereof. Moreover, it should be noted that the language used in the specification has been principally selected for readability and instructional purposes, and may not have been selected to delineate or circumscribe the inventive subject matter, resort to the claims being necessary to determine such inventive subject matter.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a sectional view of a body showing a defibrillator implanted according to the preferred embodiment of the present invention.
FIG. 2 is a cross-sectional side view of the body of FIG. 1.
FIG. 3 is a side view of an electrode showing one possible configuration that may be used with the present invention.
FIG. 4 is a top view of the electrode of FIG. 3 taken along the line 4--4 of FIG. 3.
FIG. 5 is an elevational view of an electrode showing another configuration that may be used with the present invention.
FIG. 6 is a top view of an electrode showing another configuration that may be used with the present invention.
FIG. 7 shows the first step of the preferred embodiment of making an incision into the upper abdominal wall and inserting a first catheter into the intrapericardial space.
FIG. 8 shows the subsequent step of inserting a preconfigured first electrode into the first catheter, with a stylet inside the electrode.
FIG. 9 shows the first electrode after insertion through the first catheter.
FIG. 10 shows the subsequent step of removing the stylet.
FIG. 11 shows both electrodes and catheters after insertion.
FIG. 12 shows the proximal ends of both catheters and electrodes after attachment and crimping of the fastening buttons.
FIG. 13 is a perspective view of a fastening button.
FIG. 14 shows the proximal end of one electrode after removal of the excess portion of the catheter, and the excess portion of the other catheter being removed by the cutting tool.
FIG. 15 is a perspective view of the cutting tool.
FIG. 16 is a sectional view of a body showing a defibrillator implanted according to an alternative embodiment of the present invention.
FIG. 17 is a cross-sectional side view of the body of FIG. 16.
FIG. 18 shows the first step of the alternative embodiment of making an incision in the upper abdominal wall and inserting a tool therein.
FIG. 19 is a side view of the body after insertion of the tool into the pericardial sac.
FIG. 20 is a view of the channel portion of the tool taken along line 20--20 in FIG. 19.
FIG. 21 is a side view of the tool and shows the prior step of inserting the pointed end of the tool into the pericardial sac.
FIG. 22 is a side view of a different embodiment of the tool with a different cutting end thereon.
FIG. 23 shows the next step of the alternative embodiment wherein a guide wire is inserted through the center section of the tool.
FIG. 24 shows the next steps of the alternative embodiment wherein the center section of the tool is removed and the guide wire is removed from the channel portion of the tool.
FIG. 25 shows an end view of the step of removing the guide wire from the channel portion of the tool.
FIG. 26 shows the next step of the alternative embodiment wherein a catheter having a dilating member is inserted over the guide wire and into the pericardial sac.
FIG. 27 shows the next step of the alternative embodiment wherein the dilating member is removed from the catheter.
FIG. 28 shows the next step of the alternative embodiment wherein a preconfigured electrode which is straightened by a stylet is inserted through the catheter such that the distal end is positioned on the posterior surface of the heart.
FIG. 29 shows the next step of the alternative embodiment wherein the catheter and the stylet are withdrawn, leaving the electrode in place.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
FIGS. 1 through 29 of the drawings depict various preferred embodiments of the present invention for purposes of illustration only. One skilled in the art will readily recognize from the following discussion that alternative embodiments of the structures and methods illustrated herein may be employed without departing from the principles of the invention described herein.
A defibrillator installed by the method of the present invention is shown in FIGS. 1 and 2. FIGS. 3 through 6 show various shapes of electrodes that may be used. The preferred embodiment of the method of installing the defibrillator is detailed in FIGS. 7 through 15. FIGS. 16 and 17 show a defibrillator installed pursuant to an alternative embodiment of the method of the present invention, and FIGS. 18 through 29 detail that alternative embodiment.
In FIG. 1, the defibrillator is shown after implantation, with the electrodes 40 and 42 located on the anterior and posterior surfaces of the heart respectively. The electrodes are held in place by two cannulae, or catheter sections, 44 and 46, which are in turn held by two fastening buttons 48 and 50 which are sewn to the pericardium or surrounding connective tissue. The electrode leads 52 and 54 are attached to the implanted defibrillator module 56.
The electrodes may be of various shapes, as shown in FIGS. 3 through 6. In the preferred embodiment, the electrode is preconfigured as a spiral in order to increase the contact area and thus simulate the function of a paddle electrode. In FIG. 3 the spiral is a conical one which does not lie in a single plane but spirals upward as it spirals inward. FIG. 4 is a top view of this electrode, taken along line 4--4 in FIG. 3. This three-dimensional coil gives the electrode a spring effect between the heart surface and the pericardium which tends to keep the electrode in place.
Alternatively, a flat spiral shape may be used for the electrode. In FIG. 5 a flat round spiral electrode is shown. In FIG. 6, an electrode having a "square spiral" shape is shown.
FIG. 7 shows the first step of the preferred embodiment of the method of the present invention. An incision 58 is made in the upper abdominal wall of the patient; the tissues between this incision 58 and the pericardium of the patient are separated digitally by spreading of the surgeon's fingers, and another incision 60 is made in the pericardium. The cannulus 46 is inserted into the pericardial sac through these incisions.
The preconfigured electrode 42 is then inserted into the pericardium through the cannulus 46 to the posterior of the heart, as shown in FIG. 8. To increase the ease of insertion of the electrode, a stylet 62 is inserted into the electrode to straighten it before insertion. The distal end of the electrode 42 is extended beyond the end of the cannulus 46, as shown in FIG. 9, and the stylet 62 is then removed, allowing the electrode 42 to assume its preconfigured shape. The resulting position is shown in FIG. 10.
The other cannulus 44 and corresponding electrode 40 is inserted in the same manner, but on the opposite side (anterior) of the heart, resulting in the position shown in FIG. 11. Electrode leads 52 and 54 extend from the ends of the cannulae 44 and 46.
Fastening buttons 48 and 50 are then placed on the cannulae 44 and 46, as shown in FIG. 12, and sewn to the pericardium or surrounding connective tissue with sutures 66. A detailed view of a fastening button is shown in FIG. 13; it contains a channel 64 through which the cannulus passes, and a crimping ring 68 which is made of metal. After the fastening buttons 48 and 50 are sewn in place, the cannulae 44 and 46 are manipulated until the electrodes 40 and 42 are located in the desired positions, and the crimping rings 68 are then crimped with pliers or some other tool such that the cannulae 44 and 46 are fixed in the desired positions. As mentioned above, a fluoroscope may also be used to view the electrodes for assistance in locating them where desired.
Next, the excess portions of the cannulae 44 and 46 which extend beyond the heart and the fastening buttons 48 and 50 are removed, as shown in FIG. 14. A cutting tool 70 is used to cut the cannulae 44 and 46 without cutting the electrode leads 52 and 54. Cutting tool 70 is shown in detail in FIG. 15. It includes a hinged cylindrical body comprised of stationary piece 72 and movable piece 74, which is hinged near the proximate end of cutting tool 70. Inside at the distal end is cutting edge 76. In practice, movable piece 74 is opened and cutting tool 70 is slid over one of the cannulae until the distal end is proximate to the fastening button, and the movable piece 74 is then closed. This pins the cannulus in the cutting tool 70 so that it may be cut by cutting edge 76, which extends far enough into the center of cutting tool 70 to cut the cannulus but not the electrode lead. Cutting tool 70 is then rotated to score the cannulus all the way around its circumference. In FIG. 14, cutting tool 70 is shown in place on cannulus 46, next to fastening button 50, with electrode lead 54 extending; the excess portion of cannulus 44 has already been removed, leaving electrode lead 52. The arrow shows that cutting tool 70 is being rotated.
After the excess portions of cannulae 44 and 46 have been removed, electrode leads 52 and 54 may be connected to the defibrillator module 56 and the incision in the body closed.
In using this method, it is also possible to use electrodes which do not incorporate stylets. In this case the spiral is straightened manually and then inserted into the cannula, which keeps the electrode straight until it emerges from the distal end of the cannula, at which point it again assumes a spiral shape.
FIGS. 16 and 17 show a front and side view respectively of an alternative embodiment of the present invention. Electrodes 40 and 42 are connected to defibrillator module 56 through electrode leads 52 and 54. The electrodes may be of the same shapes as in the preferred embodiment. However, there are no cannulae or fastening buttons in this embodiment.
FIG. 18 shows the first step of making an incision 58 in the upper abdominal wall and inserting a forceps tool 78 therein. The forceps tool 78 has a clamping body 80 on which is mounted a channel portion 82. Within the channel portion 82 is a hollow stylet 84 with a proximal end piece 81. Stylet 84 may have a pointed distal end 83 as shown in FIG. 21, or a flat end 85 which is beveled all the way around, as shown in FIG. 22. The stylet 84 is slidable within the channel portion 82, and the distal end 83 or 85 is limited to extending no more than approximately 1 centimeter beyond the distal end of the channel portion 82 by the end piece 81.
The clamping body 80 is used to grasp the pericardium and "tent" it by lifting it away from the heart surface, and the distal end of the stylet 84 is then advanced through the channel portion 82 and used to puncture the pericardium, as shown in FIG. 19. This "tenting" prevents the user from accidentally puncturing the heart itself while the pericardium is punctured, since the distance that the end of the stylet 84 may extend beyond the channel portion 82 is limited by end piece 81. If the end of the stylet 84 is the pointed end 83 of FIG. 21, the puncture may be made by simply advancing the stylet 84, as shown by the arrow in FIG. 21. On the other hand, if the stylet 84 has the beveled end 85 of FIG. 22, it may be necessary to rotate the stylet 84 as shown by the arrow in FIG. 22. FIG. 20 shows an end view of the channel portion 82, with the stylet 84 within, taken along line 20--20 in FIG. 19.
A guide wire 86 is then advanced through the stylet 84, as shown in FIG. 23; in FIG. 23 the wire 86 has been advanced so that its distal end is posterior to the heart. Once the guide wire is in place, the stylet 84 is removed by retracting it, as shown by the arrow in FIG. 24; the wire 86 may then be laterally removed from the channel portion 82 of the forceps tool 78, as shown in FIGS. 24 and 25, and the forceps tool 78 is itself removed, leaving only the guide wire 86 in place.
A two piece catheter is then advanced into the pericardium, as shown in FIG. 26. This catheter is composed of an internal catheter 88 with a tapered tip and an outer catheter body 90. As the internal catheter 88 is advanced, the tapered tip opens the incisions enough to permit passage of the outer catheter body 90. Once the outer catheter body 90 is in place, the guide wire 86 and inner catheter 88 may be.removed, as shown in FIG. 27. As above, here the placement shown is posterior to the heart.
Now electrode 42 may be inserted through catheter 90, as shown in FIG. 28. As in the prior embodiment, a stylet 92 may be used to straighten out the preconfigured electrode 42 to permit easier insertion. If the electrode 42 is to be placed posterior to the heart by going over the shoulder as shown here, the stylet 92 may be somewhat flexible so that the electrode 42 can be pushed as far as the distal end of catheter 90 with the stylet 92 in place. Then, as the electrode 42 is advanced further, it simultaneously exits catheter 90 and assumes its preconfigured shape.
Finally, the stylet 92 and catheter 90 are removed, leaving the electrode 42 in place, as shown in FIG. 29. The electrode lead 54 is connected to the defibrillator module 56. The other electrode 52 is inserted by the same method, but anterior to the heart. (Alternatively, the electrodes may be placed on opposite lateral sides of the heart.) The placing of the electrode 42 posterior to the heart by going over the shoulder of the heart helps to prevent migration. If more security is desired, the electrodes may be sutured in place, or small anchors may be added to the distal ends of the electrodes to anchor them.
From the above description, it will be apparent that the invention disclosed herein provides a novel and advantageous method for implanting an automatic defibrillator. The foregoing discussion discloses and describes merely exemplary methods and embodiments of the present invention. As will be understood by those familiar with the art, the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. For example, other shapes of electrodes may be used, and they may be located in other positions, as long as migration is prevented.
Accordingly, the disclosure of the present invention is intended to be illustrative, but not limiting, of the scope of the invention, which is set forth in the following claims.
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CROSS REFERENCE TO RELATED APPLICATION
The present application claims the benefit of and priority to U.S. Provisional Application Ser. No. 61/234,369 filed on Aug. 17, 2009, the entire contents of which are incorporated herein by reference.
BACKGROUND
1. Technical Field
The present disclosure relates to a surgical stapling device and, more particularly, to an endoscopic surgical stapling device having a tool assembly and an endoscopic body portion, wherein the anvil is pivoted by a motor and the staples are fired manually.
2. Background of Related Art
Surgical devices wherein tissue is first grasped or clamped between opposing jaw structure and then joined by surgical fasteners are well known in the art. In some instruments a knife is provided to cut the tissue which has been joined by the fasteners. The fasteners are typically in the form of surgical staples but two part fasteners can also be utilized.
Instruments for this purpose can include two elongated members which are respectively used to capture or clamp tissue. Typically, one of the members carries a staple cartridge which houses a plurality of staples arranged in at least two lateral rows while the other member has an anvil that defines a surface for forming the staple legs as the staples are driven from the staple cartridge. Generally, the stapling operation is effected by cam bars or cam wedge that travel longitudinally through the staple cartridge, with the cam bars or cam wedge acting upon staple pushers to sequentially eject the staples from the staple cartridge. A knife can travel between the staple rows to longitudinally cut and/or open the stapled tissue between the rows of staples. Such instruments are disclosed, for example, in U.S. Pat. Nos. 3,079,606 and 3,490,675.
A later stapler disclosed in U.S. Pat. No. 3,499,591 applies a double row of staples on each side of the incision. This is accomplished by providing a disposable loading unit in which a cam member moves through an elongate guide path between two sets of staggered staple carrying grooves. Staple drive members are located within the grooves and are positioned in such a manner so as to be contacted by the longitudinally moving cam to effect ejection of the staples from the staple cartridge of the disposable loading unit. Other examples of such staplers are disclosed in U.S. Pat. Nos. 4,429,695 and 5,065,929.
Each of the instruments described above were designed for use in conventional surgical procedures wherein surgeons have direct manual access to the operative site. However, in endoscopic or laparoscopic procedures, surgery is performed through a small incision or through a narrow cannula inserted through small entrance wounds in the skin. In order to address the specific needs of endoscopic and/or laparoscopic surgical procedures, endoscopic surgical stapling devices have been developed and are disclosed in, for example, U.S. Pat. No. 5,040,715 (Green, et al.); U.S. Pat. No.5,307,976 (Olson, et al.); U.S. Pat. No. 5,312,023 (Green, et al.); U.S. Pat. No. 5,318,221 (Green, et al.); U.S. Pat. No. 5,326,013 (Green, et al.); and U.S. Pat. No. 5,332,142 (Robinson, et al.). U.S. Surgical, the assignee of the present application, has manufactured and marketed endoscopic stapling instruments, such as the Multifire ENDO GIA* 30 and Multifire ENDO GIA* 60 instruments, for several years. These instruments have provided significant clinical benefits. Nonetheless, improvements are possible.
SUMMARY
In accordance with the present disclosure, a surgical instrument is provided. The surgical instrument has a handle assembly and an elongate body extending distally from the handle assembly. The handle assembly includes a handle and a switch. The switch allows the handle to have multiple modes of operation. At least one of the modes of operation is a firing mode, a clamping mode, or a retraction mode. The switch extends through both the left and right hand sides of the handle assembly.
The elongate body has a distal portion and defines a longitudinal axis. A first jaw member is supported by the elongate body and contains a plurality of fasteners. A second jaw member is mounted adjacent the first jaw member and is movable in relation to the first jaw member between an open position and a closed position by the handle assembly. The handle assembly is also connected to an actuation member and able to move the actuation member relative to the first jaw member to sequentially eject fasteners.
The switch is configured to move a slider cam over a rack member located within the handle assembly. The rack member has two sets of teeth that are diametrically opposed. A first set of teeth points distally along the longitudinal axis and is configured to engage a first pawl. A second set of teeth points proximally along the longitudinal axis and is configured to engage a second pawl. The first pawl pivots about a distal region of the first pawl. The second pawl pivots about a proximal region of the second pawl.
The surgical instrument has an articulation mechanism that pivots the distal portion of the elongate body about the longitudinal axis. The articulation mechanism includes a motor and power supply.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure, and together with a general description of the disclosure given above, and the detailed description of the embodiments given below, serve to explain the principles of the disclosure.
FIG. 1 is a perspective view of the surgical instrument in accordance with the principles of the present disclosure;
FIG. 2 is a perspective view of the surgical instrument of FIG. 1 , with parts separated;
FIG. 3 is a side cross-sectional view of the surgical instrument of FIG. 1 ; and
FIG. 4 is a side cross-sectional view of another embodiment of a surgical instrument.
Other features and advantages of the present disclosure will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the present disclosure.
DETAILED DESCRIPTION
In the drawings and in the description which follows, the term “proximal”, as is traditional, will refer to the end of the apparatus which is closest to the operator, while the term “distal” will refer to the end of the apparatus which is furthest from the operator.
The present disclosure can be used with any fastening device known in the art and is intended to encompass the same, shall be discussed in terms of both conventional and endoscopic procedures and apparatus. However, the use herein of terms such as “endoscopic”, “endoscopically”, and “endoscopic portion”, among others, should not be construed to limit the present disclosure to an apparatus for use only in conjunction with an endoscopic tube. The apparatus of present disclosure may find use in procedures in these and other uses including but not limited to where access is limited to a small incision such as in arthroscopic and laparoscopic procedures, or other conventional medical procedures (i.e. Open procedures).
Now referring to FIGS. 1 and 2 , a surgical instrument, e.g., a surgical stapler, in accordance with embodiments of the present disclosure is referred to as reference numeral 100 . Surgical instrument 100 includes a handle assembly 10 , an endoscopic portion 12 and an end effector 16 defining a longitudinal axis A-A extending therethrough. Further details of surgical instrument 100 are included in U.S. patent application Ser. No. 11/544,061, filed on Oct. 6, 2006, the entire contents of which are hereby incorporated by reference herein. While the features of the embodiments illustrated in FIG. 1 is shown in connection with a particular type of surgical instrument 100 , it is envisioned that the features described with respect to FIG. 1 are operable with other surgical instruments.
With continued reference to FIGS. 1 and 2 , endoscopic portion 12 extends distally from handle assembly 10 . End effector 16 is selectively connectable to a distal end of endoscopic portion 12 . The endoscopic portion 12 is rotatable about axis A-A relative to distal portion 20 of handle assembly 10 . A knob 22 is shown in mechanical cooperation with endoscopic portion 14 to facilitate such rotation.
Handle assembly 10 includes a stationary handle 50 , a moveable handle 52 , and electrical contacts (i.e., conductive rings 18 ) disposed adjacent distal portion 20 of the handle assembly 10 . Conductive rings 18 are internally wired within handle assembly 10 to a power source (either within handle assembly 10 or external thereto) and/or a micro controller. It is envisioned that conductive rings 18 are removable from handle assembly 10 .
Endoscopic portion 12 is shown having an articulation mechanism or actuator 24 disposed in mechanical cooperation therewith. As discussed above, articulation mechanism 24 is configured to pivot end effector 16 with respect to a longitudinal axis “A-A”. Here, an articulation knob 26 that is operatively disposed on endoscopic portion 12 , and a motor 28 disposed within a housing 30 of endoscopic portion 12 may be used to articulate end effector 16 engaged with endoscopic portion 12 .
The motor 28 is used to provide articulation and has at least one electrical contact 32 (a pair of electrical contacts 32 a and 32 b is shown) operably disposed with endoscopic portion 12 . Electrical contact 32 is in electrical communication with motor 28 of endoscopic portion 12 and is configured to communicate electrical power between conductive rings 18 of handle assembly 10 and motor 28 . Here, motor 28 is operatively connected to the actuation member to move the actuation member substantially along longitudinal axis A-A, i.e. to articulate end effector 16 . It is envisioned that motor 28 provides or helps provide power that is helpful for articulation of end effector 16 , rotation of endoscopic portion 12 , etc.
Conductive rings 18 are substantially circular in shape and disposed around distal portion 20 of handle assembly 10 . As can be appreciated, the shape and/or configuration of conductive rings 18 around distal portion 20 of handle assembly 10 helps allow substantially continuous contact between conductive rings 18 and electrical contacts 32 as endoscopic portion 12 is being rotated about longitudinal axis A-A with respect to handle assembly 10 . Thus, a complete 360° rotation is possible. Further, communication of power between motor 28 and electrical contact 32 is possible notwithstanding the rotational direction of endoscopic portion 12 with respect to handle assembly 10 . Additionally, it is envisioned that mechanical and/or electrical stops may be disposed on endoscopic portion 12 and/or distal portion 20 of handle assembly 10 to limit rotational displacement of endoscopic portion 12 .
While only one type of end effector 16 is illustrated in FIG. 1 , it is contemplated that several types of end effectors 16 (e.g., a pivotable cartridge assembly, end effectors including a substantially circular cartridge assembly, parallel approximating jaw members, configured for sequential firing of staples and/or configured for simultaneous firing of staples) may be used in connection with surgical instrument 100 and may be usable with different types of endoscopic portions 12 .
Referring additionally to FIG. 3 , the end effector 16 includes a cartridge assembly 40 and an anvil assembly 42 . Cartridge assembly 40 and anvil assembly 42 further define a pair of jaws. Cartridge assembly 40 houses a plurality of staples and a drive mechanism (not shown). An example of a drive mechanism is disclosed in U.S. patent application Ser. No. 10/700,250, filed on Nov. 3, 2003, the entire contents of which are hereby incorporated by reference. Anvil assembly 42 is movable in relation to cartridge assembly 40 between an open position spaced from cartridge assembly 40 and an approximated or clamped position in juxtaposed alignment with cartridge assembly 40 . End effector 16 may alternatively be arranged such that cartridge assembly 40 is movable in relation to anvil assembly 42 . Drive mechanism (not shown) is configured to eject the plurality of staples from the cartridge assembly 40 upon actuation from a drive rod 80 . The drive rod 90 is coupled through an actuation shaft 80 to the movable handle 52 .
Switch 60 ( FIG. 1 ) is configured to alternate the function of movable handle 52 between a grasping or “firing” mode and a “return” mode. In firing mode, end effector 16 is configured to operate as a grasping jaw mechanism, i.e., anvil assembly 42 is movable in relation to cartridge assembly 40 to grasp tissue therebetween and apply the fasteners therethrough. In return mode, end effector 16 is configured to operate as a releasing mechanism, i.e., anvil assembly 42 is movable in relation to cartridge assembly 40 to release the tissue.
Switch 60 includes a slide cam 62 . Switch 60 is configured to be engaged by the surgeon's finger to move slide cam 62 along an actuation shaft 80 within the handle assembly. As to be appreciated, alternatives to switch 60 are also contemplated, e.g., knobs, levers, depressible buttons, toggles, trigger assemblies, etc.
Handle assembly 10 includes a housing 11 fonned from a pair of molded half-sections 11 a and 11 b ( FIG. 2 ), which forms stationary handle 50 . Half-sections 11 a and 11 b are formed of a thermoplastic material, e.g., polycarbonate. Alternately, other materials having the requisite strength requirements may be used to form housing 11 , e.g., surgical grade metals. Housing 11 half-sections 11 a and 11 b are secured to each other using known fastening techniques, e.g., adhesives, welding, interlocking structure, screws, etc. Alternately, other fastening techniques may be used.
Referring to FIG. 1 , movable handle 52 is rotatably supported between housing half-sections 11 a and 11 b . A biasing member (not shown), e.g., a torsion spring, may be included to urge movable handle 52 away from stationary handle 50 to a non-compressed position. An advancement pawl 70 , as shown in FIG. 3 , is rotatably supported on movable handle 50 and is biased by a spring (not shown) towards the actuation shaft 80 . A return pawl 72 is also rotatably supported on movable handle 50 and is biased by a spring (not shown) towards the actuation shaft 80 .
Actuation shaft 80 is slidably supported between retracted and advanced positions within housing 11 and includes a distal end defining a recess 82 configured to rotatably receive the proximal end 92 of a drive rod 90 . Actuation shaft 80 includes a first toothed rack 84 and a second toothed rack 86 . Advancement pawl 70 has an engagement finger 70 a, which is biased by spring (not shown) towards toothed rack 84 of actuation shaft 80 . Return pawl 72 has an engagement finger 72 a, which is biased by spring (not shown) towards second toothed rack 86 of actuation shaft 80 .
Slide cam 62 is placed about actuation shaft 80 and is movable from a firing position and a return position by movement of switch 60 . In the firing position, the slide cam 62 is moved between the engagement finger 72 a of return pawl 72 and the second toothed rack 86 . When movable handle 52 is actuated while slide cam 62 is in a firing position, i.e., is pivoted towards stationary handle 50 against the bias of a torsion spring (not shown), engagement finger 70 a of advancement pawl 70 engages the first toothed rack 84 of actuation shaft 80 to advance actuation shaft 80 and drive rod 90 distally. As the drive rod 90 is advanced, the anvil assembly 42 moves toward the cartridge assembly 40 until the tissue therebetween is compressed and the drive mechanism 44 ejects the fasteners from the cartridge assembly 40 .
In the return position, the slide cam 62 is moved between the engagement finger 70 a of advancement pawl 70 and the first toothed rack 84 . When movable handle 52 is actuated while slide cam 62 is in a return position, i.e., is pivoted towards stationary handle 50 against the bias of a torsion spring (not shown), engagement finger 72 a of return pawl 72 engages the second toothed rack 86 of actuation shaft 80 to retract actuation shaft 80 and drive rod 90 proximally. As the drive rod 90 is retracted, the anvil assembly 42 moves away from the cartridge assembly 40 releasing the tissue.
Now referring to FIG. 4 , another embodiment of surgical instrument 200 includes a slide cam 262 connected to a lever 260 . Lever 260 acts similarly to switch 60 above to move the slide cam 262 from a firing position to a return position.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of various embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
Although being shown as an endoscopic surgical stapler, the present system may be used with any fastener applier known in the art.
It should be understood that the foregoing description is only illustrative of the present disclosure. Various alternatives and modifications can be devised by those skilled in the art without departing from the disclosure. Accordingly, the present disclosure is intended to embrace all such alternatives, modifications and variances. The embodiments described with reference to the attached drawing figures are presented only to demonstrate certain examples of the disclosure. Other elements, steps, methods and techniques that are insubstantially different from those described above and/or in the appended claims are also intended to be within the scope of the disclosure.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S. patent application Ser. No. 11/887,374, entitled COMBINED ACTIVE AND PASSIVE LEG PROSTHESIS SYSTEM AND A METHOD FOR PERFORMING A MOVEMENT WITH SUCH A SYSTEM, and filed Jul. 30, 2009, which is a national stage entry of International Patent Application No. PCT/SE2006/000445, entitled COMBINED ACTIVE AND PASSIVE LEG PROSTHESIS SYSTEM AND A METHOD FOR PERFORMING A MOVEMENT WITH SUCH A SYSTEM, and filed Apr. 18, 2006, the entireties of which are incorporated by reference herein.
BACKGROUND
[0002] 1. Field
[0003] The present invention relates generally to a method for a combined active and passive leg prosthesis system and a combined active and passive leg prosthesis system for replacing a missing lower extremity of an individual to perform a gait cycle (take a step) by the leg prosthesis system. The leg prosthesis system has at least one movable joint and a drive unit to drive the movable joint.
[0004] More specifically, the present invention concerns a leg prosthesis system intended for a person who has a leg amputated above or below the knee joint. Thus the system may comprise an articulated ankle joint or both an articulated knee joint and an articulated ankle joint.
[0005] 2. Description of the Related Art
[0006] A leg prosthesis system of the type stated above can be adjusted and used by wearers of a prosthesis at different amputation levels.
[0007] A person uses his entire body to perform a movement. A gait cycle, that is two steps, is divided into a support phase and a swing phase. The support phase is when the foot of the leg is in contact with the ground, and during the swing phase the foot swings freely in the air. In walking, one leg swings forward with a flexion in hip, knee and ankle joint while at the same time the arm on the opposite side swings forward. The arm on the same side swings backward and helps to increase the forward force and promotes balance. When the foot of the leg touches the ground, heel touching ground, the weight of the body is supported and the forward fall is braked. The leg supports the body and drives it forward until the next leg takes over in placing the heel on the ground.
[0008] If one or more joints and muscles are missing, in this case in lower extremities, there will be imbalance and more energy will be consumed. The more joints that are missing and the higher the amputation level, the more energy is required to perform a gait cycle.
[0009] A gait cycle, in this case for a leg prosthesis system, can be identified as the movement performed by leg prosthesis system from placing the heel on the ground to the next placing of the heel on the ground with the same leg.
[0010] A leg prosthesis system according to the invention can be used to facilitate different types of gait cycles for the prosthesis wearer, for instance to walk at varying speeds, to climb or descend stairs or walk on inclined surfaces.
[0011] With the leg prostheses that are available on the market, it is difficult or even impossible for a leg prosthesis wearer to perform certain types of gait cycles.
[0012] The leg prosthesis systems that are being sold today are completely passive, that is no external energy is supplied to the prosthesis in addition to the prosthesis wearer's kinetic energy. A passive prosthesis can only lock, dampen and decelerate a movement. With a good passive leg prosthesis system according to prior art technique, a prosthesis wearer can handle most everyday situations, such as sit down, stand, walk on flat ground and descend stairs and slopes.
[0013] However, the energy that can be supplied to a passive leg prosthesis system by the prosthesis wearer is in most cases not sufficient to perform more energy-consuming gait cycles, such as stand up from a sitting position, quick increase of speed or climb a staircase or a steep slope. Another problem is to ensure ground clearance to reduce the risk of stumbling.
[0014] The manufacture and development of active leg prosthesis systems has only started recently, that is prostheses comprising motors and power sources. By supply of power, the leg prosthesis system helps the prosthesis wearer to perform certain gait cycles such as climb a staircase.
[0015] The technique chosen to supply power in active leg prosthesis systems, according to prior art technique, has resulted in problems, such as high movement of inertia in moving the movable joints of the leg prosthesis system. All parts have to be driven when performing a gait cycle and the energy consumption in the leg prosthesis system will be high.
[0016] There is thus a need to improve prior art and many of the leg prostheses that are currently available on the market.
SUMMARY
[0017] An object of the present invention is to provide a leg prosthesis system which eliminates one of the problems described above in a simple and effective manner.
[0018] Another object of the invention is to provide a method of performing gait cycles with improved performance by means of a leg prosthesis.
[0019] The above objects and other objects that will be evident from the following description are achieved by a device and a method according to the claims.
[0020] A leg prosthesis system according to the invention comprises at least one movable joint which can be switched between being actively driven or being passively braked. Furthermore the leg prosthesis system comprises a control system for controlling the active and the passive unit in the movable joint. A number of transducers and sensors arranged on the leg prosthesis system supply input data to the control system, and a power source supplies power to control system, motors and transducers.
[0021] A leg prosthesis system according to the invention comprising control system, power source and transducers can be provided with an ankle joint comprising an active and a passive unit and/or a knee joint comprising an active and a passive unit.
[0022] The leg prosthesis system according to the invention can also be adjusted to a prosthesis wearer who lacks both lower extremities, that is who is double-leg-amputated. Each leg prosthesis system may, but need not, comprise one common or two separate or communicating control systems.
[0023] According to one aspect of the present invention, a combined active and passive leg prosthesis system is provided to replace a missing lower extremity of an individual to perform a gait cycle by means of the leg prosthesis system. The leg prosthesis system comprises at least one movable joint and an active drive unit to supply power and drive the movable joint. Moreover the active drive unit is disconnectable from driving relation with the movable joint. By the active drive unit being disconnectable, low moment of inertia can be achieved in the movable joint. The forward force in the natural swinging motion created by the wearer's body is then sufficient to move the joint. When the joint is disconnected from driving, it is possible to brake the movement of the joint when required. Braking of the movable joint performed by a passive brake unit may be varied in braking force and be varied from a completely unbraked (freely swinging) to a fully braked (locked) joint. The interaction between active driving and passive braking of a joint gives a prosthesis wearer a good possibility of performing gait cycles with improved performance. An active drive unit which can be run in two directions makes it possible to perform a movement in both directions of the joint if, in addition, it is possible to disconnect the active drive so as to perform a free movement of the joint which can be controlled by the passive brake unit. Active and passive movements are a natural part of the gait pattern, which means that a system having such possibilities can more easily imitate the energy-saving way of the human body to perform movements.
[0024] Preferably, the active drive unit of the leg prosthesis system is disconnected from driving relation with the movable joint during part of the gait cycle. For instance, the active drive unit can be disconnected during both the swing and the support phase.
[0025] Preferably, a passive brake unit acts on the movement of the joint when the active drive unit is disconnected from the joint. By using the passive brake unit when the active drive unit is disconnected, the energy-saving way of the human body to perform movements can be imitated.
[0026] Preferably, the leg prosthesis system according to the invention also comprises a control system adapted to control the active drive unit of the movable joint. The control system makes it possible to control direction, force and speed of the active drive unit. The control system also makes it possible to activate driving only at points of time when the leg prosthesis system needs supply of extra power.
[0027] Preferably, the control system according to the invention is also adapted to control the passive brake unit of the movable joint. A control system can be used to adjust the brake force from a completely unbraked (freely swinging) to a fully braked (locked) joint. If the control system controls both the active drive unit and the passive brake unit, a number of advantages can be achieved since the leg prosthesis system according to the invention can use the properties of both the active drive unit and the passive brake unit and also the possibility of switching between driving and braking the movable joint.
[0028] Preferably the leg prosthesis system comprises both a movable knee joint and a movable ankle joint. A prosthesis wearer who lacks a knee joint, that is who is amputated above the knee joint, needs a leg prosthesis which has both knee joint and ankle joint. A prosthesis wearer who lacks both lower extremities, that is who is double-leg-amputated, needs a leg prosthesis system with at least two movable joints.
[0029] Preferably, the knee joint and the ankle joint are each arranged with a disconnectable active drive unit and a passive brake unit as well as a common control system to control the movements of knee joint and ankle joint in a synchronized manner. In double amputation, two separate or communicating control systems may, but need not, be used. A leg prosthesis system which is made up in this manner can use active and passive techniques for both knee joint and ankle joint. When besides a control system coordinates the movement of the knee joint and the ankle joint, considerable improvements can be achieved compared with a completely passive prosthesis, but also compared with an active prosthesis which comprises a knee joint or a knee joint and an ankle joint which are active but not coordinated with a common control system.
[0030] Preferably the leg prosthesis system according to the invention comprises transducers for input data to the control system. Input data can be sent to the system from, for instance, a key set, transducers, sensors (speed, position, angle, pressure), nerve sensors etc.
[0031] Preferably, the knee joint and the ankle joint move by switching between the associated active drive unit and passive brake unit during a gait cycle.
[0032] A leg prosthesis system according to the invention with a movable knee joint and ankle joint which controls the direction, force and speed of the current control system for the active drive unit and the brake force for the passive brake unit in each joint independently of the other joint thus ensures an optimized and coordinated movement of the leg prosthesis system.
[0033] The control system may use information from the entire leg prosthesis system, for instance information from the knee joint when the ankle joint is to be controlled and vice versa.
[0034] According to one aspect of the present invention, a method is provided for performing a gait cycle with a combined active and passive leg prosthesis system, which replaces a lacking lower extremity of an individual. The leg prosthesis system comprises at least one movable joint and an active drive unit which supplies power and drives the movable joint. Moreover, the active drive unit is disconnected from driving relation with the movable joint during part of the gait cycle. By disconnecting the drive unit, it is, for instance, possible to use the natural swinging movement during the swing phase in walking. Thus the drive unit need not be adjusted to accomplish movements equivalent to free swinging. The active drive unit can instead be optimized for driving, and energy saving can be ensured since the drive unit is not activated during the entire time of use of the prosthesis.
[0035] Preferably the method comprises braking the movement of the joint, with a passive brake unit of the leg prosthesis system according to the invention, when the active drive unit is disconnected from the joint. When the active drive unit is disconnected and the passive brake unit is connected, the prosthesis can move freely by the forward force in the joint in question created by the wearer's body, or the movement of the joint can be braked.
[0036] Preferably the method comprises controlling of the drive unit and/or the brake unit of the movable joint by a control system of the leg prosthesis system according to the invention. By using a control system, it is possible to disconnect driving and/or activate the passive brake unit at the correct point of time or taking the outer circumstances into consideration. The braking in the leg prosthesis system is a property which advantageously is coordinated with the driving of the system to achieve a good result.
[0037] Preferably the method comprises supplying input data to the control system from transducers of the leg prosthesis system. Input data is sent, for instance, from a key set, transducers, sensors (which record speed, position, angle, pressure), nerve sensors etc.
[0038] The method preferably comprises controlling in a synchronized manner the movements of a knee joint and an ankle joint of the leg prosthesis system. The knee joint and the ankle joint each have a disconnectable active drive unit and a passive brake unit as well as a common control system. In a leg prosthesis with both knee joint and ankle joint, improved possibilities are achieved for the prosthesis wearer since a control system which is common to both joints can coordinate the movements of knee joint and ankle joint.
[0039] The knee joint and the ankle joint preferably move by switching between the associated drive unit and brake unit during a gait cycle.
[0040] Preferably the method comprises controlling, separately or in a communicating manner, the movements of at least two movable joints of leg prosthesis systems adjusted to a double-leg-amputated prosthesis wearer.
[0041] The control system may use information from the entire leg prosthesis system, for instance information from the knee joint when the ankle joint is to be controlled and vice versa.
[0042] The method preferably comprises driving and braking of knee joint and ankle joint, respectively, during a gait cycle.
BRIEF DESCRIPTION OF THE DRAWINGS
[0043] The invention will now be described in more detail with reference to the accompanying drawings, in which
[0044] FIG. 1 is a perspective view of a leg prosthesis system according to the invention,
[0045] FIG. 2 illustrates the support phase of a gait cycle on a flat surface,
[0046] FIG. 3 illustrates the swing phase of a gait cycle on a flat surface,
[0047] FIG. 4 illustrates the support phase of a gait cycle when climbing a staircase, dashed lines indicating a corresponding gait cycle with a passive/rigid foot,
[0048] FIG. 5 illustrates the swing phase of a gait cycle when climbing a staircase,
[0049] FIG. 6 illustrates the support phase and the swing phase of a gait cycle when descending a staircase,
[0050] FIG. 7 illustrates the support phase of a gait cycle when climbing a slope,
[0051] FIG. 8 illustrates the swing phase of a gait cycle when climbing a slope,
[0052] FIG. 9 illustrates the support phase of a gait cycle when descending a slope,
[0053] FIG. 10 is a side view in cross-section of a knee in an active straightening position,
[0054] FIG. 11 is a side view in cross-section of a knee in a passive braking position,
[0055] FIG. 12 is a side view in cross-section of a foot in an active position according to the invention.
DETAILED DESCRIPTION
[0056] FIG. 1 shows a leg prosthesis system 1 with both knee joint 2 and ankle joint 3 according to the invention and a method of performing a gait cycle with a leg prosthesis system. A prosthesis wearer can attach the prosthesis to the amputated leg by means of the leg-enclosing socket 13 . Furthermore the socket 13 is attached to the movable knee joint 2 in a suitable manner and the knee joint is connected to the ankle joint 3 by interconnecting elements 12 or the like. A foot prosthesis 14 is attached to the ankle joint 3 and can turn about the ankle joint 3 . Additional components that may be included in a leg prosthesis system are shock absorbers, angularly adjustable couplings etc.
[0057] Most of the people with an amputated leg have lost their leg below the knee joint. The present leg prosthesis system and/or method can be used by prosthesis wearers who need a prosthesis with both knee joint and ankle joint, but the invention can also be used for a prosthesis with only an ankle joint or only a knee joint. The leg prosthesis system and/or the method can also be used by prosthesis wearers who lack both lower extremities, that is who are double-leg-amputated and need a leg prosthesis system with at least two movable joints. One common or two separate and/or communicating control means may be used.
[0058] FIG. 2 shows the support phase for a gait cycle on a flat surface. When placing the heel on the surface, FIG. 2.1 , the body weight of the prosthesis wearer is applied to the leg prosthesis system. The knee joint then allows flexion and the foot is plantar flexed, FIG. 2.2 , that is the foot blade moves away from the lower leg. Body weight and muscular strength help to straighten knee joint and ankle joint to centered standing, FIG. 2.3 . In FIG. 2.4 , the foot blade is compressed and energy is returned in FIG. 2.5 . When performing this movement, from FIG. 2.1 to FIG. 2.5 , the leg prosthesis system is completely passive, passive braking of both ankle joint and knee joint. The joints are rotated by means of body weight and muscular strength from the remaining lower extremity. For extra power in the gait, for instance when walking faster, the active drive unit in the foot can be used in the position in FIG. 2.6 to push away.
[0059] FIG. 3 shows the swing phase in a gait cycle. FIG. 3.1 corresponds to FIG. 2.6 and when initiating a swing phase, FIG. 3.3 , the active part of the ankle joint performs a dorsal flexion, that is the foot blade moves towards the lower leg. This dorsal flexion occurs to give the prosthesis wearer ground clearance, a safe distance between the foot and the ground to prevent stumbling. A passive foot does not manage the dorsal flexion from FIG. 3.2 to FIG. 3.3 but this movement of the foot blade requires some kind of drive. The knee joint performs the swinging movement by using the forward force created by the wearer's body, and the passive braking controls the movement. When performing this movement, from FIG. 3.3 after the dorsal flexion to FIG. 3.5 , the leg prosthesis system is completely passive, passive braking of both ankle joint and knee joint. To provide extra force to the step, for instance when walking faster, the active drive unit in the knee joint can be used in the position in FIG. 3.4 to straighten the knee joint and move the lower leg forward more quickly.
[0060] To climb a staircase or slope, as illustrated in FIG. 4 , FIG. 5 , FIG. 7 and FIG. 8 , it is important for the knee joint and the ankle joint to cooperate. More energy is required in climbing, which means that cooperating active drive of both ankle joint and knee joint can advantageously help to perform the movement.
[0061] When descending a staircase or slope, as illustrated in FIG. 6 and FIG. 9 , the passive braking in both knee joint and ankle joint cooperates.
[0062] FIG. 4 to FIG. 6 illustrate the climbing of a staircase. FIG. 4 shows the support phase when climbing a staircase. In FIG. 4.1 the foot is positioned on the step, and balance is achieved. The leg prosthesis system and/or the use of the method according to the invention then push the prosthesis wearer upwards, FIG. 4.2 , to centered standing, FIG. 4.3 . The control system makes it possible for the knee joint and the ankle joint to cooperate. The active drive unit in the knee joint strives to straighten the knee joint while at the same time the active drive unit in the ankle joint presses the front of the foot towards the ground, FIG. 4.2 . In this manner, the ankle joint helps to straighten the knee joint, thereby reducing the energy consumption.
[0063] FIG. 4 illustrates the consequences of a passive foot, dashed lines, in combination with an active knee joint. The passive foot gives a higher knee joint position and the gait will be higher than it need be, and it will be more difficult and require more energy for the user to raise himself up on the step. The contact point of the passive foot on the step is moved forwards compared with a foot which can perform a dorsal flexion, which results in also the center of gravity of the body having to be moved forwards. The solid lines indicate how climbing a staircase can be performed using a leg prosthesis according to the invention.
[0064] FIG. 5 illustrates the swing phase when climbing a staircase. Also in this case the active drive units in the knee joint and the ankle joint are used. To prevent the prosthesis wearer from hitting the step with his foot and stumbling in the swing phase when climbing a staircase, it is important that the knee joint and ankle joint create a safe distance to the staircase. This is done by the active drive of the knee joint bending the joint and the drive of the ankle joint performing a dorsal flexion of the foot, FIG. 5.1 . The leg prosthesis system according to the invention has then created a safe distance to the staircase and also a good starting position for positioning for the next gait. FIG. 5 shows the consequences of a completely passive system, dashed lines. The knee joint does not bend the foot away, and the foot instead bumps into the staircase.
[0065] FIG. 6 illustrates the descending of a staircase. Here both knee joint and ankle joint are mainly passive. The movement, FIG. 6.1 to FIG. 6.3 , brakes the fall of the body by means of the passive brake units in knee joint and ankle joint. The dashed lines indicate the consequences of a passive foot which is not capable of performing a dorsal flexion. The active drive units can optionally be used to help straighten knee joint and ankle joint in the swing phase.
[0066] FIG. 7 to FIG. 9 illustrate walking on a very sloping surface. The leg prosthesis system according to the invention then functions in the same way as when climbing a staircase. The angle of knee joint and ankle joint is the only thing that distinguishes the climbing of a staircase from walking on a very sloping surface. When walking on a slightly sloping surface, the walking can be more resembled to walking on flat ground.
[0067] FIG. 4 , FIG. 5 , FIG. 7 and FIG. 8 illustrate ordinary situations which require much energy to be managed. By letting the leg prosthesis system 1 cooperate with the prosthesis wearer's body and existing lower extremities, it is possible to imitate the energy-saving way of the human body to perform the movement. For minimum consumption of energy, all joints in the lower extremities are allowed to cooperate, and the remaining stump of the prosthesis wearer can cooperate with the at least one movable joint in the leg prosthesis system. The leg prosthesis system should supplement the prosthesis wearer and should preferably, but not restrictively, be controlled by him or her.
[0068] With a leg prosthesis system 1 and/or a method according to the invention, the disconnectable active drive unit 4 , 4 ′ of a knee joint or ankle joint makes it possible for the system and the method to use a combination of active and passive operation. The control system 15 can select the optimal method of performing a movement. The knee joint 2 can be active while the ankle joint 3 is passive and vice versa. For example, the knee joint 2 can perform the swinging movement in the swing phase using only the passive brake unit 2 while the ankle joint 3 uses its active drive unit for dorsal flexion of the foot in order to create extra ground clearance.
[0069] FIG. 10 and FIG. 11 are side views in cross-section of a knee joint which, for instance, may be included in the leg prosthesis system 1 . The socket 13 is connected to the movable knee joint 2 which in turn is connected to a hydraulic piston 9 via a link arm 10 . FIG. 11 shows how the piston 9 is moved when the knee joint is angled. FIG. 10 shows a knee joint 2 according to the invention in its active state with a drive unit 4 , a brake unit 5 and a control system 15 . In this embodiment, the brake unit 5 involves throttling of the hydraulic oil which provides braking/dampening of the movement of the joint. The battery 11 drives the hydraulic pump 6 of the drive unit 4 via a motor (not shown) for operating the valve 8 of the brake unit 5 . The battery 11 also drives the control system 15 and transducers and sensors (not shown) of the leg prosthesis system 1 . The control system 15 in turn controls the drive unit 4 and the brake unit 5 and receives input data from transducers and sensors; in addition the control system 15 coordinates the movements of the knee joint 2 and the ankle joint 3 .
[0070] For activation of the drive unit 4 , according to FIG. 10 , the hydraulic pump 6 is started, the pressure increases on one side of the pump 6 and, via one of the ducts which open adjacent to the spring 17 , the valve cone 7 is pressed aside and the duct system of the drive unit will communicate with the cylinder 16 where the piston 9 works and thus the pump 6 actuates the piston 9 in one or the other direction. When the active drive unit 4 is activated, the valve 8 in the passive brake unit 5 should be completely closed to be able to use the maximum efficiency of the hydraulic pump 6 . The active drive unit can drive the knee joint 2 in both directions, in the direction towards a straightened knee joint and in the direction to bend the knee joint. In FIG. 10 , the active drive unit acts to straighten the knee joint 2 . When the piston 9 is moved in the cylinder 16 , it acts on the link arm 10 which in turn acts on the knee joint 2 to perform a movement. Alternative types of driving and motors can be used for the leg prosthesis system other than those mentioned above.
[0071] According to FIG. 11 the drive unit 4 is disconnected by the hydraulic pump 6 being switched off. The pressure decreases and the spring 17 presses the valve cone 7 back to its rest position, that is the valve cone 7 closes the ducts to the drive unit 4 . The brake unit 5 is activated when the drive unit 4 is disconnected. A movement of the knee joint 2 actuates the piston 9 via the link arm 10 , the hydraulic oil in the cylinder 16 is pressed through the valve 8 of the brake unit 5 and the degree of braking/dampening can be adjusted by varying the opening degree of the valve 8 . The braking can be varied in brake force and can be varied from a completely unbraked (freely swinging) to a completely braked (locked) knee joint 2 .
[0072] The foot 14 with the ankle joint 3 according to FIG. 12 is shown in its active state and functions similarly to the knee joint according to FIG. 10 and FIG. 11 . To activate the drive unit, the hydraulic pump 6 ′ is started, the pressure is increased on one side of the pump 6 ′ and via one of the ducts which open adjacent to the spring 17 ′, the valve cone 7 ′ is pressed aside and the duct system of the drive unit will communicate with the cylinder 16 ′ where the piston 9 ′ works. In this manner, the pump 6 ′ actuates the piston 9 ′ in one or the other direction. When the active drive unit 4 ′ is activated, the valve 8 ′ in the passive brake unit 5 ′ should be completely closed to be able to use the maximum efficiency of the hydraulic pump 6 ′. The piston 9 ′ actuates the link arm 10 ′ which in turn actuates the ankle joint 3 to perform a movement of the foot 14 relative to the interconnecting element 12 . The drive unit 4 ′ is disconnected by the hydraulic pump 6 ′ being switched off. The pressure decreases and the spring 17 ′ presses the valve cone 7 ′ back to its rest position, that is the valve cone 7 ′ closes the ducts to the drive unit 4 ′. The brake unit 5 ′ in FIG. 12 is then activated; in normal working conditions the hydraulic pump 6 ′ is then switched off.
[0073] A movement of the ankle joint 3 in the passive state actuates the piston 9 ′ via the link arm 10 ′, the hydraulic oil in the cylinder 16 ′ is pressed through the valve 8 ′ of the brake unit 5 ′ and the brake force can be adjusted by varying the opening degree of the valve 8 ′. The braking can be varied in brake force and can be varied from a completely unbraked (freely swinging) to a fully braked (locked) ankle joint 3 .
[0074] If the leg prosthesis system 1 merely comprises a foot prosthesis 3 according to the invention, for instance at an amputation level below the knee joint, the foot prosthesis still needs a battery 11 ′ and a control unit 15 ′ which may then be arranged, for instance, around the interconnecting element or on a leg-enclosing socket.
[0075] It goes without saying that the invention should not be considered limited to the embodiments described above and illustrated in the drawings, with the described variants and alternatives, and can be modified additionally in various ways within the scope of the appended claims.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to, and benefit of, U.S. Provisional Application Ser. No. 61/263,906, filed Nov. 24, 2009, the disclosure of which is hereby incorporated by reference in its entirety.
BACKGROUND
[0002] 1. Technical Field
[0003] The present disclosure relates to a seal for use in a surgical procedure. More particularly, the present disclosure relates to a seal anchor member adapted for insertion into an incision in tissue, and, for the sealed reception of one or more surgical objects such that a substantially fluid-tight seal is formed with both the tissue and the surgical object, or objects.
[0004] 2. Background of Related Art
[0005] Today, many surgical procedures are performed through small incisions in the skin, as compared to the larger incisions typically required in traditional procedures. Generally, such procedures are referred to as “endoscopic”, unless performed on the patient's abdomen, in which case the procedure is referred to as “laparoscopic”. Throughout the present disclosure, the term “minimally invasive” should be understood to encompass both endoscopic and laparoscopic procedures.
[0006] During a typical minimally invasive procedure, surgical objects, such as surgical access devices (e.g., trocar and cannula assemblies) or endoscopes, are inserted into the patient's body through an incision in tissue or into a naturally occurring orifice (e.g., mouth, anus, or vagina). In general, prior to the introduction of the surgical object into the patient's body, insufflation gases are used to enlarge the area surrounding the target surgical site to create a larger, more accessible work area. Accordingly, the maintenance of a substantially fluid-tight seal is desirable so as to prevent the escape of the insufflation gases and the deflation or collapse of the enlarged surgical site.
[0007] To this end, various valves and seals are used during the course of minimally invasive procedures and are widely known in the art. However, a continuing need exists for a seal anchor member that can be inserted directly into the incision in tissue and that can accommodate a variety of surgical objects while maintaining the integrity of an insufflated workspace.
SUMMARY
[0008] Disclosed herein is a seal anchor member that is adapted and configured to transition between a first state defining a first length and a second state defining a second length. In particular, the seal anchor member includes a leading portion and a trailing portion. Disposed between the leading and trailing portions is an intermediate portion that is transitionable between the first and second states. A biasing member is disposed in the intermediate portion for transitioning the intermediate portion between the first and second states. The biasing member may be a spring. The biasing member may be biased towards an expanded state. For example, subsequent to compressing the seal anchor member along the longitudinal axis, the seal anchor member may begin to transition back toward an expanded state.
[0009] The seal anchor member may include at least one longitudinally extending lumen that extends through the leading and trailing portions of the seal anchor member. The at least one lumen may be configured to receive therein an object in a substantially sealed relation. In an embodiment, the seal anchor member may include one or more lumens that are coaxial with the central longitudinal axis of the seal anchor or are parallel to the longitudinal axis of the seal anchor. The biasing member may be disposed longitudinally about the one or more lumens. In an embodiment, the biasing member may be disposed on or within an outer surface of the intermediate portion.
[0010] An example of a seal anchor member may be found in U.S. Pat. Pub. 2009/0093752, the entire contents of which are incorporated herein by reference. The various aspects of the present disclosure will be more readily understood from the following detailed description when read in conjunction with the appended figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] Various embodiments of the present disclosure are described hereinbelow with reference to the drawings, wherein:
[0012] FIG. 1 is a front perspective view of a seal anchor member in accordance with the principles of the present disclosure shown in an expanded condition illustrating a seal anchor member positioned relative to body tissue;
[0013] FIG. 2 is a front perspective view of the seal anchor member of FIG. 1 shown in a first state;
[0014] FIG. 2A is a front perspective view of the seal anchor member of FIG. 1 shown in a second state;
[0015] FIG. 3 is a top perspective view of an embodiment of a seal anchor member; and
[0016] FIG. 3A is a cross-sectional view of the seal anchor member taken along section line 3 A- 3 A of FIG. 3 .
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0017] In the drawings and in the description which follows, in which like reference numerals identify similar or identical elements, the term “proximal” will refer to the end of the apparatus that is closest to the clinician during use, while the term “distal” will refer to the end that is farthest from the clinician during use, as is traditional and known in the art.
[0018] With reference to FIGS. 1-2A , a seal anchor member 100 for use in minimally invasive surgical procedures will now be described. The seal anchor member 100 is configured and adapted to be inserted within tissue tract 12 defined by tissue surfaces 14 formed in tissue “T”, e.g., an incision or a naturally occurring orifice (e.g., mouth, anus, or vagina). Seal anchor member 100 defines a longitudinal axis “A” and has respective proximal and distal ends 102 , 104 and an intermediate portion 106 disposed between the proximal and distal ends 102 , 104 .
[0019] As depicted in FIGS. 1-2A , proximal and distal ends 102 , 104 define substantially planar surfaces. However, embodiments are also contemplated herein in which either or both of proximal and distal ends 102 , 104 define surfaces that are substantially concave or convex to assist in the insertion of seal anchor member 100 within tissue tract 12 . Intermediate portion 106 defines a radial dimension “R” and extends longitudinally between the proximal and distal ends 102 , 104 to define an axial dimension or length “L”. As shown in FIGS. 1-2A , the radial dimension “R” of intermediate portion 106 varies along the length “L”, i.e., the cross-sectional dimension may vary long length “L”, to facilitate anchoring of the seal anchor member 100 within tissue “T”. However, in an embodiment of the seal anchor member 100 , the radial dimension “R” may remain substantially uniform along the length “L”.
[0020] The radial dimension “R” of intermediate portion 106 is appreciably less than the respective diameters D 1 , D 2 of proximal and distal ends 102 , 104 such that seal anchor member 100 defines an “hour-glass” shape or configuration to assist in anchoring seal anchor member 100 within tissue “T”. However, in an alternate embodiment, the radial dimension “R” of intermediate portion 106 may be substantially equivalent to the respective diameters D 1 , D 2 of proximal and distal ends 102 , 104 . In cross-section, intermediate portion 106 may exhibit any suitable configuration, e.g., substantially circular, oval, or oblong.
[0021] Seal anchor member 100 includes a port 101 disposed about a central longitudinal axis “A” and will be described in more detail below. It is to be understood that in alternative embodiments, port 101 may be positioned differently, e.g., not coaxial about central longitudinal axis “A” and the seal anchor member 100 may include a plurality of ports. In addition, the seal anchor 100 may be devoid of any port.
[0022] Port 101 in the absence of a surgical object inserted therein is configured and adapted to prevent the escape of insufflation gas through the port 101 . For example, the port 101 may be a slit extending the longitudinal length of the seal anchor member 100 through the proximal and distal ends 102 , 104 . Alternatively, port 101 may define an opening within the seal anchor member 100 having an initial open state having a first inner dimension and upon the introduction of a surgical object, the port 101 transitions to a second state having a second inner dimension configured and adapted to accommodate the surgical object such that a substantially fluid-tight seal is formed therewith by substantially approximating the size and shape of the surgical object to inhibit the escape of insufflation gas through the port 101 in the presence of the surgical object.
[0023] The seal anchor member 100 is configured and adapted to transition between a first state ( FIG. 2 ) and a second state ( FIG. 2A ) to facilitate insertion of the seal anchor member 100 within tissue “T”. As shown in FIGS. 1-2A , the seal anchor member 100 includes a biasing member “S 1 ”, e.g., a spring, that facilitates the transition between a first expanded state shown in FIG. 2 in which the seal anchor member 100 has a length L 1 and a second collapsed state shown in FIG. 2A in which the seal anchor member 100 has a length L 2 . The biasing member “S 1 ” is biased towards the expanded state as shown in FIG. 2 . A surgeon may collapse the seal anchor member 100 such that the seal anchor member 100 has a collapsed length L 2 . Subsequent to insertion of the seal anchor member 100 , biasing member S 1 will facilitate transition back to the expanded condition in which the seal anchor member has a length L 1 . The seal anchor member 100 will therefore transition toward the expanded condition. The biasing member “S 1 ” is positioned within the seal anchor member 100 such that the biasing member “S 1 ” does not interfere with the function of port 101 . It is noted that in other embodiments, the seal anchor member 100 may be biased toward a collapsed state.
[0024] In an alternative embodiment shown in FIGS. 3-3A , a seal anchor member 200 having an intermediate portion 206 is shown. A biasing member “S 2 ” may be disposed on or within a surface 206 a, i.e., the outer wall, of an intermediate portion 206 extending between proximal rim (trailing end) 210 and distal rim (leading end) 212 . Biasing member “S 2 ” is configured and adapted to be biased in a direction along longitudinal axis “B” to facilitate a transition between an expanded first state and a collapsed second state. The seal anchor member 200 may include a plurality of ports 208 secured to the intermediate portion 206 by connective members 214 such that the longitudinal portion of the ports 208 remain substantially constant with respect to the respective proximal and distal rims 210 , 212 during insertion and removal of the surgical object.
[0025] It is contemplated that biasing members S 1 , S 2 may be formed from any material and have any configuration such that biasing members S 1 , S 2 will have an internal biasing force. For example, biasing members S 1 , S 2 may be a coiled wire and may be formed from a shape memory material, e.g., nitinol, such that biasing members S 1 , S 2 provide a bias in a particular direction to facilitate either the compression or expansion of seal anchor members 100 , 200 .
[0026] Although the illustrative embodiments of the present disclosure have been described herein with reference to the accompanying drawings, the above description, disclosure, and figures should not be construed as limiting, but merely as exemplifications of particular embodiments. It is to be understood, therefore, that the disclosure is not limited to those precise embodiments, and that various other changes and modifications may be effected therein by one skilled in the art without departing from the scope or spirit of the disclosure.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of U.S. Ser. No. 10/108,326, filed Mar. 28, 2002, which claims priority to U.S. Provisional Patent Application Serial No. 60/280,409, filed Mar. 30, 2001, each of which is incorporated by reference herein.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
BACKGROUND OF THE INVENTION
[0003] Soybeans are a major grain crop valued for the high levels of oil and protein found in soybean seed. Soybean breeding has resulted in significant improvements in yield potential, stability of yield, adaptation of the species to mechanical harvest, and yield protection through improved disease resistance.
[0004] Due to the nature of plant science agriculture, broadly defined as a manipulation of available plant resources to meet the needs of the growing human population, the environment in which plants are grown for agricultural production continuously offers new obstacles to agricultural production. Each new cultivar or variety released to agricultural production is selected for the purpose of increasing yield resulting from increased disease resistance to prevalent diseases, or from direct or indirect improvement in yield potential or efficiency of production. Development of stable, high yielding cultivars with superior characteristics is an ongoing goal of soybean breeders.
[0005] There is a need in the art for a novel soybean cultivar and soybean seed.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides a soybean seed designated 11939-40, wherein a sample of said seed has been deposited under ATCC Accession No. XXXXX.
[0007] In another aspect, the present invention provides a soybean plant, or a part thereof, produced by growing seed designated 11939-40, or a soybean plant having the characteristics of a plant produced by growing seed designated 11939-40, or pollen or an ovule of a soybean plant according to the present invention.
[0008] The present invention provides a tissue culture of regenerable cells from a plant, or parts thereof, produced by growing seed designated 11939-40, and a soybean plant regenerated from the tissue culture.
[0009] The present invention also provides a method for developing a soybean plant in a soybean breeding program using plant breeding techniques, comprising using a soybean plant, or part thereof, produced by growing seed designated 11939-40 as a source of breeding material.
Definitions
[0010] In the claims, descriptions and tables that follow, numerous terms are used and are defined as follows:
[0011] Flower color: Modern soybeans are characterized by two major flower colors, purple or white. Some cultivars are heterogeneous for flower color whereby some plants have purple flowers and some have white.
[0012] Leaflet shape: The leaflet may be broad or narrow and may be ovate or oval in shape.
[0013] Plant habit refers to stem termination in soybeans and the resultant differences in flower production. Indeterminate varieties continue to grow during the reproductive phase, producing new branches and nodes after flowering is well underway. Determinate varieties tend to delay the onset of flowering somewhat, and limit new node and branch development after flowering has been initiated.
[0014] Pubescence relates to the plant trichomes or hairs found on the stems, leaves and pods of soybeans.
[0015] Pubescence color in modem soybeans may be tawny, gray or light tawny.
[0016] Pod color refers to the color of the mature pod wall, as distinct from the color of the pubescence, and in modem soybeans, may be brown or tan.
[0017] Hilum refers to the point of attachment of soybean seed to maternal tissue.
[0018] Hilum color in modern soybeans may be black, brown, yellow, gray, buff, or imperfect black.
[0019] Soybean emergence scores rate the ability of the seedlings to emerge from the soil. A visual score of 1 to 5, taken 10-15 days after planting, is used whereby a score of 1 indicates an excellent emergence vigor and early growth, an intermediate score of 2.5 indicates average ratings, and a 5 score indicates a very poor emergence vigor and early growth.
[0020] Plant height is measured from the top of soil to top node of the plant in any convenient unit of length (i.e., inches, centimeters). For the data presented herein, plant height was measured just prior to harvest and is expressed in inches.
[0021] Lodging resistance relates to the stature of the plant relative to the ground. Lodging resistance is rated on a scale of 1 to 5. A score of 1 is given to an erect plant. A score of 2.5 is given to a plant that is leaning at a 45-degree angle relative to the ground. A score of 5 indicates a plant lying on the ground.
[0022] Maturity date is the date when 95% of pods have turned color from green color to their mature brown or tan color. The maturity date is counted in days and is calculated from January 1.
[0023] Maturity group refers to an industry division of groups of varieties based on the zones in which the varieties are adapted. Soybeans mature differentially in response to day-length and thus to latitude where grown. In the soybean production areas of the United States, for example, the northernmost production region of northern Minnesota is planted to soybeans that mature under very long day-lengths during early summer. In the southernmost production regions of the Southeast, soybeans that mature from the influence of short day-length during early summer are grown. Those adapted to northern day-lengths are classified as early-maturing, those adapted to the southern regions are classified as late-maturing. Maturity groups include very long day length varieties (000, 00, 0) and extend to very short day length varieties (VII, VII, IX, X). For example, maturity group I soybean cultivars are typically grown in southern Minnesota, whereas maturity group IV soybean cultivars are typically group in southern Illinois.
[0024] Relative maturity: Within maturity groups, a more precise maturity assignment is given that subdivides each maturity group into tenths. For example, a relative maturity of 3.3 is assigned to a late early maturity group III soybean cultivar.
[0025] Shattering refers to pod dehiscence prior to harvest resulting in a loss of mechanically harvestable seed. Pod dehiscence involves seeds falling from the pods to the soil. This is visually scored with a 1 to 5 scale comparing all genotypes within a given test. A score of 1 means pods have not opened and no seeds have fallen out. A score of 2.5 indicates approximately 50% of the pods have opened, with seeds falling to the ground and a score of 5 indicates 100% of the pods are opened.
[0026] Yield refers to the yield of seed harvested from a soybean crop. Yield data presented herein is expressed as bushels of seed/acre and is the actual yield of the grain at harvest.
[0027] Phytophthora tolerance to Phytophthora root rot, caused by the fungus, Phytophthora megasperma var. sojae, is rated on a visual scale of 1 to 5, with a score of 1 being the highest tolerance ranging down to a score of 5 which indicates the plants have no tolerance to Phytophthora. The visual score is based on the amount of disease-induced stunting of above-ground growth and is taken during the period 3-5 weeks prior to harvest.
[0028] Brown Stem Rot (BSR) resistance is visually scored from 1 to 5 based on interveinal leaf chlorosis (yellowing) and necrosis due to brown stem rot, which is caused by the fungus, Phialophora gregata. A score of 1 indicates no symptoms. Visual scores range to a score of 5 that indicates severe symptoms of interveinal leaf chlorosis and necrosis. Plants receiving scores of 1.0-1.6 are classified as resistant; plants receiving scores of 1.7-2.0 are classified as moderately resistant.
[0029] Sclerotinia Stem Rot (SSR) is a soil-borne fungal disease that causes above-ground disease in soybeans. Plants are infected via discharged ascospores that successfully germinate and infect through soybean structures such as flower petals. Colonization of stem tissue ultimately results in loss of yield potential. Cultivars are rated using prevalence and severity scores and converted into an estimated percent yield loss that can be used for comparison to known resistant or susceptible cultivar standards.
[0030] Soybean Cyst Nematode (SCN) resistance is based on a comparison of reproduction rates to a known susceptible cultivar as described by Schmitt et al. (Crop Sci. 32:275-277, 1992), which is incorporated by reference herein. A cultivar with a 0-10% percent reproductive rate compared to a known susceptible cultivar is classified as resistant (R); a cultivar with an 11-30% reproductive rate compared to a known susceptible cultivar is classified as moderately resistant (MR); a cultivar with an 31-59% reproductive rate compared to a known susceptible cultivar is classified as moderately susceptible (MS).
[0031] Iron-Deficiency Chlorosis (IDC) results when soybeans lack adequate iron. A visual score taken 25-30 days after planting is used to rate iron-deficiency chlorosis. A score of 1 indicates no stunting of the plants or chlorosis of the leaves, and a score of 5 indicates the plants are dead or dying as a result of iron-deficiency chlorosis. A score of 2.5 means plants have intermediate health with some leaf chlorosis.
DETAILED DESCRIPTION OF THE INVENTION
[0032] This invention relates to a soybean cultivar designated 11939-40 which was developed by single plant selection from another soybean cultivar, 11939, which was disclosed and claimed in U.S. Ser. No. 10/108,326. Soybean cultivar 11939-40 differs from its “mother” cultivar, 11939, in more than one important characteristic, as described below.
[0033] A single plant selection from soybean cultivar 11939 (developed as described in detail in U.S. Ser. No. 10/108,326) was made in a winter nursery in South America and grown in a progeny row at Gilbert, IA in plot OMR9667-34 in 2000. Seed gathered from this progeny row was used for agronomic and yield trial evaluations in subsequent seasons, and named 11939-40 on Jul. 30, 2001. This new soybean cultivar was characterized for important morphological, agronomic and performance qualities in evaluation trials, greenhouse studies, and disease nurseries. Soybean cultivar 11939-40 has uniformity and stability of its morphological and other characteristics. The variety description information (Table I) provides a summary of characteristics of soybean cultivar 11939-40 plant characteristics. As used herein, “a soybean plant having the physiological and morphological characteristics of soybean cultivar 11939-40” is a plant having the characteristics set forth in Table 1.
[0034] Soybean cultivar 11939-40 differs from cultivar 11939 in that 11939-40 breeds true for pure purple flower color. The soybean cultivar 11939-40 does not differ significantly from 11939 in important agronomic characteristics such as lodging resistance and plant height (Table 2). In Table 3, the yield and maturity date of soybean cultivars 11939-40 and 11939 are compared. As can be seen in Table 3, the soybean cultivar 11939-40 was found to mature one day later than soybean cultivar 11939 in three years of replicated, comparative studies. Therefore, 11939-40 is characterized as a maturity group II soybean cultivar with a relative maturity of 2.3, whereas 11939 is a maturity group II soybean cultivar with a relative maturity of 2.1 (Table 1). As can be seen in Table 3, a statistically significant difference (as quantified by a paired T test at a P=0.10 level of probability) exists in yield between soybean cultivar 11939-40 and cultivar 11939. Soybean cultivar 11939-40 has a nearly 1.5 bu/ac improved yield over that of cultivar 11939.
TABLE 1 VARIETY DESCRIPTION INFORMATION FOR 11939-40 Seed coat color: Yellow Hilum color: Black Leaflet size: Medium Leaflet color: Medium-green Leaflet shape: Ovate Flower Color: Purple Plant habit: Indeterminate Pubescence color: Light tawny Pod color: Brown Maturity group: II Relative maturity: 2.3 Phytophthora Root Rot resistance: plants have one of three genotypes, Rps 1 k Rps 2 k , Rps 1 k rps 1 , or rps 1 rps 1 and depending on the genotype, may be resistant or susceptible for races 1, 3, and 4 Brown Stem Rot ( Phialophora gregata ): Resistant Soybean Cyst Nematode Disease: Moderately susceptible Iron Deficiency Chlorosis Tolerance: 2.6 Roundup ™ Herbicide: Resistant
[0035] [0035] TABLE 2 Comparison of agronomic properties of soybean cultivars 11939- 40 and 11939. Years Cultivar Lod PRR Tol SSR-% IDC HT 3 11939-40 1.5 2.9 18 3.7 31 11939 1.5 2.7 9 3.4 33
[0036] [0036] TABLE 3 Summary of yield and maturity data of soybean cultivar 11939- 40 versus 11939. Years Cultivar Reps Yield Mat Days 3 11939-40 146 53.1* 264 11939 51.8 263
[0037] The present invention contemplates using the 11939-40 soybean plant, or part thereof, or a soybean plant having the physiological and morphological characteristics of the 11939-40 soybean plant, as a source of breeding material for developing a soybean plant in a soybean breeding program using plant breeding techniques. Plant breeding techniques useful in the developing soybean plants include, but are not limited to, single seed descent, modified single seed descent, recurrent selection, reselection, mass selection, bulk selection, backcrossing, pedigree breeding, mutation breeding, restriction fragment length polymorphism enhanced selection, genetic marker enhanced selection, and transformation. Plant breeding techniques are known to the art and have been described in the literature. For example, see U.S. Pat. No. 6,143,954, which, along with the references cited therein, is incorporated by reference herein.
[0038] As used herein, the term “plant” includes plant cells, plant protoplasts, plant cell tissue cultures from which soybean plants can be regenerated, plant calli, plant clumps, and plant cells that are intact in plants or parts thereof. “Plant part” includes, but is not limited to, embryos, pollen, ovules, seeds, flowers, pods, leaves, roots, root tips, anthers, and the like.
[0039] One may obtain soybean plants according to the present invention by directly by growing the seed of 11939-40 or by any other means. A soybean plant having all of the physiological and morphological characteristics of 11939-40 can be obtained by any suitable means, including, but not limited to, regenerating plants or plant parts from tissue culture or cuttings. The scope of the present invention is not limited by the method by which the plant is obtained.
Deposit Information
[0040] Seed from soybean cultivar 11939-40, disclosed above and recited in the appended claims, was deposited with the American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Virginia 20110 on ______, 2004.
[0041] The present invention is not limited to the exemplified embodiments, but is intended to encompass all such modifications and variations as come within the scope of the following claims.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit of priority to U.S. Provisional Patent Application No. 61/116,955, filed on Nov. 21, 2008, the content of which is incorporated herein by reference in its entirety. This application also relates to U.S. patent application Ser. No. 12/138,348 (Attorney Docket No. USGINZ05600), filed Jun. 12, 2008, the content of which is also incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods and apparatus for managing one or more instruments and/or tools used during endoscopic diagnostic and therapeutic procedures. More particularly, the present invention relates to methods and devices used to facilitate instrument management and use during procedures where flexible endoscopic instruments are advanced into a patient body via one or more natural orifices or other access ports.
BACKGROUND OF THE INVENTION
[0003] Endoscopic procedures and surgery typically entail the advancement and use of one or more instruments through the natural orifices and/or other access ports of a patient body and through the tortuous endoscopic pathways to reach the tissue regions of interest. Even procedures performed in body spaces within the patient may entail entry and advancement through one or more openings created in the patient body to gain entry into the desired body space, e.g., entry through a percutaneous opening or a gastrotomy to gain entry into the peritoneal space of the patient.
[0004] Because endoscopic surgery may involve the use of multiple instruments through a single conduit into the patient body, efficient management and use of these instruments may be difficult in part not only because of the number of instruments utilized, but also because these multiple instruments typically converge from a single conduit, which may be limited by the cross-sectional profile of the body lumen, organ, orifice, passageway, etc., in which the conduit is disposed. At the same time, advances in therapeutic endoscopy have led to an increase in the complexity of endoscopic operations attempted, as well as the complexity of tools advanced through the working lumens of these conduits.
[0005] Because of the number of instruments which converge typically from a single conduit, difficulties may arise in effectively handling and managing the placement, positioning, and use of these multiple instruments in an effective and safe manner.
[0006] For example, flexible endoscopes and flexible endoscopic instruments provide the ability for an operator to intubate the patient and to provide therapy to the internal anatomy by way of non-straight access pathways. Typical endoscopes have the ability to steer at the tip and provide light and visualization, gas insufflation, and lens rinsing. Such endoscopes will typically include one or two instrument channels. These instrument channels include an angled interface on the handle of the endoscope having a bend of about 45 degrees on a relatively short section of the handle. One result of this configuration is that any instrument that is to be inserted into the endoscope instrument channel must include a shaft that is flexible over its entire length.
[0007] Accordingly, there is a need for methods and devices for facilitating the introduction and management of all the instruments advanced through the relatively small conduits for performing endoscopic procedures.
SUMMARY OF THE INVENTION
[0008] An endoscopic tissue manipulation assembly may comprise, at least in part, a distal end effector assembly disposed or positionable at a distal end of a flexible and elongate body. Examples are described in further detail in U.S. Pat. Pub. No. 2005/0272977 A1, which is incorporated herein by reference in its entirety. A handle assembly may be connected to a proximal end of the elongate body and include a number of features or controls for articulating and/or manipulating both the elongate body and/or the distal end effector assembly. The elongate body may optionally utilize a plurality of locking or lockable links nested in series along the length of the elongate body which enable the elongate body to transition between a flexible state and a rigidized or shape-locked configuration. Details of such a shape-lockable body may be seen in further detail in U.S. Pat. Nos. 6,783,491; 6,790,173; and 6,837,847, each of which is incorporated herein by reference in its entirety.
[0009] One or more various instruments may be passed through the elongate body for deployment through its distal end by introducing the instruments through one or more corresponding tool ports located in the handle assembly. One instrument in particular which may be used to endoscopically visualize procedures and tissue regions of interest may include an endoscope or imaging system having a flexible shaft which may be introduced into the elongate body via a side port, e.g., Y-Port, located along the elongate body and distal to the handle assembly.
[0010] Because of the number of different instruments and the different types of tools which may be utilized in the endoscopic tissue manipulation assembly, tool or instrumentation management is one consideration for the practitioner or practitioners to facilitate efficient surgical and/or endoscopic procedures when performed upon a patient. Additionally, the division of responsibility for instrumentation management between one or more practitioners is highly desirable to ensure patient safety and procedure facilitation. Table-mounted or stand-alone instrument support members, such as instrument clamps, stands, or other devices may be used to assist with management of endoscopic access devices, tools, and/or instruments.
[0011] Aside from table-mounted or stand-alone instrument supporting members, additional instrument management systems may be employed which a single operator or user may utilize. In a first aspect, a multi-instrument support arm extending proximally from the handle assembly generally comprises a stiffened multi-lumen channel having a straight support channel extending proximally and one or more angled or curved support channels projecting at an angle therefrom support arm. Because the multi-instrument support arm is relatively stiff, it may be engaged to the handle assembly and used to support and separate its respective instruments leaving the operator to hold a single handle during a procedure. Other variations include a pivoting multi-instrument support having one or more individual instrument ports pivotably positioned within an open channel. Still other variations include a manifold that is attachable to the handle assembly and that supports one or more elongated straight docking sections each defining a substantially straight lumen for receiving an instrument shaft in a slidable docking configuration.
[0012] Another method for facilitating instrument management utilizes forming rigid portions of the instrument shafts. The elongate shaft is generally configured as a flexible length so as to traverse through the elongate body and within the patient body via endoluminal pathways. In another aspect, a portion of the elongate shaft extending between the handle and flexible length is configured as a rigid section, and may include a rigid sleeve made, e.g., from stainless steel or some other rigid metal or polymer, which is formed over the portion of the shaft extending from the handle. Alternatively, the rigid portion is formed integrally with the elongate shaft, e.g., as a section reinforced by woven metallic braids or inserts. In use, the flexible length of the elongate shaft is advanced through a tool port and through the handle assembly. The rigid section extending from the handle is advanced at least partially into the tool port such that the handle is supported or held in a linear configuration relative to the tool port and handle assembly by the rigid section.
[0013] The interface between the rigid portion(s) of the instrument shaft(s) and the straight sections of the tool port(s) provided in the handle assembly provides the operator with the ability to slidably dock the instruments within the endoscopic access device. The slidable docking interface provides several benefits. For example, the operator is able to release the instrument to use his hand for other purposes without having the instrument drop or flop downward, as would be the case with a flexible shafted instrument. In addition, the slidable docking interface facilitates instrument management using only a single support arm for the endoscopic access device, rather than requiring separate support for each instrument inserted into the device. Further, rigid shafted instruments provide improved force transmission and the slidable docking interface reduces or eliminates the possibility that an exposed shaft will bend or buckle. Still further, having a substantially straight tool port lumen in the handle assembly retains the ability to use flexible shafted instruments, if desired. Finally, having a substantially straight tool port lumen in the handle assembly facilitates insertion of instruments having longer rigid working lengths and/or larger shaft diameters. For example, a typical endoscope has an instrument channel with an inlet having a 45 degree bend. All tools used in the channel must be sufficiently flexible to pass the 45 degree bend. Having a substantially straight lumen provides the ability to use many instruments that could not be used through the instrument channel of a conventional endoscope.
[0014] Another variation of the instrument management system includes the provision of a flexible joint or flexible section of the instrument shaft between the handle and a rigid proximal section of the shaft. The flexible joint/section allows the handle to be flexed away from other instruments but retain sufficient rigidity that the handle does not droop. In this manner, the instrument handles are able to be flexed apart to prevent or reduce clashing.
[0015] In still another aspect, an endoscopic instrument management manifold is attachable to the handle assembly and provides one or more elongated pathways for passage of a flexible instrument shaft. In several embodiments, the one or more elongated pathways are defined by one or more extension tubes that extend from the proximal end of the handle assembly. In several other embodiments, the elongated pathways are defined by one or more extension tubes that are capable of being manipulated to assume a desired shape or orientation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIGS. 1A and 1B shows assembly and end views, respectively, of an endoscopic tissue manipulation system and examples of the various endoscopic instruments which may be advanced therethrough.
[0017] FIG. 2 shows the endoscopic manipulation system of FIG. 1A disassembled into its separate instrument components for illustrative purposes.
[0018] FIGS. 3 to 5 illustrate side views of a tissue manipulation assembly operable via a launch tube member which may be advanced through the endoscopic system.
[0019] FIGS. 6 and 7 illustrate perspective and top views, respectively, of a stiffened multi-instrument support arm having one or more angled or curved support channels projecting therefrom.
[0020] FIGS. 8 and 9 illustrate perspective and top views, respectively, of another stiffened multi-instrument support arm having a straight tubular member and one or more angled or curved support channels.
[0021] FIGS. 10A to 10C illustrate perspective, top, and end views, respectively, of another variation for a pivoting multi-instrument support having a fanned or angled lumen enclosure.
[0022] FIGS. 11 and 12 show top views illustrating examples for altering the entry lumen angle of the individual instrument ports.
[0023] FIGS. 13 and 14 show perspective views of a manifold supporting a pair of elongated docking sections that is attachable to the proximal end of an endoscopic access device.
[0024] FIGS. 15A to 15C illustrate side views of an instrument management system utilizing rigid portions of an instrument shaft for providing support to the instrument projecting from a handle assembly.
[0025] FIGS. 16 and 17 show end and top views, respectively, of tool ports having tapered entries for facilitating the insertion of instruments therethrough.
[0026] FIGS. 18A and 18B show exploded and perspective views of a rotating clamp adapted to be attached to an endoscopic access device.
[0027] FIGS. 19A and 19B show an endoscopic device having a straight, elongated docking lumen formed in the handle, and an instrument having a rigid shaft section near its proximal end.
[0028] FIGS. 20A and 20B show top views of an endoscopic device handle assembly having a plurality of instruments extending from its proximal end.
[0029] FIGS. 21A and 21B show top views of a physician using an endoscopic device during a procedure being performed on a patient.
[0030] FIGS. 22A and 22B are side views of an endoscopic device having a pair of endoscopic instrument management manifolds.
[0031] FIGS. 23A and 23B are a side view and an endoscopic view, respectively, of an endoscopic access device having instruments extending therethrough.
[0032] FIGS. 23C , 23 D, and 23 E are a side view and two endoscopic views, respectively, of the device of FIGS. 23A and 23B in a retroflexed position.
[0033] FIGS. 24A and 24B are a side view and an endoscopic view, respectively, of an endoscopic access device in a retroflexed orientation and having instruments extending through endoscopic instrument management manifolds that are also in a retroflexed orientation.
[0034] FIGS. 25A and 25B are a side view and an endoscopic view, respectively, of an endoscopic access device in a retroflexed orientation and having instruments extending through endoscopic instrument management manifolds that are in a crossed-over orientation.
[0035] FIG. 26 is a cross-sectional view of a telescoping endoscopic instrument management manifold.
[0036] FIGS. 27A to 27C are side views of an instrument, a manifold, and an instrument inserted into a manifold, respectively, illustrating an interlocking feature.
DETAILED DESCRIPTION OF THE INVENTION
[0037] With reference to FIG. 1A , the endoscopic tissue manipulation system 10 as described herein may comprise, at least in part, a distal end effector assembly 12 disposed or positionable at a distal end of a flexible and elongate body 14 . Examples of the tissue manipulation system 10 are described in further detail in U.S. Pat. Pub. No. 2005/0272977 A1, which is incorporated herein by reference in its entirety. Additional examples of endoscopic access devices and systems incorporating such devices are described in further detail in U.S. patent application Ser. No. 12/061,951, filed Apr. 2, 2008, which is also incorporated herein by reference in its entirety. A handle assembly 16 may be connected to a proximal end of the elongate body 14 and include a number of features or controls 26 for articulating and/or manipulating both the elongate body 14 and/or the distal end effector assembly 12 .
[0038] As shown, the system 10 may comprise a number of various instruments and devices utilized in various combinations with one another to effect any number of different procedures. Accordingly, each of the instruments and devices may require manipulation or some degree of handling by the practitioner.
[0039] The elongate body 14 may optionally utilize a plurality of locking or lockable links nested in series along the length of the elongate body 14 which enable the elongate body 14 to transition between a flexible state and a rigidized or shape-locked configuration. Details of such a shape-lockable body may be seen in further detail in U.S. Pat. Nos. 6,783,491; 6,790,173; and 6,837,847, each of which is incorporated herein by reference in its entirety. Alternatively, elongate body 14 may comprise a flexible body which is not rigidizable or shape-lockable but is flexible in the same manner as a conventional endoscopic body, if so desired. Additionally, elongate body 14 may also incorporate additional features that enable any number of therapeutic procedures to be performed endoscopically. Elongate body 14 may be accordingly sized to be introduced per-orally. However, elongate body 14 may also be configured in any number of sizes, for instance, for advancement within and for procedures in the lower gastrointestinal tract, such as the colon.
[0040] Elongate body 14 , in one variation, may comprise several controllable bending sections along its length to enable any number of configurations for the elongate body 14 . Each of these bending sections may be configured to be controllable separately by a user or they may all be configured to be controlled simultaneously via a single controller. Moreover, each of the control sections may be disposed along the length of elongate body 14 in series or they may optionally be separated by non-controllable sections. Moreover, one, several, or all the controllable sections (optionally including the remainder of elongate body 14 ) may be rigidizable or shape-lockable by the user.
[0041] In the example of endoscopic tissue manipulation system 10 , elongate body may include a first articulatable section 18 located along elongate body 14 . This first section 18 may be configured via handle assembly 16 to bend in a controlled manner within a first and/or second plane relative to elongate body 14 . In yet another variation, elongate body 14 may further comprise a second articulatable section 20 located distal of first section 18 . Second section 20 may be configured to bend or articulate in multiple planes relative to elongate body 14 and first section 18 . In yet another variation, elongate body 14 may further comprise a third articulatable section 22 located distal of second section 20 and third section 22 may be configured to articulate in multiple planes as well, e.g., 4-way articulation, relative to first and second sections 18 , 20 .
[0042] As mentioned above, one or each of the articulatable sections 18 , 20 , 22 and the rest of elongate body 14 may be configured to lock or shape-lock its configuration into a rigid set shape once the articulation has been desirably configured. Detailed examples of such an apparatus having one or multiple articulatable bending sections which may be selectively rigidized between a flexible configuration and a shape-locked configuration may be seen, e.g., in U.S. Pat. Pub. Nos. 2004/0138525 A1, 2004/0138529 A1, 2004/0249367 A1, and 2005/0065397 A1, each of which is incorporated herein by reference in its entirety. Although three articulatable sections are shown and described, this is not intended to be limiting as any number of articulatable sections may be incorporated into elongate body 14 as practicable and as desired. Moreover, one or multiple sections may be comprised of a series of nested-links which allow the one or more sections 18 , 20 , 22 to be articulated or deflected relative to one another along their lengths and optionally rigidized to conform and hold any particular shape.
[0043] Handle assembly 16 may be attached to the proximal end of elongate body 14 via a permanent or releasable connection. Handle assembly 16 may generally include a handle grip 24 configured to be grasped comfortably by the user and an optional rigidizing control 28 if the elongate body 14 and if one or more of the articulatable sections are to be rigidizable or shape-lockable. Rigidizing control 28 in this variation is shown as a levered mechanism rotatable about a pivot 30 . Depressing control 28 relative to handle 24 may compress the internal links within elongate body 14 to thus rigidize or shape-lock a configuration of the body while releasing control 28 relative to handle 24 may in turn release the internal links to allow the elongate body 14 to be in a flexible state. Further examples of rigidizing the elongate body 14 and/or articulatable sections may again be seen in further detail in U.S. Pat. Pub. Nos. 2004/0138525 A1, 2004/0138529 A1, 2004/0249367 A1, and 2005/0065397 A1, incorporated above by reference. Although the rigidizing control 28 is shown as a lever mechanism, this is merely illustrative and is not intended to be limiting as other mechanisms for rigidizing an elongate body, as generally known, may also be utilized and are intended to be within the scope of this disclosure.
[0044] Handle assembly 16 may further include a number of articulation controls 26 , as described in further detail below, to control the articulation of one or more articulatable sections 18 , 20 , 22 . Handle 16 may also include one or more ports 32 for use as insufflation and/or irrigation ports, as so desired.
[0045] Furthermore, one or more various instruments may be passed through elongate body 14 for deployment through distal end 12 by introducing the instruments through one or more corresponding tool ports 34 located in handle assembly 16 . As mentioned above, a number of different endoscopic and/or endoluminal instruments having a flexible body may be delivered through system 10 to effect any number of endoscopic procedures.
[0046] One example of such an instrument may include an endoscopic tissue manipulation and securement assembly 36 , as described in further detail below, which may be introduced into system 10 via instrument lumen 100 , as shown in the end view of distal end 12 in FIG. 1B . Any number of additional instruments may also be inserted through the system 10 . An example of such an instrument includes an elongate tissue engagement tool 74 having an elongate flexible shaft 76 with a removable handle or grip 78 located on its proximal end. The tissue engagement tool 74 may be positioned within an instrument lumen 102 adjacent to instrument lumen 100 . The distal end of flexible shaft 76 may include a rotatable helical tissue engager 80 used to temporarily engage and manipulate tissue. The helical tissue engager 80 may further include a number of visual indications or markers near or at the distal end of flexible shaft 76 . Examples of tissue engagement tool 74 are described in further detail in U.S. patent application Ser. No. 11/303,521 filed Dec. 16, 2005, which is incorporated herein by reference in its entirety.
[0047] In use, tissue manipulation assembly 40 and helical tissue engager 80 may be advanced distally out from elongate body 14 through their respective lumens 100 , 102 . Tissue engager 80 may be advanced into contact against a tissue surface and then rotated via its proximal handle 78 until the tissue is engaged. The engaged tissue may be pulled proximally relative to elongate body 14 and tissue manipulation assembly 40 may be actuated via its proximally located handle into an open expanded jaw configuration for receiving the engaged tissue.
[0048] Additional instruments may also be introduced through elongate body 14 , such as conventional endoscopic instruments including graspers, scissors, needle knives, snares, etc., through a corresponding instrument lumen 104 . In one example, an endoscopic instrument 82 having a flexible shaft 84 with a manipulatable handle or control 86 at its proximal end and a scissor mechanism 88 at its distal end may be introduced through the elongate body 14 for performing tasks such as cutting of tissue and/or sutures.
[0049] To endoscopically visualize procedures and tissue regions of interest, an endoscope or imaging system 90 having a flexible shaft 92 may be introduced into the elongate body 14 via a side port, e.g., Y-Port 96 , located along the elongate body 14 and distal to handle assembly 16 , as shown in FIG. 1A . Flexible shaft 92 may be advanced through visualization lumen 98 such that its distal end is advanced distally of the elongate body distal end 12 or it may be parked at the terminal opening of the visualization lumen 98 for providing imaging of a procedure. Although shown as an endoscope 90 in this illustration, other variations may include an imaging chip such as a CCD imager integrated into the distal end 12 of elongate body 14 . A cable 94 extending from endoscope 90 may be connected to a processor and monitor (not shown) for providing the images.
[0050] Endoscope 90 may be introduced directly through handle assembly 16 in other variations; however, positioning the imaging system 90 through a distally located Y-Port 96 relative to handle assembly 16 may allow for a longer length of the shaft 92 to be introduced through visualization lumen 98 into the patient body. As elongate body 14 is advanced into the patient body, e.g., per-orally and into the stomach, the Y-Port 96 remains outside the patient body.
[0051] FIG. 2 shows endoscopic manipulation system 10 disassembled into its separate instrument components for illustrative purposes. As seen, the handle 42 of tissue manipulation assembly 40 and its flexible shaft 38 may be removed from elongate body 14 . Removable needle deployment assembly 60 with its needle assembly control or housing 62 and its elongate shaft extending through flexible shaft 38 and terminating in needle assembly 66 may also be removed from elongate body 14 . Also shown is anchor assembly 68 comprising, e.g., distal tissue anchor 70 and proximal tissue anchor 72 , which may be deployed from needle assembly 66 through flexible shaft 38 .
[0052] Also shown is helical tissue engager 80 disposed upon flexible shaft 76 and endoscopic instrument 88 , e.g., endoscopic scissors, disposed upon flexible shaft 84 , removed from elongate body 14 and handle assembly 16 . Further shown is endoscope 90 with endoscope shaft 92 removed from Y-Port 96 .
[0053] As mentioned above, tissue manipulation assembly 40 is further described in detail in U.S. patent application Ser. No. 11/070,863 filed Mar. 1, 2005 and published as U.S. Pat. Pub. 2005/0251166 A1. An illustrative side view of one example is shown in FIG. 3 , which shows assembly 36 . The assembly 36 generally comprises a flexible catheter or tubular body 38 which may be configured to be sufficiently flexible for advancement into a body lumen, e.g., transorally, percutaneously, laparoscopically, etc. Tubular body 38 may be configured to be torqueable through various methods, e.g., utilizing a braided tubular construction, such that when handle 42 is manipulated and/or rotated by a practitioner from outside the patient's body, the longitudinal and/or torquing force is transmitted along body 38 such that the distal end of body 38 is advanced, withdrawn, or rotated in a corresponding manner.
[0054] Tissue manipulation assembly 40 is located at the distal end of tubular body 38 and is generally used to contact and form tissue folds, as mentioned above. FIG. 4 shows an illustrative detail side view in which tissue manipulation assembly 40 may be seen connected to the distal end of tubular body 38 via a pivotable coupling 44 . Lower jaw member 46 extends distally from the pivotable coupling 44 and upper jaw member 48 , in this example, may be pivotably coupled to lower jaw member 46 via jaw pivot 52 . The location of jaw pivot 52 may be positioned at various locations along lower jaw 46 depending upon a number of factors, e.g., the desired size of the “bite” or opening for accepting tissue between the jaw members, the amount of closing force between the jaw members, etc. One or both jaw members 46 , 48 may also have a number of protrusions, projections, grasping teeth, textured surfaces, etc., 50 on the surface or surfaces of the jaw members 46 , 48 facing one another to facilitate the adherence of tissue between the jaw members 46 , 48 .
[0055] Launch tube 54 may extend from handle 42 , through tubular body 38 , and distally from the end of tubular body 38 where a distal end of launch tube 54 is pivotally connected to upper jaw member 48 at launch tube pivot 56 . A distal portion of launch tube 54 may be pivoted into position within a channel or groove defined in upper jaw member 48 , to facilitate a low-profile configuration of tissue manipulation assembly 40 . When articulated, either via launch tube 54 or other mechanism, as described further below, jaw members 46 , 48 may be urged into an open configuration to receive tissue in jaw opening 58 between the jaw members 46 , 48 .
[0056] Launch tube 54 may be advanced from its proximal end at handle 42 such that the portion of launch tube 54 , which extends distally from body 38 , is forced to rotate at hinge or pivot 56 and reconfigure itself such that the exposed portion forms a curved or arcuate shape that positions the launch tube opening perpendicularly relative to upper jaw member 48 , as shown in FIG. 5 . Launch tube 54 , or at least the exposed portion of launch tube 54 , may be fabricated from a highly flexible material or it may be fabricated, e.g., from Nitinol tubing material which is adapted to flex, e.g., via circumferential slots, to permit bending.
[0057] Once the tissue has been engaged between jaw members 46 , 48 , a needle deployment assembly 60 may be urged through handle 42 and out through launch tube 54 by introducing needle deployment assembly 60 into the handle 42 and through tubular body 38 such that the needle assembly 66 is advanced from the launch tube and into or through approximated tissue. The needle deployment assembly 60 may pass through lower jaw member 46 via needle assembly opening defined in lower jaw member 46 to pierce through the grasped tissue. Once the needle assembly 66 has been passed through the engaged tissue, a distal and proximal tissue anchor 70 , 72 of the anchor assembly 68 may be deployed or ejected on one or opposing sides of a tissue fold for securing the tissue.
[0058] Anchor assembly 68 is normally positioned within the distal portion of tubular sheath 64 which extends from needle assembly control or housing 62 . Once the anchor assembly 68 has been fully deployed from sheath 64 , the spent needle deployment assembly 60 may be removed from assembly 36 and another needle deployment assembly may be introduced without having to remove assembly 36 from the patient. The length of sheath 64 is such that it may be passed entirely through the length of tubular body 38 to enable the deployment of needle assembly 66 into and/or through the tissue.
[0059] Because of the number of different instruments and the different types of tools which may be utilized in endoscopic tissue manipulation system 10 , tool or instrumentation management is one consideration for the practitioner or practitioners to facilitate efficient surgical and/or endoscopic procedures when performed upon a patient. Additionally, the division of responsibility for instrumentation management between one or more practitioners is highly desirable to ensure patient safety and procedure facilitation. Several device management systems are described in U.S. patent application Ser. No. 12/138,348 (Attorney Docket No. USGINZ05600), filed Jun. 12, 2008, which was previously incorporated by reference herein. The systems described in the foregoing application include trays, stands, tables, clamps, belts, and other supports used to support or hold the endoscopic tissue manipulation system 10 or one or more portions of the system.
[0060] Several of the instrument management system embodiments described herein and in the '348 application referenced above facilitate use of the endoscopic access system by the operator in either a “hands on tools” mode with the system retained in the stand or support arm, or a “hand on scope/hand on tool” mode in which the operator holds the handle 24 in one hand and an instrument with the other hand. Those skilled in the art will recognize that the “hands on tools” mode corresponds generally with the manner in which laparoscopic procedures are typically performed, while the “hand on scope/hand on tool” mode corresponds generally with the manner in which endoscopic procedures are performed. Each of these modes of use are facilitated using the instrument management systems described herein. For example, many surgical instrument holders are configured to clamp onto the shaft of a 5 mm or 10 mm instruments. By providing a 5 mm or 10 mm cylindrical post on the handle 24 of an endoscopic access system, the handle 24 may be selectively clamped onto and removed from the instrument holder by the operator. In this way, the operator can simply place the post in the holder and lock it in place to use the system in a “hands on tools” mode, or remove it from the holder and use the system in a “hand on handle/hand on tool” mode.
[0061] Aside from or in addition to table-mounted or stand-alone instrument supporting members, additional instrument management systems may be employed which a single operator or user may utilize. One example is shown in FIGS. 18A and 18B , which show perspective views of a handle 24 and a rotating clamp mechanism 300 that serves as a functional interface between a support arm (e.g., a stand or other holder) and the endoscopic access system. The clamp 300 includes a generally cylindrical housing 302 , a backing plate 304 , an upper clamp half 306 , and a lower clamp half 308 . The housing 302 is generally cylindrical in shape, having a central through hole having a size sufficient to allow the handle 24 to pass therethrough. The housing 302 also includes a channel formed on its inner surface and adapted to receive the upper clamp half 306 and lower clamp half 308 , each of which has a generally semi-circular shape to facilitate rotational movement within the housing channel. The backing plate 304 is attached to each of the upper clamp half 306 and lower clamp half 308 and the combined unit is fixed to the outer surface of the handle 24 . As a result, the handle 24 is allowed to rotate within the clamp housing 302 while being supported by the clamp mechanism 300 . A post 310 is attached to the clamp housing 302 . The post 310 has a size and shape that facilitates attachment to a clamp or other mechanism contained on the stand, support arm or other mechanism, thereby providing the ability to mount the endoscopic access system on the stand or support arm while providing free rotation of the handle 24 relative to the stand or support arm.
[0062] Another instrument management system is shown in FIG. 6 , which shows a perspective view of handle 24 having a multi-instrument support arm 190 extending therefrom. Support arm 190 may generally comprise a stiffened multi-lumen channel having a straight support channel 192 extending proximally and one or more angled or curved support channels 194 , 196 projecting at an angle from support arm 190 . Although two angled support channels are shown in this illustration, additional support arms may be utilized as practicable and as desired depending upon the number of tools advanced through elongate body 14 . In the example, handle 42 of tissue manipulation assembly 40 is positioned through the straight support channel 192 while instrument shafts 76 , 84 are positioned through their respective support channels 194 , 196 .
[0063] As shown in the partial cross-sectional view of FIG. 7 , each support channel may have a corresponding separate lumen defined therethrough. For instance, straight support channel 192 may have instrument lumen 198 defined therethrough, while angled support channels 194 , 196 may have respective instrument lumens 200 , 202 defined therethrough. Because multi-instrument support arm 190 is relatively stiff, e.g., support arm 190 may be comprised of a metal such as stainless steel or a stiffened polymeric material or plastic, support arm 190 may be engaged to handle 24 and used to support and separate its respective instruments leaving the operator to hold a single handle 24 during a procedure.
[0064] In an alternative configuration, portions of or the entire support arm 190 is formed of a relatively flexible material, such as a rubber or polymeric material. The flexibility of the support arm 190 allows instruments having relatively rigid shafts to pass through the instrument lumens 198 , 200 , 202 despite the presence of any non-linear portions of the lumens. For example, the support arm 190 is sufficiently flexible that the support channels 194 , 196 are able to flex in response to the rigid instrument shaft as it passes through any non-linear portions of the lumen.
[0065] Another example of a multi-instrument support arm 210 is shown in the perspective view of FIG. 8 , which illustrates a straight tubular member 210 which defines a lumen therethrough 218 and having one or more angled or curved support channels 212 , 214 , 216 each defining an instrument lumen therethrough, as shown in the partial cross-sectional view of FIG. 9 . In an alternative embodiment, each of the support channels 212 , 214 , 216 provides access to a separate instrument lumen extending through the support arm 210 , the handle 24 , and the elongate body 14 . In this variation, each of the instruments, positioned through each respective channel, may be supported by the support arm 210 and separated for individual control and manipulation. As above, support arm 210 may be made from a stiff material to enable manipulation of handle 24 while support arm 210 supports the various instruments during a procedure.
[0066] In yet another variation, a pivoting multi-instrument support 220 is illustrated as generally having a support arm 222 with a fanned or angled lumen enclosure 224 extending therefrom, as shown in FIG. 10A . Enclosure 224 may define an open channel 226 within which one or more individual instrument ports 228 , 230 , 232 may be pivotably positioned, as shown in the top and end views of FIGS. 10B and 10C , respectively. The instruments to be advanced through elongate body 14 may be passed into their respective instrument ports, each of which may be individually pivoted within open channel 226 respect to one another.
[0067] FIGS. 11 and 12 show examples of how each individual instrument port 228 , 230 , 232 may be pivoted into a straightened lumen to facilitate handling or articulation of an individual instrument positioned within a respective port. For instance, as shown in FIG. 11 , instrument port 228 may be pivoted within enclosure 224 to straighten its lumen. If another instrument, which may be positioned within instrument port 232 , were to be straightened within enclosure 224 , e.g., for withdrawal or advancement, each instrument port may be pivoted within enclosure 224 until the selected port 232 were positioned into its straightened configuration, as shown in FIG. 12 .
[0068] Turning to FIGS. 13 and 14 , an alternative multi-instrument support mechanism 320 includes a manifold 322 that is attached to the handle 24 of an endoscopic access system. In the embodiment shown, the manifold 322 includes an elongated tab 324 having a hole 326 that attaches to a post 310 on the handle 24 . The manifold 322 supports a plurality of elongated docking sections 328 a , 328 b , each of which extends from an instrument port 34 of the handle 24 . Each docking section 328 a , 328 b comprises a rigid tube having an elongated straight section adapted to receive a flexible instrument and route the instrument shaft into the respective instrument port 34 and through the handle 24 and elongate body 14 of the endoscopic access system. The docking sections 328 a , 328 b may optionally include a bend or other feature, such as the bends shown in the embodiment shown in FIGS. 13 and 14 . The bends provide a spread alignment of the instruments retained within the docking sections 328 a , 328 b to thereby reduce or prevent clashing of the instrument handles. The spread alignment may take several optional forms. For example, all of the instruments retained in the docking sections 328 may be extended an equal length beyond the proximal end of the handle 24 and spread in a single plane or in multiple planes. For illustrative purposes, the system shown in FIGS. 13 and 14 illustrates a spread in a single plane but with a central instrument extended a shorter length from the proximal end of the handle 24 . In alternative embodiments, the docking sections 328 a , 328 b are separately positionable so as to provide the user with a desired spread or orientation.
[0069] Another method for facilitating instrument management utilizes forming rigid portions of the instrument shafts. An example is shown in the side view of FIG. 15A which illustrates handle 42 and a proximal portion 250 of the elongate shaft of the tissue manipulation assembly 40 . The elongate shaft is generally configured as a flexible length 252 so as to traverse through elongate body 14 and within the patient body via endoluminal pathways. A portion of the elongate shaft extending between handle 42 and flexible length 252 may be configured as a rigid section 254 . Rigid section 254 may include a rigid sleeve made, e.g., from stainless steel or some other rigid metal or polymer, which is formed over the portion of the shaft extending from handle 42 . Alternatively, the rigid portion 254 may be formed integrally with the elongate shaft, e.g., as a section reinforced by woven metallic braids or inserts. Rather than having the rigid section 254 extend directly from handle 42 , rigid section 254 may be positioned between two flexible lengths 252 , 258 , as shown in the rigidized elongate body 256 in FIG. 15B .
[0070] In use, the flexible length of elongate shaft 252 may be advanced through a tool port 34 and through handle assembly 16 . Rigid section 254 extending from handle 42 may be advanced at least partially into tool port 34 , as shown in FIG. 15C , such that handle 42 is supported or held in a linear configuration relative to tool port 34 and handle assembly 16 by the rigid section 254 . The absence of rigid section 254 from flexible shaft 252 would allow handle 42 to flex and bend relative to tool port 34 in an uncontrolled manner. In the case where a configuration as shown in FIG. 15B is used, rigid section 254 may be positioned to extend from the entry of tool port 34 to provide some support to handle 42 while the proximal flexible section 258 extending between rigid section 254 and handle 42 may still allow for some limited flexibility in moving or articulating handle 42 in a non-linear manner relative to tool port 34 and handle assembly 16 .
[0071] Additionally, one or more visual markings or indicators 260 may be provided along the length of rigid section 254 , as shown in FIG. 15C . These visual indicators 260 may correspond to the depth which the tissue manipulation assembly 40 has been inserted into the patient body or the length which tissue manipulation assembly 40 has been advanced past the distal end of the rigidizable elongate body 14 within a body lumen of a patient.
[0072] In addition to the various device and instrument management tools and systems described above, tool ports 34 in handle assembly 16 may also be configured to facilitate device management. As shown in the end and top views of handle assembly 16 in FIGS. 16 and 17 , respectively, the entry to tool ports 34 may be configured as a tapered instrument port 270 . Tools and instruments may be inserted through the enlarged entry 272 and guided into the narrower tool lumen 274 by the narrowing tapered surface of port 270 .
[0073] Several of the features of the tools and systems described above in relation to FIGS. 6-17 are further described in relation to FIGS. 19A and 19B , which illustrate the slidable docking feature of an endoscopic access device and a flexible instrument. Referring to FIG. 19A , an endoscopic access device 320 is shown, the device having a handle 24 with an eyepiece 328 and steering controls 321 . The device includes an instrument channel 322 extending through the handle 24 that is elongated and substantially straight through at least a proximal section. The instrument 332 includes a shaft having a substantially rigid proximal section 334 and a substantially flexible distal section 336 . As described above, the slidable docking interface provided between the instrument channel 322 and the rigid proximal shaft 334 allows the operator to release the instrument, upon which the instrument will remain stably docked within the handle 24 of the access device 320 . In several embodiments, the length L of the rigid proximal section 334 of the instrument shaft is no longer than the rigid length of the instrument channel 322 so as not to interfere with the flexibility of the flexible section of the endoscopic access device 320 when the instrument shaft is inserted into the device to its intended extent. The length L of the rigid proximal section 334 should, however, be sufficient to provide additional overlap so that slidable docking occurs (i.e., no backing out to the flexible shaft section 336 ) during normal operation of the instrument.
[0074] As shown in FIG. 19B , the elongated and substantially straight section of the instrument channel 322 extending through the handle 24 need not be in line with longitudinal axis of the flexible section 14 of the endoscopic access device. In the embodiment shown in FIG. 19B , the docking section of the instrument channel 322 is inclined at an angle α relative to the longitudinal axis of the flexible section 14 . The flexible portion of the instrument shaft 336 is sufficiently flexible to accommodate the bend created by the differential.
[0075] In addition to the other instrument management tools and systems described herein, another mechanism for reducing or eliminating clashing of instrument handles is shown in FIGS. 20A and 20B . An endoscopic device handle 24 includes a plurality of instruments 342 , 344 , 346 extending from a plurality of instrument ports 34 located on the proximal end of the handle. As shown in FIG. 20B , two of the instruments include a flexible joint 350 located adjacent to the instrument handle between the handle and the rigid portion 334 of the instrument shaft. The flexible joint 350 are sufficiently flexible to allow the handle to be bent away from handles of other instruments received in the device while retaining sufficient rigidity to prevent drooping. In this manner, the handles of adjacent instruments may be flexed apart rather than clashing.
[0076] Turning next to FIGS. 21A-B , another embodiment of an endoscopic instrument management system is shown. In the embodiment, one or more selectively attachable and detachable instrument management manifolds 400 allow the user to use the endoscopic manipulation system 10 either with a compact handle (such as when not using multiple instruments), but then to attach the manifold to obtain a spread lumen configuration (such as when using multiple tools). Preferably, the endoscopic manipulation system 10 is held in a fixed or positionable stand when the tool spreading manifold is in use and multiple tools are in use so as not needing a hand to hold the system.
[0077] The instrument management manifolds 400 shown in FIG. 21B are capable of being configured to take on a desired shape or orientation. For example, as shown in FIGS. 21A-B , a female patient P is in the lithotomy position and the endoscopic manipulation system 10 is placed in a location relative to the female patient P to have the distal section of the system be introduced through the vagina in order to perform a gynecological examination or therapeutic procedure. In the embodiment shown in FIG. 21A , the instruments 402 a , 402 b are introduced into the system 10 by insertion directly into tool ports 34 in the handle 24 . This orientation requires that the physician or other user be located in the position shown in FIG. 21A , between the legs and toward the feet of the patient P. In the embodiment shown in FIG. 21B , the instruments 402 a , 402 b are introduced into the system 10 by way of a pair of instrument management manifolds 400 a , 400 b that are attached to the proximal side of the handle 24 . Each manifold 400 a , 400 b is attached at a first end to a port 34 of the handle 24 . The manifold has a generally “U”-shape or other curved shape that extends proximally from the handle 24 and then generally up and laterally to the side of the patient P. This orientation allows the physician or other user U to be located at the flank of the patient P in a conventional laparoscopic stance with the monitor at the feet of the patient P and the physician facing the monitor. In some circumstances, this positioning may be preferred to provide advantageous instrument access, comfort and/or freedom of movement of the physician, or improved monitor and/or patient visualization and control of the instruments for the physician.
[0078] Turning to FIGS. 22A-B , the manifolds 400 a , 400 b are generally tubular structures defining a lumen that extends through the length of the manifold. In some embodiments, the manifold is formed of a substantially rigid material that is resistant to bending or other deformation, such as stainless steel. In other embodiments, such as shown in FIGS. 22A-B , the manifolds 400 a , 400 b are formed of a material that is capable of bending or other deformation under manipulation by the physician or other user, such as a semi-rigid metallic or polymeric material. Examples of materials suitable for the malleable manifold structures include interlocking rolled metal structures used in conventional microphone stand gooseneck devices, or Loc-Line® modular hose system materials available from Lockwood Products, Inc. of Lake Oswego, Oreg. The Loc-Line® system products include a plurality of press-fit jointed structures defining a central lumen therethrough.
[0079] In some embodiments, the instrument management manifold 400 is transformable so that the relative positions of the lumens may be altered. For example, a manifold 400 a , 400 b having the jointed or other malleable structure is able to be bent or otherwise deformed to meet specific procedural needs. For example, the lumens defined by the manifolds 400 a , 400 b may be positioned straight and relatively close together during insertion of tools through the manifolds and/or the endoscopic manipulation system 10 (see, e.g., FIG. 22A ), and then bent or deformed to a working position in which the manifolds 400 a , 400 b are no longer straight (see, e.g., FIG. 22B ).
[0080] Positionable or bent manifold lumens also are advantageous with regard to the relative hand positions of the clinician manipulating the tools or instruments 402 and what is displayed on a visualization monitor. A phenomenon of “switching” occurs when an endoscopic delivery device is steered into a retroflexed position. The retroflexed position of the device causes the image to turn upside down and reversed. For example, compare FIGS. 23A-B in which the delivery device has a generally straight orientation, with FIGS. 23C-E in which the delivery device is steered into a retroflex position. The endoscopic view shown in FIG. 23D is reversed and upside down relative to the endoscopic view shown in FIG. 23B . To correct the image, the endoscope (located in one of the working lumens of the delivery device) is first rotated 180 degrees in order to make the image no longer appear upside down. Next, after the upside down correction is made, the instruments 402 a , 402 b extending through the access device will appear on the opposite side of the screen relative to the hands being used to manipulate the instruments 402 a , 402 b , as shown in FIG. 23E . This “switching” effect will frequently cause disorientation to the physician or other user of the device.
[0081] The “switching” phenomenon is corrected using the instrument management manifolds 400 in the following ways, as shown in FIGS. 24A-B and 25 A-B. The instrument management manifolds 400 a , 400 b are curved or deformed into a retroflexed orientation relative to the exit ports 34 of the handle 24 of the delivery device 10 . This puts the instruments 402 a , 402 b back into the correct visual and spatial configuration. See FIGS. 24A-B . Alternatively, the instrument management manifolds 400 a , 400 b are crossed or crossable with a similar result. See FIG. 25 .
[0082] In some embodiments, the endoscopic instrument manifold 400 has a construction that allows it to telescope. See FIG. 26 . For example, instead of having a rigid telescoping interface, the manifold 400 has a construction of nesting or accordionizing tubing, including a first tube 410 that is attached (directly or indirectly) to the handle 24 of the access system 10 , and a second tube 420 that is slidable within and extends proximally of the proximal opening of the first tube 410 . The first tube 410 includes an inwardly directed flange 412 formed on or attached to its proximal end, and the second tube 420 includes an outwardly directed flange 422 formed on its proximal end. The flanges 412 , 422 prevent the first tube 410 and second tube 420 from becoming separated from one another. An o-ring 414 seals the tubes relative to one another. In other embodiments, more tube sections are used and/or the relative diameters of the tubes are reversed to allow the first tube 410 to telescope within the second tube 420 . Other variations are also possible.
[0083] In still other embodiments, the instrument 402 inserted into a manifold 400 is adapted to interlock with the manifold 400 entrance, preferably at the instrument handle. See FIGS. 27A-C . For example, a handle interlocking portion 430 a is provided on the shaft or handle of the instrument 402 , and a mating manifold interlocking portion 430 b is provided on the proximal opening of the manifold 400 . The interlocking portions 430 a , 430 b are configured to mate and/or interlock to form an interlocking member 430 in which the instrument 402 is selectively attached to the proximal tube 420 of the manifold 400 . Advancement, retraction, and rotation would then be allowed and supported by the telescoping manifold 400 .
[0084] The foregoing descriptions of instrument management tools and systems includes descriptions of several components (and embodiments of components) that may be used in a standalone manner or in combination with other components. For example, a preferred embodiment of an instrument management system suitable for use with the endoscopic tissue manipulation system 10 shown in FIG. 1A includes a support stand having a base that is attachable to a bed rail or other fixed location, a first support arm having a clamp or other fixture attachable to the handle 24 of the endoscopic access device, and a second support arm that is attachable to a handle of the endoscope 90 . The first support arm and second support arm of the support stand are configured to be selectively fixed in place or to have effectively free range of motion, such as may be provided by having one or more ball joints or other pivotable connections that allow the user to selectively fix or release the system. Alternatively, the second support arm comprises a boom that is held in a fixed relationship to the first support arm, thereby allowing movement of the endoscopic access device and the endoscope 90 as a single unit. In the embodiment, a holder interface, such as a rotating clamp 300 is used to detachably attach the handle 24 to the first support arm via a post 310 , thereby providing a rotational movement capability between the handle 24 and the support stand. Another holder interface, such as a C-clamp that is detachable from the second support arm, may be used to attach the endoscope 90 to the second support arm. Further, the endoscopic access device includes a plurality of instrument lumens that support slidable docking of instruments in the handle 24 , with one or more of the instruments living a rigid proximal shaft section 254 .
[0085] Although a number of illustrative variations are described above, it will be apparent to those skilled in the art that various changes and modifications may be made thereto without departing from the scope of the invention. Moreover, although specific configurations and applications may be shown, it is intended that the various features may be utilized in various combinations and in various types of procedures as practicable. It is intended in the appended claims to cover all such changes and modifications that fall within the true spirit and scope of the invention.
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CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims priority to and the benefit under 35 USC 119(e) of U.S. provisional patent application 60/471,433, filed May 16, 2003, the entire contents of which are incorporated herein by reference.
FEDERAL FUNDING
Not applicable
BACKGROUND OF THE INVENTION
In the drying of agricultural products, efficient use of energy is a significant concern. Another concern is the time required for processing. Still other concerns relate to a specific agricultural product. For example, the quality of corn which results from a given drying process is an important concern in the corn industry.
Corn quality may be reflected in several aspects. For example, a first aspect is the proportion of cracked kernels. A lot of corn with a higher proportion of cracked kernels will have a lower value than a lot with a lower proportion of cracked kernels. A second aspect is the presence of a contaminating organism such as mold or bacteria in the corn or the potential for supporting contaminating organisms in the corn.
Kernel cracking is often a byproduct of the drying of shelled corn. It is commonly necessary to dry shelled corn due to the moisture level present upon harvesting. Unless the shelled corn has sufficiently low moisture content, the corn can spoil or support the growth of contaminating organisms.
The drying of shelled corn is conventionally achieved by using heated air employing propane or natural gas as a fuel source. To avoid the consequences of unacceptable moisture levels, however, one may dry the corn in a suboptimal manner or with suboptimal results. For example, one may dry corn too rapidly by using excessively high temperatures or by treating the corn for too long. This may result in undesirable levels of cracking or energy consumption.
Improvements in drying outcomes are being sought for agricultural products. In corn drying, energy conservation and improvements in corn quality are of particular concern. In addition to applications relevant to corn, advances would be useful in the context of other products and processes.
The drying of wood and processing of pulp in the paper industry can benefit from advances in treatments with advantages such as controlled energy usage or improved quality such as a reduction in burning or charring.
The present invention addresses one or more concerns relating to foods, plant products, agriculture, and related technologies.
SUMMARY OF THE INVENTION
The following definitions are applicable.
When used herein, the term “plant product” refers broadly to a plant or product derived therefrom. The term can encompass shelled corn (maize) kernels, often called field corn; wheat grain; wheat flour; other flours; durum pasta; soybeans; peas; other legumes; sweet corn; rice; tobacco; hay; straw; flowers, including petals or whole floral arrangements; seeds for consumption, such as sunflower seeds; seeds or cuttings for reproduction; herbs; and spices, such as peppercorns and ground pepper; other plant parts such as leaves. The term includes wood, wood pulp, and paper. The term can include material regardless of the purpose of use, for example whether for consumption, display, fuel, construction, insulation, or other purpose. The term includes materials used in industrial processes such as wet or dry milling, refining, and food processing. The term includes products to which non-plant ingredients may have been added; for example, pasta that has been prepared using flour, water, oil, salt, and egg. The term is often equivalent to what is commonly called an agricultural product.
When used herein, the term “sample quality” refers to an aspect of a plant product as defined herein. For example, applicable aspects can include moisture content, proportion of cracks in a product or product lot, and the presence or level of a contaminating organism or other hygienic aspect. In the context of a plant product example such as peppercorns, an aspect can include the presence, amount, or diversity of flavor or other compounds. In the context of a flower petal example, an aspect can include an aesthetic quality. In the context of pulp and paper, properties are known in the art such as various mechanical strength aspects. Further aspects can include stability; activity, such as ability to germinate; taste; aroma; and nutritional composition. The term can be equivalent to product quality.
When used herein, the term “contaminating organism” can refer to microbes such as bacteria, fungi, protozoa, and viruses; or organisms such as insects capable of infestation of a plant product. The term includes those organisms capable of affecting a sample quality as defined herein.
When used herein, the term “sample” refers to a quantity of a plant product. For example, a corn sample can be a mass of shelled corn kernels that aggregately has a three dimensional configuration in a bin or other container or chamber, or has a configuration distributed in a horizontal layer on a surface such as a conveyor. The term can also be equivalent to a lot of a sample.
When used herein, the term “sample parameter” refers to a property or characteristic of a sample. The term can include, for example, sample amount, sample volume, sample geometry, unit geometry, unit structure, and moisture content.
When used herein, the term “sample amount” can refer to the total mass of a sample or alternatively, by considering an “average sample density”, to the geometric volume. For example, the sample amount may be a certain number of bushels, kilograms, or liters of corn. The term can also refer to the effective volume of corn present for a given sample geometry of defined dimensions, for example a layer two feet high in a corn bin with a diameter of 27 feet. For consistency, the “average sample density” is defined as the ratio of the total mass of the sample to the apparent, total geometric volume occupied by the sample, including air spaces, such as those between grain particles, for example. Therefore, the average sample density is a function of packing density of the seeds, grains, or particles making up the sample.
When used herein, the term “sample geometry” refers to the actual dimensions or configuration of an entire sample. For example, the term can refer to the configuration of a lot or batch of shelled corn kernels.
When used herein, the term “unit geometry” refers to the dimensions or configuration of an individual item of a sample. For example, a unit can be a kernel of corn which has a geometric configuration different than a unit of a rice grain.
When used herein, the term “unit structure” can refer to the dimensional, physiologic, and mechanical attributes of an individual item, for example the structure of a corn kernel. A corn kernel can have structural components such as the endosperm, pericarp, hull, germ, etc.
When used herein, the term “moisture content” refers to the level of moisture present in a sample or fraction of a sample. An initial moisture content, therefore, can refer to the level of moisture present at about the time of commencing treatment. The moisture content of corn, for example, can be measured by any methods known to those of ordinary skill in the art.
When used herein, the term “pulse profile” refers to one or more aspects of a temporally distributed series of electromagnetic field pulses. A pulse profile can have a specified overall duration, for example in seconds, minutes, or hours, during which pulses having a pulse length are delivered in a regular or irregular pattern. A pulse may be separated in time from another pulse by a delay period of time.
When used herein, the term “pulse length” refers to a time period during which an electromagnetic field is applied. The term is equivalent to pulse width in referring to a pulse-on time.
When used herein, the term “optimal” or other forms such as “optimized” or “optimization” refer to a state of performance or conditions that approximate desired results for a given measurement while not necessarily achieving perfection in performance or idealized results. For example, a treatment process optimized for goals of energy efficiency or corn quality may better approximate desired results for one goal than another. In the context of achieving matching impedance between a sample load and an EMF source, a tuner is used to enhance efficiency by assisting in the selection of an optimal frequency for the sample load.
The following abbreviations are applicable: electromagnetic field, EMF; pulsed electromagnetic field, PEMF; continuous wave, CW; pulsed wave, PW; near infrared, NIR; megahertz, MHz; gigahertz, GHz; kilowatts, kW.
The invention provides a method of treating a plant product, comprising: providing a sample of said plant product; exposing said sample to an electromagnetic field; tuning said electromagnetic field; wherein said tuning relates to a sample parameter; and monitoring a sample quality; thereby treating said plant product.
The invention provides methods wherein said plant product is selected from the group consisting of: shelled corn (maize) kernels; wheat grain; wheat flour; other flours; durum pasta; soybeans; peas; other legumes; rice; tobacco; hay; straw; flowers, flower petals; seeds for consumption, such as sunflower seeds; seeds or cuttings for reproduction; herbs; and spices, such as peppercorns and ground pepper; other plant parts such as leaves.
The invention provides methods and apparatus wherein an electromagnetic field is preferably a pulsed electromagnetic field.
In an embodiment, an initial frequency range is from about 0.7 GHz to about 3 GHz. In a preferred embodiment, an initial frequency range is either 1+/−0.3 GHz or 2.5+/−0.5 GHz.
The invention provides a method wherein tuning comprises an initial tuning frequency scan resulting in selection of a first frequency. The tuning can further comprise at least one subsequent frequency scan resulting in selection of a second frequency. The first frequency and second frequency can be the same or different.
The invention provides a method comprising the step of measuring an energy usage value.
The invention provides a method wherein the step of exposing to an electromagnetic field is regulated by a control system. The control system comprises a DC pulse controller, a computer and a computer program, or a computer, a computer program, and a DC pulse controller.
The invention provides a method wherein a control system continually adjusts in real time a pulse profile. The control system can control a time period of treatment.
In a method of the invention, treating results in drying a plant product. The treating or drying can be to a specified end moisture level. In a method of the invention the end moisture level for corn is from about 12% to about 20%. In a method of the invention, the treating or drying can maintain a level of corn quality. In a method of the invention, a plant product is corn kernels and treating results in a percentage of cracked corn kernels wherein the percentage is less than about 15%. In a method of the invention, the percentage is less than about 10%. In a method of the invention, the percentage is less than about 8% or less than about 6%.
The invention provides a method of treating resulting in a control or reduction of a contaminating organism.
In a method of the invention, a control system operates to select an energy level, frequency value, frequency range (or ‘spectral width’) and a pulse profile (inversely related to spectral width for very short pulses). Additionally, or independently, a control system operates to enhance optimization of energy efficiency and/or operates to enhance optimization of a sample quality. In a method of the invention, a control system is adjusted for a plant product sample having a specific moisture content, total mass, and configuration.
The invention provides a plant product that is treated by a method of the invention. For example, a treated plant product is shelled corn (maize) kernels; wheat grain; wheat flour; durum pasta; soybeans; or peas.
The invention provides a device for treating a plant product, comprising: a computer; a pulse controller, communicatively connected to said computer; an EMF source generator; electrically connected to said pulse controller; a sample load chamber configured to allow exposure of a sample load to an EMF output of said EMF generator; one or more power sources supplying power to said computer, pulse controller, and EMF generator. A lower-cost alternative for controlling pulses is a Programmed Logic Circuit (PLC) that is, however, less flexible in operation than the computer-programmable pulse controller. The PLC also can limit, in some instances substantially, the drying capabilities and performance of drying systems employed for plant products to dried material of suboptimal or inferior quality.
The invention provides a device further comprising a tuner, wherein said tuner is employed to adjust the EMF frequency of said EMF generator. In an embodiment, the tuner adjusts the frequency within a specified range. In an embodiment, said tuner operates to match impedance between said EMF generator and said sample load.
In an embodiment, the invention provides a device further comprising a terminator. In an embodiment, the invention provides a device further comprising a near infrared monitoring system capable of measuring a sample parameter or adjacently positioned to said sample load chamber so as to detect spectra within or near said chamber. In an embodiment, the invention provides an auxiliary, low-power fan for smoothing out, or ‘homogenizing’, the EMF energy distribution throughout the EMF-irradiated volume.
In an embodiment, a device further comprises circulator operatively connected to said tuner so as to assist in protecting said EMF source generator from reflected power in an open circuit situation. In an embodiment, a device further comprises an applicator useful for handling of emf power to said sample load.
In an embodiment, a device further comprises one or more of the following: a tuner, a terminator, a near infrared monitoring system, a circulator, and an applicator. In a preferred embodiment, a device further comprises a tuner, a terminator, a near infrared monitoring system, a circulator, an applicator, and an auxiliary, low-power fan for smoothing out, or ‘homogenizing’, the EMF energy distribution throughout the EMF-irradiated volume.
The invention provides methods and apparatus for treating a plant product by application of an electromagnetic field. The electromagnetic field can be in the form of a pulsed wave or a continuous wave. In a preferred embodiment, the electromagnetic field is a pulsed electromagnetic field.
In an embodiment, the invention provides methods and apparatus for drying a plant product. In a preferred embodiment, the plant product is corn in the form of shelled corn kernels. In a highly preferred embodiment, the invention provides methods and apparatus for drying corn and soybeans.
In an embodiment, techniques and apparatus are combined with other techniques and apparatus as known in the art, for example with those for vacuum drying, ambient drying, or conventional hot air drying using natural gas, propane, or electric power. A particular embodiment of a method or apparatus may include enhanced ambient airflow such as from combination with an air circulation fan. In a preferred particular embodiment, the air circulation fan is a moderate-power air circulation fan. In a preferred embodiment, such combinations are able to reduce the time required to achieve a desired treatment state such as drying level, as well as improve product quality in certain cases. For example, methods and apparatus of the invention can be used in the processing of sweet corn, peas and soybeans.
In a particular embodiment, the invention provides a process of treating shelled corn kernels by exposure to a pulsed, as opposed to continuous, electromagnetic field. The preferred electromagnetic field spans the frequency range from about 30 megahertz (MHz) to about 20 gigahertz (GHz). More typically, for preferred embodiments, the frequency range is from about 500 MHz to about 10 GHz, with EMF penetration depth, p, into the drying sample being inversely related to the EMF frequency, and also dependent on the pulse EMF profile.
In an embodiment, one or more process conditions including power level, frequency, and pulse profile are selected so as to achieve a desired outcome of energy efficiency and agricultural product quality.
In a preferred embodiment, a method achieves the drying of corn wherein the dried corn has less than about 10% of the kernels cracked.
In an embodiment, there is a tuning of the frequency. In a preferred embodiment, there is a tuning and a fine tuning of the frequency. In an embodiment, the tuning process comprises selective tuning of the frequency of an applied electromagnetic field. An advantage of frequency tuning is to enhance optimization of energy usage. The process can further comprise fine tuning of the frequency. The tuning or fine tuning can be conducted at the commencement of treatment. Furthermore, the tuning or fine tuning can be conducted subsequently during treatment. Optionally the tuning or fine tuning can be conducted intermittently during treatment. Tuning is preferably adjusted to maximize absorption of electromagnetic radiation. The process optionally comprises the step of using a computer in tuning or fine tuning. In an embodiment, fine tuning can be of greater significance at lower frequencies.
In an embodiment, a method or apparatus employs a desired pulse profile. Preferably a computer and computer program are used in establishing and/or implementing a pulse profile.
In an embodiment, a computer program or algorithm is utilized with functional modules. For example, the algorithm can include a first loop that is a nested loop capable of iterating a sequence of pulses of an electromagnetic frequency. In one embodiment, there is a first pulse (pulse on) having a first pulse width followed by first delay (pulse off) having a delay width. This is followed by a second pulse and a second delay each having a respective width. The function of one module is to generate a pulse sequence. One example of such a pulse sequence can be described as [P 1 , D 1 , P 2 , D 2 , P 3 , D 3 ] n wherein n is the number of repeats of the sequence. Outside this first loop, there can be a second functional loop or module capable of specifying the pulse amplification and the pulse frequency; in an embodiment these can be constant during the treatment cycle. Outside of the second loop, there can be a third functional loop or module capable of changing the electromagnetic wave frequency, the amplitude, or both the frequency and amplitude.
In an embodiment, optimization of the electromagnetic wave frequency or amplitude can be achieved by using the third loop or module. The optimal frequency will correspond approximately to the point at which there is maximum absorption of electromagnetic radiation by a sample at that frequency. Absorption is measured by determining the level of impedance which is observed for the sample actually being treated.
One skilled in the art will appreciate that the functional loops or modules of computer programs or algorithms can be achieved by software code in various computer languages and using various computer systems. For example, in an embodiment the language can be: Basic; Quick Basic; Advanced Basic, e.g. Microsoft BASICA; Visual Basic; C++; FORTRAN; or art-recognized equivalents. Similarly, in an embodiment the computer system can utilize a personal computer (PC) and various operating system software such as DOS or Windows.
For generation of the electromagnetic field, an artisan of ordinary skill will appreciate that the field generation can be achieved by a variety of sources. In an embodiment, for example, some of the source geometries can include parallel plate, cylindrical solenoid, saddle coil, or waveguide horn technologies. A particular technology may be employed depending on the range of frequency that is desirable. For example, if the desired frequency range is lower, a cylindrical solenoid source can be preferred. For a frequency range of about 400 MHz to about 1 GHz, a saddle coil source can be preferred. For the GHz range generally, a waveguide horn source can be preferred. Those of ordinary skill in the art can select an appropriate source for a desired selected frequency range of application.
In an embodiment, an initial frequency or frequency range is selected as a function of sample parameters. The frequency selected can preferably be optimized for one or more parameters such as sample volume, sample geometry, unit geometry, unit structure, and initial moisture content.
In an embodiment, a power source can be used capable of output in the range from about 1 to about 50 kW. In a preferred embodiment, the power source can supply from about 5 to about 10 kW.
Another embodiment of the invention relates to an apparatus for treatment of a plant product. The apparatus comprises a power source, a programmable pulse controller, a pulsed electromagnetic field generator (e.g. waveguide horn), and a treatment container (e.g., storage bin). In a preferred embodiment, a PEMF generator is coupled through a waveguide, or horn, to the sample. In embodiments, a treatment container is a storage bin, conventional corn drying bin, or a chamber. In another preferred embodiment, a conveyor belt can also serve as a treatment container as application of the electromagnetic field can occur during conveyance.
In an embodiment, the particular settings for an apparatus at industrial scale may require variation from smaller or laboratory scale. For example, the following parameters may require customization at industrial scale for optimal performance: frequency of electromagnetic field, level of power, algorithm for pulse profile, and a pulse profile such as a period of time and/or pattern of pulses.
In a particular embodiment, the apparatus is adapted for drying corn.
The invention also provides embodiments wherein the target or sample material is varied. For example, the target or sample material can be a plant product as defined herein. In a preferred embodiment, the plant product is shelled corn kernels. In other embodiments, other grains such as wheat and rice can serve as samples. Moreover, agricultural products can also serve as samples such as tobacco leaves. Optional apparatus elements can be adapted for receiving and containing various sample materials.
Various embodiments of the invention can offer several advantages. One advantage is energy conservation compared with conventional thermal drying technology, such as that using propane gas or natural gas as fuel. A second advantage is improved corn quality, for example as measured by the proportion of cracked kernels from the treatment or drying process. The improved corn quality can also relate to a reduced level of contaminating organisms. For example, an embodiment of the invention can achieve disinfection or disinfestation in addition to drying. A third advantage is a reduction of undesirable environmental emissions. For example, emissions of volatile organic compounds are reduced due to the change in energy source (electricity versus a fuel).
In an embodiment, an apparatus is configured where a single power supply, EMF generator, and control system are able to treat a single sample. In another embodiment, the apparatus is adapted to treat multiple samples. In a specific example of treatment of multiple samples, the apparatus is connected or variably connected to multiple bins.
In an embodiment, methods and apparatus are used in treating seeds or cuttings for use in planting or other reproductive purposes. In a preferred embodiment, such a treatment does not substantially affect germination.
In embodiments, methods and apparatus are applied in industrial processes such as wet or dry milling, refining, ethanol production and by-product processing, and food processing. In an embodiment, methods and apparatus are employed in ethanol or butanol processing from fermented corn by differential distillation.
In an embodiment, methods and apparatus are applied in the treating of wood, paper, and paper pulp by pulsed EMF. In a preferred embodiment, wood is dried. In a preferred embodiment, wood, paper, or paper pulp is treated so as to achieve reduced burning or charring. In a highly preferred embodiment, substantially no burning or charring is achieved.
In an embodiment, methods and apparatus are applied in low-temperature treatment of foods by pulsed EMF for food preservation with improved stability, taste, or nutritional quality or composition. In an embodiment, such treatment prevents or reduces a level of potential spoilage or achieves a reduction of a contaminating organism. In an embodiment, EMF exposure can reduce the time required for a treatment or drying process, particularly in combination with other techniques as known in the art.
An embodiment of the invention is the food process of drying pasta. In a preferred embodiment of pasta drying, the pasta is processed with reduction of a processed pasta quality such as degree of cracking, burning, or browning.
The methods and apparatus in particular embodiments relate to the drying of corn with potential for high energy efficiency while achieving advantageous, high quality dried corn, with a low to very low level of cracks. In this context, high energy efficiency can include any level of efficiency that is comparable to or above that for conventional techniques such as conventional electric oven, propane gas, or natural gas methods; similarly, a low to very low level of cracks can include any level that is comparable to or below that which is achieved using such conventional techniques.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 . Efficient, moderate temperature drying of corn by pulsed EMF.
FIG. 2 . Block diagram I of PEMF equipment.
FIG. 3 . Block diagram II of PEMF equipment.
FIG. 4 illustrates a process system with a feedback feature.
FIG. 5 illustrates a process system without a feedback feature.
FIG. 6 illustrates a computer program.
FIG. 7 illustrates an EMF apparatus embodiment.
DETAILED DESCRIPTION OF THE INVENTION
The invention is further described and illustrated by the following embodiments and examples.
Example 1
Method as Applied to Corn Drying
As a particular description of a tuning example, the following is done. An initial frequency range of either 1+/−0.3 GHz or 2.5+/−0.5 GHz is considered likely to be optimal. An initial tuning scan of that frequency range is employed starting at 1 GHz. At 1 GHz, an assessment is made of the absorption by the sample in the system. If the absorption is not sufficiently optimized, then an incremental increase in the frequency is made and the absorption is observed at the new frequency. The initial tuning scan is conducted until the absorption is maximal. If the absorption is maximal, then a fine tuning scan is optionally employed to further improve absorption.
For tuning, an incremental change in frequency is selected to be approximately an order of magnitude lower than the initial frequency. For fine tuning, an incremental change is selected to be between about an order of magnitude to about three orders of magnitude lower than the initial frequency. For example, if the initial frequency is 1 GHz, then a tuning scan increment can be 0.1 GHz and a fine tuning scan increment can be 5 MHz. The increment size for tuning and fine tuning is particularly significant at the lower initial frequencies.
The frequency selection, including initial frequency selection and that achieved by tuning and fine tuning, can be influenced by the category of corn. Corn categories can include soft, medium, and hard corn.
The process can include the delivery of a first volume of corn with treatment of the first volume, followed by delivery of a second volume of corn with treatment of the second volume.
The determination of cracking in kernels is known in the art and can be performed using microscopy, back-illumination techniques, or other techniques.
Example 2
Pulse Profile as Applied to Corn Drying
As a particular description of a pulse profile, the following is done. An EMF is pulsed on for a pulse width of one second followed by a delay (pulse off) of 50 seconds. This cycle of pulse and delay is repeated for a period of one hour. Next, there is a rest period of between 2 to 8 hours at about less than 75% r.h., depending on the desired final moisture level of the drying product. During the rest period, significant migration of moisture from the inside of a corn kernel to the outside continues to occur after the pulsed EMF treatment. Reduction of moisture in the corn sample can continue to occur immediately following the one hour pulse period and also can continue during later portions of the 8 hour rest period, including portions beyond the initial 45 minutes after the one hour pulse period.
The pulse width can vary from about 100 microseconds to about 60 seconds. The delay width can vary from about 1 second to about 3600 seconds. In a particular embodiment the pulse width will have a range from about 0.5 seconds to about 5 seconds, and the delay width will range from about 10 seconds to about 5 minutes.
In specific embodiments, the invention contemplates application of pulsed EMF wherein there is a cycle of pulse and delay, ranging from about 10 minutes to several hours. Following such a cycle, the rest period can extend from about 2 hours to about 24 hours.
Example 3
Apparatus for Treating a Plant Product
For large scale systems, a power source capable of generating from about 5 to about 20 kW is used. For a particular large scale system, the power source is capable of generating about 10 kW.
A conventional fan is optionally used to facilitate removal of moist air and evaporation from the kernel surface.
In another example, multiple sources of electromagnetic fields are used. The multiple EMF sources can use the same frequency or different frequencies.
In a particular embodiment, there is safety equipment for protection of the operator from the EMF. For example, a metallic enclosure can be used, such as a metallic storage bin, also equipped with a safety relay capable of automatically shutting down the electrical power to the EMF source. As a more foolproof operation, a locked door should be also installed behind the safety relay, that could only be unlocked after the mains power to the EMF source was shut down automatically by the relay.
Example 4
Pulsed EMF Used in Corn Drying
Corn harvests from two consecutive years were employed for corn drying tests by pulsed EMF. The corn selected for such tests was divided into three categories according to the corn hardness: soft corn, medium hardness corn, and hard corn. Complete drying curves by both pulsed EMF and conventional oven drying, as well as water sorption isotherms of corn were obtained for all three categories of corn. Such corn drying curves were found to be significantly different from each other. Pulsed EMF frequencies that were tested span the range from 30 MHz to 2.45 GHz.
Fastest drying of corn was obtained at 2.45 GHz, whereas the lowest percentage of cracks in corn was obtained at 200 MHz for 6 hr exposure to pulsed EMF, and an effective applied power level of 1 kW. High-resolution, solid-state (CP-MASS) NMR and NIR techniques were employed to evaluate corn composition and quality factors related to composition. Drying of corn at 2.45 GHz and microwave pulsed power levels of 500 W achieved corn drying with 1.5 hr of PEMF energy use, with less than 6% cracks, for a 10% r.f. heating cycle. Such tests indicate that efficient corn drying from a level of 24-20% moisture to 12% is feasible by pulsed EMF, and that energy savings of about 50% are practically attained without causing an unacceptably large percentage of cracked corn. The NMR methodology was described in a previous publication (Baianu and Kumosinski, 1994).
The most difficult of the three categories to dry without cracks was found to be the soft corn, with an initial moisture content at harvest of about 24%. Table 1 shows drying efficiency and corn quality results for a pulsed EMF application at indicated times for different types and masses of corn. Table 2 indicates data corresponding to larger volumes of corn on the order of kilograms.
TABLE 1
Statistical analysis of stress cracks in hard corn and soft corn
kernels under optimized high frequency PEMF drying conditions.
Corn Types
Soft
Hard
Soft
Hard
Mass of Corn, g
110
110
150
150
Drying Conditions
1 kW EMF
1 kW EMF
1 kW EMF
1 kW EMF
Power, 120 min
Power, 120 min
Power, 120 min
Power, 120 min
Moisture Content %,
23.3
23.0
23.3
23.0
INITIAL
Moisture Content %,
16.2
18.3
14.3
16.5
FINAL
Cracked kernels, %
8
2
8
8
TABLE 2
Statistical analysis of stress cracks in hard corn and soft corn
kernels under optimized high frequency PEMF drying conditions;
kilogram scale.
Corn Types
Soft
Hard
Mass of Corn, g
1003
1001
Drying Conditions
1 kW EMF Power;
1 kW EMF Power;
time: 60 min
time: 60 min
Moisture Content %,
24.4
24.1
INITIAL
Moisture Content %,
13
14.5
FINAL
Cracked kernels, %
6
3
The results of Table 2 are consistent with higher efficiency and energy savings at the kilogram scale in comparison to tests of lots about one order of magnitude lower. A greater sample load can translate into such benefits due to the contribution of the favorable filling factor. The combined results at the kilogram scale and the 0.1 kg scale indicate the scalable nature of the methods and apparatus of the invention. Although applicant does not wish to be bound by a particular theory, a possible simplified explanation of a mechanism, or sequence of events, is as follows.
The filling factor, or Q-factor, of the equipment is defined as the ratio of the total volume occupied by the wet corn, or any other sample to be treated, to the total volume irradiated by the pulsed emf source in the enclosed system containing the corn, or any other sample. The Q-factor is therefore, a unitless real number which is less than 1.0 and larger than zero. This factor contributes to the determination of how effectively the energy of the pulsed EMF is being used for drying corn. As an example, data from drying several pounds of wet corn when compared to several ounces of wet corn, show a marked increase in the effectiveness of energy usage for drying corn in the case of samples from 2 lbs to 5 lbs, as the Q-factor increases from about 0.02 to about 0.4, e.g. about twenty-fold. Note that an additional contribution to the PEMF efficiency for drying is the dielectric ‘constant’, or ‘permitivity’, ∈ wc , of the wet corn, which—in its turn—depends on both moisture level in the corn and the PEMF frequency range.
Example 5
PEMF Drying of Corn Stored Under Various Conditions
Soft, hard, and medium hardness corn from consecutive harvest years was collected in Illinois at incoming moisture levels of about 24%. Several sets of fresh corn were dried by pulsed EMF within a week from harvesting each year; the remainder of the corn harvest was stored in 4 separate lots (see Table 3). The fewest cracks and best results were obtained only with fresh corn and lot #1 (helium-classified corn, stored at 4° C.).
TABLE 3
Storage conditions for lots of corn.
Lot
Storage Conditions
1
Stored under a Helium gas atmosphere in sealed glass bottles,
after being first subjected to vacuum (0.1 torr) for two 2 min
intervals, and repeated flushing with helium gas, and then stored
at 4° C.;
2
Stored in the refrigerator at −20° C.;
3
Frozen rapidly in liquid helium, and then stored at −20° C.;
4
Subjected to vacuum (0.1 torr), and then stored in sealed vessels
at 4° C.;
Pulsed EMF drying of corn was carried out with laboratory-built, or commercial, resonant probe circuits tuned at frequencies of 30 MHz, 200 MHz, 360 MHz and 2,450 MHz (2.45 GHz). Pulsed EMF power sources were operated at 10 levels ranging from 100 W to 1000 W (1 kW). To cover this wide range of frequencies and power levels, four different setups of lab equipment were employed.
Water sorption isotherm of individual seeds of soft, medium hardness and hard corn were obtained with the isopiestic method, and the AOAC salt solution standards, as previously reported (Lioutas et al., 1986). Such measurements allowed us to determine specific hydration levels in terms of the total amounts of ‘bound’ water (nB) for soft, medium, and hard corn, as well as the amounts of ‘weakly’ bound, or trapped, water in each type of corn for various relative vapor pressures of water in the corn kernels. This information is useful for both determining the optimum drying level of corn and for selecting the most appropriate corn drying curves/drying rates.
Corn drying curves demonstrate that pulsed EMF does achieve similar results to conventional (electrical) oven drying at 95 F, but in a shorter time, and with potential energy savings of about 50 to about 85% in comparison with conventional, electrical oven drying, as well as natural gas-based drying. FIG. 1 illustrates exemplary drying curves for corn drying by pulsed EMF.
Example 6
Apparatus
The invention is further illustrated by FIGS. 2 and 3 . In FIG. 2 , a treatment system is depicted, for example for treating a plant product. FIG. 2 specifically illustrates application to corn drying. The system includes a computer operatively connected to a pulsed electromagnetic field generator. A first power source is operatively connected to the computer, and a second power source is operatively connected to the PEMF generator. The first and second power source can be the same source or different sources. The generator is connected to an output means for distributing the pulsed EMF energy. The output means can treat the product while the product is transported by a conveyor belt. A conventional fan is connected to the corn storage area for facilitating movement of ambient air to assist in removal of moist air and evaporation from the product surface. The computer controls treatment conditions, for example the pulse length and delay, the frequency selection, and can facilitate drying while optimizing energy usage and achieving desired corn quality.
A power source 30 is connected to a computer/pulse controller 10 which is further connected to a PEMF generator source 20 . A waveguide 24 is used to deliver waves directed to a sample chamber 40 . A low power fan 50 is mounted to the chamber 40 . A conveyer 70 is used to transport a sample 60 for exposure to the waves. The treated sample 80 is conveyed to a receptacle 90 or support surface. The receptacle 90 is operatively connected to a fan 100 . The corn to be treated or wet corn is represented by the open circles, and the treated corn or dried corn is represented by the filled circles. The receptacle 90 can be a storage bin or conventional corn drying bin or system for further processing.
FIG. 3 illustrates another system for drying agricultural products, particularly applicable for drying corn or other grains. The system includes a computer operatively connected to a pulsed electromagnetic field generator. The generator is connected to an output means for distributing the PEMF energy. The output means can be variably placed along a vertical axis that is perpendicular to the product container bottom. Upon distribution of a sample material in a layer within the container, the treatment can occur while the output means is located vertically so as to maximize irradiation of the sample layer. Irradiation is applied until a desired level of drying is achieved for the layer. Upon further distribution of a second layer, the output means may be moved so as to maximize irradiation for the second layer. Additional layers are further contemplated with analogous treatment.
A conventional fan is optionally connected to the corn storage area for facilitating movement of ambient air to assist in removal of moist air and evaporation from the product surface. The computer controls treatment conditions, for example the pulse length and delay, the frequency selection, and can facilitate drying while optimizing energy usage and achieving desired corn quality.
A power source 30 is connected to a computer/pulse controller 10 which is further connected to a PEMF generator source 20 . A waveguide 24 is used to deliver waves directed to a sample chamber 94 . The waveguide 24 is mounted to 94 in an adjustable, such as vertically adjustable manner. Optionally it can be horizontally adjustable or rotatably adjustable around the perimeter of the chamber. A transporting or delivery means 74 is used to provide a sample 60 for exposure to the waves. The treated sample 80 is retained in a storage chamber 94 or support surface. The chamber 94 is operatively connected to a fan 100 . The corn to be treated or wet corn is represented by the open circles, and the treated corn or dried corn is represented by the filled circles. As the corn is deposited in the chamber, layers are formed. In a specific embodiment, the waveguide is positioned initially towards a bottom layer and after time is moved up to be adjacent to an upper layer.
Example 7
Method of Drying Soybeans
Soybeans obtained in the United States were treated with a method and apparatus of the invention. Results are shown in Table 4. Soybeans are sensitive to harsh drying conditions in that certain valuable oils can be reduced or degraded. Therefore, the application of PEMF is useful in enhancing the optimal retention of such compounds.
TABLE 4
Soybean drying by high frequency PEMF.
Soybean description
Yellow Coat
Yellow Coat
Protein dry weight, %
43
41
Mass of Soybean seeds, g
50
100
Drying Conditions
1 kW EMF Power;
1 kW EMF Power;
time: 2 × 2 min
time: 2 × 2 min
Moisture Content %, INITIAL
9
11
Moisture Content %, FINAL
6
7
Example 8
Processes
FIG. 4 and FIG. 5 illustrate processes in embodiments of the invention. FIG. 4 illustrates a process system that has a feedback feature. The feedback is accomplished using an NIR monitor. An NIR monitor can monitor spectra for water but can also be used to monitor the whole corn composition including extractable starch and protein content. FIG. 5 illustrates a process system without a feedback feature.
An example of a potential advantage of a system with feedback (as illustrated in FIG. 5 ) is the optimization of results such as corn quality and drying efficiency. In contrast, a system without feedback is likely to produce dried corn of suboptimal, or inferior, quality. In a feedback system, the NIR monitor can be used to signal/control further treatment depending on the drying state as measured on a continuous, regular, or intermittent basis. If a desired moisture content for corn is 12% and the NIR monitor reflects a determination corresponding to 18%, then further treatment cycles can be signaled. If the NIR monitor reflects an observed drying curve that deviates from a desired standard drying curve, a signal can alter the pulse profile. For example, if the observed drying data indicates too rapid drying that could degrade corn quality, a signal can delay or alter further treatment, such as by temporally spacing pulses further apart or reducing the number of pulses. On the other hand, observed drying data that correlates with a drying process that is proceeding too slowly can lead to a signal that increases the number of pulses or decreases pulse delay times. The NIR monitor thus accomplishes the optimization of a drying curve resulting in advantages such as one or more of energy efficiency, time efficiency, and quality control.
FIG. 6 illustrates a computer program in flow chart form. The diagram depicts logical steps of the computer program that was employed for controlling the EMF source with DC square pulses. The program is implemented in the Basic language (IBM Co., USA) and was also tested under Microsoft Windows(™) 1998, 2000, and XP. The program is also performed as known in the art, for example in Visual Basic or higher level languages (e.g. C-language), as well as older programming languages such as FORTRAN and ALGOL. The program in Basic is preferred because of the simpler hardware and lower operation costs for the DC pulse generating board/source.
Example 9
Further Apparatus
FIG. 7 illustrates an apparatus embodiment. The apparatus employs an EMF generator and demonstrates applicable connections among a sample load, applicator, dummy load, tuner, and terminator or short-circuit. Here, a TUNER matches impedance between an EMF SOURCE and a SAMPLE LOAD (a bin at least partially filled with corn, for example), so that power transmission is optimal when the impedance at source and at sample load are equal. The CIRCULATOR next to the TUNER assists in protecting the EMF SOURCE from reflected power in an open circuit situation (in this case the impedance matching is occurring either through the dummy load or the power out is short-circuited by the shown TERMINATOR at the end of the waveguide or ‘horn’). The APPLICATOR is also useful for proper handling of emf power to the sample.
The equipment has an electrical circuit that can be adjusted to obtain maximum EMF output for the same power type employed, for example either direct current (DC) or more typically, alternating current (AC) power. This circuit can therefore be specified as a matching network. In some instances for EMF systems, such an adjustment is carried out by a manufacturer either under “no load” conditions, with no sample in the EMF enclosure of selected design but with a ‘dummy’ load instead, or with an average load for the expected most frequent samples to be treated. Further energy savings and increased effectiveness of energy use are however achieved by matching the impedance of a sample, for example, wet corn, with that of the matching network in the EMF source. Achievement of such matching impedance thus allows for maximum transfer of energy from the EMF source to the sample to be treated, or dried, such as wet corn. The matching impedance can be established at the beginning of the drying process. Optionally, the matching impedance can be established subsequently on an intermittent or continuous basis during the drying process. The establishment of matching networks and matching impedance can result in efficient tuning and operation over a wide range of EMF frequencies and with pulsed EMF power.
A suggested computer component is a personal computer (PC) with Windows or DOS operating system and Basica(™) or VisualBasic(™) installed. A pulse controller component can be a PC, DC-pulse board, either 8-bit, 12- or 16-bit. A near infrared monitoring system can be an NIR spectrometer system obtained from Ocean Optics (Dunedin, Fla., USA), a NIR spectrometer system such as Model No. ZX-50 from Zeltex, Inc. (Hagerstown, Md.) or other equivalent as known in the art.
Other components for apparatus that are suggested include a high power, continuously controllable emf source, such as those manufactured by Boonton Electronics (Parsippany, N.J.), CA, Varian, Bruker (USA) or GE (Schenectady, N.Y.) models, 1 kW emf power, either CW (continuous wave) or pulsed power (PW), the latter being preferred. Further appropriate options for emf power source include an industrial CW magnetron capable of 896 MHz and 915 MHz transmission such as Model CWM-50L by California Tube Laboratory, Inc. (Watsonville, Calif.); and a 1 to 6 kW emf power magnetron model such as those manufactured by Varian, Inc. (Palo Alto, Calif.).
A suggested power source component for a particular application can have specifications dependent on the particular application and variables such as bin size. For a corn drying application, the emf power range is specified as a 1 kW to 50 kW emf source, for example from Varian, Inc. or GE. Preferred ranges are about 1 kW to about 10 kW and about 1 kW to about 20 kW. The emf can be either pulsed or continuous. In a preferred example, the emf is capable of pulsed operation with an external trigger.
Statements Regarding Incorporation by Reference and Variations
All references throughout this application, for example publications, patents, and patent documents, are hereby incorporated by reference herein in their entireties, as though individually incorporated by reference, to the extent each reference is at least partially not inconsistent with the disclosure in this application (for example, a reference that is partially inconsistent is incorporated by reference except for the partially inconsistent portion of the reference).
The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be apparent to one of ordinary skill in the art that methods, devices, device elements, materials, procedures and techniques other than those specifically described herein can be applied to the practice of the invention as broadly disclosed herein without resort to undue experimentation. All art-known functional equivalents of methods, devices, device elements, materials, procedures and techniques described herein are intended to be encompassed by this invention. Whenever a range is disclosed, all subranges and individual values are intended to be encompassed. This invention is not to be limited by the embodiments disclosed, including any shown in the drawings or exemplified in the specification, which are given by way of example and not of limitation.
REFERENCES CITED
Lioutas, T., Baianu, I. C. & M. P. Steinberg. 1986 . Arch. Biochem. Biophys . 23: 236-247.
Baianu, I. C. & Kumosinski, T. 1994. ; “NMR Principles and Applications to the Structure and Hydration of Food Systems with Emphasis on Proteins,” Ch. 9 in ‘Physical Chemistry of Food Processes: Advanced Techniques, Structures and Applications’. Vol. 2. , I. C. Baianu, H. Pessen & T. Kumosinski, T., Eds., New York: Van Nostrand Reinhold-.Intl. Thompson Pubis., pp. 338-420.
Baianu, I. C., K. A. Rubinson and J. Patterson. 1979. Ferromagnetic Resonance and Spin Wave Excitations in Metallic Glasses. J. Phys. Chem. Solids, 40: 940-951.
Baianu, I. C., J. Patterson and K. A. Rubinson. 1979. Ferromagnetic Resonance Observations of Surface Effects, Magnetic Ordering and Inhomogeneous Anisotropy in a Metallic Glass, Material Sci. and Engineering , 40: 273-284.
Baianu, I. C., K. A. Rubinson and J. Patterson.1979. The Observation of Structural Relaxation in a FeNiPB Glass by X-ray Scattering and Ferromagnetic Resonance., Physica Status Solidi (a), 53: K133-135.
Scott, T. C., Klungness, J., Lentz, M, Horn, E. and Akhtar, M. 2002. Microwaving Logs for Energy Savings and Improved Paper Properties for Mechanical Pulps. In: Proceed. 2002 TAPPI Technical Conf. Trade Fair, San Diego, Calif., TAPPI Press: Atlanta, Ga., 10 pp.
Emam O A, Farag S A, Aziz N H, Z Lebensm Unters Forsch. 1995, Dec. 201(6): 557-61, Comparative effects of gamma and microwave irradiation on the quality of black pepper.
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CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of U.S. patent application Ser. No. 12/146,090 filed Jun. 25, 2008, now allowed as U.S. Pat. No. 8,261,399, the content of which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
The present application pertains to an oral care implement, in particular to a toothbrush with mechanical energy harvesting device and circuitry. Tooth brushing is part of a daily oral hygiene activity. Proper dental care involves regular flossing, brushing and dental checkups. Dentists generally recommend that an individual brush his or her teeth for a minimum interval per cleaning, such as two minutes. Despite such recommendations, many individuals, especially young children, do not regularly brush their teeth for the recommended minimum interval. Such habits often can be attributed to the individual regarding tooth brushing as a mundane duty with few pleasurable aspects.
BRIEF SUMMARY OF THE INVENTION
The present invention pertains to an oral care implement with mechanical energy harvesting device and circuitry. In one aspect, the oral care implement can signal to a user when a suitable level of brushing has been accomplished.
A number of mechanical energy harvesting circuits may be used in an oral care implement to capture mechanical energy from brushing, and to convert that mechanical energy into electrical energy that can be used at a later time. For example, an oral care implement may have a handle, head with tooth cleaning elements, a mechanical energy harvesting device or circuit (to convert mechanical energy into electrical energy), an electrical energy storage device (to store the electrical energy) and a switching circuit to close an electrical connection with the storage device when a predetermined voltage has been reached.
In one aspect, the predetermined voltage may be determined by taking into account typical brush stroke length, stroke number and force of brushing.
In one aspect, the mechanical energy harvesting circuit can include one or more piezoelectric devices positioned to generate electricity in response to deflections or bending of the toothbrush head and/or tooth cleaning elements.
In one aspect, the harvesting circuit can include one or more electromagnetic generators, having wire coils and moveable magnets, to induce an electric current as the magnets pass through the coils due to movement of the toothbrush during brushing.
In another aspect, a rectifier circuit may be used to rectify the electricity generated by the harvesting circuit before storage in the storage device, and a voltage regulator may be used to provide a constant level output when the storage device is being discharged.
Other features and embodiments are described in the sections that follow.
BRIEF DESCRIPTION OF THE DRAWINGS
The features herein will become more fully understood from the detailed description given herein below, and the accompanying drawings, which are given by way of non-limiting illustration only.
FIG. 1A is a longitudinal cross-sectional view of a toothbrush construction in accordance with at least one aspect of the invention.
FIG. 1B is a longitudinal cross-sectional view of an alternative toothbrush construction in accordance with at least one aspect of the invention.
FIG. 1C is a longitudinal cross-sectional view of an alternative toothbrush construction in accordance with at least one aspect of the invention.
FIG. 1D is a longitudinal cross-sectional view of an alternative toothbrush in accordance with at least one aspect of the invention.
FIG. 2 is an electrical schematic illustrating an exemplary circuit configuration in accordance with at least one aspect of the invention.
FIG. 3 is a cross-section view of an alternative head construction taken along the width of a toothbrush in accordance with at least one aspect of the invention.
FIG. 4 is an electrical schematic illustrating an alternative circuit configuration.
DETAILED DESCRIPTION OF THE INVENTION
The following detailed description refers to the accompanying drawings. The same reference numbers in different figures identify the same or similar elements.
As illustrated in FIGS. 1A-1D , an oral care implement, such as toothbrush construction 100 , 300 , 400 , 500 , may include a brush head 101 and a handle 102 . The head 101 may be a refill head that is removably connected to handle 102 , or it may be integrally formed and attached to the handle 102 .
The head 101 may include one or more tooth cleaning elements, such as a field of bristles 103 . As used herein, the term “tooth cleaning elements” or “cleaning elements” includes any type of structure that is commonly used or is suitable for use in providing oral health benefits (e.g., tooth cleaning, tooth polishing, tooth whitening, massaging, stimulating, etc.) by making contact with portions of the teeth and gums. Such tooth cleaning elements include but are not limited to tufts of bristles that can be formed to have a number of different shapes and sizes and elastomeric cleaning members that can be formed to have a number of different shapes and sizes, or a combination of both tufts of bristles and elastomeric cleaning members.
Referring to the toothbrush construction 100 of FIG. 1A , the head 101 may also include one or more energy producing devices, such as piezoelectric devices 104 . The piezoelectric devices 104 may be arranged in contact with, or proximate to, the bristles 103 , so that movement of the bristles causes stress or strain on the devices 104 . For example, a given bristle may be attached to a cantilever portion of a micro-electro-mechanical system (MEMS) device to stress or strain the device 104 . MEMS cantilevers are conventionally fabricated from silicon nitride (SiN), silicon (Si), or various polymers. In a cantilever MEMS device, the proximal end of the cleaning element (e.g., bristle or elastomeric element) is attached to the “cantilevered” portion of the MEMS device. In this construction, z-axis movement of the cleaning element causes deflections in the MEMS device which invokes electrical potential. Nevertheless, the amount of electrical energy depends on the modulus of elasticity of the material, the thickness of the cantilevered portion and the piezo-resistive material of the MEMS device.
The stress or strain causes the piezoelectric device 104 to generate a small amount of electrical energy, such as a voltage. As will be explained below, the head 101 may also include wiring and circuitry to carry this voltage to other parts of the toothbrush 100 , and that electrical energy may eventually be used to power one or more output devices 105 .
Referring to the toothbrush construction 300 of FIG. 1B , the head 101 may also include one or more piezoelectric devices 106 that are stressed or strained by the natural bending of the head 101 along the longitudinal axis X-X that occurs during a normal tooth brushing operation. The amount of bending or deflection along the longitudinal axis can depend on the type of material and thickness of the head 101 . For example, rigid plastics or resins, such as polypropylene, may be used to form the head 101 . To provide a controlled deflection profile and/or focus the bending in regional areas, the head 101 may include one or more flexing joints 107 disposed transverse (e.g., along a Y-axis) to the longitudinal axis X-X. In the one construction, the joints 107 may be disposed perpendicular to the longitudinal axis of the toothbrush. In other constructions, the joints 107 may be notches or grooves, having less head material in the area than in the immediate surrounding portion of the head 101 . In the alternative construction, the joints 107 may be formed of a less rigid material than other portions of the head (e.g., rubberized or elastomeric sections at the joints 107 ). The flexibility of the head 101 (e.g., Z-axis movement) facilitates enhanced cleaning of the lingual and facial surfaces with dentifrice on the tooth cleaning elements. In addition, Z-axis movement of the tooth cleaning elements facilitates improved interproximal cleaning as well as cleaning of the crowns of the molars of the teeth of a human. In this way, a toothbrush provides improved cleaning capabilities and energy harvesting features.
The piezoelectric devices 106 may be placed near the joints 107 to maximize the stress or strain experienced by the device 106 as the head deflects or bends along the longitudinal axis X-X during brushing. Nevertheless, the head 101 may twist to have a torsional component which causes strain on the piezoelectric device 106 . The changes in strain on device 106 invoke an electrical response in the piezoelectric device. Hence, during a brushing operation, piezoelectric devices 106 can experience a combination of different types of movements including, for example, a deflection along the longitudinal axis and a twisting component about the same longitudinal axis.
As illustrated in FIG. 1B , the piezoelectric devices 106 may be placed directly above and centered relative a flexing joint 107 . In alternative head construction shown in FIG. 3 , the joints or grooves 308 may be disposed along or generally parallel to the longitudinal axis X-X of the toothbrush. In this construction, the grooves 308 are disposed across the width W of the head. Piezoelectric device 304 may be placed directly above and centered with respect to a flexing joint 308 . Alternatively, the device 304 may be placed under the bristle field similar to device 104 . In these longitudinal joint constructions, the head 101 may flex in side-to-side motions (e.g., width) and provide improved energy harvesting features.
Referring to FIGS. 1A and 1B , with the piezoelectric devices 104 , 106 , the amount of electrical energy generated will vary proportionally with the amount of force used to brush a user's teeth. Individual performance ranges will depend on the piezoelectric material type and configuration chosen, and any piezoelectric material type and configuration may be used as desired. Additionally, different types of piezoelectric devices may be used. The device 106 may be larger in structure than device 104 . In one construction, device 104 , 106 may be a microelectromechanical system (MEMS) device that includes a cantilever portion attached to each of a plurality of the bristles 103 .
Referring to the toothbrush construction 400 of FIG. 1C , the toothbrush 400 may also include one or more electromagnetic generators 108 . Each generator 108 may include a wire coil 109 and a magnet 110 that is configured to freely move through the coil 109 as the toothbrush 100 is moved back and forth along its longitudinal axis (horizontal, as depicted in FIG. 1 ). This configuration may be accomplished in a variety of ways. For example, the coil 109 may be embedded within a tube of a non-conducting material having a low coefficient of friction, and the magnet 110 (which may also be encased in a similar material) may be centrally aligned within the tube. The non-conducting material having a low friction should be biocompatible. An example of such a material is polycarbonate.
As the toothbrush 400 is moved back and forth, the magnet 110 moves back and forth through the coil 109 , inducing a small amount of current in the coil 109 . The amount of current generated will depend on several factors, such as the strength of the magnet, the number of loops in the coil, and the speed at which the magnet travels. The head 101 may include additional wiring and circuitry to convey this current to other parts of the toothbrush, as will be explained below.
Referring to FIG. 1D , toothbrush construction 500 may include a combination of the features of toothbrush constructions 100 , 300 , and 400 for energy harvesting.
FIG. 2 illustrates an electrical schematic that can be used with the toothbrush 100 . As illustrated, an energy harvesting device 201 represents the devices 104 , 106 and/or electromagnetic generators 108 that are in the toothbrush 100 . The toothbrush 100 may have one, some, or all of these as energy harvesting devices, and they are generically represented in FIG. 2 .
The energy harvesting device 201 may generate an alternating current (AC) output due to the back-and-forth motion of the toothbrush 100 and/or bending of the head 101 and/or bristles 103 . For example, the generator 108 may generate an alternating current (AC) output in use (e.g., generating a positive current when the toothbrush is moved in one direction, and a negative current when the toothbrush is moved in an opposite direction). This output may be supplied to a rectifier circuit 202 to convert the AC output to a DC output. Any type of rectifier circuit 202 may be used, depending on the type of output generated by the particular piezoelectric devices 104 , 106 and/or the generator 108 , and on the type of output desired.
The rectifier circuit 202 may then be coupled to an electrical energy storage device 203 . Device 203 may be any type of device that can receive electrical energy (a charge) and store it for later use. For example, a capacitor or rechargeable battery may be used to store the electrical energy from the rectifier 202 in the form of a stored charge. The actual amount of charge stored will depend on the type and number of energy harvesting devices 201 used in the toothbrush, and the electrical energy storage device 203 may act as an integrator summing the charges generated by each movement, bending, or stroke of the toothbrush.
The energy stored in energy storage device 203 will accumulate as the toothbrush is used, and a switch circuit 204 may be used to regulate the release of that energy. The switch circuit 204 may keep an electrical connection between the storage device 203 and an output load 206 in an open state until the voltage level in the storage device 203 reaches a predetermined level, and then close that connection when the voltage reaches that predetermined level to discharge the device 203 and to allow the output load 206 to use the stored energy. One example embodiment of the switch circuit 204 is a silicon-controlled rectifier (SCR), or a thyristor, configuration, as illustrated in FIG. 2 . By knowing the SCR's turn-on voltage, and the desired predetermined voltage for the storage device 203 , the ratio of resistor values R 1 /R 2 can be chosen so that the SCR turns on when the voltage across the device 203 has reached that predetermined voltage level.
That predetermined voltage level can be chosen to reflect a suitable amount of tooth brushing. For example, this can be based on a typical stroke length and/or force of brushing. If a typical tooth brushing is expected to run for S strokes at a force of F Newtons before the switch 204 is to be closed, and a typical stroke is L m in length, then it is known that the typical brushing will generate (S strokes)*(L m/stroke)*F N=X Joules of energy. When the accumulated voltage in the storage device 203 corresponds to that amount of work done during the brushing, the switch will close.
During brushing, the piezoelectric devices 104 , 106 will generate a known amount of voltage for a given amount of bending force, and the electromagnetic generator 108 will generate a known amount of current for each time the magnet 110 passes through coil 109 . This energy will be stored in the storage device 203 , and accordingly, the storage device 203 acts as a form of integrator, totaling up the mechanical work performed by the user's brushing. If the user brushes faster, or harder, the storage device 203 will accumulate charge faster than if the user brushes slower or with less force.
When the predetermined voltage has been accumulated, the switch circuit 204 may close the electrical connection, and the stored voltage in device 203 may be discharged and used for a variety of purposes. For example, output devices 206 may include devices that signal to the user when sufficient brushing has occurred. Such signaling devices may take many forms, such as a light-emitting diode (LED) or other illuminated display, a speaker generating an audible tone, and/or a mechanical vibrator. For example, a display may be placed on the toothbrush to assist in reporting output. The display may include light-emitting diode (LED) displays, an alphanumeric display screen, individual lights, or any other desired form of visual output. For example, the display may be an Organic LED or electroluminescent sheet that can be tuned to provide a desired luminescent characteristic such as color, temperature, intensity etc. OLED or EL (electroluminescent) technology can be embedded into the toothbrush molding, or can be applied to the surface of the toothbrush body. It should be understood by those skilled in the art that the present invention is not limited to any particular type of display.
In some implementations, the toothbrush relies entirely on the mechanically-harvested energy to run these output devices, so the devices may be configured to be very low power devices. For example, an energy-efficient LED with a current limiting resistor may be used, or a DC piezoelectric buzzer as an audio device, or a piezoelectric vibrator as a vibrating device.
Output devices 206 can perform other functions besides informing the user when brushing is complete. For example, the energy can be used to power components, such as micro pumps and pump valves, to deliver actives at predetermined stages during brushing. For example, a separate active or flavor can be automatically delivered midway through the brushing. The energy can alternatively be used as a supplement to energy provided by another battery on the toothbrush (e.g., for playing video games, playing music, or any other battery-operated function), or to recharge such a separate battery. In some configurations, toothbrush 100 , 300 , 400 , 500 may be a traditional electric vibratory toothbrush (with vibrating head/bristles, motor, power supply, etc.), and the energy harvesting circuitry may be used as a supplement to recycle some of the mechanical energy in the brushing and vibration of the toothbrush and use that energy to assist in powering and/or recharging a battery of the device.
The toothbrush may include a voltage regulator 205 to provide a constant voltage to the output device 206 . For example, National Instrument's LM2674 or LM3670 integrated circuit may be used for this purpose.
Other embodiments will be apparent to those skilled in the art from consideration of the specification disclosed herein. For example, the FIG. 2 schematic is merely an example. While FIG. 2 represents energy harvesting devices 201 generically, and shows a single example rectifier 202 , storage 203 , switch, 204 , etc., multiple devices 201 may be used and separate circuitry can be supplied for different types of devices 201 .
FIG. 4 illustrates an alternate circuit configuration. This alternate configuration can use an integrated circuit (e.g., part no. LM3670_SOT23 — 5 U1), instead of the SCR in FIG. 2 , to control the switching of the circuit. The use of this integrate circuit for the switching may allow the easier turning on/off of the device at the enable pin (labeled pin 3 , or “EB”, in the Figure), allowing for a more efficient system. The FIG. 3 configuration also shows the addition of a Zener diode D5. The Zener diode may protect against the generation of too much voltage, by short-circuiting the source if too much voltage is generated. Such a component may help prevent damage to the circuitry if, for example, the user vigorously brushes or shakes the toothbrush for an extended period of time.
It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
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BACKGROUND OF THE INVENTION
This invention relates to operation of a halogen lamp in a dental curing process and, more particularly, to the obtaining of more power in a usefull spectral region without diminishing useful lifetime of the lamp.
A halogen lamp has a tungsten filament which is heated by electric current during operation of the lamp. The lamp's lifetime is based on the integrity of the filament. Once the filament burns out, the lamp no longer operates. While the lamp is operating, heat produced by electric current in the filament induces evaporation of the filament. Thus, the filament is continuously evaporating during operation of the lamp and, when the diameter of the filament reaches the critical point, the lamp burns out. A higher current flow in the filament results in a more rapid evaporation. Thus, during the start-up interval of the lamp, before the filament has attained its operating temperature, a much larger current flows with a resultant higher rate of evaporation.
In order to preserve the lifetime of a lamp having a tungsten filament during operation wherein the lamp may be turned on and off frequently, it is known to use a current limiter such as an NTC (negative temperature coefficient) thermistor to suppress the initial inrush current while providing negligible electrical resistance once the filament has heated to operating temperature. Unfortunately, such a current limiter develops significant heat after suppressing the initial inrush current, and requires a cool-town (recovery) time after power is removed from the lamp and prior to reactivation of the lamp. Due to the temperature dependent operating characteristic of the thermistor, the thermistor must be allowed to cool down in order to restore its resistance to the appropriate value for reactivation of the lamp. The cool-town time is approximately one minute. This presents an inconvenience in the situation wherein it is desired to turn the lamp off momentarily before reactivating the lamp. Also, the current limiter suffers from the disadvantage of dissipating some of the electric power which would otherwise be employed usefully in operation of the lamp.
In the use of a halogen lamp for curing dental material, it is advantageous to operate the lamp in a fashion which accelerates the rate of the curing. Thereby, the curing can be accomplished advantageously in a lesser amount of time. One way to accomplish this is to raise the operating voltage of the lamp, resulting in increased power dissipation in the lamp with increased light output. However, this introduces the disadvantage of reduced lifetime of the lamp. Another factor to consider in accelerating the curing process is the spectral distribution of light produced by the lamp. The curing process is accomplished best with a light wavelength of approximately 450 nm (nanometers). However, more than 95 percent of halogen lamp light, in the case of a typical halogen lamp heated by a tungsten filament, has a wavelength over 600 nm. Therefore, normal operation of a halogen lamp suffers from a lack of optimization of the spectral distribution of the light for use in the curing of dental material.
SUMMARY OF THE INVENTION
In view of the aforementioned disadvantages and problems, it is an object of the present invention to operate a halogen lamp in a manner which accomplishes a more rapid curing of dental material while substantially retaining the expected lifetime of the lamp. In accordance with a feature of the practice of the invention, it is recognized that the spectrum of light radiated by the lamp is dependent on the electrical voltage employed for exciting the lamp. Thus, an increase of the operating voltage by 10 percent shifts the color temperature to give a 6 percent color temperature rise, in the case of a typical halogen lamp heated by a tungsten filament. The increase of the operating voltage by 10 percent in this lamp also results in an increase of radiated light energy by 34 percent. The increase in color temperature is manifested by a shifting of the maximum spectral radiation output from longer wavelength toward shorter wavelength. In the case of the foregoing example, the spectrum shifting results in an additional 5 percent light output. While the increase in applied voltage provides the foregoing advantageous features in the operation of the lamp, it is noted that the increased voltage is accompanied by a disadvantage in that the foregoing 10 percent increase in the operating voltage results in a shortening of the lamp's life by 40 percent.
In accordance with the methodology and the apparatus of the invention, enhanced usage of the halogen lamp for the curing of dental material is obtained by increasing the voltage applied to the lamp to shift the spectrum and obtain better utilization of the frequency spectrum of the output light, and to increase intensity of the output light, while regulating the applied voltage for a gradual increase of the voltage at the time of initial turn on of the lamp so as to avoid the initial surge current with its associated rapid evaporation of the filament. The design lifetime of the lamp is retained because the loss in use of the lamp associated with the increased voltage is balanced by the improved utilization of the spectrum, and the avoidance of the initial surge current so as to maintain an upper bound on the magnitude of the current.
BRIEF DESCRIPTION OF THE DRAWING
The aforementioned aspects and other features of the invention are explained in the following description, taken in connection with the accompanying drawing figures wherein:
FIG. 1 shows a stylized view of a halogen lamp heated by an internal electrical filament, and radiating light useful in the curing of dental material;
FIG. 2 provides two graphs representative of spectral emission characteristics of the halogen lamp as a function of voltage applied to the lamp filament, the upper graph being unfiltered light and the lower graph being filtered light;
FIG. 3 is a diagram of an electric circuit for controlling voltage and current applied to the filament of the lamp in the practice of the invention; and
FIG. 4 is a set of graphs showing voltage as a function of time employed for heating the lamp filament.
Identically labeled elements appearing in different ones of the figures refer to the same element but may not be referenced in the description for all figures.
DETAILED DESCRIPTION OF THE INVENTION
With reference to FIG. 1, a halogen lamp 10 comprises an envelope 12 containing a halogen gas and enclosing a heating element in the form of an electrical filament 14 for heating the lamp 10 . A source of electric power for the lamp 10 is represented by a variable voltage source, depicted as a variable battery 16 , for applying voltage and current to the filament 14 . Upon providing sufficient current by the battery 16 to heat the filament 14 to operating temperature of the lamp 10 , the lamp 10 radiates light 18 through a filter 19 to illuminate dental material 20 held within a tray 22 . The rays of the light 18 incident upon the filter 19 are further identified by the legend 1 8 A, and the rays of the light 18 outputted by the filter 19 are further identified by the legend 18 B. The filter 19 has a spectral passband of 300 nm to 600 nm. The filtered light 18 B aids in the curing of the dental material 20 . A higher intensity of the light 18 results in a decreased time to accomplish the curing. Also, an adjustment of the spectral distribution of the light 18 to provide increased intensity in the vicinity of 450 nm light wavelength results in a decreased time to accomplish the curing. Increased lifetime of the lamp 10 is accomplished by a gradual application of the excitation voltage to limit the magnitude of the heating current to the filament 14 as the electrical resistance of the filament 14 rises with the temperature of the filament 14 .
The heating element has a resistance characterized by a positive temperature coefficient such that, at a relatively low temperature, the resistance is relatively low, and that at relatively high temperature, the resistance is relatively high, and wherein the resistance rises immediately after application of voltage to the heating element due to the rise in temperature of the heating element. By applying voltage of reduced magnitude during the initial stages of heating the filament, and allowing the voltage to rise in a manner substantially proportional to the resistance of the filament, the magnitude of the current is maintained substantially constant during the initial heating stage of the filament, thereby to place an upper bound on the magnitude of the current and to avoid the sudden inrush of current to the filament. This avoids unwanted evaporation of the filament to promote longevity in usage of the lamp. By use of the term “substantially proportional”, it is to be understood that the applied voltage may not follow the changes in resistance exactly and that the relationship may not be perfectly linear. However, the voltage follows the resistance sufficiently closely to maintain an upper bound on the current.
In FIG. 2, the graph shows the intensity of light emitted by the lamp 10 as a function of frequency of the light. The intensity is shown along the vertical axis, and increasing wavelength is shown toward the right along the horizontal axis. For ease of reference, the light 18 A incident upon the filter 19 is identified in FIG. 2 as white light, and the filtered light 18 B outputted by the filter 19 is identified in FIG. 2 as blue light. In both the upper graph for the unfiltered light and the lower graph for the filtered light, there are two traces of which the lower trace represents the light output for normal energization of the lamp, and the upper trace represents the light output for excitation at increased current and voltage to the filament. The value of 450 nm is shown in the graph, and represents a preferred value of light wavelength for the curing of the dental material. It is noted that while the invention is being demonstrated for the case of the curing of dental material, the invention may be employed also for the processing of other material wherein the intensity and the spectral distribution of the radiation may be chosen to optimize the processing.
FIG. 3 shows connection of a power source 24 to the halogen lamp 10 . Input line voltage, such as that of the power provided to homes and offices, is applied by a terminal pair 26 . Electric power at the terminal pair 26 is coupled by a step-down transformer 28 and a diode bridge rectifier 30 to the power source 24 . The transformer 28 reduces the AC (alternating current) line voltage to a lower value of AC voltage across terminals 32 and 34 for driving the bridge rectifier 30 . The AC voltage is converted by the bridge rectifier 30 to a DC (direct current) voltage appearing between line 36 and ground 38 , the DC voltage being applied via line 36 and ground 38 to the power source 24 . Voltage is outputted from the power source 24 to the halogen lamp 10 via line 40 and ground.
The power source 24 comprises a power regulator 42 , three capacitors C 1 , C 2 and C 3 , four resistors R 1 , R 2 , R 3 and R 4 , two diodes D 1 and D 2 , and a switch 44 . The capacitor C 1 connects between the line 36 and ground for filtering the input voltage on line 36 . The capacitor C 2 connects between line 40 and ground for filtering the output voltage on line 40 . The input voltage on line 36 is applied to the first input voltage terminal 46 of the power regulator 42 . The output voltage on line 40 is provided by an output voltage terminal 48 of the power regulator 42 . A second input terminal 50 of the regulator 42 is responsive to a DC voltage, such as the voltage on line 36 , to activate the regulator 42 to output the desired voltage on line 40 ; removal of the voltage from terminal 50 terminates the presence of the output voltage on line 40 . Also included in the regulator 42 is a negative feedback terminal 52 by which operation of the regulator 42 is responsive to a feedback signal for maintaining the output voltage on line 40 at a desired value.
The resistors R 1 and R 2 are connected in series between line 40 and ground for providing a sample of the output voltage of line 40 at the junction between the resistors R 1 and R 2 . The sample of the output voltage has a magnitude equal to only a fraction of the output voltage, and is applied, as feedback signal, to the feedback terminal 52 of the regulator 42 . This constitutes a feedback circuit of the power source 24 for control of the magnitude of the output voltage on line 40 . The magnitude of the feedback signal at terminal 52 establishes the magnitude of the voltage appearing on line 40 . By way of example in the construction of the circuit, the resistors R 1 and R 2 are shown as fixed resistors wherein their values are selected to provide the desired output voltage. However, if desired, the voltage divider circuit of the resistors R 1 and R 2 may include a variable resistor (not shown) allowing for manual adjustment of the output voltage.
The switch 44 has two positions, a first position, as shown in FIG. 3, for grounding the second input terminal 50 of the regulator 42 , and a second position in which the voltage of the line 36 is applied by the switch 44 to the second input terminal 50 of the regulator 42 . In the first position of the switch 44 , the regulator 42 is turned off so as to output no voltage on line 40 to the lamp 10 . In the second position of the switch 44 , the regulator 42 is turned on to output the voltage on line 40 for energizing the lamp 10 .
A feedforward circuit 54 connects between the second input terminal 50 and the feedback terminal 52 of the regulator 42 . The feedforward circuit 54 comprises the capacitor C 3 , the diodes D 1 and D 2 , and the resistors R 3 and R 4 . The feedforward circuit 54 is active immediately after the throwing of the switch 44 from the first position to the second position. The feedforward circuit 54 receives a step voltage upon the throwing of the switch 44 to its second position, and converts the step voltage to a ramp voltage which is applied to the feedback terminal 52 . The ramp voltage initially is sufficiently great to overpower the feedback voltage provided by the resistors R 1 and R 2 so as to direct the regulator 42 to output a relatively low value of output voltage on line 40 to the lamp 10 . As the ramp voltage decreases in magnitude, its effect is reduced so that the regulator 42 begins to increase the magnitude of the output voltage on line 40 . At the conclusion of the ramp voltage, the operation of the regulator 42 is controlled only by the feedback voltage provided by the resistors R 1 and R 2 so that the full value of the desired output voltage appears on line 40 .
In the operation of the feedforward circuit 54 , the leading edge of the step voltage is coupled by the capacitor C 3 to the diode D 2 , and then via the resistor R 3 to the feedback terminal 52 . The connection of the resistor R 3 to the junction of the resistors R 1 and R 2 provides the configuration of a voltage divider which reduces the magnitude of the ramp voltage to a small fraction of the input voltage appearing on line 36 . After the closure of the switch 44 to bring it into its second position, current flows through the capacitor C 3 , through the diode D 2 , and through the resistors R 3 and R 2 to ground, this current charging the capacitor C 3 to produce an ever increasing voltage drop across the capacitor C 3 . The increasing voltage drop across the capacitor C 3 results in a decreasing current through the capacitor C 3 and the resistor R 2 to provide the ramp voltage of decreasing amplitude at the feedback terminal 52 . At the conclusion of the energization of the lamp 10 , when the switch 44 is opened to bring it into its first position, the capacitor C 3 discharges by current flow through a series circuit consisting of the diode D 3 , the resistor R 4 , the switch 44 and ground. The value of the resistor R 4 is selected to provide for a discharge time which is sufficiently fast to ready the feedforward circuit 54 for the next interval of activation of the lamp 10 .
In the set of graphs shown in FIG. 4 respective ones of the graphs are identified by the legends 1 , 2 , 3 and 4 which correspond to the numbering of selected nodes 1 , 2 , 3 and 4 in the circuitry of FIG. 3 . Node 1 is at the junction of terminal 50 , the switch 44 , and capacitor C 3 . Node 2 is at the junction of the capacitor C 3 , resistor R 4 and diode D 2 . Node 3 and is at the junction of terminal 52 , resistor R 3 , resistor R 1 and resistor R 2 . Node 4 is at the junction of terminal 48 , the lamp 10 , resistor R 1 and capacitor C 2 . The first, the second, the third and the fourth graphs of FIG. 4 show the waveforms of the voltages appearing respectively at the nodes 1 , 2 , 3 and 4 . In each of the four graphs, voltage is shown along the vertical axis, and increasing time is shown toward the right along the horizontal axis. The voltage waveforms shown in all of the four graphs are presented in time registration with each other.
With respect to the waveform at node 1 , the voltage is zero when the node is grounded by the switch 44 . When the circuitry is turned ON by movement of the switch 44 to the second position, the voltage is equal to the voltage on line 36 as is outputted by the diode bridge rectifier 30 . These two voltage states are shown in the first graph.
With respect to the waveform at node 2 , the voltage is proportional to the current flowing through the capacitor C 3 , wherein the waveform begins with the operation of the switch 44 to turn the circuitry to the ON state. The graph shows that, as the capacitor C 3 charges, the current diminishes with time to approximate, during the initial stage of the charging, a ramp voltage. Eventually, the voltage passed by the capacitor C 3 drops below the level necessary to keep the diode D 2 in a state of conduction. From that point on, the ramp voltage no longer has an effect at node 3 . The charging time is significantly less than the ON time of the switch 44 .
With respect to the waveform at node 3 , there is a scaling of the voltage waveform of the second node to reduce its value, and a summation of the voltage of the second node with the voltage produced by the voltage-divider circuit of resistors R 1 and R 2 . Therefore, the initial stage (identified in FIG. 4 as the ramp period) of the voltage waveform at node 3 includes a ramp, while the balance of the waveform shows a voltage of substantially constant amplitude. The value of resistor R 4 is much smaller than the value of the resistor R 3 so that the discharging process of the capacitor C 3 requires less time than the charging process.
With respect in the waveform at node 4 there is shown the voltage outputted to the lamp 10 by the regulator 42 in response to the voltage (at node 3 ) fed back to the feedback terminal 52 . During the interval of time identified in FIG. 4 as the ramp period, there is a gradual rise in the amplitude of the voltage fed to the lamp 10 to provide a desired “soft” start which avoids a heavy inrush current to the lamp 10 . Thereafter, the voltage fed to the lamp 10 has a constant amplitude until the throwing of the switch 44 to the OFF state wherein node 1 is grounded. Thereupon, the regulator 42 terminates the voltage fed to the lamp 10 .
It is to be understood that the above described embodiments of the invention are illustrative only, and that modifications thereof may occur to those skilled in the art. Accordingly, this invention is not to be regarded as limited to the embodiments disclosed herein, but is to be limited only as defined by the appended claims.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] Generally, the present invention relates to surgical instruments. More specifically, the present invention relates to trocars that can be used in conjunction with other surgical instruments.
[0003] 2. Description of Related Art
[0004] For many years most surgery was performed using an open field technique. The surgeon made an incision dictated by the need to directly observe the area or field of interest and to insert his or her hand or hands, and/or one or more instruments therein to perform manipulations within the body cavity accessed through the incision. Retractors and assistants help to provide means of access. For many procedures these incisions are as long as 20 centimeters, traumatic, and painful. This translates into a painful recovery, prolonged hospitalization with a slow return to a normal functional state, and significant cost.
[0005] An alternative to open surgery, endoscopic surgery, has also been available for many years, though not as widely applied. Through an endoscope, a tubular optical system for viewing the interior of an organ or body cavity, tissues can be observed. An endoscope is used by making a small incision in the appropriate body covering. A hollow tube, or port, usually 10-25 cm in length and 5-30 mm in diameter, is placed through the incision and the endoscope is placed through the hollow tube. Through various other incisions and ports, other instruments can be placed into a body space for manipulation, grasping, cutting, coagulation etc., similar to open surgery. In the abdomen and pelvis, the optical tube is called a laparoscope and the method is referred to as laparoscopic surgery.
[0006] Laparoscopic surgery usually includes a step of expanding the body cavity with air, inducing a state of pneumoperitoneum, which enhances the surgeon's view and ability to make manipulations. This is accomplished by one of two techniques, air insufflation or abdominal wall lifting. Abdominal wall lifting creates negative pressure within the cavity in relation to the atmosphere, drawing in air through a small incision when the wall is lifted. The disadvantage with this technique is that observation is imperfect. A tent is created with a central peak and a collapsed perimeter. Though most-structures have midline attachments, most endoscopic manipulations take place in the periphery. This is where visualization with this technique is worst. Insufflation is a positive pressure system using a medicinal vapor such as carbon dioxide or nitrogen injected into the peritoneal cavity to balloon the abdominal wall. Expansion is more uniform; vision is better. This is the most widely used technique. Because of the positive pressure, however, the abdomen must be sealed to maintain expansion. This requires that all incisions and ports be sealed. Insufflation also has adverse respiratory and hemodynamic consequences due to positive pressure inhibiting chest expansion and venous blood return to the heart.
[0007] Though endoscopic surgery has been available for many years, its application has recently increased due primarily to the development of video monitoring equipment This has allowed all members of the surgical team to observe, though indirectly what the surgeon could previously observe through a laparoscope. In some cases visualization is better than with direct observation. This has led to renewed interest and investigation of these techniques.
[0008] The benefit of endoscopic surgery is the limited incisional trauma, improved cosmesis, and decreased pain. For several simple techniques, such as laparoscopic cholecystectomy, this has translated into decreased hospitalization and earlier return to normal function, though cost savings is debated.
[0009] While some open surgical procedures have been adapted to laparoscopic technique, there are limitations with this method, particularly with more complex procedures. Fundamental problems relate to the access tubes used for inserting the various manipulative instruments. While limiting incisional trauma, the small diameter of these tubes dictates and limits the design of the inserted instruments. To achieve similar function as in open surgery, equipment becomes complex and therefore more expensive. There is also added risk with each access tube. Each tube requires a stab-wound of the body wall, risking injury to contained viscera with each puncture.
[0010] Equally important has been the impact on the surgeon's ability to manipulate tissue. While the visual field may have been improved, tactile sensation, depth perception, and proprioceptive awareness of tissues have been markedly reduced by instruments that insulate the surgeon from the operative field. As the surgeon continually confirms that that which is done is that which is desired, procedural and anesthesia time increase. Furthermore, the limited access enabled by each port dictates that multiple ports be used. As procedural complexity increases, the surgeon must adapt to a continuously changing and less predictable environment than with simple procedures. The number of ports, and the risk and incidence of complications increases. The requirement for highly skilled and coordinated surgical teams also increases. This has resulted in long learning curves and has limited wide application of these procedures for complex cases.
[0011] One device in common usage to establish relatively small incisions for the insertion of equipment therethrough is the trocar. The trocar has a sharp end designed to pierce the skin as the surgeon presses it down to pierce through the skin. It may also pierce the underlying viscera unless great care is taken, particularly in view of the flexibility of the body wall. The trocar includes a cannula or tube used for drainage or for the insertion of a device into the body cavity. Since it is desirable to minimize the patient's wounds, there is an effort made to minimize the size of an incision associated with trocar use. As a result, the size of the tube used in the trocar-created incision is generally relatively small. It therefore can only be used to pass relatively small devices into the body cavity. Moreover, the narrow tube severely restricts maneuverability of the device contained therein. Therefore, though trocars offer the advantage of wound minimization, they are of some danger to the viscera, they are of restricted dimensions for allowing the passage of devices of interest there through, and they permit limited tactile manipulation.
[0012] There has been concern about wound contamination during laparoscopic surgery, particularly the implantation of tumor cells. The etiology of this problem is unclear. It may be a systematic problem with a particular element of the technique, such as insufflation where positive pressure venting through the incision results in contamination. Another systematic problem might be direct contamination during specimen removal. The anecdotal occurrence of these problems suggests a more isolated and less systematic error, such as poor tissue handling technique. However, these concerns and the lack of understanding have limited the application of the technique.
[0013] It would therefore be useful to develop a surgical instrument that enables endoscopy to be utilized in more delicate surgeries. More specifically, it would be useful to develop an instrument that enables endoscopy to be used without concern for contamination of the tissue wherein the surgery is being performed. For example, major heart surgery has been accomplished by procedures that require full cardiopulmonary bypass (CPB), and complete cessation of cardiopulmonary activity. Open-heart surgery typically requires significant hospitalization and recuperation time for the patient. The average mortality rate with this type of procedure is low, but is associated with a complication rate that is often much higher compared to when cessation and CPB are not required. While very effective in many cases, the use of open-heart surgery to perform various surgical procedures such as coronary artery bypass grafting (CABG) is highly traumatic to the patient. These procedures require immediate postoperative care in an intensive care unit, a period of hospitalization for at least several days, and an extended recovery period. In addition, open-heart procedures require the use of CPB, which continues to represent a major assault on a host of body systems. For example, there is noticeable degradation of mental faculties following such surgeries in a significant percentage of CABG patients. This degradation is commonly attributed to cerebral arterial blockage and emboli from debris in the blood generated by the use of CPB during the surgical procedure. At the same time, the dramatic increase in the life expectancy of the general population has resulted in patients that are more likely to be older and in poor health, with less cardiovascular, systemic, and neurologic reserve needed to recover from the trauma caused by the use of CPB. As a consequence, inflammatory, hemostatic, endocrinologic, and neurologic stresses are tolerated to a much lesser degree by a significant number of patients today, and play a more significant role in CPB-induced morbidity.
[0014] The CABG procedure generally involves open chest surgical techniques to treat diseased vessels. During this procedure, the sternum of the patient is cut in order to spread the chest apart and provide access to the heart. During surgery the heart is stopped, and by the use of CPB, blood is diverted from the lungs to an artificial oxygenator. During CABG procedures, a source of arterial blood is connected to a coronary artery downstream from the occlusion. The source of blood is often an internal mammary artery, and the target coronary artery is typically among the anterior or posterior arteries, which may be narrowed or occluded. The same or similar CPB procedure is used in conjunction with other cardiac surgical procedures, such as value repair or replacement and heart transplant.
[0015] The combined statistics of postoperative morbidity and mortality continue to illustrate the shortcomings of CPB. The extracorporeal shunting and artificially induced oxygenation of blood activates a system wide roster of plasma proteins and blood components in the body including those that were designed to act locally in response to infection or injury. When these potent actors are disseminated throughout the body without normal regulatory controls, the entire body becomes a virtual battleground. The adverse hemostatic consequences of CPB also include prolonged and potentially excessive bleeding. CPB-induced platelet activation, adhesion, and aggregation also contribute to depletion in platelet number, and are further compounded by the reversibly depressed functioning of platelets remaining in circulation. The coagulation and fibrinolytic systems both contribute to hemostatic disturbances during and following CPB. However, the leading cause of morbidity and disability following cardiac surgery is cerebral complications. Gaseous and solid micro and macro emboli, and less often perioperative cerebral hypoperfusion, produce neurologic effects ranging from subtle neuropsychologic deficits to fatal stroke. Advances in computer tomography, magnetic resonance imaging, ultrasound, and other imaging and diagnostic techniques have added to the understanding of these complications. But with the possible exception of perioperative electroencephalography, these technologies do not yet permit real time surgical adjustments that are capable of preventing emboli or strokes in the making. Doppler and ultrasound evaluation of the carotid artery and ascending aorta, and other diagnostic measures, can help identify surgical patients at elevated risk for stroke and are among the growing list of pharmacologic and procedural measures for reducing that risk.
[0016] CPB also affects various endocrine systems, including the thyroid gland, adrenal medulla and cortex, pituitary gland, pancreas, and parathyroid gland. These systems are markedly affected not only by inflammatory processes, but also by physical and biochemical stresses imposed by extracorporeal perfusion. Most notably, CPB is now clearly understood to induce euthyroid-sick syndrome that is marked by profoundly depressed triiodothyronine levels persisting for days following cardiothoracic surgery. The efficacy of hormone replacement regimens to counteract this effect, are currently undergoing clinical investigation. By contrast, levels of the stress hormones epinephrine, norepinephrine, and cortisol are markedly elevated during and following CPB, and hyperglycemia is also possible.
[0017] Alternatives to CPB are limited to a few commercially available devices that may further require major surgery for their placement and operation such as a sternotomy or multiple anastomoses to vessels or heart chambers. For example, some present day devices used in CPB may require a sternotomy and an anastomosis to the ascending aorta for placement. The main drawbacks of these devices include their limited circulatory capacity, which may not totally support patient requirements, and their limited application for only certain regions of the heart, such as a left ventricular assist device. Other available devices that permit percutaneous access to the heart similarly have disadvantages, such as their limited circulatory capabilities due to the strict size constraints for their positioning even within major blood vessels. Moreover, the relative miniaturization of these types of devices present a high likelihood of mechanical failure. In further attempts to reduce the physical dimensions for cardiac circulatory apparatus, the flow capacity of these devices is significantly diminished.
[0018] During cardiac surgery, the heart is either beating, in which case the heart continues to circulate the blood through the lungs to maintain the patient, or immobilized entirely in which case oxygenation and circulation of blood to maintain the patient requires use of CPB. Bypass surgery on a beating heart has been limited to only a small percentage of patients requiring the surgical bypass of an occluded anterior heart vessel. These patients typically could not be placed on CPB and were operated on while the heart was kept beating. These patients are at risk of having to be placed on CPB on an emergency basis in the event the heart stops or becomes unstable or is damaged during the surgical procedure on the beating heart. Meanwhile, patients requiring surgery on posterior or lateral heart vessels and whose hearts must be immobilized and placed on CPB often suffer major side effects as previously described.
[0019] The medical community is currently performing more beating heart bypass surgery in an effort to avoid the use of artificial heart-lung machines. The need is increasing for apparatus systems, methods and associated equipment to enhance the capability and versatility of beating heart surgery and to avoid CPB procedures in any heart surgery. The current trend toward thoracoscopic methods of performing bypass surgery, without opening the chest cavity, have resulted in limited success and applicability primarily due to the limited number of heart vessels which can be accessed through thorascopic methods. A major limitation of thorascopic bypass surgery methods is due to the fact that only the anterior heart vessels are accessible for surgery. More importantly, even open chest surgery providing full access to the heart also requires CPB when bypass surgery is performed on the lateral or posterior vessels of the heart, due to the fact that in conventional procedures the heart must be stopped when it is lifted or rotated from its normal position and manipulated for surgical access to the various heart vessels. Obviously, the heart is also stopped when valve repair or replacement is performed and when heart transplant is performed.
[0020] Further, tens of thousands of people are born each year with congenital defects of the heart. Some of the more common types of congenital cardiac defects include atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosis (PDA). An ASD is a hole in the cardiac septum between the left and right atria, while a VSD is a hole in the septum between the left and right ventricles. Patent ductus arteriosis is incomplete closure of the opening between the pulmonary artery and the aorta that is present during fetal development. These conditions may cause blood to abnormally shunt from the right side of the heart to the left side of the heart without being properly oxygenated in the lungs, so that the body tissues supplied by the blood are deprived of oxygen. In addition, blood in the left side of the heart may shunt back to the right side through the defect rather than being pumped into the arterial system, causing abnormal enlargement of the right chambers of the heart.
[0021] ASD's, VSD's and PDA can frequently be surgically repaired with significant success. Smaller defects may be repairable by simply suturing the defect closed, while larger defects may require a patch of polyester, expanded polytetrafluoroethylene, or a portion of the patient's own pericardium to be sutured into the heart to cover and occlude the defect.
[0022] Ordinarily, such surgery is performed using open-chest techniques while the heart is under cardioplegic arrest and circulation is maintained by cardiopulmonary bypass. Using such techniques, a gross sternotomy or thoracotomy is created in order to gain access to the heart and great vessels, facilitating clamping and cannulation of the aorta for inducing cardioplegic arrest, and allowing instruments to be introduced into the chest cavity and into the heart to perform the surgical repair. The necessity of stopping the heart significantly heightens the risks attendant such procedures, particularly the risks of causing ischemic damage to the heart muscle, and of causing stroke or other injury due to circulatory emboli produced by aortic clamping and vascular cannulation. In addition, the creation of a gross thoracotomy produces significant morbidity and mortality, lengthens hospital stay and subsequent recovery, increases costs, and worsens the pain and trauma suffered by the patient. Moreover, many congenital defects are repaired in children under the age of ten years for whom the morbidity and mortality of open-chest surgery and cardioplegic arrest can be even greater than for older patients.
[0023] In an effort to avoid the necessity of grossly opening the chest and stopping the heart, a number of intravascular devices have been developed for repair of ASD's, VSD's, and PDA For example. U.S. Pat. No. 3,874,388 to King et al. discloses an intravascular delivery catheter introduced intraluminally from a peripheral vein into the right side of the heart which can be used to position an artificial umbrella-like patch across a septal defect and to anchor the patch to the cardiac septum. Other intravascular delivery devices and artificial patches for the repair of septal defects can be seen in U.S. Pat. No. 5,334,217, U.S. Pat. No. 5,284,488, U.S. Pat. No. 4,917,089, U.S. Pat. No. 4,007,743, and PCT Application No. PCT/US92/10141.
[0024] While intravascular approaches to the repair of congenital defects can provide certain advantages, the most significant of which is the elimination of the need for gross thoracotomy and cardioplegic arrest, these techniques have suffered from a number of problems. One such problem is the difficulty in manipulating the artificial patches into position across a defect using only the proximal end of a long and flexible delivery catheter positioned through a tortuous right lumen. Also problematic is the inadequacy of fixation of endovascularly-placed patches, creating a tendency of such patches to migrate or embolize after placement, which can allow blood to again shunt through the defect. In addition, once such a patch has been placed and the delivery catheter detached from the patch, relocating and repositioning the patch with the catheter is difficult, if not impossible, and may require open surgical correction. Moreover, in young children, the size of the peripheral vessels is extremely small, and damage to such vessels could have serious effects upon the growth of the child. Thus, the size of the devices that can be introduced through such vessels is greatly limited.
[0025] In addition to ASD, VSD, and PDA, various other types of cardiac disease also may be diagnosed and treated by intervention within the interior chambers of the heart. For example, some cardiac arrhythmias such as ventricular tachycardias, supraventricular tachycardias, and atrial fibrillation, may be diagnosed by obtaining access into an interior chamber of the heart and by performing electrophysiological mapping to identify abnormal conduction pathways. Once these abnormal conduction pathways are identified, in some cases the disease may be treated by ablating selected cardiac tissue using radiofrequency (RF) energy or a medical laser to eliminate the abnormal pathways. A number of endovascular approaches a have been developed which attempt to allow intracardiac mapping and ablation using catheters introduced transluminally from peripheral vessels into the heart. Such devices are disclosed, for example, in U.S. Pat. Nos. 4,960,134, 4,573,473, 4,628,937,and 5,327,889. However, endovascular mapping and ablation devices suffer from many of the same problems suffered by endovascular septal defect repair devices, including a lack of control and precise positionability from the proximal end of these highly flexible and elongated devices, the significant size constraints of peripheral vessels, and the inability to position the devices in all potentially diseased sites within the heart.
[0026] What are needed, therefore, are devices and methods to enable the repair of ASD, VSD, PDA, and other congenital defects, as well as cardiac arrhythmias and other diseases of the heart, which eliminate the need for gross thoracotomy and cardioplegic arrest, but which overcome the aforementioned problems with intravascular techniques. The devices and methods should facilitate a high level of control for precise manipulation within the heart. The devices and methods should produce a septal defect or PDA repair that is reliable and long-lasting, and should not be susceptible to migration, embolization, or reopening of a defect. The devices and methods for septal defect and PDA repair should allow the position of a repair patch to be inspected after initial placement and to be repositioned if necessary. Finally, the devices and methods should not risk damaging the peripheral vessels of the patient, nor should the size and configuration of the devices be limited by the size of the patient's peripheral vessels.
SUMMARY OF THE INVENTION
[0027] According to the present invention, there is provided a trocar including an insert end. the insert end including a fluid and airtight chamber. Also provided is a method of maintaining a fluid and airtight environment when introducing a surgical instrument into a patient by inserting the instrument into the patient through a fluid and airtight chamber of a trocar.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] Other advantages of the present invention are readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:
[0029] FIG. 1 is a perspective view of the trocar of the present invention;
[0030] FIG. 2 is a cut-away view of the seals and gasket/o-ring of the present invention;
[0031] FIG. 3 is a side view of the trocar of the present invention;
[0032] FIG. 4 is a side view broken away of the lumen of the trocar of the present invention in the neutral position; and
[0033] FIG. 5 is a side view broken away of the lumen of the trocar of the present invention in the engaged position.
DETAILED DESCRIPTION OF THE INVENTION
[0034] Generally, the present invention provides a trocar 10 , generally shown at 10 in the figures, that includes an insertion end 16 that is both fluid and airtight. That is, the insertion end 16 includes structure, described below, that perfects a seal at the insertion end 16 of the trocar 10 whether or not an instrument 32 , such as a surgical device, extends through the trocar 10 .
[0035] The trocar 10 of the present invention is preferably formed in a manner known to those of skill in the art. The trocar 10 can be formed of a rigid or a resilient plastic, from a metal, such as 304 or 316 stainless steel, or of any desired material suitable for use as a trocar 10 . For example the trocar 10 can be formed of a plastic-metal composite. Alternatively, the trocar 10 can be formed of a plastic material that can be seen through upon the application of ultrasonic technology. The trocar 10 is preferably constructed of material approved by the United States Food and Drug Administration for use in surgical procedures, that the materials be durable, and capable of being sterilized completely for subsequent re-use. It is also anticipated, however, that the trocar 10 can be constructed as a disposable one-time or throw-away device without the need for subsequent resterilization of the trocar 10 .
[0036] The trocar 10 of the present invention does not necessarily include an ubturator. Instead the trocar 10 can be inserted into a hole created by a knife. Such insertion enables the trocar 10 to be placed in a small hole that can be stretched to accommodate the trocar 10 . The benefit of such insertion is that the small hole into which the trocar 10 is inserted also maintains the trocar 10 in position without allowing the trocar 10 to move once inserted.
[0037] More specifically, the trocar 10 of the present invention includes a neck 12 and a body 14 . The neck 12 and the body 14 are in fluid and airtight communication, such that there is no leakage between the body and the neck 12 . Preferably, the body 14 and neck 12 are formed as a single unit. Alternatively, the body 14 and neck 12 can be separate pieces that are capable of being joined to one another. The neck 12 includes two ends; an insertion end 16 that is inserted into the body of the patient and an opposite end 18 that is the location at which the body 14 attaches to the neck 12 .
[0038] The insertion end 16 includes devices necessary for maintaining a sealed environment within the trocar 10 . In other words, within the insertion end 16 , there are devices that prevent fluid and foreign bodies present in the neck 12 or body 14 of the trocar 10 from entering the patient into which the trocar 10 is being place while also preventing substances from within the patient from entering the insertion end 16 and neck 12 of the trocar 10 .
[0039] The trocar 10 of the present invention can also include an agitator. The agitator can be used to facilitate the movement of air bubbles or foreign objects from the insertion end 16 to the opposite end 18 . The agitator can be any device that is capable of manipulating the trocar 10 of the present invention in such a way as to move the air or foreign objects away from the body into which the trocar 10 is inserted. For example, the agitator can be a manual device that lightly taps the trocar 10 or the agitator can be an ultrasonic device that causes vibration of the particles within the trocar 10 .
[0040] In order to form a fluid and air-tight environment within the trocar 10 the insertion end 16 includes a sealing device. In the preferred embodiment, the sealing device is a series of at least two deformable diaphragms or seals 20 , 22 and at least one gasket 24 . More than two seals 20 , 22 and more than a single gasket 24 can be included without departing from the spirit of the present invention. It is this configuration of the seals and gasket that prevents fluid and foreign bodies from entering the body 14 and from blood and other particles from the body 14 from entering the trocar 10 . The sealing device can be sized to fit any trocar 10 and ensures a complete seal of the trocar 10 so that insufflation of a body cavity can be maintained when insufflation is used.
[0041] In general, the seals 20 , 22 are either adjustable so that the seals 20 , 22 fit any number of differently sized trocars or are in a plurality of fixed sizes to be selected as required for a particular trocar 10 being used. The seals 20 , 22 of the present invention are fabricated of a material and of a thickness sufficient to manipulate the seals 20 , 22 into place in the trocar 10 . It is expected that a viscoelastic material such as latex is suitable, though metal variations are possible. The seals 20 , 22 function to maintain an instrument 32 passed through the trocar 10 in proper sealing engagement within the trocar 10 . The seals 20 , 22 each include a slit 28 . The slit 28 is of a size sufficient to encompass an instrument 32 there through.
[0042] In a particular embodiment of the invention, the seals 20 , 22 are fixed, non-inflatable devices that are sufficiently compliant so that they can be moved about without causing a loss of sealing contact with the trocar 10 . As the device does not have to be pressurized, the possibility of undesirable failure and, therefore, loss of a seal, does not exist. In addition, the seals 20 , 22 can also be pliable or compliant, rather than stiff or rigid, so as to provide sufficient sealing of the trocar 10 . The portions of the seals 20 , 22 running along the interior body wall are no thicker than the outer section and are preferably much thinner, on the order of 0.1 millimeter to 10 millimeters.
[0043] The gasket 24 disclosed above is preferably an 0 -ring. The gasket 24 perfects the fluid and air-tight seal about an instrument 32 within the trocar 10 . Any sized gasket 24 that is sized to fit within the trocar 10 can be disposed in the trocar 10 of the present invention. Preferably, the gasket 24 is made of rubber, however other resilient materials can also be used, such materials are known to those of skill in the art. The gasket 24 is sufficiently pliable as to allow instruments 32 to pass there through of a range of cross-sectional diameters while maintaining a perfected seal thereabout.
[0044] A trocar tip 26 is disposed at an end of the insertion end 16 furthest from the body 14 . The trocar tip 26 is preferably sharp and made of a resilient material such as stainless steel. However, other materials as are known to those of skill in the art can be used as long as the material can be inserted into the human body 14 .
[0045] Within the trocar 10 there are at least two lumen. These lumen are completely separate from one another. The first is an instrument lumen 30 . The instrument lumen 30 is of a size to enable instruments to be placed there through. The instrument lumen 30 extends from an opening in the body 14 through to the insertion end 16 as shown in FIGS. 4 and 5 . The instrument lumen 30 ends at the sealing device disclosed above such that the series of seals and gasket 20 , 22 , and 24 create a fluid tight lumen.
[0046] The second lumen a down flow lumen 34 , extends from the body 14 and through the wall of the trocar 10 . An outlet 40 opens proximate to the instrument lumen 30 . The down flow lumen 34 is made of any resilient material that is fluid tight, and is capable of having a fluid flow there through.
[0047] The body 14 of the trocar 10 preferably includes an inlet port 36 fluidly connected to the down flow lumen 24 . The inlet port 36 enables the flow of an inert fluid through the port 36 into the down flow lumen 40 within the trocar 10 . Additionally, the body 14 includes at least one outlet port 38 . The outlet port 38 allows air trapped within the body 14 and neck 12 of the trocar 10 to escape from the trocar 10 .
[0048] In use, an inert fluid, such as saline, is flowed into the down flow lumen 34 , via the inlet port 26 , out the outlet port 40 proximate to the instrument lumen 30 of the trocar 10 . The fluid contacts any substances, such as air bubbles, that are present within the instrument lumen 30 of the trocar 10 . The air bubbles then flow with the fluid up the instrument lumen 30 to the outlet port 38 . In other words, fluid is constantly forcibly passed through the instrument lumen 30 of the trocar 10 such that any air bubbles found within the trocar 10 are captured within the fluid and the flow of the fluid carries the air bubbles away from the insertion end 16 of the trocar 10 .
[0049] Of vital importance in surgery is that air not be allowed to enter the bloodstream of a patient. This is most critical when beating heart cardiac surgery is being performed because the insertion of oxygen into a blood stream can cause a fatal problem for the patient. Thus, the flowing of the fluid into the instrument lumen 30 of the trocar 10 enables air, and any other substances present in the trocar 10 , to be removed from the patient, thereby preventing air or other foreign substances from entering the blood stream of a patient.
[0050] The sealing device of the trocar 10 ensures that the fluid flowing through the trocar 10 and air bubbles present in the trocar 10 do not enter the patient In order to accomplish this sealing device functions as follows. When in a neutral or non-use condition, the trocar 10 is inserted into the patient during a scoping procedure. As shown in FIG. 4 , the seals 20 , 22 are in a closed position and the gasket 24 is in a sealing engagement with both of the seals 20 , 22 . It is vital that the gasket 24 keep the seals 20 , 22 in proper engagement, thus preventing any leakage therethrough. Additionally, it is vital that the seals 20 , 22 themselves are in a closed position versus an open position. By maintaining the closed position no fluid or air can flow either into or out of the trocar 10 . The slits 28 are designed such that no two slits 28 consecutively have the same orientation. The slits 28 center an instrument 32 passing there through because of this configuration. That is, the non-alignment of the slits 28 cooperate as the instrument 32 passes there through to center the instrument 32 as it approaches the gasket 24 . Further, in conjunction with the gasket 24 of the present invention, there is created a fluid tight seal whether or not an instrument 32 passes there through. The gasket 24 holds the seals 20 , 22 in place and perfects the seal of the trocar 10 . Thus, absent the use of a gasket 24 , a fluid tight seal could not be created. The seals 20 , 22 assist the gasket 24 in limiting the amount of fluid that is able to reach the gasket 24 , thus not overwhelming the gasket 24 with enormous pressure. While a rectangular opening is the preferred shape of the slit 28 and as such is shown in the figures, any slit 28 can be used so long as the slit 28 enables the configuration disclosed above while maintaining the integrity of the sealing device.
[0051] FIG. 5 shows the neck 12 when an instrument is inserted there through, in an engaged configuration. The instrument 32 is inserted through the instrument lumen 30 within the neck 12 of the trocar 10 . The engaged configuration of the seals 20 , 22 , when an instrument 32 is placed through instrument lumen 30 of the trocar 10 , is such that seals 20 , 22 are both in an open condition and the gasket 24 is in sealing engagement about the instrument 32 . In the open condition the seals 20 , 22 allow for the instrument 32 to travel there through while having minimal extraneous openings. In other words, the seals 20 , 22 allow the instrument 32 to pass through openings 28 in the seals 20 , 22 , but limit the translational movement of the instrument 32 . This limits the amount of air and fluid that can flow past the seals 20 , 22 about the instrument 32 . In the engaged position, a first seal 20 opens, then a second seal 22 opens, and then an o-ring or gasket 24 perfects the seal about the instrument 32 as the it passes through the consecutive seal members. Accordingly, when the instrument 32 is being withdrawn, the second seal 22 closes, and then a first seal 20 closes, thus ensuring that there is always a proper air and fluid tight engagement of the trocar 10 within the patient.
[0052] Throughout this application, author and year and patents by number reference various publications, including United States patents. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
[0053] The invention has been described in an illustrative manner, and it is to be understood that the terminology that has been used is intended to be in the nature of words of description rather than of limitation.
[0054] Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention can be practiced otherwise than as specifically described.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. §119 from Provisional Application Ser. No. 61/066,800, filed Feb. 22, 2008, the disclosure of which is incorporated herein by reference.
FIELD OF THE INVENTION
The invention generally relates to the field of transducers. More specifically, this invention relates to transducers configured to produce torsional motion or longitudinal-torsional motion at ultrasonic frequencies.
BACKGROUND OF THE INVENTION
Torsional mode transducer systems have been described extensively in a book entitled “Sources of High-intensity Ultrasound,” Volume 2, and more specifically in Part IV, which is entitled “Torsional Mode Vibration Systems,” written by A. M. Mitskevich and edited by Rozenberg in 1969. FIG. 1 illustrates one type of a torsional mode system disclosed therein. The system illustrated in FIG. 1 is normally used for welding, for example, in specialist applications such as the helium tight sealing of cans and containers. Magnetostrictive vibrators with longitudinal waveguides 101 are attached to a rod 102 with an end mass 103 , wherein they excite torsional vibrations, which are transmitted to the welded parts 104 situated on the supporting platform 105 . Various known modifications to this system include the replacement of the magnetostrictive vibrators with more efficient piezo-electric vibrators and the use of two vibrators in a push-pull mode. Mitskevich concludes that the system illustrated in FIG. 1 is awkward, inconvenient and extremely unsuitable from the energy point of view.
Torsional mode transducer systems that include an end effector for surgical applications, specifically for cutting and coagulating tissue have been described by Young (U.S. Pat. No. 6,425,906). The transducer system disclosed by Young is illustrated in FIG. 2 . Young attempted to eliminate longitudinal motion by attaching the longitudinal transducer 202 at right angles to the torsional mode waveguide 204 . The motive force for transducer 202 is provided by piezo electric drive elements 203 . Young noted that the use of torsional mode vibration for ultrasonic scalpel/coagulation applications is safer because energy is absorbed into the target tissue and not transmitted along the waveguide axis into distant regions. One disadvantage of this design geometry is that it is difficult to incorporate within a slim ergonomic surgical tool that is both compact and light weight.
In addition to torsional mode transducer systems, there are longitudinal-torsional (L-T) mode transducer systems. These L-T mode transducer systems are rod systems, which, when driven in a longitudinal mode, are capable of generating a torsional vibration component by virtue of a certain inhomogeneity in the cross section of the rod. Mitskevich (cited above) has described such systems. One such device consisted of an ultrasonic horn 300 , as is shown in FIG. 3 . The horn, itself, is marked with gradually deepening grooves 303 ; these form a helix with a smooth diminishing pitch. Excitation over the frequency range 15 kHz to 21 kHz was accomplished by means of a ferrite or magnetostrictive transducer (not shown) attached by the screwed thread 301 at the proximal end of the horn. The variation in the tangential (x) and longitudinal (y) components of vibration at the distal tip of the horn 302 as a function of driving frequency is shown in FIG. 4 . As can be seen in FIG. 4 , the longitudinal component (y) at the distal tip of the horn 302 is reduced to zero at a frequency of 16.5 kHz resulting in a single tangential mode of vibration. FIG. 4 also shows that the tangential or torsional mode of vibration is reduced to zero at a frequency of approximately 17.8 kHz resulting in a single longitudinal mode of vibration. Additionally, the tip of the horn 302 vibrates in a combined L-T mode at frequencies other than 16.5 kHz and 17.8 kHz (see FIG. 4 ). For example, at a frequency of approximately 16.3 kHz the component of longitudinal vibration is similar to the component of tangential vibration. Mitskevich also describes L-T resonators made by creating an inhomogeneous cross section along the length of an otherwise uniform bar and then twisting the bar along its length. The same structure can be obtained by using a conventional twist drill or by machining the grooves into the bar.
Wuchinich (U.S. Pat. No. 6,984,220) disclosed the design of a similar longitudinal-torsional device that operates at a combined L-T resonance and is used to dissect biological tissue. The transducer and L-T resonator system 500 disclosed by Wuchinich is reproduced in FIG. 5 . The motive force for transducer 519 can be either magnetostrictive or piezoelectric and is designed to operate as a half-wave resonator. The longitudinal vibrations 523 at the distal tip of the transducer are coupled to resonator section 521 that has an inhomogeneous cross section that converts the single longitudinal motion into a combined L-T motion at the tissue contacting tip 524 . The inhomogeneous cross section can be in the form of a helical spiral spring similar to that illustrated in FIG. 3 .
Use of the Wuchinich design for ultrasonic handpieces used for surgical procedures such as cataract removal (phacoemulsification) and dental teeth cleaning would result in suboptimal handpiece in terms of length and weight. Typically, these handpieces operate at frequencies>28 kHz and <40 kHz. Operating above 28 kHz reduces the risk of an audible sub-harmonic frequency and operating below 40 kHz optimizes the design for maximum displacement of the end effector at the operative site. The maximum operational frequency for a medical handpiece is about 250 kHz. Designing a 28 kHz piezoelectric transducer/L-T resonator using the teachings of Wuchinich would result in a handpiece design that would have an overall length of about 200 mm (8 inches) if allowance is made for electrical connection at the proximal end of the transducer. This length is significantly longer than existing current designs and would be heavier, thus making it impractical to use for these applications.
Boukhny (U.S. Pat. No. 6,077,285) also described an apparatus for providing both longitudinal and torsional ultrasonic motion for the purpose of enhancing tissue dissection. His device utilizes separate torsional and longitudinal transducers systems to provide this motion. To obtain the desired result requires the simultaneous operation of both transducer systems. To supply the power required the use of two electrical generators, one for each of the different transducer systems. Furthermore, all such devices as described by Boukhny, whether longitudinal, transverse or torsional must be fixed within an enclosure, such as a handpiece, preferably at points where there is no motion, known as motional nodes. However, because the wavelength of torsional and longitudinal vibration is substantially different, the node or nodes for longitudinal vibration and torsional motion will be located at different points on the transducer system and other portions of other resonators attached to the transducer system. Hence, no true motionless point may be found. The result being that either longitudinal or torsional motion will be communicated to the handpiece and thereby to the operator holding the handpiece. Although, vibration isolators can be utilized to prevent the communication of such unintended motion, if they are truly isolating they invariably complicate construction of the device and, if simple, consume power in the form of heat generated by contact with a moving surface. Hence, Boukhny's device is both complicated to operate, needing two separate power sources, and is difficult to construct.
Although the magnetostrictive transducers have been replaced by more efficient piezo-electric transducers, the coupling of energy into the torsional mode is much lower than the coupling of energy into the longitudinal mode. Typical measured values of effective coupling coefficient for torsional mode are between 0.04 and 0.08 whereas the effective coupling of longitudinal mode is typically >0.1. FIG. 4 shows a damped torsional mode characteristic (x) compared with the longitudinal mode (y). This results in significantly higher value of electrical impedance that typically has a large reactive component. This can present a system control problem and the high operating voltage limits the torsional mode power that can be delivered to the operative site.
Therefore, as to these L-T transducer systems, Rozenberg in “Sources of High-intensity Ultrasound,” Volume 2 concludes that “despite the number of obvious advantages of Longitudinal-Torsional mode (L-T) systems, they have not been put to use on a sufficient scale. One of the main reasons for this is a lack of at least an approximate method for the calculation of such systems” This problem is compounded because the experimental optimization process is complex and involves the fabrication of a large number of sample L-T waveguides.
For reasons stated above, there is a need for optimized ultrasonic transducers that provide torsional modes of motion and/or L-T modes of motion. In particular, there is a need for small, uniaxial, light weight relatively low power torsional and L-T handpieces for medical applications including phacoemulsification applications and dental applications, such as for example, but not limited to, teeth cleaning and tooth extraction. Additionally, there is a need for higher power L-T transducer systems for industrial applications and also medical orthopedic applications such as bone cutting. The invention described herein addresses these and other needs.
SUMMARY OF THE INVENTION
The present invention relates to the design of torsional mode and L-T mode piezoelectric transducer subassemblies and systems primarily intended for medical and dental applications. Similar transducer subassemblies and systems could also be used for industrial applications. The invention provides transducers systems with improved performance and a capability to operate more efficiently in a combined longitudinal-torsional mode of vibration.
One aspect of the invention, provides for piezoelectric transducer subassemblies and systems comprising inhomogeneous resonator sandwiched between two piezoelectric stacks. This aspect of the invention improves on prior art by enabling the size and weight of torsional mode and L-T transducers subassemblies and systems to be reduced. The power handling capability of these transducer subassemblies or systems is also improved over prior art when the stacks are operating in a push-pull mode, as this enhances the torsional motion within the resonator
In various embodiments of the invention, an inhomogeneous resonator is coupled to and in-between two piezoelectric stacks. One of the piezoelectric stacks is also coupled to a horn that may optionally include a end-effector, which is designed to couple torsional vibrations or a combination of torsional and longitudinal vibrations to a solid or fluid medium.
The piezoelectric stacks are comprised of piezoelectric elements and optionally end masses. The piezoelectric elements are polarized and electrically connected in parallel. In certain embodiments, one piezoelectric stack in a subassembly or system operates with in-phase synchronism and the second piezoelectric stack operates with phase-opposite synchronism (see e.g., FIG. 6 ). In other embodiments, both piezoelectric stacks operate with in-phase synchronism.
A horn is coupled to the subassembly system (resonator and piezoelectric stacks). In some embodiments, the horn is attached to the piezoelectric stack. In other embodiments, that horn extends through the center of the piezoelectric stack and is coupled at a nodal region distal from inhomogeneous resonator and proximal to the piezoelectric stack through which the horn is passing.
In a second aspect, the present invention provides for transducer systems that comprise a piezoelectric stack sandwiched between an inhomogeneous resonator and a horn.
In yet another aspect of this invention, mountings and methods suitable for mounting a transducer in a stationary structure such as a handpiece housing are provided.
These and other aspects of the invention will be apparent upon reference to the following detailed description and attached figures. To that end, patents, patent applications, and other documents are cited throughout the specification to describe and more specifically set forth various aspects of this invention. Each of these references cited herein is hereby incorporated by reference in its entirety, including the drawings
BRIEF DESCRIPTION OF THE DRAWINGS
The novel features of the invention are set forth with particularity in the claims. The invention itself, however, both as to organization and methods of operation, together with further objects and advantages thereof, may best be understood by reference to the following description, taken in conjunction with the accompanying drawings described below.
FIG. 1 is an illustration of a prior art industrial torsional welding system.
FIG. 2 is an illustration of a prior art transducer assembly that converts longitudinal motion to torsional motion.
FIG. 3 is an illustration of a prior art L-T horn.
FIG. 4 is a graph illustrating the variation of L-T vibrations at the distal tip of a prior art horn as a function of frequency.
FIG. 5 is an illustration of a prior art L-T medical transducer for biological tissue dissection.
FIG. 6 is a method of electrical connection for a torsional mode transducer system in accordance with embodiments of the present invention.
FIG. 7 illustrates a system configured to measure the performance of torsional mode transducers in accordance with embodiments of the present invention.
FIG. 8 illustrates a torsional mode transducer system configured for measurement using the measurement system illustrated in FIG. 7 in accordance with embodiments of the present invention.
FIG. 9 is a graph of velocity versus frequency for one transducer stack with reverse polarity in accordance with embodiments of the present invention.
FIG. 10 is a graph of velocity versus frequency for transducer stacks with similar polarity in accordance with embodiments of the present invention.
FIG. 11 is a torsional mode transducer system in accordance with embodiments of the present invention.
FIG. 12 is a distal horn portion of the torsional mode transducer system illustrated in FIG. 11 .
FIG. 13 is a graph of velocity versus frequency for the torsional mode transducer system illustrated in FIG. 11 .
FIG. 14A is a prior art torsional mode transducer system; and FIG. 14B illustrates a transducer system in accordance with embodiments of the present invention.
FIG. 15 is a cross-sectional view of a torsional mode transducer in accordance with embodiments of the present invention.
FIG. 16A illustrates the location of torsional mode nodes and antinodes for a transducer system in accordance with embodiments of the present invention.
FIG. 16B illustrates the location of longitudinal mode nodes and antinodes for a transducer system in accordance with embodiments of the present invention.
FIG. 17A illustrates a prior art method of positioning the transducer system within a cylindrical housing.
FIG. 17 B illustrates a transducer system in accordance with embodiments of the present invention, wherein the vibrations between the transducer system and a cylindrical housing are decoupled.
In the following description of the invention, references are made to the accompanying drawings, which form a part hereof, and in which is shown by way of illustration various embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized, and structural and functional changes may be made without departing from the scope of the present invention. It is also to be understood that components and functionality depicted as separate or discrete blocks/elements in the figures may be implemented in combination with other components and functionality, and that the depiction of such components and functionality in individual or integral form is for purposes of clarity of explanation, and not of limitation.
DETAILED DESCRIPTION OF THE INVENTION
A. Terms and Definitions
The following terminology and definitions apply as used in the present application.
The phrase “inhomogeneous resonator” refers to a component, such as for example, but not limitation, a rod, bar, spring, with a non-uniform cross sectional region that generates torsional and longitudinal motion. In some embodiments, an inhomogeneous resonator is a spiral spring or a twisted bar. In other embodiments, a inhomogeneous resonator is a rod with one or more slots.
The phrase “piezoelectric stack” means a two or more piezoelectric elements, such as for example, but not limited to, piezoelectric rings, electrically connected in parallel, which are stacked or held in compression by a bolt or other means. A piezoelectric stack can optionally have an endmass coupled to one or both of the outer piezoelectric elements.
B. Transducer Subassemblies and Systems of the Invention
The present invention is directed to ultrasonic transducer subassemblies and systems designed to operate in torsional modes of vibration or L-T modes of vibrations and, more particularly, to those used for surgical, dental, and industrial welding applications.
Methods and devices employing ultrasonic torsional or L-T mode transducers subassemblies and systems in accordance with the present invention may incorporate one or more of the features, structures, methods, or combinations thereof described herein below. For example, but not limited to, ultrasonic L-T mode transducers can be designed to include one or more of the features and/or processes described below. It is intended that such a device or method need not include all of the features and functions described herein, but may be implemented to include one or more features and functions that, alone or in combination, provide for unique structures and/or functionality.
One aspect of the invention provides piezoelectric transducer subassemblies and systems comprising an inhomogeneous resonator between two piezoelectric stacks, For simplicity the first embodiment is best illustrated by initially considering the mode of operation of a subassembly prior to the attachment of a horn as shown in FIG. 6 .
In FIG. 6 piezoelectric stacks 601 and 602 are coupled to a resonator 603 that comprises an inhomogeneous cross section region including one or more slots 625 . This inhomogeneous resonator performs a helical spring function by converting longitudinal motion to torsional motion. Any component that allows for this converting longitudinal motion to torsional motion can be used. Some non-limiting examples of inhomogeneous resonators include a spiral spring or a twisted bar. In other embodiments, a inhomogeneous resonator is a rod with one or more slots.
Piezoelectric stack 601 contains piezoelectric elements, e.g., rings 607 that are electrically connected in parallel and have their negative poles at ground potential. There can be any even number of piezoelectric elements 607 that are stacked together and held in compression by bolt 610 . Piezoelectric stack 602 contains piezoelectric elements 608 that are electrically connected in parallel and have their positive poles at ground potential. In one preferred embodiment, piezoelectric stack 602 has the same number of piezoelectric elements as piezoelectric stack 601 . In other embodiments, piezoelectric stack 602 has a different number of piezoelectric elements than piezoelectric stack 601 . Piezoelectric elements 608 are stacked together and held in compression by bolt 610 . The components within the subassembly shown are generally of annular cross section. The subassembly is electrically connected to a generator 611 . In some embodiments, the metal components within piezoelectric stacks 601 and 602 are at ground potential as shown. In other alternate embodiments, electrical insulators such as alumina oxide ceramic rings (not shown) could be disposed between the distal and proximal ends of the stacks of piezoelectric elements 607 and 608 and end masses 605 and 606 . The generator can then be configured to operate in a manner whereby the output is isolated from ground potential. It is also possible that when the generator is isolated from ground potential that piezoelectric stack 601 can be electrically connected with reverse polarity with respect the polarity of piezoelectric stack 602 , thereby enabling the poles of the piezoelectric rings within each stack to be the same (i.e.), one piezoelectric stack operates with in-phase synchronism and the second piezoelectric stack operates with phase-opposite synchronism).
To determine the optimal configuration, the high power measurement instrumentation shown in FIG. 7 was used. The torsional mode of vibration was measured at points signified by an * in FIG. 8 . An end mill was used to machine a reflective surface approximately 1 mm in diameter that is perpendicular to the focused laser beam. The transducer subassembly 800 was compliantly mounted by means of Teflon cradles 810 , 820 located at the positions shown. The laser vibrometer was used to measure the velocity at points A 8 , B 8 , C 8 , and D 8 . For each measurement the power was adjusted to 1 watt and the frequency fine tuned for maximum velocity (at the 29 kHz torsional resonance). The displacements were calculated from the velocity and frequency measurements and the results are tabulated in Table 1.
TABLE 1
Displacement data
A8
B8
C8
D8
1.9 μm p-p
0.36 μm p-p
5.1 μm p-p
0.4 μm p-p
The results indicate that point B 8 is located very close to a node, defined as a region of minimum displacement. Anti-nodes defined as regions of maximum displacement occur at point A 8 and close to point C 8 . The results also confirm that the longitudinal component of vibration is very small (0.4 μm p-p). With the laser focused at point A, the frequency was swept over the range 5 kHz to 70 kHz in order to search for torsional resonances. The search procedure was repeated for longitudinal resonances with the laser focused at point D 8 . For each resonance frequency the power was adjusted to 1 watt and the velocity was measured using the laser vibrometer. A map of the relative intensity of the resonant modes is shown in FIG. 9 .
The transducer system was then reconfigured such that the negative poles of the piezoelectric rings were at ground potential for both piezoelectric stack 801 and piezoelectric stack 802 . The resonance search procedure for both torsional and longitudinal modes was repeated and a map of the relative intensity of the resonant modes is shown in FIG. 10 .
An analysis of the experimental data indicates that configuring piezoelectric stack 801 and piezoelectric stack 802 so that both piezoelectric stacks operate with in-phase synchronism suppresses the level longitudinal vibration over the frequency range of 5 kHz to 70 kHz. A relatively strong torsional mode was detected at 39.6 kHz. Configuring piezoelectric stack 801 and piezoelectric stack 802 such that one piezoelectric stack operates with in-phase synchronism and the second piezoelectric stack operates with phase-opposite synchronism (i.e., with reverse polarity) is the preferred embodiment because it has the most efficient torsional mode at the lowest frequency (29 kHz). It can also be operated in a combined L-T mode at 50 kHz.
The subassembly's relatively low measured torsional and longitudinal displacements can be amplified by attaching a horn as illustrated in FIG. 11 . The bias bolt for piezoelectric stack 1102 can be an integral part of horn 1104 and is coupled (for example, but not limited to threadingly engaged) to end mass 1105 . The bias bolt 1110 applies a compressive force to the piezoelectric stack 1107 . Piezo stacks 1107 and 1108 include a metal terminating washer 1106 . Stacks 1107 and 1108 are coupled to a resonator 1103 that incorporates an inhomogeneous cross section region including one or more slots 1125 . Horn 1104 is proximally coupled to piezoelectric stack 1102 . The horn is typically designed such that a cross section of the horn distal to the piezoelectric stack is smaller than a cross section proximal to the piezoelectric stack. The components within the assembly shown are generally of annular cross section with the exception of the end effector 1109 .
For purposes of an illustrative example, flats were formed in order to facilitate the measurement of torsional velocity as shown in FIG. 12 . The flats also help demonstrate functionality by coupling torsional mode energy into a fluid medium such as water. A laser vibrometer was used to measure both the longitudinal and torsional vibrations of the distal horn region 1209 . The laser beam at point A 12 was aligned with the longitudinal motion of the distal tip of the horn 1204 . The laser beam at point B 12 was perpendicular to the machined flats at the distal tip 1209 of the horn, illustrated in cross-section 1225 . The beam was adjusted such that it is focused off the axis rotation in order to measure the maximum torsional vibration. The high power performance of the transducer system shown in FIG. 11 was measured using the instrumentation shown in FIG. 7 . The input power was held constant at 1 watt and the frequency fine tuned for the maximum velocity measured by the laser vibrometer. A velocity map of the torsional and longitudinal resonant modes is shown in FIG. 13 .
The same measurement method was used for a more detailed analysis of the torsional mode at 31.7 kHz. In all cases, the frequency was in the range 31.7 kHz±0.1 kHz. The transducer system shown in FIG. 11 was electrically connected to the power source in 3 different configurations. Initially, just piezoelectric stack 1101 was driven with piezoelectric stack 1102 not connected and left in an open circuit condition. Following this, piezoelectric stack 1102 was driven with piezoelectric stack 1101 not connected and left in an open circuit condition. Finally, both piezoelectric stacks were connected as shown in FIG. 11 (with one piezoelectric stack operating with in-phase synchronism and the second piezoelectric stack operating with phase-opposite synchronism; i.e., with piezoelectric stack 1101 having a reverse polarity with respect to piezoelectric stack 1102 ). The measured data is tabulated below in Table 2.
TABLE 2
Multiple transducer tabulated data.
L Mode A
T Mode B
Volts
Phase
System
μm p-p
μm p-p
r.m.s
Z Ω
degrees
1101 only
2.1
52.2
106
1760
−82
1102 only
2.7
53
44
1396
−52
1101 + 1102
1.7
64.2
33
611
−47
The system with only piezoelectric stack 1101 is representative of the geometry used in prior art transducers, such as those illustrated by Wuchinich in FIG. 5 . The distal piezoelectric elements 1108 become passive components that form part of a modified resonator section. One aspect of this invention is based on the measured performance improvement when a resonator is sandwiched between two separate piezoelectric stacks (System 1101 + 1102 ) in table 2. For this configuration, the drive voltage was reduced as a result of lower impedance and a more favorable phase angle between the voltage and current. Reducing the drive voltage to an absolute minimum improves patient safety for medical applications and improves reliability by reducing the risk of voltage breakdown.
In yet further embodiments of this aspect of the invention, the horn is attached at a nodal position on torsional mode transducer systems. In U.S. Pat. No. 3,681,627, Murry et al describes a method whereby the shaft of an operative tool is attached at a nodal position and reverses direction such that it passes back through the center of the transducer. The Murry patent is limited, however, only to longitudinal modes of vibration. The present invention provides for configurations that are applicable for use with torsional mode transducers. The measured data relating to FIG. 11 indicates the presence of a shear mode displacement node in the region distal to the inhomogeneous resonator section 1103 and proximal to piezoelectric stack 1102 . Referring now to FIG. 15 ; by anchoring a reverse direction torsional mode horn at the nodal location Ns, the overall length of the transducer assembly can be reduced as shown. In FIG. 15 , the piezoelectric elements 1507 are stacked together and held in compression by bolt 1510 . The bolt 1510 differs in the design illustrated in FIG. 11 in that it has an annular hollow cross section. Also, for this embodiment the piezoelectric elements 1507 and 1508 have a relatively large internal diameter such that horn 1512 can pass through the center of piezoelectric stack 1502 . Stacks 1507 and 1508 are coupled to a resonator that incorporates an inhomogeneous cross section region including one or more slots 1525 . Horn 1512 is attached at a torsional (shear wave) nodal location defined in FIG. 15 as Ns. The horn can be attached to the body of the transducer system by means known to those skilled in the art. Examples include, by are not limited to, a threading engagement of the horn 1512 or by dimensioning the diameter of the horn 1512 and the hole in the transducer system to achieve an interference press fit. The length of the horn is typically one quarter wavelength with the physical length being related to the shear mode velocity and the frequency of operation. Any number of additional half wavelength sections can be added to the length of the horn.
A second aspect of this invention provides for piezoelectric transducer subassemblies and systems comprising an inhomogeneous resonator coupled proximal to a single piezoelectric stack. This design is based on the measured performance improvement when the torsional mode resonator is coupled proximal to a single piezoelectric stack ( 1102 only in table 2).
By means of an illustrative example of the second aspect of this invention, an improved phacoemulsification transducer system design is compared with a prior art design geometry which is illustrated in FIG. 14A . This prior art transducer system design geometry has a longitudinal resonant frequency corresponding with an accumulated component length of one and a half wavelengths (1.5λ). A central annular aspiration lumen extends along the entire length of the assembly and extends proximally as a tube 1401 and distally through a hollow needle 1406 . The rear mass 1402 is attached to piezoelectric rings that are stacked together and pre-compressed by a bolt section (not shown) that is an integral part of the rear mass 1402 and is threadingly engaged in front mass 1407 . When connected to an electrical generator, the piezoelectric ceramic stack provides the motive force and couples mechanical vibrations to front mass 1407 . Front mass 1407 is mechanically attached to an inhomogeneous resonator section 1403 . The resonator has one or more slots, which performs a helical spring function and converts longitudinal motion to torsional motion. The resonator section 1403 is mechanically coupled to a velocity amplifying horn 1405 . Solid horns are sometimes referred to as concentrators, rods, tools, and amplitude or velocity transformers. The horn illustrated has a stepped geometry with transitional radius but other geometries such as conical and exponential could be used. The distal tip of hollow needle is the end effector 1406 and is threadingly engaged in horn 1405 . For torsional out of plane motion, the distal end of the needle is bent such that torsional motion within the needle shaft is translated into transverse motion at the operative tip.
The second aspect of this invention is illustrated in FIG. 14B . The design geometry has been changed from the prior art design discussed above, in that the transducer system has a longitudinal resonant frequency corresponding with a half wavelength (λ/2). The location of the inhomogeneous resonator 1403 has been changed such that it is coupled proximal to the piezoelectric stack 1403 . The rear mass 1407 in the prior art transducer has been eliminated. In this illustrative example of the invention, all the metal components were fabricated from 6Al-4V titanium alloy and the piezoelectric elements 1404 were fabricated from a generic Navy Type III material. Alternative materials for component manufacture include aluminum alloy for horn 1405 . Alternate materials for the inhomogeneous resonator 1403 and end mass 1402 include aluminum alloy, stainless steel and beryllium copper. The inhomogeneous resonator could also be fabricated from fiberglass composite. Alternative piezoelectric materials include those that conform to US Navy Type I specifications and also lead free materials such as barium titanate. The four piezoelectric elements 1404 are electrically connected in parallel and have an outside diameter of 12 mm an inside diameter of 5 mm and a thickness of 2 mm. For medical handpiece applications the outside diameter of the piezoelectric elements can be in the range 6 mm to 35 mm, the inside diameter can be in the range 3 mm to 25 mm, and the thickness in the range 1 mm to 5 mm. The end effector 1406 (e.g., a bent hollow titanium needle) is available from Micro Surgical Technologies. Referring to FIG. 14B , the lengths of the component parts are as follows: 1401 6 mm; 1402 5 mm; 1403 17 mm; 1405 29 mm. The major diameter of horn 1405 is 12 mm and the minor diameter is 3.8 mm. The inhomogeneous resonator 1403 has an outside diameter of 12 mm, and a total length of 17 mm. 8 slots on the resonator have a width of 1 mm, a depth of 3.5 mm and a pitch of 34 mm. As will be apparent to one of skill in the art various pitches, and widths of slots can be used. Mitskevich (cited above) concludes that the degree of transformation of longitudinal into torsional vibration depends on the depth of the helical grooves and their pitch and increases within defined limits as the depth of the grooves is increased and their pitch is decreased.
The transducer design illustrated in FIG. 14B was tested using the instrumentation illustrated in FIG. 7 . The laser was focused side on to the tip of the needle 1406 and the frequency adjusted for maximum displacement. A pure torsional mode could only be sustained up to a maximum value of 21 μm p-p at a frequency of 32.644 kHz. The test results are summarized in table 3
TABLE 3
Test Data
Tip stroke
Frequency
Power
Voltage
Phase
Mode
μm p-p
kHz
watts
Volt r.m.s.
Angle °
Torsional
21
32.644
0.265
40.5
−52
Longitudinal
13
38.127
1.1
31.6
2
The above test data relates to measurements made with the transducer operating in air. Under operational conditions water would be continuously aspirated through the central lumen and this would increase the impedance and drive voltage. The aspiration water also cools the piezoelectric rings and allows operation at power levels up to a maximum of about 30 watts. As can be seen the design has been optimized for torsional mode rather than longitudinal mode of operation.
In another aspect of this invention, a means of mechanically decoupling the torsional and longitudinal vibrations within the transducer assembly from the housing is disclosed. In U.S. Pat. No. 6,984,220 B2, Wuchinich gives a detailed description of the problem but concludes that possible simple solutions would ineffective. For medical ultrasonic handpieces mechanical coupling of either longitudinal or torsional motion will cause localized heat and the generation of audible sub-harmonic frequencies. The fundamental design problem is associated with the difference in the longitudinal speed of sound C L in a cylindrical or rectangular bar shaped component compared with the shear mode speed of sound C S . For example, titanium alloy 6Al-4V has a longitudinal speed of sound C L ≈4916 m/s and a shear mode speed of sound C S ≈3100 m/s. For the piezoelectric material PZT4 the stiffened shear wave propagation is ≈2630 m/s and the longitudinal wave propagation is ≈2900 m/s. The wavelength (λ) □ frequency (F) and speed of sound (C) by the formula:
C=λF
For example, the longitudinal resonance of a 12 mm diameter titanium alloy bar occurs when the length of the bar equals one half wavelength (λ/2). For a bar that is 100 mm in length the longitudinal resonant frequency will be 24.58 kHz and the torsional mode resonance frequency will be 15.5 kHz. However, as can be seen in FIG. 14 , practical transducers contain components that have complex shapes such as the inhomogeneous resonator 1403 , horn 1405 and end effector 1406 .
The mode of vibration of the resonator 1403 can be determined using finite element analysis or by practical measurements using a laser vibrometer. FIG. 16A illustrates the position of the nodes (N S ) and antinodes (A S ) at the torsional mode resonance frequency of 32.644 kHz. A node is defined as a point of minimum torsional displacement and is ideally positioned close to the step in the horn. FIG. 16B illustrates the position of the node (N L ) and antinodes (A L ) at the longitudinal mode resonance frequency of 38.127 kHz. As can be seen the torsional mode node and longitudinal mode node are spatially separated.
Thus a design optimized for torsional mode would have the housing attached close to the node at the step of the horn. However, while operating at the longitudinal resonance frequency, there will be significant motion at the horn step and this will result in energy being coupled into the housing. Within a transducer system, the coupling of torsional energy (k eff ) from the relatively small longitudinal motion within the piezoelectric stack is typically within the range 0.02 to 0.08. For unity gain longitudinal transducer systems without a horn attached, i.e., subassemblies, the effective coupling coefficient (k eff ) is typically within the range 0.2 to 0.4. As low values of k eff result in higher impedance and drive voltage, it is therefore, more important to optimize the decoupling mechanism for torsional rather than longitudinal motion.
A typical method used to decouple energy within an ultrasonic handpiece designed for phacoemulsification is illustrated in FIG. 17A . The transducer system 1700 is located within a cylindrical housing (not shown). The inside diameter of the housing is dimensioned such that the ‘O’ ring seals 1701 and 1703 are compressed but still provide an air gap between the internal components and the housing. Typical ‘O’ ring materials include Nitrile, Neoprene, Butyl, Silicone, Ethylene Propylene (EPDM), and Polytetrafluoroethylene (PTFE). The housing is permanently attached to the heel mass 1704 by either bonding adhesive, brazing, or laser welding. Typically a silicone rubber adhesive such as Dow Corning 577 is used. Additional mechanical decoupling of both torsional and longitudinal motion is achieved by attaching the heel mass 1704 to the transducer assembly by means of a very thin walled small diameter tube 1702 . Typically this tube would be fabricated from titanium alloy or stainless steel, have a length between 10 mm and 20 mm, an outside diameter between 2.5 mm and 3.5 mm and the thinnest possible wall thickness (between 0.3 mm and 0.5 mm). The combination of this very compliant tube 1702 and the relatively large heel mass 1704 provide decoupling for both torsional and longitudinal motion that is generated within the transducer assembly. The problem is associated with the distal mounting location at the step of the horn in that ‘O’ ring 1701 will tend to convert motional energy into heat and will not anchor or adequately center the transducer assembly within the housing.
In this aspect of the invention, a means is provided that properly anchors the assembly within the housing while maintaining electrical continuity between components. One embodiment of the means used is a spring. In some embodiments, the spring is a metal coil spring. In more preferred embodiments, the spring is a canted coil Spring™ manufactured by Bal Seal Engineering Inc. This spring is illustrated in FIG. 17B as component 1705 . The spring is designed to perform a latching and holding function that centrally locates annular shaped components within the bore of a housing and to maintain electrical continuity between components. Preferable grooves are placed in a surface region of the transducer system for mounting or holding the transducer system in the housing and the spring is frictionally engaged between the groove on the transducer system and the housing.
The prototype transducer used to evaluate the performance of this aspect of this invention was initially tested with a prior art ‘O’ 1701 and then modified to substitute a Bal Seal 1705 with the following specification: Spring ID 2.9 mm; Coil Width (ref) 2.3 mm; Coil Height (ref) 2.0 mm; Wire Diameter 0.4 mm; Deflection 1.4 mm; Material Type 316 Stainless steel. A cylindrical housing was slid over the transducer assembly thereby compressing the Bal seal and clamping the transducer assembly within the housing. The tabulated data in Table 4 is the longitudinal mode low power Impedance Analyzer measurements.
TABLE 4
Longitudinal Mode Test Data
Resonant
Frequency
Mechanical
Real Impedance
Coupling
(kHz)
Q Factor
Ohms
Coefficient
‘O’Ring
34.766
280
548
0.116
Bal Seal
34.773
415
353
0.117
The tabulated data in Table 5 is the torsional mode low power Impedance Analyzer measurements.
TABLE 5
Torsional Mode Test Data
Resonant
Frequency
Mechanical
Real Impedance
Coupling
(kHz)
Q Factor
Ohms
Coefficient
‘O’Ring
33.682
317
870
0.09
Bal Seal
33.473
464
843
0.074
The Table 4 test data indicates that the Bal Seal has very low losses compared with the ‘O’ ring at the longitudinal mode resonance frequency. As can be seen in FIG. 16B , the longitudinal node N L is spatially separated from the Bal Seal or ‘O’ring located at the step in the horn. Under typical operational conditions, the stroke at the distal tip of the end effector would be approximately 50 μmp-p resulting in a computed longitudinal displacement at the step in the horn of 10 μmp-p. The table 5 torsional mode test data has a smaller variation in mechanical Q and real impedance because the Bal seal and ‘O’Ring are located very close to the node at the step of the horn as illustrated in FIG. 16A .
In this aspect of the invention, any seal that is functionally similar can be used, including but not limited to springs encapsulated in a polymer or plastic material. For example, Bal Seal Engineering Inc. manufactures a range of seals that incorporate the canted metal coil springs and Parker Seals also manufacture a PTFE FlexiSeals™ that incorporates a metal coil spring. In the certain embodiments, of this invention the Bal Seal can be located at a torsional shear wave node at the step of a horn. Alternatively, it could also be located within any metal component within the transducer subassembly. A Bal Seal could also be used to replace ‘O’ring 1703 that is located in heel mass 1704 .
One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein, as presently representative of preferred embodiments, are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.
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This application claims priority to U.S. 60/042,353 filed Mar. 24, 1997 and GB 9706295.4 filed Mar. 26, 1997.
FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical compositions containing (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one ((-)-2',3'-dideoxy,3'-thiacytidine, Epivir®, lamivudine) and their use in medical therapy.
BACKGROUND OF THE INVENTION
Retroviruses form a sub-group of RNA viruses which, in order to replicate, must first "reverse transcribe" the RNA of their genome into DNA ("transcription" conventionally describes the synthesis of RNA from DNA). Once in the form of DNA, the viral genome may be incorporated into the host cell genome, allowing it to take advantage of the host cell's transcription/translation machinery for the purposes of replication. Once incorporated, the viral DNA is virtually indistinguishable from the host's DNA and, in this state, the virus may persist for the life of the cell.
A species of retrovirus, the Human immunodeficiency virus (HIV) has been reproducibly isolated from patients with AIDS (acquired immunodeficiency syndrome) or with the symptoms that frequently precede AIDS. AIDS is an immunosuppressive or immunodestructive disease that predisposes subjects to fatal opportunistic infections. Characteristically, AIDS is associated with a progressive depletion of T-cells, especially the helper-inducer subset bearing the CD4 surface marker. HIV is cytopathic and appears to preferentially infect and destroy T-cells bearing the CD4 marker, and it is now generally recognized that HIV is the etiological agent of AIDS. Clinical conditions such as AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), Karposi's sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions, such as AIDS dementia complex, multiple sclerosis or tropical paraparesis, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients, are also conditions which may be treated by appropriate anti-viral therapy.
Another RNA virus which has been recognized as the causative agent of an increasingly serious international health problem is the non-A, non-B hepatitis virus. At least 80% of cases of chronic post-transfusional non-A, non-B hepatitis have been shown to be due to the virus now identified as hepatitis C and this virus probably accounts for virtually all cases of post-transfusional hepatitis in clinical settings where blood products are screened for hepatitis B. Whereas approximately half of the cases of acute hepatitis C infection resolve spontaneously over a period of months, the remainder become chronic and in many if not all such cases chronic active hepatitis ensues with the potential for cirrhosis and hepatocellular carcinoma. The structure of the hepatitis C virus genome has been elucidated and the virus has been characterized as a single stranded RNA virus with similarities to flaviviruses.
Hepatitis B virus (HBV) is a small DNA containing virus which infects humans. It is a member of the class of closely related viruses known as the hepadnaviruses, each member of which selectively infects either mammalian or avian hosts, such as the woodchuck and the duck. Recent insights into the mechanism of replication of the hepadnavirus genome indicate the importance of reverse transcription of an RNA intermediate, suggesting that the reverse transcriptase is a logical chemotherapeutic target. HBV is a viral pathogen of major world-wide importance. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer. Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease outlined above.
U.S. Pat. No. 5,047,407 discloses (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (Epivir®, lamivudine) and its use in the treatment and prophylaxis of viral infections. Lamivudine has proven antiviral activity against HIV and other viruses such as HBV. Current liquid formulations of lamivudine used in the clinic contain disodium(ethylenedinitrilo)tetraacetate dihydrate (edetate disodium, EDTA) and 6% (v/v) ethanol. However, liquid formulations without ethanol or other sedatives and EDTA or other unnecessary anti-oxidants are considered advantageous, particularly for pediatric use and in renally or hepatically impaired adults.
The addition of alcohol and EDTA. is thought to be necessary in order to maintain preservative efficacy against bacteria, yeasts, and mold. EDTA, a chelating agent, has been shown to potentiate the activity of many antimicrobial agents by chelating Mg 2+ and Ca 2+ ions which are normally responsible for the stability of the cell wall of Gram-negative organisms. In a study of factors affecting preservative efficacy of lamivudine oral solution, Nguyen et. al. reported that preservative efficacy improved with increasing EDTA concentrations and with increasing pH from 4.5 to 7.5 (Nguyen, N-A. T., et. al., Drug Development and Industrial Pharmacy 21, 14, 1671-1682, 1995). The same study reported that the chemical stability of lamivudine increased with increasing pH from 4.5 to 7.5. Preservative efficacy was greatest at pH 7.5, but increasing the pH from 4.5 to 7.5 resulted in extensive degradation of preservatives such as esters of hydroxybenzoate (hereinafter referred to as parabens). All formulations were effective against bacteria and yeasts, but not against the mold, Aspergillus niger.
In a study evaluating the effects of alcohol concentration on preservative efficacy of lamivudine oral solution, Wells et. al. reported that the reduction or elimination of alcohol from lamivudine oral solutions resulted in unacceptable preservative efficacy (Wells et al., Pharmaceutical Research, 10(10), S171, 1993).
Lamivudine is currently formulated at pH 5.5 with 0.01% EDTA, 0.12% (w/v) methyl paraben, 0.015% propyl paraben, and 6% ethanol. In this formulation, EDTA functions both to maintain pH and preservative efficacy. At this concentration of parabens and pH, ethanol is needed in order to pass the Antimicrobial Preservatives Effectiveness (APE) test according to United States Pharmacopeia (USP) standards (United States Pharmacopeia 23, <51>, p. 1681, 1995), BP standards (Efficacy of Antimicrobial Preservation, Appendix XVI C, 1995), and PhEur standards (Efficacy of Antimicrobial Preservation, Chapter VIII.14, 1992). The pH was maintained at 5.5 in order to preserve the chemical stability of the parabens. We have surprisingly found that there is a sharp increase in preservative efficacy when lamivudine is formulated at pH>5.5 (FIG. 1) and the concentrations of parabens are increased by 20-25% of the concentration of parabens in the ethanol-containing formulation.
We have found that the oral formulations of lamivudine according to the present invention surprisingly maintain preservative efficacy and chemical stability while eliminating ethanol and EDTA.
An object of the present invention is to provide pharmaceutical compositions comprising lamivudine and a preservative system that allows the elimination of ethanol and EDTA, while maintaining preservative efficacy.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition, substantially free of ethanol and EDTA, comprising a safe and therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof and a preservative system comprising parabens in concentrations sufficient to confer and maintain preservative efficacy and a pH of greater than 5.5.
BRIEF DESCRIPTION OF THE FIGURE
FIG. 1 is a graph of the Aspergillus niger in lamivudine oral solution.
DETAILED DESCRIPTION OF THE INVENTION
The phrase "safe and therapeutically effective amount'" as used herein, means a sufficient amount of a drug, compound, composition, product or pharmaceutical agent to abate or reverse or treat a malady in a human or other mammal without severely harming the tissues of the mammal to which the drug or pharmaceutical agent is administered.
The phrase "pharmaceutically acceptable derivative," as used herein, means any pharmaceutically acceptable salt, solvate, ester, or salt of such ester or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) the intended active ingredient or any active metabolite or residue thereof.
The term "substantially free of", as used herein, means present in quantities that have less than a material effect on, or confer less than a material advantage to, the pharmaceutical composition. A pharmaceutical composition substantially free of ethanol may contain, for example, less than 30% ethanol, advantageously 0-1% ethanol. A pharmaceutical composition substantially free of EDTA may contain, for example, less than 0.005% EDTA.
The term "preservative efficacy" or "preservative effectiveness", as used herein, means that the composition satisfies USP standards as defined in protocol <51>, p.1681, United States Pharmacopeia, 1995). The preservative is effective in the product examined if (a) the concentrations of viable bacteria are reduced to not more than 0.1% of the initial concentrations by the fourteenth day; (b) the concentrations of viable yeasts and molds remain at or below the initial concentrations during the first 14 days; and (c) the concentration of each test microorganism remains at or below these designated levels during the remainder of the 28-day test period. Similar criteria are defined for BP standards (Efficacy of Antimicrobial Preservation, Appendix XVI C, 1995), and PhEur standards (Efficacy of Antimicrobial Preservation, Chapter VIII.14, 1992).
The term "preservative system", as used herein, means ingredients and conditions (for example, pH) which result in preservative efficacy.
It will be appreciated by those skilled in the art that reference herein to "treatment" extends to both the prophylaxis and the treatment of an established malady, infection or its symptoms.
The term "EDTA", as used herein, means ethylenediaminetetraacetic acid, and includes disodium EDTA (edetate disodium, (ethylenedinitrilo)tetraacetic acid disodium salt, disodium ethylenediaminetetraacetate), calcium disodium EDTA, sodium iron(III) EDTA, and the like.
The compositions of the present invention employ a safe and therapeutically effective amount of lamivudine or pharmaceutically acceptable salts, solvates and derivatives thereof, together with a safe and effective amount of pharmaceutically acceptable carriers.
According to one aspect of the present invention, there is provided a pharmaceutical composition, substantially free of ethanol and EDTA, comprising lamivudine and parabens, wherein said composition is formulated at pH>5.5.
The pH of the formulation of the present invention may be in the range of 5.56-7.4, advantageously in the range of 5.6-6.5, and most advantageously in the range of 5.8-6.2, particularly about 6.0.
According to the present invention, any ester of hydroxybenzoate (parabens) or combination of such esters may be used, including methyl and propyl paraben and butyl and propyl paraben combinations.
In a further aspect of the present invention, there is provided lamivudine formulations containing methyl paraben and propyl paraben. For oral solutions and suspensions, the range of methyl paraben concentration may be 0.096-0.2% (0.96 mg/mL to 2 mg/mL) and the range of propyl paraben concentration may be 0.01% to 0.02% (0.1 to 0.2 mg/mL).
Advantageously the range of methyl paraben concentration may be 0.15-0.2% (1.5 mg/mL to 2 mg/mL) and the range of propyl paraben concentration may be 0.018% to 0.019% (0.18 to 0.19 mg/mL).
According to a further aspect of the present invention, any suitable buffer may be used to provide a pH>5.5. Advantageously, sodium citrate or phosphate may be used.
The compositions of the present invention may optionally employ diluents, solubilizers, flavoring agents, viscosity-increasing agents (e.g. polyethylene glycol), sweeteners, buffers, or any other excipients commonly used in the art.
Methods for the preparation of lamivudine are described in WO92/20669 and WO95/29174 both incorporated by reference herein.
Included in the invention are the pharmaceutically acceptable salts, esters, or salts of such esters of lamivudine, or any other compound which, upon administration of a safe and therapeutically effective amount of the compound to a human subject, is capable of providing (directly or indirectly) the antivirally active metabolite or residue thereof.
The compositions of the present invention may be formulated using methods and techniques suitable for the compositions' physical and chemical characteristics and that are commonly employed by persons skilled in the art of preparing oral dosage forms (Remington, The Science and Practice of Pharmacy, 19th ed., 1995).
The formulations according to the invention may be presented in various forms adapted for direct oral administration including liquid forms, for example, syrups, suspensions, or solutions. The formulations, according to the invention, may include other pharmaceutically acceptable carriers as excipients conventionally used in such formulations. Thus, for example, syrups may include sugar syrup, sorbitol or hydrogenated glucose syrup. Suspensions may include suspending agents such as methylcellulose, microcrystalline cellulose, croscarmellose sodium or dispersible cellulose. Solutions may include sweeteners such as liquid glucose, laevulose, xylitol, maltitol, or lycasin. The formulations may optionally be flavored with artificial or natural flavors.
The formulations include those suitable for oral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations can be prepared by uniformly and intimately bringing into association the active ingredient with carriers. Formulations of the present invention suitable for oral administration may be presented as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
The formulations of the present invention may be made using methods and techniques that are commonly employed in preparing preparations within the pharmaceutical industry.
In the formulations according to the invention, the amount required of lamivudine will depend upon a number of factors including the severity of the condition to be treated and the age and condition of the recipient and will ultimately be at the discretion of the attendant physician. In general, however, a suitable, effective dose may be in the range of 0.1-20 mg/kg body weight of recipient per day, advantageously 0.1-5 mg/kg/day. The desired dose may preferably presented as one, two, three, four or more sub-doses, for example, containing 0.1-100 mg/mL, advantageously 5-20 mg/mL.
The formulations according to the invention may be used for the treatment or prophylaxis of human retroviral infections including HIV infections, and the consequent clinical conditions resulting from such infections, for example, AIDS, ARC, progressive generalized lymphadenopathy (PGL) and HIV-seropositive and AIDS-antibody-positive conditions.
The formulations according to the invention may be used for the treatment or prophylaxis of human hepatitis B (HBV) infections and the consequent clinical conditions resulting from such infections.
The formulations according to the invention may be employed in medical therapy in combination with other therapeutic agents suitable in the treatment of HIV infections, such as nucleoside reverse transcriptase inhibitors for example zidovudine, zalcitabine, didanosine, stavudine, 5-chloro-2',3'-dideoxy-3'-fluorouridine and (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)1,3-oxathiolan-5-yl]cytosine, 1592U89; non-nucleoside reverse transcriptase inhibitors for example nevirapine, TIBO, and α-APA; HIV protease inhibitors for example saquinavir, indinavir, ritonavir, 141W94; other anti-HIV agents for example soluble CD4; immune modulators fcr example interleukin II, erythropoetin, tucaresol; and interferons for example α-interferon.
The formulations according to the present invention may be employed in medical therapy in combination with other therapeutic agents suitable in the treatment of HBV infections, such as α-interferon.
The components of such combination therapy may be administered simultaneously, in either separate or combined formulations or at different times, e.g. sequentially such that a combined effect is achieved.
The following non-limiting examples are included to illustrate the present invention but are not intended to limit the reasonable scope thereof.
EXAMPLE 1
A liquid formulation was prepared as follows:
1) Composition
______________________________________Ingredient Quantity/1000 L Batch______________________________________Lamivudine* 10.00 kg Sucrose 200.0 kg Methyl Hydroxybenzoate 1.50 kg Propyl Hydroxybenzoate 180 g Artificial Strawberry Flavor 800 g Artificial Banana Flavor 600 g Sodium citrate dihydrate 11 g Citric acid anhydrous 1 g Propylene Glycol** 19.4 L NaOH/HCl, adjust as necessary pH 6.0 Purified Water to 1000 L______________________________________ *Quantity may be corrected for purity. **Volume of Propylene Glycol is calculated by weight using the true density of 1.033 g/mL
2) Method of Preparation
To an appropriately sized auxiliary vessel, 19.4L of propylene glycol was added. While mixing, 1.50 kg of methyl hydroxybenzoate and 180 g of propyl hydroxybenzoate were added to the propylene glycol and mixed to dissolve. Purified water was dispensed into a stainless steel vessel with an attached mixer. While mixing, the parabens and glycol solution, 200.0 kg sucrose, 1 g citric acid anhydrous, 11 g sodium citrate dihyrate, 800 g artificial strawberry flavor, 600 g artificial banana flavor and 10 kg of lamivudine were added and mixed. A sufficient quantity of purified water to make 201.65 kg was added and mixed. The solution was sampled and the pH was measured and adjusted to pH 6.0. The solution was filtered through a clarifying filter into an appropriately sized receiving vessel.
EXAMPLE 2
Antimicrobial preservative effectiveness testing was performed using the method described in The United States Pharmacopeia 23 <51>(1995), United States Pharmacopeial Convention, Rockville, Md., 1994, p. 1681.
Table 1. Antimicrobial Preservative Efficacy Testing Results for Lamivudine 10 mg/mL Ethanol-free Oral Solution (Example 1)
Specifications
Yeast and mold (A. niger, C. albicans,): 1 log reduction by day 14, no increase to day 28.
Bacteria: 3 log reduction by day 14, no increase to day 28.
pH 6.0
______________________________________ Log Reduction at each Test Inoculum Incubation Time (days)Organism per mL 7 14 21 28______________________________________Staphylococcus 9.6 × 10.sup.5 5.50 5.98 5.98 5.98 aureus Escherichia 8.0 × 10.sup.5 5.90 5.90 5.90 5.90 coli Pseudomonas 1.7 × 10.sup.5 5.23 5.23 5.23 5.23 aeruginosa Candida 9.6 × 10.sup.5 3.69 5.98 5.98 5.98 albicans Aspergillus 1.4 × 10.sup.5 4.55 5.15 5.15 5.15 niger______________________________________
EXAMPLE 3
Antimicrobial preservative effectiveness testing was performed using the method described in The United States Pharmacopeia 23 <51>(1995), United States Pharmacopeial Convention, Rockville, Md., 1994, p. 1681.
Table 2. 14 Day log reduction values for lamivudine formulations (10 mg/mL).
Specifications
Yeast and mold (A. niger, C. albicans, Z rouxii): 1 log reduction by day 14, no increase to day 28.
Bacteria: 3 log reduction by day 14, no increase to day 28.
__________________________________________________________________________pH m-para p-para C. albicans A. niger Z. rouxii S. aureus E. coli P. cepacia P. aeru.__________________________________________________________________________5.7 0.960 0.12 2.120 3.850 3.66 5.03 5.34 5.01 5.28 6.3 0.960 0.12 1.980 5.230 5.04 5.15 5.04 5.19 4.98 5.5 1.350 0.16 5.630** 5.230 5.04 5.15 5.34 5.49 4.98 6.5 1.350 0.16 5.630 5.230 5.04 5.33 5.16 5.49 4.80 5.5 1.440 0.16 5.630 5.230 5.04 5.15 5.34 5.49 5.28 6.5 1.440 0.16 5.630 5.230 5.04 5.63 5.64 5.49 4.98 6.0 1.800 0.20 5.630 5.230 5.04 5.15 5.64 5.19 5.28 6.0* 1.800 0.20 5.630 5.230 5.04 5.63 5.64 5.19 5.28 5.5 1.200 0.15 1.36 5.5 0.960 0.12 0.77__________________________________________________________________________ *Placebo **Bold numbers represent 100% reduction
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of and claims domestic priority benefits to U.S. application Ser. No. 15/093,810, filed on Apr. 8, 2016, now pending, which is a continuation-in-part of International Patent Application No. PCT/CN2013/084832 with an international filing date of Oct. 8, 2013, designating the United States. The contents of all of the aforementioned applications, including any intervening amendments thereto, are incorporated herein by reference. Inquiries from the public to applicants or assignees concerning this document or the related applications should be directed to: Matthias Scholl P.C., Attn.: Dr. Matthias Scholl Esq., 245 First Street, 18th Floor, and Cambridge, Mass. 02142.
BACKGROUND OF THE INVENTION
[0002] Field of the Invention
[0003] The invention relates to use of 1-(alkylsulfinyl)-2-isothiocyanatoalkyl-1-alkene for treating or preventing human or mammalian cancers and tumors.
[0004] Description of the Related Art
[0005] The antitumor activity of 1-(alkylsulfinyl)-2-isothiocyanatoalkyl-1-alkene has not been reported heretofore.
SUMMARY OF THE INVENTION
[0006] Unexpectedly, the inventors found sulforaphene is superior to conventional anti-tumor drugs including sulforaphane, erlotinib, gemcitabine and paclitaxel in inhibiting the growth of many kinds of cancer cells, and has higher security than sulforaphane, cis-platinum, 5-fluorouracil, paclitaxel, and adriamycin. So, sulforaphene has potential antitumor activities against lung cancer, lung squamous cell carcinoma, pancreas cancer, liver cancer, mammary cancer, cervical carcinoma, malignant melanoma, and so on.
[0007] In view of the above-described findings, in accordance with one embodiment of the invention, there is provided a method of treating or preventing human or mammalian cancer and tumor comprising administering to a patient or an animal in need thereof a pharmaceutical composition, health product, or food additive comprising 1-(alkylsulfinyl)-2-isothiocyanatoalkyl-1-alkene having the formula I
[0000]
[0008] wherein R 1 is a methyl; R 2 and R 3 at each occurrence independently represent a substituted or unsubstituted alkyl, vinyl, alkynyl, aryl, alkoxy, epoxy group, heterocyclic nitrogen and aryloxy; R 4 is a substituted or unsubstituted alkylidene, —CH 2 —O—CH 2 —, and alkoxyl aryl; and n is an integer from 1 to 10. Preferably, n is an integer from 1 to 5, and more preferably, n is 2. The double bond in R 2 —C 1 ═C 2 —R 3 is a cis-structure or a trans-structure.
[0009] The invention also provides a method of treating or preventing human or mammalian cancer and tumor comprising administering to a patient or an animal in need thereof 4-isothiocyanato-1-(methylsulfinyl)-1-butene having the formula II
[0000]
[0010] Sulforaphene is a member of the family of isothiocyanate. Sulforaphane, that is, 1-isothiocyanato-4-(methylsulfinyl)-butane, has the formula III
[0000]
[0011] The difference between sulforaphene and sulforaphane is that the former has an unsaturated C═C bond at the alpha carbon position.
[0012] In a class of this embodiment, sulforaphene is extracted from radish seeds, radish seedlings, or radish.
[0013] In a class of this embodiment, the pharmaceutical composition, health product, and food additive comprise a pharmaceutically acceptable carrier, an additive, and a pharmaceutically acceptable excipient.
[0014] In a class of this embodiment, the human or mammalian cancer and tumor comprise lung cancer, gastric cancer, colon cancer, rectal cancer, ovarian cancer, mammary cancer, thyroid cancer, pancreas cancer, esophageal cancer, head and neck cancer, cervical carcinoma, endometrial carcinoma, malignant melanoma, and bladder cancer.
[0015] Specifically, sulforaphene having the formula II in the invention is a medicinal compound and extracted from Brassica plants including but not limited to radish, broccoli, cabbage, mustard and horseradish. The compound has effective treatment and prevention for the abovementioned cancers and tumors.
[0016] Sulforaphene of the invention can also be prepared as food, additives and health products for the treatment and prevention of the cancers and tumors.
[0017] Based on a series of in vitro anti-cancer experiments against A549 cell line, the inventors found that sulforaphene exhibits stronger inhibition than sulforaphane against the growth and proliferation of human lung adenocarcinoma cells. Experiments showed that, when subjects were administered with sulforaphene and sulforaphane, respectively, with different administration concentrations (for example, the administration concentrations of the two compounds are 10, 20, 30, 40, and 50 μM), 48 hours later, calculation results show the half maximal inhibitory concentration (IC50) of sulforaphene against human lung adenocarcinoma cells A549 is 10.5 μM, and the IC50 of sulforaphane is 14.7 μM.
[0018] Based on a series of in vitro anti-cancer experiments against H460 cell line, the inventors found that sulforaphene exhibits stronger inhibition than sulforaphane against the growth and proliferation of human lung squamous carcinoma cells. Experiments showed that, when subjects were administered with sulforaphene and sulforaphane, respectively, with different administration concentrations (for example, the administration concentrations of the two compounds are 10, 20, 30, 40, and 50 μM), 48 hours later, calculation results show the half maximal inhibitory concentration (IC50) of sulforaphene against human lung squamous carcinoma cells H460 is 25.7 μM, and the IC50 of sulforaphane is 34.62 μM.
[0019] Based on a series of in vitro anti-cancer experiments against PANC-1 cell line, the inventors found that sulforaphene exhibits stronger inhibition than sulforaphane against the growth and proliferation of human pancreatic cancer cells. Experiments showed that, when subjects were administered with sulforaphene and sulforaphane, respectively, with different administration concentrations (for example, the administration concentrations of the two compounds are 10, 20, 30, 40, and 50 μM), 48 hours later, calculation results show the half maximal inhibitory concentration (IC50) of sulforaphene against human pancreatic cancer cells PANC-1 is 5.18 μM, and the IC50 of sulforaphane is 6.73 μM.
[0020] Based on a series of in vitro anti-cancer experiments against MCF-7 cell line, the inventors found that sulforaphene exhibits stronger inhibition than sulforaphane against the growth and proliferation of human breast cancer cells. Experiments showed that, when subjects were administered with sulforaphene and sulforaphane, respectively, with different administration concentrations (for example, the administration concentrations of the two compounds are 10, 20, 30, 40, and 50 μM), 48 hours later, calculation results show the half maximal inhibitory concentration (IC50) of sulforaphene against human breast cancer cells MCF-7 is 14.3 μM, and the IC50 of sulforaphane is 19.46 μM.
[0021] Based on a series of in vitro anti-cancer experiments against HepG2 cell line, the inventors found that sulforaphene exhibits stronger inhibition than sulforaphane against the growth and proliferation of human liver cancer cells. Experiments showed that, when subjects were administered with sulforaphene and sulforaphane, respectively, with different administration concentrations (for example, the administration concentrations of the two compounds are 10, 20, 30, 40, and 50 μM), 48 hours later, calculation results show the half maximal inhibitory concentration (IC50) of sulforaphene against human liver cancer cells HepG2 is 59.0 μM, and the IC50 of sulforaphane is 47.33 μM.
[0022] Based on a series of in vitro anti-cancer experiments against HeLa cell line, the inventors found that sulforaphene exhibits stronger inhibition than sulforaphane against the growth and proliferation of human cervical cancer cells. Experiments showed that, when subjects were administered with sulforaphene and sulforaphane, respectively, with different administration concentrations (for example, the administration concentrations of the two compounds are 10, 20, 30, 40, and 50 μM), 48 hours later, calculation results show the half maximal inhibitory concentration (IC50) of sulforaphene against human cervical cancer cells HeLa is 24.1 μM, and the IC50 of sulforaphane is 25.8 μM.
[0023] Based on a series of in vitro anti-cancer experiments against A375 cell line, the inventors found that sulforaphene exhibits stronger inhibition than sulforaphane against the growth and proliferation of human malignant melanoma cancer cells. Experiments showed that, when subjects were administered with sulforaphene and sulforaphane, respectively, with different administration concentrations (for example, the administration concentrations of the two compounds are 10, 20, 30, 40, and 50 μM), 48 hours later, calculation results show the half maximal inhibitory concentration (IC50) of sulforaphene against human malignant melanoma cancer cells A375 is 26.088 μM, and the IC50 of sulforaphane is 33.11 μM.
[0024] The half maximal inhibitory concentrations (IC50) of sulforaphene against leukemia cell lines K562 and HL60 are 4.54 and 11.0 μM, respectively.
[0025] The half maximal inhibitory concentrations (IC50) of sulforaphene against prostate cancer line PC-3 is 6.90 μM.
[0026] The half maximal inhibitory concentrations (IC50) of sulforaphene against ovarian cancer lines CAROV-3 and SK-OV-3 are 6.847667 and 7.37 μM, respectively.
[0027] The half maximal inhibitory concentrations (IC50) of sulforaphene against gastric cancer cell lines HGC-27, MGC-803, and AGS are 6.892, 8.258, and 4.662 μM, respectively.
[0028] The half maximal inhibitory concentrations (IC50) of sulforaphene against esophageal cancer cell lines EC109, kyse 180, and TE-1 are 9, 7, and 12.6 μM, respectively.
[0029] Based on a series of in vitro anti-cancer experiments against A549 and H460 cell line, the inventors found that sulforaphene exhibits stronger inhibition against the growth and proliferation of human lung cancer cells compared with erlotinib, gemcitabine and paclitaxel.
[0030] Based on a series of in vitro anti-cancer experiments against MCF-7 cell line, the inventors found that sulforaphene exhibits stronger inhibition against the growth and proliferation of human cancer cells compared with erlotinib and gemcitabine, but the activity is slightly lower than that of paclitaxel.
[0031] Based on cytotoxicity tests of peripheral blood mononuclear cells, the results show the cytotoxicity of sulforaphene against leukocyte is significantly lower than that of sulforaphane, cis-platinum, 5-fluorouracil, paclitaxel, and adriamycin. Further cytotoxicity tests of rat myocardial cells show that, the cytotoxicity of sulforaphene is significantly lower than that of sulforaphane and adriamycin.
[0032] The experiment subjects of the pharmaceutical composition comprising sulforaphene can be human beings, primates and other mammals. The administration mode can be oral administration, nasal administration, parenteral administration, or external use (for example, drops or transdermal patches). The term “parenteral administration” includes intravenous injection, intramuscular injection, sternum injection, hypodermic injection, and intra-articular injection.
[0033] The pharmaceutical composition comprising sulforaphene can be a solid, such as tablets, sugar-coated tablets, pills, capsules, granules, or microgranules (including powders or small-sized packings). A solid preparation of the pharmaceutical composition can be obtained by mixing pharmaceutically acceptable inert ingredients and the solid sulforaphene.
[0034] The dosage form of the pharmaceutical composition comprising sulforaphene can be oral liquid, which includes but is not limited to pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Besides sulforaphene, the liquid dosage form can include an inert diluent, such as water, solubilizer and emulsifier. The inert diluent can further include an adjuvant, such as wetting agent, emulsifier, and suspending agent, sweeteners, taste masking agent, and fragrances.
[0035] The dosage form of the pharmaceutical composition comprising sulforaphene can be injections, which include and are not limited to emulsions and solutions.
[0036] The dosage form of the pharmaceutical composition comprising sulforaphene can be suspensions, which are isostearyl alcohol, polysorbitolum, sorbitan, microcrystalline cellulose, bentonite, agar, tragacanth gum, or a mixture thereof.
[0037] The pharmaceutical composition comprising sulforaphene of the invention can be administered in the form of liposome which is derived from phospholipids and other lipids. Liposome is a specific preparation in which the active ingredients are coated by vesicles which are originated from lipid bilayer membrane. Liposome can act as a carrier for nutrients and drugs. Liposome can be prepared by destroying biomembranes, for example, by ultrasonic processing.
[0038] The pharmaceutical composition comprising 1-(alkylsulfinyl)-2-isothiocyanatoalkyl-1-alkene of the invention can also comprise one or more pharmaceutically acceptable carriers, additives, and pharmaceutically acceptable excipients. The pharmaceutically acceptable carriers are 8-[(2-hydroxy-4-methoxy benzoyl) amino]-octanoic sodium, as disclosed in U.S. Pat. No. 5,650,386, which can be used following the teaching in the literature. The additives can be Vitamin A or C. The excipients include but are not limited to solid or liquid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIG. 1 shows comparison graphs of the half maximal inhibitory concentration (IC50) of sulforaphene and sulforaphane against human lung adenocarcinoma cells A549;
[0040] FIG. 2 shows comparison graphs of the half maximal inhibitory concentration (IC50) of sulforaphene and sulforaphane against human lung squamous carcinoma cells H460;
[0041] FIG. 3 shows comparison graphs of the half maximal inhibitory concentration (IC50) of sulforaphene and sulforaphane against human pancreatic cancer cells PANC-1;
[0042] FIG. 4 shows comparison graphs of the half maximal inhibitory concentration (IC50) of sulforaphene and sulforaphane against human breast cancer cells MCF-7;
[0043] FIG. 5 shows comparison graphs of the half maximal inhibitory concentration (IC50) of sulforaphene and sulforaphane against human liver cancer cells HepG2;
[0044] FIG. 6 shows comparison graphs of the half maximal inhibitory concentration (IC50) of sulforaphene and sulforaphane against human cervical cancer cells HeLa;
[0045] FIG. 7 shows comparison graphs of the half maximal inhibitory concentration (IC50) of sulforaphene and sulforaphane against human malignant melanoma cancer cells A375;
[0046] FIG. 8 shows antitumor results of sulforaphene against human lung squamous carcinoma cells H460 xenograft in nude mice;
[0047] FIG. 9 shows antitumor results of sulforaphene and sulforaphane against human lung squamous carcinoma cells H460 xenograft in nude mice;
[0048] FIG. 10 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against leukemia cell line K562;
[0049] FIG. 11 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against leukemia cell line HL60;
[0050] FIG. 12 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against prostate cancer line PC-3;
[0051] FIG. 13 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against ovarian cancer line SK-OV-3;
[0052] FIG. 14 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against gastric cancer cell line HGC-27;
[0053] FIG. 15 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against gastric cancer cell line MGC-803;
[0054] FIG. 16 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against gastric cancer cell line AGS;
[0055] FIG. 17 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against esophageal cancer cell line EC109;
[0056] FIG. 18 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against esophageal cancer cell line kyse 180; and
[0057] FIG. 19 shows the half maximal inhibitory concentrations (IC50) of sulforaphene against esophageal cancer cell line TE-1.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0058] For further illustrating the invention, experiments detailing use of 1-(alkylsulfinyl)-2-isothiocyanatoalkyl-1-alkene for treating or preventing human or mammalian cancers and tumors are described below. It should be noted that the following examples are intended to describe and not to limit the invention.
I. Growth Inhibition of Human Cancer Cells In Vitro
[0059] Preparation of sulforaphene: glucosinolates in pre-ground radish seeds were hydrolyzed by an endogenous myrosinase in a phosphate buffer solution (PBS) having a pH value of 7 at the room temperature. In order to remove proteins and other impurities, the pH value was regulated to be 2.0, and a resulting solution was filtered, extracted, and dried to obtain a natural crude extract, and sulforaphene having a purity of larger than 98 wt. % was yielded by a high-speed counter-current chromatography (HSCCC).
[0060] General operations: human cancer cells are cultured in a RPMI-1640 (HyClone) culture medium comprising 10 v. % of a fetal bovine serum (FBS), and the culture medium is then placed in an incubator (37° C., 5% CO 2 ) for 24 hrs. A 0.25% trypsin solution and 0.02% EDTA solution are utilized after cell proliferation for common digestion and subculture. The EDTA solution is a traditional digestion mean. Trypsin is a serine protease possessing substrate specificity and used to digest adherent cells. However, divalent cations, such as calcium ions and magnesium ions, exist in the cells and are able to inhibit the digestion. EDTA is used to chelate these divalent cations so as to enhance the digestion effect of the trypsin. MTT assay is commonly used to measure the cell proliferation, the percentage of viable cells, and the cytotoxicity. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (also called thiazolyl blue tetrazolium bromide) is a kind of yellow dye. The principle of the MTT assay is that the succinate dehydrogenase in mitochondria of living cells is capable of reducing the exogenous MTT into water-insoluble blue-purple crystalline formazan, which forms a precipitate in the cells, while dead cells do not have such function. Dimethyl sulfoxide (DMSO) dissolves formazan in cells. The absorbance measured at a 490 nm wavelength using an enzyme-linked immunosorbent assay indirectly represents the number of viable cells. In a certain range of the cell numbers, the amount of the formed MTT crystals is in positive proportion to the cell number. Thus, the MTT assay is used to evaluate and determine the survival rate or the inhibition rate of the cells. Such method has been widely applied in activity detection of some bioactive factors, large scale screen of antitumor drugs, cytotoxicity test, and determination of tumor radiosensitity and features high sensibility.
[0061] Specific embodiments of the invention are described hereinbelow for further explaining the advantages of the invention, however, the following embodiments should not be considered as limitations of the protection scope of any or all of the claims.
Example 1
[0062] Materials and Methods
[0063] 1. Experimental cell lines and related chemical reagents: human lung adenocarcinoma cell line A549 purchased from US ATCC cell bank was cultured in the RPMI-1640 (HyClone) culture medium comprising 10 v. % of the FBS, digested by the 0.25% trypsin solution and 0.02% EDTA solution, and then subcultured. All related chemical reagents in this experiment were purchased from Sigma.
[0064] 2. Inhibition of A549 cells in vitro by sulforaphene and sulforaphane: A549 cells at exponential growth phase were collected, digested into single cells, and inoculated to 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into an incubator (37° C., 5% CO 2 ) for culture. Sulforaphene and sulforaphane were respectively dissolved by sterile deionized water, resulting solutions were then allowed to pass through 0.22 μM filters for removing bacteria. Filtrates were then diluted by a serum-containing medium to enable final concentrations of the sulforaphene or sulforaphane to be 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. After 24 hrs of cultivation, the A549 cells were then cultured by the culture solutions comprising the sulforaphene or sulforaphane of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 48 hrs of cultivation, 20 μL of MTT was added to each hole, and the plates were incubated for 3 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed and replaced by 150 μL of DMSO. Thereafter, the plates were cultured in a shaking table for 10 min, and the absorbance of each hole was measured at the wavelength of 490 nm. The number of viable cells in the negative control group at 0 hr was taken as a basis, and a 50% inhibitory concentration (IC 50) on the cell growth was calculated. The experiment results were listed in FIG. 1 .
[0065] Experiment Results
[0066] It was indicated from FIG. 1 that sulforaphene has significant inhibition effect on the growth and proliferation of the human lung adenocarcinoma cells A549. After 48 hrs of treatment, the IC50 of sulforaphene on the growth of the A549 cells was 10.5 μM. Sulforaphane has significant inhibition effect on the growth and proliferation of the human lung adenocarcinoma cells A549. After 48 hrs of treatment, the IC50 of sulforaphane on the growth of the A549 cells was 14.7 μM.
Example 2
[0067] Materials and Methods
[0068] 1. Experimental cell lines and related chemical reagents: human lung squamous carcinoma cell line H460 purchased from US ATCC cell bank was cultured in the RPMI-1640 (HyClone) culture medium comprising 10 v. % of the FBS, digested by the 0.25% trypsin solution and 0.02% EDTA solution, and then subcultured. All related chemical reagents in this experiment were purchased from Sigma.
[0069] 2. Inhibition of H460 cells in vitro by sulforaphene and sulforaphane: H460 cells at exponential growth phase were collected, digested into single cells, and inoculated to 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into an incubator (37° C., 5% CO 2 ) for culture. Sulforaphene and sulforaphane were respectively dissolved by sterile deionized water, resulting solutions were then allowed to pass through 0.22 μM filters for removing bacteria. Filtrates were then diluted by a serum-containing medium to enable final concentrations of the sulforaphene or sulforaphane to be 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. After 24 hrs of cultivation, the H460 cells were then cultured by the culture solutions comprising the sulforaphene or sulforaphane of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 48 hrs of cultivation, 20 μL of MTT was added to each hole, and the plates were incubated for 3 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed and replaced by 150 μL of DMSO. Thereafter, the plates were cultured in a shaking table for 10 min, and the absorbance of each hole was measured at the wavelength of 490 nm. The number of viable cells in the negative control group at 0 hr was taken as a basis, and the IC 50 on the cell growth was calculated. The experiment results were listed in FIG. 2 .
[0070] Experiment Results
[0071] It was indicated from FIG. 2 that sulforaphene has significant inhibition effect on the growth and proliferation of the human lung squamous carcinoma cells H460. After 48 hrs of treatment, the IC50 of sulforaphene on the growth of the H460 cells was 25.7 μM. Sulforaphane has significant inhibition effect on the growth and proliferation of the human lung squamous carcinoma cells H460. After 48 hrs of treatment, the IC50 of sulforaphane on the growth of the H460 cells was 34.62 μM.
Example 3
[0072] Materials and Methods
[0073] 1. Experimental cell lines and related chemical reagents: human pancreatic carcinoma cell line PANC-I purchased from US ATCC cell bank was cultured in the RPMI-1640 (HyClone) culture medium comprising 10 v. % of the FBS, digested by the 0.25% trypsin solution and 0.02% EDTA solution, and then subcultured. All related chemical reagents in this experiment were purchased from Sigma.
[0074] 2. Inhibition of PANC-I cells in vitro by sulforaphene and sulforaphane: PANC-I cells at exponential growth phase were collected, digested into single cells, and inoculated to 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into an incubator (37° C., 5% CO 2 ) for culture. Sulforaphene and sulforaphane were respectively dissolved by sterile deionized water, resulting solutions were then allowed to pass through 0.22 μM filters for removing bacteria. Filtrates were then diluted by a serum-containing medium to enable final concentrations of the sulforaphene or sulforaphane to be 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. After 24 hrs of cultivation, the PANC-I cells were then cultured by the culture solutions comprising the sulforaphene or sulforaphane of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 48 hrs of cultivation, 20 μL of MTT was added to each hole, and the plates were incubated for 3 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed and replaced by 150 μL of DMSO. Thereafter, the plates were cultured in a shaking table for 10 min, and the absorbance of each hole was measured at the wavelength of 490 nm. The number of viable cells in the negative control group at 0 hr was taken as a basis, and the IC 50 on the cell growth was calculated. The experiment results were listed in FIG. 3 .
[0075] Experiment Results
[0076] It was indicated from FIG. 3 that sulforaphene has significant inhibition effect on the growth and proliferation of the human pancreatic carcinoma cells PANC-I. After 48 hrs of treatment, the IC50 of sulforaphene on the growth of the PANC-I cells was 5.18 μM. Sulforaphane has significant inhibition effect on the growth and proliferation of the human pancreatic carcinoma cells PANC-I. After 48 hrs of treatment, the IC50 of sulforaphane on the growth of the PANC-I cells was 6.73 μM.
Example 4
[0077] Materials and Methods
[0078] 1. Experimental cell lines and related chemical reagents: human breast carcinoma cell line MCF-7 purchased from US ATCC cell bank was cultured in the RPMI-1640 (HyClone) culture medium comprising 10 v. % of the FBS, digested by the 0.25% trypsin solution and 0.02% EDTA solution, and then subcultured. All related chemical reagents in this experiment were purchased from Sigma.
[0079] 2. Inhibition of MCF-7 cells in vitro by sulforaphene and sulforaphane: MCF-7 cells at exponential growth phase were collected, digested into single cells, and inoculated to 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into an incubator (37° C., 5% CO 2 ) for culture. Sulforaphene and sulforaphane were respectively dissolved by sterile deionized water, resulting solutions were then allowed to pass through 0.22 μM filters for removing bacteria. Filtrates were then diluted by a serum-containing medium to enable final concentrations of the sulforaphene or sulforaphane to be 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. After 24 hrs of cultivation, the MCF-7 cells were then cultured by the culture solutions comprising the sulforaphene or sulforaphane of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 48 hrs of cultivation, 20 μL of MTT was added to each hole, and the plates were incubated for 3 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed and replaced by 150 μL of DMSO. Thereafter, the plates were cultured in a shaking table for 10 min, and the absorbance of each hole was measured at the wavelength of 490 nm. The number of viable cells in the negative control group at 0 hr was taken as a basis, and the IC 50 on the cell growth was calculated. The experiment results were listed in FIG. 4 .
[0080] Experiment Results
[0081] It was indicated from FIG. 4 that sulforaphene has significant inhibition effect on the growth and proliferation of the human breast carcinoma cells MCF-7. After 48 hrs of treatment, the IC50 of sulforaphene on the growth of the MCF-7 cells was 14.3 μM. Sulforaphane has significant inhibition effect on the growth and proliferation of the human breast carcinoma cells MCF-7. After 48 hrs of treatment, the IC50 of sulforaphane on the growth of the MCF-7 cells was 19.46 μM.
Example 5
[0082] Materials and Methods
[0083] 1. Experimental cell lines and related chemical reagents: human hepatocarcinoma cell line HepG2 purchased from US ATCC cell bank was cultured in the RPMI-1640 (HyClone) culture medium comprising 10 v. % of the FBS, digested by the 0.25% trypsin solution and 0.02% EDTA solution, and then subcultured. All related chemical reagents in this experiment were purchased from Sigma.
[0084] 2. Inhibition of HepG2 cells in vitro by sulforaphene and sulforaphane: HepG2 cells at exponential growth phase were collected, digested into single cells, and inoculated to 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into an incubator (37° C., 5% CO 2 ) for culture. Sulforaphene and sulforaphane were respectively dissolved by sterile deionized water, resulting solutions were then allowed to pass through 0.22 μM filters for removing bacteria. Filtrates were then diluted by a serum-containing medium to enable final concentrations of the sulforaphene or sulforaphane to be 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. After 24 hrs of cultivation, the HepG2 cells were then cultured by the culture solutions comprising the sulforaphene or sulforaphane of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 48 hrs of cultivation, 20 μL of MTT was added to each hole, and the plates were incubated for 3 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed and replaced by 150 μL of DMSO. Thereafter, the plates were cultured in a shaking table for 10 min, and the absorbance of each hole was measured at the wavelength of 490 nm. The number of viable cells in the negative control group at 0 hr was taken as a basis, and the IC 50 on the cell growth was calculated. The experiment results were listed in FIG. 5 .
[0085] Experiment Results
[0086] It was indicated from FIG. 5 that sulforaphene has significant inhibition effect on the growth and proliferation of the human hepatocarcinoma cells HepG2. After 48 hrs of treatment, the IC50 of sulforaphene on the growth of the HepG2 cells was 59.0 μM. Sulforaphane has significant inhibition effect on the growth and proliferation of the human hepatocarcinoma cells HepG2. After 48 hrs of treatment, the IC50 of sulforaphane on the growth of the HepG2 cells was 47.33 μM.
Example 6
[0087] Materials and Methods
[0088] 1. Experimental cell lines and related chemical reagents: human cervical carcinoma cell line HeLa purchased from US ATCC cell bank was cultured in the RPMI-1640 (HyClone) culture medium comprising 10 v. % of the FBS, digested by the 0.25% trypsin solution and 0.02% EDTA solution, and then subcultured. All related chemical reagents in this experiment were purchased from Sigma.
[0089] 2. Inhibition of HeLa cells in vitro by sulforaphene and sulforaphane: HeLa cells at exponential growth phase were collected, digested into single cells, and inoculated to 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into an incubator (37° C., 5% CO 2 ) for culture. Sulforaphene and sulforaphane were respectively dissolved by sterile deionized water, resulting solutions were then allowed to pass through 0.22 μM filters for removing bacteria. Filtrates were then diluted by a serum-containing medium to enable final concentrations of the sulforaphene or sulforaphane to be 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. After 24 hrs of cultivation, the HeLa cells were then cultured by the culture solutions comprising the sulforaphene or sulforaphane of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 48 hrs of cultivation, 20 μL of MTT was added to each hole, and the plates were incubated for 3 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed and replaced by 150 μL of DMSO. Thereafter, the plates were cultured in a shaking table for 10 min, and the absorbance of each hole was measured at the wavelength of 490 nm. The number of viable cells in the negative control group at 0 hr was taken as a basis, and the IC 50 on the cell growth was calculated. The experiment results were listed in FIG. 6 .
[0090] Experiment Results
[0091] It was indicated from FIG. 6 that sulforaphene has significant inhibition effect on the growth and proliferation of the human cervical carcinoma cells HeLa. After 48 hrs of treatment, the IC50 of sulforaphene on the growth of the HeLa cells was 24.1 μM. Sulforaphane has significant inhibition effect on the growth and proliferation of the human cervical carcinoma cells HeLa. After 48 hrs of treatment, the IC50 of sulforaphane on the growth of the HeLa cells was 25.8 μM.
Example 7
[0092] Materials and Methods
[0093] 1. Experimental cell lines and related chemical reagents: human malignant melanoma cell line A375 purchased from US ATCC cell bank was cultured in the RPMI-1640 (HyClone) culture medium comprising 10 v. % of the FBS, digested by the 0.25% trypsin solution and 0.02% EDTA solution, and then subcultured. All related chemical reagents in this experiment were purchased from Sigma.
[0094] 2. Inhibition of A375 cells in vitro by sulforaphene and sulforaphane: A375 cells at exponential growth phase were collected, digested into single cells, and inoculated to 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into an incubator (37° C., 5% CO 2 ) for culture. Sulforaphene and sulforaphane were respectively dissolved by sterile deionized water, resulting solutions were then allowed to pass through 0.22 μM filters for removing bacteria. Filtrates were then diluted by a serum-containing medium to enable final concentrations of the sulforaphene or sulforaphane to be 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. After 24 hrs of cultivation, the A375 cells were then cultured by the culture solutions comprising the sulforaphene or sulforaphane of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 48 hrs of cultivation, 20 μL of MTT was added to each hole, and the plates were incubated for 3 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed and replaced by 150 μL of DMSO. Thereafter, the plates were cultured in a shaking table for 10 min, and the absorbance of each hole was measured at the wavelength of 490 nm. The number of viable cells in the negative control group at 0 hr was taken as a basis, and the IC 50 on the cell growth was calculated. The experiment results were listed in FIG. 7 .
[0095] Experiment Results
[0096] It was indicated from FIG. 7 that sulforaphene has significant inhibition effect on the growth and proliferation of the human malignant melanoma cells A375. After 48 hrs of treatment, the IC50 of sulforaphene on the growth of the A375 cells was 7.8 μM. Sulforaphane has significant inhibition effect on the growth and proliferation of the human malignant melanoma cells A375. After 48 hrs of treatment, the IC50 of sulforaphane on the growth of the A375 cells was 9.11 μM.
Example 8
[0097] Materials and Methods
[0098] Erlotinib, gemcitabine, paclitaxel, and 5-FU are four effective drugs for treating lung cancer and mammary cancer. As a drug for target therapy, the erlotinib is applicable to a third-line treatment of locally advanced or metastatic non-small cell lung cancer when two or more than two chemotherapies are failed. Currently, the gemcitabine is clinically utilized as the drug of the first-line therapy in treating advanced non-small cell lung cancer and the metastatic breast cancer. The paclitaxel is primarily applied in the mammary cancer and has a certain efficacy in treating the lung cancer as well. The 5-FU has relatively good efficacy in treating the mammary cancer and the digestive system cancer (esophageal cancer, stomach cancer, colon cancer, pancreatic cancer, and liver cancer). Thus, the above four drugs are selected as the chemotherapeutic drugs in the control groups to study the differences antitumor effects compared with the sulforaphene. 1. Experimental cell lines and related chemical reagents: sources and cultivation of the human lung adenocarcinoma cells A549, the human lung squamous carcinoma cell line H460, the human breast carcinoma cell line MCF-7 are described in the above. The related chemical reagents in the experiment are all purchased from Sigma. 2. Inhibition of cells A549, H460, and MCF-7 in vitro by the sulforaphene and other chemotherapeutic drugs: cells A549, H460, and MCF-7 at exponential growth phase were collected, digested into single cells, and inoculated to 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into the incubator (37° C., 5% CO 2 ) for culture. The cells were respectively treated by 10 μM of the sulforaphene and 10 μM of other chemotherapeutic drugs (erlotinib, gemcitabine, paclitaxel, and 5-FU), cells in culture media of negative control groups were cultured by equal volume of sterile deionized water. The anti-tumor effects of the above drugs were measured by the MTT assay. The number of viable cells in the negative control groups at 0 hr was taken as a basis to calculate the anti-tumor effects. The inhibition rates of the drugs against the tumor cells were specifically listed in Table 1.
[0000]
TABLE 1
Inhibition rate (%) of sulforaphene
and contrast chemotherapeutic drugs
Cell line
Sulforaphene
Erlotinib
Gemcitabine
Paclitaxel
5-FU
A549
46.8
30.3
6.9
28.8
—
H460
34.2
33.1
4.3
17.3
—
MCF-7
41.9
NA
40.1
89.6
15.8
[0099] It is known from the experiment results in Table 1 that compared with the erlotinib, the gemcitabine, and the paclitaxel, the sulforaphene has much significant inhibition effect against the growth and proliferation of cells A549 and H460. In cells MCF-7, the anti-tumor effect of the sulforaphene is not comparable with the paclitaxel of the same concentration but is significantly higher than the gemcitabine and the 5-FU.
[0100] Thus, the sulforaphene has comparable or much superior inhibition effect against most tumor cells compared with the sulforaphane and other third-line chemotherapeutic or targeting drugs, which include but are not limited to the erlotinib, the gemcitabine, and the paclitaxel. Thus, sulforaphene possesses significant inhibition effect on the growth of the following tumor cells, which include but are not limited to human lung adenocarcinoma, human lung squamous carcinoma, human pancreatic cancer, human liver cancer, human breast cancer, human cervical cancer, and human malignant melanoma.
II. Growth Inhibition of Animal Cancer Cells In Vivo
Example 9
[0101] 1. Inoculation of tumor cells into armpit
[0102] 1.1 Preparation of experimental animals: 30 nude mice with equal numbers of females and males were fed in normal conditions in the laboratory for between 3 and 5 days.
[0103] 1.2. Preparation of H460 cells: H460 tumor cells were normally cultured, and diluted using the PBS so as to prepare a suspension of tumor cells having a concentration of 7.5×10 6 tumor cells per milliliter.
[0104] 1.3 Inoculation of tumor cells: the suspension of the tumor cells was fully shaken and 0.2 mL of the suspension was then sucked by a sterile syringe having a capacity of 1 mL. The tumor cells were then inoculated into armpits of the nude mice via subcutaneous injection. The inoculated mice were then fed for between 2 and 3 days in normal conditions. When the tumor tissue grew to a size with a long axis of approximately 3 mm and a short axis of approximately 2 mm, all the nude mice having the tumor tissues were randomly divided into three groups, which were utilized in subsequent administration experiments.
[0105] 2. Design of the experimental groups: an aqueous solution of an orally administrated drug had a concentration of 35.37×10 −3 mol-L −1 ;
[0106] 2.1 Control group: five male mice and five female mice having tumor tissues were orally administered with ultrapure water for three times each week (respectively at Monday, Wednesday, and Friday afternoons), and the administered volume was 0.3 mL for each time.
[0107] 2.2 Experimental group 1: five male mice and five female mice having tumor tissues were orally administered with sulforaphene with a dosage of 75 mg of the sulforaphene per kg of weight for three times each week (respectively at Monday, Wednesday, and Friday afternoons), and the administered volume was 0.3 mL for each time.
[0108] 2.3 Experimental group 2: five male mice and five female mice having tumor tissues were orally administered with sulforaphane with a dosage of 75 mg of the sulforaphane per kg of weight for three times each week (respectively at Monday, Wednesday, and Friday afternoons), and the administered volume was 0.3 mL for each time.
[0109] 3. Acquisition of experimental data
[0110] 3.1 Acquisition of weight data of nude mice: weight data of the nude mice were collected three times per week (respectively at Monday, Wednesday, and Friday afternoons). An electronic balance was utilized to record the weight data, and an accuracy of the weight data was 0.01 g.
[0111] 3.2. Acquisition of sizes of tumor tissues in the nude mice: the sizes of the tumor tissues in the nude mice were measured three times per week (respectively at Monday, Wednesday, and Friday afternoons). An electronic vernier caliper was utilized to measure the long axis and the short axis of the tumor tissues, and an accuracy of the data was 0.01 mm.
[0112] 3.3. Observations of other data and phenomenon: the survival conditions of the nude mice were closely observed. In case of death, the time of death, the number of the nude mouse, and the corresponding group were timely recorded. And in case of abnormal conditions of the nude mice, the time of the occurrence and the symptoms were timely recorded.
[0113] 3.4 Finish time of the experiments: when the tumor tissues in the nude mice of the control group reach an average size of 1000 mm3 (Volume=long axis×short axis 2×0.5236), the weights and the sizes of the tumor tissues of the nude mice were recorded, and then the experiments were stopped and the nude mice were treated.
[0114] 3.5 Treatment of nude mice when finishing the experiments: the nude mice were killed, arranged according to different groups, and photographed. Six representative mice were selected from each group and photographed. Then the tumor tissues were respectively isolated, weighed, placed at corresponding positions, and photographed. Experiment results were listed in Table 2:
[0000]
TABLE 2
Tumor volumes of sulforaphene administered group, sulforaphane
administered group, and negative control group
Tumor
Tumor
Tumor
Tumor
Tumor
volume
volume
volume
volume
volume
on 1 st
on 3 rd
on 6 st
on 8 th
on 10 th
day
day
day
day
day
Negative
63.23745
159.603
413.2829
750.5499
1055.276
control
group (not
administered
with drugs)
Sulforaphene
35.99841
68.41752
217.957
336.6193
530.4369
(75 mg/kg)
Sulforaphane
30.55106
78.80789
257.8812
389.6022
552.7308
(75 mg/kg)
[0115] Each group of the nude mice was orally administered with the sulforaphene or drugs of the control groups (with 75 mg/kg each time). It is known from the above results that the sulforaphene has significant inhibition effect on the growth of the tumor cells in vivo (as shown in FIG. 8 ), and the inhibition effect of the sulforaphene is superior to that of the sulforaphane (as shown in FIG. 9 ).
III. Toxicity Experiment on Human Peripheral Blood Mononuclear Cell (PBMC)
[0116] General operations: normal peripheral blood cells were isolated by Ficoll to obtain mononuclear cells. The mononuclear cells were rinsed by the PBS for three times, and added with IMDM+10% FBS to prepare suspensions. 10 μM, 30 μM, and 50 μM of sulforaphene or sulforaphane and other four chemotherapeutic drugs were added to the suspensions for treatment, respectively. The suspensions were then inoculated into 96-well plates, with each hole containing 25 thousands cells per 100 μL of the culture medium, and cultured overnight at 37° C.
[0117] Treatment: because the proliferation of the PBMCs is very limited and the PBMCs quickly enter a decline phase. Thus, the cell viability was measured by the MTT assay after 24 hrs of culture. Four drugs with different mechanisms were employed to treat leukocytes, which were cis-platinum, 5-fluorouracil (5-FU), paclitaxel, and adriamycin, respectively, and a drug concentration of thereof was 10 μM. A total of eleven experiment groups were divided: sulforaphene treated groups with concentrations of 10 μM, 30 μM, and 50 μM, sulforaphane treated groups with concentrations of 10 μM, 30 μM, and 50 μM, a cis-platinum treated group, a paclitaxel treated group, an adriamycin treated group, a 5-FU treated group, and a negative control group, specific data of which are listed in Table 3. The group where PBMCs were treated by the sterile deionized water was selected as the negative control group.
[0000]
TABLE 3
Experiment results of toxicity of sulforaphene, sulforaphane,
and construct chemotherapeutic drugs on PBMCs
Cell
viability
1
2
3
4
Mean value
(%)
10 μM Sulforaphene
0.886
0.833
0.824
0.763
0.827
103.5
30 μM Sulforaphene
0.782
0.706
0.713
0.671
0.718
89.9
50 μM Sulforaphene
0.718
0.685
0.674
0.661
0.685
85.7
10 μM Sulforaphane
0.702
0.633
0.705
0.593
0.658
82.4
30 μM Sulforaphane
0.655
0.616
0.58
0.628
0.620
77.6
50 μM Sulforaphane
0.663
0.621
0.610
0.610
0.626
78.4
Paclitaxel
0.712
0.743
0.683
0.650
0.697
87.2
Adriamycin
0.482
0.482
0.496
0.530
0.498
62.3
Cis-platinum
0.470
0.518
0.530
0.482
0.500
62.6
5-FU
0.493
0.484
0.525
0.461
0.491
61.4
Negative control
0.81
0.809
0.786
0.790
0.799
100
Example 10
[0118] Materials and Methods
[0119] 1. Experimental cells: normal peripheral blood cells were isolated by Ficoll to obtain mononuclear cells. The mononuclear cells were rinsed by the PBS for three times, added with IMDM+10% FBS to prepare suspensions, commonly digested by 0.25% trypsin solution and 0.02% EDTA solution, and then subcultured.
[0120] 2. Inhibition of PBMCs in vitro by sulforaphene and the contrast chemotherapeutic drugs: signal cells of the digested PBMCs were inoculated to the 96-well plates with each hole containing 3000 cells. Then the 96-well plates were transferred into an incubator at 37° C. for culture. The sulforaphene was dissolved by the sterile deionized water, and a resulting solution was then allowed to pass through a 0.22 μM filter for removing bacteria. A filtrate was thereafter diluted by a serum-containing medium to enable final concentrations of the sulforaphene to be 10 μM, 30 μM, and 50 μM, respectively. The sulforaphane was prepared in the same way. Concentrations of the contrast chemotherapeutic drugs were as follows: 50 μM of the cis-platinum, 60 μM of the 5-FU, 20 μM of the paclitaxel, 5 μM of the adriamycin. After 12 hrs of cultivation, the PBMCs were then cultured by culture solutions comprising the sulforaphene of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 24 hrs of cultivation, 20 μL of MTT was added to each hole, and the plates were incubated for 3 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed and replaced by 150 μL of DMSO. Thereafter, the plates were cultured in a shaking table for 10 min, and the absorbance of each hole was measured at the wavelength of 490 nm Experiment results were listed in Table 3.
[0121] Experiment Results
[0122] It is indicated from Table 3 that the toxicity of the sulforaphene on the PBMCs is significantly lower than the sulforaphane and the other selected chemotherapeutic drug treated groups. The contrast chemotherapeutic drugs have significant inhibition effect on the growth and proliferation of the PBMCs. The sulforaphane has certain effect on the proliferation of the cells, while the effect of the sulforaphene on the proliferation of the cells is not significant.
IV. Toxicity Experiment on Rat Cardiomyocytes
[0123] General operations: 1-2 day old neonatal SD rats (female or male) were selected and cardiomyocytes were isolated in sterile condition. Cardiomyocytes were cultured for 3 days and then treated with sulforaphene or sulforaphane of concentrations of 10 μM, 30 μM, and 50 μM, or adriamycin of the concentration of 10 μM for 24 hrs. The cardiotoxicity of the above drugs were represented by a ratio of ATP/total protein. The experiment was performed in 8 groups: sulforaphene treated groups with concentrations of 10 μM, 30 μM, and 50 μM, sulforaphane treated groups with concentrations of 10 μM, 30 μM, and 50 μM, an adriamycin treated group, and a negative control group, specific data were listed in Table 3. The group where PBMCs were treated by the sterile deionized water was selected as the negative control group.
Example 11
[0124] Materials and Methods
[0125] 1. Experimental cells: 1-2 day old neonatal SD rats (female or male) were selected and sterilized. Then ventricular muscles were collected and digested by trypsin to prepare cardiomyocyte suspensions. The suspensions were cultured in the incubator (37° C., 5% CO 2 ), and primary cardiomyocytes were cultured by differential adhesion. An average viability of the cardiomyocytes evaluated by Trypan blue staining was 98.2%, and a purity of the cardiomyocytes evaluated by immunofluorescence method is 98.7%.
[0126] 2. Inhibition of the rat primary cardiomyocytes in vitro by sulforaphene and the contrast chemotherapeutic drugs: single cells of the digested rat primary cardiomyocytes were inoculated to 24-well plates and incubated in the incubator (37° C., 5% CO 2 ). The sulforaphene, the sulforaphane, and the adriamycin were prepared by the same methods as described in the above. After 12 hrs of cultivation, the rat primary cardiomyocytes were then cultured by culture solutions comprising the sulforaphene, the sulforaphane, or the adriamycin of corresponding concentrations, and to the culture media of the negative control group an equal volume of sterile deionized water was added for cell culture. After another 6 hrs of cultivation, the culture solution in each hole was replaced by the normal culture solution not containing any drugs, and incubated for 42 hrs in the incubator (37° C., 5% CO 2 ). Solution in each hole was then removed, and cells therein were rinsed by the PBS for three times, digested by the trypsin, and gathered into two parts. One part of the cells was utilized to measure the ATP level by the reporter gene assay, and the other part of the cells was utilized to measure the cellular protein concentration by BAC assay. The ratio of ATP (ng) to the protein concentration (ng) was calculated, and the ratio of each experimental group is divided by the ratio of the contrast group to obtain the relative ratio of ATP/total protein, experimental results were listed in Table 4.
[0000]
TABLE 4
Experiment results of toxicity of sulforaphene, sulforaphane,
and adriamycin on rat cardiomyocytes
1
2
3
Mean value (%)
10 μM Sulforaphene
98.2
99.4
95.9
97.83
30 μM Sulforaphene
94.1
95.5
93.2
94.27
50 μM Sulforaphene
91.0
92.3
88.7
90.67
10 μM Sulforaphane
90.0
88.2
91.4
89.87
30 μM Sulforaphane
85.1
83.3
81.6
83.33
50 μM Sulforaphane
77.5
76.7
73.9
76.03
Adriamycin
47.3
43.1
50.5
46.97
[0127] Experiment Results
[0128] It is known in Table 4 that the toxicity of the sulforaphene on the cardiomyocytes is significantly lower than that of the sulforaphane, and the Adriamycin has obvious toxicity on the cardiomyocytes.
[0129] Conclusion: it is indicated from the systematic study of the invention that sulforaphene is superior to conventional antitumor drugs including sulforaphane, erlotinib, gemcitabine, and paclitaxel in inhibiting the growth of many kinds of cancer cells, and has higher security than sulforaphane, cis-platinum, 5-fluorouracil, paclitaxel, and adriamycin. So, sulforaphene has potential antitumor activities against lung cancer, lung squamous cell carcinoma, pancreas cancer, liver cancer, mammary cancer, cervical carcinoma, malignant melanoma, and so on.
[0130] Unless otherwise indicated, the numerical ranges involved in the invention include the end values. While particular embodiments of the invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the invention in its broader aspects, and therefore, the aim in the appended claims is to cover all such changes and modifications as fall within the true spirit and scope of the invention.
| 1a
|
This application claims the benefit of U.S. Provisional Application Ser. No. 60/174,260 filed Jan. 3, 2000, the teachings of which are incorporated herein by reference.
FIELD OF INVENTION
The present invention relates to methods for performing surgery and instruments used therewith, in particular micro-surgical methods and techniques and the instrumentalities used therewith to determine anatomical structure of the surgical site. The present invention more particularly relates to surgical methods involving the eye (e.g., retinal tear or detachment surgery, macular hole surgery) as well as the instruments or devices used during such surgical procedures to determine the physiological state of the tissue within the eye, such as the retina.
BACKGROUND OF THE INVENTION
The execution of microsurgical procedures, such as those involving the eye, is primarily driven by visual information available to the surgeon during the surgical procedure. For example, to aid in viewing the interior structures and regions of the eye when performing intraocular surgery, such as for example a retinal tear or detachment surgery and macular hole surgery, one or more surgical contact lenses are fitted into a lens ring that is sutured in place and spans the cornea. A cushion of transparent Healon or similar material is typically applied to the anterior surface of the eye to prevent corneal abrasion and to enhance optical clarity. In addition, a light source is introduced into the intra-ocular volume of the eye. The surgeon looks through the surgical contact lens and through the lens of the eye lens to observe the interior of the eye lighted by the light source.
Visual queues such as structure, color and the way the tissue responds to manipulation by a surgical instrument are used by the surgeon to determine anatomical structure and to make assumptions about the corresponding physiological state of the surrounding tissue. Based on these observations and assumptions, the surgeon develops a mental plan of a desired surgical approach. The surgeon then executes that plan manually. Unfortunately, in many microsurgical environments the visualization provided by existing optical microscopes is limited due to obstructed views or optical limitations.
Additionally, following execution of the plan, the surgeon typically evaluates the results or outcomes of the surgical procedure by means of such visual observations to determine if the procedure appears to be successful. Following eye surgery, the ophthalmic surgeon performs one or more diagnostics tests to determine the effectiveness of the surgical procedure. In a number of cases, however, the diagnostics test(s) performed show that the surgery was not as effective as indicated by the visual queues. Consequently, the patient again can be scheduled for surgery, whereupon the process is repeated. As a result, the patient experiences further risk for the additional surgery, experiences added discomfort because of the additional procedure(s) and increases the risk that the corrective action may be less than hoped for. Moreover, the added surgery results in increased cost to the patient or insurance carrier because of the additional corrective surgery.
There also are micro-surgical procedures such as those for example involving the middle ear, where the surgical site must be opened up or externalized in order for the surgeon to effectively visualize the surgical site. For example, in micro-surgical procedures involving the the middle ear, the middle ear is externalized (i.e., opened up) for the surgeon to observe the area.
There is disclosed in U.S. Pat. No. 5,152,295 an intra-operative diagnostic imaging device. This imaging device is in the form of a finger mounted probe and is disposed on a finger of the technician/doctor when imaging. Consequently, the use of this imaging device is limited to those situations in which the finger and finger mounted probe can access the area of interest. Such an imaging device, however, because of its physical size and arrangement cannot be used in the intraocular space of an eye.
There are ultrasonic imaging devices for ophthalmologic uses, however, such devices are external probes that are placed on an outside surface of the eye such as on the conjunctiva 4 (FIG. 1 ). In order for such external probes to view the retina, the ultrasonic sound must penetrate through several tissue layers (e.g., the cornea and the lens) and through approximately one inch of fluid in the intraocular space. Thus, a low frequency ultrasound wave (for example, on the order of 2 mHz) is used to image the retina. A low frequency must be used because higher frequencies are not capable of penetrating through to the retina. A low frequency ultrasonic signal, however, returns a low resolution image, whereas high frequency ultrasonic sound is capable of returning a high resolution image. Thus, fine detail of the retina is not available when using low frequency ultrasonic sound.
It thus would be desirable to provide a new imaging device and methods for performing micro-surgery that would allow the surgeon to intra-operatively image the surgical site and selected areas about the site. It would be particularly desirable to provide such an imaging device and such methods using an improved ultrasonic imaging technique that would provide intra-operative images of a higher quality in comparison to the images obtained with prior art ultrasonic imaging devices. It also would be desirable to provide such a device and methods that are particularly suited for providing high quality images of the anatomical structure of the eye such as the retina during the conduct of a surgical procedure as compared to the images using prior art ultrasonic devices. Such imaging devices preferably would be simple in construction and such methods would not require highly skilled users to utilize the device.
SUMMARY OF THE INVENTION
The present invention features a device that provides a mechanism for imaging structure and/or tissue of a surgical site during and after performing a microsurgical procedure such as ophthalmic surgical procedures. Such an intra-operative imaging device also allows a high frequency ultrasonic imaging mechanism to be disposed in close proximity to the area to be scanned/imaged (e.g., surgical site) so a surgeon is provided with high quality/high resolution images. The high quality/high resolution images provide a source of information to the surgeon that can be used to adjust the planned surgical approach so as to accommodate for any conditions not accounted for in the initial planning of the surgical approach to be taken.
An exemplary embodiment of the intra-operative imaging device includes a probe member having a predetermined length and an ultrasonic signal transmitting and receiving mechanism secured to the probe member. The predetermined length is established such that the ultrasonic signal transmitting and receiving mechanism is positioned in close proximity to the particular area or region to be scanned and disposed with a cavity of the body. In specific embodiments, the ultrasonic signal transmitting and receiving mechanism is an ultrasonic transducer, more particularly a high frequency ultrasonic transducer. The frequency of the ultrasonic signals is general established so the scanned image provides a desired amount of detail, particularly, as compared to the detail available when using prior art techniques, for the surgeon to evaluate the effectiveness of the procedure being performed and to make any adjustments to the procedure.
An imaging methodology according to the present invention includes steps of positioning an ultrasonic signal transmitting and receiving apparatus in proximity to a region to be scanned and performing an ultrasound scanning process using the ultrasonic signal transmitting and receiving mechanism during an in-process stage of a microsurgical procedure. Such a methodology includes providing an intra-operative imaging device of the present invention and inserting the probe member into a member of body such that the ultrasonic signal transmitting and receiving mechanism is proximal the region to be scanned for imaging. The method further includes evaluating the results of the scanning process performed and adjusting the surgical procedure/approach when such evaluating determines that adjustment should be performed.
Also featured are micro-surgical procedures including surgical methods involving the eye, for example, retinal tear or detachment surgery and macular hole surgery. Further featured are device kits that comprise such intra-operative microsurgical devices alone or in conjunction with other microsurgical instruments such as entry alignment devices.
Other aspects and embodiments of the invention are discussed below.
BRIEF DESCRIPTION OF THE DRAWING
For a fuller understanding of the nature and desired objects of the present invention, reference is made to the following detailed description taken in conjunction with the accompanying drawing figures wherein like reference character denote corresponding parts throughout the several views and wherein:
FIG. 1 is a cross-sectional schematic view of a non-diseased eye where the conjunctiva is pulled back for surgery, a conventional technique;
FIG. 2 is a schematic view of an ultrasonic viewing system including a intraoperative microsurgical device according to the present invention;
FIG. 3 is a top view of an intra-operative microsurgical device according to the present invention;
FIGS. 4A-C are cross-sectional schematic views of an eye undergoing a retinal tear repair procedure;
FIGS. 5 A,B are cross-sectional schematic views of an eye undergoing a retinal tear repair procedure to illustrate use of the intra-operative microsurgical imaging device to image portions of the retina during the repair procedure;
FIGS. 6 A,B are front and side views of the entry alignment device of FIG. 5A; and
FIG. 6C is a perspective view of the entry alignment device of FIG. 5 B.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the various figures of the drawing wherein like reference characters refer to like parts, there is shown in FIG. 2 a schematic view of an ultrasonic viewing system 100 including a intra-operative microsurgical device 200 according to the present invention. The intra-operative microsurgical device 200 includes a handle member 202 , a probe member 204 and an ultrasonic transducer 206 affixed to the distal end of the probe member. In an illustrative embodiment, and as shown in FIG. 3, the handle member 202 is arranged and configured so as to allow the member to be gripped by a surgeon or technician that is performing the intra-operative ultrasonic scanning so as to provide an image of the scanned area.
This, however, shall not constitute a limitation as it is within the scope of the present invention for the intra-operative microsurgical device 200 to be held by or secured to a member (not shown) of an automated arm assembly or a manually operated arm assembly, each controlling the motion of the intra-operative microsurgical device. In such cases, the arm assembly provides a mechanism to control movement of the intra-operative microsurgical device 200 along predetermined and position determinable paths. Thus, a volume of material can be scanned and reconstructed for viewing and evaluation.
The handle member 202 also is constructed of any of a number of materials known to those skilled in the art that are appropriate for the intended use and structural loads imposed thereon during use. Such materials include metals such as stainless steel and plastics such as polymides.
The probe member 204 is secured to and extends from one end 203 of the handle member 202 , more particularly, the probe member extends a predetermined distance or length from the handle member end so that the ultrasonic transducer 206 is remote from the handle member. The length also is set so that for a given application, the ultrasonic transducer 206 is disposable proximal the surgical cavity or site to be scanned and imaged. Further such a length is such that the handle member 202 is at a location where it can be grasped for manually or automated manipulation. In this way, the surgical cavity or opening in the body need not be sized to accommodate the handle member 202 or the mechanism for manual or automated manipulation. In an illustrative embodiment, the length of the probe member 204 is about 2.5 cm or larger so that the ultrasonic transducer 206 is proximal the back of the eye such as illustrated in FIGS. 5 A,B. In an illustrative embodiment, the length of the probe member 204 is set so that the ultrasonic transducer 206 can be positioned about 0.5 mm from the surface of the retina.
In a more particular embodiment, the cross section of the probe member 204 transverse to the long axis of the probe member also is set so that the probe member is generally needle-like thereby minimizing the size of the opening in the body required to receive the probe member. In specific embodiments, the cross-sectional width of the probe member 204 is set so as to be about 1 mm or smaller and more specifically about 0.5 mm or 25 gauge. Such cross-sectional widths are particularly adaptable for use in imaging the anatomical structure of the eye. In an illustrative embodiment, the probe member 204 is a cylindrically shaped, however, other geometric shapes are contemplated and adaptable for use.
The ultrasonic transducer 206 , is any of a number of devices, mechanisms or arrangements known to those skilled in the art that outputs an ultrasonic signal of a predetermined frequency, which is acoustically coupled to the area to be imaged, and receives the sound energy being reflected back by the material making up the area to be imaged. The ultrasonic transducer 206 also is preferably configured so that a high frequency signal is outputted and received by the transducer. In specific embodiments for high quality imaging, the ultrasonic transducer is configured so as to output a signal in the frequency range of about 20-100 mHz, more particularly in the range of about 40-70 mHz, more specifically to output a signal greater than or equal to about 50 mHz, or to output a signal of about 50 mHz.
Such frequencies are sufficient to provide high resolution information to the surgeon, information that is generally above and beyond what is currently possible using either conventional microscopes or conventional high resolution ultrasound imaging devices. Additionally, by setting the length of the probe member 204 to an appropriate length, the ultrasonic transducer 206 can be optimally positioned such that such high resolution imaging information can be obtained for structures relatively inaccessible to conventional high resolution ultrasound devices. Further, the capability of positioning the ultrasonic transducer 206 proximal the structure to be imaged, minimizes if not eliminates the short penetration depth characteristic of high frequency ultrasounds shortcoming of conventional externally located transducers or ultrasound probes.
Although the intra-operative imaging device 200 of the present invention is particularly configured for obtaining high quality or high resolution images, images having fine detail observable, such a use shall not be construed as a limitation. The ultrasonic transducer 206 is configurable to provide any available frequency appropriate for the tissue or material to be imaged for a given application, including frequencies lower than those provided above.
Each of the handle member 202 and the probe member 204 include a passage or lumen therein so that the ultrasonic transducer 206 can be operably coupled, electrically or optically, to the monitor 104 via the interconnecting cable 102 . The interconnecting cable 102 is any of a number of cables known in the art to operably couple the output signals from the ultrasonic transducer 206 to the components, circuitry and devices making up the monitor 104 . The monitor 104 is any of a number of apparatuses known to those skilled in the art which are capable of receiving output signals from an ultrasonic transducer and converting these signals into visual or computer useable output representative of the scanned image. Such a monitor 104 can include processing units and other components for storing and further manipulating the ultrasonic output signals and images for viewing.
In use, the ultrasonic transducer 206 returns A-scan information to the technician/surgeon, which information comprises the ultrasonic reflections from the tissues or structure beneath the ultrasonic transducer. As indicated above, during use the surgeon/technician manipulates the handle member 202 so as to cause the ultrasonic transducer 206 to move with respect to the surface of the area to be imaged/scanned. Typically, the surgeon/technician moves the ultrasonic transducer 206 at a slow rate to acquire a series of A-scans so as to form a line or slice of information. The surgeon/technician also can manipulate the handle member 202 so as to acquire a plurality of slices or lines of information displaced from each other or to acquire a matrix of A-scans, which can be re-constructed to form a volume of scanned tissue/structure.
The use of the intra-operative microsurgical imaging device 200 and the related methodologies of the present invention can be further understood from the following discussion concerning a method for treating a retinal tear or detachment by means of the laser photocoagulation technique and with reference to FIGS. 4A-C and FIGS. 5 A,B. Reference also shall be made to FIGS. 1-3 for specific components or elements of the intra-operative microsurgical imaging device 200 of the present invention not otherwise shown in FIGS. 4A-C. In the following, the treatment or method for treating a retinal tear or detachment is described first in general terms and then in regards to performing intra-operative imaging using the intra-operative microsurgical imaging device 200 of the present invention. Reference also should be to co-pending application U.S. Ser. No. 09/523,767, filed Mar. 11, 2000 the teachings of which are incorporated herein by reference, for further details regarding the below described entry alignment devices and related methods.
In treating a retinal tear or detachment using the photocoagulation technique employing a laser, a cutting/aspirating instrument 300 , a cannula 302 and a light transmitting instrument 304 are inserted through the sclera so one end of each resides intraocular. The light transmitting instrument 304 is configured so the light from the laser (not shown) can be directed to specific locations on the retina. The cutting/aspirating instrument 300 is disposed so an end thereof is proximate the retinal tear.
Alternatively, and as shown in FIGS. 5A-B, an entry alignment device 350 a,b is used to provide or form an entry aperture in each of the conjunctiva and the sclera and to keep the apertures in each of the sclera and conjunctiva aligned during a procedure. As also illustrated, each of the cutting/aspirating instrument 300 , the cannula 302 and the light transmitting instrument 304 can be received within the entry aperture formed by the entry alignment devices 350 a,b.
Initially, the vitreous gel, especially all strands causing traction on the retinal tear are removed or aspirated by means of the cutting/aspirating instrument 300 . As the vitreous gel is being aspirated, the intraocular volume is maintained by a continuous infusion of a fluid, such as a balanced salt solution (BSS), through the cannula 302 . Any subretinal fluid is also aspirated through the retinal tear. Thereafter, the vitreous fluid is aspirated and exchanged with a gas such as air passing through the cannula 302 . As taught in U.S. Pat. No. 5,997,498, the teachings of which are incorporated herein by reference, the gas or air being exchanged is humidified by means of an in-line humidifier and humidification system as described therein.
The retina surrounding the tear is then repeatedly exposed to the laser light from the light transmitting instrument 304 so as to form a plurality of heat spots on the retina surrounding the retinal tear. In particular, the practitioner manipulates the light transmitting instrument 304 so that a plurality of rows of a plurality of such heat spots surrounds the retinal tear. In this way, the retinal tear is photocoagulated with a laser to achieve a thermal adhesive injury. The heat spots also produce scars that prevent fluid from passing through and collecting under the retina.
Thereafter, the intraocular gas or air, infused while exposing the retina surrounding the retinal tear to laser light, is totally exchanged for a longer-lasting gas, such as sulfur hexafluorine or perfluoro propane. This gas allows an adequate tamponade time for the therapeutic chorioretinal scar to develop. Preferably, the longer lasting gas being infused is humidified using the in-line humidifier as described above. After completing the “in eye” portion of the treatment procedure, the inserted instruments and cannula are removed from the eye.
In the present invention, the intra-operative microsurgical imaging device 200 can be utilized at various times during a surgical procedure to provide additional information regarding the microsurgical environment including anatomical structural information and the effectiveness of the surgical approach being executed by the surgeon. There is shown in FIGS. 5 A,B cross-sectional schematic views of an eye undergoing the retinal tear repair procedure of FIGS. 4A-C to illustrate use of the intra-operative microsurgical imaging device 200 to image portions of the retina.
Referring now to FIG. 5A, there is shown the use of the intra-operative microsurgical imaging device 200 at some point during the repair procedure. In the illustrated embodiment, an entry alignment device 350 a (see also FIGS. 6 A,B) is inserted through the conjunctiva and the sclera to form an entry aperture. As shown more clearly in FIG. 6B, the inserted portion 356 of the entry alignment device 350 a is configured so as to include a dished portion 357 that extends between the stop portion 354 and the pointed end 358 . Thus, the exterior surfaces of the probe member 204 are received in the dished portion 357 so as to guide the probe member and the ultrasonic transducer 206 through the conjunctiva 4 and the sclera 6 into the intra-ocular volume as they are being inserted.
Referring now to FIG. 5B, there is shown the use of the intra-operative microsurgical imaging device 200 after performing the photocoagulation of the retina according to the repair procedure. In the illustrated embodiment, another entry alignment device 350 b (see also FIGS. 6 A,B) is inserted through the conjunctiva 4 and the sclera 6 to form an entry aperture. This entry alignment device 350 b includes an insertion member 360 and a stop member 362 that is affixed about the exterior of the insertion member 360 . The entry alignment device 350 b of this embodiment is configured and arranged so that in use, the portion of the insertion member 360 that is below the stop member 362 is passed through each of the conjunctiva 4 and the sclera 6 . Additionally, in use the entry alignment member 350 b is inserted until the stop member 362 is proximal the exterior surface of the eye 2 similar to that shown for the stop portion 354 in FIG. 6 A.
In the illustrated embodiment, an end of the insertion member 360 is securably received in the stop member 362 . Alternatively, the entry alignment device is constructed such that the insertion and stop members 360 , 362 form an integral structure. In yet another embodiment, the insertion member 360 and stop member 362 are configured and arranged so the insertion member extends through an aperture in the stop member. In this case an end of the insertion member is disposed proximal an end surface 368 of the stop member or the insertion member extends outwardly from the stop portion end surface. The insertion member 360 also is a tubular member having a lumen 364 extending between the ends of the insertion member and the stop portion includes therein a through aperture 366 that communicates with the insertion member lumen. In use, the lumen 364 and the through aperture 366 comprises the entry aperture formed in the eye 2 through which the surgical instruments and the probe member 204 and ultrasonic transducer 206 introduced.
The inserted end 369 of the insertion member 360 is illustrated as being substantially flat. It is within the scope of the present invention, however, for the inserted end 369 to be pointed, cut on a bias or other wise configured so as to form a tissue piercing type of end.
In either of the illustrated embodiments, the probe member 204 is inserted into the intra-ocular volume of the eye until the ultrasonic transducer 206 is positioned proximal the retina. As noted above, in an illustrative embodiment, the ultrasonic transducer 206 is spaced about 0.5 mm from the surface of the retina. Thereafter, the handle member 202 is manipulated so as to cause the ultrasonic transducer 206 to scan an area or strip of the retina. The reflections from the tissue and/or anatomical structure of the eye are received by the transducer and outputted to the monitor 104 for viewing by the surgeon.
The use of such an entry alignment device 350 a,b advantageously avoids the dissection of the conjunctiva 4 and its subsequent reattachment to the eye, a requirement of existing prior art surgical methods and techniques. The foregoing procedure, in conjunction with the instruments and devices used in conjunction with this procedure, reduce the size or make smaller the incisions that are made through the sclera 6 for the passage of instruments and infusion cannula, and thus reduce trauma to the eye. Further because there is no need to dissect and reattach the conjunctiva, the time required for the surgical procedure to be performed is reduced, thus also reducing the time the patient is on the operating table and the overall cost of the procedure. The entry alignment devices illustrated herein shall not be construed as a limitation, as it is within the scope of the present invention to utilize any of the entry alignment devices disclosed in U.S. Ser. No. 09/523,767.
Thus, the intra-operative microsurgical imaging device 200 of the present invention provides a mechanism or tool by which a surgeon or technician can scan the retina during the retinal repair procedure to evaluate the effectiveness of the actions taken. In other words, the surgeon can evaluate the effectiveness of the surgical procedure at any time during the procedure and thus has the ability to revise the planned actions to deal with any indications of less than effective results.
This capability to evaluate the effectiveness of a surgical procedure, while performing the procedure has a number of beneficial effects. Because the effectiveness of the procedure can be accomplished during the conduct of the procedure, the net effect is to reduce the chance that the subsequently performed diagnostic test will reveal a problem requiring a further surgical procedure(s). Consequently, the number of operations or procedures being performed should be reduced as compared to prior art techniques. This also should result in reductions in the amount of time a patient spends recovering as compared to prior art techniques.
In the foregoing, the use of the intra-operative microsurgical imaging device 200 of the present invention is illustrated in connection with a retinal tear repair procedure, this shall not be construed as imposing limitation on the usage of the imaging device for other microsurgical procedures. For example, the intra-operative microsurgical imaging device is contemplated for use in connection with middle ear surgery so that the imaging of the middle ear does not involve externalizing. Such an imaging device also is adaptable for diagnostic procedures involving the eye and for invasive diagnostic procedures or tests where there is a risk involved with placement of a test instrumentality and the imaging device can be used to reduce such risks. For example, diagnostic procedures or tests involving the use of needles to extract a tissue sample or extract a fluid sample (amniotic fluid).
Although a preferred embodiment of the invention has been described using specific terms, such description is for illustrative purposes only, and it is to be understood that changes and variations may be made without departing from the spirit or scope of the following claims.
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THE PRIOR ART
Of great importance for the dyeing of hair are the so-called oxidation dyestuffs because of their intensive colors and very good fastness. These dyestuffs are formed by the oxidative coupling of a developer component with a coupling component. The developers customarily used are nitrogenous bases, such as p-phenylenediamine derivatives, diaminopyridines, 4-aminopyrazolone derivatives or heterocyclic hydrazones. Useful as so-called coupling components are m-phenylenediamine derivatives, phenols, naphthols, resorcinol derivatives and pyrazolones.
Good oxidation dyestuff components for hair dyeing must fulfill all of the following requirements.
They have to be able to develop a sufficient intensity of the desired color shades when oxidatively coupled with the respective developer component or coupling component. Furthermore, they have to possess a capacity for being absorbed by human hair, which capacity ranges from sufficient to very good; and in addition, they should be unobjectionable from toxicological and dermatological viewpoints.
As developers, it is customary to use the class of compounds consisting of substituted or unsubstituted p-phenylenediamines. However, this class of compounds has the disadvantage that sensitivity reactions and subsequently severe allergies are caused in numerous persons. The developers which have been recently proposed for avoiding these dermatological disadvantages are not always fully satisfactory with respect to their technical application.
U.S. Pat. No. 4,003,699, Jan. 18, 1977, discloses oxidation hair dyes based upon tetraaminopyrimidine developers which can react with the known couplers generally used in oxidation hair dyestuffs to give very intensive, varying shades which previously could not be obtained with these known couplers. U.S. Pat. No. 4,003,699 also discloses the special usefulness of its tetraaminopyrimidines employed as developers in combination with certain m-aminophenols as blue-coupling components.
It is further disclosed in the above patent that the tetraaminopyrimidines disclosed therein are characterized by very good fastness of the dyeings produced with them, good water-solubility, good storage stability, and toxicological and dermatological harmlessness.
Among the various tints producable by oxidation hair dyes, great importance is attached to the intensive yellow and yellowish-brown tints and some special shades. The coupler components normally used as red and yellow coupler components and for special tints have not produced satisfactory results when combined with the tetraaminopyrimidines which otherwise give very satisfactory results when used as developer components. Thus, the task arose of providing coupler components which, when combined with the tetraaminopyrimidines used as developer substances, produce intensive yellow, yellowish-brown, brown and special tints which meet all requirements with respect to fastness, stability and toxicological and dermatological harmlessness desirable in oxidation hair dyes.
OBJECTS OF THE INVENTION
An object of the invention is to provide usable oxidation hair dyes containing suitable components which optimally satisfy the above requirements.
Another object of the present invention is to provide an oxidation dyestuff combination of a developer component and a coupling component, which is based on tetraaminopyrimidines as the developer component and certain aromatic compounds as the coupler component.
These and further objects of the present invention will become apparent as the description thereof proceeds.
DESCRIPTION OF THE INVENTION
The present invention provides a composition and process for dyeing hair based upon an oxidation dyestuff combination of a developer component which is a tetraaminopyrimidine and a coupling component therefor. It has now been found that the above-specified requirements can be fulfilled to an especially significant extent by the use of hair coloring preparations that are based on oxidation dyestuff combinations containing tetraaminopyrimidines of the formula ##STR1## and their inorganic or organic water-soluble acid addition salts as developers, in which R 1 to R 6 are each selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms, aryl, substituted aryl, and --(CH 2 ) n --X, in which n is an integer from 1 to 4, and X is selected from the group consisting of hydroxy, halogen and --NR 7 R 8 wherein R 7 and R 8 are selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms and can form with the nitrogen atom a heterocyclic ring which may contain one additional nitrogen atom or an oxygen atom, and in which R 1 to R 6 , together with the respective nitrogen atom, likewise can designate an optionally substituted five-membered or six-membered heterocyclic ring containing one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, and containing at least one coupling component selected from the group consisting of
(a) 2,4-diaminophenol
(b) 2,4-diamino-3-chlorophenol
(c) 2-amino-4-methylphenol
(d) 3-amino-2,6-dimethylphenol
(e) 2,2',4,4'-tetrahydroxybenzophenone
(f) 2,4-diamino-6-methylphenol
(g) 3,4-diaminophenetole
(h) 1,3-dihydroxy-5-methylaminobenzene
(i) 1-hydroxy-7-aminonaphthalene
(j) 1-hydroxy-8-aminonaphthalene
(k) 1,6-dihydroxynaphthalene
(l) 2,7-dihydroxynaphthalene
(m) 3,5-dimethoxyphenol.
More particularly, the present invention is directed to an aqueous preparation for the dyeing of hair consisting essentially of (1) from 0.2% to 5% by weight of an oxidation dyestuff combination of a developer component, and a coupling component in substantially equimolar amounts, said developer component consisting essentially of (A) a tetraaminopyrimidine of the formula ##STR2## wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each selected from the group consisting of hydrogen, phenyl, alkyl having 1 to 4 carbon atoms, phenylalkyl having 7 to 10 carbon atoms, phenylalkenyl having 7 to 10 carbon atoms,
X--(CH.sub.2).sub.n --
wherein n is an integer from 1 to 4, and X is selected from the group consisting of hydroxyl, halogen and NR 7 R 8 -- in which R 7 and R 8 are each hydrogen or alkyl having 1 to 4 carbon atoms, and together with the nitrogen atom R 7 and R 8 form a member selected from the group consisting of a 5 to 6 membered heterocyclic ring optionally containing an additional nitrogen atom or oxygen atom, and wherein R 1 and R 2 , or R 3 and R 4 , or R 5 and R 6 , together with the nitrogen atom form a five to six membered heterocyclic ring optionally containing another nitrogen or oxygen atom in the ring and (B) a water-soluble acid addition salt of (A), and said coupler component consisting essentially of at least one compound selected from the group consisting of
(a) 2,4-diaminophenol
(b) 2,4-diamino-3-chlorophenol
(c) 2-amino-4-methylphenol
(d) 3-amino-2,6-dimethylphenol
(e) 2,2',4,4'-tetrahydroxybenzophenone
(f) 2,4-diamino-6-methylphenol
(g) 3,4-diaminophenetole
(h) 1,3-dihydroxy-5-methylaminobenzene
(i) 1-hydroxy-7-aminonaphthalene
(j) 1-hydroxy-8-aminonaphthalene
(k) 1,6-dihydroxynaphthalene
(l) 2,7-dihydroxynaphthalene
(m) 3,5-dimethoxyphenol;
(2) from 0% to 5% by weight of a direct dyestuff; (3) 0% to 30% by weight of a surfactant; (4) from 0% to 25% by weight of thickeners; and (5) the balance up to 100% by weight of water.
A particularly preferred subgenus of the above-mentioned developer component is wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, n-propyl, butyl, phenyl, benzyl and benzylidene, or --(CH 2 ) n --X, and wherein R 1 and R 2 , or R 3 and R 4 , or R 5 and R 6 , together with the nitrogen atom form a substituent selected from the group consisting of piperidino and morpholino; and wherein n is 1, 2 or 3 and X is selected from the group consisting of hydroxyl, halogen and --NR 7 R 8 in which R 7 and R 8 are each hydrogen or alkyl having 1 to 4 carbon atoms.
The above tetraaminopyrimidines are disclosed in U.S. Pat. No. 4,003,699, the teachings of which are incorporated herein by reference.
The tetraaminopyrimidines which are to be used as developer components according to the invention can be used either as such or in form of their water-soluble acid addition salts with non-toxic inorganic acids or organic acids, such as for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid or citric acid.
The preparation of most tetraaminopyrimidines to be used as developer components according to the invention is already known in the literature and can be taken from the monograph by D. J. Brown, in the series "Heterocyclic Compounds", Interscience Publishers, 1962, Vols. I and II, "The Pyrimidines". The preparation of some of the tetraaminopyrimidines of the invention is disclosed in U.S. Pat. No. 4,003,699.
To synthesize the tetraaminopyrimidine compounds to be used according to the invention, the starting material generally is a 2,4,6-aminopyrimidine, into which the 5-amino group is introduced by nitrosation and subsequent reduction. It is also possible to start from the correspondingly substituted triaminoalkylmercaptopyrimides and to replace the alkylmercapto group with an amino group. The latter method is especially suitable for the introduction of substituted amino groups into the 2-, 4-, or 6-positions of the pyrimidine ring.
Suitable examples of developer components to be used according to the invention, are for example: 2,4,5,6-tetraamino-pyrimidine, 4,5-diamino-2,6-bis(methylamino)-pyrimidine, 2,5-diamino-4,6-bis-(methylamino)-pyrimidine, 4,5-diamino-6-(butylamino)-2-(dimethylamino)-pyrimidine, 2,5-diamino-4-(diethylamino)-6-(methylamino)-pyrimidine, 4,5-diamino-6-(diethylamino)-(2-dimethylamino)-pyrimidine, 4,5-diamino-2-(diethylamino)-6-(methylamino)-pyrimidine, 4,5-diamino-2-(dimethylamino)-6-(ethylamino)-pyrimidine, 4,5-diamino-2-(dimethylamino)-6-(isopropylamino)-pyrimidine, 4,5-diamino-2-(dimethylamino)-6-(methylamino)-pyrimidine, 4,5-diamino-6-(dimethylamino)-2-(methylamino)-pyrimidine, 4,5-diamino-2-(dimethylamino)-6-(propylamino)-pyrimidine, 2,4,5-triamino-6-(dimethylamino)-pyrimidine, 4,5,6-triamino-2-(dimethylamino)-pyrimidine, 2,4,5-triamino-6-(methylamino)-pyrimidine, 4,5,6-triamino-2-(methylamino)pyrimidine, 4,5-diamino-2-(dimethylamino)-6-piperidinopyrimidine, 4,5-diamino-6-(methylamino)-2-piperidino-pyrimidine, 2,4,5-triamino-6-piperidino-pyrimidine, 2,4,5-triamino-6-anilino-pyrimidine, 2,4,5-triamino-6-(benzylamino)-pyrimidine, 2,4,5-triamino-6-(benzylideneamino)-pyrimidine, 4,5,6-triamino-2-piperidino-pyrimidine, 5-amino-2,4,6-tris-(methylamino)pyrimidine, 2,4,5-triamino-6-(di-n-propylamino)pyrimidine, 2,4,5-triamino-6-morpholino-pyrimidine, 2,5,6-triamino-4-(dimethylamino)-pyrimidine, 4,5,6-triamino-2-morpholino-pyrimidine, 2,4,5-triamino-6-(β-hydroxyethyl-amino) pyrimidine, 4,5,6-triamino-2-[(β-aminoethyl)amino]-pyrimidine, 2,5,6-triamino-4-[(β-methylamino)-ethylamino]-pyrimidine, 2,5-diamino-4,6-[(bis-γ-diethylamino)-propylamino]-pyrimidine, 4,5-diamino-6-[β-hydroxyethyl)-amino]-2-(methylamino)pyrimidine, 5-amino-2,4,6-(triethylamino)-pyrimidine, and 5-amino-6-anilino-2,4-[bis-(β-hydroxyethyl)-amino]-pyrimidine.
The coupler components that can be used according to the present invention are compounds known in the literature and are commercially available products.
In the hair coloring preparations according to the invention, the coupler substances are generally used in substantially equimolar amounts, relative to the developer substances used. Although an equimolar amount is preferred, it is possible to use more or less of either component in a certain excess or deficiency, as for example the molar range of 2:1 to 1:2, more preferably up to a 10% excess or deficiency.
Furthermore, the developer component and the coupling component may be used as pure ingredients or as mixtures. Not only can the developer component consist of mixtures of the tetraaminopyrimidines to be used according to the invention, but the coupler substance can also consist of mixtures of the above-mentioned compounds.
In addition, the hair coloring preparations according to the invention can contain admixtures of other customary developing components. Besides developer and/or coupler components they, if necessary, also contain the customary direct dyestuffs in case the latter are needed for obtaining certain shades. From 0% to 5% direct dyestuffs may be employed.
As in the case of other oxidation hair dyes, the oxidative coupling, i.e., the developing of the dye, can in principle be effected by atmospheric oxygen. However, it is advantageous to use chemical oxidizing agents. Suitable examples are especially hydrogen peroxide or its products of addition to urea, melamine and sodium borate, as well as mixtures of such hydrogen peroxide addition products with potassium peroxydisulfate.
As developer components the tetraaminopyrimidines according to the invention have the advantage that they readily yield fully satisfactory hair dyeing results in oxidative coupling with atmospheric oxygen. Thus hair damage by the oxidizing agents, otherwise used in oxidative coupling, can be avoided. But if a brightening or bleaching effect is desired in the hair, in addition to the coloring effect, then the concurrent use of chemical oxidizing agents is necessary.
In their use, the hair dyes according to the invention are incorporated into suitable aqueous cosmetic preparations, such as creams, emulsions, gels or simple solutions and immediately before application to the hair, one of the above-mentioned oxidizing agents is added. These hair dyeing compositions contain coupling and developing components in amounts of from 0.2% to 5% by weight, preferably from 1% to 3% by weight.
For the preparation of creams, emulsions or gels, the dye components are mixed with the additional ingredients customarily used in such preparations. Such additional ingredients are, for example, wetting agents or emulsifiers of the anionic or nonionic type, such as alkybenzenesulfonates, higher fatty alcohol sulfates, higher alkylsulfonates, higher fatty acid alkanolamides, addition products of ethylene oxide on higher fatty alcohols, thickeners, such as methyl cellulose, starch, higher fatty alcohols, paraffin oil and higher fatty acids. Furthermore, perfumes and hair-conditioning and grooming agents, such as pantothenic acid and cholesterol may be included.
Effective amounts of the above-mentioned additives are those customarily employed for this purpose. For example, effective amounts of wetting agents and emulsifiers range from 0.5% to 30% by weight, preferably from 1% to 15% by weight; and for thickeners, an effective amount ranges from 0.1% to 25% by weight, preferably from 1% to 15% by weight, based in each case on the total weight of the preparation. As a lower limit for the above additives, a zero percent lower limit is possible, if none of the additive is utilized.
The hair coloring preparations according to the invention can be applied in a weakly acid medium, a neutral medium or especially in an alkaline medium, preferably at a pH of 8 to 10, regardless of whether a solution, an emulsion, a cream, or a gel is employed.
These preparations are applied at a temperature which usually ranges from 15° C. to 40° C. and preferably is room temperature.
After the preparation has been allowed to react for about 30 minutes, the hair coloring preparation is removed from the hair to be dyed, by rinsing. Then the hair is washed with a mild shampoo, and finally is dried.
The compounds to be used in accordance with the invention as coupler components produce, when combined with the tetraaminopyrimidine developers, very intensive tints which are distinguished by particularly satisfactory lightfastness, a satisfactory penetrating capacity, and toxicological harmlessness.
The following examples are merely illustrative of the present invention without being deemed limitative in any manner thereof.
EXAMPLES
The following compounds were used as coupler components in the examples presented hereinafter:
______________________________________Coupler component:______________________________________K 1 2,4-diaminophenolK 2 2,4-diamino-3-chlorophenolK 3 2-amino-4-methylphenolK 4 3-amino-2,6-dimethylphenolK 5 2,2',4,4'-tetrahydroxybenzophenoneK 6 2,4-diamino-6-methylphenolK 7 3,4-diaminophenetoleK 8 1,3-dihydroxy-5-methylaminobenzeneK 9 1-hydroxy-7-aminonaphthaleneK 10 1-hydroxy-8-aminonaphthaleneK 11 1,6-dihydroxynaphthaleneK 12 2,7-dihydroxynaphthaleneK 13 3,5-dimethoxyphenol______________________________________
The following compound was used as a developer component in the examples presented hereinafter:
E 1: 2,4,5,6-tetraaminopyrimidine
EXAMPLE 1
The hair dyes according to the invention were used in the form of a cream emulsion. 0.01 mole of 2,4,5,6-tetraaminopyrimidine and 0.01 mole of the coupler components listed in the following Table were in each case incorporated into an emulsion containing
10 parts by weight of fatty alcohols having 12 to 18 carbon atoms,
10 parts by weight of fatty alcohol sulfate (sodium salt) having 12 to 18 carbon atoms, and
75 parts by weight of water.
The pH value of the emulsion was then adjusted to 9.5 by means of ammonia, and the emulsion was made up to 100 parts by weight with water. Oxidative coupling was effected with a 1% hydrogen peroxide solution acting as an oxidation agent, 10 parts by weight of the hydrogen peroxide solution being added to 100 parts by weight of the emulsion. The particular dyeing cream, with additional oxidation agent, was applied to human hair which was 90% grey and which had not been specially pretreated, and the cream was left on the hair for 30 minutes. After the dyeing process was completed, the hair was washed out with a conventional shampoo and subsequently dried. The colors obtained are given in the following Table.
TABLE______________________________________ Shade obtained withExample (a) Developer (b) Coupler 1% H.sub.2 O.sub.2 solution______________________________________1 E 1 K 1 Medium Brown2 E 1 K 2 Yellowish brown3 E 1 K 3 Yellowish brown4 E 1 K 4 Violet5 E 1 K 5 Auburn6 E 1 K 6 Yellowish brown7 E 1 K 7 Olive yellow8 E 1 K 8 Chestnut brown9 E 1 K 9 Reddish brown10 E 1 K 10 Greyish violet11 E 1 K 11 Green12 E 1 K 12 Yellowish brown13 E 1 K 13 Olive yellow______________________________________
The above colors are to be contrasted with those reported in Table I of U.S. Pat. No. 4,003,699.
The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, however, that other expedients known to those skilled in the art or disclosed herein, may be employed without departing from the spirit of the invention or the scope of the appended claims.
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RELATED APPLICATIONS
This application claims the benefit of the filing date of U.S. patent application Ser. No. 60/201,168, entitled “REMOTE CONTROLLED FLOOR MOPPING APPARATUS”, filed on May 2, 2000, which is hereby incorporated by reference.
This patent application is related to U.S. patent application Ser. No. 09/847,600 for “APPARATUS AND METHOD FOR IMPROVING TRACTION FOR A MOBILE ROBOT”, concurrently filed May 2, 2001, and which is hereby incorporated by reference.
BACKGROUND
1. Field of the Invention
Aspects of the present invention relate to automated, robotic floor mopping. More specifically, embodiments of the present invention relate to a unique electric floor cleaning system that can be incorporated into a wide variety of robot or remote control platforms.
2. Description of the Related Technology
Robotic technology is under development in many academic and industrial environments. A great challenge for mobile robots is robust navigation, which has been solved in a variety of applications. Computer processing power, batteries, electronic sensors such as cameras, and efficient electric motors are all either just becoming available, cost effective or reliable enough to use in consumer robots. Industry has finally reached the point where commercial success of household robots has become an implementation issue, rather than a technology issue.
Mobile robots have been designed, developed and deployed to handle a variety of tasks, such as manufacturing and security. As robots become more prevalent in society, they will continue to automate tasks currently performed by people. Household cleaning and maintenance is an obvious application for robotics, and pool cleaning, lawn mowing and vacuuming robots have been developed.
Mopping is another obvious candidate for automation, but automated mopping is not as simple as making a robot that mops like a person. The methods humans use to perform household tasks have evolved over time based on the tools available, but a robot will not necessarily perform tasks in the same manner as a person. For example, people use their arms and legs to walk and work, while most robots use motors and wheels.
While it is possible to automate current manual or electric mopping devices and methods, the result would be a poorly performing machine based on a compromise of ideas. People clean surfaces, such as floors, using mops and buckets of water. A mopping robot would have to be large enough to hold both clean and dirty water reservoirs, and, therefore, could not clean small, hard-to-reach areas. The clean water and cleaning solution require refilling, the dirty water needs emptying, and the mop head needs to be cleaned and occasionally replaced. Water and drains would need to be plumbed to locations the robot could reach. Even if this was done in new construction, leaks in the robot or in the filling station would be potentially catastrophic. Designing failsafe machines to work with water is complicated and expensive. Therefore, a robot mop needs a unique and innovative cleaning apparatus to work effectively.
Most mopping is done manually with a mop and a bucket of water. The Swiffer™ is a product that uses small disposable towels to damp mop smooth floors. In addition to being a manual device, this product is inconvenient because it is does not deep clean and each individual towel only cleans a small area. Current electric mopping machines and waxers use spinning brushes, either flat disks that spin on an axis perpendicular to the ground or cylindrical brushes that spin on an axis parallel to the ground.
Another mopping approach uses a long damp towel on two rollers. The towel in this system is configured similar to a scroll such that it is wound on two rollers, feed and take-up reels, mounted on a handle. Typically, the feed reel is exposed, and the user presses it against the ground to mop. When the area of towel gets dirty, the user manually winds the towel further onto the take-up reel to expose a clean towel area. Trigger mechanisms that wind the towel with a press of a button have also been developed. A disposable cartridge/towel system has also been developed for this type of mopping approach.
A robot mopping system is appealing to consumers. However, all the heretofore proposed robot mops are simply automated versions of electric mopping devices. A variety of water and plumbing issues make the viability of such a system questionable.
SUMMARY OF THE INVENTION
Aspects of the present invention are directed toward a system and method of automated, robotic floor mopping. The unique electric cleaning system can be incorporated into a wide variety of robot or remote control platforms. One embodiment includes a fully automated robotic floor mopping machine that damp mops the floor using a pre-moistened roll of towels or webbing that automatically advances from a feed roll to a take-up roll. While this embodiment is directed to a self-contained robot mopping apparatus, another embodiment of the mopping system could also be incorporated in a slave platform that operates in conjunction with a controller robot.
Unlike all current electric and robot mopping devices that use spinning brushes and onboard water reservoirs, this system uses a pre-moistened web or towel on a roller system. The general cleaning process is similar to how a person works with a sponge. The robot moves back and forth while pressing the towel against the floor. Instead of rinsing the towel, the robot turns its rollers exposing a clean section of towel. For convenience, the towel can be delivered on a roll that is pre-moistened with a cleaning solution and is disposable.
While it is possible to use the take-up or feed reel as the cleaning head, such as in previous mechanical devices, one embodiment presses the towel against the floor by a pliable, sponge-like object. The dual benefits are increasing the size of cleaning area, and the soft pressure improves cleaning because the towel will contour to irregularities in the floor such as grout between tiles.
Typically, the roll of toweling is transferred between two reels at a controlled rate as the robot moves in a mopping motion across the floor. However, the robot can use optical or other sensors to determine when the exposed portion of the towel is dirty and advance the towel on the reels when appropriate. Research has shown that one square foot of toweling cleans approximately 25 square feet of flooring. The towel can be made of any cloth, paper or other appropriate material, but a tough, disposable paper-based material is preferable in one embodiment. Simple water can be used as the cleaning solution, but adding soap or other cleaner improves the mop efficacy. It is also feasible to use a dry towel and have the robot apply a cleaning solution. This necessitates a reservoir on the robot in one embodiment.
In one aspect of the present invention, there is a floor mopping assembly, comprising a first roller configured to let out a web mounted on a roll; a second roller configured to reel in the web; a motor system configured to cause transfer of the web between the first roller and the second roller; a pad configured to press the web against a surface; and a housing to enclose the motor system, the first roller, the second roller and the pad, wherein the motor system, the first and second rollers, and the pad are mounted in the housing such that the motor causes transfer of the web between the first and second rollers and between the pad and the surface.
In another aspect of the present invention, there is a floor mopping assembly, comprising a computerized mobile chassis, a first roller configured to let out a roll of webbing, a second roller configured to reel in the webbing, and a motor system configured to cause transfer of the webbing between the first roller and the second roller, wherein the motor system and the first and second rollers are conveyed by the chassis.
In another aspect of the present invention, there is a floor mopping assembly, comprising a computerized mobile chassis, a first means for letting out a portion of webbing, a second means for taking up the webbing, and a motor means for causing transfer of the webbing between the first means and the second means.
In yet another aspect of the present invention, there is a method of mopping a surface with a floor mopping device, the method comprising a) connecting a roll of webbing on a feed roller to a take-up roller, b) moving the floor mopping device without human intervention, c) pressing on a portion of the webbing such that the webbing cleans the surface, and d) transferring the portion of the webbing to the take-up roller.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front perspective diagram of a single robot embodiment of an automated floor-mopping device.
FIG. 2 is an exploded view diagram of exemplary components of the single robot, automated floor mopping device shown in FIG. 1 .
FIG. 3 is a sectional view diagram of the single robot, automated floor mopping device shown in FIG. 1 further showing the towel, feed and take-up rollers and the pliable cleaning head conforming to irregularities to the floor shape.
FIG. 4 a and FIG. 4 b are lower and upper perspective view diagrams, respectively, of an embodiment of a remotely controlled, automated floor-mopping device.
FIG. 5 is a front perspective diagram of an embodiment of a remote control, automated floor mopping device under the direction of an independent controller robot.
FIG. 6 is a sectional view diagram showing the feed roll as the cleaning head as may be used in the automated floor mopping device shown in FIGS. 1 and 4.
FIGS. 7 a and 7 b show a mechanism in schematic form that raises and lowers the towel mechanism as may be used in the automated floor mopping device shown in FIGS. 1 and 4 .
DETAILED DESCRIPTION
The following detailed description presents a description of certain specific embodiments of the present invention. However, the present invention may be embodied in a multitude of different ways as defined and covered by the claims. In this description, reference is made to the drawings wherein like parts are designated with like numerals throughout.
Aspects of the present invention are directed towards a system and robotic or remote control method for mopping a floor. In particular, the system overcomes the drawbacks of having a mopping device carry reservoirs of clean and dirty water as well as a detergent or other cleaning or waxing solutions.
FIG. 1 shows a front perspective of one embodiment of an autonomous robot mop 100 . The overall shape and configuration of the robot may affect its ability to autonomously clean and navigate an environment, but generally does not affect, nor is affected by, the automated floor-mopping aspects of this invention.
FIG. 2 is an exploded view of the robot mop 100 embodiment shown in FIG. 1 . Wires, hardware and other components have been removed in the view of FIG. 2 for simplification. In one embodiment, the robot is housed inside a plastic shell 101 , and controlled by a custom computer assembly 102 that includes a Central Processing Unit (CPU) or processor, Random Access Memory (RAM), and non-volatile storage. There are many CPUs that are sufficient for use including, for example, those manufactured by Intel, Motorola, and Microchip (PIC). The computer assembly 102 processes information received from sensors 103 to determine its position, the room types and so on, in order to determine what should be done next. Additionally, the computer assembly 102 controls all the motors on the robot in one embodiment. Information about the environment, such as a map and task schedule, is maintained in non-volatile memory. The computer assembly 102 includes two camera sensors 103 that view through lenses 104 to provide stereo vision. Wide angle lenses such as those found in some readily available Web and security cameras are preferred in this embodiment. While cameras are the sensors in one embodiment, the robot can also use ultrasonic, radar or lidar sensors in place of or in conjunction with the cameras. The cameras are the primary sensors facing the forward direction, and additional cameras or other sensors may optionally be oriented around the periphery of the robot. The robot may also use short range ultrasonic or touch sensors, floor type sensors or other additional ways to improve its performance.
A left drive wheel and drive motor assembly 107 and a right drive wheel and drive motor assembly 108 mounted on a bracket 109 within the shell propel the robot 100 . A battery 106 powers the system. Ideally, the battery 106 provides sufficient voltage for the computer, sensors and motors. Otherwise, the system may require one or more transformers. In one embodiment, a rechargeable battery is utilized and is sized to provide an hour or more of power for the robot to effectively clean between charges. NiCad, lithium ion, lead acid and other battery technologies may be successfully used. The mopping system is mounted on a bottom plastic shell 110 . It includes a pre-moistened web or towel 115 assembled onto a feed roll, reel or roller 116 and a take-up roll 117 . The entire towel assembly is configured in a manner similar to a scroll where the paper is wound from one roll onto the other roll. The ends of both rollers 116 , 117 have details that snap into mating features 119 on the lower shell 110 . One end of the take-up roll has a gear 118 that meshes with a gear 112 mounted on a towel drive motor 111 . When the towel 115 is in place within the robot 100 , the cleaning area passes over a non-absorbent cushioning pad 114 adhered to a mounting plate 113 , which may be a solid mounting plate. One or more weights 105 may be added to the robot system to ensure that the towel 115 is pressed against the floor with an appropriate pressure. In one embodiment, closed cell foams are utilized for the pad because they are durable and do not absorb water. However, self-skinning open cell foams such as urethane and neoprene are acceptable as are other sponge type materials enclosed in a watertight bag.
As the robot 100 moves back and forth across the floor of an area or room, the towel 115 mops the floor. During use, the towel is transferred between the feed reel 116 and the take-up reel 117 at a controlled rate. Tests indicate that one square foot of towel can clean approximately 25 square feet of floor. The computer assembly 102 can advance the towel a specific amount based on the amount of floor that is cleaned. Alternatively, the robot 100 could include a sensor, such as a camera, to determine when the active cleaning area of the towel is dirty. One embodiment uses one motor 111 on the take-up reel 117 and assumes there is sufficient friction on the feed reel 116 to prevent it from inadvertently unwinding in use. Alternate embodiments can include drive motors on both rollers and/or clutches or friction brakes to ensure tension on the towel.
In one embodiment, the towel 115 is embodied in a disposable assembly that snaps into the robot and is removed when the entire length has been used. A paper-based towel similar to a paper towel or a handiwipe™ is used in one embodiment, but a cloth towel is an alternative. Alternatively, a non-disposable cloth towel could be removed and washed between uses. Regardless of the material, the towel is to be pre-moistened. Adding soap or other cleaning agent to the mixture improves the cleaning characteristics. Similarly, the towel could be pre-moistened with a wax so as to wax, rather than mop, a floor.
In many embodiments, a length of the towel on the roll is independent of the amount of towel needed to clean the floor. Therefore, the towel may remain on the robot mop for an indefinite period. For these embodiments, it may be preferable to encase the feed roll in a watertight compartment including a seal around where the towel exits the compartment. This will enable the towel to remain wet between uses.
Minimizing the robot size allows it to clean smaller spaces. However, the smaller the robot, the smaller the towel roll it can carry and the smaller the amount of floor it can clean before the towel needs replacing. An alternative is to provide a large roll of toweling and have the robot automatically load a length of towel as required. The robot can either load a standard length, or it could determine the amount it needs for a day and take that amount. In such an automated system, the robot disposes of the dirty towels.
As shown in FIG. 3, the use of the non-absorbent pad 121 (which is similar to the pad 114 ) offers several improvements to previous cleaning devices. It provides a relatively large cleaning surface and ensures constant pressure when the towel 122 (which is similar to towel 115 ) is pressed against a surface or floor 120 . The towel is transported from a feed roller 123 to a take-up roller 124 In one embodiment, the pad 121 , the towel 122 , the feed roller 123 , the take-up roller 124 , and drive wheels 125 (only one wheel is shown) are configured in a robot housing 126 as shown. In another embodiment, the position of the feed roller and the take-up roller may be interchanged. Since the pad is soft and compliant in one embodiment, it conforms to irregularities in the floor, such as grout lines 127 in tile flooring. This feature improves the cleaning ability of the robot mopping system.
FIG. 4 shows a top perspective view (FIG. 4 b ) and bottom perspective view (FIG. 4 a ) of a remotely controlled mopping device 130 . This device 130 includes a pre-moistened cleaning towel 131 , a non-absorbent cushioning pad 132 and a drive system 133 mounted in a plastic shell 134 . However, the mopping device 130 does not include the sensors and electronics to autonomously navigate through its environment. A person using a joystick or other similar controller could control this device in a manner similar to that done with toy cars.
Alternatively, the mopping device could be a slave robot in a master/slave system 142 such as shown in FIG. 5 . In this configuration, the mop 141 (which is similar to the mopping device 130 ) performs the cleaning under the control of the master robot 140 . The master robot 140 includes most or all of the electronics and sensors, and directs the slave's movement such as described in Applicant's copending U.S. patent application Ser. No. 09/449,177, filed on Nov. 24, 1999, entitled “Autonomous Multi-Platform Robot System”, which is hereby incorporated by reference. In this system 142 , a single control robot such as master robot 140 could work with multiple cleaning devices, such as sweepers and vacuums. It is possible for the master controller to be a stationary computer provided there are sufficient sensors for it to track the slave device throughout a house or other building.
Referring again to FIG. 4, a leading (or trailing) wheel 135 that is not on the same axis as the drive system 133 may be incorporated into the robot or remote device to improve the drive system. In such a three wheel system, or alternatively, in a four or more wheel system, the robot or remote device is balanced better than a two wheel system and the extra wheel(s) provides a limit as to how much the absorbent pad 132 can be compressed by the weight of the robot or device 130 . Therefore, such (wheels in more than one axis) configurations provide for the absorbent pad 132 to be compressed by a specific and constant amount. Alternatively, the foam pad 132 can be weighted or spring loaded to apply a specific and constant cleaning pressure to the towel that is less than the weight of the entire robot 130 .
As shown in FIG. 6, it is possible to remove the non-absorbent pad, such as pad 121 shown in FIG. 3, and have either the feed roll 150 or the take-up roll 151 directly contact the floor as in similar non-automated systems. The robot housing 152 and the entire robot system is designed to adjust for the change in size of the towel roll. In one embodiment, the housing adapts mechanically because the height of the contact area changes as the towel is transferred between rolls. Electronically, the feed rate also varies because the effective cleaning head changes size during use.
FIGS. 7 a and 7 b show an embodiment where a motor 162 and lead screw 161 raise the non-absorbent pad from a lowered position 160 (FIG. 7 a ) to a raised position 164 (FIG. 7 b ) when the device is not mopping. In this embodiment, the robot mop rides on a skid pad 163 , or a trailing wheel, when the pad is raised. This configuration enables the robot to traverse a floor, such as carpet, without mopping it. Raising the pad to position 164 also helps the robot move if it gets stuck or if the wheels slip.
In an alternate embodiment, the robot can automatically load the towel from a base station. The system can either change an entire towel cartridge, or can wind the towel from a large roll using a feed mechanism similar to a movie projector or printer. In this situation, the robot can calculate and the load the amount of towel required to mop the floor.
Conclusion
Specific blocks, sections, devices, functions and modules may have been set forth. However, a skilled technologist will realize that there are many ways to partition the system of the present invention, and that there are many parts, components, modules or functions that may be substituted for those listed above.
While the above detailed description has shown, described, and pointed out the fundamental novel features of the invention as applied to various embodiments, it will be understood that various omissions and substitutions and changes in the form and details of the system illustrated may be made by those skilled in the art, without departing from the intent of the invention.
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BACKGROUND OF THE INVENTION
The present invention concerns a device for the treatment of peripheral circulatory disorders that consists of at least one treatment cylinder into which a body limb to be treated can be introduced at least in part through a closing device, and in which by means of a device for the admission and evacuation of air and of control elements a compression or/and decompression can be created, and in particular the closing device for the treatment cylinder which prevents the veins from becoming obstructed when a compression or/and decompression is created in the treatment cylinder.
As early as 1834 JUNOD studied the effects of compression on the body or one of the body extremities and invented devices with which he took hyperbaric baths.
At the end of the 19 th century BIER subjected arms or legs to a decompression that caused a venous congestion which he put to use as a therapeutic measure for rheumatic pain.
1932 HERRMANN studied the literature concerning hypobaric treatments and found that this method could activate arterial blood flow in the extremities. In the same year he established that the effect was enhanced when an extremity was subjected to alternating hypobaric and hyperbaric phases.
Since that time the devices subsequently built possess programmes with hyperbaric and hypobaric phases. They had a cylinder consisting of glass or Plexiglas that was closed off with a rubber hose while advantage was taken of the elasticity of the rubber for closing.
This procedure inevitably brought about an obstruction of the veins and, depending on the intensity of the decompression, an obstruction of the arteries, so that the treatment as such only made use of the venous congestion that had been applied as a therapeutic measure by Bier.
One also knows inflatable boots made of flexible material (JOBST), but these can only exert a compression on an extremity, while the effect of this compression, since it is limited to the surface, never can attain the effect exerted by direct air pressure.
1956 the VASOTRAIN device appeared on the market, where the treatment cylinder was sealed with an inflatable sleeve. Despite this improvement of the method of exerting compression and decompression on an extremity, the VASOTRAIN also produced venous congestion, and BARBEY reports that because of the appearance of petechia, treatments with the VASOTRAIN had to be discontinued.
WERDING in 1960 designed the VASCULATOR, which also had inflatable sleeves, with the new feature, however, that these sleeves always maintained their pressure on the extremities at a minimum value, i.e., their internal pressure only rose until the desired compression was attained, whereupon a certain, intended loss of compression could be, both compensated with the pump or kept constant by slight inflation of the sleeve.
During automatic changeover of the device to decompression, the sleeve emptied continuously in proportion to the intensity of the decompression.
This method very largely reduced an obstruction of the veins, but not enough, as the VASCULATOR had to place the extremity in a high position in order to aid venous return to the heart.
It is the aim of the present invention to eliminate the problems of venous congestion described above, and it is proposed to provide a closing device for treatment cylinders which is capable of keeping even the veins that are located at the surface of an extremity, as pervious as possible during a hypobaric phase.
SUMMARY OF THE INVENTION
According to the invention, this problem is resolved by the fact that the closing device is provided with a sleeve having a thick-walled disk covered on its two flat sides by thin-walled, highly elastic membranes, that the disk is provided with a first opening and the membranes are provided with second openings which are situated opposite to the first opening and have diameters smaller than that of the first opening, and that the treatment cylinder is provided with a rigid support element against which the entire sleeve is sealingly pressed with the aid of clamping means. By virtue of their elasticity, these membranes adapt to the form of the extremity so as to function as a membrane sleeve, while between the two rubber membranes an air cushion is created which also serves as a closing means that will not compress. The treatment cylinder is then closed in such a way that the intensity of the pressure variation is attained and kept constant during a specific period of time without a need for inflation of the sleeve, while an obstruction of the venous return to the heart is prevented by this solution for the entire duration of the treatment.
It is particularly advantageous to select a rubber disk, since this can be supported on an annular ridge provided at the entrance of the treatment cylinder and then pressed against this ridge with the aid of a rigid ring and clamps in such a way that the annular ridge penetrates into the rubber and thus seals the treatment cylinder hermetically.
It is advantageous, too, to provide the opening of the treatment is cylinder opposite to the closing device with an identical device which gives access to the interior of the treatment cylinder and can be provided with a heating or cooling device.
The closing device can advantageously be characterised by the fact that the treatment cylinder is axially mobile so as to facilitate introduction of an extremity.
It is particularly advantageous to continuously keep the treatment cylinder in a high position even during a hypobaric phase, while the blocking system of the high position at the same time blocks the treatment cylinder axially.
With this continuous high position of the treatment cylinder, even during the hypobaric phase, on one hand one attains a expanded state of capillaries, venules, and veins by means of the decompression, and an arteriolar dilation and thus a hyperemia by reflex action, on the other hand one attains at the same time an increased venous return to the heart, which in its volume is practically proportional to the arterial capacity of the vessels of the extremity, since the veins of the extremity remain pervious thanks to the closing device of the invention.
It is particularly advantageous that the closing device need not be inflated, which substantially simplifies the electronic controls, since these controls only regulate the hyperbaric and hypobaric phases as well as the periods of time during which they are kept constant, which largely eliminates possible breakdowns or malfunction. These features lead to a device exhibiting a precise and safe functioning.
DESCRIPTION OF THE DRAWINGS
Further details will become evident from the dependent claims and subsequent description of an exemplified embodiment represented in the drawing.
Shown are
in FIG. 1 a sectional view of a treatment cylinder with closing device,
in FIG. 2 a front view of the treatment cylinder with closing device according to FIG. 1,
in FIG. 3 a sectional view of the closing device with an extremity during a hyperbaric phase in the cylinder,
in FIG. 4 a sectional view of the closing device with an extremity during a hypobaric phase in the cylinder,
in FIG. 5 a partly sectional side elevation of a device with treatment cylinder and closing device,
in FIG. 6 a plan view of the device of FIG. 5 with a double treatment cylinder for two extremities,
in FIG. 7 a schematic representation of the control elements of the device,
in FIG. 8 a sectional view of a control valve for regulation of the intensity of compression and decompression in the closed position,
in FIG. 9 a sectional view of the control valve of FIG. 8 in the open position,
in FIG. 10 a sectional view of an electric control valve for regulation of the intensity of compression and decompression.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows a treatment cylinder 1 , preferably made of Plexiglas, which at ends A and B is provided with a ring 2 made of the same material and provided with an annular ridge 3 . End A supports a thick-walled rubber disk 4 that has an opening 5 . The flat sides of rubber disk 4 are lined with highly elastic, thin-walled rubber membranes 6 and 7 , this lining being applied only to an outer ring of the rubber disk 4 as shown in FIGS. 3 and 4. The diameters of openings 8 and 9 of rubber membranes 6 and 7 are smaller than the diameter of opening 5 of the rubber disk 4 . This arrangement serves as closing sleeve C enveloping an extremity E to be treated as shown in FIGS. 3 and 4. FIG. 3 shows that the rubber membrane 7 during a hyperbaric phase in cylinder 1 adapts to the form of the extremity E and that the rubber membrane 6 inflates thanks to an intentional leak between the extremity E and the rubber membrane 7 so that an air cushion 6 A is created between the two which serves as a noncompressing seal. During a hypobaric phase this process occurs in the opposite direction as illustrated by FIG. 4 .
End B of the treatment cylinder 1 also supports a thick-walled rubber disk 10 which, however, has no opening 5 and hence hermetically seals the treatment cylinder 1 at end B.
The sleeve C is pressed against the annular ridge 3 by means of a rigid ring 11 and clamps 12 , and the ridge penetrates into the rubber material and hence secures a hermetic seal at this point.
The rubber disk 10 at end B of the cylinder 1 is pressed against an annular ridge 3 by means of a rigid ring 13 and clamps 14 , so that end B is hermetically sealed.
It is advantageous that end B can be opened, especially in the case of paralysed patients which cannot move the extremity to be treated, and thus cannot place it correctly into the treatment cylinder 1 .
The periphery of the treatment cylinder 1 is provided with a metal ring 15 at end A and with a metal ring 16 at end B, while a flat part 17 is fastened to bulges 15 a and 16 a of these rings.
The flat part 17 is provided with rollers 18 which move along a supporting beam 22 and enable the treatment cylinder 1 to be moved axially, thus facilitating the introduction of an extremity.
The flat part 17 has an articulation 19 at end A which allows the treatment cylinder 1 to be moved to a high position as shown in dashed lines in FIG. 5, in which case a strut 20 engages into grooves 21 of the supporting beam 22 and hence will also prevent an axial motion of the treatment cylinder.
The use of rollers 18 enabling an axial displacement of the treatment cylinder 1 is intended in particular for portable treatment cylinders 1 , in which case the control means and the vacuum pump and pressure pump are to be found in a housing which also is portable, but not shown. Such an embodiment may have utility when a patient unable to walk must be treated in his home, or during sports events when a hyperbaric and hypobaric treatment is highly effective in the case of sprains, cramps or contusions with hematomas.
If, on the other hand, the treatment cylinder as shown in FIG. 5 is supported by a device G in which the supporting beam 22 is movably connected with the device G, the rollers 18 can be omitted inasmuch as the entire device G provided with rollers 23 is mobile, so that for easier introduction of an extremity into the treatment cylinder 1 the entire device G can be displaced. A blocking device (not shown) prevents a shifting of the device G.
The embodiment according to FIG. 5 is advantageous, since the treatment cylinder 1 can be vertically displaced, which as shown allows a patient to be treated who is seated on a chair, or the treatment cylinder 1 to be arranged so high up that the patient can be stretched out on a massage table or bed, as illustrated with the height D. Lastly, position F of the treatment cylinder 1 shows the high position into which it can be brought for the entire duration of the treatment session.
Device G has a base 24 provided with the rollers 23 and with a seat in which a support 26 is movably retained. A housing 27 in which as shown in FIG. 7 a vacuum and pressure pump 28 , a magnetic valve 29 for decompression and a magnetic valve 30 for compression are to be found is mounted onto the base. The magnetic valve 29 is connected with a timing relay 31 , the magnetic valve 30 is connected with a timing relay 32 . The timing relais 31 , 32 allow the decompression compression to be kept constant for a predetermined period of time, for instance in a stage II obliterative arteriopathy with walking distance 200 m one maintains constancy of the hypobaric phase for 45 s and of the hyperbaric phase for 30 s, in which case the timing relay 31 will close the magnetic valve 29 and open the magnetic valve 30 , or timing relay 32 will close the magnetic valve 30 and open the magnetic valve 29 when the set times have elapsed.
The intensities of the compression and decompression are regulated via control valves 33 and 34 as illustrated in FIGS. 8 and 9. Valves 33 and 34 consist of a valve body 35 , an elastomer seal 36 which is pressed into its seat 38 by a screw member 37 , a piston 39 and a rotary head 40 .
The control valves 33 and 34 are in the open position as shown in FIG. 9 before the pressure values are set. This position is set by means of the piston 39 which has a thread 41 and is moved by the turning head 40 . To this effect the piston 39 deforms the elastomer seal 36 in such a way that a lower transverse bore 42 of the piston 39 which opens into an axial channel 43 and hence into an upper transverse 44 is opened. When turning the rotary head clockwise, for instance, the seal 36 gradually returns to its initial position and thus progressively closes off the lower transverse bore 42 . The flow cross section of this bore is varied in such a way that a degree of throttling is achieved which corresponds to the compression or decompression that ought to be attained. In the instance of control valve 33 , pump 28 draws air from the outside via the upper transverse bore 44 , the axial channel 43 and the lower transverse bore 42 when the magnetic valve 29 is open, while in the instance of control valve 34 , pump 28 rejects air to the outside via the lower transverse bore 42 , the axial channel 43 and the upper transverse bore. Via these intended leaks one can set the desired pressure values, in which case compressor 28 will maintain the set pressure values constant despite the leaks.
It goes without saying that the pitch of thread 41 is selected so that a rotation through 300° will allow a maximum excess pressure of 152 mmHg. Higher pressure values are prevented by safety valves (not shown).
FIG. 10 shows an entirely novel, electronically regulated control valve for setting the compression and decompression values. It consists of a valve body 49 holding an electric traction magnet 50 on the armature axis 51 of which there is a piston 52 provided with an O-ring 53 and pressed into its seat 55 by means of a spring 54 , the force of the spring being selected so that on one hand it counterbalances the weight of the piston 52 and on the other hand it presses O-ring 53 to the seat 55 in such a way that compression must prevail in chamber 56 , and decompression in chamber 57 , before O-ring 53 will be pushed from its seat 55 . To this effect chamber 56 has a tapped hole 58 through which an excess pressure coming from the treatment cylinder will enter, and chamber 57 has a tapped hole 59 through which the treatment cylinder 1 draws air. The regulation of the pressure values is accomplished via a variable supply voltage to traction magnet 50 , for instance 24 V for a pressure or suction of 152 mmHg and 9 V for a pressure or suction of 0.38 mmHg (0.05 atmospheres excess pressure). As soon as the set pressure values are attained in chambers 56 and 57 they will push or pull piston 52 , and thus O-ring 53 , from its seat 55 , so that excessive compression or decompression can be relieved via magnetic valves and 34 , and the set pressure values can be kept constant. Valve body 49 is sealingly closed off on the side of chamber 57 with a screw lid 88 and an O-ring 61 . The opposite side of valve body 49 is sealingly closed off with a screw lid 62 and an O-ring 63 , and screw lid 62 is provided with a gland 64 which serves to seal the valve body along a cable lead 65 of the traction magnet 50 .
FIG. 6 shows the device G provided with two treatment cylinders 1 in order to treat two extremities simultaneously, which via a reflex action of the more healthy extremity may lead to a favorable effect on the more strongly affected extremity. A panel 46 reveals a time switch 47 with which the duration of a session is set, a pressure indicator 48 as well as the scales 33 and 34 of the control valves and their timing relays 31 and 32 .
Device G is delivered with a treatment table which enables the device G to be used at once for the treatment of peripheral circulatory disorders, as this table takes into account the pathology and its severity. It is left to the physician to adapt the compression and decompression values and the periods of time during which they are to be kept constant, individually to each case.
A treatment session always starts with a compression phase which is followed by a decompression phase, while the period of time during which the compression and decompression are kept constant depends on the pathology and its severity, so that on one hand the rubber membranes 6 and 7 will optimally adapt to the shape of the extremity to be treated, and on the other hand the metabolites which are produced in excessive amounts on account of circulatory disorders will be eliminated.
The embodiment examples described above should of course not have any limiting character but may be subject to any desirable modification within the scope defined by the independent claim. Thus, the disk 4 and the membranes 6 , 7 may consist of any appropriate material, for instance a synthetic or natural elastomer. It has also been found to be advantageous to make disk 4 and membranes 6 , 7 of the same rubber, with a Shore hardness of less than 50°. Advantageously the diameter of the opening 5 of disk 4 is at least 4 cm larger than that of openings 8 , 9 of the membranes 6 , 7 . The devices for air admission and evacuation as well as the control and regulation means can be realised in a different way, for instance with pulsed electric valves of adjustable frequency that are controlled by computer. The treatment cylinders could also have a cross section that is not round but, for instance, polygonal or rectangular. The openings of the disk and membranes can be centered or eccentric, where a centered arrangement may improve the venous return, depending on the outfitting of the treatment cylinders, and in these cylinders padded support means can also be provided for the body limb to be treated.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to milking machines and more specifically to the short milk tube ferrule on the milking claw portion of the milking unit.
2. Setting of the Invention
A major problem for milk producers and regulatory agencies has been the milk residue and other deposits which collect on the interior of the short milk tubes between the teatcup assembly and the claw mechanism. One particular area which is most troublesome is the area between the ferrule of the milking claw and the short milk tube, which is placed some distance over the end of the ferrule. Milk, dirt, debris and microorganisms may collect in this area and remain after washing and sanitizing. The area of contamination is posterior to the ferrule opening, in the overlap between the inside wall of the short milk tube and the outside wall of the ferrule itself. FIGS. 20, 21, and 22 show a prior an form of a ferrule with the contaminated area stippled. This residue will frequently contaminate any milk which subsequently flows through the tubing when the milk phase is resumed. It is generally recognized that the annual loss in milk production due to contamination is very large.
It is well documented that completely washing and sanitizing a milking unit of residual deposits of milk and debris is difficult. This is partly because contamination readily collect between the ferrule and tubing structures. Efforts have been made to develop improved techniques to wash and sanitize the milking units. These efforts include flushing with detergents and sanitizers, improved valve designs as well as alterations in the structure of the milking unit. However, none of the design changes or cleaning methods have been successful in completely washing and sanitizing the space between the short milk tubes and the ferrules. Repetitive milking inevitably causes the formation of a pocket between the ferrule and short milk tube. A pocket develops in almost all designs which utilize a ferrule on the milking claw. This condition is exacerbated by the following:
1. The bending of the short milk tubes over the ferrule when they are inverted from non-milking to milking orientation during the process of attachment.
2. The natural bending of the short milk tubes over the ferrules as the milking unit is in the actual process of milking.
3. The bending of the short milk tubes over the ferrule when they are inverted from milking orientation to the washing and sanitizing orientation.
Since automated washing has not been effective to completely clean the short milk tubes due to the existence of the pockets between the tubes and the ferrules, the only way to remove milk and debris from the pockets is by manual disassembly, cleaning, and reassembly of the short milk tube-ferrule combination. Because this manual cleaning is labor intensive and time consuming, in actuality, it is rarely performed. As a result, dairy producers may suffer financial penalties due to decrease in the quality of the milk.
OBJECTS OF THE INVENTION
Accordingly, the principal object of the present invention is to provide a novel ferrule design which enables the milking unit to be completely washed and sanitized after each milking operation without manual disassembly.
Another object is to provide a ferrule which enables the complete removal or flushing of milk and debris from the pockets which are formed between the short milk tubes and the ferrule of the milking claw.
Another object of the invention is to provide a methodology to increase the quality of milk produced by the dairy industry.
A still further object of the invention is to provide a methodology to prevent financial loss to the dairy producer as a result of lowering the quality of milk.
A further object of the invention is to provide a novel ferrule, designed to reduce the necessity for manual disassembly and cleaning after each milking.
These and still further objects will become apparent hereinafter.
SUMMARY OF THE INVENTION
The present invention provides a simple and cost effective means for a more thorough washing and sanitizing of milking units and removing of debris from the short milk tube-ferrule pockets without the need for removal or replacement of the short milk tubes or teatcup assembly. An aperture is located near the tip of the ferrule of the milking claw, adjacent to the potentially contaminated pocket. This aperture particularly diverts the washing and sanitizing solutions toward and through the pocket during forward or reverse circulation. This turbulence aids in the removal of the contamination and allows a more thorough washing and sanitizing. It appears that the aperture causes a series of eddy currents formed by a divergence from laminar flow. Eddy current in this context means a series of circulating flow patterns. Such flow may be the result of the difference in pressure between the pressure in the short milk tube and the pressure in the collecting area of the claw; known as a venturi effect.
The present invention consists of an improved milking claw ferrule, which is comprised of a tube-like body, attached at one end to a base, and having, at the other end, a main opening and an aperture. The aperture is designed to cause removal of debris from a pocket formed between the ferrule and the interior of the wall of the short milk tube.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front elevational view of a conventional milking machine, into which the present invention is designed to be incorporated. It is understood that this invention would apply to all types of milking claw designs, for the specific purpose of milk removal from mammals where milk harvesting is customary or possible.
FIG. 2 is a side elevational view of a milking claw of the present invention and associated tubing in a milking orientation.
FIG. 3 is a side elevational view of the milking claw and short milk tube in a washing and sanitizing orientation.
FIG. 4 is a side elevational view of a milking claw embodying the principles of the present invention, without the short milking tubes,
FIG. 5 is a rear elevational view of a milking claw embodying the principles of the present invention, without the short milking tubes,
FIG. 6 is a top plan view of the milking claw without the short milking tubes.
FIG. 7 is a side elevational view of the milking claw ferrule incorporating a lateral aperture and embodying the principles of the present invention.
FIG. 8 is a top view of the milking claw ferrule incorporating a lateral aperture and embodying the principles of the present invention.
FIG. 9 is a side elevational view of a milking claw with a ferrule embodying the principles of the present invention, showing the short milk tube, in section, on the ferrule and in the milking position,
FIG. 10 is a close-up view of the ferrule in FIG. 9,
FIG. 11 is a side elevational view of a milking claw with a ferrule embodying the principles of the present invention, showing the short milk tube, in section, on the ferrule and in the between-milking position, with the claw in the milking position and the short milk tube hanging down,
FIG. 12 is a close-up view of the ferrule in FIG. 11,
FIG. 13 is a side view of a milking claw with a ferrule embodying the principles of the present invention, showing the short milk tube, in section, on the ferrule and in the washing and sanitizing position, with the claw inverted and the short milk tube hanging down,
FIG. 14 is a close-up view of the ferrule in FIG. 13,
FIG. 15 is a view of the ferrule and incorporated aperture with a cross-sectional view of the attached short milk tube depicting the pockets created by bending stress on the short milk tube,
FIG. 16 is a side elevational view of a second embodiment of a milking claw ferrule of the present invention,
FIG. 17 is a top view of the second embodiment,
FIG. 18 is a side elevational view of a third embodiment of the milking claw ferrule of the present invention,
FIG. 19 is a top view of the third embodiment,
FIG. 20 is a side elevational view of a ferrule of the prior an design (without the aperture of this invention) showing the debris accumulation area as stippled,
FIG. 21 is a top view of the prior art design of the ferrule (without the aperture of this invention), and
FIG. 22 is a bottom view of the prior art design of the ferrule (without the aperture of this invention) showing the debris accumulation as stippled.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to the drawings, FIG. 1 shows one embodiment of a typical milking system in which the present invention is designed to be incorporated. Where necessary, pan numbers will be printed, double-primed, etc., to designate identical but separate pans. The milking unit includes a milking claw 21, short milk tubes (7, 7', 7", 7'"), which are attached to inflations 15, which in turn are attached to the teats 13 of the utter 3 of the cow 1. One end of the long milk hose 17 is connected to the milking claw 21 and the other end is connected to the milk line 10.
FIG. 2 is an enlarged view of the milking claw 21 in the milking orientation. The short air tubes (23, 23', 23", 23 "') lead from the pulsation chambers in the teatcup assembly to an airfork 25 on the claw 21. The long air hose 29 is connected to the airfork 25 and to a source of alternating (ambient to system vacuum) impulses to induce and maintain proper milk flow. The milk claw 21 includes a plurality of ferrules 37 and a rigid milk outlet 30. The ferrules 37 are positioned in the body 22 of the claw 21 and operatively connected to the main chamber 27 and to the short milk tubes 7.
FIG. 3 shows the milking claw in the washing or sanitizing orientation. In this orientation, washing and sanitizing solutions can be circulated through wash cups 32 which are attached to the teatcup assemblies 33, through the inflations 15 and the short milk tubes 7 to clean the insides of the assembly. Solutions continue to flow through the milk entry port 30 in the milking claw 27 into the long milk hose 17. In some systems, the circulation process occurs in the reverse of the aforementioned sequence.
FIGS. 4, 5, and 6 show side, rear, and top views, respectively, of a commercially available milking claw, without any tubes attached, and modified in accordance with the preferred embodiment of the present invention. More specifically, the modification involves forming an aperture 45, 45', 45", 45"' in each of the ferrules 37, 37', 37", 37"'.
FIGS. 7 and 8 show a milking claw ferrule 37 separated from the milking claw 21. The ferrule 37 is made of a cylindrical tube 41, and a first end 31 which is attachable to the housing 22 of the claw 21. The ferrule 37 is fixed to the milking claw by welding. A second end 39 has an outlet opening 47 being defined by an edge 48 at an acute angle to the longitudinal axis 38 so that a portion of the wall 52 faces the inlet opening 47. Note that wall portion 52 is part of tube 41. The wall portion 52 has at least one aperture 45, which faces the outlet opening 47. The short milk tubes 7 are applied over the outside of the second end 39 and forced along the outside length of the ferrule until a prescribed placement is reached. FIG. 8 shows the same ferrule as shown in FIG. 7, but FIG. 8 is a view looking down on the ferrule and into the opening 47. The aperture 45 and wall portion 52 can be seen through the opening 47.
FIG. 9 shows a side view of a milking claw in a milking orientation. Two of the four ferrules 37 and 37"' are shown. One ferrule 33 is encased in the sectioned end of a short milk tube 7.
FIG. 10 shows a close-up view of an outwardly and upwardly disposed branch unit 33 made up of a ferrule 37 and short milk tube 7 (cross-sectional). The milking claw 21 of the milking unit in a milking orientation. When the milking claw is disposed in the milking orientation, the ferrules 37 extend upwardly. The second end 39 of the ferrule fits snugly within the lumen 42 of the short milk tube 7. Milk flow proceeds from the inflations (not shown), through a pressure area P2 in the tube and through the ferrule opening 47 to a lower pressure area P1 in the ferrule 37 and milking claw 21. In the milking orientation, the short milk tube forms a bend as indicated by the reference numeral 53. The region of the short milk tube around the ferrule outer tip 40 is severely angularly strained and distorted because the tubes are holding the weight of the claw. This causes a separation and therefore a debris pocket 57 to form between the outer surface of the ferrule and the inner surface 51 of the short milk tube 7. The debris pocket encircles the outer surface of the extended tip of the ferrule and opens into and communicates with the lumen of the tube through openings 66 and 67, best shown in FIG. 15. FIG. 15 shows a view looking into the ferrule opening 47, with a cross-sectional cut of the short milk tube 7 to show the distortions and short milk tube-ferrule separation that causes openings 66 and 67 to form debris pocket 57. Note that the pocket 57 could be continuous from one side 66, around the bottom or back of the ferrule, to the other side 67. Contamination can enter the pocket 57 through the pocket openings 66 and 67.
When the aperture 45 is not formed in the wall of the ferrule, stale milk and other debris accumulate on the outer surface 51 of the ferrule 37. The area of major accumulation is shown as stippled in FIGS. 20, 21, and 22. This area approximates the part of the ferrule wall that defines the debris pocket 57. The presence of an aperture 45 of the present invention causes milk flow through the pocket and essentially eliminates accumulation in the debris pocket.
FIG. 11 is similar to FIG. 9 in that the milking claw 21 is in the milking orientation. However, FIG. 11 represents the orientation in which the teatcup assembly 15 is removed from the cow and fie teatcup and the short milk tube 7 are allowed to hang down over the ferrule 37. As shown in more detail in FIG. 12, the weight of the teatcup assembly and the short milk tube 7, and the shape of the short milk tube 7 open up the pocket so that the pocket becomes an open crevice. This crevice provides an additional means by which sediment and milk residue can enter and remain in the pocket, but this accumulation is avoided by the presence of the aperture. In the preferred embodiment design, the aperture is positioned so that, when the short milk tube is in this position, the inside wall of the short milk tube seals the aperture, thus maintaining the reduced pressure inside the claw.
FIG. 13 shows the milk claw 21 upside down with the short milk tube 7 hanging down. The aperture 45 of the present invention forms a passageway between the debris pocket 57 and the interior of the ferrule 37. This is the orientation of the milking claw when it is flushed out with washing and sanitizing solutions. As the washing and sanitizing solutions flow through the short milk tube 7 and through the ferrule, the flow is automatically diverted through the aperture and pocket, thereby constantly washing the debris from the pocket.
FIGS. 16 and 17 show the same ferrule as in FIG. 7 and 8, but with a variation in the orientation of the aperture 145. Whereas long axis of the orientation in FIG. 7 and 8 is lateral (perpendicular to the ferrule axis), the long axis in FIG. 16 and 17 is longitudinal (parallel to the ferrule axis).
FIGS. 18 and 19 show the same ferrule as in FIGS. 7 and 8, but with a variation in the design of aperture 245 and 246. The ferrule apertures 245 and 246 are similar in position to the aperture 45 except that they are separated by a bridge 250. The bridge 250 provides structural reinforcement of the ferrule for situations where a slot-type aperture, like aperture 45, may unacceptably weaken the ferrule. This weakening of the ferrule is primarily of concern if the claw falls off the animal and is stepped on by the animal. The pocket cleaning effects of the eddy currents caused by the apertures are not significantly reduced by the bridge 250.
The action by which the aperture 45 substantially eliminates accumulation of debris in the pocket 57 occurs throughout the milking and cleaning process. During the milking process, the flow of milk through the openings 66 and 67, pocket 57 and the aperture 45, and turbulence of eddy current around those structures, constantly flushes out accumulation with fresh milk. This eliminates the long residence time that debris spends in the pocket and thereby eliminates build up of debris in the pocket which, in turn, results in little or no bacteria multiplication. This same flushing effect allows the washing and sanitizing solutions of the normal cleaning cycle to effectively clean out debris from the pocket far more effectively than can be accomplished without the aperture 45. Finally, when the milking claw is in the milking orientation with the short milk tube 7 hanging down, the aperture 45 tends to neutralize physical forces that might draw milk up into the pocket 45, thereby reducing potential accumulations in the pocket.
Further modifications of the invention herein disclosed will occur to persons skilled in the art and all such modifications are deemed to be within the scope of the invention as defined by the appended claims.
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Background of the Invention
An enema tip retention apparatus for retaining an inserted enema tip in a patient during the administering of an enema to the patient includes an adjustable belt for encompassing the waist of the patient and including two depending straps which couple to a substantially flat mounting plate. The mounting plate has an adjustable, releasable clamp disposed thereon and a first clearance aperture therethrough. The mounting plate further includes two collar buttons which are arranged on opposite sides of the releasable clamp for connection to the two depending straps. The clamp includes a second clearance aperture extending therethrough and defined by a part-circular portion, a deformable tab portion and cooperating locking portion. The tab portion and locking portion are arranged relative to each other such that the second clearance aperture diameter may be varied, depending upon the outside diameter of the enema tube which is inserted therethrough. The first and second clearance apertures are substantially coincident with each other. With the depending straps coupled to the collar buttons, the mounting plate may be drawn adjacent the rectal opening of the patient and with the enema tip and tube anchored by the clamp, this tip and tube may be held in position throughout a fluoroscopy examination and will be retained in its desired position, regardless of the movements and the maneuvers the patient is subjected to.
Most radiologists have had barium spill on the examining table when they conduct colon examinations of incontinent, seriously ill and hard-to-manage patients. Such patients include the mentally retarded, the mentally ill, the aged, the uncooperative, the severely handicapped, the paraplegic and the patient with an extremely relaxed anal canal. One problem with such patients involves their inability to retain an enema tip which is inserted for the administration of a diagnostic contrast medium for either cleansing or medication purposes. The enema tip frequently slips out because of the turning of the patient and the various maneuvers required, after the barium has been introduced, as part of the fluoroscopy X-ray examination.
One retention technique which has often been employed is to insert and then inflate a balloon on either or on both sides of the rectum. However, some physicians object to these balloons because of the dangers of perforation or over inflation. Therefore, it would be an improvement to enema tip retention devices and procedures if a means and structure could be devised to securely hold an enema tip in position without reliance on inflatable balloons. A further improvement would be to structure such a device so that it would be suitable for use with remotely controlled fluoroscopy tables where the operator (technician and/or physician and/or radiologist) is some distance from the patient. A retention device such as the suggested improved device is beneficial in that such attending medical personnel do not have to hold the device in the patient while X-rays are taken and subject themselves to additional radiation exposure.
Various retention techniques have been conceived as set forth by the disclosures of the following listed patents. However, none of these disclosures set forth a device with advantages equal to the advantages of the present invention to be described in detail hereinafter. Thus, the present invention is an improvement to all prior art devices of which the inventor is aware.
______________________________________U.S. Pat. No. Patentee Issue Date______________________________________3,543,744 LePar 12/01/703,575,160 Vass 4/20/713,581,732 Ruiz 6/01/713,841,304 Jones 10/15/743,893,446 Miller 7/08/753,906,948 Vass 9/23/754,069,826 Sessions et al. 1/24/783,802,418 Clayton 4/09/743,765,401 Vass 10/16/733,408,092 Appleton 10/29/683,154,078 Goodrich, Jr. 10/27/643,429,985 Czigler 2/25/693,516,631 Santucci 6/23/70______________________________________
LePar discloses equipment for administering enemas, particularly for radiological purposes and includes an obturator which is adapted to be positioned externally of the body in the region of an intestinal opening. The obturator is flexible and distendable or inflatable. The equipment further includes an annular sealing element at the interface of the obturator which is adapted to provide a liquid-tight seal between the obturator and the surface of the body in the region around the intestinal opening.
Vass U.S. Pat. No. 3,575,160 discloses an instrument for administering fluid into the intestinal tract, which includes a tube having a rectum entering end portion and enlargements distally of the end portion which are engageable against the body area surrounding the anal opening of the rectum and entering thereinto for sealing the same when the end portion is disposed within the rectum.
Ruiz discloses a device for conveying fluids, such as aqueous suspensions of barium sulfate, into and out of a body opening such as a colostomy opening, and includes conduit means, a radial flange integral with the conduit means, pressure means for maintaining the flange in direct contact with a stoma, base means for engaging the abdominal wall and body-encircling means for maintaining the base means in place.
Jones discloses an inflatable balloon-like bulb attached to the end of a check-valved catheter tube which is removably attachable to an inflating bulb and further includes stop means slidable along the catheter tube. This arrangement is such that when the balloon is deflated on the end of the catheter tube, it may be inserted through the urethra into the bladder, and then inflated by the bulb and held in that position by the sliding stop pushed up against the urethral outlet walls to hold the inflated balloon in sealing relationship.
Miller discloses a catheter structure for insertion in an opening of a body and includes a support member which is frictionally slidable along the catheter to a desired position. The support member portion which enters the body as an annular extension engaged by an adhesive patch which extends beyond the annular extension and may engage the skin of the body in order to position the catheter. A closure member is also provided for the outer end of the catheter in order to prevent loss of contents of inserted material until such time as the closure member is removed.
Vass U.S. Pat. No. 3,906,948 discloses a rectal applicator for the administration of an enema as practiced in the roentgen examination of the intestinal tract and includes a device formed by joining a tubular nozzle section with a tubular stem section. The device is provided at the junction of its two sections with an enlargement, the proximal face of which is formed with concentric annular ridges spaced from the nozzle tube and one another and is engageable against the perianal surface of a body to seal externally the anal opening.
Sessions et al. discloses a surgical tube adapter clamp for effecting a tube connection to a blood vessel in which a tubular member is constructed for insertion of its free end into a blood vessel and the opposite end is adapted to be operatively connected to the cooperable end of the tube. A pair of relatively deformable members are provided and encircle the tubular member such that one of said deformable members is adapted to be disposed adjacent the exterior wall of the blood vessel and the other member includes a portion disposed within the blood vessel which is adapted to be deformed to increase the effective diameter thereof within the blood vessel and thereby clamp the adjacent wall of such blood vessel between the deformable members to secure the clamp to the vessel.
Clayton discloses a colon catheter for removing and collecting waste colon material through the anal canal. One end of a hollow tube is inserted into the anal canal and held therein by an expandable member and limiting elements outside of the anal opening against the perineum.
Vass U.S. Pat. No. 3,765,401 discloses a belt for sustaining an article in site in the rectal or uro-genital area formed by a waist-surrounding band having independent dorsal and frontal aprons laterally adjustably held thereon and a bridge which is engageable against the article to be held by the ends of the aprons.
Appleton discloses a single-piece tubular connector for connecting one end of a length of flexible hose to other apparatus and includes a central flanged tubular body separating a preferably externally threaded hose end from another end which is also threaded but preferably with oppositely-handed threads.
Goodrich, Jr. discloses a catheter combination which includes a fluid-containing squeeze-bulb syringe which has a discharge end securely bonded to an inflating tube in order to form a fluid-tight connection. The squeeze-bulb syringe is preloaded with the desired kind of inert fluid in the exact amount desired for the size and type of balloon employed so that the fluid is sealed into the system and cannot escape or become contaminated. A clip guard is provided about the syringe in order to prevent accidental squeezing of the syringe, and this clip guard is ratcheted so that the syringe may be held in partially collapsed positions and thereby prevent the undesired return of fluid.
Czigler discloses an adjustable clamp for elongated articles and includes a substantially rigid base member, a substantially rigid inverted J-shaped locking member extending upwardly from the base member and a deformable tab which may be flexible extending upwardly from the base member. Cooperating locking means on the locking member and flexible tab are adapted to inter-engage and releasably lock the clamp.
Santucci discloses a cable clamp device for mounting one or more cables on a suitable substructure. The clamp is provided with adhesive or mechanical means for securing the clamp to a substructure. The cable clamp includes at least a pair of legs which cooperate with the base member to provide a cable enclosure. This enclosure is open initially for the installation of a cable and can then be locked to positively retain the cable or cables.
SUMMARY OF THE INVENTION
An enema tip retention apparatus for retaining an inserted enema tip in a patient during the administering of an enema according to one embodiment of the present invention comprises a mounting plate, enema tube attachment means joined to said mounting plate and having a clearance aperture disposed therethrough, strap means securable to the body of the patient and having a retaining portion positionable adjacent the patient's rectum and retaining means joined to the mounting plate and disposed on opposite sides of the attachment means, the retaining means being suitably arranged for connection to the retaining portion of the strap means.
One object of the present invention is to provide an improved enema tip retention apparatus.
Related objects and advantages of the present invention will be apparent from the following description.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an exploded perspective view of an enema tip retention apparatus according to a typical embodiment of the present invention.
FIG. 1a is a front elevation view of a clamp device comprising a portion of the FIG. 1 enema tip retention apparatus.
FIG. 2 is a bottom plan view of the FIG. 1a clamp device.
FIG. 3 is a front elevation view of an alternative clamp device also suitable for use with alternative arrangements of the FIG. 1 enema tip retention apparatus and the like.
FIG. 4 is a partial front elevation view of an alternative clamp device including enema tip and tube portions joined therewith.
FIG. 5 is a front elevation view of yet another alternative clamp device also suitable for use with alternatives of the FIG. 1 enema tip retention apparatus.
FIG. 6 is an exploded perspective view of an enema tip retention apparatus according to a typical embodiment of the present invention.
FIG. 7 is a partial side elevation view of adjustable strap means comprising a portion of the FIG. 1 and FIG. 6 enema tip retention apparata.
FIG. 8 is a partial perspective view of a retaining portion comprising a part of the FIG. 6 enema tip retention apparatus.
FIG. 9 is an exploded perspective view of an alternate retaining portion arrangement suitable for use with the FIG. 6 enema tip retention apparatus.
FIG. 10 is an exploded front elevation view of enema tube attachment means suitable for use with the FIG. 1 and FIG. 6 enema tip retention apparata.
FIG. 11 is an exploded front elevation view of alternative enema tube attachment means similarly suitable for use with the FIG. 1 and FIG. 6 enema tip retention apparata.
DESCRIPTION OF THE PREFERRED EMBODIMENT
For the purposes of promoting an understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and further modifications in the illustrated device, and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates.
Referring to FIG. 1, there is illustrated an enema tip retention apparatus 20 including clamp member 21, adjustable belt arrangement 22, enema tube 23 and enema tip 24. Clamp member 21 includes a mounting plate portion 27 adjustable, releasable clamp 28 and collar buttons 29 and 30 which provide retaining means for securing clamp member 21 to adjustable belt arrangement 22.
Belt arrangement 22 includes a first strap portion 31 which is variable in circumferential encompassing size by means of belt buckle 32 and adjustment holes 33. Looped around first strap portion 31 are retaining straps 36 and 37 whose length extension from first strap portions 31 in a downwardly direction is controlled by adjustment means 38 and 39. Adjustment means 38 and 39 (see FIG. 7) include a collar stickpin-type arrangement wherein the outermost enlarged end portions of pin 40 are inserted through strap holes and thereby disposed on opposite outwardly facing surfaces of their corresponding retaining straps. This arrangement securely forms an enclosing loop for each strap which surrounds first strap portion 31.
The free ends of retaining straps 36 and 37 each include a keyhole-shaped slot 41 and 42, respectively, which are suitably sized and arranged for engagement with and receipt of collar buttons 29 and 30. Collar buttons 29 and 30 (see FIGS. 1a and 2) each include a base portion 45, an enlarged head portion 46 and a reduced diameter portion 47 therebetween. The size and shape of collar buttons 29 and 30 is such that enlarged head portion 46 is able to pass through larger opening 48 of keyhole-shaped slots 41 and 42 but not the smaller oblong opening portion 49. Thus, the means of attachment of clamp member 21 to adjustable belt arrangement 22 is to insert collar buttons 29 and 30 into keyhole-shaped slots 41 and 42 and then pull outwardly on retaining straps 36 and 37 such that reduced diameter portions 47 are snugly anchored within smaller oblong openings 49, and retained there due to the larger sizes of head portion 46 and base portion 45.
Referring to FIG. 2, clamp member 21 is illustrated in greater detail and includes a deformable tab portion 52, a cooperating locking portion 53, which has a series of ratchet teeth 54, and a clearance aperture 55 located adjacent the common end of portions 52 and 53. Clearance aperture 55 extends through clamp member 21, including mounting plate portion 27. Enema tube 23 is partially shown in both FIG. 1a and FIG. 2 illustrations and is disposed within clearance aperture 55. As deformable tab portion 52 and cooperating locking portion 53 are drawn together, by squeezing, the dimensional size of clearance aperture 55 is reduced, and a clamping action occurs around enema tube 23 thereby holding this tube in position. Inasmuch as the longitudinal axis of clearance aperture 55 is substantially perpendicular to mounting plate portion 27, it should be apparent that when clamp member 21 is oriented near the rectal opening of a patient and first strap portion is secured around the patient's waist, that retaining straps 36 and 37 may be adjusted in length until clamp member 21 is drawn snugly up against the patient's rectal opening so that the enema tube 23 and its joined enema tip 24 are retained in position within the patient. By securing the enema tube and tip in such a manner, the enema tip is unable to slip out of the patient as the patient turns from one side to the other and orients his body in various positions which the radiologist or physician may request as part of the fluoroscopy X-ray examination procedure.
Referring to FIGS. 3, 4 and 5, alternative arrangements of clamp member 21 are illustrated. While it should be understood that the preferred arrangement of clamp member 21 with respect to the remainder of apparatus 20 is to have the smooth surface of mounting plate portion 27 closest to the patient, it is possible to use an orientation wherein the collar button side of mounting plate portion 27 is closest to the patient. It is also possible to arrange adjustable, releasable clamp 28 such that the longitudinal axis of its clearance aperture is parallel with the surface of mounting plate portion 27 rather than being perpendicular to it. FIG. 3 illustrates such an arrangement where clamp 28 is disposed on mounting plate portion 27 so that the longitudinal axis of clearance aperture 55 is substantially parallel with the surface of mounting plate portion 27. Also included is a tube 56 which is shown in section only and secured by clamp 28. This tube may be a drainage tube or similar device and thus, the arrangement of FIG. 3 is suitable for retaining such tubes in a fixed position so that drainage of the patient cavities can be achieved, such as the sinuses. While this particular arrangement may not be best suited for enema administering, the clamping concept is virtually the same as clamp member 21 and collar buttons 29 and 30 are provided for retention of this alternative clamp member when such drainage of cavities is desired to be achieved.
Referring to FIG. 4, there is illustrated a clamp, enema tube and enema tip combination 59 which is a one-piece, integral, molded assembly. Combination 59 includes an enema tube 60, an enema tip 61, a mounting plate 62, a clearance hole grommet 63, collar button 64 and collar button 65. Although fabricated as a molded, one-piece combination, it is possible that these various component parts could be individually molded and then fitted together in a press-fit manner such that grommet 63 would be anchored within mounting plate 62 and would provide a snug fit around the outside diameter of enema tube 60 such that the tube and tip 61 would be held securely in position within the patient. In this manner, collar buttons 64 and 65 would be utilized as has been previously explained for collar buttons 29 and 30 of FIG. 1.
Referring to FIG. 5, the alternative clamp member of FIG. 3 is illustrated and includes a tubular insert 69 which has a lateral cross section of a "C" shape. This insert is generally concentric with clearance aperture 55 and is suitable to adapt the inside diameter size of clearance aperture 55 to the outside diameter of tube 70 such that various-sized tubes can be held by the clamp member. All that is required for adaptation is to select the appropriately sized C-shaped insert with the desired thickness. The use of such inserts is also envisioned with clamp member 21 inasmuch as the orientation of the clamp 28 with respect to the mounting plate portion 27, whether parallel or perpendicular, is equally well suited for the addition of such inserts.
Referring to FIG. 6 an alternative arrangement of the FIG. 1 apparatus is illustrated and although belt arrangement 71 is similar to belt arrangement 22, the noted difference involves the design of retaining straps 72 and 73 which are joined together at the general location of the enema tube 74 and enema tip 75 by means of retaining portion 76. Retaining portion 76 serves virtually the same purpose as did the free ends of retaining straps 36 and 37 which were provided with keyhole-shaped slots 41 and 42, respectively. In the FIG. 6 illustration, keyhole-shaped slots 77 and 78 (see FIG. 8) are provided and the only difference between the retaining portion arrangement of FIG. 1 and that of FIG. 6 is that the two retaining straps 72 and 73 are joined together wherein their Y-shaped configuration and union at two locations creates a clearance opening 79. Enema tube 74 and enema tip 75 are joined together and extend through a retaining flange 82 which includes two oppositely disposed collar buttons 83 and 84 which are suitably positioned and sized to fit within keyhole-shaped slots 77 and 78. In order to insert retaining flange 82 into retaining portion 76, the outer ends of flange 82 must be drawn together by bending flange 82 and then insert collar buttons 83 and 84 into the enlarged opening portions of slots 77 and 78. By fabricating retaining flange 82 out of a resilient, flexible material, release from this bent position will cause the collar buttons to flip outwardly thereby locking them in position in the smaller oblong opening portions of slots 77 and 78. This locking engagement securely retains the enema tube and enema tip as part of belt arrangement 71. The free end of enema tube 74 is provided with a series of angularly arranged layers or serrations 85 and these provide a snug fit arrangement with flexible tube 86 which may be forced over the free end of enema tube 74. Tube 86 may then be connected to a source of barium for introduction into the patient.
Referring to FIG. 9, an alternative arrangement to the retaining portion designs of FIGS. 1 and 6 is illustrated. Retaining flange 89 is a separate component and includes keyhole-shaped slots 90 and 91 and a clearance opening 92. Retaining straps 93 and 94 are provided with collar buttons 95 and 96, respectively, disposed at their free ends. As has been previously described, collar buttons 95 and 96 are arranged to be received by slots 90 and 91 for fixed retention of retaining flange 89. The clearance opening 92 of retaining flange 89 is suitably sized to receive in a snugly-fit arrangement an enema tip and tube combination or similar tubular member.
Referring to FIGS. 10 and 11, still further alternative arrangements are illustrated. In FIG. 10, mounting plate 99 is provided with a serrated tubular member 100 secured therethrough as well as collar buttons 101 and 102. Serrated tubular member 100 extends beyond each surface of mounting plate 99 a distance sufficient for the connection of enema tip 103 and enema tube 104. By fabricating the enema tip and enema tube members out of a flexible resilient material, they may be easily axially forced over the extending portions of serrated tubular member 100 and firmly lock onto the serrated surfaces, thereby providing a fixed and integrally appearing arrangement.
In FIG. 11, the enema tip 107 is secured to mounting plate 108 and has a free end 109 of a serrated tube design. In this arrangement, enema tube 110 will fit over the extending serrations of free end 109 and although the enema tip and mounting plate are an integral design, various enema tubes may be used in this particular combination.
Although a conventional enema tip and enema tube combination have been illustrated throughout this specification, it is to be understood that the retaining and clamping arrangements disclosed herein are equally suitable for use with various types and styles of enema tips and tubes, including, but not limited to, those disclosed in my copending patent application, Ser. No. 39,502, filed on May 16, 1979 now abandoned. Thus the arrangements disclosed herein are suitable for double-contrast studies in which air is introduced after the barium is evacuated. In fact, the arrangements disclosed in the specification are particularly well suited to such double-contrast studies in that the enema tube and tip can be retained within the patient throughout the study in a well-secured and comfortable manner and is not subject to slipping out or otherwise separating from its inserted position within the patient. Thus, in combination with any of one the various barium and air combination tubes of my copending patent application, barium is first introduced and then evacuated and then air is subsequently introduced into the patient and all of these operations may be performed without the necessity to remove the enema tip from the patient.
While the invention has been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only the preferred embodiment has been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected.
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CROSS-REFERENCE TO OTHER APPLICATIONS
[0001] This application is a continuation-in-part of, claims the benefit of, U.S. Provisional Patent Application Serial No. 60/306,315, filed Jul. 17, 2001.
FIELD OF THE INVENTION
[0002] The devices and related methods of the invention relate to the controlled introduction and removal of fluids in diagnostic, therapeutic and imaging applications within the body. Specifically, the invention relates to the advantageous use of a fluid exchange device in combination with a catheter to produce a system for controlled aspiration and irrigation and the selective and localized exchange of fluids within a body conduit, for example, in the diseased region of a blood vessel having a blockage or lesion. The devices of the invention, and the methods enabled by the use of the devices, have several different components that can be used individually or integrated into a system for use within an organ and within the vasculature of the body where controlled and localized irrigation and aspiration are performed together as a therapeutic procedure or in tandem with a separate therapeutic procedure.
BACKGROUND OF THE INVENTION
[0003] Irrigation and aspiration are clinically important in many surgical procedures when fluids are selectively introduced into and removed from a target site within the body, usually while a surgery or other therapeutic medical procedure is performed. When the site of the therapeutic treatment is inside a body cavity or in the vasculature of the body, such as in a blood vessel, the irrigation and aspiration functions require special apparatus and methods. Surgical and percutaneous systems that both irrigate and aspirate have been developed, and some of these systems are catheter-based such that the introduction and removal of fluids is performed within an organ or a vessel by using the catheter as the conduit to introduce and remove fluids from a target site. As will be readily appreciated, the catheter allows the control elements to be remotely located, e.g., outside the body while the actual irrigation and aspiration functions are selectively provided within the body by selectively orienting the distal end of the catheter to the target site. In such cases, as is the case in open surgeries, the irrigation and aspiration functions accompany a therapeutic procedure that is performed at the target site along with the irrigation and aspiration.
[0004] Catheter-based irrigation and aspiration systems are unique in many respects due to their use in clinical situations where blockages or lesions exist inside a blood vessel, such as a coronary or carotid artery, and dangers arise from the creation and release of emboli within the vessel. In many intravessel therapeutic procedures, the danger from the creation of emboli is an unavoidable aspect of the therapeutic procedure. For example, lesions of atherosclerotic plaques inside a blood vessel are treated by several therapeutic procedures including endarterectomy, atherectomy, the placement of intravessel stents, balloon angioplasty, surgical ablation of the lesion, thrombectomy, OCT, dialysis shunt clearing and others. However, while each of these procedures has great therapeutic value in treating the lesion, each carries the risk of creating emboli during the procedure. As with any procedure conducted in the cardiovascular system, the risk is particularly great where plaque dislodged from inside a blood vessel can travel to the brain causing serious brain injury or death. For example, treating lesions of the carotids necessarily involve high risk. Currently, carotid treatments are attempted together with deployment of a filter to attempt to track emboli generated by or released from a carotid lesion. Unfortunately, crossing a carotid lesion with a filter or other structure can generate a cerebral ischemia or stroke. Schlueter et al. 2001, Circulation 104 (17) II-368. Moreover, studies have shown that merely crossing a carotid lesion with a guide wire can generate emboli. Al-Mubarak et al.: Circulation 2001 OCT 23:104 (17): 1999-2002. Also, some lesions carry such a high risk of generating emboli that therapeutic treatments are attempted only in the most severe cases. Where a chronic total occlusion exists, the diagnosis is particularly poor because it is impossible to place a structure distal of the occlusion such that emboli generated by the removal of the occlusion can be captured before circulating in the bloodstream. Such occlusions can only be treated by removing the occlusion from the proximal side, where emboli removal is uniquely difficult. Accordingly, if the capability existed to dramatically reduce the dangers of emboli creation during therapeutic procedures inside a vessel or organ of the body, the existing procedures would be safer and more widely practiced, and new procedures would be performed.
[0005] A variety of systems to contain and remove emboli have been proposed wherein a portion of a vessel that contains a lesion is segregated by two occluding members, typically two balloons, which are inflated proximate and distal to the lesion to effectively seal the inside of a region of the vessel containing a lesion prior to treatment of the lesion. Once treatment is complete, embolic particles such as dislodged plaque are removed by applying suction between the balloons. However, the tissue affected by a lesion is notoriously delicate and the treatment of the lesion has the capability to generate or release emboli whenever any mechanical manipulation of the lesion occurs. The generation and/or release of emboli is a concern virtually anytime a structure is passed through a susceptible vessel. Such circumstances include the placement of a balloon or stent, the placement of a filter, or simply the use of a catheter or guide wire for imaging, diagnostic, or any other procedure. In many procedures, the internal portion of a vessel is occluded to provide a segregated region of a vessel through which fluid does not flow. Moreover, virtually anytime structures are inserted into the vessel, the generation of release of emboli is a concern. For example, in the common practice of placing a stent inside an artery, a filter may be placed distally of the stent to attempt to collect emboli generated when the stent is expanded to engage plaques or lesions inside the vessel. All devices placed distal involve the crossing of the lesion. All crossings of lesions create emboli of some quantity and significance. Such systems cannot protect the patient against the potential harm inherent in the placing the device. Additionally, once the stent is in place, the filter must be removed by pulling it through the portion of the vessel in which the stent has been inserted. This carries the risk that the filter will impact the vessel and cause the release of emboli and/or contact the stent and either displace the stent or similarly cause the release of embolic particles. The use of occluding members of any type has certain drawbacks. Anytime a structure is used as an occlusive member inside a vessel, the structure must deform the vessel from the inside to create a seal about the periphery thereof with the internal surface of the vessel. For example, to make the seal tight enough to prevent the passage of fluid and emboli past the balloon, the expansion of the balloon typically deforms the vessel outward and may disrupt plaque in and about the point of contact between the vessel and the balloon. Moreover, any plaque that becomes dislodged outside the barrier formed by the balloon is released into the blood stream because there is no mechanism distal of the balloon to remove the emboli. For this reason, irrigation and aspiration proximate to the lesion are particularly important.
[0006] To create a segregated region of a vessel, a two-balloon system may be used. However, certain disadvantages of a two-balloon system also arise from the placement of balloons on both sides of a lesion and the nature of the blood flow that occurs in the region of the vessel containing the lesion once the balloon is removed. At the point of contact between the balloon and the vessel, plaque may be compressed underneath the balloon and may become dislodged upon reestablishment of flow through the vessel. Furthermore, many clinicians have observed that the region distal of a lesion is more likely to exhibit plaque formation than the region proximal of a lesion. Thus, the use of an occluding member distal of a lesion does not eliminate the risk of creating emboli that may enter the vessel. The risk is particularly great when a second balloon is used because the balloon is not advantageously placed for the removal of emboli created by the use of the balloon itself and because the balloon must be removed by passing it across the lesion upon completion of a procedure. This drawback is present in all circumstances when a balloon is advanced across a lesion because, when any occluding member is placed distally of the lesion, the occluding member must be drawn back across the lesion to remove the occluding member at the end of a procedure. Each passage of an occluding member across the lesion, even in a retracted or deflated state, carries a substantial risk that additional emboli will be produced.
[0007] Also, the placement of two balloons requires additional time to inflate the second balloon and adds to the complexity of a device due to an additional lumen that must be incorporated into the catheter to inflate the balloon. In a finite number of cases, the occluding member that is distal of a lesion, and is required to retain emboli in a defined area within the vessel, has been observed to fail, thereby releasing the emboli into the bloodstream. Because the second balloon is relied upon to prevent the flow of emboli past the region of the vessel containing the lesion, the failure of the balloon is a critical event that threatens the health of a patient undergoing the procedure. Furthermore, due to geometric constraints, the second balloon often acts as the guide wire as well. When delivering tools to perform the therapeutic or diagnostic procedure within the vessel, the balloon may move and disrupt the vessel wall. Introduction of tools and other manipulations of a distally located balloon can also result in deflating the balloon or otherwise causing the balloon to lose patency on the interior of the vessel.
[0008] Anytime that a balloon is placed distal to a lesion, the contact between the balloon and the lesion carries the risk of damaging the vessel. For these reasons, the use of balloons inside the vessel is preferred to be minimized and the length of time and extent of contact between a balloon and the inside of a vessel should be reduced. Ideally, the balloon or other occluding member could be placed proximal to a lesion so that the area containing the lesion would be isolated. To achieve this, the irrigation and aspiration functions would have to be provided by a structure that is positioned distal of the occluding element, such that the occluding element could be placed proximal of the lesion, and the aspiration and irrigation functions achieved distal of the occluding member.
[0009] Even under existing technologies where aspiration and irrigation are applied in a catheter based system, the parameters of fluid flow, as well as the placement of the aspiration and irrigation ports relative to an occluding member, are important to the physiological outcome for any given procedure. For example, removal of fluid and/or embolic particles by simple suction from within a body conduit may only remove a portion of the fluid present in the vessel and may leave emboli in place even if all of the fluid is removed and replaced. Deposits of plaque and other debris that may exist inside a vessel have a tendency to adhere to one another and particulate emboli tend to adhere to the sidewalls of the vessel. Thus, a system that provides limited fluid exchange is particularly unlikely to achieve a complete removal of emboli. Also, given that the interior walls of a vessel may have been contacted from within during a therapeutic procedure, a high likelihood exists that additional particles may be dislodged upon the establishment of a robust fluid flow through the vessel.
[0010] Ideally, a system for aspirating and irrigating the interior or a vessel or organ would provide both fluid exchange and fluid flow parameters that are at least similar to that experienced during ordinary physiological functions and preferably would create a turbulent fluid flow that would proactively assist in the removal of particles and other emboli. Such a system would require both a catheter element that achieved aspiration and irrigation as well as a fluid exchange apparatus that would be coupled with the catheter to produce the desired fluid flow rates and other fluid parameters. Because of the wide variation in intravessel procedures and the location of disease, an irrigation and aspiration system would also be particularly useful if the catheter element could be selectively positioned along a specified length of a vessel where emboli may be created together with operation of the fluid exchange apparatus to control the irrigation and aspiration flow. This capability in the catheter element is most readily created with only a single balloon system having a separate, movable, irrigation and aspiration catheter.
[0011] In the prior art two-balloon system described above, where a region of a vessel is segregated by a pair of balloons located both proximally and distally of a lesion, the area of fluid flow is limited to the region defined by the placement of the two balloons. The problem is particularly acute when a vessel is treated with a procedure that installs a stent or manipulates the plaque in a vessel, such as with an angioplasty, where the lesion is physically manipulated as part of the therapeutic treatment. Assuming that the therapeutic treatment is successful, the vessel is treated by virtue of expanding the interior volume and promoting the flow of blood through the vessel. Under these circumstances, the portions of the vessel distal of the lesion have been contacted by a balloon and are then exposed to a higher volume of fluid flow than existed before the procedure. In the context of a typical patient, a vessel which had become slowly blocked due to the deposit of plaque over a large number of years has been expanded by the treatment of the lesion and this therapeutic treatment at an upstream point subjects the region in which the lesion is located and those downstream internal portions to a rate and volume of blood flow that has not been experienced in the many years since the vessel began to become occluded.
[0012] Under these circumstances, an additional risk exists that plaques located downstream from the lesion will be dislodged and will enter the circulation causing serious injury.
[0013] As with ordinary irrigation and aspiration in an open surgery, the irrigation and aspiration that are applied through existing catheter systems are typically regulated only by setting the positive or negative pressure that is applied to the aspiration or irrigation lumen of the catheter and is in turn communicated to the distal end of the catheter to insert or remove fluid respectively. However, to create the specific fluid flow parameters that maximize the removal of emboli and the fluid displacement within a vessel, thereby establishing fluid change in the vessel in the most physiologically relevant manner, a specialized fluid exchange device would have to be created to regulate the fluid flow parameters of both the irrigation and aspiration functions of the system.
[0014] An ideal irrigation and aspiration system could be an additive component to several other apparatus that are used in therapeutic, diagnostic, or imaging applications in the body such that the capability of the system would not be exclusive of other technologies that have been applied to enhance the safety of an intravessel procedure. Several different approaches apart from irrigation and aspiration have been attempted to physically capture emboli downstream at a lesion, most notably through the use of filters. However, filters have inherent drawbacks that cannot be completely eliminated. For example, embolic particles smaller than the filter pore size, commonly on the order of 100 microns evade filters, which must not be so small that physiologically important elements such as red and white blood cells are captured by the filter. Also, particles larger than the pore size tend to become trapped in the filter such that the filter itself becomes an occlusive element and blood flow through the filter is impeded. Also, as described above for occluding structures, whenever a filter is introduced distally to the lesion in a vessel, a finite probability exists that the removal of the filter will generate emboli. Still further, where a stent is placed at a lesion, the movement of the filter past the stent and through the vessel has the capability to catch or displace the stent.
[0015] Although certain portions of the discussion herein are directed towards a preferred embodiment of the apparatus of the invention used in an intravessel procedure, the devices and methodologies of the invention can readily be applied to non-vessel sites within the body such as within any body conduit such as an ear canal, colon, intestine, the trachea, lung passages, sinus cartilages, or any internal volume wherein a controlled and localized irrigation and aspiration function are desired. For example, in a diagnostic colonoscopy an endoscope may be introduced to aid in optical visualization of the site. However, the colon responds to fluid pressure changes and thus while trying to clear the field the tissue of note may move. To aid in this diagnostic situation, a controlled introduction of a clear fluid could be introduced in concert with an equivalent aspiration of dirty fluid. As such, the tissue may remain in the field of view while the process occurs. For imaging purposes the introduction of a contrast agent while simultaneously extracting an equivalent fluid will allow a vessel or organ to maintain its normal fluid level and pressure. As the imaging is completed, the same system could then return a more normal fluid to the site while extracting the foreign contrast agent. Imaging “pig-tail” catheters are presently used to introduce contrast agents to vascular system, even though radiopaque contrast agents are known to maintain a level of toxicity (Solomon, Kidney International, 1998, vol. 53, pp. 230-242). If the field of contrast was introduced and extracted as proposed by Courtney, et al., the patient's exposure would be substantially reduced.
SUMMARY OF THE INVENTION
[0016] The present invention provides control of both irrigation and aspiration functions at a selected location within a body cavity or conduit, such as a target region of a blood vessel. The region of the vessel to which an irrigation and aspiration function are provided may include both a therapeutic treatment site, the site proximal to the placement of a balloon, or a length of a vessel both proximal to and distal of a lesion wherein a surgical treatment was performed, where a diagnostic or therapeutic procedure caused the insertion of a dye or other solution, such as a clot dissolver, or where a total chronic occlusion occurs. Because the irrigation and aspiration functions are performed simultaneously, the fluid exchange apparatus of the invention is able to simultaneously regulate both irrigation and aspiration in a manner that advantageously controls the fluid flow rates and fluid flow parameters. This capability can be achieved both by controlling the flow rates using an electronic control system, as well as providing a mechanical apparatus that controls irrigation and aspiration flows when actuated by a user. When the catheter and fluid exchange device are combined into the system of the invention, the combination provides unique capabilities for treating or diagnosing a lesion contained within a vessel. For example, the lesion may be pre-treated prior to the therapeutic treatment which typically comprises ablation of a lesion or placement of a stent or expansion of the diameter of the vessel, i.e., through an angioplasty procedure. In a diagnostic embodiment, dye or other diagnostic markers can be infused distally of the occluding member and proximate to the lesion while avoiding the potential hazards of passing a collapsed balloon across the lesion. This provides a diagnostic capability which has substantially reduced risk relative to a therapeutic treatment that requires expansion of an occluding member distal of the lesion. Because of the added safety margin, the diagnostic procedures can be more readily performed without the risk of producing emboli and thus are a more available complement to the therapeutic procedure.
[0017] Preferably, the system of the invention includes a catheter element having specific features designed to facilitate the desirable fluid flow parameters when connected to the fluid exchange apparatus. Ideally, when coupled with an apparatus that inherently provides controlled and regulated fluid flows for both aspiration and irrigation, the catheter works in tandem with the apparatus to create both controlled and localized irrigation and aspiration through a catheter-based system. For example, the apparatus of the invention allow the user to control the irrigation and aspiration flow volumes, and by virtue of a specially designed catheter system, provide improved fluid flow parameters that facilitate quantitative volume exchange within a vessel or other cavity and produce defined fluid flow parameters in a region bordered by an occluding element. Accordingly, the aspiration and irrigation functions provided by the fluid exchange device can be added to several existing devices such as balloon occluding elements or filters, or can be used alone as a catheter-based fluid exchange system without any additional device. Thus, the fluid exchange capabilities can be added to an existing device such as a straight catheter or filter, or an existing device can be integrated into the remaining components of the present invention to provide the advantageous irrigation and aspiration functions as described herein. For example, to decrease time during a therapeutic or diagnostic procedure, the portion of the catheter element providing the irrigation function could be combined with a catheter used to perform an angioplasty procedure.
[0018] When so integrated, the irrigation and aspiration finctions of the invention are located distal to the angioplasty balloon and the enhanced removal of emboli is facilitated. Also, the location of the irrigation and aspiration lumens can occur such that the aspiration ports are on opposite sides of an occluding member or other structure such that a direct irrigant to aspirant volume exchange may or may not occur in the lesion of a vessel. In preferred embodiments of the system of the invention, the catheter element provides turbulent, rather than laminar, flow within the vessel. Turbulence is introduced locally at the region of fluid exchange within the body. In a turbulent flow, the velocity at a point fluctuates at random with high frequency and mixing of the fluid is much more intense than in a laminar flow. Turbulent flow is specifically preferred because it reaches the walls of a body structure and facilitates both fluid exchange and dislodging of particulate matter. To reach the walls, the irrigation ports exit the catheter element in the direction of the wall. To accomplish this, the catheter element preferably has ports that exit orthogonal to the wall of the distal end of the irrigation lumen of the catheter. The aspiration lumen may establish a local laminar flow profile. This results in laminar flow about the vessel.
[0019] Also, in a turbulent flow, the velocity at a point fluctuates at random with high frequency and mixing of the fluid is much more intense than in a laminar flow. This is of particular value when attempting to clear any site of debris. Without turbulence, the flow along the sides of a vessel/lumen is approximately 0. When trying to remove/clear or exchange fluids thoroughly is it imperative to facilitate mixing. Mixing can only reach the vessel walls through the application of turbulence. This is appreciated by the vessels as well, since turbulence can be achieved with this invention without high-powered injection systems that carry physiological risks associated with their inherent power and abnormally high flow rates.
[0020] In more scientific terms, when a laminar flow is made turbulent, then the velocity will become more uniform and higher, and as a result, fluid particles in the boundary layer can move farther downstream before separation takes place. This turbulence is generally local to the irrigation area and controlled by the dimensions and orientation of the ports of the irrigation lumen.
[0021] The flow and velocity exchange rate through the entire system is not altered significantly since the turbulence is local area around the irrigation ports. But turbulence for an equivalent flow produces a much more uniform flow across the vessel. This results in higher velocities along the wall where emboli and thrombus are known to be in residence. From a physiological relevance standpoint, blood clots, or thrombi, are much more likely to be released into turbulent than in laminar flow. (Berne & Levy, 2001 , Cardiovascular Physiology , p. 126).
[0022] Because flow is proportional to viscosity, irrigation with any number of fluids can increase the flow over just aspiration of the site. For example, the viscosity of blood is 5 times that of water in a vessel larger than 0.3 mm in diameter, (from graph 5-14, in Beme and Levy, p. 129). The resulting combination of turbulence and the introduction of various fluids allows for substantially variable fluid flows which cannot be achieved without the combination herein disclosed.
[0023] Those of skill in the art will appreciate that the fluid exchange capabilities and fluid flow parameters provided by the invention can be integrated into a number of systems to provide irrigation and aspiration and essentially any physiological context where near quantitative removal of fluid or particles from a site is desired. As noted above, the enhanced fluid flow parameters can be strategically oriented relative to the placement of an occluding member, such as a balloon, to effectively remove fluids or solid matter either proximal to or distal of the occluding device. The catheter element of the apparatus can also be positioned to facilitate the removal of dyes, or therapeutic or diagnostic compounds as part of the fluid exchange function of the apparatus of the invention.
[0024] In a preferred embodiment, the invention provides both irrigation and aspiration in a selected region of a vessel proximate to a lesion, but without any occlusion distal of the lesion such that the occluding element may be both inserted and removed without passing across the lesion. Because of the design of the catheter-based system, a single catheter element may both aspirate and irrigate and may be moved within the vessel whether or not used in combination with other apparatus. When used in combination with an occluding element, the irrigation and aspiration factors may be fixed in place proximate to a lesion within a vessel or may be movable such that a single catheter element having both aspiration and irrigation functions can be advanced into an area proximate a lesion and actuated to perform the irrigation and aspiration function both proximate to the lesion and distal to the occlusion element. Similarly, if there exists a distal device (filter or occlusion balloon) this system can be activated to accomplish the following optimum clinical benefit. The irrigation ports being just proximal, but not exclusively proximal, to the aspiration port, then the vessel can be irrigated actively with the local flow moving prograde. This drives the emboli up against a more distal occluder/filter and there the aspiration port evacuates the emboli. Used in concert with existing filters or balloons this results in optimum retrieval of emboli from the active irrigation. This embodiment does not require a proximal occlusion for clinical benefit.
[0025] In procedures where emboli may be present, this device may be used as part of a method to extract the emboli generated during either a therapeutic, surgical, imaging or diagnostic procedure. The volume exchange provided by the current invention is also adapted to facilitate removal of fluids within a measured portion of a vessel where vessel dimensions and fluid volumes are known. This device affords a simple mechanical means through which these may occur in concert. Primary applications have been identified that produce a 1:1 exchange of fluids, but further applications include pulsatile exchange rates and ratios other than 1:1.
[0026] The control aspect of the invention is derived in part from measured volumes that may be inserted and removed through a catheter system comprising an irrigation lumen and an aspiration lumen in fluid communication with irrigation and aspiration port(s) that insert and remove a defined or predetermined volume of solution. The design of the catheter and the fluid flow parameters achieved at the target site produce specific fluid dynamics within a vessel or body conduit that promote the removal of emboli and/or the near quantitative removal of a fluid contained in the region of a body conduit. In a preferred embodiment, a catheter coupled to a fluid exchange apparatus is actuated to create turbulence within the vessel or organ and proximate to the ports or exit holes of the irrigation lumen. As described in detail below, the size and orientation of the ports and lumen changes the fluid flow parameters such that defined flow rates, volumes, vortices, turbulence and ratios of fluids exchanged within the body can be custom designed for any application, vessel, or organ, as well as for specific diagnostic, therapeutic or imaging applications. Because many of the embodiments of the invention are used within the cardiovascular system, the irrigation and aspiration function can be designed such that fluids move into the vasculature in a pulsatile manner as with the movement of blood within the vessel caused by the beating heart. This type of fluid movement and fluid exchange provided by the aspiration and irrigation functions of the invention is advantageous because the insertion and removal of fluid in this manner exposes the vessels or other structures to fluid flow that is physiologically relevant. In the sense that the vessel experiences fluid flow that is similar to that experienced after the therapeutic, diagnostic, or imaging procedure is performed and any emboli that would be released following the procedure are more likely to be released during the irrigation or aspiration process performed by the devices of the invention.
[0027] As described in more detail below, the design also facilitates a defined fluid exchange rate, such as 1:1 volume exchange that avoids damage to the vessel while producing turbulence to facilitate the removal of emboli. Generally, turbulent flows provided by the device of the invention are localized and controlled in both volume and location and are typically higher than that provided by the existing devices in terms of both flow and velocity. Target flows of 1 cc/sec are relevant to vessels such as the vein grafts, flows up to 2 cc/sec are relevant for vessels such as the carotids. (Louagie et al., 1994 , Thorac Cardiovasc Surg 42(3):175-81; Ascher et al., 2002 , J Vasc Surg 35(3):439-44).
[0028] As noted above, an advantage of the invention is the generation of localized turbulence in the vicinity of the infusion catheter such that volume exchange within the vessel promotes the disruption of embolic particles that are only loosely attached to the interior walls of a vessel. This advantage is derived from both the design of the catheter, which affects the location in which fluids are inserted and removed into a vessel or an organ, as well as the specific design and function of the fluid exchange apparatus that, when coupled with the catheter of the invention, combine to produce improved fluid exchange and fluid flow parameters. For example, in an ordinary vessel that is roughly cylindrical within a defined axial distance along the length of a vessel, the removal of liquid generally produces a laminar flow through the center of the annular structure of the vessel and the fluid along the walls of the vessel are largely left in place. With a turbulent fluid flow profile, the fluid introduced into the vessel causes an exchange between the irrigant the existing fluid that is localized along the vessel walls and generally causes a more thorough mixing of the fluids within the vessel such that a more complete fluid volume exchange occurs and the removal of embolic particles is enhanced.
[0029] Although the particular parameters vary according to the designs described below, the fluid exchange achieved by the fluid exchange apparatus and the irrigation/aspiration catheter results in an insertion and removal of a defined volume within a vessel. As described in further detail below, the overall system is comprised of a fluid exchange apparatus that may have a mechanical or electrical, or both, fluid exchange component that converts a defined volume of fluid exchange with a defined axial movement of the catheter such that the volume of fluid exchanged per measure of distance of axial movement of the catheter through a vessel is known. Preferred embodiments of the fluid exchange apparatus are a substantially closed system wherein a reservoir containing irrigating fluid is combined with a reservoir containing the aspirated fluid such that known volumes are exchanged through a system that is essentially “closed” except for the exchange site within the vessel. The terms “substantially closed” mean that the system is closed because the volume of fluid inserted as irrigant solution is removed as aspirant solution in a predetermined ratio and any deviance from the ratio is attributed to only a volume of solution that is retained within the body at the target exchange site. For example, when a system of the invention is applied to irrigate and aspirate fluid from within a vessel, the system is substantially closed because the only difference between the fluid inserted as irrigant and removed as aspirant is that which is purposefully left behind in the vessel. When the volume exchange ratio of the device is set at a 1:1 ratio, the volumetric exchange of fluids is very near to equivalent. The fluid exchange apparatus may also be actuated in such a manner that the flow produced by actuating the fluid exchange apparatus is a defined increment. Thus, a known volume of fluid is exchanged at the target site and the clinician knows with certainty the volume of irrigant fluid that is inserted as well as the volume of fluid that is aspirated out of the target site.
[0030] In one embodiment, the device of the invention provides a 1:1 ratio of irrigation to aspiration fluid exchange such that the volume of fluid introduced to a vessel or organ is exactly matched by the volume removed. Through control of the location and movement of the device of the invention, the interior of a vessel or organ can undergo a complete fluid exchange by advancing the infusion catheter along the length of a vessel where removal of fluid is desired. By this process, several results are achieved that are beneficial therapeutically. First, the vessel experiences a turbulence and a fluid flow that is physiologically relevant in the sense that both the volume of fluid moving across a vessel as well as the turbulence are similar to the parameters that the vessel would experience under blood pressure. This similarity has several aspects. First, the turbulence that occurs in a vessel is similar to the turbulence caused by the motion of blood moved by a beating heart. Second, the pulsatile nature of the fluid exchange is also similar to the varying pressures and pressure profile caused by ventricular contraction and the ordinary movement of blood throughout the arterial system. Finally, these specific fluid flow characteristics are achieved without producing substantially increased pressures within a vessel and without distending the vessel through the application of increased fluid pressures. Thus, the combined irrigation and aspiration of controlled volumes of liquid treat the vessel with a physiologically relevant fluid profile.
[0031] Because the device of the invention offers the ability to introduce and remove a defined volume of fluid, the clinician can have a high degree of certainty that the entire internal volume of a region of a vessel has been rinsed with an irrigation fluid by knowing the approximate internal volume of the vessel and the length of the vessel in which irrigation and aspiration are performed. For example, assuming that a specified region of a vessel has an internal volume of 20 ml over a defined axial length. The device of the invention can be used to insert predetermined volumes of solution greater than, less than, or equal to 20 mls over the defined length of the vessel. Depending on the clinical environment, the ratio may be altered to remove greater volume by establishing a smaller ratio of irrigation to aspiration. One could, for example, irrigate with one volume of solution while removing twice the volume through the aspiration portion of the system to yield a 1:2 irrigation to aspiration volume.
[0032] In a preferred embodiment, the fluid exchange device has the ability to perform a controlled exchange of fluid with predetermined ratios including a 1:1 irrigation to aspiration ratio and varying ratios particularly values ranging between a 1:2 irrigation to aspiration ratio and a 2:1 irrigation to aspiration ratio. Preferably, this is achieved by having irrigant and aspirant reservoirs of defined volumes built into the fluid exchange device. However, the device can also feature a selectable control that alters the ratio of fluid exchange between a minimum and a maximum as a function of the operation of the device. In the mechanical embodiment of the fluid exchange device, each actuation of the device may cause a defined volume of fluid to be propelled through an outlet that is in fluid communication with the irrigant lumen of a catheter element. In combination, the device also features an aspirant reservoir which is expanded by a predetermined volume relative to the volume of the irrigant that is expelled.
[0033] The control of these parameters, in some aspects, by the fluid exchange device is the result of designing the fluid exchange device to cooperate with both conventional catheters as well as those specially designed to produce turbulent flow at the target fluid exchange site. The fluid control functions of the exchange device can also cooperate with the catheter element by incorporating the capability for the fluid exchange device to control motion of the catheter, specifically axial movement within a body conduit such as a blood vessel. In this embodiment, the catheter element is coupled to the actuation of the fluid exchange device by a coupled translation mechanism wherein, as described in further detail below, each actuation of the device results in automatic advancement or retraction of the catheter. Thus, a defined exchange of fluid volume at the target site occurs in combination with advancement or retraction of the aspiration and/or irrigation element of the catheter by a defined distance. In this manner, repeated actuation of the device provides a step-wise motion of the irrigation and evacuation functions and can insure a near quantitative volume exchange over a defined distance. As will be apparent from the following description, this aspect of the invention provides the ability to insert and/or remove a defined volume of fluid distal of an occluding member given an approximate knowledge of the dimensions of the vessel. As with the other embodiments, the operation of the system may provide fluid exchange with a pulsatile fluid flow by virtue of the application and dissipation of pressure achieved through the catheter.
[0034] Any number of designs for the fluid exchange apparatus can be used to provide controlled volumes of irrigation and aspiration fluids, through the catheter element of the invention to the target exchange site. The simplest embodiment of the invention provides a squeeze bulb wherein the irrigant and aspirant reservoirs are typically separated by a membrane and are in fluid communication with a irrigation and aspiration lumen that communicate fluids to and from the target site. In this embodiment, a one-way valve is provided preferably on both the irrigant and aspirant side of the fluid flow, to prevent aspirated fluid from flowing back to the target site. In another embodiment, a mechanical device causes pressure to be exerted on an irrigant reservoir that is in fluid communication with an irrigation lumen that provides fluid flow to at least one irrigation port at the distal end of a catheter. The catheter element also comprises an aspiration lumen, that may or may not be integral with the irrigation lumen, and which facilitates fluid communication of the aspirant fluid back to an aspirant reservoir. In this embodiment, the irrigant is expelled from a reservoir by the application of mechanical force to reduce the volume of the irrigation reservoir and the mechanical force is preferably coupled to an expansion of the volume of the aspirant reservoir to yield a defined fluid exchange between the irrigant reservoir and the aspirant reservoir.
[0035] Those skilled in the art of medical devices will appreciate that all of the component parts of the invention are assembled from biocompatible materials, typically medical plastics or stainless steel. The syringes described below may be ordinary medical-use syringes or may be custom fitted to be replaceable and to fit engagingly with the fluid exchange apparatus. An irrigant reservoir that is integral with the device may be pre-filled or a pre-filled syringe may be used to supply the irrigant fluid. In either a stainless steel or plastic embodiment, the device is stabilized. Typically, stainless steel devices are exposed to heat and steam in an autoclave, while medical plastics may be exposed to gamma irradiation or microbicidal gases such as EtO. The methods of the invention specifically include the use of any component of the system of the invention followed by sterilization of the components, or the entire system, and re-packaging for subsequent use. Although plastic embodiments are designed for single use, sterilization may be performed to functionally reconstruct the utility of the device after use with a patient.
[0036] In one preferred embodiment, a hand-held mechanical device is actuated by a trigger to insert and remove controlled volumes of fluid through the catheter element. The hand-held embodiment is comprised of an actuator such as a movable trigger that is mechanically operated by being grasped by the hand and pulled towards a stationary structural housing of a complementary portion of a housing to cause a reduction in the volume of an irrigant reservoir and, accordingly, fluid movement through an irrigation lumen and out one or more irrigation ports at the distal end of a catheter. Fluid provided to the target site in this manner is recovered through one or more aspiration ports and communicated through an aspiration lumen and returned to the aspirant reservoir of the fluid exchange device. The irrigant and/or aspirant fluids are preferably contained in a sealed reservoir system such as a cylindrical chamber having a piston and a rod wherein the piston is mechanically coupled to the actuating element. Motion of the actuating element transfers force to the piston and causes contraction of the irrigant reservoir and expulsion of liquid from the reservoir. Simultaneously, the motion of the actuator causes the expansion of the volume of the aspirant reservoir and causes withdrawal of fluid through the aspiration lumen and into an aspirant reservoir. In such an embodiment, the actuation of the trigger may translate into varying amounts of fluid flow depending on the mechanical expedients used. A single actuation of the trigger may translate into an incremental movement of a piston that exerts force on an irrigant and/or aspirant reservoir. By the use of several conventional mechanical apparatus, such as a ratchet and gear mechanism, a lever and pivot system, or others, the mechanical fluid exchange device exerts a direct control over the exchange of fluid communicated through the irrigation and aspiration lumens. The control of the fluid and the particular features can be provided in several designs that achieve the same function. For example, in addition to the hand-held apparatus described below, the force needed to create the fluid flow in both the aspiration and irrigation sides of the system could be provided by a mechanical foot pump, vacuum pump or virtually any component device that provides controllable fluid flow. Moreover, to provide total reproducibility in the operation of the system, a console controlled by a computer with appropriate commands or a software program is readily used to produce the same fluid flows, fluid exchange parameters, including exchange ratios, and essentially all of the functions of the purely mechanical embodiments described below. Therefore, those of ordinary skill in the art will appreciate that any number of mechanical or electrical variations give rise to the same fundamental principle wherein controlled volumes are applied to a target site through a segregated irrigation and aspiration system, preferably comprised of irrigation and aspiration lumens that pass through at least one catheter element and engage in fluid exchange at a target exchange site by virtue of specially designed irrigation and aspiration ports at the distal end of the catheter element.
[0037] By altering the dimensions of the irrigation reservoir and the aspiration reservoir, the ratio of fluid exchange between the irrigant and aspirant reservoirs is altered and, accordingly, the fluid exchange in the target vessel is adjusted. For example, where the irrigant reservoir and aspirant reservoir are of identical sizes, an actuation of the fluid exchange device may yield a 1:1 fluid exchange within the target vessel. Where, as described above, a different fluid exchange ratio is desired, the difference in the ratio may be achieved by a corresponding difference in the dimensions of the irrigant and aspirant reservoirs that are emptied and filled through the operation of the fluid exchange device. Also, variations in ratio may be accomplished by corresponding changes in the dimensions of in-line chambers as described below. Likewise, with a 1:1 ratio, equal volumes of irrigant and aspirant are exchanged in a single cycle of the fluid exchange apparatus. In the 1:1 embodiment, the entire irrigation and aspiration volumes may be exchanged within a defined number of cycles of the apparatus. For example, one may provide that each cycle of the hand-held apparatus provides 1 ml of irrigant volume and removes 1 ml of aspirant volume. By providing an irrigation and aspiration reservoir with known volumes, a known number of cycles translates into a known volume of irrigation and aspiration. As noted above, in one specific embodiment, the actuation of the device also causes translation of the infusion catheter along a defined axial path such that a known volume of solution is provided in both the irrigation and aspiration aspects as a function of the distance that is traveled by the infusion catheter.
[0038] Clearly, the irrigation reservoir may advantageously be divided into subparts and is not limited to ordinary aqueous solutions used in a surgical context. Given the utility of the present device for diagnostic and imaging applications, the irrigation reservoir could be filled with dyes, contrast agents, or other solutions that aid in the diagnosis or treatment of the vessel. Given that the fluid exchange device of the invention also provides unique fluid flow parameters, the irrigation reservoir could contain therapeutically valuable solutions such as heparinized ringers lactate, streptokinase, urokinase, tissue plasminogen activator, or other thrombus or emboli treatment fluids that are used to perform the therapeutic procedure on the internal portion of a vessel or organ. Given the ability to specifically tailor the fluid exchange parameters for a target vessel, the device offers the ability to use therapeutic compounds that might not otherwise be available because the clinician can be certain of the enhanced ability to remove solutions introduced via the irrigation reservoir. The fluid exchange apparatus can also be used to promote absorption of a therapeutic layer on a vessel wall. If a drug coated stent is produced that can reabsorb drugs after they have eluted, then with this device a high concentration of the drug can be introduced and pooled about the stent for a brief period. This high dose may then be absorbed or bonded back to the structure or one of its components and thereby recharging the drug coated stent.
[0039] Finally, in a system where it may be advantageous to have ratios other than 1:1 in the system it is also directly applicable. For example, in another vascular situation a virtual shunt may be created where a proximal fluid can be circulating and a fluid is infused distally. This would involve a ratio of greater than 1:1 irrigation to aspiration. Furthermore such an arrangement could introduce a second fluid to be the primarily distally delivered fluid. The second fluid could be blood, blood substitute, plasma or oxygenated fluid to produce a virtual shunt.
[0040] In the diagnostic use of optical coherence tomography, OCT, the fields of applications are presently limited by the need for a clear field. Similarly the use of intravascular ultrasound, IVUS, is somewhat limited by the attenuation associated with the blood in vivo. A substantial volume exchange of the vessel region in proximity of the distal end of the OCT or IVUS catheter would provide the opportunity to replace blood or other fluids with transparencies other than that found in blood, thus improving and/or modifying the imaging quality.
DESCRIPTION OF THE DRAWINGS
[0041] [0041]FIG. 1 shows the basic components of the device necessary for implementation with the optional inclusion of components that generate a minimum flow rate of exchange, components that incorporate an upper flow rate of exchange, and a configuration where a combination of flow threshold and ceiling provide a flow rate bandwidth.
[0042] [0042]FIGS. 2A-2D are cross-sections of a vessel showing the catheter element of the invention with aspiration and irrigation lumens combined in the same catheter element and terminating at an aspiration and irrigation port, respectively. FIG. 2A is a section of the catheter showing the aspiration and irrigation lumens. FIG. 2B is insertion of the catheter element into an exchange region established at a terminal lumen characterized by a total occlusion such as a clot, lesion, abscess, a ball of wax or a body conduit or organ that is closed-ended such as an ear canal. FIG. 2C shows a cross-section of the system with an occlusion balloon to establish a defined region of fluid exchange between the irrigation lumen and the aspiration lumen. FIG. 2D shows one example of the placement of an aspiration port and an irrigation port that is in fluid communication with the aspiration lumen and irrigation lumen, respectively.
[0043] [0043]FIGS. 3A-3F show the catheter element in various configurations and illustrate the difference between laminar and turbulent flow. FIG. 3A is a catheter element having an occlusion member and comprising an occluding guiding catheter having an aspiration lumen and with the irrigation provided by a separate catheter to aid in defining a field of exchange. FIG. 3B shows a catheter element providing an isolated, localized region for fluid exchange that is maintained by irrigation occurring both proximal and distal to a centrally disposed aspiration port. FIG. 3C shows a typical laminar flow that fluids will naturally assume when passing through a cylindrical tube. The flow velocities are highest at the center of the tube and approach zero velocity at the walls of the tube. The length of the arrows indicate the magnitude of the velocity.
[0044] [0044]FIG. 3D shows the turbulent region of flow created by a catheter element of the invention adjacent to a region where the flow transitions to a laminar flow, but still has a comparatively higher velocity along the walls of the tube. At a distance from the irrigation ports, the flow achieves laminar flow.
[0045] [0045]FIG. 3E shows a catheter element with 3 rows of perfusion holes. The figure illustrates how the turbulent flow is most pronounced in the immediate vicinity of the infusion ports and begins to assume laminar characteristics until the next row of infusion ports is encountered. In the region designated “A,” turbulent flow is provided by the irrigation port geometry. In region “B,” flow is tending toward laminar flow. In region “C,” laminar flow is established.
[0046] In FIG. 3F, the various regions of flow show the relative distances necessary for each activity. The transition region has typically been shown to be about the same length as the perforated region of the catheter element.
[0047] [0047]FIG. 4A is a schematic of an embodiment of the fluid exchange device that produces pulsatile flow through the application of leverage to a hand-held unit that is actuated to communicate force to the irrigant reservoir and which collects fluid in the aspirant reservoir. FIG. 4B is an embodiment that accepts interchangeable fluid cartridges, similar to syringes, for irrigation and aspiration and where the exchange rates can be altered to other than a 1:1 ratio. In this example there is a 2:1 ratio of irrigant to aspirant dictated by the relative sizes of the fluid cartridges.
[0048] [0048]FIG. 5A is a fluid exchange device incorporating a segregate irrigant reservoir that uses different types of irrigants, while FIG. 5B segregates the irrigant fluid into a sample to be inserted both proximal to and distal at a point of the target site.
[0049] [0049]FIG. 6 is a tabletop version of the fluid exchange device that is suitable for either a mechanically drive hand system or an electronically controlled, pump-driven system, including an optional in-line air trap for the irrigant and a filter for the aspirant.
[0050] [0050]FIG. 7A and 7B are a grip lever activated embodiment of the hand-held fluid exchange device of the invention wherein the actuation of a trigger relative to the body of the handle translates into the motion of a piston that propels fluid from the irrigant chamber and collects fluid in an aspiration chamber (not shown).
[0051] [0051]FIG. 8 is a preferred embodiment of the hand-held fluid exchange apparatus of the invention having a spring tensioned trigger mechanism that is actuated by manual motion of the trigger relative to the body of a handle. Actuation causes linear or incremental motion of a dedicated irrigant and aspirant carriage that move in opposite directions to control the force supplied to the irrigant and aspirant reservoir, respectively.
[0052] [0052]FIGS. 9A and 9B illustrate an embodiment at the hand-held fluid exchange device having an adjustable pivot point on a trigger to produce different flow rates and peak pressures.
[0053] [0053]FIG. 10 is an embodiment wherein the control of the movement of pistons that propel fluid from a cylindrical irrigant reservoir and into an aspirant reservoir is provided by a ratchet mechanism.
[0054] [0054]FIG. 11 is a fluid exchange device with two chambers, such that both an irrigation and aspiration chamber are arranged to operate in concert, with one filling and one expelling fluid in each direction and having separate input and output pathways for connecting to the reservoir and lumen elements.
[0055] [0055]FIGS. 12A and 12B show the apparatus configured as a compressible ball squeezed by the hand with the internal volume divided into irrigant and aspirant chambers and designed to be connected in-line with irrigation and aspiration lumens and reservoirs.
[0056] [0056]FIG. 13A and 13B are an embodiment wherein the fluid exchange device is a hand ball pump configured with an internal reservoir of irrigant fluid and a flexible member to separate the irrigant from in-flowing aspirant fluid. This device is initially loaded with a volume of irrigant that encompasses most of the initial internal volume of the ball and which flows through the target site to the internal aspirant reservoir. FIG. 13C is an embodiment having a substantially rigid external housing and an internal balloon. The interior of the housing is filled with fluid and an internal balloon containing air or a non-volatile gas. A volumetric pump changes the internal configuration of the balloon to force fluid from an internal irrigant reservoir to an internal aspirant reservoir.
[0057] [0057]FIG. 14 is a device with both irrigant and aspirant chambers combined into one housing separated by a movable piston into two distinct chambers to allow for the simultaneous rinsing and aspirating.
[0058] [0058]FIG. 15 shows a slidable and threaded combination configuration where an irrigant can be driven out and an aspirant simultaneously drawn in by both a sliding and a screw-type mechanism. The sliding provides gross travel and the rotation of the member about the axis produces a fine-tuning mechanism.
[0059] [0059]FIG. 16 is an embodiment of the fluid exchange device that can be comprised of as few as the structural elements that preferably attach to a cylinder body of one reservoir and piston of the other.
[0060] [0060]FIGS. 17A and 17B are a mechanical fixture for providing a self-advancing or retractors catheter element in combination with the fluid exchange device.
[0061] [0061]FIGS. 18A-18C are an embodiment of the invention with a staging capability such that the means for aspiration and irrigation are linked mechanically to travel in equivalent and opposite directions.
DETAILED DESCRIPTION OF THE INVENTION
[0062] The present invention may be used in a number of different environments and for a variety of purposes including, but not limited to all physiological uses of peristaltic or other pump for aspiration and irrigation including, IVUS, OCT, angioplasty, endortarectomy, cardiac stent placement, vessel treatment, diagnosis and repair, surgical placement of non-cardiac stents, insertion of pig-tail catheters, ear rinsers, etc. The following detailed description is exemplary of possible embodiments of the invention.
[0063] Referring to FIG. 1, a schematic representation of the invention shows the basic components of the device necessary for implementation. The core fluid exchange or activation system maintains a substantially closed loop system with the target site for fluid exchange, e.g. the site within the body where aspiration and irrigation are applied. The irrigation component of the invention is conveniently provided by a dedicated irrigation reservoir 1 , particularly when the fluid exchange system is the mechanical embodiment described in greater detail below. The exchange site is in fluid communication with the fluid exchange system via the irrigation lumen 2 and the aspiration lumen 3 which have exit or entry ports (not shown) at the distal end of each lumen. The aspiration component may also feature an aspiration reservoir 4 in fluid communication with the aspiration lumen 3 and aspiration ports (not shown) such that fluids removed from the exchange site are stored in the aspiration reservoir 4 . As is apparent to one of ordinary skill in the art, the irrigation 1 and aspiration 4 reservoirs may be controlled electronically by valves or pumps to provide the controlled fluid exchange ratios described herein. Thus, while the embodiments of the invention featuring fluid exchange apparatus that are mechanically controlled by the user are preferred in certain versions of any system, controlled rate of fluid exchange at a target site may be used in a system of the invention. Alternatively, fluids in the aspiration reservoir 4 may be discarded. In one embodiment of the invention, fluids communicated from the target exchange site through the aspiration component of the invention are analyzed for chemical or particulate content to determine a level of removal of fluids or solid matter from the exchange site.
[0064] Referring again to FIG. 1, an optional configuration of the. components includes a flow valve 6 that produces a minimum lower threshold for irrigation flow. This minimum delivery flow is beneficial to ensure a minimum amount of exchange flow when the clinical indication dictates maintaining a minimum flow through the irrigation catheter. The flow threshold insures that the fluid exchange does not fall below a predetermined ratio as described herein. For example, although 1:1 fluid exchange rates are provided in several embodiments described herein, the exchange ratio may be altered such that a larger volume of fluid is aspirated compared to that which is used for irrigation or vice versa. Under such circumstances, the fluid exchange ratio would vary to, for example, a 1:2 irrigation to aspiration ratio under circumstances where a larger volume of liquid is desired to be removed from the exchange site.
[0065] The components of the invention could also incorporate an upper flow rate of exchange or flow ceiling 6 . When conditions dictate that there is motivation to limit the velocity or overall flow parameters during a usage, a configuration that provides an upper limit may be provided. Accordingly, this embodiment would apply where a larger volume of fluid was desired to be inserted by irrigation compared to that which is removed by aspiration and the corresponding irrigation to aspiration exchange ratio would be increased to, for example, 2:1. The combination of a flow threshold and flow ceiling capability provide a flow rate bandwidth yielding a range of values between two extremes. In this embodiment, the exchange site can be irrigated and aspirated at a consistent level that is either fixed or varies within a range. This may also allow the activation system to sustain a change in the pressure level at the exchange site while delivering irrigant fluid or removing aspirant fluid at a steady rate or within a range of rates. As will be appreciated by one of ordinary skill in the art, the irrigation side of the system of the invention requires active force provided by the fluid exchange apparatus such that irrigant fluid flow is established at the target site. However, while the aspiration side may also be controlled through application of force to withdraw fluid from the target site, the aspiration side may also be passive such that the inherent pressure at the target site propels the aspirant fluid. The inherent pressure is typically provided both by the fluid pressure inside the body, e.g. the blood pressure within a vessel, and the pressure of the irrigant fluid entering the target site. This characteristically passive flow may be described as an efflux flow, see U.S. Pat. No. 4,921,478 which is specifically incorporated by reference herein. The passive flow of aspirant fluid is one way through the aspiration lumen and the fluid pathway is comprised of one-way valve, such as conventional duck bill valves having a minimal cracking pressure to allow passive fluid flow while preventing retrograde flow through the aspiration side of the system. This capability provides for constant extraction of embolic particles throughout a clinical procedure while irrigant fluid flow is maintained and/or when fluid existing at the target site flows from endogenous body pressure.
[0066] [0066]FIG. 2A is a cross-section of a catheter element 7 of the invention at the exchange site. The irrigation lumen 2 in this configuration terminates at or proximate to the distal end of the catheter element. While the aspiration lumen 3 terminates proximally and both lumens terminate with exit ports 8 , 9 . FIG. 2B depicts the insertion of fluid into an exchange region at a terminal lumen. The irrigation port 6 in this depiction is dislodging a terminal occluding clot. The terminal occlusion may include but is not limited to a clot, lesion, abscess, a ball of wax or an ear canal. In such situations, simple aspiration may not eliminate the lesion and a non-traumatic irrigation of the lesion with a therapeutic formulation, in concert with aspiration after an improved treatment methodology. For example, even if the irrigation fluid is able to produce a substantial breakdown of a terminal occlusion, the occlusion itself must still be cleared. Moreover, the combination of irrigation and aspiration to yield fluid exchange after the ability to introduce pharmaceutical agents proximate to the occlusion and the ability to remove the agents before they enter the bloodstream. A specific example of this is a thrombolytic agent used to remove the occlusion or potentially dangerous thrombus, wherein the thrombus or occlusion must be both treated and removed to treat the condition and wherein the necessary dosage of the agent exceeds that which could otherwise be introduced without drug-related toxicity.
[0067] [0067]FIG. 2C is a cross-section of the catheter element of the system incorporated with a proximal occlusion balloon 11 to establish a defined region of fluid exchange. This configuration may be useful for, but is not limited to, occluding flow, limiting a diagnostic agents field of deployment or limiting the bodies exposure to a high intensity agent. A dedicated balloon lumen 12 is provided for inflation of the occluding device. FIG. 2D is the catheter element of the system of the invention having an occlusion member 11 to aid in establishing an exchange site and having irrigation and aspiration functions distal to the occluding member wherein the arrows depict the general direction of fluid flow, distal to proximal, relative to the occluding member 11 .
[0068] [0068]FIG. 3A is the device incorporated with a combined aspiration lumen 3 and occluding element 11 integral in the same catheter element with the irrigation driven by a separate catheter 2 to aid in defining a target site or field of fluid exchange. The irrigation lumen's 2 independent travel affords a means of adjusting the location of the fluid exchange site while maintaining the occlusion at a predetermined location. Furthermore, a treatment, diagnostic or imaging tool (not shown) can also be affixed to the irrigation catheter 2 . This is productive where the resident fluids are desired to be replaced with a dye or contract agent and then removed in turn prior to re-establishing normal blood flow. In optical coherence tomography (OCT), for example, it is advantageous to introduce and remove a low attenuating fluid. FIG. 3B is a fluid isolated region that is maintained by irrigation occurring through ports 8 located both proximal and distal to the aspiration port 9 . This configuration presents a means of maintaining a controlled introduced field of fluid between the proximal and distal irrigation ports 8 . As in the embodiment of FIG. 3A, a treatment, diagnostic or imaging tool could be attached or moved along in concert between the irrigation ports. Referring to FIG. 3C, a catheter element (not shown) that merely inserts and removes fluid from a vessel achieves only laminar flow in the direction of the arrows and with velocity illustrated by the size of the arrows. Near the vessel wall the total fluid flow approaches zero such that fluid containing emboli at the walls is not disturbed and loosely affixed emboli remain in place. FIG. 3D is a preferred embodiment of the catheter element of the invention having orthogonally disposed aspiration ports 8 located at the distal end of the catheter element 7 . The region “A” experiences turbulent flow, while region “B” experiences a flow profile that is in transition from turbulence to laminar flow. FIG. 3E shows a series of irrigation ports 8 spaced at intervals along the length of the distal end of a catheter 7 such that either turbulent flows, designated as “A” or regions where turbulence is transitioning to laminar flows, designated as “B” are established along a length of the catheter 7 to substantially eliminate areas of laminar flow. FIG. 3F shows a configuration wherein the irrigation ports are provided as a perforated region 8 ′ at the distal end of the catheter 7 . The arrows indicate the direction and magnitude of flow showing that the perforated region establishes turbulence in a defined region, and as the distance away from the perforated portion 81 increases, the flow reverts to a laminar flow at a certain distance along the length of the vessel.
[0069] [0069]FIG. 4A is an embodiment of the device 10 that produces pulsatile flow through the application of a mechanical force to an apparatus that propels fluid through the catheter element of the invention. In use, the action of a trigger 20 pulled toward a handle 21 exerts a force on a dedicated irrigant piston 22 that compresses the irrigant reservoir 1 thereby reducing the volume of the irrigant reservoir 1 and forcing fluid through the irrigant lumen (not shown) and simultaneously withdraws the dedicated aspirant 23 piston of the aspirant reservoir 4 to accomplish the fluid exchange at the target site. Actuation of the trigger 20 may cause the relative motion of the pistons 22 , 23 by connection handle to a ratchet or other gear mechanism that provides the exertion of force in an incremental amount based on the actuation of the handle in a cyclical fashion. See e.g. FIG. 10 below and accompanying text. As shown in FIG. 4A, the irrigant and aspirant reservoirs may advantageously be provided by conventional syringes or similar devices that provide for fluid containment and the controlled application of fluid flow. The syringes of FIG. 4A are merely examples of the use of replaceable cartridges that may be readily inserted and removed from the device. Such cartridges are particularly useful when pharmaceutically active solutions are pre-filled and used in specific clinical procedures where medicaments are provided to a body conduit or vessel by the system of this invention. In this respect, the use of this invention allows the selective introduction of pharmaceutical compositions of any type during the performance of an ordinary irrigation and aspiration operation. In the embodiment of FIG. 4A, the syringes comprising the irrigant reservoir 1 and aspirant reservoir 3 may be removably inserted into the hand-held fluid exchange apparatus 10 and used to both provide and expel a predetermined volume of fluid through the target exchange site. In this manner, both the volume and content of the irrigant fluid can be controlled by exchanging syringes and the contents of the aspirant reservoir can be retained and analyzed for fluid or particular content. The operation of preferred embodiments of the hand-held embodiment of the invention is also described at FIGS. 7-10 below and the accompanying text.
[0070] [0070]FIG. 4B is an example of interchangeable fluid cartridges 24 a 24 b , similar to the syringes described in other embodiments, for irrigation and aspiration. As described in greater detail herein, the irrigant 1 and/or aspirant 3 fluid reservoirs may be provided by cartridges or reservoirs of differing sizes to accomplish the predetermined volume exchange ratio desired for the particular clinical indication. In the embodiment of FIG. 4B, the irrigant fluid cartridge 24 a has double the volume of the aspirant cartridge 24 b thereby providing a 2:1 fluid exchange ratio of irrigant to aspirant at the target site. In this respect, the loop established by the fluid exchange system is not a completely closed loop, but is described as a substantially closed loop, in that a difference exists between the volume expelled through the irrigant reservoir 1 via the irrigant lumen 2 and into the exchange site versus the difference in the aspirant volume taken up through the aspirant lumen and into the aspirant reservoir 40 although the volumes are not identical, the volumes are predetermined and known with certainty as is the volume of fluid that remains at the target site, which is the difference between the volume of the irrigant fluid introduced to the site and the volume of the aspirant fluid removed therefrom. As in the embodiment of FIG. 4A, the irrigant fluid cartridge 24 a has a dedicated piston 22 for expelling fluid from the cartridge. The aspirant cartridge 24 b similarly has a dedicated piston 23 for collecting fluid introduced to the aspirant reservoir via the aspiration lumen 3 . In this specific embodiment, more irrigant fluid is introduced due to the larger cross-section of the irrigant cartridge 24 a while the overall length of the cartridge that fits into the fluid exchange apparatus remains constant. This technique for providing varying fluid cartridge volumes is advantageous when the irrigant and aspirant cartridges are replaceable in a fluid exchange device.
[0071] [0071]FIG. 5A is a revolving cartridge 25 that can rapidly provide a series of irrigant solutions. This revolver-style orientation of irrigant solution is advantageous for delivery of a sequence of different fluids or for delivery of a pharmaceutical composition at an intermediate point during a procedure. In use, the revolving cartridge 25 is oriented such that the series of irrigant fluids 24 b , 24 c , 24 d are positioned in line with the dedicated irrigant reservoir piston 22 to expel the selected irrigant solution placed in line with the piston 22 . Under certain clinical circumstances, the application of the system of the invention may provide an ordinary rinsing solution such as saline at the beginning of a procedure to clear resident fluids and/or emboli from a site, followed by the introduction of a pharmaceutical solution, followed by the removal of the pharmaceutical solution and the subsequent introduction of a neutral solution. In such a use, the saline solution would be confined in the first irrigant reservoir 24 b , which would be infused by actuating the handle 20 as in the embodiment of FIG. 4A described above. Subsequently, the contents of the second irrigant reservoir 24 c , such as a thrombolytic agent, dye, contrast agent or other formulation, is inserted by rotating irrigant reservoir 24 c in line with the irrigant reservoir piston 22 , and similar actuation of trigger 20 . Once the desired effect provided by the solution of reservoir 24 c has been achieved, the solution may be rinsed from the vessel by rotating the dedicated irrigant reservoir 24 d into place and actuating the fluid exchange system as above. Similarly, a variety of aspirant chambers (not shown) can be used to facilitate collection and testing of the aspirant fluid by segregating discrete volumes into containers that can be processed for analysis.
[0072] [0072]FIG. 5B is an embodiment where two different irrigant fluids can be delivered at equal time and measure in a pair of cartridges 243 , 24 f that are designed to be delivered through one or a pair of irrigant lumens 2 , 2 ′ such that one irrigant lumen 2 delivers fluid distal to a predetermined point at the target site and the other irrigant lumen 2 ′ delivers fluid proximal to a predetermined point at the target site. In such a case, each of the two irrigant lumens 2 , 2 ′ has a dedicated irrigant port or ports located at the distal end of the catheter element. The division of the irrigant reservoir 1 into two components 24 e , 24 f allows for the selective introduction of irrigant fluids, which may be the same solutions or different solutions at two or more points within the target site. The predetermined point in the target site that separates the proximal and distal delivery of irrigant fluid may be an aspirant port located therebetween (as in the embodiment of FIG. 2D) or any other structure where separation of irrigant fluid is desired. For example, some irrigants may mix advantageously only at the exchange site and could not be combined outside the body based on their chemical reactivity.
[0073] [0073]FIG. 6 is a tabletop version of the fluid exchange device of the invention. As is described elsewhere herein, the fluid exchange apparatus of the invention may be controlled by the simple mechanical operation of a device by a user or by an electronic system that controls a mechanical or electrical pump- or valve-driven system to control the irrigant 1 and aspirant 4 reservoirs. In the embodiment of FIG. 6, a variable position lever 30 drives the stroke of a dedicated piston 22 , 23 that forces fluid from the irrigant reservoir and draws fluid into the aspirant reservoir. As with the embodiments described above, the cycle and the volume of the reservoirs or motion of the pistons can be altered to match the fluid exchange volume needed for any flow in the vessel or body conduit. Because the rotation of the individual levers is variable, the ratio of fluid exchange can be achieved by different positioning of the lever arms 31 , 32 rather than by altering the volume of the individual irrigant 1 and aspirant 4 reservoirs. Although this embodiment shows the mechanical application of force through levers, a tabletop version of the apparatus of the invention is advantageous when electronically controlled pumps are provided to control the fluid exchange and fluid exchange ratios. The embodiment of FIG. 6 also may include an in-line air trap 33 for the irrigant reservoir 1 and/or a filter 34 for the aspirant reservoir 4 . As it may be advantageous to eliminate debris upon extraction of irrigant fluid and/or prevent air upon entry of irrigant fluid, the inclusion of a filter or trap 33 , 34 for air and/or emboli is appropriate in some cases.
[0074] [0074]FIG. 7A and 7B show the internal structure and function of a fluid exchange device 40 where a pair of reservoirs control fluid flow via the force exerted by pistons or plungers following the action of a trigger 20 and handle 21 connected to or integral with a lever 36 that rotates about a pivot 35 . In this embodiment, the actuation of the trigger 20 rotates the level 36 about pivot 35 and forces the irrigant reservoir piston 22 into the irrigant reservoir 1 and simultaneously withdraws the aspirant reservoir piston 23 out of the aspirant reservoir. From the relaxed position (FIG. 7A), the trigger 20 can be activated to drive the pistons 22 , 23 through either a direct coupling or a mechanism for incremental cycles. If desired, the trigger 20 can return to the relaxed position after a cycle from spring action in the handle or pivot 35 other automatic return mechanism. The reservoirs may be integral to the device 10 or the volume of the reservoir 1 may be attached to a separate reservoir (not shown) together with the appropriate lumens, and preferably in-line one-way valves, to facilitate the exchange between the separate reservoir and the chamber of the device. In the former embodiment, the reservoirs are integral to the handle-operated device such that the piston exerts a direct force on the irrigant 1 and/or aspirant 4 reservoir to exert the force necessary for fluid exchange. In the above embodiment, the internal structure of the device acts as an in-line chamber that is intermediate between the separate reservoir and the lumen such that irrigant fluid residing in a separate reservoir is drawn into the chamber prior to being expelled from the chamber through the irrigation lumen. In this embodiment, a pair of lumens are required, a first intermediate lumen connecting the separate reservoir to the chamber, and a second lumen communicating the irrigant fluid from the chamber through the irrigant lumen and via the irrigant ports to the target exchange site.
[0075] [0075]FIG. 8 is a preferred embodiment of the invention having a trigger 20 that is squeezed by the hand to operate a syringe that acts as the aspirant reservoir 54 and the irrigant reservoir (not shown). As the trigger 20 moves toward the body of the handle 21 , the force is transmitted both to the piston 55 dedicated to the aspirant reservoir 54 and a separate piston (not shown) dedicated to the irrigant reservoir. Although the internal configurations can be varied to incorporate other mechanical expedients, the orientation of the lever 56 and pivot 62 of the present embodiment provide an advantageous mechanism for a 1:1 ratio fluid exchange. The action of trigger 20 is communicated to a lever 56 that is connected to the trigger 20 by a first terminal lever connector 58 a . When the trigger 20 moves toward the body of the handle 21 , the force exerted on the lever 56 rotates the lever 56 around pivot 57 to exert a force, via a second terminal lever connector 58 b that is attached to an irrigant carriage 52 . Simultaneously, the motion of the trigger 20 exerts force on a second lever (not shown) that is connected to the aspirant carriage 51 in a similar matter as for the irrigant carriage 52 . The motion of the trigger 20 provides a simultaneous but opposite force on the aspirant cartridge 51 compared to the irrigant cartridge 52 . The simultaneous forces that are applied to the pistons dedicated to the irrigant reservoir and aspirant reservoir 54 , respectively, occur in opposite directions to yield a substantially equivalent volume exchange into the aspirant reservoir 4 and out of the irrigant reservoir 1 via the aspirant and irrigant lumens 4 , 2 respectively. The motion of the irrigant carriage 52 is translated to the piston dedicated to the irrigant reservoir by virtue of a connector 53 that is noncompressible and that is aligned with the length of the irrigant reservoir 1 .
[0076] As noted specifically with the embodiments described at FIG. 4A herein, the irrigant and aspirant reservoirs 1 , 4 may be interchangeable syringes or cartridges that can be inserted and removed to introduce specific solutions or fluid volumes. In a preferred embodiment, the irrigant and aspirant reservoir 1 , 4 may be molded into the body of the device such that the fluid volumes for the irrigant and aspirant reservoirs are separately filled via a fixture that acts as an input valve to the irrigant and/or aspirant reservoir. The irrigant and aspirant reservoirs 1 , 4 preferably have removable fixtures at the output 60 thereof for attachment of the respective lumens 2 , 3 .
[0077] The motion of the trigger 20 is rendered linear and reproducible by slots 61 cut into a portion of the trigger 20 that are engaged by the first pivot 57 and the second pivot 61 such that the body of the handle 21 and/or the trigger 20 slidingly move about either of the pivot structures. A second lever 63 operates parallel to the lever 56 to enable the trigger 20 to travel smoothly along its path. This configuration provides for reproducible motion of the trigger 20 relative to the body of the housing 21 and also facilitates attachment of a spring 62 that biases the trigger in the forward position so that actuation of the trigger 20 relative to the handle 21 produces a complete cycle that translates into a defined movement of both the irrigant cartridge 52 and the aspirant cartridge 51 . The volume exchange ratio provided by the device of this invention may be altered by changing the relative lengths of the lever 56 relative to the pivot 57 or by altering a ratcheting mechanism disposed at the connection point between the lever 56 and the irrigant cartridge 52 such that a complete cycle of the trigger 20 from the forward most position when moved toward the body of the handle 21 constitutes a complete cycle that moves the irrigant 52 and/or aspirant cartridge by fixed distance. The spring tension automatically returns the trigger 20 to the forward most position to prepare for a second cycle.
[0078] [0078]FIG. 9A is an embodiment where the travel of the lever in the fluid exchange device is adjustable so that the amount of fluid displaced in a single cycle can be controlled, and both the distance traveled and the force generated can be adjusted by relative positions of the trigger 20 and the handle body 21 . The embodiments of FIGS. 9A and 9B illustrate the ability to alter the fluid flow parameters of the fluid exchange device by changing the configuration of the mechanical components that exert force on the irrigant reservoir 1 and aspirant reservoir 4 , respectively. FIG. 9B illustrates the adjustment of the pivot point 57 a to produce different flow ratios and peak pressures based on the relative position of the pivot point 57 a about which the trigger 20 rotates. In such an embodiment, if more fluid flow is desired the apparatus can be easily adjusted to accomplish a variable number of flows for a given grip cycle. The travel distance provided by the motion of the trigger 20 as exerted at the point of attachment by the second terminal lever connector 58 c dictates the amount of fluid flow expelled from the irrigant and/or aspirant reservoir 1 , 4 based on the action by a syringe or aspirant reservoir piston or carriage as described above. Accordingly, an increase in the motion of a piston compressing fluid in an irrigant or aspirant reservoir or chamber, due to changing the pivot point, results in an increased exchange rate for a given activation of the trigger 20 . As is shown in FIGS. 9A and 9B, the adjustment to the degree of travel of the trigger 20 relative to the handle 21 , when combined with aspiration 51 and irrigant 52 carriages and reservoirs as described in, for example FIG. 8 above, produces the variable fluid flow of this embodiment. As with the embodiments described above, the mechanical movement of the trigger 20 relative to the handle 21 is translated into fluid flow from an irrigant reservoir 1 , via irrigation lumen 2 , aspiration lumen 3 , and aspirant reservoir 4 by the configurations described herein.
[0079] [0079]FIG. 10 is a hand-held fluid exchange apparatus of the invention wherein a ratchet mechanism provides for incremental movement of a piston, in this embodiment, a general set of pistons 71 , 71 a for driving fluid out of the irrigant reservoir 1 and into the aspirant reservoir 4 , respectively. As in the embodiment of FIG. 8, the motion of a trigger 20 relative to a body handle 21 completes one cycle. This embodiment may also contain a mechanical or electrical counter that provides a readout indicating the number of cycles that have been performed, the volume of fluid introduced or removed, or the amount of fluid present, or remaining in either reservoir. In this embodiment, the motion of the dedicated, geared piston 71 in the irrigant reservoir 1 is controlled by the ratchet mechanism which is comprised of the trigger 20 , a pivot 70 , about which the trigger 20 rotates, and gear 70 b that engages a first ratchet wheel 77 . Preferably, the ratchet mechanism is one-way such that motion of the trigger 20 toward the body handle 21 rotates the first ratchet wheel 72 that rotates to advance or contract the piston 71 . In the example of FIG. 10, actuation of the trigger 20 about pivot 70 a translates to rotation of the first ratchet wheel 72 via gear 70 b . The rotation of the first ratchet wheel 72 is translated to the geared piston 71 and this rotation is in turn translated to a second ratchet wheel 73 that rotates in the opposite direction to the first ratchet wheel 72 that is in turn connected to a geared piston 71 a in the other reservoir.
[0080] In the embodiment of FIG. 10, the device is designed to be hand-operated such that the manual actuation of the trigger 20 causes automatic motion of the two ratchet wheels 72 , 73 and the geared pistons 71 . The equivalent dimensions of the reservoirs 1 , 4 , pistons 71 , 71 a , and the two ratchet wheels 72 , 73 shown in FIG. 10 yields an approximate 1:1 fluid exchange ratio. In addition to altering the dimensions of the aspirant 4 or irrigant 1 reservoirs, the alteration of the fluid exchange ratio can be achieved by altering the dimensions of the ratchet wheels 72 , 73 .
[0081] [0081]FIG. 11 shows the principles of a fluid exchange device with a segregated irrigant 75 and aspirant chambers 76 each having a dedicated inflow and outflow line. In this embodiment, the inflow line of the irrigation chamber 75 is an irrigation inflow line 2 ′ that communicates fluid held in the irrigation reservoir 1 to the irrigation chamber 75 . The fluid is drawn into irrigation chamber 75 by the dedicated piston 22 and is subsequently expelled through the irrigation lumen 2 into the target site for fluid exchange as described previously. Similarly, fluid is drawn from the target site through the aspiration lumen 3 and into the aspiration chamber 76 by operation of the dedicated piston 23 whose motion both pulls fluid through the aspiration lumen 3 and into the aspiration chamber 76 , but also expels fluid from the aspiration chamber 76 to the aspiration reservoir 3 , via the aspiration reservoir outflow line 3 ′. This embodiment of the invention operates much like a two-stroke engine wherein fluid is pulled into the irrigation 76 and aspiration 75 chambers and. subsequently expelled through the appropriate lumen. To control the flow of fluids, each of the dedicated inflow and outflow lines for each chamber have valves 77 a, b, c, d that control the fluid flow. For example, when fluid is drawn into the irrigation chamber 75 , a valve 77 a on the chamber inflow line 2 ′ is opened while the piston 22 is pulled back. Subsequently, the inflow valve 77 a closes and an outflow valve 77 b that is in line with the irrigation lumen is opened while the irrigation chamber piston 22 is forced into the irrigation chamber 75 to expel fluids through the irrigation lumen 2 . Similarly, when the action of the aspiration chamber piston 23 is used to draw out fluid into the aspiration chamber 70 via aspiration lumen 3 , an inflow valve 77 d on the aspiration chamber inflow line 3 is opened and the in-line valve 77 b in the aspiration chamber outflow line 3 ′ is closed. To expel fluid from the aspiration chamber 76 through the outflow line 3 ′ and into the aspiration reservoir 4 , the in-line valve 77 d on the aspiration lumen 3 is closed and the in-line valve 77 c on the aspiration reservoir outflow line 3 ′ is opened. As for the embodiments described above, the action of the individual pistons 22 and 23 used to cause the fluid flow throughout the system can be controlled manually by mechanical expedients affixed to the pistons. Alternatively, electronic circuitry can control the speed motion and cycle parameters of both pistons such that the fluid flow is electronically controlled according to a user interface or a predetermined fluid exchange profile. As will be apparent to one of skill in the art, the cycling action of this embodiment produces a pulsatile flow with the relative motion of both pistons 22 , 23 . Moreover, the particular minimum and maximum pressures in each pulsatile flow can be controlled by the relative action of the pistons 22 , 23 .
[0082] In another embodiment, the in-line valves are not actively controlled, but are provided as simple one-way valves that only allow fluid inflow from the irrigation 1 reservoir into the irrigation chamber 75 and, likewise only allow fluid outflow from the irrigation chamber 75 through the irrigation lumen 2 . On the aspiration side of the system, one-way valves allow fluid flow only from the aspiration. lumen 3 to the aspiration chamber 76 , and from the chamber 76 to the aspiration reservoir 4 . In use, when the device is activated, the piston plunger in either chamber will produce a positive flow through the lumen. When the lever begins to relax, the one-way valve will close and the irrigation reservoir 1 will fill the chamber. On the aspiration side, one-way valves on both the lumen 3 and the reservoir 4 ensures that the aspirant fluid is purged into the reservoir and, during relaxation, the aspirant is extracted from the exchange site via the aspiration lumen 3 . Actuation of the pistons simultaneously causes simultaneous fluid flow to and from the target site while a ½ cycle out of phase yields a transient pressure increase within the system.
[0083] [0083]FIGS. 12A and 12B show a hand-held fluid exchange apparatus configured as a compressible handball with the internal volume divided into irrigant and aspirant aspirant chambers 78 , 79 in series with dedicated inflow and outflow lines connecting irrigation 1 and aspiration 4 reservoirs, respectively. With a fluid impermeable wall disposed between the irrigant 78 and aspirant 79 chambers, the collapse of the ball under force will circulate the fluids appropriately. Referring to FIG. 12A, the apparatus is divided into an irrigation chamber 78 and an aspiration chamber 79 by a fluid impermeable barrier 80 that completely segregates the two chambers 78 , 79 within the device. The expansion and contraction of the irrigant chamber 78 causes fluid flow through a dedicated inflow line 2 ′ between the irrigation reservoir 1 and the irrigant chamber 78 and out to the target exchange site via the irrigation lumen 2 and terminates at the target site as in the other embodiments described herein. Similarly, aspirant fluid is drawn in through the aspiration lumen 3 into the aspiration chamber 79 and out through the dedicated aspiration chamber outflow line 3 ′ and into the aspiration reservoir 4 . As in the embodiment of FIG. 11, one-way flow valves are advantageously disposed in each inflow and outflow line between the lumen and chamber, and chamber and reservoir. Thus, a one-way flow valve 81 a allows fluid flow only in the direction from the irrigation reservoir, via inflow line 2 ′, into the irrigation chamber 78 . The fluid inside the irrigation chamber 78 may only flow in the direction through one-way valve 81 b and out through the irrigation lumen 2 . Aspiration fluid entering aspiration chamber 79 via aspiration lumen 3 may enter only in the direction through one-way valve 81 c and aspiration fluid inside the aspiration chamber 79 may pass only in the direction of the aspiration reservoir 4 through one-way valve 81 d.
[0084] Referring to FIG. 12B, pressure exerted on the compressible structure of the device, as indicated by the bold arrows in FIG. 12B, compresses both irrigant chamber 78 and aspirant chamber 79 such that fluid flows in the direction of the arrows i.e. irrigant fluid flows through one-way valve 81 b , through irrigation lumen 2 and to the target exchange site. Aspirant fluid flows from the aspiration chamber 79 through the one-way valve 81 d and into the aspiration reservoir 4 . Fluid flow is prevented by one-way valves 81 c and 81 a from entering either the aspiration lumen 3 or the irrigation reservoir 1 . Upon relaxation, the outer surface of the handball moves in a direction opposite to the bold arrows in FIG. 12B and the flow is reversed. Thus, fluid flows from the irrigation reservoir 1 through the one-way valve 81 a and into the irrigation chamber 78 . Likewise, fluid flows from the aspiration lumen 3 , through one-way valve 81 c , and into the aspiration chamber 79 . This configuration is similar to the embodiment of FIG. 11 because a chamber 78 or 79 is provided at an intermediate position between the exchange site and the reservoir such that a volume of fluid is held at an intermediate position between each reservoir 78 , 79 and the exchange site for purposes of exerting control over a discrete volume of fluid separate from the irrigation and aspiration reservoirs 1 , 4 .
[0085] However, the compressible handball configuration can be constructed to allow direct manipulation of the irrigation reservoir 1 to expel fluid while simultaneously collecting aspirant fluid within the discrete structure of the handball itself. FIGS. 13A and 13B show a handball pump configured with an internal reservoir of irrigant and a flexible barrier 82 to separate the irrigant and aspirant reservoirs 1 , 4 , which are disposed inside the handball. Referring to the embodiment of FIG. 13A, prior to connection of this embodiment of the invention to a catheter element, the irrigant reservoir 1 is preferably filled with fluid to substantially encompass the entire internal volume of the handball. The flexible and fluid impermeable barrier 82 deforms towards the outer wall of the handball to accept irrigant solution and to simultaneously minimize the internal volume of the aspirant reservoir 4 . When used in a clinical setting, the irrigant reservoir 1 is filled with the pharmaceutically acceptable composition to be used as the irrigant and the apparatus is sealed and may be sterilized while intact. Before using, the device is connected to the irrigation lumen 2 and aspiration lumen 3 which may be filled with fluid to establish the substantially closed loop as described previously. As in the embodiment of FIG. 12A and 12B, one-way valves 83 a , 83 b are positioned in-line between the irrigant reservoir 1 and the irrigation lumen 2 , and between the aspiration lumen 3 and the aspirant reservoir 4 . As the handball is compressed, fluid flow generally occurs in the area of the arrows to force fluid out of the irrigant reservoir 1 , through the irrigation lumen 2 and into the target site while any backflow is prevented by the one-way valve 83 a . Accordingly, aspiration fluid is drawn through the aspiration lumen 3 and collects in the aspirant reservoir 4 . FIG. 13B shows an embodiment of the invention wherein approximately half of the irrigant solution has been expelled through the irrigation lumen 2 , exchanged at the target site, and collected back in the aspirant reservoir 4 via aspiration lumen 3 . As above, fluid flow generally occurs in the direction of the arrows as the internal irrigant volume is exchanged between the irrigant reservoir 1 and the aspirant reservoir 4 .
[0086] As noted above, the principal of the invention may be achieved by both user operated, generally mechanically controlled embodiments of the invention, or through electronically controlled apparatus that usually require electronically controlled pumps and/or valves. In the embodiment of FIG. 13C, a volume metric pump 86 with an internal balloon 85 is provided to achieve the fluid exchange function of the invention. Generally, the device is comprised of a housing 84 that is preferably substantially rigid and which contains an internal irrigant reservoir 1 and aspirant reservoir 4 connected to dedicated irrigation and aspiration lumens 2 , 3 , as described previously. Volumetric control is achieved by selectively expanding an internal balloon 85 within the housing 84 to be positioned in either the irrigant reservoir 1 or aspiration reservoir 4 . As with the embodiments of FIG. 13A and 13B, at a preliminary point in the use of the device the irrigant reservoir 1 is generally full and the internal volume balloon 85 is confined in the aspirant reservoir such that the internal volume of the balloon 85 is maximized within the aspiration reservoir 4 and does not displace a substantial volume of the irrigant reservoir 1 . This allows the maximum amount of irrigation fluid to exist within the irrigant reservoir 1 prior to use of the device. As the fluid exchange process occurs, the volumetric pump 86 functions by forcing a portion of the internal volume of the balloon 85 into the irrigant reservoir 1 . The volumetric pump 86 may be controlled by the user or through an electrical circuitry that provides an output reading to dictate the volumes or relative percentage volumes between the reservoirs 1 , 4 . As the volume exchange process continues, the internal volume of the balloon 85 is transferred to a greater and greater degree from the aspirant reservoir 4 to the irrigant reservoir 1 to displace the internal volume of the irrigation fluid. At a half-way point, the internal volume of the balloon is equally disposed between the two reservoirs (assuming that the beginning volume of the two reservoirs is equal) and the volumes of the fluid contained in both the irrigant 1 and aspirant 4 reservoirs is equal. As described previously, a simple modification of the dimensions of the apparatus allow variation of the volume exchange ratio from a 1:1 value to any prescribed ratio dictated by the clinical circumstances.
[0087] [0087]FIG. 14 shows a side view of the device where the irrigation 90 and aspiration 91 fluid impermeable chambers are contained in the same, preferably rigid housing 92 and are separated by a centrally disposed piston 93 that engages the interior of the housing 92 about the entire periphery thereof to segregate the irrigant fluid from the aspirant fluid and allows the piston 93 to slide within the housing 92 . By moving the piston 93 within the interior of the housing, typically from one extreme end to another, the irrigant is forced out of the irrigant chamber 90 and into the irrigation lumen 2 . Fluid exchanged at the target site is collected through the aspiration lumens and into the aspirant chamber 91 . Thus, in the example of FIG. 14, when the piston 93 slides from one end to the other, the irrigant chamber 90 expels irrigant, while the aspirant chamber 91 simultaneously draws in aspirant fluid. Then, as the piston 93 is moved back in the other direction, the irrigant chamber 91 refills itself with fluid from the irrigant reservoir 1 while the aspirant chamber 91 expels its contents into the aspiration reservoir 4 . As in other embodiments described herein, this simple, compact arrangement allows for simultaneous irrigation and aspiration and yield a pulsatile flow. Although shown as a cylindrical housing 92 , the construction and arrangement of the input, output, reservoir and piston elements could be altered without departing from the spirit of the invention. In the embodiment of FIG. 14, the piston is designed to move repeatedly and reproducibly within the housing to expel and collect a defined volume of fluid with each operation cycle.
[0088] The volume of fluid exchanged at the target site with each cycle of the piston 93 is substantially equivalent to the internal volume of the housing 92 assuming that the piston 93 is moved from one extreme to another extreme inside the housing 92 during each cycle of the operation of the device. This embodiment also demonstrates, as in the foregoing embodiments, that the fluid exchange device of the invention is readily adapted to be controlled either manually, in this case through the application of force to a handle 94 attached to the piston 93 , or by electronic control, which in this embodiment would be provided by a simple pump or electrical or magnetic force to move the piston 91 within the housing 92 . The separation of the irrigant and aspirant reservoirs 1 , 4 from an irrigant and aspirant chamber 90 , 91 permits the device to be repeatedly cycled to draw a defined volume into each chamber 90 , 91 for propulsion through the irrigation lumen 2 and collection through the aspiration lumen 3 . In an alternate embodiment, the entirety of the irrigant fluid to be exchanged at the target site would begin contained within an aspirant reservoir that is entirely located within the housing such that movement of the piston 91 from one extreme of the housing 92 to the other would communicate the entire volume of the irrigant reservoir 1 through the irrigation lumen 2 , to the target exchange site, and back into the aspirant reservoir 4 via the aspiration lumen 3 . A further example of this embodiment is shown in FIG. 15 below, having an alternate mechanical expedient for propelling fluid from the irrigant reservoir 1 into an aspirant reservoir 4 .
[0089] In the embodiment of FIG. 15, the irrigant and aspirant reservoirs 1 , 4 are separated by a fluid impermeable barrier 95 that is movable about a threaded axis 97 or other structure that passes within a slidable member 96 that rotates and slides about the threaded axis 97 to move the barrier 95 along the axis 97 to propel the irrigant fluid. Ideally, the slidable member 96 provide for a high rate of translation, while the member 97 provides for fine travel about the threaded axis 97 . The sliding element can be selectively disengaged from the threads to allow it to slide rapidly along the threaded axis for gross adjustment. When engaged, the sliding element can be rotated for fine adjustment. Interior to the sliding element is a mechanism which permits this selective thread engagement by retracting the thread contact when activated.
[0090] Referring to FIG. 15, this embodiment of the fluid exchange device is comprised of two main elements to achieve a configuration that allows for the body or cylinder actuation of both syringes in the desired and opposite manner. Essentially, a unitary body 101 connects of one syringe element 102 a and is connected rigidly to the piston 103 b of the other syringe element. A slidable element 104 engages the unitary body 101 and slides reproducibly in engagement therewith. As shown in FIG. 16, the slidable element 104 is also attached to the cylinder 103 a of one syringe and the piston 102 b of the other. Motion of the slidable element 104 exerts a force withdrawing one piston while advancing the other and braces the application of force by the attachment of the body 101 or element 104 to the cylinder or body of each syringe 102 a , 103 a . The design could incorporate existing syringes or have the syringe elements molded into the piece. There are several distinct advantages to this embodiment. One is that it ensures a 1:1 exchange ratio in terms of travel distance between the syringes. Another is that the geometric arrangement allows for a balancing of the forces involved in the device. Finally, the realization of the complex mechanics through just two moving parts is a significant advantage for the manufacturing and efficiency of the device.
[0091] As described above, the element of turbulence is important to the efficacy of the device. Since fluids tend to assimilate to laminar flow, proximity of the irrigant ports or perforations that facilitates turbulence is important for optimal rinsing of the interior of a body structure. For this reason, translation of the catheter element may accompany the irrigation or aspiration or both. All embodiments described herein can be manually translated by means of the operator's hand. Additionally, the catheter can be translated using an automated translation system similar to those used in IVUS and similar applications. Alternatively, the catheter could be translated by an element incorporated into the fluid delivery device. Referring to FIG. 17A a simple mechanism that could be used to realize this self-advancing aspect. When the catheter 7 element is moved to the left in the direction of the arrows in FIG. 17A, the round engaging element 110 slides up in the slot 111 and engages the catheter 7 to move it to the left as well.
[0092] [0092]FIG. 17B shows the same mechanism. Once the catheter element 7 is slid to the right the round engaging element 110 slides down in the slot 11 and allows the catheter element 7 to slide freely to the right in the direction of the arrow without interacting or affecting the catheter's position. This allows for the selective retraction or advancement of the catheter 7 by a predetermined amount with each squeeze of the device. There are many ways in which this element could be realized. The simplest would be an apparatus that selectively grasps the catheter when moving one direction and idles or does not grasp when moving in the opposite direction. A guiding track that biases the element could be used to apply pressure and grasp the catheter moving in one direction and then release and allow idle sliding to the reset position in the other direction. This element could be selectively engaged by the operator when needed, and could be developed to allow for selection between advancement and retraction of the catheter.
[0093] In the present preferred embodiment of the fluid exchange device, it is necessary to have a reset force supplied by an element such as a spring inherent in the device. This reset force is added to the resistance in the system that must be overcome by the operator to utilize the device. In some cases, an embodiment where this force was minimized or eliminated would allow more of the force generated by the operator to be directed to the work the device is performing and not to overcoming the reset force element. Referring to FIGS. 18A-18C, this function could be achieved through the use of a staged device. FIG. 18A shows a simple mechanical way in which the two sides of the device could be linked mechanically. It is important in this embodiment that the two sides be linked mechanically so that they behave in an equal and opposite manner. This is necessary so that the trigger can be actuated repeatedly in the same manner but engage just one of the sides while still driving the entire system. This allows the benefit of having the operator not realize the changes occurring internally in the device. The squeezes would not feel substantially different. In this embodiment, the first squeeze would activate the two chambers and the second squeeze would reset the two chambers. A simple mechanical setup could achieve this result. Similar mechanisms are commonly used in objects such as retractable ball point pens. Essentially, an element attached to the trigger element would be slightly biased to selectively engage one side or the other of the device. FIG. 18B shows a top view of the track layout that would guide the selectively engaging element of the trigger. With the two sides linked mechanically to travel in equivalent and opposite manners as described elsewhere, the force of the trigger element could always be applied in the same manner with varying effect. With the aid of the minimal return force element, the trigger is brought back to its full and extended position and biased to one side so that it will slip into the opposite track for the next actuation of the trigger. After that actuation, as the trigger is returning to its default position, it will be biased to one side of the device and slip easily into the track of the opposite side.
[0094] [0094]FIG. 18C is a diagram of how the system could be achieved such that each time the trigger is expanded, it engages the other side of the device and pulls it back when squeezed.
[0095] Many features have been listed with particular configurations, options, and embodiments. Any one or more of the features described may be added to or combined with any of the other embodiments or other standard devices to create alternate combinations and embodiments. Although the examples given include many specificities, they are intended as illustrative of only a few possible embodiments of the invention. Other embodiments and modifications will, no doubt, occur to those skilled in the art. Thus, the examples given should only be interpreted as illustrations of some of the preferred embodiments of the invention.
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CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] (NOT APPLICABLE)
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] (NOT APPLICABLE)
BACKGROUND OF THE INVENTION
[0003] The invention relates to a support surface suitable for use with a stretcher and, more particularly, to a support surface that provides patient pressure redistribution by incorporating multiple pads of independent zonal pressure support.
[0004] Conventionally, stretchers are used without pads or may include a single padded layer for increased patient comfort. Such a padded layer, however, provides only minimal support particularly in the patient's higher pressure areas such as the head or heels.
[0005] Additionally, due to the construction of the pad layer, pressure in one area of the pad necessarily causes tension in another area of the pad, for example, when a more pointed body part such as the patient's head or heels is supported by the pad, the pad beneath the patient's head or heels is deflected, thereby also deflecting adjacent areas. This pressure distribution renders the stretcher less comfortable and may actually unintentionally aggravate a wound or injury.
BRIEF SUMMARY OF THE INVENTION
[0006] It would thus be desirable for a stretcher support surface or pad that is constructed to accommodate body areas that require less or more support. Additionally, it would be desirable to provide such a support surface that provides excellent patient pressure redistribution while preventing pressure on one area of the pad to be transferred to an adjacent area of the pad.
[0007] In an exemplary embodiment, a support surface suitable for use with a stretcher includes a base layer and a plurality of foam support zones supported by the base layer. The foam support zones include a head section, a body section, and a foot section separated by a plurality of lateral channels. Densities of the foam support zones vary by section. The lateral channels may extend through the plurality of support zones to the base layer. In one arrangement, the body section includes an upper body section, a middle body section, and a lower body section, where densities of the foam support zones in the upper, middle and lower body sections vary by section. In another arrangement, the foam support zones further include a longitudinal channel dividing the head, body and foot sections into left side and right side head, body and foot sections. Preferably, the longitudinal channel extends through the plurality of support zones to the base layer.
[0008] The density of the head section is preferably lower than the density of the body section, and the density of the foot section is preferably lower than the density of the body section. Moreover, the density of the foot section is preferably lower than the density of the head section.
[0009] The foot section slopes downward, preferably in an arc, from the body section.
[0010] The support surface may additionally include a top layer disposed over the plurality of foam support zones. In this context, the top layer is formed of a visco-elastic foam material.
[0011] In one arrangement, the head section includes a foam block having a lateral slot therein parallel to the lateral channels separating the head section, the body section, and the foot section. The body section may comprise a plurality of foam blocks separated by body lateral channels parallel to the lateral channels separating the head section, the body section, and the foot section. The foot section may comprise a foam block having at least one lateral slot therein parallel to the lateral channels separating the head section, the body section, and the foot section.
[0012] In another exemplary embodiment, a support surface suitable for use with a stretcher includes multiple foam pads of independent zonal pressure support such that a transfer of force by pressure on one foam pad to an adjacent foam pad is limited.
[0013] In yet another exemplary embodiment, a stretcher pad includes a foam base layer, a middle layer, and a foam top layer. The middle layer has a plurality of foam pads defining independent support zones of varying densities. The plurality of foam pads are separated by a plurality of channels such that a transfer of force by pressure on one foam pad to an adjacent foam pad is limited.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] These and other aspects and advantages will be described in detail with reference to the accompanying drawings, in which:
[0015] FIG. 1 is a first perspective view of the support surface described herein; and
[0016] FIG. 2 is an alternative perspective view.
DETAILED DESCRIPTION OF THE INVENTION
[0017] With reference to FIGS. 1 and 2 , a support surface or pad 10 suitable for use with a stretcher is constructed of a plurality of foam layers. A base layer 12 is preferably formed of HR (high resiliency) foam (e.g., 1″ thick) for substantial deep support. An open cell foam middle layer 14 is supported on the base layer 12 , and a top layer 15 preferably formed of a visco-elastic foam material (so called “memory foam”) may be disposed over the middle layer 14 .
[0018] The middle layer 14 includes a plurality of foam pads that define independent support zones of varying densities. As shown, the plurality of pads define a head section 16 , a body section 18 , and a foot section 20 separated by a plurality of lateral channels 22 . In a preferred arrangement, the lateral channels 22 extend through the respective sections or “foam support zones” 16 , 18 , 20 to the base layer 12 . The foam support zones 16 , 18 , 20 may additionally include a longitudinal channel 24 dividing the head 16 , body 18 , and foot 20 sections into left and right side head, body and foot sections as shown. The longitudinal channel preferably also extends through the support zones 16 , 18 , 20 to the base layer 12 .
[0019] In a preferred construction, densities of the foam support zones vary by section 16 , 18 , 20 . That is, the density of the head section 16 is preferably lower than the density of the body section 18 , and the density of the foot section 20 is also preferably lower than the density of the body section 18 . Moreover, the density of the foot section 20 is preferably lower than the density of the head section 16 . The head 16 and foot 20 sections are generally softer than the body section 18 since the head and heels exert a higher pressure on the support surface 10 .
[0020] With continued reference to FIG. 1 , the body section 18 includes an upper body section 18 a, a middle body section 18 b and a lower body section 18 c. Densities of the foam support zones in the upper 18 a, middle 18 b and lower 18 c body section preferably also vary by section. The variances in the zones/sections of the stretcher have been specified in an attempt to manage the anatomic characteristics of the average human body. An example would be that generally the sacral and scapulae carry the bulk of the weight in a back lie orientation. These areas therefore require a stackup that reacts(supports the body) quicker than the upper thigh for instances which can be allowed to sink deeper before the real support layers begin to hold the body more substantially.
[0021] As shown, the head section 16 is formed of a foam block 26 having a lateral slot 28 parallel to the lateral channels 22 . The lateral slot 28 in the foam block 26 of the head section 16 preferably extends about halfway into the foam block 26 . The foam block 26 is preferably formed of a soft foam treated with tighter shallower cuts to create initial very soft immersion. That is, when cuts are made into the top of a foam block, the surface between the cuts collapse easier than the same type of foam without the cuts. Additionally, the amount of space between the cuts contributes to the overall softness/firmness of that particular area. Deeper closer cuts are softer than shallow widely spaced cuts.
[0022] The body section 18 includes a plurality of foam blocks 30 (six shown in FIGS. 1 and 2 , preferably about 3″ thick progressively supportive foam pads) separated by body lateral channels 22 ′ parallel to the lateral channels 22 separating the head section 16 , the body section 18 and the foot section 20 . The foot section 20 is constructed of a foam block 32 having at least one lateral slot 34 therein parallel to the lateral channels 22 . As shown in FIGS. 1 and 2 , the foam block 32 of the foot section 20 is provided with two lateral slots 34 . The lateral slots 34 are shown in a keyhole shape to facilitate a downward orientation of the foot section 20 relative to the body section 18 . That is, the foot section 20 preferably slopes downward in an arc from the body section 18 . The downward slope serves to shift heel pressure toward the patient's calves, resulting in increased comfort. Additionally, the lateral slots 34 serve to better distribute pressure in the patient foot area. The foot section 20 foam allows excellent immersion.
[0023] The assembly may additionally include a top cover formed of a suitable material such as 4-way stretch polycarbonate and a bottom cover formed of a suitable material such as non-slip vinyl (not shown) surrounding the support surface.
[0024] In use, the lateral channels 22 , 22 ′ and lateral slots 28 , 34 along with the longitudinal channel 24 serve to break tension through the supportive layers and create independent/separate progressively supportive pressure displacement areas across the entire length and width of the support surface 10 . The foam support zones address load requirements (firmness and support characteristics) to localized areas of the pad 10 . The top layer 15 provides an excellent interface and relaxed continuity to the underlying support pads. The base layer 12 provides a firm foundation of support and continuity to the pad. The channels and slots additionally provide for better air circulation within the pad, resulting in a cooler and more comfortable surface.
[0025] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiments, it is to be understood that the invention is not to be limited to the disclosed embodiments, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
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CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. Provisional Application Ser. No. 60/238,771, filed Oct. 6, 2000 (the entire contents of which are fully incorporated herein by reference).
BACKGROUND
Urinary incontinence, or the inability to control urination, is a major and debilitating problem affecting millions of people, especially women. The female's natural support system for the urethra is a hammock-like supportive layer composed of endopelvic fascia, the anterior vaginal wall, and a distal attachment to the pubic bone. Weakening and elongation of the pubourethral ligaments and the arcus tendineus fascia pelvis, weakening of the endopelvic fascia and pubourethral prolapse of the anterior vaginal wall are some common characteristics of a patient with urinary incontinence.
Many procedures have been devised to treat urinary incontinence. Some have the goal of elevating the neck of the bladder to return it to a higher retropubic position. Many pubovaginal sling procedures have been developed to treat urinary incontinence. Some of these procedures involve positioning anatomical sling material under the urethra to provide elevation and support of the urethra and/or the bladder neck. Examples of attachment sites for the sling include the anterior or superior portion of the pubis (e.g. with bone anchors and associated sutures), Cooper's ligament, or rectus abdominus fascia. Examples of procedures for treating incontinence are disclosed in U.S. Pat. Nos. 5,112,344; 5,611,515; 5,842,478; 5,860,425; 5,899,909; 6,039,686, 6,042,534 and 6,110,101.
Slings used for pubovaginal procedures differ in the type of implantable material and anchoring methods. In some cases, the sling is placed under the bladder neck and secured via suspension sutures to a point of attachment (e.g. bone) through an abdominal and/or vaginal incision.
Complications associated with procedures for treating incontinence include urinary retention, bladder instability and erosion of an implanted article into surrounding tissue. See Spencer et al, A Comparison of Endoscopic Suspension of the Vesical Neck With Suprapubic Vesicourethropexy for Treatment of Stress Urinary Incontinence, J. Urol. 137: 411, (1987); Araki et al, The Loop Loosening Procedure for Urination Difficulties After Stamey Suspension of the Vesical Neck, J. Urol., 144; (1990); and Webster et al., Voiding Dysfunction Following Cystourethropexy: Its Evaluation and Management, J. Urol., 144; (1990).
With respect to sling procedures, if the sling mesh is too loosely associated with its intended physiological environment, the mesh may be ineffective in supporting the urethra and treating incontinence. Several complications can arise from a mesh that is too tightly placed including retention, sling erosion and other damage to surrounding tissue such as the urethra and vagina.
The TVT Tension-free Vaginal Tape procedure utilizes a knitted Prolene™ nonabsorbable, polypropylene mesh. The mesh is a substantially flat, rectangular woven article. The mesh includes a plurality of holes that are sized to allow tissue ingrowth to help avoid infection. A removable plastic sheath surrounds the mesh and is used during insertion of the mesh. The sling is positioned near the urethra without the use of bone anchors. Once the sheath is removed from the mesh of the TVT product, friction between the mesh and tissue keeps the mesh in position and it becomes very difficult to subsequently adjust the position of the mesh relative to tissue. Attempts to move the sling once the sheath is removed may damage the sling or adjacent tissue such as the urethra or vagina.
Proper tension of a sling is an important factor for a successful surgical procedure. Surgical approaches to applying tension or slack in a sling procedure vary widely. See Decter, Use of the Fascial Sling for Neurogenic Incontinence: Lessons Learned, The Journal of Urology, Vol. 150, 683-686 (1993). While the TVT procedure suggests using a scissors or hemostat placed between the sling and urethra to set the looseness of the TVT mesh sling, a flat blunt surgical instrument is placed between the sling and urethra in other procedures. See Moir et al., The Gauze - Hammock Operation, The Journal of Obstetrics and Gynaecology of the British Commonwealth, Vol. 75, No. 1 (January 1968) Pps. 1-9.
The TVT sling procedure instructs users to place a scissors or hemostat between the urethra and the sling to ensure ample looseness of the sling. There are several problems associated with this approach. First, the type of scissors or hemostat used to tension the sling may differ in size, potentially causing application of different amounts of looseness for the sling. For example, one surgeon may use a Mayo scissors while another surgeon may use a hemostat or flat, blunt instrument. It is believed that the use of different instruments with different sizes inherently leads to inconsistency in the amount of slack or looseness provided in a sling. This inconsistency could lead to inconsistent therapeutic results, misleading medical data and other clinical errors. Second, even if the same surgical instrument is used, the precise portion of the surgical instrument used to set the looseness of the sling may vary along the length instrument. For example, some surgeons use the tips of closed Mayo scissors to tension a sling. Mayo scissors are curved and the precise thickness of a scissors along its length varies significantly. See FIG. 5 of Rackley et al., Tension - free Vaginal Tape and Percutaneous Vaginal Tape Sling Procedures, Techniques in Urology, Vol. 7, No. 2, pp. 90-100 (2001). Depending upon how far the Mayo scissors tips are inserted between the sling and the urethra, the actual amount of looseness provided can vary significantly.
Other prior art sling procedures use bone anchors or other methods of securing a sling. A difficulty that contributes to the unnatural positioning of the urethra is that some attachment sites, such as the rectus abdominus fascia or the top of the pubic bone, require very long sutures. Long sutures increase the difficulty in achieving the proper tension in the sutures and sling and increase the chances that intervening anatomical structures may interfere with proper tension. Improper sling tension or sling suture tension can result in increased lateral movement and momentum of the support structures or mesh sling when they are moved due to intra-abdominal pressures.
U.S. Pat. No. 5,863,315 discloses a method of tensioning a suspended tissue mass. The method utilizes a suture tensioner comprising a handle, a main body and an annular recess.
More than a year prior to the filing date of the present application, Vesica Sling Kits were sold (by Boston Scientific, Microvasive, USA) in the United States that included a Suture Spacer. Surgeons were instructed to place the Suture Spacer on the top of the pubic tubercle (which is a location remote from the sling and remote from the urethra, vagina and bladder neck). The surgeon then places a suture about the Suture Spacer and ties a knot. As a knot is tied, the Suture Spacer is pulled downward onto the top of the pubic bone. Six or seven additional throws are tied and the Suture Spacer is withdrawn.
U.S. Pat. No. 5,474,518 discloses a device for correcting urinary incontinence by use of vesical suspension. The device includes a box that houses a drum with a toothed wheel that engages a worm gear.
U.S. Pat. Nos. 4,938,760 and 4,969,892 disclose a method of suspending the urethrovesical junction in females. An anchoring means for anchoring a suture in tissue is disclosed. The anchoring means comprises a rotating spool, a driving gear and an adjusting means.
PCT International Pub. No. WO 01/39670 discloses an implantable support sheet for providing suburethral stabilization for female patients. A clip is disclosed that inhibits folding of a central part of the sheet about its longitudinal axis.
U.S. Pat. No. 6,106,545 discloses a suture tensioning and fixation device for attachment of tendon to muscle or reattachment of ligaments to bone. The device includes a retaining element and suture thread engaging portions.
U.S. Pat. No. 6,117,067 discloses a device for the height-adjustable fixing and support of internal organs. The device includes a sling, threads, tube, small capsule and chamber. A needle is used to introduce or extract liquid.
U.S. Pat. No. 6,068,591 discloses an apparatus for treatment of female stress urinary incontinence with a support harness. The patent discloses an adjustable setting and Carter pin.
BRIEF SUMMARY
The present invention is directed to an article useful in surgical procedures. The article assists surgeons in providing consistent, repeatable relationships between implantable materials such as slings, and target tissue such as urethra tissue. In use with a plurality of different surgeons and a plurality of different patients, the present invention can contribute to consistent, repeatable medical results, more reliable medical data and improved medical decisions.
The article comprises a portion adapted to be grasped, and at least one tensioning member that is sized and shaped to afford predetermined looseness of an anatomical support material, such as a sling, relative to anatomical tissue, such as a urethra.
A variety of procedures are contemplated, including, for example, pubovaginal sling procedures. The present invention is particularly suitable for use in a sling procedure that places a sling in a therapeutically effective position. Preferably, the sling is placed to control the pressure applied to the urethra to obtain or restore normal anatomy and continence.
In a preferred embodiment, the article comprises a plurality of tensioning members. In one embodiment the article includes movement means for moving at least one tensioning member between an open position for receiving the anatomical support material and a closed position that associates the article with the anatomical support material. Preferably, the movement means comprises means for affording substantial parallel movement between tensioning members to resist wrinkling of the anatomical support material.
In another preferred embodiment, the plurality of tensioning members are arranged to afford a plurality of tortuous paths of different lengths, and the anatomical support material may be associated with the article along one of the tortuous paths.
In another embodiment, the article includes means for moving at least one of the tensioning members relative to another tensioning member to change the length of a tortuous path.
In another aspect, the present invention comprises a device for applying tension to a surgical sling.
In another aspect, the invention comprises a tensioning device comprises a base member having a plurality of tensioning members extending outwardly from the base member, thereby creating a tortuous pathway for sling material positioned thereon. When the sling material is used in a pubovaginal sling procedure, the tensioning device provides additional tensioning support to the urethral body, the bladder neck, or both.
The tensioning device of the present invention may have a number of different configurations. For example, in one embodiment, the base member is arcuate. In an alternate embodiment, the base member is rectangular. Additionally, the base member may include a directional indicator to aid the user in applying the device. In yet another embodiment, the base member may include an integral or detachable grasping member. The base member may further include at least one sling material locking member having an open position which allows removal of the sling material from the device, and a closed position to the retain sling material within the device.
The tensioning members of the present invention may comprise a plurality of configurations, including circular members, oval members, or other shaped members capable of retaining material disposed therein. Similarly, the tensioning members may be manufactured from a plurality of materials including, without limitation, silicone elastomer, acetate, acetal polyurethane, acrylic, elastomer, stainless steel, polysulfone, nylon, polycarbonate, polyethermide, acetal, ABS, bioresorbable materials or other biologically-compatible materials for temporary or permanent implantation.
In another form, the device remains implanted and can be adjusted in the subsequent post operative period by removing all or some of the tensioning members or by constructing the tensioning members of a bioresorbable material.
Additionally, the tensioning members may be constructed so that they indicate the preload on the sling through a deflection or alignment of the tensioning members.
The present invention may further include various methods of using the tensioning device for creating and using a tortuous pathway to apply tensioning force to a material disposed therein.
In another aspect, the present invention comprises a method of providing a uniform distance between the urethra and a sling comprising: providing a sling and tensioning article, associating the tensioning article with the sling, implanting the sling and associated tensioning article in a position substantially adjacent or, alternatively, just touching the urethra, and then removing the tensioning article. Optionally, the step of providing a sling and tensioning article includes the step of providing an insertion sheath surrounding the sling; and the step of associating the tensioning article with the sling includes the step of associating the sling and sheath combination with the tensioning article.
In another aspect, the present invention comprises a method of treating incontinence comprising the steps of: (i) providing a support material with at least a portion that is elastically deformable, (ii) elastically deforming at least a portion of the support material to tension the support material; (iii) providing a tensioning article, (iv) applying the tensioning article to the tensioned support material to retain at least a portion of the support material in an elastically deformed condition; (v) implanting the support material with applied tensioning article in a patient; removing the tensioning article to increase the tension provided by the support material.
In another method, the present invention comprises a method of reducing the looseness of an implanted sling comprising the steps of: providing a tensioning article, and associating the tensioning article with the sling in vivo to tighten the sling.
In another method, the tensioning member remains implanted and provides an elastic stress relieving component to the sling in the immediate or long term post operative period. This is particularly useful when the sling is made of an elastic material such as a silicone elastomer.
In another aspect, the present invention comprises a kit for treating incontinence. The kit comprises surgical articles for implanting a surgical sling, and a tensioning article.
Other features and advantages of the present invention will become apparent from a consideration of the following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
Other features and advantages of the present invention will be seen as the following description of particular embodiments progresses in conjunction with the drawings, in which:
FIG. 1 shows a perspective view of an embodiment of tensioning device of the present invention;
FIG. 2 a is a perspective view of the tensioning device of FIG. 1 engaging sling material positioned thereon;
FIG. 2 b is a perspective view of an alternate embodiment of the tensioning device of the present invention engaging sling material positioned therein;
FIG. 3 shows a perspective view of an embodiment of tensioning device of the present invention having an orientation indicator positioned thereon;
FIG. 4 a shows a perspective view of another embodiment of tensioning device of the present invention having a grasping structure disposed on the base member;
FIG. 4 b shows a perspective view of an alternate embodiment of the tensioning device of the present invention having a grasping member disposing a directional indicator thereon positioned on the base member;
FIG. 5 a shows a perspective view of another embodiment of tensioning device of the present invention having a locking member positioned thereon;
FIG. 5 b shows a perspective view of an alternate embodiment of the tensioning device of the present invention having another embodiment of locking member positioned thereon;
FIG. 6 shows a perspective view of an alternate embodiment of the tension device of the present invention wherein at least one tensioning member is oval;
FIG. 7 is another embodiment of tensioning device according to the present invention that includes a securement member;
FIGS. 8 a - 8 d are views of an alternative embodiment of the present invention wherein:
FIG. 8 a shows an end view of an alternative embodiment of tensioning device shown in a closed position;
FIG. 8 b shows a side view of the device of FIG. 8 a;
FIG. 8 c is an end view of the device of FIG. 8 a shown in an open position;
FIG. 8 d is a side view of the device of FIG. 8 c;
FIGS. 9 a - 9 d are views of an alternative embodiment of the present invention wherein:
FIG. 9 a shows an end view of an alternative embodiment of tensioning device shown in a closed position;
FIG. 9 b shows a side view of the device of FIG. 9 a;
FIG. 9 c is an end view of the device of FIG. 9 a shown in an open position;
FIG. 9 d is a side view of the device of FIG. 9 c;
FIGS. 10 a - 10 d are views of an alternative embodiment of the present invention wherein:
FIG. 10 a shows an end view of an alternative embodiment of tensioning device shown in an open position;
FIG. 10 b shows a side view of the device of FIG. 10 a;
FIG. 10 c is an end view of the device of FIG. 10 a shown in a closed position;
FIG. 10 d is a side view of the device of FIG. 10 c;
FIG. 11 a is an end view of another embodiment of tensioning article and sling according to the present invention with tensioning indicia located thereon, which tensioning article is shown in an open position;
FIG. 11 b illustrates the assembly of FIG. 11 a in a closed position;
FIG. 12 is a perspective view of another embodiment according to the present invention which embodiment includes an adjustment feature;
FIG. 13 is a perspective view of another embodiment of tensioning device according to the present invention;
FIG. 14 is an end view of the article of FIG. 13 with a sling threaded through the article in a first orientation;
FIG. 15 is another end view of the article of FIG. 13 with a sling threaded through the article in a second orientation;
FIG. 16 a is a side view of another embodiment of surgical article according to the present invention;
FIG. 16 b is an end view of the article of FIG. 16;
FIG. 17 a is a side view of another embodiment of tensioning device according to the present invention;
FIG. 17 b is a side view of the tensioning device of FIG. 17 a with a sling inserted therebetween;
FIG. 18 a is a side view of another embodiment of tensioning device according to the present invention shown in a closed position;
FIG. 18 b is a side view of another embodiment of tensioning device according to the present invention shown in an open position;
FIG. 18 c is a view of the tensioning device of FIGS. 18 a and 18 b with a sling placed therein;
FIG. 19 is a flow chart showing a surgical procedure according to the present invention;
FIG. 20 is a schematic view of a tensioning article, sling and selected portions of the anatomy of a patient, which view illustrates removal of the tensioning article after it sets sling tension;
FIG. 21 is a schematic view of a tensioning article, sling and selected portions of the anatomy of a patient, which view illustrates implantation of the tensioning article to increase the tension of the sling;
FIG. 22 is a flowchart showing an example of a method according to the present invention; and
FIG. 23 is a perspective view of an embodiment of a removable sheath according to the present invention.
DETAILED DESCRIPTION
The present invention comprises an article, preferably a tension control article, for use in conjunction with an implantable article such as a sling. In a preferred embodiment, the tension control article is utilized in conjunction with a sling for treating urinary incontinence. The tension control article may be used in conjunction with a wide variety of slings and other surgical procedures. For example, the present invention may be utilized in conjunction with the slings and procedures described in U.S. Pat. Nos. 5,520,700; 5,611,515; 5,842,478; 5,860,425; 5,972,000; 6,039,686, 6,042,534 and 6,110,101 (the entire contents of which are herein incorporated by reference in their entirety) and U.S. patent application Ser. No. 09/917,562 (entitled: Implantable Article and Method) and Ser. No. 09/917,443 (entitled: Sling Delivery System and Method of Use); and Ser. No. 09/917,445 (entitled: Surgical Instrument and Method); both filed Jul. 27, 2001 (the entire contents of each of which are herein incorporated by reference. Commercial examples of slings, instructions for use and kits that may be modified to incorporate the present invention include the In-Fast Sling System and the SPARC Sling System available from American Medical Systems of Minnetonka, Minn., and the transvaginal TVT Sling System available from Ethicon (a division of Johnson & Johnson).
Preferably, the tension control article is associated with an implantable material (e.g. a sling). Suitable implantable materials associated with the present invention include synthetic and non-synthetic materials. Suitable non-synthetic implantable materials include human fascia lata, treated animal (e.g. bovine or porcine or equine pericardium) tissue, autologous tissue, cadaver tissue, homografts, xenografts, heterografts, allografts and combinations of such materials. Suitable synthetic materials include knitted polypropylene slings alone, such slings with surrounding sheaths, or silicone coated polymer slings, such as those described in U.S. patent application Ser. No. 09/939,098 (entitled Coated Sling Material), filed Aug. 4, 2001 (the entire contents of which are herein incorporated by reference). Alternatively, the tension control article may be associated with sutures associated with slings. Such sutures typically extend from an implanted bone anchor on the pubic bone, or from the rectus abdominus fascia. These sutures hold the sling in place in the body.
The present invention may also be used in conjunction with surgical procedures other than those designed to strictly address incontinence. For example, the present invention may be used in conjunction with a sacral colpopexy procedure designed to treat vaginal prolapse.
The tension control article of the present invention, when used with transvaginal or suprapubic surgical anatomical support material (e.g. a sling) or sutures, is designed to provide an adjustable tensioning or spacing mechanism as an objective aid for surgeons in associating the sling or suture with a therapeutically effective position. The article of the present invention assists surgeons in consistently and repeatably associating a sling with its intended physiological environment (e.g. the bladder neck or urethra, or both).
The tension control article is preferably positioned on a portion of anatomical support material. In one embodiment, the tension control article has a plurality of tensioning members that are sized and shaped to provide a tortuous pathway for the sling material. When the tension control article is associated with the sling material and the sling material is placed at its intended anatomical location, the tension control article results in an increase in the supportive tension that is applied by the sling to anatomical structures relative to that supportive tension that would be applied to the anatomical structures in the absence of the tension control article.
In one embodiment, the size and shape of the tensioning members are selected to provide a predetermined slack in the sling material once the article is removed from the sling material. For example, for a tension free surgical sling procedure for treating incontinence, the tension control article may be associated with the sling and the sling/tension control article combination may be implanted to just touch the urethra of a patient. In this example, once this penultimate orientation of the sling and urethra is achieved, the tension control article may then be removed to ensure a consistent, uniform amount of slack is provided between the sling and the urethra. Providing a uniform, consistent, repeatable amount of looseness in each surgical procedure reduces the chances that patient data is corrupted by the vagaries associated with a particular surgeon's preferences or lack of training or experience. As a result, it is believed that the present invention can lead to more consistent medical results.
The tension control article of the present invention may be constructed of a wide variety of materials. Suitable materials include those that may be permanently implanted in the body, temporarily implanted, and/or completely removed prior to the end of the surgical procedure. The material used to construct the tension control article should be biocompatible and may comprise bioresorbable materials or permanent, biocompatible materials or combinations thereof.
FIG. 1 shows an embodiment of the anatomical support adjustment and tension control article 10 for use with suspension sutures, surgical slings, or other anatomical supports. In this embodiment, the present invention includes a base member 12 and three tensioning members 14 , 16 , and 18 attached thereto. Optionally, more than three tensioning members may be positioned on the base member. The base member 12 is preferably arcuate and includes beveled edges to reduce or eliminate damage to the surrounding tissue and anatomical support material disposed thereon. In an alternate embodiment, the body member 12 may form any other configuration which facilitates support of the urethra and which minimizes damage to the surrounding tissue and anatomical structures. The device 10 may be manufactured in a plurality of sizes to accommodate the physiological or anatomical constraints of the patient and the location of use. The configuration of the device 10 enables a user to adjust the length of anatomical support material positioned therein and adjustably control the supportive tension applied to tissue.
The device 10 may be constructed of a plurality of materials, including, for example, titanium, stainless steel, nylon, polycarbonate, polysulfone, ABS, ultem, polyetherimide, and polyacetate or combinations thereof, thereby providing a relatively rigid device. In an alternate embodiment of the present invention, the device 10 may be manufactured from moderately flexible materials, such as acetal, or soft flexible materials, such as silicon elastomer or polyurethane, should a more flexible support mechanism be desired. In yet another embodiment, the device 10 may be manufactured from biodegradable materials or polymers. The device 10 may further include or be manufactured from materials having distinct radio opacities or echogenic properties, thereby enabling location of the device 10 in post-surgical procedures. In yet another embodiment, the present invention may be manufactured from materials having distinct optical properties, wherein the application of force to device 10 alters the visual appearance of, or light transmission through, the device 10 . Furthermore, it is considered within the scope of the claimed invention to construct the device 10 from multiple materials. For example, the device 10 may comprise a base member 12 constructed of polyacetate, or a similar rigid material, and the tensioning members 14 , 16 , and 18 , respectively, constructed of a flexible material. Other biocompatible materials and material combinations not specifically listed herein, may also be used to fabricate the device 10 and are included within the scope of the claimed invention.
The members 14 , 16 and 18 may be integrally molded with the base portion. Alternatively, they could be releasably attached to the base portion to afford adjustment of the sling. For example, the members 14 , 16 and 18 may be constructed to be separable from the base portion by use of a remotely actuated device (e.g. a device that utilizes electromagnetic energy). In particular, a magnetic attachment of one or more of the members 14 , 16 and 18 and the base portion 12 may be provided. This magnetic attachment may be eliminated by a remotely activated device. This embodiment affords adjustment in the tension of a sling post operatively without requiring a subsequent incision.
FIGS. 2 a and 2 b show alternative methods of positioning the present invention on a portion of anatomical support material. FIG. 2 a shows one method of using the tensioning device 10 to engage a portion of anatomical support material 20 , wherein the material 20 is positioned within a tortuous pathway formed by the plurality of tensioning members 14 , 16 , and 18 respectively. FIG. 2 b shows an another method of using the tensioning device 10 , wherein the anatomical support material 20 traverses an alternate tortuous pathway formed by the plurality of tensioning members 14 , 16 , and 18 .
Generally, the longer the tortuous path, the greater the slack provided in the sling 20 once the tension control article 10 is removed. Also, the longer the tortuous path, the more slack is taken up in a sling 20 once the tension control article 10 is associated with the sling. For the same clip 10 , the length of the tortuous path in FIG. 2 a is different than the length of the tortuous path in FIG. 2 b. As a result, the same tension control article may be utilized to provide a plurality of different slacks in the anatomical support material (e.g. sling) 20 .
A second embodiment of tension control article 10 A is illustrated in FIG. 3 . The tension control article 10 A has tensioning members 14 A, 16 A and 18 A, and base member 12 A. The tension control article 10 A further comprises a directional indicator 22 A included on the body member 12 A. The directional indicator 22 A assists the user in properly applying the device 10 A to a portion of anatomical support material. As shown in FIG. 3, the directional indicator 22 A may comprise an arrow printed on, embossed or integrally disposed on a surface of the base member 12 A. Alternatively, the directional indicator may include figures, shapes, letters, or other markings formed, printed, or otherwise included on the device 10 A. In another embodiment, the base member 12 A may include a tension scale, enabling the user to determine the amount of load imposed on the tensioning members. Alternatively, displacement of flexible members may be used to indicate the applied load. For example, deflection or alignment of the tensioning members may be used to indicate the relative preload on the sling 20 .
FIGS. 4 a and 4 b show additional embodiments of the present invention. Tension control article 10 B has tensioning members 14 B, 16 B and 18 B, and base member 12 B. Tension control article 10 C has tensioning members 14 C, 16 C and 18 C, and base member 12 C. As shown in FIG. 4 b, the device 10 C may include a grasping member 24 C disposed on or attachable to the base member 12 C. In FIG. 4 a, the grasping member 24 B is integral with the base member and comprises an arcuate discontinuity in the base member 12 B. Optionally, the free (unattached) ends of tensioning members 14 , 16 and 18 could include an enlarged portion or ledge that retains the sling material or sutures in place.
The grasping member 24 C aids the user in applying, positioning, and removing the device 10 C from the anatomical support material 20 C. FIG. 4 b shows the grasping member 24 C further comprising a directional indicator 22 C positioned thereon, thereby aiding the user in applying the device 10 C. In an alternative embodiment of the present invention, a detachable grasping member 24 C is contemplated.
Additional embodiments of the present invention are shown in FIGS. 5 a and 5 b. Tension control article 10 D has tensioning members 14 D, 16 D and 18 D, and base member 12 D. Tension control article 10 E has tensioning members 14 E, 16 E and 18 E, and base member 12 E. Base member 12 D of the device 10 D includes at least one material locking member 26 D. The locking member 26 D has an open position permitting the movement of anatomical support material 20 (see FIG. 2 a ) between the tensioning members 14 D, 16 D, and 18 D, respectively, and a closed position restricting the movement of the anatomical support material 20 relative to the tension control article 10 D. The at least one locking member may be manufactured from a plurality of materials having sufficient structural rigidity to prevent material movement, thereby preventing accidental or unintentional adjustment of the tension applied by the anatomical support material. The locking member 26 E of FIG. 5 b is located on the sides of the base portion 12 E, as opposed to the ends (see FIG. 5 a ).
In another embodiment, the article of the present invention may include a spring biased locking member that is biased toward the closed position. In the closed position, the locking position retains a portion of the sling 20 in a pre-tensioned, elastically deformed condition. Placing the pretensioned sling and associated article in the patient and then subsequently removing the association between the article and the pre-tensioned sling can result in an increase in the tension encountered by a target anatomical structure such a urethra.
The tensioning members 14 , 16 , and 18 (and those to which a letter suffix has been added herein) may be manufactured from a plurality of materials. For example, the tensioning members 14 , 16 , and 18 may be manufactured from a flexible material, thereby providing a dynamic tensioning device capable of absorbing temporary variations in supportive loading. If desired, in an alternative embodiment the tensioning members 14 , 16 , and 18 may be manufactured from a rigid material, permitting the operator to forcibly remove a tensioning member if desired, thereby resulting in decreased support tension applied by the anatomical support material. In an alternate embodiment, the tensioning member may be manufactured from a pliable material, thereby permitting the user to easily position and apply the device 10 .
The spacing and number of tensioning members may be adapted to adjust the tension of the anatomical support material disposed on the device 10 . For example, a greater number of tensioning members would provide a more tortuous pathway, resulting in greater anatomical support tension or spacing adjustment. The exterior of the tensioning members are preferably smooth. In another embodiment of the present invention, the exterior of at least one of the plurality of tensioning members may be textured to increase anatomical support material retention, or to increase stability within the body if the tension control article is permanently implanted, or to promote tissue ingrowth.
FIG. 6 shows another embodiment of tension control article 10 F including tensioning components 14 F, 16 F, and 18 F. In FIG. 6, tensioning member 16 F is oval. The tensioning members 14 F, 16 F, and 18 F may be formed in a plurality of shapes and combinations thereof, including, without limitation, triangular, rectangular, oval, hexagonal, octagonal and diamond.
FIG. 7 illustrates another embodiment of tension control article 10 G. Tension control article 10 G has tensioning members 14 G, 16 G and 18 G, and base member 12 G. A band 25 may also be used in conjunction with tension control article 10 G to retain the association between the sling 20 and tension control article 10 G. The band 25 is placed on the tension control article 10 G after the sling is associated with the tension control article 10 G so that the band 25 prevents or blocks separation of the tension control article 10 G from the support material 20 .
FIGS. 8 a- 8 d show another embodiment of tension control article 20 ′ according to the present invention. The tension control article 20 ′ comprises a base portion 22 with integral tensioning member 24 , handle 34 , and movable tensioning members 27 and 29 .
The tension control article 20 ′ is movable between an open position (FIGS. 8 c and 8 d ) with the tensioning members 27 and 29 spaced from base portion 22 so that the tension control article 20 ′ may readily receive a sling, and a closed position (FIGS. 8 a and 8 b ) with the tensioning members 27 , 29 closer to the base portion 22 than in the open position.
A spring 32 biases the tension control article 20 ′ toward the closed position. Manual pressure on handle 34 moves the tension control article from the closed toward the open position. The handle 34 is preferably designed so that major surfaces of the base portion 22 and tensioning members 27 , 29 remain substantially parallel between the open and closed positions. Substantial parallel movement resists binding or wrinkling of the sling when the tension members 27 and 29 clamp onto the sling.
FIGS. 9 a - 9 d show another embodiment of tension control article 40 according to the present invention. The tension control article 40 comprises a base portion 42 with integral tensioning member 44 , handle 54 , and movable tensioning members 47 and 49 .
The tension control article 40 is movable between an open position (FIGS. 9 c and 9 d ) with the tensioning members 47 and 49 spaced from base portion 42 so that the tension control article 40 may readily receive a sling, and a closed position (FIGS. 9 a and 9 b ) with the tensioning members 47 , 49 closer to the base portion 42 than in the open position.
A spring 52 biases the tension control article 40 toward the closed position. Manual pressure on handle 54 moves the tension control article from the closed toward the open position. The movement between the open and closed positions is pivotal movement about a point on or substantially adjacent handle 54 .
FIGS. 10 a - 10 d show another embodiment of tension control article 60 according to the present invention. The tension control article 60 comprises a base portion 62 with integral tensioning member 64 , handle 76 , and movable tensioning members 67 and 69 .
The tension control article 60 is movable between an open position (FIGS. 10 c and 10 d ) with the tensioning members 67 and 69 spaced from base portion 62 so that the tension control article 60 may readily receive a sling, and a closed position (FIGS. 10 a and 10 b ) with the tensioning members 67 , 69 closer to the base portion 62 than in the open position.
A spring 72 biases the tension control article 60 toward the closed position. Manual pressure on handle 76 moves the tension control article from the closed toward the open position. The tension control article includes a hinge structure 74 that is preferably designed so that major surfaces of the base portion 62 and tensioning members 67 , 69 remain substantially parallel during movement between the open and closed positions. Parallel movement between these structures is believed to avoid sling material extruding out of the open end of the tension control article 60 as the sling is being associated with the tension control article 60 .
FIGS. 11 a - 11 b show another embodiment of tension control article 80 . The tension control article comprises a base portion 82 with integral tensioning member 84 , a handle, and movable tensioning members 87 and 89 . The tension control article 80 is movable between an open position (FIG. 11 a ) with the tensioning members 87 and 89 spaced from base portion 82 so that the tension control article 80 may readily receive a sling 85 ′, and a closed position (FIGS. 11 b ) with the tensioning members 87 , 89 closer to the base portion 82 than in the open position.
The tension control article 80 includes tension level indicators 81 , 83 and 85 on tensioning member 84 . The indicators 81 , 83 and 85 may comprise printing, molded in indicia or other forms of indicia. Members 87 and 89 may also include indicia thereon. The position of the indicators 81 , 83 and 85 relative to the indicia on members 87 and 89 provide an indication of the tension provided by the tension control article 80 .
Preferably, the tension control article 80 includes structure that releasably indexes the tension members 87 , 89 between locations adjacent indicators 81 , 83 and 85 . A releasable detent and groove associated with a hinge provides suitable structure. Locations 81 , 83 and 85 correspond to predetermined positions between the open (FIG. 11 a ) and fully closed (FIG. 11 b ) positions. Generally, the closer the tension members 87 and 89 are to the base portion 82 , the more slack will be provided in sling 85 ′ when the tension control article 80 is removed.
FIG. 12 illustrates another embodiment of tension control article 100 . The tension control article 100 comprises tensioning members 102 , 104 and 106 , base member 105 , and adjustment member 110 . The tensioning members 102 and 106 are located on arms 112 and 111 that are movable relative to tensioning member 104 . By rotating a geared wheel 110 that engages gears on arms 111 and 112 , the tensioning members 102 and 106 may be moved away from or closer to tensioning member 104 . Indicia 109 may be printed on or embossed on the arms 111 and 112 to provide an indication of the preselected tension provided by the tension control article 100 . Adjustable tension control article 100 allows the surgeon to preselect a tension to account for the vagaries in human anatomy sizes, surgical procedure requirements or personal preference.
FIGS. 13-15 illustrate another embodiment of tension control article 120 according to the present invention. The tension control article 120 includes major tensioning member 124 and minor retention members 122 and 126 . FIGS. 14 and 15 illustrate different tortuous paths associated with tension control article 120 . Sling 127 is associated with article 120 by being threaded within tension control article 120 along one of the tortuous paths. The tortuous path of FIG. 14 is shorter than the tortuous path of FIG. 15 . Generally, the longer the tortuous path, the more slack will be provided in the sling 127 when the tension control article 120 is removed. Also, the longer the tortuous path, the more slack is taken up in an implanted sling when the article 120 is applied to the sling.
FIGS. 16 a and 16 b illustrate another embodiment of tension control article 130 according to the present invention. The tension control article 130 includes spacer jaws 136 and 138 , hinge 134 , handles 132 and over opening stops 137 and 139 . The tension control article 130 is preferably a unitary structure with an inherent bias of the jaws toward a closed or clamped position.
The hinge 134 may comprise an integral or living hinge that biases the jaws 136 and 138 toward a closed position. In use, manual pressure is applied to handles 132 to open the jaws. A sling is placed in the open jaws and the handle is released. Upon release, the sling is clamped between the jaws 136 and 138 . The sling is then placed next to the urethra with jaw 136 located between the sling and the urethra. The jaw 136 is sized and shaped to provide a predetermined distance between the urethra and sling. The tension control article 130 is then removed. The predetermined distance or size of jaw 146 assists the surgeon in providing a consistent, uniform and repeatable amount of looseness in a sling.
Another embodiment of tension control article 140 is shown in FIGS. 17 a and 17 b. Tension control article 140 includes jaws 142 and 144 . A sling 141 is shown placed within the jaws in FIG. 17 b. Optionally, jaw 142 may be constructed to be a different size than jaw 144 to afford two different spacing options for the surgeon.
FIGS. 18 a through 18 c show another embodiment of tension control article 150 according to the present invention. The tension control article 150 includes jaws 152 and 154 , a hinge and a spring 151 for biasing jaws 152 and 154 toward a closed position. Sling 151 ′ is shown placed between jaws 152 and 154 in FIG. 18 C.
The device according to the invention may be easily tailored to provide increased or decreased urethral support. Optionally, the tension control article may allow the surgeon to remove, or break the tensioning members during the surgical procedure or during a post operative period.
Method
In another aspect, the present invention comprises a method of changing tension of an implantable article using an article according to the present invention. The article may be implanted in the body during a surgical procedure. Alternatively it may be removed prior to the end of a surgical procedure. The article of the present invention may be modified in a subsequent surgical procedure or by substantially non-invasive means.
FIGS. 19 and 20 illustrate a method where the surgical article is removed prior to the end of the surgical procedure. FIG. 19 is a flowchart illustrating an embodiment of method 200 according to the present invention.
Step 202 provides a tension control article (tension accessory) and a sling. Preferably, the tension control article (e.g. 10 ) may be part of a surgical kit. The kit may be a surgical kit having tools for treating incontinence, such a sling kit. Alternatively, the tension control article, sling and the rest of the surgical articles may be independently provided to the surgeon. The latter case is desirable when the elements of the kit have drastically different shelf lives or storage condition requirements (e.g. refrigeration).
Step 204 associates the tension accessory (the tension control article) with the sling. Optionally, the manufacturer can conduct this step so that a sling/tension control article preassembly is provided to the surgeon in the kit. Alternatively, this step may be conducted by the surgeon or other healthcare professional prior to implanting the sling, especially if the tension control article provides a plurality of different tension options.
Using tension control article 10 as an example, to associate the article 10 with a sling, the operator threads the sling along one of the tortuous paths provided by the article 10 . It is noted that, if the sling includes a surrounding, removable plastic sheath, the sling/sheath combination may be threaded along the tortuous path. FIG. 23 illustrates a removable plastic sheath 502 . As shown in FIG. 23, the sheath 502 preferably comprises two elongate sections 504 . Alternatively, other configurations of the sheath 502 are within the scope of the present invention. In particular, the sheath may be unitary as opposed to telescoping with perforations, holes, scores or tear lines designed to allow separation and removal of the sheath 502 .
In step 206 , the sling is inserted in the body and adjusted to a predetermined position. For example, some sling procedures call for a tension free sling. For such a procedure, the sling/tension control article combination can be situated in a fully inserted position such that the sling and/or the tension control article are just adjacent or even slightly touching the urethra.
FIG. 20 schematically illustrates article 10 in a fully inserted position with solid lines. The article 10 is just adjacent urethra 304 . Vaginal incision 306 , vagina 302 , and sling S are also shown. In step 208 (FIG. 19 ), the surgeon verifies that the sling/tension control article combination are in this fully inserted position. If not, the surgeon continues to adjust 207 the sling. If the combination is fully inserted, then the surgeon verifies the fully inserted position 209 . Once the fully inserted position is verified, the surgeon may remove the tension control article in step 210 . This removal step is illustrated with an arrow and dotted lines in FIG. 20 . Step 210 may be conducted before or after any optional insertion sheath is removed from the sling, but it preferably occurs after any such optional insertion sheath is removed.
Changing the tension of the sling S at a location substantially adjacent the urethra 304 is more effective than attempting to modify the tension of a sling at a location remote from the urethra. This is particularly the case where a synthetic sling (a polypropylene sling with holes) and insertion sheath are used as, once the insertion sheath is removed, adjustment of the entire length of the sling is particularly difficult or problematic due to the interaction between tissue and the sling.
FIG. 21 illustrates another embodiment of method according to the present invention. In this embodiment, the sling is excessively loose. Article 10 is placed on the sling (see the arrow and solid lines) to take up excessive slack in the sling. In this instance, article 10 is preferably left in the body after the surgical procedure. Preferably, by positioning the sling within the tortuous pathway formed by the plurality of tensioning members, article 10 effectively increases the path length traversed by the support material, thereby resulting in a reduction or elimination of slack from the support material and an increase in supportive tension unless and until the tension control article is removed. As shown in FIGS. 2 a and 2 b, multiple degrees of retentive force may be applied to anatomical support material by a device 10 . For example, FIG. 2 a shows one method of practice wherein the device 10 provides a tortuous pathway for a section of anatomical support material 20 disposed thereon. An alternative method of practice is shown in FIG. 2 b, wherein an alternate tortuous pathway is created. FIG. 12 illustrates an article with a feature that allows the surgeon to adjust the tension provided by the clip. In preferred embodiments, the present invention permits the user to vary the supportive tension applied to the anatomical support material disposed therein by altering the tortuous pathway traversed by the anatomical support material.
It is also noted that removal of an article from its association with the sling can be exploited to increase the tension of the sling on the urethra. FIG. 22 is a flow chart illustrating a method of increasing the tension of a sling by removing a tension control article from its association with the sling.
FIG. 22 illustrates a method of treating incontinence comprising the steps of: (i) providing a support material with at least a portion that is elastically deformable, (ii) elastically deforming at least a portion of the support material to tension the support material (see step 462 ); (iii) providing a tensioning article, (iv) applying the tensioning article to the tensioned support material to retain at least a portion of the support material in an elastically deformed condition (see step 464 ); (v) implanting the support material with applied tensioning article in a patient ( 466 ); and removing the tensioning article to increase the tension provided by the support material 468 . The tension control article used in this method is preferably one with a locking member (FIG. 5 a or 5 b ) or one that can clamp the sling between jaw members (e.g. FIGS. 10 a - 10 b ) so that the elastic deformation can be held in the sling material.
The tension control article may be provided in a kit or provided independent of other surgical articles. One or more articles may be used during a surgical procedure. The tension control article may be positioned on a portion of anatomical support material at the time of manufacture, immediately prior to, or following the surgical implantation of the anatomical support. For example, one surgical urethral stabilization procedure comprises attaching anchors to an internal structure, for example, the posterior or inferior pubic bone, and affixing a mesh sling to said anchors, thereby resulting in supportive force being applied to the urethra. The tension control article 10 may be applied to the anatomical support material according to FIG. 2 a or 2 b should the anatomical support fail to provide adequate support to the anatomical structure. Applying the tensioning device 10 to the anatomical support material increases the pathway between the attaching anchors traversed by the anatomical support and increases the support tension applied by the device. The practitioner may easily vary the amount of supportive tension by applying more or fewer anatomical support tension control articles. Alternatively, the amount of supportive tension applied by the anatomical support tensioning device may be varied by applying tensioning device having more or fewer tensioning members disposed thereon.
It is understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications may be employed which are within the scope of the invention; thus, by way of example but not of limitation, alternate base member shapes, alternative tensioning member shapes, and use with alternative anatomical support materials. Accordingly, the present invention is not limited to that precisely as shown and described in the present invention.
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BACKGROUND OF THE INVENTION
(a) Field of the Invention
The present invention relates to an apparatus and method used to determine angles of inclination and the range of motion of various human joints therefrom, such as, for example, cervical flexion. The apparatus of one preferred embodiment is e computerized arthrometer which is a stand-alone automated apparatus. Output can be provided to a printer for hard copy or to a computer for storage or further manipulation of data. Each sensor or inclinometer used in the preferred embodiment employs a pair of Hall effect transducers spaced about a rotating ring magnet. The voltage output from the transducers can be evaluated to accurately determine the angle of inclination. In another preferred embodiment, instead of the magnet and transducers, the sensors can include circular sensor having six capacitive sectors, each sector changing capacitance as the circular sensor is rotated. The six capacitance values are evaluated to determine the angle of inclination. Another embodiment incorporates the apparatus into readily available "personal computers" ("PCs"). By employing a pair of sensors for selected range of motion tests, measurement accuracy is increased by compensating for the effects of secondary motion, for example, compensating for forward or backward movement of the torso when measuring cervical flexion or cervical extension, respectively.
(b) Description of the Prior Art
There are known single inclinometers which can be determine and display the angle to which they are oriented. It is known to use multiple inclinometers, to position them at different locations on the body, and take readings from the multiple instruments. It is also known to measure an initial starting angle and an ending angle, with the angle therebetween being the range of motion. Further, inclinometers are known which display the angle difference between a first position and a second position.
For example, U.S. Pat. No. 4,912,662, to Butler et al., teaches an inclinometer having a capacitive sensing unit which provides varying capacitance depending upon the orientation of the inclinometer. By comparing the capacitance values to calibrated values stored in look-up tables, the angle of inclination can be determined.
Examples of available inclinometers which can display the difference in motion from a first position to a second position are the Autotilt digital inclinometer from the J-Tech Corporation and the Model SR360 Flexometer from SR Associates.
SUMMARY OF THE INVENTION
The present invention is for an apparatus and method used to determine the range of motion of various human joints, such as, for example, cervical flexion. The apparatus of one preferred embodiment is a computerized arthrometer which is a stand-alone automated apparatus. A main console assembly houses the processor, which interfaces with the operator or user, the output device, the first sensor attached to an adjustable cervical helmet worn by the person being tested by the operator, and the second sensor in a hand-held attachment. Alternatively, the apparatus sensors can be interfaced into a readily available "personal computer" ("PC").
Each sensor or inclinometer used in the preferred embodiment employs a pair of Hall effect transducers spaced about a rotating ring magnet. By placing the transducers about 120 degrees apart, the sinusoidal-shaped voltage output curve of one transducer is in a linear region when the sinusoidal-shaped voltage output curve of the other transducer is not in a linear region. To determine an inclination angle, the two transducer voltage outputs can be evaluated to determine which transducer voltage is in a more linear region of its sinusoidal-shaped curve. Interpolation is then accomplished by the processor using the more linear transducer voltage to accurately determine the angle of inclination.
In another preferred embodiment, instead of the magnet and Hall effect transducers, the sensors can include circular sensor having six capacitive sectors, three sectors on each of two parallel plates with the parallel plates having some fluid therebetween, each sector changing capacitance as the circular sensor is rotated causing movement of the fluid. To determine an angle of inclination, representations of the six capacitance values are sequentially determined and the two most linear are used.
By employing a pair of sensors (either being a Hall effect/magnet sensor or a capacitive sector sensor), for selected range of motion tests, measurement accuracy is increased by compensating for the effects of secondary motion, for example, compensating for forward or backward movement of the torso when measuring cervical flexion or cervical extension, respectively. Based on the sensor measurements, the raw measured data can be processed to not only convert the data into inclination angles, but to further analyze the data from both sensors to compensate for the secondary motion and to produce evaluation reports which are user friendly.
More particularly, one embodiment of the present invention comprises an apparatus for measuring an angle, including a support having a preselected zero degree point; a shaft rotatably connected to the support and protruding perpendicularly therefrom; a ring magnet connected to the shaft, the ring magnet having an outer cylindrical surface, the ring magnet being parallel to the support; a first Hall effect transducer, the first transducer connected to the support at a first preselected location and protruding perpendicularly therefrom, the first transducer being proximate said outer cylindrical surface of the ring magnet, the first transducer providing a first voltage output signal, the first voltage output signal representing a measurable first transducer magnetic field intensity; a second Hall effect transducer, the second transducer connected to the support at a second preselected location and protruding perpendicularly therefrom, the second transducer being proximate the outer cylindrical surface of the ring magnet, the second transducer providing a second voltage output signal, the second voltage output signal representing a measurable second transducer magnetic field intensity; and, means for evaluating the first voltage output signal and the second voltage output signal to determine an inclination angle, the inclination angle representing a measure of tilt of the support from the preselected zero degree point.
More particularly, a pair of these apparatuses for measuring an angle of this preferred embodiment can be employed with a cervical helmet and a hand-held assembly, and a programmed controller to permit conduct of a variety of range of motion tests and the calculation of related impairment results. Employing a pair of these apparatuses permits secondary motion to be discounted, thereby increasing more accurate representations of the tested ranges of motion. Alternative angle measuring apparatuses may be employed, such as one employing a six-sector capacitive sensor assembly.
For example, the apparatus for determining a range of motion can comprise a primary sensor producing at least one primary output signal representing an angle of inclination of the primary sensor; a secondary sensor producing at least one secondary output signal representing an angle of inclination of the secondary sensor; and, means for controlling the apparatus, the controlling means communicating with the primary sensor and the secondary sensor, the controlling means including means for initially evaluating the at least one primary output signal to determine a primary calibration angle of inclination and initially evaluating the at least one secondary output signal to determine a secondary calibration angle of inclination, means for evaluating the at least one primary output signal to determine a primary angle of inclination and evaluating the at least one secondary output signal to determine a secondary angle of inclination, means for comparing the primary angle of inclination and the primary calibration angle of inclination to determine a primary range of motion, means for comparing the secondary angle of inclination and the secondary calibration angle of inclination to determine a secondary range of motion, and means for comparing the primary range of motion and the secondary range of motion to determine an actual range of motion.
Even more particularly, the operator of the apparatus for determining range of motion employs a method comprising the steps of placing a helmet having a primary sensor on a head of a person to be tested; positioning the person to be tested in a neutral test position; selecting a range of motion test to be conducted; aligning the primary sensor for the selected test; aligning a secondary sensor in a desired body location of the person to be tested; calibrating a range of motion apparatus which is in communication with the primary and the secondary sensors; having the person to be tested move from the neutral test position to a range of motion measurement position; and, activating the range of motion apparatus to determine an actual range of motion.
BRIEF DESCRIPTION OF THE DRAWINGS
A better understanding of the present invention will be had upon reference to the following description in conjunction with the accompanying drawings, wherein:
FIG. 1 shows the interconnectable components of the fully assembled apparatus of the preferred embodiment;
FIG. 2 shows the face of the main console assembly of the preferred embodiment of FIG. 1;
FIG. 3 shows an exploded view of the main console assembly, the cervical helmet sensor assembly, and the handheld sensor assembly of the apparatus of the preferred embodiment of FIG. 1, the sensors being magnetic sensors;
FIG. 4 shows an exploded view of the handheld sensor assembly of the apparatus of another preferred embodiment, the sensor being a six sector capacitive sensor;
FIG. 5 shows a front perspective view of the magnetic sensor assembly of FIGS. 1 and 3;
FIG. 6 shows a rear perspective view of the magnetic sensor of FIG. 5;
FIG. 7 depicts the interface circuit board connectivity to the controller board and the input/output connectivity to the interface circuit board from the two sensors and the printer, the power supply source, and the user input/output interface board of the apparatus of the preferred embodiment of FIGS. 1 and 3;
FIG. 8 shows voltage response curves from two Hall effect transducers for a typical magnetic sensor rotated through 360 degrees;
FIG. 9 shows part of an output matrix for the magnetic sensor two voltage output levels for each one degree of magnetic rotation;
FIG. 10a shows a schematic of the circuit connectivity for the six sector capacitive sensor assembly of FIG. 4;
FIG. 10b shows the six sectors of the capacitive sensor in more detail;
FIG. 10c shows a basic astable circuit employing a 7555 timer integrated circuit chip and having a variable capacitor;
FIG. 10d shows a graph of capacitance versus 7555 timer output frequency as the variable capacitor of FIG. 10c is varied from 20 to 40 picofarads;
FIG. 11 shows a time response curve for a typical six sector capacitive sensor assembly through 360 degrees of rotation;
FIG. 12 shows a graph depicting the ratio of the appropriate two of the six capacitive sensor sectors of FIG. 11 used to determine the inclination angle;
FIG. 13 shows a portion of an output matrix for the six sectors of the capacitive sensor and the ratio of the two most linear sectors in the shown portion;
FIG. 14 shows a general flow chart of the operation of the apparatus of the preferred embodiment of FIG. 1;
FIG. 15 shows an expanded flow chart for measuring cervical flexion;
FIG. 16 shows an expanded flow chart of the flow chart of FIG. 15 for taking readings from the magnetic sensors;
FIG. 17 shows an expanded flow chart of the flow chart of FIG. 15 for taking readings from the six sector capacitive sensors;
FIGS. 18a-e depict sample cervical tests;
FIG. 19 is a sample of a printer output showing the results of cervical tests; and,
FIGS. 20a-b show another preferred embodiment employing a personal computer.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The stand-alone embodiment of the apparatus 10 for measuring range of motion is shown in FIG. 1. Apparatus 10, is shown including a main console assembly 20, a power supply and cord 80, a helmet sensor assembly 90 having an adjustable first sensor 140 attached thereto, a hand-held sensor assembly 180 having a second sensor 140 attached thereto, a pair of sensor/console interface cables 148, and a printer 200 having a printer/console interface cable 202.
FIG. 3 shows an exploded view of the embodiment of FIG. 1 except for the printer 200 and its interface cable 202. Main console assembly 20 is shown having an outer bottom case 22, having battery pack receptacles 24 therein for receiving battery pack 26. Battery pack 26 is shown, for example, as containing six 1.5 volt rechargeable batteries connected electrically in series. External power to assembly 20 is provided by nine volt power supply and cord 80. The on/off power switch is designated by the numeral 30. For example, battery pack 26 can permit remote operation of the apparatus 10 for 3 to 4 hours with the battery being fully charged, if testing is to be completed where an external power source is unavailable or inconvenient.
Case 22 has circuit board standoffs 28 extending upward which provide support for the interface circuit board 32 and the controller circuit board 36. Interface circuit board 32 provides connectivity between the user input/output interface board the controller circuit board 36, the two sensors 140, and the printer 200. Board 32 input/output connectivity and board 32/board 36 connectivity is explained hereinafter with the discussion of FIG. 7.
For the preferred embodiment of FIG. 3, the controller circuit board 36 is a programmable miniature controller, sold by Z-World under the trademark "LITTLE GIANT" and having a Z180 processor with a 9.216 MegaHertz clock. The programming of the controller is discussed hereinafter, with reference to FIGS 14-17.
The user input/output interface board 40 is used by the user to select the desired operation and displays messages to the user. Control button interfaces 42 and control buttons 44 are touched by the user. LCD module 46 provides the display. Interconnect cable 48 interfaces user input/output interface board 40 and interface circuit board 32. Front face cover 66, seen in greater detail in FIG. 2, details the function of buttons 44.
Back plate 50 fits to the rear of outer bottom case 22 and provides the sensors, power, and output device connectivity. Each sensor input/output jack 52 receives one of sensor connecting cables 148. Cables 148 provide direct current operating voltage (V cc ) and ground from assembly 20 to sensors 140 and sensor information from sensors 140 to assembly 20. Printer output jack 54 connects to printer cable 202, or to another output device cable. Jacks 52 and 54 are connected to interface circuit board 32 by interconnect cable 56. Power supply and cord 80 connect to power input jack 58, which is connected to interface circuit board 32 by interconnect cable 60. Back plate 50 has a face cover designated by the numeral 62.
Outer top case 64 fits atop outer bottom case 22, back plate 50, and user input/output interface board 40. Front face cover 66 is received thereon. Also, for example, to aid the user when using apparatus 10, an instruction manual 70 can be provided. Secured to main console assembly 20 by booklet securing rod 72 and supported by booklet page rest 74, the user has easy access to information needed during operation of apparatus 10.
As shown in more detail in FIG. 7, interface circuit board 32 is depicted atop controller circuit board 36. For clarity, this is inverted from the exploded view of FIG. 3. One side of interface circuit board 32 contains plugs (321-326), shown in phantom, positioned to directly interface the "LITTLE GIANT" controller board 36. The other side of interface circuit board 32 contains jacks (327-329) which receive the plugs connected to the wires from the two sensors and the printer (56), the power source (60), and the user input/output interface board (48). Board 32 simply provides the necessary connectivity between the various components. For example, the 9 volts direct current from wire 60 is fed to jack 327 and to controller board 36 through power interface plug 321, to the sensors 140 (or 240 if the hereinafter explained embodiment of FIG. 4 is employed) through jack 328, and to the user input/output interface board 48 through jack 329. Data counter interface plug 322 provides input square wave timing pulses from the capacitive sensors 240, explained hereinafter, to a counter timer on board 36. Analog to digital converter plug 326 provides input from the Hall effect transducers 164 and 166 of sensors 140 to the analog/digital subsystem of board 36. Input/output interface plug 323 provides the output from control buttons 44 to board 36. Display interface plug 324 provides output information from board 36 to liquid crystal display module 46. Serial interface plug 325 provides connectivity from board 36 to printer 200.
With reference back to FIG. 3, helmet sensor assembly 90 is adjustable and straps to a patient's head. Assembly 90 supports the sensor 140 which provides primary inclination information. Handheld sensor assembly 180 supports the sensor 140 which provides secondary inclination information.
Helmet sensor assembly 90 includes a helmet 92 having an adjustable strap 94 which extends around a patient's head and a pair of sensor straps 96 which extend toward the top of a patient's head to support sensor 140. Connected to straps 96 are a pair of adapting straps 104, each having a bore 106 therethrough. Mounting block 100 has a hollow post 102 extending upward therefrom. Post 102 is received upward through bores 106. Securing block 108 having a bore 110 therethrough fits atop adapting straps 104 and receives post 102. Securing flange 112 having a spring bore 114 therethrough sits atop securing block 108 and receives post 102.
Coil spring 116 is received in spring bore 114. Securing flange lid 118, having a bore 120 therethrough, is placed atop securing flange 112. Bore 120 is sized approximate the hollow portion of post 102 of mounting block 100. With mounting rod 122 having a pin 98 inserted through an upper bore 124 placed downward through bore 120 of securing flange lid 118, an L-shaped helmet sensor mount 128 is screwed to the top of securing flange lid 118. Hollow post 102, bores 106 in adapting straps 104, bore 110 in securing block 108, spring bore 114 in securing flange 112, coil spring 116, and bore 120 in securing flange lid 118 are axially aligned and a mounting rod 122 is inserted therethrough. Another securing pin 98 is then inserted through a lower bore 126 in mounting rod 122 to rotatably secure the L-shaped helmet sensor mount 128 to the helmet assembly 90. This connectivity permits the L-shaped helmet sensor mount 128, and hence the sensor assembly 140 attached thereto, as described hereinafter, to be rotated about the axis of mounting rod 122 to properly align the sensor 140 for proper testing of a patient wearing the helmet sensor assembly 90.
L-shaped helmet sensor mount 128 has a horizontal arm 130 and a vertical arm 132. Arm 132 has a bore 134 therethrough. As explained hereinafter, washer 136 and 138 can be used in conjunction with bore 134 to attach sensor assembly 140. It is noted that mounting rod 122 and screw 138 are in transverse alignment. This permits adjustment of sensor about the axes of both rod 122 and screw 138 to, therefore, adjust the sensor for any plane of motion.
Sensor assemblies 140 of the preferred embodiment of FIGS. 1 and 3 each employ a pair of Hall effect transducers 164 and 166 positioned about a one pole pair ring magnet 162. Sensor assemblies 140 are shown in greater detail in FIGS. 5 and 6 and their output is discussed hereinafter with FIGS. 8 and 9.
As previously mentioned, a primary sensor assembly 140 is pivotally attached to vertical arm 132 of L-shaped helmet sensor mount 128 and a secondary sensor assembly 140 is attached to handheld sensor assembly 180. Sensor assembly 140 is shown having a housing 142 having a threaded bore 144 therethrough. Bore 144 is used to pivotally attach primary sensor assembly 140 to arm 132 using screw 138. Handheld sensor assembly 180 has a housing 182 which includes a sensor receptacle 190. A bore 184 passes through housing 182 to receptacle 190. Washer 186 and screw 188 are used to fixedly secure secondary sensor assembly 140 into receptacle 190 by inserting screw 188 having washer 186 inserted thereover into bore 184 through housing 182 and into bore 144 of secondary sensor assembly 140.
Each sensor 140 housing 142 contains a circuit board support 150 and a connector 168. Lid 146 attaches to housing 142. As shown in FIGS. 3, 5, and 6, circuit board 150 is quadrilateral-shaped support, for example, 11/2 inch by 11/2 inch, having a reinforcing mounting block 152 attached on one side. Block 152 and board 150 have a bore 154 therethrough. Bore 156 has rotating shaft assembly 156 inserted therethrough, the shaft assembly 156 being perpendicular to board 150. Shaft assembly 156, for example, extends about 3/8 inch from each side of board 150. A pendulum weight 158 of, for example, a triangular or bell shape, has a bore 160 therethrough. Using bore 160, weight 158 is attached to one end of shaft assembly 156. A one pole circular ring magnet 162 having a central bore is attached to the other end of shaft assembly 156, this being on the other side of board 150 from weight 158.
A first Hall effect transducer 164 and a second Hall effect transducer 166 are attached to board 150 and transverse thereto. Transducers 164 and 166 are also parallel to shaft assembly 156 and circumferentially aligned with ring magnet 162. It is noted, for example, that in this preferred embodiment, transducers 104 and 166 are spaced about 120 degrees apart, using shaft assembly 156 as a center reference. As is explained hereinafter, no matter the polar alignment of the magnet with respect to transducers 164 and 166, this spacing ensures the voltage output of at least one of the transducers 164 and 166 will be in a linear range. Connector 168 receives a connecting cable 148 which is then attached to proper input/output jack 52 of assembly 20. Connector 168 is electrically tied to board connectivity 170. Board connectivity 170 provides V cc and ground to each transducer 164 and 166 and provides a path for the direct current voltage output signal from each transducer 164 and 166. As mentioned, the output signals from the magnet/Hall effect transducer sensors assemblies 140 are passed to the analog to digital converter subsystem of the "LITTLE GIANT" controller 36 for sampling by controller 36 and evaluating to determine angles of inclination.
As seen in FIG. 8, as the magnet 162 is rotated through 360 degrees of rotation the output signal of each transducer 164 and 166 varies in proportion to the intensity of the magnetic field to which each transducer 164 and 166 is exposed. These output voltage curves are generally of a sinusoidal shape, having non-linear peaks and valleys and linear portions therebetween. The output curves of FIG. 8 represent measured data from actual Hall effect transducers configured as shown in FIGS. 5 and 6. FIG. 8 shows that with the about 120 degree spacing between transducer 164 and 166, output 1 from transducer 164 is in a linear range when output 2 from transducer 166 is in a non-linear range. Also, output 2 from transducer 166 is in a linear range when output 1 from transducer 164 is in a non-linear range. The controller 36 has the measured data for each one degree of rotation stored in a look-up matrix. The controller 36 is programmed, as is explained hereinafter, to select the transducer 164 or 166 output voltage which is in the most linear range and interpolate from the data in the look-up matrix for that most linear transducer 164 or 166 to determine the angle of inclination.
FIG. 9 shows a look-up matrix which would be stored for the curves of FIG. 8 from 45 degrees to 90 degrees of rotation. It is noted generally that output 2 from transducer 166 is the most linear over this range. To demonstrate this, for example, it is noted that the voltage change from 45 to 46 degrees for output 1 is only 0.002 volts, but for output 2 is 0.031 volts. Between 89 and 90 degrees, output 1 changes 0.015 volts and output 2 changes 0.040 volts. Therefore, over this range, the output 2 signal would be used for interpolation. To illustrate, assume that output 1 was measured at 6.537 volts and output 2 was measured at 3.097 volts. Looking at FIG. 8, the angle of inclination can only be around 50 degrees. Looking at the matrix of FIG. 9 shows that the angle of inclination must be between 50 and 51 degrees. Over this degree, output 1 changes only 0.005 volts and output 2 changes 0.034 volts. The output 2 signal is therefore used for interpolation and 3.097 volts is 0.017 volts above the output 2 50 degree voltage of 3.080 volts and 0.017 volts below the output 2 51 degree voltage of 3.114 volts. Therefore, the angle of inclination would be 50.5 degrees. If only one degree accuracy is desired, interpolation as described could still be accomplished, 0.5 degree could be added to the result, with the result truncated to eliminate any decimal, thus determining the angle of inclination to the nearest degree.
FIGS. 4, 10a-d, 11, 12, 13, and 17 relate to another preferred embodiment employing capacitive sensor assemblies 240, instead of the magnet/Hall effect transducer sensor assemblies 140. As with each assembly 140, each assembly 240 includes a housing 242, a bore 244, a lid 246, a jack 268, and a circuit board 250. Primary sensor assembly 240 is rotatably connected to L-shaped sensor mount 128, just like a sensor 140. Secondary sensor 240 is secured in sensor receptacle 190 of handheld sensor assembly 180 just like a sensor 140.
As seen in FIGS. 4 and 10a-b, circuit board 250 includes a capacitive sensor 252 having a pair of spaced apart parallel plates 254, each plate having three 120 degree sectors 258. Plates 254 are contained by a grounded case 253. The space between plates 254 is partway filed with a conductive fluid 256. It is noted that the 120 degree sectors 258 of one of plates 254 are off-set 60 degrees from the 120 degree sectors 258 of the other plate 254. Each of the six sectors 258 have a lead 260 electrically connecting the sector to an input of a 4051 multiplexer integrated circuit 262. Based on the fluid 256 position, the output from each sector 258 represents a capacitance through the sector and the fluid, if any, to the case ground. As the sensor 252 is rotated, the fluid 256 changes position and the output from the six sectors changes. A 7555 timer chip 264 and a precision resistor R1 are employed with the multiplex chip 262 to determine the angle of inclination of the sensor 252.
Before explaining the operation of the multiplex chip 262 and timer chip 264, reference is made to FIGS. 10c-d. FIG. 10c shows a basic astable circuit employing a 7555 timer integrated circuit chip, a fixed 10 Megohm resistor R1 and a variable capacitor C1. This circuit produces an output train of timing cycles having a period T1 which varies as C1 is varied. Frequency is 1 divided by period T1. FIG. 10d shows a graph of the output frequency of the circuit of FIG. 10c as C1 is varied from 40 picofarads to 20 picofarads. With C1 equal 40 picofarads, 1/T1 is 1.8 kilohertz. Thus T1 is approximately 0.55 milliseconds. With C1 equal 20 picofarads, 1/T1 is 3.6 kilohertz. Thus T1 is approximately 0.27 milliseconds. The relationship between C1 and frequency is linear.
With reference now to FIGS. 10a-b and 11-13, the operation of the multiplex/timer circuit on the circuit board 250 of sensor assembly 240 is explained. The multiplex/timer circuit output, as well as the multiplex 262 BCD addressing inputs are electrically connected to the "LITTLE GIANT" controller 36. When controller 36 is asked to measure an angle of inclination, the controller 36, through the BCD addressing inputs of multiplex 262, sequentially samples the six sensor sectors 258. Each sector's capacitance is dependent upon the position of the fluid 258 between the parallel sector plates 254. The software of this preferred embodiment is, for example, designed to measure the time it takes for the 7555 timer 264 to produce 36 clock pulses, skipping the first clock pulse for rise time of the capacitor for each of the six sectors 258. These six time measurements are then used to determine the angle of inclination.
FIG. 11 shows typical response curves for the six sectors 258 of a sensor assembly 240 as the assembly 240 is rotated through 360 degrees. These curves for each sector are generally sinusoidal-shaped. From FIG. 10b, it is seen that the geometrical spacing of the sectors 258 is such that the arc midpoints of the six sectors are spaced about every 60 degrees with relation to case 253. The curves of FIG. 11 depict this geometric relationship, with the sector curves having their maximum timing about every 60 degrees of rotation.
While many methods could be employed to calculate an inclination angle, the program of this preferred embodiment looks to the sector with the longest time measurement to decide which 60 degree portion the angle is in. Then, similarly to the magnet/Hall effect transducer sensor assembly 140, a matrix is referred to determine the angle of inclination. It is noted that, for each 60 degree portion, the timing outputs of two of the six sensors change in a nice linear relationship. For example, for the 60 degree portion of the curves of FIG. 11 when sector 1 produces the longest time output (from about 3 degrees to about 63 degrees), the timing outputs of sectors 2 and 6 provide nice linear change. FIG. 12, at the left hand side from about 3 to 63 degrees, shows the ratio of the time for sector 6 to produce 35 pulses divided by the time for sector 2 to produce 35 pulses. From FIGS. 11 and 12, it is similarly seen that when sector 2 has the longest time to produce 35 pulses, sectors 1 and 3 are the most linear; when sector 3 has the longest time to produce 35 pulses, sectors 2 and 4 are the most linear; when sector 4 has the longest time to produce 35 pulses, sectors 3 and 5 are the most linear; when sector 5 has the longest time to produce 35 pulses, sectors 4 and 6 are the most linear; and, when sector 6 has the longest time to produce 35 pulses, sectors 5 and 1 are the most linear. For each one degree of rotation, the ratio of the two most linear sectors is stored in a lookup matrix. FIG. 13 shows a sample of the time measurements for each sector from 358 degrees to 31 degrees and the ratio of sectors 6 and 2. The program of this preferred embodiment, when making a determination of the angle of inclination first looks to the longest measured time for 35 pulse cycles to determine which two sectors times should be ratioed. For example, if the sector 1 time measurement is the longest at 51.862 milliseconds for 35 pulse periods, the time for sector 6 is divided by the time for sector 2, yielding, for this example, a ratio of 1.229635. Controller 36 refers to the 3 to 63 degree portion of the lookup matrix and sees that the ratio of sector 6 to sector 2 for 15 degrees is 1.23603 and for 16 degrees is 1.22324, the ratio 1.229635 being therebetween. Controller 36 uses these ratios to interpolate, giving a measured angle of inclination of 151/2 degrees. As with sensor assembly 140, if inclination only to the nearest degree is required, 0.5 degree can be added to the interpolated result and the decimal truncated.
FIGS. 18a-e show a person wearing helmet sensor assembly 90 having a primary sensor 140 thereon and also shows the employment of a secondary handheld sensor assembly 180 having a secondary sensor 140 thereon. The sensors 140 are positioned depending on the test to be performed. The circuit boards 150 are always positioned to lie is a vertical plane. Also, for example, using FIGS. 18a-b as a guide, the person is being tested for cervical flexion and extension, respectively. Assuming the person is aligned so that his head movement is to the north or south, the sensors 140 are aligned so that the circuit boards 150 lie in the vertical north/south plane of motion. The same applies if a capacitive sensor assembly 240 is employed.
As seen in FIGS. 18a-b, the purpose of the primary sensor 140 is to measure the respective forward and reverse tilt of the head. As the person's neck and spine move in concert and not at one specific point, the purpose of the secondary sensor 140 is to make any necessary adjustment to the primary sensor 140 measurement to eliminate the effects of secondary motion by the person. In FIGS. 18d-e, the person is tilting his head from the neutral upright position (FIG. 18d) to the right (FIG. 18e) to determine right lateral flexion. Secondary sensor assembly 180 is positioned to measure the right tilt of the spine to eliminate this secondary motion. In FIG. 18c, the person is laying flat on a table and is twisting his neck to the right to measure right cervical rotation. As the spine may only twist during this measurement, no secondary motion need be eliminated. Therefore, the secondary sensor assembly is shown placed on the table beside the person being tested. The controller 36 is programmed, for this cervical rotation test, to only use input from the primary sensor assembly 140 attached to helmet assembly 90.
FIG. 19 depicts a typical data output sheet from a test of a person's cervical range of motion and the calculations of impairment which can be performed and produced on printer 200. It is seen that cervical flexion, extension, left and right lateral flexion, and left and right rotation have been measured. Using standards from the American Medical Association, cervical impairment has been calculated. To help ensure accuracy, it is noted that the tests have been repeated at least three times, with the greatest range of motion reported. It is also noted that the at least three tests must yield similar results, for example, within a ten percent range or no more than a five degree difference.
Various flow charts which permit the "LITTLE GIANT" controller 36 to perform the various tests and present the results are shown in FIGS. 14-17. FIG. 14 depicts a general flow chart from power up through test selection and testing and reporting. FIG. 14 shows that a person can have tests of the cervix, thorax, lumbar, and extremities selected, for example. FIG. 15 provides a more detailed flow chart assuming that a test of a person's cervical flexion has been selected. Toward the center of FIG. 15, a block is labeled "Take Reading from Sensor A & B". FIG. 16 expands on this block if a magnet/Hall effect transducer sensor assembly 140 is employed. FIG. 17 expands on this block if a capacitive sensor assembly 240 is employed.
In addition to being able to refer to the handy instruction manual 70 atop main console assembly 20, interface with the apparatus 10 by the operator is through the main console assembly 20. The operator responds to the messages displayed on LCD module 46. The operator uses the scroll and select menu control buttons 44 to select the desired test. Then, the operator has the person being tested move when appropriate and presses the appropriate calibrate and input measurement control buttons 44 to step through the desired testing sequences.
It is noted that with the primary and secondary sensors 140 and/or 240 properly positioned and with the person to be tested in the proper neutral position the controller 36 determines the angle of inclination for the primary and secondary sensors at this neutral position when the operator presses the calibrate control button 44. This neutral position is "remembered" so that the person being tested, when returned to the neutral position, hears a beep to indicate proper positioning to repeat the test. As previously mentioned, the desired test is to be completed at least three times and the results must be closely related or the test is considered invalid. Having the same neutral position as a starting point for all test repetitions helps test repeatability, rather than recalibrating for each test repetition. After calibration of the neutral position the person being tested is told how to move. When the person moves, the operator presses the input control button 44 and controller 36 takes the readings from sensors 140 or 240 and calculates the angles of inclination using the linear sensor relationships and the interpolation and truncation techniques previously described. This flow is shown for sensor 140 in FIG. 16 and for sensor 240 in FIG. 17.
After the selected test sequence is complete, controller 36 performs the range of motion calculations, eliminating the effects of secondary motion, and calculates impairment. Then, for example, as seen in FIG. 19, the results can be printed. As an example, in testing cervical flexion, as shown in FIG. 18a, assuming that both the primary and secondary sensors 140 measure zero degrees with the person being tested in the neutral position and further assuming that the primary sensor 140 measures 22 degrees and the secondary sensor 140 measures 2 degrees with the person being tested having his head tilted fully forward; the controller 36 would determine that the person had tilted his head forward 22 degrees, but, at the spinal location of the secondary sensor, had also tilted his spine forward 2 degrees. Therefore, the primary 22 degree reading would be adjusted by the secondary 2 degree reading to determine that the measured cervical flexion was 20 degrees. If this is the "best" measurement of cervical flexion for the at least three tests of the person being tested, this 20 degree result will be shown on the printout of FIG. 19.
The apparatus 10 of FIG. 1 has no means for long term storage of data. Therefore, once a test sequence is completed and before conducting another test sequence, the results must be printed. With proper interface, instead of connecting printer 200 to main console 20 by plugging cable 202 into jack 54, a cable can connect a "smart" device which can receive the printout data and store or further manipulate the data. For example, historic files by patient identification can be maintained which permit automated comparisons of test data over time. Another alternative, as seen in FIGS. 20a-b, is to provide a PC interface card 222 which plugs into a personal computer 220 and interfaces the primary and secondary sensors (140 or 240) to the computer 220. Computer 220 can then be similarly programmed, as shown in FIGS. 14-17, like the "LITTLE GIANT" controller 36 of the previously described preferred embodiments. Computer 220 can be used for standard PC functions in addition to being used to perform range of motion/impairment testing. Computer 220 can also easily provide data storage means, for example on a hard or floppy disk, and can easily permit data manipulation not permitted by the "LITTLE GIANT" controller 36.
The foregoing detailed description is given primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom for modifications can be made by those skilled in the art upon reading this disclosure and may be made without departing from the spirit of the invention and scope the appended claims.
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CO-PENDING APPLICATIONS
The present application claims priority to U.S. Provisional application Ser. No. 60/060,922, filed Oct. 3, 1997, and relates to U.S. patent application Ser. No. 09/143669, filed Aug. 31, 1998, now abandoned which is a continuation of U.S. patent application Ser. No. 08/626,170, filed Mar. 29, 1996, now U.S. Pat. No. 5,824,062, which is a continuation-in-part of both U.S. patent application Ser. No. 08/412,696 filed Mar. 29, 1995, now abandoned, and U.S. patent application Ser. No. 08/546,210 filed Oct. 20, 1995, now abandoned, each of which is entitled BILEAFLET HEART VALVE.
FIELD OF THE INVENTION
The present invention relates generally to bileaflet hemodynamic heart valve prostheses of the type permitting translational and rotational movement of the leaflets, and particularly to a low-excursion prosthetic heart valve suitable for mitral valve replacement involving preservation of the papillary muscle and chordal structure wherein the valve may be oriented in either an anatomical or anti-anatomical configuration.
BACKGROUND OF THE INVENTION
The replacement of defective heart valves with hemodynamic prostheses is the most prevalent course of treatment for certain types of heart disease and dysfunction affecting the atrioventricular valves—namely the right AV (tricuspid) and the left AV (bicuspid) valves. Although a variety of tissue and prosthetic heart valve mechanisms have been developed, monoleaflet (tilting disc) and bileaflet valves currently hold the greatest measure of acceptance among practitioners. These valves include one or two pivoting leaflets or occluders retained within a seating collar or suture ring that is implanted in place of the physiological valve.
Replacement of a bicuspid (mitral) valve using a procedure that preserves portions of the papillary muscle and chordal apparatus is discussed herein for exemplary purposes. In that procedure, the anterior leaflet is bisected and detached from the annulus, and the two halves are groomed and then sutured to the posterior mitral annulus with the papillary muscle and chordal apparatus substantially intact. Such a procedure and its benefits are described in significant detail by H. Feikes, et al., Preservation of All Chordae Tendineae and Papillary Muscle During Mitral Valve Replacement with a Titling Disc Valve, 5 J. Cardiac Surg., No. 2 pp. 81-85 (1990). The authors conclude that this mitral valve replacement procedure can be practical using both monoleaflet and bileaflet valves. However, it is readily apparent to those skilled in reconstructive cardiac surgery that selection of a suitable valve type and proper orientation of the prosthesis can be important factors impacting the long term success of this procedure for a given patient. In particular, due to the position at which the valve tissue is sutured to the posterior mitral annulus, care must be taken to ensure that the peripheral edge of a leaflet does not contact the tissue during normal operation of the valve. Such contact can result in the intermittent, partial, or complete malfunction of the valve, as well as damage to or dislodgement of the valve tissue.
Four primary combinations of valve types and orientation are considered, as diagramed in FIGS. 25-28 herein. The four combinations ranked by ascending level of risk include: (1) monoleaflet valve M with anterior orientation (FIG. 25 ); (2) bileaflet valve with anti-anatomical orientation (FIG. 26 ); (3) bileaflet valve with anatomical orientation (FIG. 27 ); and (4) monoleaflet valve M with posterior orientation (FIG. 28 ). While the monoleaflet with posterior orientation is generally regarded as a high risk configuration and the monoleaflet with anterior orientation is considered to have little or no risk, the degree of risk associated with a bileaflet valve oriented in either the anatomical or anti-anatomical configuration depends upon the particular type of valve selected (particularly its range of excursions, radial exposure, and lateral exposure), the post-procedure anatomical characteristics of the annuls, and the patient's requirement for certain operational parameters associate with the valve.
While a monoleaflet valve may be preferred in order to achieve the lowest risk level with an anterior orientation, a physician may prefer to implant a bileaflet valve to obtain specific functional benefits associated with or unique to the particular bileaflet valve structure.
The bileaflet valve has been extensively developed and refined. However, there is still room for further improvement. Problems associated with the weakening or structural failure of critical components in the valve are linked both to dynamic mechanical stresses and cavitation. It is noted that a certain amount of antegrade and retrograde leakage is generally anticipated. However, the amount of leakage is preferably maintained within acceptable limits corresponding roughly to normal anatomical valves. In addition, minimizing the physical size of the valve prosthesis, particularly the longitudinal dimensions of the annular base, produces greater excursion along the peripheral edges of the leaflets, while simultaneously increasing the difficulty in raising the heights of the pivot axis. Furthermore, recesses, crevices, corners, and obstructions required to restrain the leaflets within the annular base and maintain pivotal movement also interfere with circulation, create turbulence, and produce zones of stagnation, each potentially providing a thrombogenic nidus that may eventually lead to an embolism. Although bileaflet valves are hemodynamic, spacing the fixed axis of rotation of the leaflets significantly apart from the secondary natural axis of rotation limits the maximum speed or angular rate which the leaflets may attain during opening and closing.
In regard to the selection of suitable materials, there is an inherent balancing between the selection of materials for ease of fabrication, biocompatibility, strength, and weight versus selection with respect to the acceptable level of fragility of the resulting components, particularly those involving delicate structures such as wire guides, cages, and pins that bear significant loads. In addition, the structure of many pivot mechanisms requires the annular bases to have opposing flat sides rather than a substantially or completely circular bore, thereby restricting the maximum flow volume and increasing the valve's nominal fluid pressure.
U.S. Pat. No. 4,276,658 to Hanson provides a representative example of a conventional bileaflet heart valve. That valve utilizes a pair of semicircular pivot “ears” disposes on opposing sides of each leaflet received within “hourglass-shaped” slots to control the pivotal movement of the leaflets—including the angular sweep between the open and closed positions, the tiling of the valve away from its restrained pivotal axis, and the translational movement of the leaflet both parallel with its normal plane and along the linear flow path through the bore of the annular base. The Hanson '658 patent also describes the use of a pyrolytic carbon coating over a metallic or synthetic substrate for fabrication of the valve's components.
For comparison, U.S. Pat. Nos. 4,240,161 to Huffstutler and 3,859,668 to Anderson provide representative examples of the features, structure, and operation of monoleaflet or “titling disc” heart valves.
Various improvements directed toward correcting the deficiencies described above have been developed, each achieving varying degrees of success and accompanied by inherent tradeoffs with other beneficial features.
U.S. Pat. No. 3,903,548 to Nakib discloses an effort to utilize the beneficial features of the monoleaflet principle in a bileaflet valve that similarly omits fixed pivotal axis, however the resulting cage structure produces an unacceptably small effective bore and correspondingly high pressure gradient across the valve.
In a bileaflet valve structure such as disclosed in the Hanson '658 patent, the leaflets may each pivot filly between the open and closed portions on the order of 80,000-120,000 times per day given a standard pulse of 60-80 beats per minute. Movement of the leaflets through a viscous aerated fluid such as blood may produce significant cavitation —the formation of partial vacuums caused by sudden movement of the flowing fluid away from the surface of the leaflets as a result of mechanical forces exerted by the leaflets. These partial vacuums produce “micro bubbles” on or near the surface of the leaflets, and when the pressure is released, vacuums change into positive pressure regions which lead to implosion of bubbles which can cause pitting of the surface of the leaflet. The cavitation potential is amplified greatly by the virtually instantaneous stopping and starting of the leaflets as they contact a rim along the annular base and also, in the case stopping, by the rate of speed at which the leaflet is traveling when it stops. Contact between the leaflet and the rim greatly increases the compressive forces on the adjacent fluid, and as the leaflet pivots away from the rim the corresponding effects of the expansions are magnified by increased negative pressures and stronger partial vacuums. Whereas standard cavitation produces pitting of metal surfaces due only to mechanical contact between the flowing fluid and moving object, introducing reciprocal movement and mechanical contact within the fluid cause the collapsing cavitation bubbles to strip or shear material from the leaflet surfaces at an accelerated rate. Although the surface pitting occurs at a near microscopic level, the result is surface degradation of the leaflet which can induce stress fractures and fragmentation leading to the premature failure of a leaflet.
U.S. Pat. No. 4,078,268 to Possis discloses a substantially circular bore through the annular base, as well as a nearly complete separation between the peripheral edges of the leaflets and the annular base around the circumference of the valve. While this design obviates certain cavitation problems, it permits high levels of antegrade and retrograde leakage and places the entire load of restraining each leaflet on a pair of pivot pins received within adjustable bearing plugs. The combination of increased torque, absorbed impact forces, vibration, and normal frictional contact are believed to exert undue mechanical stresses on the relatively delicate pivot pins and bearing plugs.
U.S. Pat. No. 5,080,669 to Tascon discloses an annular base that defines channels which intersect the pivot axis of the leaflets at various angles to direct flow of blood around enlargements in the leaflets that serve as the pivot axis, in an effort to cleanse the surfaces of the enlargements and prevent zones of thrombogenic stagnation from forming. However, the inward projections forming the channels and barriers restraining the leaflets in the Tascon '669 design create obstacles to uniform blood flow through the bore of the annular base, and define acute corners and crevices which can accelerate the formation of a thrombus. In addition, the enlargements continuously block a majority of the potential flow through each of the channels, thereby minimizing any cleansing effect that is realized.
U.S. Pat. No. 4,892,540 to Vallana discloses a pair of vertical “chimneys” defined by the lobes of the annular base and communicating with the recesses in which the ears of the respective leaflets are received. In concept, blood flow in either the antegrade or retrograde direction passes between the pivot ears and the side wall of the annular base to cleanse the recess. However, the angled base portions forming each wedge-shaped separator body hold the pivot ears and leaflets in an elevated position proximate to the inlet from the chimney into the recess, thereby minimizing flow through the chimney. The pivot ears either reduce the flow rate within the recess or divert the flow away from portions of the recess where stagnation could occur, thus diminishing the effectiveness of any cleansing action. Whereas Tascon '669 contemplates alternating between multiple flow paths oriented at diverse angles to enhance the “scrubbing” effect, Vallana '540 only contemplates cleansing that is substantially repetitive and reciprocal along one path for both antegrade and retrograde flow. Finally, to the extent that Vallana '540 would produce an acceptable retrograde cleansing action due to the pressure differential created within the recess feeding into the chimney, it is at the expense of a significantly restricted non-circular bore through the annular base accounting for a substantial reduction in antegrade circulation.
Although the Hanson '658 patent discloses the pivot ears preventing blood stagnation in the area of engagement with the recesses, the use of transesophageal echocardiography in patients receiving mitral valve replacements has shown the formation of dangling fibrin strands along the interior surface of the valve in the areas between and proximate to the pivot recesses. These small filamentous abnormal echoes (SAE) are considered non-obstructive while within the valve, however their frequent disappearance strongly suggests a thrombotic origin and a significant correlation with the risk of early thrombogenic episode has been observed.
Many factors may be responsible for the formation of the fibrin strands, including regions of blood stagnation which provide a nidus for thrombogenic formations, or defects in the materials or structure of the valve that permit the direct attachment of blood cells. It may therefore readily be appreciated that two important goals when designing a bileaflet heart valve are maintaining optimal antegrade and retrograde circulation, and eliminating regions of reduced circulation within the valve that might foster the development of a thrombogenic mass. It is suggested that while the Hanson '658 patent shows a relatively shallow semi-circular recess, in practice it has not been possible to achieve a workable commercial embodiment of a bileaflet valve having pivot ears with a suitably shallow recess to enhance cleansing of the recess by normal antegrade and retrograde circulation. For example, the commercially available embodiments of the Hanson '658 valve have recesses forming entrance angles ranging from 35° to 48° measured between the lateral wall of the bore and the tangentially adjoining surface of the recess, depending upon overall size of the valve. Recesses forming an angle of 35° or less with the adjoining lateral wall have been achieved in monoleaflet valves, however the significantly different structure and operation of monoleaflet valves has not permitted the successful utilization of many comparable features in bileaflet valves.
Various adaptations have also been made in an effort to improve the pivot mechanism. One option is to eliminate the pivot ears or pins, and allow the leaflet to rock on projections extending inwardly from the annular base. These configurations generally require some engagement between the leaflet and the projections—either the projection being received within a notch or recess in the leaflet, or the leaflet forming a trapping flange that prevents egress from between two spaced-apart projections. For example, U.S. Pat. Nos. 4,863,459 to Olin and 4,935,030 to Alonso describe leaflets that include a swelled area or camming surface trapped between two projections. U.S. Pat. Nos. 4,373,216 to Klawitter, 4,692,165 to Bokros, 4,872,875 to Hwang, and 5,354,330 to Hanson each describe a variation in which the leaflet defines a peripheral notch or recess receiving a projection the annular base. While designs utilizing a notch in the leaflet are more secure than the trapped flange configurations, they are also more difficult to assemble without placing undue stress on the leaflets or projections. In addition, these designs similarly present flat-sided bores and projections which extend into the bore and obstruct antegrade flow. As the complexity of these projections increases, the opportunity for a crevice or recess providing a thrombogenic nidus also increases. Representative examples of relatively complex pivot structures that present several potential stagnation sites include U.S. Pat. Nos. 5,116,367 to Hwang and 5,123,920 to Bokros.
One prominent feature of the bileaflet valves discussed above is the degree of exposure or incursion that is exhibited by the leaflets relative to the annular base. Excursion can be thought of as the maximum distance which the distal ends of the leaflets protrude from the bottom of the annular base when the valve is completely open, measured from the lowermost planar surface of the base to the most distal point on the peripheral edge of the respective leaflet. However, when comparing the anatomical and anti-anatomical orientation of a bileaflet valve with reference to the mitral valve replacement procure discussed above, incursion can also encompass two more complex relationships.
U.S. Pat. Nos. 5,246,453 to Bokros and 5,002,567 to Bona disclose alternate configurations in which the leaflets are not generally planar, and are supported by and pivot about fulcrums disposed on the lower portion of each leaflet. While these designs present an incursion both above and below the annular base, it allows the height of the annular base to be reduced somewhat relative to comparable bileaflet valves. While such a design is considered to be more responsive to reversal in the antegrade flow, it also relies upon shifting the axis of rotation relative to the leaflet's moment of inertia and therefore produces different operational characteristics than might normally be expected.
One factor previously alluded to which affects the speed at which the valve operates, is the displacement between the fixed axis of rotation and the corresponding En moment of inertia of the leaflet. Another factor is the shape of the leaflet. In this regard, optimization of several physical parameters must be contemplated. The leaflets must move through an arcuate path in response to fluid pressure applied from both the antegrade and retrograde directions, starting from differential initial orientations relative to the fluid pressure, and within an initially static versus initially dynamic environment. Consequently, valves having superior opening characteristics may be slow to close or resist complete closure, and vice versa. Leaflets having an angled, curved, or bicurved design to enhance the immediate responsiveness to changes in hemodynamic forces can be employed to address this problem. Other factors include reducing turbulence or backwash that might resist the leaflet's momentum or increase its apparent resting inertia, reducing the weight or thickness of the leaflet, allowing the leaflet to rock or cam differently in response to antegrade or retrograde pressures, maximizing the laminar flow through the valve body over the entire leaflet surface, and eliminating sources of friction, vibration, or misalignment that could adversely affect the mechanical operation of the valve.
Another approach mentioned above is to increase the translational movement of the leaflet within the annular body, thereby permitting the leaflet to pivot more naturally about its inertial axis in direct response to the hemodynamic forces. This approach can potentially be more beneficial than merely moving the fixed axis of rotation nearer to the moment of inertia, since it also serves to reduce frictional forces and other physical impediments to proper valve operation. One limitation is the need to maintain proper alignment and seating of the leaflet without encumbering the flow passage with obstructions or incorporating free structures that increase the likelihood of valve failure.
U.S. Pat. No. 4,535,484 to Marconi describes a bileaflet valve in which the leaflets are “free-floating”, thereby increasing translational movement and reducing the mechanical stresses imposed at localized pivot points and other load bearing surfaces. However, the Marconi '484 design requires a complex and fragile cage structure to restrain the leaflets, thereby producing a significant risk of damage to the valve during manufacturing or handling and increasing the potential for catastrophic failure of a valve component that would result in death or severe injury to the patient, mitigating against the use of certain materials such as pyrolytic carbon, and greatly increasing the cost and complexity of fabrication.
For comparison, U.S. Pat. No. 4,689,046 to Bokros describes a trapezoidal pivot ear having beveled edges, arguably decreasing the translational freedom, but enhancing the “sweeping” effect of the pivot ear to prevent thrombogenic formations within the recesses and distributing lateral stresses over a wider surface area.
It will also be appreciated from analyzing bileaflet heart valves, such as disclosed by the Hanson '658 and Possis '268 patents, that the leaflets divide the bore into three passages having unequal cross-sectional areas, and that corresponding effects on fluid dynamics should be expected. Observation of these valves in operation shows that flow rates through the passages will vary generally inversely with the corresponding cross-sectional area. As such, in a valve such as Hanson '658 which present a relatively narrow central passage, the flow rate of blood passing through that central passage is greater than through the two passages on opposing sides. The faster blood flow in the center, relative to the sides, can cause additional turbulence within or downstream of the valve, or produce a pressure differential or venturi effect within the valve that can impede or retard the optimal translational or pivotal movement of the leaflets. The Possis '268 valve presents a larger central passage with narrower cross-sectional passages on each side, thereby reversing the fluid dynamics compared with the Hanson '658 design.
While many common functional goals have been recognized among designers of bileaflet heart valve prostheses, there are strongly divergent opinions concerning the prioritization of those goals and how best to achieve specific results or advantages. Accordingly it will be readily appreciated that these competing factors significantly influence the design and optimization of all bileaflet heart valves and that further improvements may be made. The present invention provides advantages over the prior art bileaflet heart valves and solves problems associated therewith.
SUMMARY OF THE INVENTION
Briefly described, the bileaflet heart valve prosthesis of the present invention comprises an annular base defining a substantially circular bore, and a pair of pivoting leaflets; each of the respective leaflets having first and second sides, the first side being a top side and the second side being a bottom side, the bottom sides of the respective leaflets generally facing one another when the respective leaflets are in an open position; each bottom side having an upper half and a lower half, a major portion of the upper half providing an upper surface lying generally in a first plane and a lower half providing a lower surface lying generally in a second plane, the first plane lying at an angle to the second plane; a third plane passing through a horizontal cross-section of the annular base, the first and second planes lying at angles to the third plane when the leaflets are in either the open or closed positions; wherein the first plane of each of the respective leaflets extends beyond an angle of 90° with respect to the third plane when the leaflets go from the fully closed position to the fully open position.
The first plane can extend beyond a 90° angle with respect to the third plane when the leaflets go from the fully closed position to the fully open position without diminishing the leverage for closure of the leaflets when the leaflets are in the fully open position. This is because the lower portion of the bottom side of the leaflets remain at a suitable angle to allow for adequate leverage against the lower portion of the leaflet, to shift the leaflets within the respective recesses and pivot the leaflets to the closed position once the upper fulcrum edge comes into contact with the upper sidewall of the respective recess.
In preferred embodiments the leaflets have a beveled bottom side which minimizes the travel angle “k′” between the open and closed positions. The lateral ends of each leaflet are received within “open channel” recesses where the ends are “free floating”, permitting translational and rotational movement of the leaflets within the respective recesses. In preferred embodiments, each recess communicates with at least one groove extending around an inner peripheral surface of the annular base, and a cleansing flow is directed vertically or angularly through the recess to the groove during antegrade circulation, and from the grooves through the recess during retrograde flow and valve closure. The direction of this cleansing flow through the recesses varies depending upon the direction of circulation and the orientation of the leaflets, and is mostly unobstructed within the recesses by the leaflets. The peripheral edges of the leaflets present minimal incursion or exposure beneath the bottom of the annular base when the valve is completely open. When the leaflets of the valve are closed, the peripheral edge of each leaflet in the central region is preferably slightly spaced apart from the annular base to allow free movement of the leaflet and to avoid unsuccessful wear and/or stress. The peripheral edge of each leaflet in preferred embodiments only contacts the annular base adjacent the groove proximate the lateral regions of the leaflet.
In preferred embodiments, the angle at which fluid washing the surfaces of the annular base flows into the recesses is less than 35° to permit better washing dynamics. The preferred valve also has a dynamic pivot constructed primarily on the lateral sides of the leaflets where two fulcrum edges are created by notches in the peripheral edge. The leaflets pivot on each of the respective fulcrum edges at different points in the opening and closing cycle of the valve. This swivel pivot mechanism also permits significant translational movement of the leaflets especially in the fully open position. This mechanism is believed to provide a pivot mechanism which permits the valve to open and close more rapidly than prior art bileaflet valves.
It is one object of this invention to design a bileaflet heart valve prosthesis of the type used for tricuspid or bicuspid (mitral) valve replacement, and particularly one which provides superior operating capabilities and minimizes the risk to the patient when implanted using a procedure involving preservation of the papillary muscle and chordal structure by fixation to the posterior mitral annulus.
It is a related object of this invention to design the above bileaflet valve for implantation in either the anatomical or anti-anatomical configuration, such that the peripheral edges of the leaflets present an extremely low incursion below the bottom surface of the annular base, and further present minimal radial and lateral exposure.
It is an additional object of this invention to design the above bileaflet valve such that the passages through the bore of the valve between the leaflets provide substantially equal relative flow rates, thereby mitigating against flow differentials, gradients, or venturi effects which would otherwise cause turbulence or impede the translational or pivotal movement of the leaflets.
It is another object of this invention to design the present bileaflet valve such that it utilizes a “free floating leaflet” configuration with no pivot ears or projections, to thereby reduce and redistribute mechanical or contact stresses otherwise focused on these pivot axis in conventional bileaflet valves.
It is a further object of this invention to design the above bileaflet valve such that it defines a cleansing channel or recess within the annular base in the region traversed by the lateral ends of the leaflets, and such that the cleansing channel is unobstructed within that region in a generally vertical direction, and induces or “steers” both vertical and angular fluid flow through that region during antegrade and retrograde circulation.
It is another object of this invention to provide a bileaflet valve such that a shallow angle of less than about 35° may be formed between the lateral surfaces of the annular bore and the adjoining surfaces of the recesses which restrain the leaflets. It is believed that this will enhance cleansing of the recesses by normal antegrade and retrograde circulation. Furthermore, because the recesses have unobstructed open channels permitting easy antegrade and retrograde flow through the recesses, the surfaces within the respective recesses will permit enhanced washing action.
It is a further object of this invention to provide a bileaflet valve such that the peripheral edge of each leaflet is received within a recess and beneath a seat defined by the annular base, such that there are no observable gaps between the annular base and peripheral edge in the contact regions between the leaflets and annular base when viewed from a perspective along the longitudinal axis of the valve.
It is a fisher object of this invention to design the above bileaflet valve such that the annular base of the valve defines beveled arcuate surfaces which contact the edges of the leaflets as the leaflets move between the open and closed positions, thereby creating a generally smooth and continuous arcuate path along which the leaflets roll when pivoting between the open and closed positions to distribute stress forces over an extended region of the leaflet and annular base.
The above-described features, advantages and objects, along with various other advantages and features of novelty are pointed out with particularity in the claims of the present invention annexed hereto and forming a part thereof. However, for a better understanding of the invention, its advantages, and objects attained by its use, reference should be made to the drawings which form a further part hereof and to the accompanying descriptive matter in which there is illustrated and described preferred embodiments of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawing, in which like reference numerals indicate corresponding parts throughout the several views:
FIG. 1 is a perspective view of a preferred embodiment of the present invention showing the leaflets in a fully open position;
FIG. 2 is a lateral side view of the preferred bileaflet heart valve of the present invention shown in FIG. 1;
FIG. 3 is a lateral side view of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 4 is a top plan view of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 5 is a bottom plan view of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 6 is a partially broken away elevated perspective view of the annular base of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 7 is a cross-sectional side view of the lateral side of the annular base of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 8 is a cross-sectional side view of the traverse side of the annular base of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 9A is an elevated perspective view of the bottom side of the preferred leaflet shown in FIG. 1;
FIG. 9B is a cross-sectional perspective view of the preferred leaflet shown in FIG. 1, in a manner similar to that shown in FIG. 9A, but providing a perspective view only of a cross-section of the leaflet as seen from the line 9 B- 9 B of FIG. 9A;
FIG. 10 is a bottom plan view of a leaflet of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 11 is a top plan view of a leaflet of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 12 is a vertical side view of a first lateral side of the leaflet of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 13 is a vertical side view of a second lateral side of the leaflet of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 14 is a horizontal side view of an upper edge, including the mating edge, of a leaflet of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 15 is a horizontal side view of the peripheral edge of the leaflet of the preferred bileaflet heart valve shown in FIG. 1;
FIG. 16 is a diagrammatic cross-sectional view of the preferred bileaflet heart valve shown in FIG. 1 with the leaflets in a fully open position;
FIG. 17 is a diagrammatic cross-sectional view of the preferred bileaflet heart valve shown in FIG. 1 illustrating the transition of the leaflets from a fully open position to a fully closed position;
FIG. 18 is a partially broken away cross-sectional view of the recess as seen from the line 18 — 18 of FIG. 7;
FIG. 19 is a partially broken away cross-sectional view of the recess as seen from the line 19 — 19 of FIG. 7;
FIG. 20 is a partially broken away cross-sectional view of the recess similar to that shown in FIG. 19 but generally showing a lateral side portion of a leaflet within the recess when the leaflet is in a fully closed position as shown diagrammatically in FIG. 17 ;
FIG. 21 is a partially broken away cross-sectional view similar to FIG. 20, but showing the leaflet in an open position as shown in FIG. 1;
FIG. 22 is an elevated perspective view of the preferred bileaflet heart valve of the present invention similar to that shown in FIG. 1, except that the leaflets are in a fully closed position;
FIG. 23 is a partially broken away bottom plan view of the preferred bileaflet heart valve shown in FIG. 22 when the leaflets are in a fully closed position;
FIG. 24 provides a graphic representation of the quantity of blood flowing through a bileaflet heart valve during a single heart contraction cycle wherein the positive quantity indicates blood flowing in an antegrade direction and the negative quantity below the “y” axis indicates the quantity of blood flowing in the retrograde direction;
FIG. 25 is a perspective view of a monoleaflet heart valve with anterior orientation as known to the prior art;
FIG. 26 is a perspective view of a bileaflet heart valve with anti-anatomical orientation;
FIG. 27 is a perspective view of a bileaflet heart valve with anatomical orientation;
FIG. 28 is a perspective view of a monoleaflet heart valve with posterior orientation as known to the prior art; and
FIG. 29 is a perspective view of a bileaflet heart valve of the present invention implanted in an anatomical orientation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to the drawings, a preferred bileaflet heart valve prosthesis 110 of the present invention and parts thereof are illustrated. The bileaflet heart valve prosthesis 110 of the present invention is preferably fabricated from a metal such a titanium, a carbon compound (or carbon with a minor percentage of silicon) such as pyrolytic carbon or the like, a metal alloy, or a suitable substrate coated with pyrolytic carbon as are well known in the art.
Referring now to FIGS. 25-29, a bileaflet heart valve 10 similar to the preferred heart valve prosthesis 110 of the present invention is shown diagrammatically implanted within the heart 101 of a patient, with the valve 10 sutured in place proximate to the mitral annulus 103 of the anatomical coronary valve and disposed above the papillary muscle and tendineae chordae 105 fixed to the posterior mitral annulus as described previously. The bileaflet valve 10 may be implanted in either the fully anatomical orientation or the fully anti-anatomical orientation as shown in FIGS. 26 and 27, respectively, or adjusted between the fully anatomical and anti-anatomical orientations by rotating the valve 10 within the corresponding suture ring (not shown) as is well known to the art. These orientations may be compared with the anterior and posterior orientations of a monoleaflet valve M shown in FIGS. 25 and 28.
Referring now to FIGS. 1-5, a preferred embodiment of the bileaflet heart valve prosthesis 110 is described. The preferred bileaflet heart valve 110 of the present invention shown in FIG. 1 includes an annular base 112 and first and second leaflets 114 . The fist and second leaflets 114 are mounted within the annular base 112 for pivotal movement between a fully open position, shown in FIGS. 1-5 and diagrammatically in FIG. 16, and in phantom in FIG. 17, and in a fully closed position shown in FIGS. 22-23 and diagrammatically in FIG. 17 . Referring now also to FIGS. 68, the annular base 112 has a top surface 124 and an inner wall 126 which defines a generally circular bore 116 passing through the annular base 112 in a direction generally parallel with a longitudinal axis 128 oriented generally in parallel with a vertical path for circulation of fluid or blood through the generally circular bore 116 .
The top surface 124 of the annular base 112 is raised proximate opposing lateral sides 129 . On the inner wall 2 inner surface sidewall 126 of the annular base 112 proximate the opposing lateral sides 129 , are flat portions 130 of lateral surfaces 133 which define flat lateral sides of the generally circular bore 116 . The flat portions 130 of the lateral surfaces 133 include a pair of recesses 132 in each of the respective lateral sides 129 of the base 112 . Further lateral depressions 135 are centrally located in a lower portion of the inner surface 126 proximate each of the two lateral sides 129 , below and between the respective recesses 132 on each side, in the respective flat portions. In preferred embodiments, these depressions have a curvilinear surface which would define a portion of one side of a cone. The recesses 132 extend into the respective flat portions 130 of the lateral surfaces 133 , thereby displacing a cylindrical bottom surface 140 of the recess 132 from the respective lateral surface 133 proximate the respective lateral side 129 . In preferred embodiments of the present invention, each of the cylindrical bottom surfaces 140 of the respective recesses 132 pass through a cylindrical radius which is “feathered out” as the cylindrical surface 140 approaches a junction with the respective lateral surface 133 .
Referring now also to FIGS. 18-21, a line 181 , shown in FIG. 19, which is tangential with a point on the cylindrical bottom surface 140 of the recess 132 just prior to a further point at which the cylindrical surface 140 is “feathered out” to form a junction with the lateral surface 133 , lies at an angle “g′” to a tangent line 184 which intersects line 181 and is tangential to the lateral surface 133 . In order to properly measure the entrance angle “g′” to the recess 132 , a number of lines similar to line 181 which are tangential to a point on the cylindrical surface 140 must be considered. This may be an infinite number of lines. The entrance angle, “g′”, will be the angle between the lines 184 and 181 which will be the greatest angle that exists between the line 184 and any of the lines which can be drawn which intersect with line 184 and are tangential to a point on the cylindrical surface 140 . This angle “g′”, is representative of a recess entrance angle to the cylindrical recess 132 . In preferred embodiments the recess entrance angle is less than about 35°. Preferably, the recess entrance angle “g′” is between about 20° and about 35°. More preferably, the recess entrance angle “g′” is from about 25° to about 34°. In even more preferred embodiments, the recess entrance angle “g′” ranges from about 28° to about 33.5°. There is no preferred angle because the preferred angle may vary in response to changes in other parameters, especially the diameter of the annular base 112 . It will be appreciated that recesses to retain pivotal leaflets have existed in the bileaflet heart valve prostheses of the prior art for some time. It is believed, however, that a lower recess entrance angle will facilitate washing of the recess to minimize stagnation and potential for thrombogenic events in proximity to the recess 132 . Therefore, it is believed that diminishing the angle of entrance to the recess 132 will provide for better washing activity and lessen any potential for embolism which may exist in patients utilizing prosthetic heart valves.
Referring now also to FIGS. 9-15, the leaflets 114 have two sides, a top planar surface 142 and a beveled bottom side 143 . The bottom surface 143 has a peripheral bevel portion 144 proximate the peripheral edge 150 and a central portion or central bevel 145 proximate a mating edge 148 . The mating edge 148 has a narrow planar surface running nearly the entire width of the leaflet 114 . The respective leaflets are mirror images of one another in preferred embodiments so that when the respective leaflets 114 pivot to reside in the fully closed position, the mating edges 148 of the respective leaflets mate together to significantly obstruct blood flow through the very limited space between the respective mating surfaces 148 .
It will be appreciated that some blood will “regurgitate” between the mating edges 148 of the respective leaflets 114 when they are closed. However, this is to be expected. In fact, such blood flow, while it should be minimized, performs an important function of cleansing the mating edges 148 as the blood regurgitates between the respective edges 148 .
The central beveled portion 145 of the beveled bottom side includes a flat planar surface 146 which is flanked on either side along the width W of the leaflets 114 , by curvilinear side surfaces 147 a and 147 b which rise up proximate lateral sides 151 of the leaflets 114 to flat side bevels 147 c and 147 d which separate the mating edges 148 from the peripheral bevel 144 on the beveled bottom side 143 proximate the respective lateral sides 151 . The width Wps of the flat planar surface 146 is greater than one-half of the width W of the leaflet 114 , and is therefore a major portion of the central bevel 145 . As used herein, the phrase “a major portion” means a portion of the whole which has a width dimension which is at least as great as that of one-half of the width of the whole.
The respective lateral sides 151 of the respective leaflets 114 each have a cylindrical surface proximate the diamond-shaped cylindrical surface 154 . Notches 153 , 155 are located adjacent to the diamond-shaped cylindrical surface 154 . The inflow notches 153 are located generally between the diamond-shaped cylindrical surface 154 and the top edge of the leaflet 114 . The generally V-shaped notch 153 is created and defined by an inflow flat 160 and an inflow side wall 156 of the diamond-shaped cylindrical surface 154 . The generally V-shaped notch 155 , called the outflow notch 155 , is created and defined by an outflow flat 162 and an outflow side wall 158 of the diamond surface 154 .
As previously discussed herein, washing of the various surfaces, crevices and the like by blood fluid passing through the heart valve prosthesis 110 is believed to be particularly important to reduce stagnation and potentially thrombogenic activity. The present bileaflet heart valve 110 is designed with this in mind. All of the surfaces of the present valve 110 are actively washed at one time or another in the pumping cycle of the heart in which the valve 110 is implanted. When the valve 110 is in the fully opened position all of the surfaces of the side wall 126 are actively washed by blood flowing over the surfaces, as are the recesses 132 . The leaflets 114 are also actively washed as the blood flows in the antegrade direction through the bore 116 .
The diamond-shaped cylindrical surface 154 also has a cylindrical radius generally consistent with the cylindrical radius of the bottom surface 140 of the recess 132 . As shown particularly in FIG. 22, when the leaflets 114 are in a fully closed position, some regurgitation of blood through the bileaflet valve 110 occurs in the retrograde direction. The regurgitation is desirable to a certain degree, so long as the energy efficiency of the pumping activity of the heart is not compromised. The regurgitation occurs in a number of areas. Referring now also to FIG. 22, and the other illustrations of the preferred bileaflet heart valve 110 , retrograde blood flow may pass between the mating surfaces 148 of the respective leaflets 114 as demonstrated by arrows 194 , 195 and 196 in FIG. 22 . The bottom of the leaflets 114 also channel retrograde blood flow into the recesses 132 by directing the blood against the seats 136 created by the separation between the cylindrical bottom surface 140 and the upper edge 134 of the recesses 132 . An outflow side wall 158 of the diamond surface 154 may also channel retrograde blood flow to the recesses 132 and particularly to the seat 136 . This flow will then regurgitate between the leaflet 114 and the side wall 126 after it flows over the seat 136 and come out proximate the regurgitation representation arrows 191 , 192 and 193 . It will be appreciated that flow through areas where the top planar surface 142 meets the seat 136 will be minimized and that this flow can be further minimized by widening the seat 136 further into the transverse side 131 . Additional retrograde blood flow will wash other portions of the valve 110 , especially portions of the inner wall 126 , including the lateral depressions 135 and the flat portions of the lateral surfaces 133 , and channel upwards proximate arrow 192 in FIG. 22 . It will be appreciated that there will almost always be at least some separation between the peripheral edge 150 of the leaflet 114 and the side wall 126 . This enables retrograde blood flow to regurgitate between the peripheral edge 150 and the side wall 126 proximate the entire peripheral edge 150 . Even where the top planar surface 142 of the respective leaflets 114 are pressed against the respective seats 136 , there is at least some space between the opposing surfaces for a very limited amount of “regurgitating” retrograde blood flow. The regurgitation is particularly significant proximate the transverse sides 131 . This is particularly true because of the side wall surface 126 proximate the center of the peripheral edge 150 is flush, thereby providing no obstruction to the retrograde flow of blood. It will be appreciated that the seat 136 is fully diminished to nothing in this area in preferred embodiments. A further discussion of the seats 136 follows a further description of the leaflets 114 immediately below.
Referring now particularly to FIGS. 16-21, a certain amount of “play” exists between the respective surfaces in the area of the diamond surface 154 and the recess 132 when the leaflets 114 are in the open position. This “play” permits a significant amount of translational movement. Because of the increased potential for translational movement between these surfaces when in the open position, the leaflets 114 have greater freedom for translational motion than is either exhibited or generally possible in any of the prior art valves which have “matched” or “parallel” surfaces in both the open and closed positions. As shown diagrammatically in FIG. 17, when the leaflets 114 are in the fully closed position, the top planar surface 142 is pressed against the seat 136 proximate the upper edge 134 of the recess 132 . Although considerable separation appears to exist between these surfaces in FIG. 17, this separation is exaggerated for clarity. During use of the valve 110 , the top planar surface 142 abuts against the seat 136 . In actual fact, the spacial relationship between the top planar surface 142 and the seat 136 , when the leaflets 114 are in the closed position, is that shown in FIG. 22, where the seat 136 cannot be separately called out because it is not visible in the view.
An axis 165 , parallel with respective cylindrical surfaces on diamond-shaped cylindrical surfaces 154 of the respective leaflets 114 , and perpendicular the top surface 142 will lie at an angle “k” to an axis 167 , parallel with the respective cylindrical bottom surface 140 of respective recess 132 , and perpendicular with the upper edge 134 of the recess 132 , when the leaflets 114 are in the fully opened position. When the leaflets 114 are in the fully closed position these respective axes 165 and 167 will be either superimposed upon one another, or in parallel with one another and the angle “k” will generally be about zero. In this position, therefore, the cylindrical surfaces 140 will be “matched” or “parallel” with the diamond-shaped surfaces 154 of the respective lateral sides 151 of the respective leaflets 114 . The angle “k”, shown diagrammatically in FIG. 17, is equal to the travel angle “k′”, when the leaflets 114 are in the fully open position.
It will be appreciated that significant translational movement is permitted when the leaflets 114 are in the open position. This can be seen in FIG. 16 where the first axis 165 of the leaflet 114 lies at an angle “k” with respect to the second axis 167 of the cylindrical recess bottom surface 140 . This translational movement of the leaflet 114 , when in the fully open position, is believed to allow the leaflet 114 to move from its fully open position to its fully closed position much faster than prior art devices. This is because the initial movement, when a retrograde flow of fluid begins, is an upward translational movement of the diamond-shaped surface 154 within the recess 132 , until the top side fulcrum edge 166 engages the upper edge sidewall or seat 136 within the recess 132 . When the top side fulcrum edge 166 engages the seat 136 within the recess 132 , the leaflet 114 has already overcome any inertia it may have had when “resting” in the fully opened position. The translational movement will subsequently give way to pivotal movement of the leaflet toward the fully closed position. This pivotal movement will occur rapidly since the initial translational movement will provide some momentum which will be translated into pivotal or annular movement toward closure of the leaflets 114 .
When the leaflet 114 is in the fully closed position, the initial movement of the leaflet is more likely to be followed immediately by a pivotal movement, because the cylindrical diamond-shaped surface 154 and the cylindrical recess bottom surface 140 are more closely mated as shown in FIG. 20 and the separation allowing translational movement from end to end is more limited. The leaflet 114 is likely to slip quickly from the upper side edge 134 toward the lower side sidewall 138 of the leaflet 114 . The leaflet will only begin to pivot after the bottom side fulcrum edge 164 is engaged with the lower side sidewall 138 . It will be appreciated, however, that the mechanism employed by the respective leaflets for pivoting is still a matter of inquiry and is not fully understood at this time. It is believed, however, this dynamic pivot mechanism allows for faster opening and closing of the respective valves 110 . When the valve is in the open position, and the flow direction changes from antegrade to retrograde, it is believed that the leaflet 114 begins its linear motion immediately with the change in the flow direction and the linear momentum is transferred into angular momentum as soon as the top side fulcrum edge or pivot 166 contacts the seat 136 proximate the upper edge 134 of the recess 132 . This is believed to result in quicker closing than is exhibited by prior art devices.
It is believed that the preferred bileaflet heart valve prosthesis 110 of the present invention provides for a lowered thrombus potential due to the consideration given to access for washing in both the antegrade and retrograde directions. Furthermore, the dynamic pivot mechanism of the preferred leaflets 114 in cooperation with the preferred recesses 132 are believed to provide for faster opening and closing of the valve and less friction in the pivot area due to the use of a “rolling” pivot mechanism wherein the pivot activity changes focus from the top side fulcrum edge 166 to the bottom side fulcrum edge 164 . The preferred valve 110 also provides for a minimized travel angle “k′” between the fully opened position and the fully closed position. It is believed that the travel angle provided in the preferred valve 110 may represent at least about 15-10° reduction in the travel angle as compared to many of the prior art devices. This reduction in the travel angle is believed to minimize angular velocity, wear, cavitation potential, and regurgitation volume, while increasing overall efficiency.
The upper edges 134 for the preferred leaflets 114 are believed to slow the leaflet 114 just before closure due to the presence of significant amounts of fluids which may be “squeezed” or compressed against the sidewall 126 of the annular base 112 . Because the seats slow the leaflet 114 just before closure, they are believed to have a minimizing effect on the cavitation potential. It is also believed that the use of discontinuous seats, or seats which diminish prior to continuing into a seat extending from an opposite recess allows for a slight increase in regurgitation potential proximate the center portion of the leaflet where cavitation potential is generally highest due to the likelihood that this area is likely to be subjected to a greater angular velocity as it comes toward closure against the sidewall 126 . The seats 134 also decrease leakage or regurgitation proximate the lateral sides 129 of the annular base 112 when the leaflets 114 are in the closed position. The seats 134 are also believed to provide for increased antegrade flow to wash the flow channels or recesses 132 as the leaflets 114 close. As the leaflets 114 close the fluid in the recesses 132 begins to be “squeezed” or compressed within an upper portion of the recess distal to the transverse sides 131 of the annular base 112 . The width of the seats 134 decreases as they extend from the recess 132 to the transverse side 131 . Since there is no seat 134 in the center most region of the transverse side 131 in the preferred bileaflet heart valve 110 , the fluid “squeezed” or compressed against the seats 134 is generally believed to be released through the bore 116 after it washes at least a portion of the seat 134 . While the leaflets 114 are in the closed position, the seats 134 serve to reduce retrograde leakage or regurgitation and at least a portion of the retrograde flow is channeled around the diamond surface 154 , so as to thoroughly wash these areas when the leaflets 114 are in a closed position.
The bottom surface of the recess 132 is in the form of a curvilinear cylindrical surface and is considered to have a generally cylindrical shape. As used herein, cylindrical surface or cylindrical shape means a surface formed by linear translation of a curve, or a surface which has a radius similar to a portion of a surface of a cylinder. The diamond surface 154 at the lateral sides 151 of the leaflets 114 have a cylindrical shape which is “consistent” with or “mates” with the cylindrical recess bottom surfaces 140 of the recesses 132 . However, as shown in FIG. 20, the diamond surface 154 is consistent with and mates with the bottom surface 140 of the recess 132 only when the leaflet 114 is in the closed position. However, when the leaflet is in the open position, as shown in FIG. 21, and as previously discussed, significant room for translational movement is provided. Furthermore, it will be appreciated that the bottom surface of the recess 140 and the matched cylindrical diamond surface 154 of the leaflet 114 will not be in alignment when the leaflet is in any position other than a fully closed position, thus allowing for significant clearance between the extreme edges of the diamond surfaces 154 and the extreme edges of the recesses 132 . Because of the increased potential for translational movement when the leaflets 114 are in positions other than the fully closed position, the leaflets 114 will exhibit greater translational freedom for motion than is possible with prior art valves having parallel or matched surfaces in all positions as described and defined in descriptions of the prior art devices.
As shown particularly in FIG. 16, the flat planar surface 146 of the central bevel 145 and the peripheral bevel 144 of the bottom surface of the leaflet each lie generally in a plane respectively designated by tangent lines 172 and 174 . As measured by the angle “a” between tangent lines 172 and 174 , the peripheral bevel 144 and the flat planar surface 146 of the central bevel 145 lie generally in planes which lie at an angle to one another. In preferred embodiments this angle will be less than 180°, or preferably at an angle of about 161° to about 178°, more preferably about 166° to about 173°. In preferred embodiments, the angle “a” will be about 167° to about 172°. In the most preferred embodiment under consideration, the angle “a” is about 169°. This bevel in the bottom surfaces of the leaflet 114 , allows the angle of incidence for a flow of blood in the retrograde direction parallel with the longitudinal axis 128 to be a greater angle of incidence in respect to the peripheral bevel 144 than with the flat planar surface 146 of the central bevel 145 . This is believed to be advantageous for at least two reasons. First, since there is a greater angle of incidence, the force of the blood flowing in the retrograde direction will have greater impact upon the leaflet 114 and cause it to pivot toward the fully closed position more rapidly than might otherwise be expected. Furthermore, the difference between the respective bevels, and the angle of the tangent line 176 to the top planar surface 142 allow the peripheral edge 150 to have a shorter radial closing distance to travel before the leaflet 114 is in the fully closed position than might be expected for a leaflet having parallel surfaces.
In preferred embodiments, the angle of the plane in which the flat planar surface 146 of the central bevel 145 rests, to a horizontal plane 170 , which angle is consistent with the angle between tangent line 172 and the plane 170 , will be an angle “a′”. In preferred embodiments, “a′” may range from about 84° to about 97°, preferably about 86° to about 95°, more preferably about 88° to about 94°, more preferably about 90° to about 92°, more preferably more than 90°, and in the most preferred embodiments, “a′” will be either 91°, or 91° or more. Similarly, the angle between the plane in which the peripheral bevel 144 rests, and the horizontal plane 170 may be measured by taking the angle “b′” between the tangent line 174 and the horizontal plane 170 . In preferred embodiments, the angle “b′” will be less than 87°, preferably less than 86°. In preferred embodiments, “b′” will range from about 78° to about 84°, preferably about 80° to about 82°, and most preferably, it will be about 81°. Similarly, the angle of the plane in which the top planar surface 142 of the top side of the leaflet 114 rests, will lie at an angle “c′” to the horizontal plane 170 as measured between the tangent line 176 and the horizontal plane 170 when the leaflet is in the fully open position. In preferred embodiments, “c′” is greater than about 78° and less than 90°, and preferably in a range of from about 82° to about 89°, preferably about 84° to about 88°. In the most preferred embodiment, “c′” is about 86°.
As shown particularly in phantom in FIG. 17, when the leaflet 114 begins to pivot from the fully open position to the fully closed position in response to force exerted upon the peripheral bevel 144 , the force is believed to result in an initial translational movement of the leaflet to lift leaflet 114 within the recess 132 . When the leaflet 114 has reached the fully closed position shown diagrammatically in FIG. 17, an area on the top planar surface 142 proximate the peripheral edge 150 generally proximate the respective lateral sides 151 will abut against the seat 136 on either lateral side 129 and extending at least partially into the adjacent transverse side 131 . When the leaflet 114 is in the fully closed position, the respective mating edges 148 will generally rest against one another while generally allowing at least some retrograde regurgitation of blood between the respective mating surfaces 148 .
It will be appreciated that the preferred embodiment of the bileaflet heart valve prosthesis 110 of the present invention will not have any sharp edges and that all edges will in fact be polished, smoothed or feathered so as to minimize shearing of blood as it passes over any of these edges. These smooth “transitions” between surfaces of all kinds will be obtained by shaving and polishing all edges so that the edges are rounded and have a smooth transition from one plane to another. Any radial surfaces of course will be polished as well.
As shown in FIG. 22, the amount of regurgitation of blood in the retrograde direction is believed to be significant enough to provide appropriate cleansing of the valve 110 . Heart valves are generally designed with at least some regurgitation in mind so long as the regurgitation does not reduce the efficiency of the heart. It is believed that the regurgitation is important to permit the washing of the various surfaces of the present prosthetic device. FIG. 24 generally provides a representation of the quantity (Q) of blood flowing through a bileaflet heart valve during a contraction cycle when the valve is in the aortic position. During systole, the quantity of blood passing through the valve in the antegrade direction (+) is fairly significant. As the force from the contraction diminishes from its highest point, indicated at the apex of the curve (Qsys), until the antegrade flow ends and blood begins to flow in the retrograde direction (−), the leaflets 114 remain in an open position. The retrograde flow then begins to push the leaflets 114 toward the closed position at the lowest point of the curve below the “y” axis (Qcl). As the leaflets 114 close, most of the retrograde flow is obstructed, but not all of it. The remaining retrograde flow is due to leakage around the leaflets 114 . The retrograde leakage (Ql) has been discussed herein and is believed to have a positive effect in respect to washing the various surfaces of the prosthetic heart valve, in that this “regurgitation” will “wash” the surfaces to reduce stagnation of blood as a measure against potential thrombus.
As shown particularly in FIGS. 6 and 7 and demonstrated diagrammatically in FIG. 23, the upper edge 134 blends or “feathers” into the inner wall 126 of the annular base 112 , as does the seat 136 , in preferred embodiments. It is believed that this has a very positive effect upon preservation of the integrity of the top planar surface 142 of the respective leaflets 114 by reducing cavitation potential. This is particularly true in an area approximately 15° to either side of a center line 184 bisecting a leaflet 114 , and in the areas most proximate to the peripheral edge 150 . The potential for negative effects of cavitation upon the top planar surface 142 is also reduced by the shortened travel angle “k′” between the location of the top planar surface 142 when the leaflet is in the fully open position, and the top planar surface 142 when the leaflet is in the fully closed position as represented by tangent line 179 of FIG. 17 . Because the preferred leaflet 114 of the present invention has a “double-beveled” bottom surface, the position of the top planar surface 142 in relation to the side wall 126 can be minimized to reduce the radial distance “k′” traveled by the top planar surface 142 in moving to the closed position. In this way, the angular speed of the movement of the most distal portion of the top planar surface 142 proximate the peripheral edge 150 , where the cavitation potential is generally believed to be the greatest, is diminished gradually when the leaflet 114 approaches the closed position. Cavitation potential is also minimized because the distance is minimized by the beveled design of the leaflets 114 . In this regard, it will be appreciated that the leaflet will continue to gain speed as it pivots through a greater radial distance. Therefore, by minimizing the radial distance between the open position and the closed position, the radial speed of the leaflet 114 can be minimized. In preferred embodiments, the travel angle “k′” will be from about 37° to about 58°, preferably about 39° to about 56°, even more preferably about 40° to about 55°, and most preferably about 45° to about 50°. Cavitation potential is also reduced because the seats 136 , extending from the respective recesses 132 on the respective lateral sides of the leaflet 114 , help to slow the closure or “cushion” the closure of the leaflet against the side wall 126 because the blood between the peripheral edge 150 and the proximate portions of the top planar surface 142 must be “squeezed” out of the intervening space adjacent the respective seat 136 as the leaflet 114 is pivoting toward the fully closed position. Furthermore, a gap 171 (shown in FIG. 8) between the seats 136 of the opposing lateral sides extending into the transverse side permits a continuing flow of blood in the retrograde direction which also helps to prevent the formation of a vacuum on the top planar surface 142 proximate the peripheral edge 150 which is generally the genesis of cavitation damage on the planar surfaces of a leaflet 114 . The “cushioning” effect of the partial or “discontinuous” seats 136 also helps to prevent stress to other portions of the leaflet 114 as they collide with the side wall 126 or the seat 136 .
In FIG. 23, a center line 184 extending from a center point 182 is shown superimposed upon a bottom surface of a leaflet 114 . In preferred embodiments, the respective seats 136 extending from respective recesses 132 will extend only as far as the radius lines 185 and 186 which are radially equidistance from the center line 184 . For this reason, the radial angle “i′” will equal the radial angle “h′” between the radius lines 186 , 185 and the center line 184 , respectively, and the radial angle “j′” will equal twice either of the equal angles “i′” and “h′”. In preferred embodiments, the radial angle of “j′” will range from about 5° to about 55°, preferably about 10° to about 50°, more preferably about 15° to about 45°, even more preferably about 20° to about 40°, even more preferably about 25° to about 35°, and even more preferably about 30°. The reason for limiting the extension of the seats 136 entirely through the inner wall 126 proximate the transverse surface 131 is in part because of a desire to minimize the cavitation potential which is generally greatest within 15° on either side of a center line 184 bisecting the top planar surface 142 of a pivotal leaflet 114 of a bileaflet heart valve. It will be understood that the area having the greatest cavitation potential is likely to be at the most distal portion of the top planar surface 142 from the center point 182 , because it is this portion of the leaflet 114 which gains the most angular speed when the leaflet is pivoting toward closure and is most capable of generating the force required to create cavitation bubbles on the top planar surface 142 . Therefore, eliminating the seat 136 in this particular area, is expected to minimize cavitation potential by permitting more regurgitation through the gap 171 .
While the preferred embodiments of the above bileaflet heart valve 10 , 110 have been described in detail with reference to the attached drawings, it will be understood that various changes and adaptations may be made in the bileaflet heart valve 10 , 110 without departing from the spirit and scope of the appended claims. It is to be understood that even though numerous characteristics and advantages of various embodiments of the present invention have been set forth in the foregoing description, together with details of the structure and function of various embodiments of the invention, this disclosure is illustrative only and changes may be made in detail, especially in matters of shape, size and arrangement of parts, within the principles of the present invention, to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed.
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CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional application 60/387,125, filed Jun. 7, 2002, which is hereby incorporated by reference.
BACKGROUND
[0002] 1. Technical Field
[0003] This invention relates to the coenzyme lipoic acid and more particularly to a method of stabilizing lipoic acid with nicotinamide.
[0004] 2. Description of Related Art
[0005] One of the strongest naturally occurring antioxidants is lipoic acid (LA). α-Lipoic acid is also known as thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric acid and 6,8-thioctic acid. α-LA has a chiral carbon atom and occurs in two enantiomeric forms (R- and S-). The form of LA sold in stores is α-lipoic acid, a synthetic mixture of the natural isomer (R-) and the unnatural isomer (S-). The natural form of R-LA is not as stable as the synthetic mixture. One manufacturer, Asta Medica, sells R-LA for diabetes and has made a stable form of R-LA by crystallizing it with Tris buffer, a commonly used synthetic, but unnatural, buffer.
[0006] Biologically, LA exists as lipoamide in at least five proteins where it is covalently linked to a lysyl residue. Four of these proteins are α-ketoacid dehydrogenase complexes, the pyruvate dehydrogenase complex, the branched chain keto-acid dehydrogenase complex and the α-ketoglutarate dehydrogenase complex. Three lipoamide-containing proteins are present in the E2 enzyme dihydrolipoyl acyltransferase, which is different in each of the complexes and specific for the substrate of the complex. One lipoyl residue is found in protein X, which is the same in each complex. The fifth lipoamide residue is present in the glycine cleavage system.
[0007] Recently LA has been detected in the form of lipoyllysine in various natural sources. In the plant material studied, lipoyllysine content was highest in spinach (3.15 μg/g dry weight; 92.51 μg/mg protein). When expressed as weight per dry weight of lyophilized vegetables, the abundance of naturally existing lipoate in spinach was over three- and five-fold higher than that in broccoli and tomatoes, respectively. Lower concentrations of lipoyllysine were also detected in garden pea, Brussels sprouts and rice bran. Lipoyllysine concentration was below detection limits in acetone powders of banana, orange peel, soybean and horseradish, however.
[0008] In animal tissues, the abundance of lipoyllysine in bovine acetone powders can be represented in the following order: kidney>heart>liver>spleen>brain>pancreas>lung. The concentrations of lipoyllysine in bovine kidney and heart were 2.64±1.23 and 1.51±0.75 μg/g dry weight, respectively.
[0009] LA in its reduced form as dihydrolipoate (DHLA) possesses two—SH groups which provide a very low oxidation potential to the molecule (−0.29 V). Thus, LA and the DHLA redox together are excellent antioxidants capable of interacting with most forms of reactive oxygen species, recycling other antioxidants and additionally reducing oxidized disulfide groups in biological systems. These molecules then may recuperate their biological reducing power and function. These qualities of LA and DHLA make it also one of the most important molecules in redox signaling. A good example of this is the ability of this metabolically active pair to increase glucose uptake in an insulin-mimic effect.
[0010] Various enantiomeric forms of α-LA, and combinations and derivatives thereof (including its reduced form), have been used to treat numerous conditions. For example, U.S. Pat. Nos. 5,650,429 and 5,532,269 disclose the use of LAs in the treatment of circulatory disorders. U.S. Pat. No. 5,569,670 discloses combinations of LAs and vitamins in compositions useful for producing analgesic, anti-inflammatory, antinecrotic, anti-diabetic and other therapeutic effects. U.S. Pat. No. 5,334,612 describes certain alkylated derivatives of LA and their use in treatment of retroviral diseases. U.S. Pat. No. 5,084,481 discloses the use of reduced LA (DHLA) and salts thereof in treating inflammatory diseases. U.S. Pat. No. 6,693,664 discloses use of LA and DHLA in the treatment of diabetes. U.S. Pat. No. 5,508,275 discloses a variety of lipid-selective antioxidants, including lipoic acid derivatives.
[0011] LA suffers from certain disadvantages, however. In particular, the natural form R-LA is unstable above 40° C., so it can degrade under some warehousing conditions. Also LA is hygroscopic. What is needed is stabilization of this natural form of LA with a natural salt.
SUMMARY OF THE INVENTION
[0012] It is an object of this invention to provide a more stable formulation of LA and to make LA readily usable by the body.
[0013] A method of stabilizing R-α-lipoic acid includes combining R-α-lipoic acid with nicotinamide in a weight ratio between about 10:4 to about 10:8, preferably between about 10:5 to about 10:7, and most preferably 10:6. A composition for treating oxidative stress includes R-α-lipoic acid and nicotinamide in a weight ratio of between about 10:4 and about 10:8, preferably between about 10:5 to about 10:7, and most preferably about 10:6.
[0014] Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. It is to be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the present invention, are given by way of illustration and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof, and the invention includes all such modifications.
BRIEF DESCRIPTION OF THE FIGURE
[0015] [0015]FIG. 1 is an infrared spectra of nicotinamide-a-lipoate crystals as mineral oil mulls spread on sodium chloride-polished crystal plates.
DETAILED DESCRIPTION
[0016] Those of ordinary skill in the art will realize that the following description of the present invention is illustrative only and not in any way limiting. Other embodiments of the invention will readily suggest themselves to such skilled persons.
[0017] The present invention is a method of stabilizing R-LA. The method comprises the crystallization of R-LA with nicotinamide. Nicotinamide is a natural form of the vitamin niacin and thus, provides a stable crystalline form of R-LA that is all natural. The amount of nicotinamide at non-toxic doses is about 20 milligrams (mg) to about 100 mg.
[0018] The resulting product can be utilized alone, or in combination with vitamin supplements, food products, and the like.
[0019] Pharmaceutical compositions including the inventive combinations are also provided. The preparation of the pharmaceutical compositions of the invention is carried out in a known manner.
[0020] Useful carriers and auxiliaries for the inventive combinations include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (e.g., corn starch or amylose), cyclodextrins and cyclodextrin derivatives, dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, xylose, talcum, lycopodium, silica gel (e.g., colloidal silica gel), cellulose, cellulose derivatives such as cellulose ethers (e.g., HPMC), C 12-22 fatty acids and magnesium, calcium or aluminum salts thereof (e.g., stearates), emulsifiers, oils and fats, in particular vegetable (e.g., peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil), glycerol esters and partial or complete polyglycerol esters of saturated fatty acids, pharmaceutically acceptably mono- or multivalent alcohols and polyglycols (e.g., polyethylene glycol and derivatives thereof), esters of C 2-22 aliphatic saturated or unsaturated fatty acids (preferably C 10-18 acids) with monovalent C 1-20 aliphatic alcohols or multivalent alcohols such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol and the like (which may optionally also be etherified), esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glyceroforrnals, tetrahydrofurfuryl alcohol, polyglycol ethers with C 1-12 alcohols, dimethylacetamide, lactamides, lactates, ethylcarbonales, silicones (e.g., medium-viscosity polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, etc.
[0021] Additional useful additives include disintegrants, such as cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose.
[0022] The inventive combinations can be coated with conventional coating materials such as polymers and copolymers of acrylic acid and/or methacrylic acid and/or their esters (e.g., Eudragit® copolymers), polyvinyl acetate, fats, oils, waxes, fatty alcohols, hydroxypropyl methyl cellulose phthalate or -acetate succinate, cellulose acetate phthalate, starch acetate phthalate, polyvinyl acetate phthalate, carboxy methyl cellulose, methyl cellulose phthalate, methyl cellulose succinate, zein, ethyl cellulose, ethyl cellulose succinate, shellac, gluten, ethylcarboxyethyl cellulose, ethacrylate-maleic acid anhydride copolymer, maleic acid anhydride-vinyl methyl ether copolymer, styrol-maleic acid copolymer, 2-ethyl-hexyl-acrylate maleic acid anhydride, crotonic acid-vinyl acetate copolymer, glutaminic acid/glutamic acid ester copolymer, carboxymethylethyl-cellulose glycerol monooctanoate, cellulose acetate succinate, and polyarginin.
[0023] Useful plasticizing agents that can be used as coating materials include citric and tartaric acid esters (acetyltriethyl citrate, acetyl tributyl-, tributyl-, triethyl-citrate), glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil), phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate, benzophenone; diethyl- and dibutylsebacate, dibutylsuccinate, dibutyltartrate, diethylene glycol dipropionate, ethyleneglycol diacetate, -dibutyrate, -dipropionate, tributyl phosphate, tributyrin, polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbate 80), and sorbitan monooleate.
[0024] Then the inventive combinations are solutions or suspensions, it is useful to employ solvents such as water or physiologically acceptable organic solvents including alcohols such as ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol, oils such as peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil, paraffins, dimethyl sulphoxide, triglycerides and the like.
[0025] Injectable solutions or suspensions including the inventive combinations can be prepared using non-toxic parenterally acceptable diluting agents or solvents, such as water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, glycerol, Ringer's solution, isotonic salt solution or also hardened oils including synthetic mono- or diglycerides or fatty acids such as oleic acid.
[0026] Solubilizers and emulsifiers useful in preparing compositions according to the invention include polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols and fatty acids.
[0027] For aqueous injection and drinkable solutions, the following stabilizers and solubilizers can be advantageously employed: C 2-4 aliphatic mono- and multivalent alcohols such as ethanol, n-propanol and glycerol, polyethylene glycols with molecular weights between 200-600, diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides (e.g., amides of aliphatic C 1-6 carboxylic acids with ammonia or primary, secondary or tertiary C 1-4 amines or C 1-4 hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide, N,N-dimethyl acetamide, C 2-6 aliphatic amines and diamines such as ethylene diamine, hydroxyethyl theophylline, tromethamine (e.g., as 0.1 to 20% aqueous solution), and aliphatic amino acids.
[0028] Preservatives, stabilizers, buffer substances, flavor correcting agents, sweeteners, colorants and antioxidants can also be employed. Antioxidants can be employed as preservatives, but at higher concentrations antioxidants may serve as co-active ingredients with the inventive combinations (i.e., synergistic activity may occur).
[0029] Useful antioxidants include sodium sulphite, sodium hydrogen sulphite, sodium metabisulphite, selenium, inorganic and organic selenium compounds and salts such as sodium selenite, ascorbic acid, ascorbyl palmitate, myristate and stearate, gallic acid, gallic acid alkyl ester, butylhydroxyanisol, nordihydroguaiacic acid and tocopherols, as well as synergists (substances which bind heavy metals through complex formation, for example lecithin, ascorbic acid, phosphoric acid ethylene, diamine tetraacetic acid, citrates, and tartrates). Compositions including selenium salts such as sodium selenite may be beneficial.
[0030] Preservatives useful in the inventive compositions include, for example, sorbic acid, p-hydroxybenzoic acid esters, benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride, chlorhexidine and formalin derivatives.
[0031] The pharmaceutical compositions may be applied to the skin or mucous membranes or to the inside of the body. Application methods include but are not limited to, oral, enteral, pulmonal, nasal, lingual, intravenous, intra-arterial, intracardial, intramuscular, intraperitoneal, intracutaneous, subcutaneous and transdermal.
[0032] The inventive compositions can also be formulated as cosmetic preparations, such as lotions, sun screens, ointments, solutions, creams, liposomes and emulsions. Conventional cosmetic additives, carriers, etc. can be combined with the inventive compositions to produce the desired cosmetic preparations in accordance with methods known to those skilled in the art.
[0033] Tablet and capsule compositions of the invention advantageously include up to about 1000 mg of R-LA and about 600 mg of nicotinamide. Emulsions and liposomes advantageously include up to about 10% (w/v) of R-LA and 6% of nicotinamide. Micellar solutions beneficially contain up to about 20 wt % (w/v) of R-LA and 12% of nicotinamide.
[0034] The exact dosage used will vary depending on the particular compound of the invention selected, the age, size, and health of the subject, and the nature and severity of the condition to be treated. However, the appropriate dosage may be determined by one of ordinary skill by routine experimentation, following the guidance set forth herein. As a general guideline, a compound of the invention may be administered daily in a dose of one or two tablets (see below) as a dietary supplement for aiding mitochondrial metabolism.
[0035] Suitable subjects include, without limitation, mammals, such as humans, horses, cattle, swine, dogs, cats, and the like, and cells in culture, including mammalian cells, yeast, bacterial cells and the like.
[0036] The present invention is illustrated by the following non-limiting example.
EXAMPLE 1
[0037] A solution of 3.3 g of (R)-(+)-α-lipoic acid in 20 mL methanol was added to a solution of 2.0 g nicotinamide (Sigma) in 20 mL methanol. The mixture was stripped of solvent on the rotary evaporator to yield an off-white solid. This was triturated under 25 mL of anhydrous ether, stirred well and separated by filtration. There was obtained 3.1 g of a pale yellow crystalline powder.
[0038] A small quantity of the powder as a mineral oil mull spread was spread on NaCl polished crystal plates. The plate was placed in a Beckman Infrared Spectrophotometer AccuLab 2 grating machine, linear in wave number. The results are shown in FIG. 1. Spectrophotometry was repeated at about 3 and 17 months and was essentially the same, indicating essentially no change in either the crystal form or chemical composition of this salt on standing under ambient conditions (light and temperature) for over a year.
EXAMPLE 2
[0039] Serving Size: 1 Tablet
[0040] Servings Per Container: 60
Content Amount Per % Daily of tablet Serving Value Sodium 3 mg <1 Nicotinamide 59 mg 300 R-α-Lipoic Acid 100 mg * Acetyl-L-Carnitine HCl 500 mg *
[0041] Ingredients include stearic acid, silicon dioxide, croscarmellose sodium, acacia, magnesium stearate and a white cellulose film coat containing titanium dioxide.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates in general to putters and, more particularly, to a structural improvement in such putters for allowing the putter head to knock the center of a golf ball regardless of the golfer's putting postures and allowing the weight of the putter head to be freely adjusted by a golfer.
2. Description of the Prior Art
As well known to those skilled in the art, a putter is used for putting on a putting green. The term "putting" means that a golfer slightly knocks a golf ball on the putting green toward a hole on the putting green.
The construction of a typical putter is shown in FIG. 1A. As shown in the drawing, the head 50 of the typical putter has a generally-rectangular hexahedral configuration. The knocking surface of the putter head 50 is a flat surface. The handle 51 of the putter extends from the head 50. While putting, a golfer slightly swings the putter close to the green to knock the golf ball.
However, the above putter has the following problems.
That is, when a golfer putts with the above putter in a putting posture where he is leaning forward as shown in the left-handed phantom line of FIG. 1B, the putter head 50 knocks the upper portion of the golf ball, which is higher than the central portion of the ball, thereby increasing the frictional force between the ball and the green. In this case, the putting force of the golfer which should be precisely transmitted to the ball through the putter is somewhat lost, causing the ball to fail to roll on the green as desired.
When the golfer putts in a putting posture where he is leaning backward as shown in the right-handed phantom line of FIG. 1B, the putter head 50 knocks the lower portion of the golf ball, which is lower than the central portion of the ball, thereby causing the ball to take off. In this case, the ball fails to roll on the green well.
In this regard, the golfer with the above putter has to carefully and precisely hit the central portion of the ball in a fine putting posture as shown in the solid line of FIG. 1B while putting.
Another disadvantage of the above putter is caused by the fact that the putter has the solid head 50. That is, the solid head 50 of the above putter scarcely transmits the knocking impact of the head 50 to the handle 51 even when the golfer precisely knocks the central portion of the ball while putting. The golfer thus has dull putting senses and fails to putt precisely. In addition, the weight of the typical putters is fixed, so the golfers cannot use putters with a weight agreeable to one's own weight. This causes the golfers to putt unstably.
The above problems caused by the typical putters are linked directly with golfing score and makes it difficult for beginners to learn golfing.
SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide a structurally improved putter in which the above problems can be overcome and which is provided with a cylindrical head suitable to easily knock the central portion of a golf ball regardless of the putting postures of a golfer while putting.
It is another object of the present invention to provide a putter of which the head is provided with an internal cavity thereby transmitting the putting impact and vibrations of the head to the golfer's hands through the grip without failure and allowing the golfer to precisely feel both the putting senses and rolling directions of the ball and improving the putting precision.
It is a further object of the present invention to provide a putter which allows a golfer to easily adjust the weight of the putter in accordance with the putting conditions.
In order to accomplish the above objects, a putter in accordance with a preferred embodiment of the present invention comprises a cylindrical hollow head body having a cavity divided into parts by partition means, a pair of caps fitted into both ends of the cylindrical body thereby blocking the cavity of the head body, a rod axially extending from the center of an inside surface of each cap, an weight fitted over the rod inside the cavity and adapted for adjusting the weight of the head, and biasing means fitted over the rod in order to prevent the weight from moving inside the cavity.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
FIG. 1A is a perspective view showing the construction of a typical putter;
FIG. 1B is a view showing the different knocking positions of the above putter relative to a golf ball in accordance with the putting postures of a golfer;
FIG. 2 is an exploded perspective view showing the construction of a putter in accordance with a primary embodiment of the present invention;
FIG. 3 is a perspective view of the assembled putter of FIG. 2;
FIG. 4 is a sectional view of the head of the putter of FIG. 3;
FIG. 5 is a view corresponding to FIG. 1B, but showing the putter of this invention; and
FIG. 6 is a view corresponding to FIG. 4, but showing another embodiment of this invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIGS. 2 to 4 show a putter in accordance with a primary embodiment of the present invention. As shown in the drawings, the head 10 of the putter according to the present invention has a hollow cylindrical head body having a diameter of 35 mm-45 mm, preferably 38 mm. In the above head body, a pair of vertical partitions 11a are placed in the front and rear portions inside the head body, thereby forming a central cavity 11 having a volume V 1 . The cavity 11 has either circular or polygonal cross-section.
Each partition 11a has at least one threaded hole. The above threaded hole of each partition 11a engages with coupling means of a cap 20, 20a which will be described later herein. The caps 20 and 20a are coupled to the front and rear ends of the head body, respectively. Each cap 20, 20a cooperates with an associated partition 11a in order to form a side cavity having a volume V 2 .
As shown in FIG. 2, a handle 12 extends from a given portion of the above head 10.
In the present invention, it is preferable to make the ratio of volume (V 1 , V 2 ) of the cavities inside the head 10 be V 1 :V 2 =2:1. However, it should be understood that the volume ratio between the cavities may be changed without affecting the functioning of this invention. In addition, the head 10 may be provided with one or more partitions for forming the cavities.
In the above head 10, both ends of the above cylindrical head body are coupled to the hollow hemispherical caps 20 and 20a. Each cap 20, 20a has the above coupling means engaging with the threaded hole of an associated partition 11a. The above coupling means comprises a rod 21 which axially extends from the center of the inside surface of each cap 20, 20a. The above rod 21 is at least partially threaded in order to form a screw portion which will be threaded into the threaded hole of the partition 11a.
In accordance with the present invention, a plurality of annular weights 26 and 26a may be fitted over the rod 21 of each cap 20, 20a. Each weight 26, 26a has an inner diameter of larger than the outer diameter of the rod 21 and is used for adjusting the weight of the head 10.
In order to prevent the weights 26 and 26a from suddenly moving on the rods 21 and 21a of the caps 20a and 20a, it is preferable to fit a biasing means or a compression coil spring over each rod 21, 21a between the inside surface of an associated cap 20, 20a and the weights 26 and 26a.
As shown in FIG. 2, the peak of each hemispherical cap 20, 20a may be provided with a depression. A transparent tap 24 is fitted in the depression of the above cap 20, 20a with a label of a putter producer interposed between the tap 24 and depression. In this case, the putter will have an additional effect of showing the putter producer and good appearance.
In the present invention, an annular groove having a given depth is preferably formed on the coupling edge of each of the cap 20, 20a and the body 10. An O-ring 14, 14a formed of an appropriate material is fitted over the above annular grooves when the caps 20 and 20a are fitted into both ends of the head 10. The above O-ring 14, 14a prevents foreign substances such as moisture, grass and sand from being introduced into the cavity 11 of the head 10.
While putting, a golfer selects one of the putters having different weights in accordance with the putting conditions, such as the putting green conditions, that is, wet green or dry green, golfer's weight and the weather. While selecting the putters, a golfer selects a putter in accordance with one's subjective preference.
As described above, the putter head 10 of the present invention may be provided with the weights 26 and 26a for adjusting the weight of the putter head 10 as shown in FIGS. 2 to 4. In accordance with the primary embodiment of the invention, each weight has an annular configuration suitable to be fitted over the rod 21, 21a. However, it should be understood that there exist various polygonal configurations of each weight 26, 26a which yield the same result as that described for the primary embodiment without affecting the functioning of this invention. Each annular weight 26, 26a has an weight of 5-50 g, preferably 15 g. In the present invention, it is preferable to fit 0-20 weights 26 and 26a, preferably 10 weights, over each rod 21, 21a. However, a golfer may freely select the number of the weights 26 and 26a, which will be fitted over the rod 21, 21a, in accordance with one's preference. The net weight of the head 10 without having any weight 26, 26a is 250-300 g.
In order to install the weights 26, 26a in the head 10, the biasing means 27, 27a is fitted over the rod 21, 21a of each cap 20, 20a prior to fitting an appropriate number of weights 26 and 26a over the rod 21, 21a. After fitting the weights 27 and 27a over the rods 21 and 21a of the caps 20 and 20a, the caps 20 and 20a are tightly fitted into both ends of the head 10, respectively. Of course, the weights 26 and 26a may be exclusively fitted over the rod 21, 21a of either cap 20 or 20a.
The above biasing means 27 and 27a interposed between the inside surfaces of the caps 20 and 20a and the weights 26 and 26a prevent the weights 26 and 26a from moving on the rods 21 and 21 inside the head 10. In addition, A plurality of O-rings (not shown) formed of elastic rubber may be interposed between the weights 26 and 26a in order to prevent noises generated from the weights 26 and 26a while putting.
In the present invention, it is preferable to fit the caps 20 and 20a into both ends of the head 10 through screw-type fitting. In order to achieve the above screw-type fitting of the caps 20 and 20a into the head 10, the fitting edges of the caps 20 and 20a and of the head 10 are preferable provided with threaded portions. Of course, the caps 20 and 20a may be fitted into both ends of the head 10 through another method, such as interference fit. In order to make it easy to fit the caps 20 and 20a into both ends of the head 10, the fitting edge of each cap 20, 20a is preferably provided with a knurled portion 22, 22a.
The putter head 10 of the present invention is a cylindrical body. With the cylindrical body of the head 10, the putter head 10 knocks the center of a golf ball regardless of the putting postures of a golfer while putting as shown in FIG. 5. The putting force of the golfer is thus precisely transmitted to the ball through the putter regardless of the golfer's putting postures, thereby improving the putting precision of the golfer.
As described above, the present invention provides a structurally improved putter. The head of the above putter is a cylindrical body with a cavity. With the cylindrical configuration of the putter head, the putter head knocks the center of a golf ball regardless of the golfer's putting postures while putting. A plurality of annular weights are provided in the cavity of the head. The number of the weights in the head can be freely changed by a golfer thereby freely adjusting the weight of the head. The above weights are prevented from moving in the cavity by a biasing means.
Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
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BACKGROUND OF THE INVENTION
This invention relates to an expanded board of sheet-like structure and a process for manufacturing the same, and particularly to a novel food product in the form of a thin wafer-like sheet expanded in thickness and having a plurality of elongated chambers rectangular in cross section and the process for manufacturing the same.
In the prior art, many types of board or sheet-like structures were used in many fields from the view point of shock absorbing characteristics, improved solubility, increased surface area, decreased weight, etc. However, in the prior art, expanded board or sheet like structure can be obtained only with many difficulties, for example corrugated board or sheet can be obtained by only two processes.
One such process includes an extrusion through a nozzle means. The other is a conventional corrugated cardboard manufacturing process wherein corrugated board is produced by coating both sides, that is, the tops of the mountain parts of the corrugated medium moulded into the shape of wave, with starch solution, putting on the both sides, surface and back side liners, and further passing it onto a hot plate heated at 160° C - 180° C to make the starch solution pasty by heated liners, followed by drying.
However, the former process has the disadvantages of expensive machine costs and the difficulty of maintaining quality product control, particularly for the productionof a thin sheet. The latter process also has similar disadvantages accompanied by large sized machine installation and the difficulty in obtaining a small sized product. A small sized product has been needed for many years and for many fields, particularly for food industries.
Accordingly, it is the object of the present invention to provide a novel process for the production of a novel expanded board or sheet-like structure improved in strength and appearance, and without using conventional machinery.
SUMMARY OF THE INVENTION
According to the process of the present invention, a viscoelastic material is passed through a gap between a pair of oppositely rotating rollers. The viscoelastic film sheet obtained adheres to the roller surfaces and is forced to expand in thickness until it advances to a gap between a pair of scrapers where the expanded film surfaces are torn or scraped off the roller surfaces to form an expanded board or sheet-like structure. This structure is characterized by a cross section having a plurality of elongated chambers rectangular in cross section. That is, the cross section comprises a surface sheet, back sheet and a number of longitudinally spaced bulk-heads, the respective rectangular chambers being surrounded by the surface sheet wall, the back sheet wall and next adjacent but spaced bulkheads walls.This is schematically illustrated best in FIG. 5 of the drawings.
This structure according to the present invention is quite novel, refined, aesthetic in appearance, and very different from products obtained byconventional processes in the prior art. The expanded board or sheet-like structure of this invention has remarkably improved structural strength due to the presence of the large number of bulkheads between the chambers. Further it should be noted that by the process of the present invention, highly refined thinner and smaller products can be obtained than conventional processes. This is a great advantage of the process according to the present invention and many applications can be expected in many fields in future.
Any viscoelastic material may be employed, for examples, synthetic polymers, natural polymer, etc. for the raw material, and many new type products of shock absorbers, catalytic contactors, insulating materials, food products, building materials, etc. can be obtained through the process of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view in vertical section illustrating a preferred embodiment of the invention;
FIG. 2 is a schematic cross sectional view taken along line a--a in FIG. 1 to illustrate the structure of the viscoelastic material as it emerges from between a pair of rollers;
FIG. 3 is a schematic cross sectional view taken along line b--b in FIG. 1 to illustrate the resulting structure;
FIG. 4 is a view similar to FIG. 1 illustrating an alternative embodiment of the invention using a pair of endless belts; and
FIG. 5 is a perspective view partially in cross section of the product obtained according to the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The process of the present invention will be further illustrated with reference to the drawings.
With reference to FIGS. 1 and 4, a viscoelastic material 2 is passed through a gap between a pair of rollers 1, 1 or a pair of endless belts 1, 1 and torn or scraped off the surfaces of the rollers 1, 1 or endless belts 1, 1 by a pair of scrapers 3, 3 to form a board or sheet-like material. The structures of viscoelastic material in cross section are shown in FIGS. 2 and 3.
From the above explanation, it is obvious to those skilled in the art that any strict controls or regulations for the process, physically or chemically, are not needed and any troublesome additives are not needed for the production of the structure according to the present invention.
Thus, superior quality of an expanded board or sheet-like product can be quite easily obtained without any strict control of the ingredients or physical conditions. For example, any starch containing material like rice, wheat, corn or other cereals, potatoes, etc. can be applied to the process of the present invention. That is, the viscoelastic material of the present invention can be easily prepared from the starches contained in the above materials by a conventional gelatinizing process like water addition, heating, etc. by means of, for example, heat exchanging double oven, direct steam injection or hot water addition. Gelatinizing of starches under heating is effected, preferably with starches containing 35% by weight or more of water, and heating is not always necessary for gluten-containing material like wheat or gluten added materials.
The invention will be further illustrated but is not limited by the following examples.
EXAMPLE 1
After adding water to adjust the water content to 46%, 10 kg of non-glutinous steamed rice flour of 300 mesh in particle size was again steamed under the pressure of 0.25 kg/cm 2 for 8 minutes in a steam kneader, and then sufficiently kneaded in a kneader to obtain a dough cake. The dough cake was passed through a gap of 0.3 mm between a pair of rotating rollers and subsequently a gap of 9 mm between a pair of scrapers. The rolled dough cake was torn off the surfaces of the rollers by the scrapers to form a board or sheet-like structure expanded in thickness, having a plurality of enlongated rectangular perforations or chambers in cross section. The rectangular perforations were 2.2 mm in length and 2.6 mm in width.
In the same manner, the process of the invention was carried out by setting the gap between a pair of rotating rollers at 0.6 mm and 0.9 mm, respectively, to obtain an expanded board structure with a plurality of elongated rectangular perforations or chambers in cross section. The rectangular perforations were respectively 3 mm × 3.7 mm and 3.8 mm × 4.3 mm.
The board structure obtained was cut into desired pieces, dried to adjust the water content to about 13% and baked to give non-glutinous wafer-like rice crackers with such a structure as shown above.
The rice crackers were very excellent and refined in both appearance and taste, as compared with so-called rice crackers produced in the prior art.
EXAMPLE 2
1 kg of wheat flour, 200 g of sugar, 200 g of butter, 2 g of sodium bicarbonate, 2 g of ammonium carbonate and 230 g of hot water at 90° C was sufficiently mixed and kneaded in a mixer to obtain a viscoelastic dough cake. The dough cake was passed through the gap of 0.9 mm between a pair of rotating rollers, and then the gap of 9 mm between a pair of scrapers. The rolled cake was thus torn off the surface of the rollers to form an expanded board or sheet-like structure with a plurality of elongated spaced rectangular perforations or chambers in cross section.
EXAMPLE 3
Water was added to corn starch and homogeneously mixed up to 50% of the water content. The mixture was heated under the pressure of 0.5 kg/cm 2 for 12 minutes in an autoclave to obtain a gelatinized dough cake, which was further kneaded sufficiently. This viscoelastic dough cake was passed through a pair of rotating rollers and torn off the surfaces of the rollers by a pair of scrapers to form an expanded board or sheet-like structure. The gaps between the pair of rollers and between the pair of scrapers were 0.3 mm and 9 mm, respectively. The expanded board or sheet-like structure had a plurality of elongated rectangular perforations or chambers which were 2.4 mm in length and 2.5 mm in width in cross section.
The expanded board was dried to 16% of water content, thereby obtaining a semitransparent expanded board. In the cross section of the semitransparent expanded board, the wall thickness of the surface and back sheets, and the inner bulkheads were 0.25 mm and 0.5 mm, respectively. The rectangular perforations were 2.0 mm in length and 1.9 mm in width.
EXAMPLE 4
5 parts by weight of water was added to a mixture comprising 7 parts by weight of potato flakes and 3 parts by weight of waxy corn starch and then mixed sufficiently in a mixer. This homogeneous mixture was kneaded with steam under the pressure of 0.2 kg/cm 2 for 8 minutes to give a dough cake. The dough cake was passed through between a pair of rotating rollers having a gap of 0.2 mm, and then between a pair of scrapers having a gap of 7.5 mm. The rolled dough cake was torn off the surfaces of the rollers by the scrapers to form an expanded board or sheet-like structure having a plurality of enlongated spaced rectangular perforation chambers in cross section. In cross section, the rectangular perforations were 2.0 mm in length and 2.2 mm in width.
The expanded board was then cut into desired pieces, and dried at 60° C in a drier, whereby the water content was adjusted to about 10%. The dried pieces were fried in an oil bath at 150° C to give tasty food like potato chips having rectangular perforations in cross section.
As is understood from the above explained examples, a novel refined expanded wafer-like food product, that is quite different from those known in the prior art, is easily obtained according to the present invention, without employing any expensive machine or any special ingredients. Further, the food product of the present invention is quite excellent and refined in appearance and taste.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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[0001] This application is a division of U.S. application Ser. No. 12/901,636, filed Oct. 11, 2010, which is currently pending.
[0002] The present disclosure is directed to an automated mix in-cup apparatus and the related method of operation. The disclosure relates generally to the field of mixing consumable material. More specifically, the disclosure relates to a mixer that is automatically operable to lower a mixing blade into a cup or vessel that contains material to be blended/mixed when the cup is positioned on cup-receiving position of the apparatus. A shield and lid surround the sides and top of the mixing blade. For a mixing operation, the shield and lid are automatically lowered to close and at least partially surround the cup. After mixing, the shield and blade are automatically retracted, and the cup is removed from the apparatus. The shield and blade may be automatically lowered again to enclose the cup-receiving position on the apparatus in order to perform a cleaning operation. The apparatus contains various structural and safety elements that provide a unique construction and method of operating the apparatus. The apparatus is effective, fast, easy to operate, safe, and clean.
BACKGROUND
[0003] In a commercial food environment, it is often important to prepare items as quickly as possible. This objective runs counter to the mandate that all food preparation devices remain as sanitary as possible. That is, in the rush to deliver an item to a customer, it is possible that best practices regarding sanitation are not observed. It is also understood that human error increases as a person more quickly repeats a repetitive task. In other words, the person preparing the food or drink may “get sloppy” as the food or drink preparation is accelerated.
[0004] A conventional blender requires that the food/drink components are separately loaded into a blender jar. The jar is closed and placed on a blender base. The machine is activated to blend the contents, which are then placed into another receptacle. The blender and/or blender base is cleaned between consecutive blending operations.
[0005] Other commercial food preparation and drink delivery units include drink and ice dispensers and mixers for frozen drinks or confections. Drink and ice dispensers can be manually operated by a customer, as found in many ‘fast food’ establishments, or they can include the automated filling of various cup sizes.
[0006] Commercial mixers for frozen drinks or confections typically involve a user (i.e., employee) loading a metal cup with the beverage ingredients onto a machine. The cup is positioned so that a mixing blade is located in the cup. The user then activates the machine in order to spin the blade. In this conventional machine, it is possible to remove the cup while the mixing blade is still spinning, which results in the beverage/confection splashing onto the machine and/or user. To achieve a more even mix, a user may also manually move the cup up-and-down during the mix cycle. However, this practice increases the chances that the beverage or confection will splash out of the cup. Basically, the operation becomes less sanitary and less safe as the operator attempts to more quickly complete the task. The mixed material must be transferred to another receptacle.
[0007] Machines for automatically accomplishing the mixing operation have also been envisioned. For the automated units, there is still the question of cleaning the blade and apparatus used in the mixing operation. It is important that a flavor from one mix cycle does not contaminate the next mix cycle, which might be for a different flavor. In addition, the drink or confection must be cleaned from the machine regularly to avoid build up and contamination on the machine. It is thought that the operation of known automated machines is relatively slow and complex.
[0008] There remains a need for an apparatus for mixing consumable material in-cup, and a method of operating the same, that is fast, effective, safe, clean, and easy to operate. An automated mix in-cup apparatus and the method of operating the same as disclosed below addresses at least one of these or other needs.
SUMMARY
[0009] The present disclosure is directed to an automated mix in-cup apparatus adapted to mix consumable material. An ‘in-cup mixer’, ‘mix in-cup’ or ‘blend in-cup’ apparatus is understood to be a mixer where the consumable contents are not transferred to another vessel after the mix cycle and prior to consumption. Conventional mixers and blenders use dedicated mixing vessels and then all or part of the mixed material is transferred to a serving vessel (glass, Styrofoam cup, etc.).
[0010] Among other advantages, the automated mix in-cup apparatus disclosed herein is thought to be fast, clean, easy to operate, safe, and effective. The automated mix in-cup apparatus for mixing consumable material includes a frame supporting a stepper motor to move a carriage up and down on the frame. The carriage supports a mixing motor, a shield prop, and a combined splash shield and lid. The frame comprises a vertically aligned stand and a horizontal, cup-supporting leg. An optional cup-receiving holder is positioned on the leg of the frame.
[0011] In one embodiment, movement of the carriage is accomplished via the stepper motor and a lead screw. The lead screw passes though the carriage, and the carriage is supported on the lead screw via a nut. The stepper motor rotates the lead screw, also known as a translation screw, to translate the radial motion imparted by the stepper motor into a linear movement for the carriage. Rotation of the lead screw either raises or lowers the carriage on the frame. One or more guide rails pass through the carriage to keep the carriage aligned on the frame.
[0012] The mixing motor is attached to the carriage, and a rotatable mixing blade extends downwardly from the mixing motor. The mixing motor moves along with the carriage. The mixing blade is reciprocally moveable along with the mixing motor and carriage. When engaged, the mixing motor is operable to rotate the mixing blade in order to mix the consumable contents of the cup.
[0013] The horizontal portion of the frame may comprise a flat floor to support a cup or a cup-receiving holder. The floor may include liquid nozzles (small diameter apertures) from a manifold to eject a fluid upwardly from the floor. A drain aperture might also be employed in the floor as a liquid outlet. The drain is preferably proximate the cup-receiving position.
[0014] In another embodiment, the horizontal portion of the frame further comprises a liquid well comprising a recessed floor and a sidewall. The well could further include a liquid inlet manifold having at least one nozzle fluidly connecting the manifold and well. The well might further include a drain to serve as at least one liquid outlet for the well. In this embodiment, the optional cup-receiving holder is positioned above the floor of the well. The cup is positioned in the well or on the cup-receiving holder above the floor of the well. The cup-receiving holder may be selectively removed from the apparatus for cleaning.
[0015] The splash shield includes at least one sidewall, a closed lid or top, and a lower opening. The lid and shield might be integral parts or the shield might be secured to the lid via known fasteners. The splash shield and lid surround the mixing blade. The blade is connected to the mixing motor via a shaft that extends through an aperture in the shield's top end. A seal can be employed about the shaft in the lid aperture to prevent a fluid escaping upwardly from the shield. The seal is in close proximity to the shaft and may contain an internal helix groove. The helical groove on the inside surface of the seal directs any liquid between the shaft and seal downwardly.
[0016] The subject splash shield, mixing blade, and mixing motor are all reciprocally movable along a shared axis via the movement of the carriage on the lead screw. However, the splash shield can be moved independently of the mixing blade and motor via the shield prop, as described below.
[0017] Once engaged, the apparatus automatically moves the mixing blade, mixing motor, and splash shield from a home position to a mixing position. In the mixing position, the mixing blade is located within the dimensions of the cup. The shield rests on the cup, and the lid of the shield closes the cup. During a mix cycle, the blade can move up and down through the consumable material without displacing the shield.
[0018] The mixing motor, mixing blade, and splash shield return to the home position. The user removes the cup, and the apparatus moves the carriage to a cleaning position whereby the shield comes into contact with the frame, such as at the well floor, to selectively encase the cup-receiving position and optional cup-receiving holder on the frame. The blade can be positioned so as to pass through the cup-receiving holder during a cleaning cycle.
[0019] In one embodiment, a pulley system acts as a cord a cord management system for a power cord connected to the mixing motor. The power cord, which might also enclose sensor wires, is fixedly secured to the carriage at a first end and is fixedly secured to the frame at a second end. The carriage moves up and down on the frame. As a cord management system, the pulley system includes one stationary and one moveable, spring-biased pulley to manage slack in the power cord as the carriage moves up and down. As the carriage moves down on the frame, the moveable pulley is lifted by the tension placed on the power cord. As the carriage moves up on the frame, a spring biases the moveable pulley down to take up slack in the power cord.
[0020] In use, the machine starts at a first home or open position. A user places a cup with consumable material on the cup-receiving holder and activates the apparatus. The stepper motor rotates the lead screw in order to lower the carriage. The downward movement of the carriage lowers the mixing motor, mixing blade, and splash shield to a mixing position. As a result, the shield is lowered around the cup until the lid contacts and closes the open top of the cup. Similarly, the mixing blade enters the interior space of the cup.
[0021] In this mixing position, the shield at least partially isolates the cup from the user. The lid also prevents the material in the cup from exiting the cup during a mix cycle. Once the apparatus is in the mixing position, the motor is activated to rotate the mixing blade thereby causing the consumable material to be mixed. The speed of the blade may be variable, and a speed sensor can be included so as to output motor speed feedback to a control board. In addition, the blade may move up and down within the cup during the mix cycle without displacing the splash shield.
[0022] After the mix cycle is completed, the shield and blade automatically retract to an open or home position so as to allow access to the cup. The cup is then removed. A cleaning cycle is then manually or automatically activated. The carriage is again lowered. In the cleaning position, the shield comes into contact with the frame to create a sealed, enclosed space. For the cleaning cycle, the blade can be positioned at various distances from the floor of the frame/well, including beneath the level of the cup-receiving holder.
[0023] Fluid is injected into the interior of the shield via the inlet manifold so as to contact the shield and blade during the cleaning cycle. The fluid is used to rinse the shield and blade. The blade may rotate during the cleaning cycle to increase fluid distribution or force. The rinse fluid is removed via the drain. In this manner, the automated mixing of the material and subsequent cleaning of the apparatus can be achieved. The cleaning cycle is fast and effective. The blade is isolated from the user during the mixing and cleaning operations. The cleaning operation is thought to remove all food or drink material and to prevent any flavor contamination between mix cycles.
[0024] In at least one embodiment, it is also envisioned that a number of sensors could be employed. The sensors are used to electronically determine the position of the motor, blade, and/or shield and to act as interlock mechanisms to disengage the mixing motor if a user displaces the shield during the mixing or cleaning cycles. In other words, the feedback from the sensors is used to automatically prevent the rotation of the blade unless the splash shield is properly positioned. In one embodiment, the failure to remove a cup from the cup-receiving position prior to initiating the cleaning cycle would also prevent the movement of the mixing blade to the blade's cleaning position. The blade or blade shaft would contact the cup. In response, the unit would return the shield to the home position.
[0025] Further features and advantages of the present disclosure will become apparent to those of skill in the art from the following detailed description of a preferred embodiment taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The features and objects of the subject mix in-cup apparatus and related method will be better understood from the following detailed description taken in conjunction with the drawings wherein:
[0027] FIG. 1 is a perspective view of the housing for a combined fluid or ice dispensing and mixing unit wherein the mixing apparatus is envisioned as the apparatus disclosed herein;
[0028] FIG. 2 is a perspective view of the automated mix in-cup apparatus as disclosed herein wherein a mixing blade and a splash shield are shown in an elevated or home position;
[0029] FIG. 3 is a side cut-away view of the same wherein a well, a cup-receiving holder, and a drain are further illustrated;
[0030] FIG. 3A is a side view of a seal member as further disclosed herein;
[0031] FIG. 4 is a perspective, semi-transparent view of one embodiment of the subject apparatus wherein a mixing blade and splash shield are shown in an mixing or down position so that the shield is in the well and at least partially encloses the opening of a cup;
[0032] FIG. 5 is a side cut-away view of the same;
[0033] FIG. 5A further illustrates a cord management pulley system as disclosed herein;
[0034] FIG. 6 is a perspective, semi-transparent view of an embodiment of the subject apparatus wherein the splash shield is in a mixing or down position and the blade is in a mixing position so as to engage the contents of a cup;
[0035] FIG. 7 is a side cut-away view of the same;
[0036] FIG. 8 is a perspective, semi-transparent view of an embodiment of the subject apparatus wherein the splash shield and blade are in a cleaning position;
[0037] FIG. 9 is a side cut-away view of the same;
[0038] FIG. 10 is a top-down view of the well and the cup-receiving holder as disclosed herein in at least one embodiment;
[0039] FIG. 11 is a top-down cut-away view of the a water inlet manifold and the drain as disclosed herein;
[0040] FIG. 12 is an exploded view of the selectively removable cup-receiving holder, a liquid well, and a manifold cover as found in one embodiment disclosed herein;
[0041] FIG. 13 is a perspective view of the subject apparatus further illustrating a selectively removable cup-receiving holder as found in one embodiment disclosed herein
[0042] FIG. 14 is a close-up, semi-transparent view of the splash shield in the well and a related interlock safety mechanism; and
[0043] FIG. 15 is a three quarter front view of one embodiment of the subject apparatus illustrating sensors located on the apparatus.
DETAILED DESCRIPTION
[0044] The present disclosure is directed to an automated mix in-cup apparatus and the method of using the same. In general, the automated mix in-cup apparatus is thought to be more effective, safer, faster, cleaner and easier to operate than known devices. The apparatus and method are described and illustrated in terms of various embodiments. Of course, the present disclosure is not limited to the embodiments disclosed herein but also includes variations and equivalent structures that would be apparent to one of skill in the art, having studied the subject disclosure.
[0045] Turning now to the drawings, FIG. 1 illustrates a combined commercial fluid/ice dispensing and mixing unit 2 . Unit 2 comprises an outer housing to cover both the dispensing and mixing machinery. Unit 2 may also include a cabinet 6 accommodating a plurality of fluid containers 8 fluidly connected to a dispenser. An ice or frozen slurry dispenser and/or hopper may also be included in the unit.
[0046] The overall operation of unit 2 comprises a user selecting the cup 4 , which may be selected from a single size or a plurality of differently sized cups, and placing cup 4 on unit 2 proximate to a dispensing mechanism (not illustrated or described further herein). The dispensing mechanism is actuated to at least partially fill cup 4 from fluid containers 8 and/or a frozen fluid dispenser. The fluid containers 8 could contain various flavors of consumable drink mix. The cup would also at least partially be filled with ice or other frozen consumable material from unit 2 .
[0047] One or more automated mix in-cup apparatuses 10 are located next to the dispensing apparatus for mixing/blending drinks such as smoothies, milkshakes, ice coffee drinks, or the like. After the step of dispensing a fluid into the cup, the user positions cup 4 containing the selected flavor and frozen material at a cup-receiving position on mix in-cup apparatus 10 . Mix in-cup apparatus 10 is then engaged to commence an automated mixing operation of the cup contents, as explained further below. The user does not contact the apparatus 10 other than to select mix cycles or otherwise actuate the switches or buttons necessary to begin the operation of the unit.
[0048] With respect to FIGS. 2-14 , there is illustrated one or more embodiments of the mix in-cup apparatus and the method of operation of the same as described herein. The apparatus moves between three operational positions, as detailed further below with specific reference to the figures and labeled elements.
[0049] In general, the first position is the open or “home” position where a mixing blade, a mixing motor, and a splash shield are elevated above a cup-receiving position so as to allow a user access to the cup-receiving position. In the mixing position, the splash shield is lowered until it engages and closes cup 4 . The shield is held on the cup by gravity. While the shield always surrounds the sides and top of the mixing blade, the shield also surrounds the sides of cup 4 and closes the top of cup 4 in the mixing position. The mixing blade is positioned inside cup 4 when the apparatus is in the mixing position. During a mix cycle, the blade may move up and down within the cup independent of the movement of the splash shield.
[0050] In a cleaning position, the cup is first removed from the cup-receiving position, and the shield is again lowered until it contacts a floor. The floor and shield act to create a sealed interior space. In the cleaning position, the blade is moved into a position that may be below the cup-receiving position. A user cannot access the mixing blade in the cleaning or mixing positions without manually displacing the shield.
[0051] Turning to FIGS. 2 and 3 in further detail and with specific reference to the labeled elements, there is illustrated a mix in-cup apparatus 10 in accordance with at least one embodiment of this disclosure. The automated mix in-cup apparatus 10 for mixing consumable material includes a frame 12 supporting a stepper motor 13 . Frame 12 in this embodiment is generally an L-shaped, substantially vertical structure with sufficient width to support mechanical components as described below. Frame 12 could in turn be mounted to the structure of the combined unit 2 and be largely enclosed behind a housing. It is also envisioned that mix in-cup apparatus 10 might instead serve as a standalone device for mixing consumable material in cup 4 .
[0052] FIGS. 2 and 3 illustrate the home position of apparatus 10 . As illustrated, the horizontal portion of the L-shaped frame 12 supports cup 4 at a cup-receiving position. The stand portion of frame 12 supports a vertically aligned lead screw 15 connected to stepper motor 13 . Stepper motor 13 is positioned at the top of frame 12 . The distal end of lead screw 15 is mounted in a bearing (not illustrated).
[0053] One or more guide rails 16 are vertically aligned on frame 12 and are parallel to lead screw 15 . Lead screw 15 and guide rails 16 pass through a carriage 17 . A nut (not illustrated) under carriage 17 on lead screw 15 retains carriage 17 in place on lead screw 15 . As stepper motor 13 rotates lead screw 15 , the nut moves up and down on the screw. As a result, carriage 17 moves up and down relative to frame 12 . Guide rails 16 further support carriage 17 and maintain the alignment of carriage 17 as it moves. Overall, activating stepper motor 13 rotates lead screw 15 , and lead screw 15 translates the rotational movement into the linear up-and-down movement of carriage 17 .
[0054] In one embodiment, as explained further below, a pulley system acts as a cord management system for a power cord 19 connected to carriage 17 . Power cord 19 , which might also enclose sensor wires, is fixedly secured to carriage 17 at a first end and is fixedly secured to frame 12 at a second end. To account for the movement of carriage 17 , the pulley system includes one stationary pulley 18 and one moveable, spring-biased pulley 21 .
[0055] Moveable pulley 21 is at least partially placed within a pulley housing that slides within a vertical track defined by frame 12 . Moveable pulley 21 includes an axle mounted to the sliding housing. A spring 23 is secured to the housing a proximate end. Distal end of spring 23 is attached to a point on frame 12 beneath the pulley housing so as to maintain a tension force on the pulley housing. As carriage 17 moves down on lead screw 15 , moveable pulley 21 is lifted by the tension placed on power cord 19 . That is, the downward force on carriage 17 overcomes the tension force of spring 23 . As carriage 17 is lifted on lead screw 15 so as to move up relative to frame 12 , spring 23 biases moveable the pulley housing downwards so that pulley 21 move down within the frame's track. In this manner, any slack in cord 19 is controlled by the pulley system.
[0056] Carriage 17 supports a mixing motor 14 , a shield prop 70 , and a splash shield 50 . Any suitable type of electric motor may be employed as mixing motor 14 , as would be known or used in the mixing art. A mixing motor housing 54 surrounds and supports mixing motor 14 and housing 54 , in turn, is secured to carriage 17 . In this manner, carriage 17 supports motor 14 . Mixing motor 14 is axially aligned above cup 4 when cup 4 is in the cup-receiving position. The horizontal portion of the frame defines a floor to support cup 4 or an optional cup-receiving holder 40 may be positioned on frame 12 at the cup-receiving position. In an embodiment where frame 12 defines a fluid-receiving well, holder 40 is at least partially placed in the well. With the holder, a cup never contacts a drain or floor of the apparatus, which is thought to be more sanitary.
[0057] A rotatable mixing blade 20 extends vertically downwardly from mixing motor 14 via a shaft 22 . Blade 20 is used for mixing a consumable material in cup 4 . Motor 14 is operable to rotate mixing blade 20 and shaft 22 . Blade 20 moves relative to frame 12 when mixing motor 14 is raised or lowered via carriage 17 . Shaft 22 extends from mixing motor 14 at a fixed length. As such, blade 20 is reciprocally moveable along a shared axis with mixing motor 14 .
[0058] In one embodiment, frame 12 further comprises a liquid well 30 sharing a vertical axis with cup 4 , mixing motor 14 , shaft 22 , and splash shield 50 . Well 30 is a recess in the horizontal portion of the L-shaped frame 12 including a floor 32 and a sidewall 34 . In this embodiment, floor 32 is considered to be a part of frame 12 . Well 30 may be a plastic molded part inserted into frame 12 .
[0059] A liquid inlet manifold 36 is integral to or connected to frame 12 , and manifold 36 includes at least one nozzle fluidly connecting the manifold to the exterior of frame 12 (see also FIGS. 10 and 11 ). In the illustrated embodiments where an optional recessed well 30 is employed, manifold 36 is integral to or connected to well 30 . A cleaning liquid, which might be water or a combination of water and a known cleaning agent, is selectively ejected from manifold 36 . A drain 38 acts as at least one liquid outlet. In the embodiment containing the well, drain 38 is integral to or connected to well 30 . In either embodiment, a drainpipe would connect to the drain so that the cleaning fluid is removed from apparatus 10 .
[0060] The optional cup-receiving holder 40 is positioned to support a cup above frame 12 , such as above floor 32 of well 30 . Holder 40 may be selectively removable from the apparatus for cleaning, as further described below (see also FIG. 14 ).
[0061] Splash shield 50 may consist of an opaque, semi-transparent or transparent material. In the cup-receiving position, such as when cup 4 is placed on holder 40 , cup 4 is axially aligned beneath shield 50 .
[0062] Shield 50 comprises a shield lid 52 and a cylindrical sidewall 56 depending from lid 52 . Shield 50 defines an open bottom end 60 into which cup 4 and/or cup-receiving holder 40 can be placed. Shield 50 is suspended from motor housing 54 by a shield prop 70 . Prop 70 includes two guide rods 72 and upper stop plate 74 . In a home position, stop plate 74 rests atop mixing motor 14 or mixing motor housing 54 with guide rods 72 securely fixed to shield lid 52 .
[0063] As carriage 17 moves to a mixing position, shield lid 52 engages the open top of cup 4 so as to close the lid. Shield sidewall 56 at least partially surrounds cup 4 at the cup-receiving position. In the mixing position, the downward movement of shield 50 is limited by the height of cup 4 , and shield 50 rests atop cup 4 . However, carriage 17 may continue to move downward along lead screw 15 after shield 50 engages cup 4 . The continued downward motion of carriage 17 causes motor housing 54 to move along shield god rods 72 . The upper stop plate separates from mixing motor 14 and motor housing 54 . Carriage 17 can continue downwards until motor housing 53 engages the top of lid 52 .
[0064] Moving carriage 17 upwards will not displace shield 50 until mixing motor 14 and/or motor housing 54 engage upper stop plate 74 . Once engaged, the continued upward movement of carriage 17 lifts stop plate 74 . Guide rods 72 , which are fixed at a first end to plate 74 and at a second end to shield 50 , then lift shield 50 . For aesthetic purposes, an outer housing 53 can selectively nest over motor housing 54 . Outer housing 53 is supported atop lid 52 . As motor housing 54 moves away from shield 50 , outer housing 53 encases guide rods 72 and shaft 22 between motor housing 54 and lid 52 . As the motor housing 54 is brought into closer proximity to lid 52 , outer housing 53 nests over motor housing 54 .
[0065] Splash shield 50 surrounds blade 20 on all sides and covers the top of blade 20 . Shaft 22 extends through an aperture 62 in the shield's top end. A seal 63 is employed to prevent the escape of a fluid up and through lid 52 . One embodiment of seal 63 is illustrated in FIG. 3A . Seal 63 is in the lid aperture 62 through which shaft 22 passes. Seal 63 reduces or prevents fluid from passing around shaft 22 upwardly through the shield's top end. Shaft 22 can move independently of shield 50 so seal 63 allows for the linear movement of shaft 22 into and out of shield 50 . The inside face of seal 63 in contact or close proximity with shaft 22 includes a helical groove 64 . Groove 64 permits and encourages the downward flow of fluid were any fluid to enter seal 63 .
[0066] FIGS. 2 and 3 illustrate motor 14 and shield in the home position whereby a user can access cup 4 and the cup-receiving position. In this home position, mixing motor 14 cannot be activated, as further described below.
[0067] Turning then to FIGS. 4 and 5 , there is illustrated the embodiment of FIGS. 1 and 2 but where carriage 17 has been moved downwards to the mixing position. In the mixing position, as briefly referenced above, shield 50 comes to rest on a cup 4 . In the absence of a cup, shield 50 would rest on frame 12 . In this illustrated embodiment, shield 50 does not contact frame 12 or floor 32 of well 30 due to the height of the cup. In the mixing position, cup 4 is closed by lid 52 and is at least partially surrounded by shield 50 .
[0068] In one embodiment, the connection of shield sidewall 56 to closed top end 58 forms a frustoconical shape or portion 59 . That is, the connection between sidewall 56 and lid 52 is sloped as if to form a cone. However, the cone tip is truncated.
[0069] Conical portion 59 creates an effective seal on cup 4 despite the use of cups that might be of different diameters. Conical portion 59 also serves to center cup 4 on the cup-receiving position or holder. Where the conical portion engages a cup disproportionally on one side, the slope of lid 52 translates the downward motion of shield 50 into a lateral motion to better position cup 4 within shield 50 .
[0070] FIG. 5A further illustrates the pulley-based cord management system. A portion of frame 12 , which helps to define a vertical track, is removed to better illustrate the cord management system. Moveable pulley 21 is secured via an axle to the moveable pulley housing. The pulley housing slides within the vertical track defined by frame 12 .
[0071] The downward movement of carriage 17 places tension on cord 19 . This tension exceeds the spring bias provided by spring 23 . As a result, pulley 21 moves up within frame 12 . As carriage 17 is lifted on lead screw 15 so as to move up relative to frame 12 , spring 23 biases pulley 21 , via the pulley housing, downwards. In this manner, any slack in cord 19 is controlled by the pulley system.
[0072] With respect to FIGS. 6 and 7 , it is evident that blade 20 and motor 14 may continue to move down relative to frame 12 even after shield 50 comes into contact, and is stopped by, cup 4 . Prop 70 is fixed to shield 50 by guide rods 72 . Motor 14 slidably moves along guide rods 72 . As carriage 17 continues to move mixing motor 14 closer to shield 50 , upper stop plate 74 moves away from mixing motor 14 . In this manner, mixing motor 14 can be reciprocally moved up and down without displacing shield 50 during the mix cycle. The ability to move blade 20 up and down during a mix cycle increases the quality and consistency of the blended product.
[0073] Following the mix cycle, which can comprise a pre-programmed sequence of blade movements and variable blade speed changes, stepper motor 13 is actuated to rotate lead screw 15 to lift carriage 17 . The motor engages the stop plate 74 . As a result, shield 50 and blade 20 are withdrawn from cup 4 . Cup 4 is then removed.
[0074] Turning now to FIGS. 8 and 9 , apparatus 10 or a user then engages a cleaning cycle. Carriage 17 is positioned, via the stepper motor and lead screw, in a cleaning position. In the cleaning position, shield 50 brought into contact with frame 12 (such as well 30 ) to create an enclosed space about the cup-receiving position. Cup-receiving holder 40 would be encased by shield 50 and well floor 32 , for example.
[0075] As further illustrated in FIGS. 8 and 9 , with cup 4 removed, motor 14 can be lowered past the lowest mix position. As a result, blade 20 and/or shaft 22 extend below the cup-receiving position. For example, blade 20 can pass through the cup-receiving holder 40 . During the cleaning operation or cycle, it would again be possible to reciprocally move blade 20 up and down without displacing shield 50 .
[0076] In the cleaning operation, and with reference to FIGS. 10 and 11 , fluid enters a manifold 36 via pipe 35 . The fluid is transmitted to the space enclosed by shield 50 via manifold 36 and fluid nozzles 37 . The fluid will strike blade 20 , which can be rotated during the cleaning cycle to further disperse the fluid. The cleaning operation rinses the interior of shield 50 (including shield lid 52 ), cup-receiving holder 40 , blade 20 , and shaft 22 . Cleaning fluid exits the frame via the drain 38 , which is tied to an outlet pipe. The cleaning operation is automatic and requires little to no user involvement. As such, the automated mix in-cup apparatus is self-cleaning, which permits a user to fill another cup during the cleaning operation.
[0077] FIG. 12 illustrates the underside of well 30 with manifold 36 in an exploded view. A bottom plate 39 of manifold 36 is removed to reveal one embodiment of the interior of manifold 36 . Holder 40 is illustrated as being removed from well 30 .
[0078] Turning to FIG. 12 , cup-receiving holder 40 includes an open ring 42 upon which cup 4 rests. Ring 42 provides an aperture through which blade 20 passes when carriage 17 is in the cleaning position.
[0079] As briefly noted above, holder 40 may be selectively removable from frame 12 . Holder 40 could include one or more hollow posts 44 that engage vertical posts 46 on frame 12 . For instance, vertical posts 46 might be integral to well floor 32 . Vertical posts 46 nest within hollow posts 44 of the holder in order to frictionally retain holder 40 in place. A user could lift holder 40 off frame 12 to independently clean holder 40 , if necessary. Removing holder 40 provides the means to further clean the holder and/or the drain and frame that are located beneath holder 40 .
[0080] Overall, apparatus 10 is easy to operate, safe, and fast in that shield 50 and mixing blade 20 automatically move into and out of the mix position. A user is provided one-handed operation in that they merely need to place the cup before the mix cycle and remove the cup after the mix cycle. There is no need to manually manipulate the cup, the shield, or any other components of the apparatus besides cup 4 . Nevertheless, a user may mistakenly attempt to access or manipulate the splash shield or to otherwise access the cup during a mix cycle.
[0081] Turning now to FIG. 14 , there is illustrated a close-up view of shield 50 in the mixing position. In the illustrated embodiment, a magnetic strip 80 is integrated into or otherwise secured to sidewall 56 of shield 50 . Corresponding shield sensors 82 on frame 12 (e.g., in well 30 ) are operable to detect magnetic strip 80 . In the mix and cleaning positions, mixing motor 14 will not rotate blade 20 unless shield sensors 82 detect magnetic strip 80 . A control unit will disengage mixing motor 14 once strip 80 is displaced. As such, a user cannot lift shield 50 to access cup 4 without disengaging mixer motor 14 .
[0082] Additional sensors provide feedback to the control unit, as further illustrated in FIG. 15 . A home sensor 84 is used to determine if carriage 17 is properly returned to the home position after each mix and cleaning cycle. Home sensor 84 is operable to detect a magnet 86 located on carriage 17 . Stepper motor 13 runs until home sensor 84 detects magnet 86 or until there is a time-out condition. For example, if carriage 17 is obstructed, stepper motor 13 will run for a predetermined period of time that is longer than it takes for carriage 17 to return to the home position. If the magnet 86 is not detected within that time period, stepper motor 13 is deactivated and apparatus 10 would be reset.
[0083] Once home sensor 84 detects magnet 86 , stepper motor 13 reverses lead screw 15 until magnet 86 is no longer detected. Carriage 17 is then raised a second time until magnet 86 is detected by home sensor 84 . This provides an optional calibration mechanism so that the position of carriage 17 is calibrated prior to a mix or cleaning cycle.
[0084] A cup sensor 88 also works in conjunction with magnet 86 and the control unit. The failure to detect magnet 86 at cup sensor 88 indicates to the control unit that shield 50 is not in the cleaning position. As referenced above, in the cleaning position, shield 50 contacts frame 12 (e.g., well floor 32 ). Shield 50 creates an enclosed interior space to capture the cleaning fluid during the cleaning cycle. With the cup in place, shield 50 does not reach the frame or well floor. As a result, shield 50 will not properly rest against frame 12 or well floor 32 . The shield will not create an enclosed interior space so that the cleaning fluid will not be fully contained during the cleaning cycle. Cup sensor 88 prevents the initiation of the cleaning cycle where a user leaves the cup in place.
[0085] In addition, carriage 17 moves blade 20 to a cleaning position that is below the blade's “mixing position” and below the cup-receiving portion of holder 40 . If a user forgets to remove cup 4 , blade 20 will move downwardly until it contacts the floor of the cup. The floor will resist the further movement of blade 20 on shaft 22 . The extra load on the stepper motor causes it to stall. As a result, carriage 17 will not be in the proper position for cup sensor 88 to detect magnet 86 on carriage 17 .
[0086] The method of using the subject apparatus provides for one-handed operation that is fast, safe, clean, easy to use, and effective. In use, a user places a cup with consumable material at the cup-receiving position, such as on the cup-receiving holder, and activates the apparatus via a switch, button, touchpad, or the like. The apparatus automatically lowers the carriage to the mixing position. In the mixing position, the shield lid closes the top of the cup, and the mixing blade is positioned within the cup and consumable material.
[0087] The mixing motor is automatically activated to rotate the mixing blade thereby causing the consumable material to be mixed. The speed of the blade may be variable, and the blade may move up and down within the cup during the mix cycle without displacing the splash shield.
[0088] After the mix cycle is completed, the carriage is returned to the home position whereby the splash shield and mixing blade are lifted from the cup. The user can access and remove the cup from the cup-receiving position.
[0089] A cleaning cycle is then manually or automatically activated. The splash shield, which still surrounds the blade, is again lowered into contact with the frame. The splash shield and frame (such as well floor 32 ) create an enclosed entire space. The cup-receiving position and/or cup-receiving holder are encased by the splash shield and frame. The blade can be positioned at various distances from the frame including beneath the level of the cup-receiving holder. Mixing blade could be moved during the cleaning cycle without displacing the splash shield.
[0090] The cleaning cycle is initiated, and fluid is injected into the interior of the shield via an inlet manifold. The fluid contacts and cleans the shield (including the lid), blade, cup-receiving position, and optional cup-receiving holder. The mixing motor can be engaged to rotate the mixing blade during the cleaning cycle to increase fluid distribution or force. The rinse fluid is removed via the drain. In this manner, the automated mixing of the material and subsequent cleaning of the apparatus can be achieved. A user may select the flavors to be dispensed for the next order while the mix in-cup apparatus mixes a previous order and executes a self-clean operation. The mixing blade is isolated from the user during the mixing and cleaning operations. An attempt to displace the splash shield during the mixing or cleaning cycles deactivates the mixing motor.
[0091] While the disclosure has been described with reference to specific embodiments thereof, it will be understood that numerous variations, modifications and additional embodiments are possible, and all such variations, modifications, and embodiments are to be regarded as being within the spirit and scope of the disclosure.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present continuation-in-part patent application claims priority benefit under 35 U.S.C. 120 and 365(c) of the PCT international patent application designating the United States serial number PCT/US11/52066, filed 18 Sep. 2011, entitled “Dental Tape and Floss Holder with installation cassette”. This application further claims benefit of priority under 35 U.S.C. §119(e) to U.S. provisional patent application No. 61/403,635, filed Sep. 20, 2010, entitled “Dental Floss Holder with installation cassette,” The contents of these related patent application(s) are incorporated herein by reference for all purposes to the extent that such subject matter is not inconsistent herewith or limiting hereof.
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
REFERENCE TO SEQUENCE LISTING, A TABLE, OR A COMPUTER LISTING APPENDIX
[0003] Not applicable.
COPYRIGHT NOTICE
[0004] A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure as it appears in the Patent and Trademark Office, patent file or records, but otherwise reserves all copyright rights whatsoever.
FIELD OF THE INVENTION
[0005] The present invention relates generally to dental care. More particularly, the invention relates to a dental floss holder.
BACKGROUND OF THE INVENTION
[0006] The present invention relates to a dental floss holder. Daily flossing is highly recommended by dentists for good oral health. However, many people do not practice daily flossing. Some people do not floss because the floss can be difficult to use as it may break, tangle or pinch the fingers during use. It is therefore an objective of the present invention to provide a device that holds dental floss during use.
[0007] Currently, dental floss holders exist. However, when using these dental floss holders it is often difficult to hold the floss firmly in the desired position. Also, the floss may stretch or become tangled during flossing or when removing used floss from the holder. Furthermore, many dental floss holders require the user to install a piece of floss in the holder before each use or are not reusable and are thrown away after one use. Some floss holders accept only limited types of floss and may not be suitable for using dental tape and flosses using modern technologies. Some floss holders require large pieces of floss to be replaced at a time, creating waste. In other floss holders replacing is time consuming and the floss can be tangled or twisted. Yet other floss holders are designed for right hand users and are not as equally convenient for left hand users. Still other floss holders are not designed for easy access to all areas in the mouth.
[0008] In view of the foregoing, there is a need for improved techniques for providing a dental floss holder that firmly holds the floss, generally prevents the floss from stretching or becoming tangled and is easily reused.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] The present invention is illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings and in which like reference numerals refer to similar elements and in which:
[0010] FIGS. 1A , 1 B and 1 C illustrate an exemplary dental floss holder, in accordance with an embodiment of the present invention. FIG. 1A is a diagrammatic side view. FIG. 1B is a diagrammatic front view, and FIG. 1C is a diagrammatic rear view;
[0011] FIGS. 2A , 2 B, 2 C and 2 D illustrate an exemplary floss cassette from a dental floss holder, in accordance with an embodiment of the present invention. FIG. 2A is a side perspective view of the floss cassette in a closed position. FIG. 2B is a side perspective view of locking plates of the floss cassette, FIG. 2C is a diagrammatic top view of the floss cassette in an open position, and FIG. 2D is a diagrammatic side view of the floss cassette in an open position;
[0012] FIGS. 3A , 3 B and 3 C illustrate an exemplary locking button of a dental floss holder, in accordance with an embodiment of the present invention. FIG. 3A is a side perspective view. FIG. 3B is a diagrammatic front view, and FIG. 3C is a diagrammatic bottom view;
[0013] FIGS. 4A and 4B illustrate an exemplary dental floss holder, in accordance with an embodiment of the present invention. FIG. 4A is a diagrammatic side view of the floss holder in an open position, and FIG. 4B is a side perspective view of the floss holder in the open position with a locking button, a floss cassette and a blade removed;
[0014] FIG. 5 illustrates an exemplary water resistant dental floss holder, in accordance with an alternative embodiment of the present invention. The dental floss holder in FIG. 5 includes a water resistant container which helps avoid water penetration to the dental floss held within the water resistant container; and,
[0015] FIG. 6 illustrates an exemplary dental floss holder having a wall partition member, in accordance with an alternative embodiment of the present invention. The dental floss holder in FIG. 6 includes a wall partition member which helps provide a better partition between new and used dental floss material.
[0016] Unless otherwise indicated illustrations in the figures are not necessarily drawn to scale.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] The present invention is best understood by reference to the detailed figures and description set forth herein.
[0018] Embodiments of the invention are discussed below with reference to the Figures. However, those skilled in the art will readily appreciate that the detailed description given herein with respect to these figures is for explanatory purposes as the invention extends beyond these limited embodiments. For example, it should be appreciated that those skilled in the art will, in light of the teachings of the present invention, recognize a multiplicity of alternate and suitable approaches, depending upon the needs of the particular application, to implement the functionality of any given detail described herein, beyond the particular implementation choices in the following embodiments described and shown. That is, there are numerous modifications and variations of the invention that are too numerous to be listed but that all fit within the scope of the invention. Also, singular words should be read as plural and vice versa and masculine as feminine and vice versa, where appropriate, and alternative embodiments do not necessarily imply that the two are mutually exclusive.
[0019] It is to be further understood that the present invention is not limited to the particular methodology, compounds, materials, manufacturing techniques, uses, and applications, described herein, as these may vary. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “an element” is a reference to one or more elements and includes equivalents thereof known to those skilled in the art. Similarly, for another example, a reference to “a step” or “a means” is a reference to one or more steps or means and may include sub-steps and subservient means. All conjunctions used are to be understood in the most inclusive sense possible. Thus, the word “or” should be understood as having the definition of a logical “or” rather than that of a logical “exclusive or” unless the context clearly necessitates otherwise. Structures described herein are to be understood also to refer to functional equivalents of such structures. Language that may be construed to express approximation should be so understood unless the context clearly dictates otherwise.
[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Preferred methods, techniques, devices, and materials are described, although any methods, techniques, devices, or materials similar or equivalent to those described herein may be used in the practice or testing of the present invention. Structures described herein are to be understood also to refer to functional equivalents of such structures. The present invention will now be described in detail with reference to embodiments thereof as illustrated in the accompanying drawings.
[0021] From reading the present disclosure, other variations and modifications will be apparent to persons skilled in the art. Such variations and modifications may involve equivalent and other features which are already known in the art, and which may be used instead of or in addition to features already described herein.
[0022] Although Claims have been formulated in this Application to particular combinations of features, it should be understood that the scope of the disclosure of the present invention also includes any novel feature or any novel combination of features disclosed herein either explicitly or implicitly or any generalization thereof, whether or not it relates to the same invention as presently claimed in any Claim and whether or not it mitigates any or all of the same technical problems as does the present invention.
[0023] Features which are described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination. The Applicants hereby give notice that new Claims may be formulated to such features and/or combinations of such features during the prosecution of the present Application or of any further Application derived therefrom.
[0024] As is well known to those skilled in the art many careful considerations and compromises typically must be made when designing for the optimal manufacture of a commercial implementation any system, and in particular, the embodiments of the present invention. A commercial implementation in accordance with the spirit and teachings of the present invention may configured according to the needs of the particular application, whereby any aspect(s), feature(s), function(s), result(s), component(s), approach(s), or step(s) of the teachings related to any described embodiment of the present invention may be suitably omitted, included, adapted, mixed and matched, or improved and/or optimized by those skilled in the art, using their average skills and known techniques, to achieve the desired implementation that addresses the needs of the particular application.
[0025] Detailed descriptions of the preferred embodiments are provided herein. It is to be understood, however, that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or manner.
[0026] It is to be understood that any exact measurements/dimensions or particular construction materials indicated herein are solely provided as examples of suitable configurations and are not intended to be limiting in any way. Depending on the needs of the particular application, those skilled in the art will readily recognize, in light of the following teachings, a multiplicity of suitable alternative implementation details.
[0027] A preferred embodiment of the present invention and some variations thereof provide a dental floss holder, which may be used with conventional round floss or dental tape. Some preferred embodiments allow for the use of many types of floss including, but not limited to, round floss, dental tape, flosses using modern technologies developed for new applications of synthetic materials with elastic effect, ultra thin floss, wax covered floss, etc. Some preferred embodiments may be designed to enable them to be produced from plastic with existing technologies used for manufacturing containers for conventional dental flosses and tapes. However, some alternate embodiments may be produced using different techniques and from different materials including, but not limited to, metals, composites, rubber, or a combination of materials. Some preferred embodiments comprise a small number of parts, which allows for quick and easy installation of the floss and generally ensures minimum costs in the production of the device.
[0028] FIGS. 1A , 1 B and 1 C illustrate an exemplary dental floss holder, in accordance with an embodiment of the present invention. FIG. 1A is a diagrammatic side view. FIG. 1B is a diagrammatic front view, and FIG. 1C is a diagrammatic rear view. In the present embodiment, the floss holder is preferably made for effective use of dental tape. However, the floss holder also allows for the use of conventional round floss, waxed floss, ultra thin floss, synthetic floss, elastic floss, etc. In the present embodiment, the floss holder comprises a housing 2 , a floss cassette, as shown by way of example in FIGS. 2A through 2C , a locking button 1 , which locks a stretched portion of floss 5 within a locking mechanism in housing 2 , and a rounded blade 3 . The design of floss holder housing 2 and particularly a fork 204 comprising fork-shaped protruding ends enables smooth flossing by holding a piece of floss 5 firmly in the desired position and generally preventing floss 5 from stretching and tangling during flossing or while removing used floss. Indent 217 on housing 2 enables the user to rest the floss holder on a finger while operating locking button 1 to prevent the floss holder from slipping.
[0029] A free end 5 A of floss 5 is pulled out through an opening 207 , which enables a user to pull floss 5 through the floss holder after housing 2 is locked in a closed position. In the present embodiment opening 207 is located at the end of housing 2 opposite fork 204 ; however, this opening may be placed in various different locations in alternate embodiments such as, but not limited to, on the front or side of the housing. In the present embodiment, housing 2 is held in place in the closed position with two housing fixating plates 201 , which are locked firmly in place with the help of a locking mechanism, shown by way of example in FIG. 4B . To open housing 2 , fixating plates 201 are unlocked and the two portions of housing 2 are spread apart along a seam 213 on the back with a hinge 214 on the front. Free end 5 A of floss 5 , which is the used portion of floss 5 , is manually pulled through opening 207 and into a channel 215 , which guides free end 5 A in the direction of cutting blade 3 where the used portion of floss 5 is cut off. Alternate embodiments may be implemented without a channel for guiding the free end of the floss and also be implemented without a blade. In the present embodiment, protrusions 208 , which are also located on the inside of housing 2 as shown by way of example in FIG. 4B , reduce friction on floss 5 in the process of sliding floss 5 through the floss holder when the used portion is replaced with a clean portion. Dimples 216 enable a user to firmly grasp housing 2 when floss 5 is manually pulled through opening 207 and into a channel 215 and capture free end 5 A in the process of cutting by the blade 3 .
[0030] In the present embodiment, the floss holder is designed to allow equally easy operation for left or right-handed users. For example, without limitation, dimples 216 and channels 215 are provided on both sides of housing 2 to enable the used portion of floss 5 to be cut on either side of housing 2 . However, alternate embodiments may be implemented as specifically right-handed or left-handed devices. In the present embodiment, the floss holder provides considerable savings of floss since during the replacement of floss 5 on fork 204 only about one to one and a half inches of floss are used. Also, the process of replacing floss 5 is fast and simple, often taking only one to two seconds to complete. The floss holder is designed so that the clean portion of floss 5 does not come into contact with the used portion at any time during flossing or during the replacement of floss 5 on fork 204 .
[0031] FIGS. 2A , 2 B, 2 C and 2 D illustrate an exemplary floss cassette 4 from a dental floss holder, in accordance with an embodiment of the present invention. FIG. 2A is a side perspective view of floss cassette 4 in a closed position. FIG. 2B is a side perspective view of locking plates 401 and 402 of floss cassette 4 . FIG. 2C is a diagrammatic top view of floss cassette 4 in an open position, and FIG. 2D is a diagrammatic side view of floss cassette 4 in an open position. In the present embodiment floss 5 is installed in floss cassette 4 by being coiled around a cylinder 406 then being fed between locking plates 401 and 402 around a plate 404 and a plate portion 404 A. In some embodiments, plate portion 404 A includes a notch 412 , shown in FIG. 4B , to capture floss 5 . In other alternate embodiments, various other means may be used to capture floss 5 . From here, floss 5 is placed back through locking plates 401 and 402 then into one of notches 409 and out of cassette 4 so that a free end 5 A of floss 5 can exit the floss holder once cassette 4 is installed in the floss holder, as shown by way of example in FIG. 4A . Floss cassette 4 comprises a stretching mechanism 403 , which holds floss 5 in place and stretches floss 5 on the fork of the floss holder and maintains floss 5 in the stretched position for smooth and easy flossing, as described by way of example in accordance with FIG. 4A . In order for floss 5 to be coiled around cylinder 406 , a user may manually wind a long piece of floss around cylinder 406 or a pre-wound spool of floss may be placed on cylinder 406 . In some embodiments the cassette may be preloaded with floss. In these embodiments, the user may obtain the cassette preloaded with a type of floss of his/her choosing. During the installation in the present embodiment, protruding segments 407 hold floss 5 in place on locking plate 402 . A hole 408 locks the top of cassette 4 upon cylinder 406 . Openings 411 enable hole 408 to decrease the diameter of cylinder 406 . During installation of the floss roll, tight contact of the floss roll and the cylinder 406 allows convenient installation of the floss on the cassette and prevents the floss on the roll from twisting in the process of floss installation. This reduces the amount of the friction during the replacement of the used portion of floss 5 . In alternate embodiments cylinder 406 may not have openings 411 . In these embodiments the floss roll does not tightly contact cylinder 406 and during the installation of the floss, the roll is held in place by user's fingers to prevent twisting. In some embodiments cylinder 406 has a top portion with a smaller outside diameter than the rest of the cylinder. This top portion fits into a raised lip of hole 408 . After floss 5 is installed in cassette 4 , cassette 4 is inserted into the housing of the floss holder. Openings 405 on locking plates 401 and 402 are installed upon protrusions inside the housing, shown by way of example in FIGS. 4A and 4B .
[0032] In the present embodiment, locking plates 401 and 402 comprise zigzagged surfaces with a multiplicity of protrusions. In alternate embodiments the zigzagged surface may only be on locking plate 401 or only on locking plate 402 . The number of protrusions and corresponding hollow segments on locking plates 401 and 402 depends on the size of the floss holder. In alternate embodiments only one of the locking plates may have a zigzagged surface or the surfaces may have different textures such as, but not limited to, a bumpy or rough texture. Plates 410 on the top portion of cassette 4 and plate 401 provide unlocking of locking plates 401 and 402 , as described by way of example in accordance with FIG. 4A .
[0033] FIGS. 3A , 3 B and 3 C illustrate an exemplary locking button 1 of a dental floss holder, in accordance with an embodiment of the present invention. FIG. 3A is a side perspective view. FIG. 3B is a diagrammatic front view, and FIG. 3C is a diagrammatic bottom view. In the present embodiment, locking button 1 comprises an irregular bottom surface with protrusions 101 extending from a horizontal element 102 . When locking button 1 is installed in the floss holder, pushing down on locking button 1 causes the floss in the floss holder to be held in place.
[0034] FIGS. 4A and 4B illustrate an exemplary dental floss holder, in accordance with an embodiment of the present invention. FIG. 4A is a diagrammatic side view of the floss holder in an open position, and FIG. 4B is a side perspective view of the floss holder in the open position with a locking button 1 , a floss cassette 4 and a blade 3 removed. In the present embodiment, a housing 2 opens by pivoting at a hinge 214 . In alternate embodiments, the housing may comprise two halves that are separate from each other that snap together to close. Other alternate embodiments may comprise doors that swing open, slide open, or snap on and off of the housing to provide access to the inside of the housing to load the floss. Referring to FIG. 4A , after the installation of floss 5 , cassette 4 is closed and inserted into housing 2 of the floss holder. In the present embodiment, floss cassette 4 is slid into the side of housing 2 ; however, alternate embodiments may be implemented where the floss cassette is installed in different ways for example, without limitation, dropped in from the top or bottom of the housing. Referring to FIGS. 4A and 4B , in the present embodiment, a protrusion 212 provides stable positioning for plates 410 on the front of cassette 4 . Openings 405 on locking plates 401 and 402 of cassette 4 are installed upon protrusions 211 inside housing 2 and hold and stabilize locking plate 401 over locking plate 402 .
[0035] Once floss cassette 4 is in place, locking button 1 is installed above floss cassette 4 . An opening 207 in housing 2 enables a user to pull a free end 5 A of floss 5 out of housing 2 so that the used portions of floss 5 can be replaced with clean floss when floss locking plates 401 and 402 are unlocked, as shown by way of example in FIG. 4A . The portion of floss 5 around a plate 404 is installed on a fork 204 of the floss holder once housing 2 is closed. Referring to FIG. 4B , in the closed position, housing 2 is held closed by two fixating plates 201 , which are locked firmly in place by locking mechanisms 202 locking into openings 203 on the opposite end of housing 2 . Plate portion 404 A is removed from plate 404 and discarded after floss 5 is installed on fork 204 .
[0036] In the present embodiment, the floss holder allows for effective and convenient flossing thanks to a mechanism for locking and stretching floss 5 on fork 204 . This mechanism is located on floss cassette 4 and comprises locking plates 401 and 402 with zigzagged surfaces. Referring to FIG. 4A , locking button 1 and locking plates 401 and 402 are shown in an unlocked position. Once housing 2 is closed and floss 5 is placed on fork 204 , pushing down locking button 1 causes floss 5 to be locked between locking plates 401 and 402 , and sliding locking button 1 towards fork 204 causes a horizontal element 102 of locking button 1 to push down upon a stretching mechanism 403 of floss cassette 4 , which results in stretching mechanism 403 being pushed down onto and stretching floss 5 on fork 204 of housing 2 . After it is pushed down and slid forward towards fork 204 , locking button 1 holds its position and holds plate 401 in place against plate 402 with the help of protrusions 101 located on locking button 1 , which engage with protruding elements 206 on the inside of housing 2 . This double locking mechanism provides effecting locking of floss 5 between plates 401 and 402 of floss cassette 4 and stretching of floss 5 on fork 204 by virtue of horizontal element 102 pressing upon stretching mechanism 403 . In alternate embodiments, the locking mechanism may be actuated by various different means other than a sliding button such as, but not limited to, a push button, a lever, a dial, etc. In the present embodiment to unlock floss 5 , locking button 1 is slid away from fork 204 and slides off of protruding elements 206 . This releases locking button 1 upward away from plates 401 and 402 and therefore enables plate 401 to move upward, away from plate 402 . Plates 410 on the top portion of cassette 4 and plate 401 facilitate the unlocking of locking plates 401 and 402 by Initially plate 401 is located above the plate 402 with a space between the plates 401 and 402 which is needed for smooth removal of the used portion of the floss. In the process of locking, elements 410 bend and provide locking of the floss between the plates. After unlocking, elements 410 return plate 401 to its previous position allowing space to be created for removal of the used portion of the floss.
[0037] Referring to FIG. 4B , the openings located on plate 402 of floss cassette 4 generally prevent wax build-up and allow for smooth sliding of floss 5 even when wax-covered floss and dental tape is used. The openings on the plate 402 are aligned with protruding ends of plate 401 . This enables protruding ends on the plate 401 to block floss inside the openings of the plate 402 . The wax build-up is pushed away under plate 402 thus preventing wax build-up between the plates, which can cause inconvenience to the user in the process of removing used portion of the floss. A multiplicity of protrusions 208 located on housing 2 reduces friction of floss 5 while floss 5 slides through the floss holder in order to replace used floss with clean floss. Alternate embodiments may be implemented without these protrusions. In the present embodiment, rounded blade 3 , used for cutting off used floss, is located on the lower portion of housing 2 on a blade plate 205 . As shown in FIG. 1A , this location of blade 3 enables blade 3 to be recessed from the bottom surface of housing 2 for the user's safety while leaving a sufficient length of floss outside housing 2 for easy grasping. However, the cutting blade may be located in various different locations in alternate embodiments such as, but not limited to, near the opening from which the floss exits the floss holder, and other alternate embodiments may be implemented without a blade. In the present embodiment, fork 204 , which is formed when housing 2 is closed, comprises extensions 209 that form a hollow shape which allows for the installation of floss 5 on fork 204 and holds floss 5 in place during flossing. The rounded shape of ends 210 of fork 204 facilitates smooth sliding of floss 5 and generally prevents twisting or breaking during use. Those skilled in the art will readily recognize, in accordance with the teachings of the present invention that the forks in alternate embodiments may vary in shape. For example, without limitation, the ends of the fork may comprise holes into which the floss is threaded, or the ends may comprise shallow grooves into which the floss is placed. In some embodiments the ends of the fork may be made of rubber or may be covered by rubber tips to protect the mouth of the user and to more securely grip the floss.
[0038] In typical use of the present embodiment, which is illustrated by way of example in FIGS. 1A through 4B , a user opens housing 2 of the floss holder along seam 213 and inserts a loaded floss cassette 4 into housing 2 , as shown by way of example in FIG. 4A . Then, the user installs locking button 1 above locking plates 401 and 402 and closes housing 2 by locking fixating plates 201 . The user then pulls floss 5 wrapped around plate 404 and plate portion 404 A from the floss holder and inserts floss 5 between extensions 209 on fork 204 . Once floss 5 is installed on fork 204 , the user may break off plate portion 404 A. To tighten and lock floss 5 in place, the user then slides locking button 1 toward fork 204 . The user may now hold the floss holder in either hand to use the portion of floss 5 in fork 204 to floss his teeth.
[0039] In order to replace the used portion of floss 5 with an unused portion, the user slides locking button 1 away from fork 204 to unlock locking plates 401 and 402 and pulls on free end 5 A to slide floss 5 through the floss holder and out opening 207 . Once the used portion of floss 5 is pulled out of fork 204 , the user slides locking button 1 back toward fork 204 to lock the clean portion of floss 5 in place. If desired, the user may then take free end 5 A of floss 5 up through channel 215 to cut off the excess floss with blade 3 . Those skilled in the art will readily recognize, in accordance with the teachings of the present invention, that any of the foregoing steps may be suitably replaced, reordered, removed and additional steps may be inserted depending upon the needs of the particular application. For example, without limitation, locking button 1 may be installed before floss cassette 4 , and the user may skip the step of cutting the excess floss from free end 5 A.
[0040] An alternate embodiment of the present invention may provide a floss holder that does not use a floss cassette. In this embodiment, the locking mechanism is built into the housing of the floss holder along with floss holding means. A user installs the floss directly into the housing and feeds the floss through the built in locking mechanism prior to use.
[0041] FIG. 5 illustrates an exemplary water resistant dental floss holder, in accordance with an alternative embodiment of the present invention. The dental floss holder in FIG. 5 includes a water resistant container which helps avoid water penetration to the dental floss held within the water resistant container.
[0042] FIG. 6 illustrates an exemplary dental floss holder having a wall partition member, in accordance with an alternative embodiment of the present invention. The dental floss holder in FIG. 6 includes a wall partition member which helps provide a better partition between new and used dental floss material.
[0043] Those skilled in the art will readily recognize, in accordance with the teachings of the present invention, that various features of the floss holder illustrated by way of example in the foregoing may vary in alternate embodiments. For example, without limitation, the forks in alternate embodiments may have various different shapes such as, but not limited to, square forks, the housings may have various different shapes including, but not limited to, housings with finger grooves for improved grip or rectangular housings, floss holders in alternate embodiments may come in various different sizes for example, without limitation, adult and children's sizes, etc. Furthermore, there are various protrusions illustrated in the foregoing embodiment for guiding the floss and reducing friction. In alternate embodiments the number and locations of these protrusions may vary greatly, and some embodiments may be implemented without these protrusions. Yet other alternate embodiments may comprise additional features such as, but not limited to, a dental pick, a tongue scraper, an electric motor to provide vibration, etc.
[0044] Having fully described at least one embodiment of the present invention, other equivalent or alternative methods of providing a floss holder according to the present invention will be apparent to those skilled in the art. The invention has been described above by way of illustration, and the specific embodiments disclosed are not intended to limit the invention to the particular forms disclosed. For example, the particular implementation of the floss cassette may vary depending upon the particular type of floss used. The floss spools described in the foregoing were directed to relatively short implementations; however, similar techniques are to provide floss cassettes to accommodate floss spools of various different sizes such as, but not limited to, tall spools or wide spools. In some of these implementations, the configuration of the floss within the cassette may vary depending on the size of the spool in order to fit the floss within the floss holder; for example, without limitation, the spool may be held in the cassette vertically rather than horizontally. Implementations of the present invention for use with different sizes of floss spools are contemplated as within the scope of the present invention. The invention is thus to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the following claims.
[0045] Claim elements and steps herein may have been numbered and/or lettered solely as an aid in readability and understanding. Any such numbering and lettering in itself is not intended to and should not be taken to indicate the ordering of elements and/or steps in the claims.
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[0001] This application Claims Priority of Non-Provisional application Ser. No. 12428465 filed Apr. 22, 2009.
FIELD OF INVENTION
[0002] This invention relates to compositions and methods that treat bacterial, viral, or parasitic infection including malaria and gastrointestinal infections presenting as acute diarrhea.
[0003] Malaria
[0004] This once widespread disease is now mainly confined to Africa, Asia and Latin America but still affects approximately 120 million people worldwide and results in over 1 million deaths per year. Controlling malaria in these countries is difficult because of inadequate health structures and poor socioeconomic conditions and the last few years have seen an increase in resistance to the drugs normally used to combat the parasite that causes the disease. Malaria is caused by four species of the protozoan parasites of the genus Plasmodium: Plasmodium falciparum, Plasmodium vivax Plasmodium ovale , and Plasmodium malaria. P. falciparum is the most widespread and dangerous of the four and if untreated can lead to fatal cerebral malaria.
[0005] Malaria parasites are transmitted from one person to another by the female anopheline mosquito that feeds on human flesh, as the males feed only on plant juices and do not transmit the disease. There are about 380 species of anopheline mosquito, but only about 60 transmit the parasite. Like all other mosquitos, the anophelines breed in water and each species has its preferred breeding grounds, feeding patterns and resting place. Their sensitivity to insecticides is highly variable between species.
[0006] The plasmodium develops in the gut of the mosquito and is passed on in the saliva of an infected insect each time it takes a new blood meal. The parasites are then carried by the blood in the victim's liver where they invade the cells and multiply. After 9-16 days they return to the blood and penetrate the red cells, where they multiply again, progressively break down the red cells and induce fever and anaemia in the infected individual. In cerebral malaria, the infected red cells obstruct the blood vessels in the brain and other vital organs leading to the death of the patient.
[0007] Malaria is diagnosed by the clinical symptoms and microscopic examination of the blood and can usually be cured by antimalarial drugs. The symptoms, fever, shivering, pain in the joints and headache quickly disappear once the parasite is destroyed. In certain regions, however, the parasites have developed resistance to certain antimalarial drugs, particularly chloroquine. Patients in these areas require treatment with other more expensive drugs and hospitalization of Cases of severe disease including cerebral malaria. In endemic regions, where transmission is high, people are continuously infected.
[0008] Systematic control of malaria started after the discovery of the malaria parasite by Laveran in 1889, for which he received the 1907 Nobel Prize for medicine, and the demonstration by Ross in 1897 that the mosquito was the vector of malaria. These discoveries quickly led to control strategies and with the invention of DDT during the World War II, and the notion of global eradication of the disease. Effective and inexpensive drugs of the chloroquine group were also synthesized around this time. In 1969 it was recognized that global eradication of malaria was unlikely ever to be achieved and ongoing control programs remain essential in endemic areas. Malaria is currently endemic in 91 countries with small pockets of transmission occurring in an additional eight countries. Plasmodium falciparum remains the predominant parasite. More than 120 million clinical cases and over 1 million deaths occur in the world each year.
[0009] Children remain the most highly vulnerable to death from malaria followed by pregnant women whose natural immunity is reduced. Eighty per cent of the cases occur in tropical Africa, where malaria accounts for 10% to 30% of all hospital admissions and is responsible for 15% to 25% of all deaths of children under the age of five. Around 800,000 children under the age of five die from malaria every year, making this disease one of the major causes of infant and juvenile mortality and a substantial number of miscarriages and low birth weight babies.
[0010] Malaria thus has social consequences and is a heavy burden on economic development. It is estimated that a single bout of malaria costs a sum equivalent to over 10 working days in Africa. The cost of treatment is between eight cents (US $0.08) and five dollars and thirty cents (US $5.30) according to the type of drugs prescribed as determined by drug resistance in the locality. In 1987, the total “cost” of malaria—health care, treatment, lost production, etc. was estimated to be eight hundred million United States dollars (US $800 million) for tropical Africa and this figure is currently estimated to be more than US $1,800 million.
[0011] The geographic distribution of malaria is in tropical and subtropical countries and its prevalence varies greatly from country to country and within the countries themselves. In 1990, seventy-five percent (75%) of all recorded cases outside of Africa were concentrated in nine countries: India, Brazil, Afghanistan, Sri Lanka, Thailand, Indonesia, Vietnam, Cambodia and China. The incidence rates in South American and Caribbean countries have also significantly increased. Traditional endemic zones where transmission had once been eradicated have suffered epidemics, increasing malaria's significance as a world health problem. These outbreaks are generally associated with deteriorating social and economic conditions, and the victims are travelers and underprivileged rural populations. Demographic, economic and political pressures compel entire populations of seasonal workers, nomadic tribes and farmers to leave malaria free areas and move into newly developed agricultural and urban areas in endemic zones. The vast majority of people are non-immune and at high risk of severe disease. Unfortunately, these population movements and the intensive urbanization are not always accompanied by adequate development of sanitation and health care. This frequently results in a recourse to self-administration of drugs, incomplete treatment, and parasitic resistance to previously effective drugs.
[0012] Infectious Diarrhea
[0013] Chronic diarrhea is usually related to functional disorders such as irritable bowel syndrome or inflammatory bowel disease and acute diarrhea is most often caused by bacterial, viral, or parasitic infection but may be caused by food intolerances to artificial sweeteners, lactose, and other food components. The more common bacterial causes of diarrhea include several types of bacteria consumed through contaminated food or water including Campylobacter, Salmonella, Shigella , and Escherichia coli ( E. coli ). Viral etiologies include rotavirus, Norwalk virus, cytomegalovirus, herpes simplex virus, and viral hepatitis. Parasites can enter the body through food or water and settle in the digestive system. Diarrhea may be caused by Giardia lamblia, Entamoeba histolytica , and Cryptosporidiu.
[0014] Enterotoxins
[0015] Certain forms of diarrhea, namely those caused by the production of enterotoxins by certain bacteria are often difficult to treat and can be life threatening. The use of normal antidiarrheal agents which merely are absorbents, such as kaolin, or agents that reduce intestinal muscle activity have little or no effect on this enterotoxin-caused diarrhea. Cholera is an acute infection of Vibrio cholerae ( V. Cholerae ) in man involving the entire small bowel, characterized by a debilitating diarrhea. Enterotoxigenic Escherichia coli are a major cause of diarrhea in neonatal food-producing animals and “travelers diarrhea” in man.
[0016] These enteric bacteria release enterotoxins released by these enteric bacteria reverse the transport of water and electrolytes in the epithelium of the small intestine, from absorption to secretion. V. cholerae enterotoxin and Escherichia coli LT enterotoxin stimulate adenylate cyclase causing increased formation of cAMP which, through a cascade of reactions, inhibits active absorption and stimulates active secretion of water and sodium, chloride and bicarbonate electrolytes. In contrast to these two enterotoxins, Escherichia coli ST enterotoxin stimulates guanylate cyclase, increases cGMP levels and causes diarrhea primarily by inhibiting active absorption of water and electrolyte.
[0017] Travelers' Diarrhea
[0018] Travelers' diarrhea (TD) is the most common travelers' illness, affecting 20%-50% of international travelers, an estimated 10 million persons, per year. The onset of TD usually occurs within the first week of travel but may occur at any time while traveling, and even after returning home. Risk is a factor of destination and is highest in the developing countries of Latin America, Africa, the Middle East, and Asia. Persons at particular high-risk include young adults, immunosuppressed persons, persons with inflammatory-bowel disease or diabetes, and persons taking H-2 blockers or antacids. Incidence rates are similar for men and women. The primary source of infection is ingestion of fecally contaminated food or water. TD begins abruptly with stool of increased frequency, volume, and weight and altered consistency, typically, four to five loose or watery bowel movements each day. Other commonly associated symptoms are nausea, vomiting, abdominal cramping, bloating, fever, urgency, and malaise.
[0019] TD is rarely life-threatening. Ninety percent (90%) of cases resolve naturally within 1 week, and ninety eight percent (98%) resolve within 1 month. Infectious bacterial, viral and parasitic enteric pathogens are the primary cause of TD and bacterial enteropathogens, most commonly enterotoxigenic E. Coli (ETEC), are responsible for approximately 80% of cases. ETEC produces watery diarrhea with associated cramps and low-grade or no fever.
[0020] Dysentery
[0021] Dysentery is a term used for diarrhea when there is evidence of pathogenic invasion of the intestinal wall, causing pus, mucus, and blood to appear in the stool and frequently fever and abdominal cramps. There is no bright-line distinctions between diarrhea and dysentery. Attempts to define their differences in medical and travel advice books is misplaced as treatments are often the same.
[0022] Dengue Fever
[0023] In 2005, dengue (DF) was the most important mosquito-borne viral disease affecting humans; its global distribution is comparable to that of malaria, and an estimated 2.5 billion people live in areas at risk for epidemic transmission (FIG. 4). Each year, tens of millions of cases of DF occur and, depending on the year, up to hundreds of thousands of cases of dengue hemorrhagic fever (DHF). The case fatality rate of DHF in most countries is about 5%, mostly in children and young adults, but proper treatment can reduced it to less than 1%. There is a small risk for dengue outbreaks in the continental United States. Two competent mosquito vectors, Ae. aegypti and Aedes albopictus , are present and, under certain circumstances, could transmit dengue viruses. This type of transmission has been detected six times in the last 25 years in south Texas (1980 -2004) and has been associated with dengue epidemics in northern Mexico by Aedes aegypti and in Hawaii (2001-02) due to Ae. albopictus . Moreover, numerous viruses are introduced annually by travelers returning from tropical areas where dengue viruses are endemic. From 1977 to 2004, a total of 3,806 suspected cases of imported dengue were reported in the United States. Although some specimens collected were not adequate for laboratory diagnosis, 864 (23%) cases were confirmed as dengue and many more cases are likely to be unreported. Surveillance in the United States is passive and relies on physicians to recognize the disease, inquire about the patient's travel history, obtain proper diagnostic samples, and report the case. These data suggest that southern and southeastern states, where Ae. aegypti is found, are at risk for dengue transmission and sporadic outbreaks. Although travel-associated dengue and limited outbreaks do occur in the continental United States, most dengue cases in US citizens occur as endemic transmission among residents in some of the US territories. The Center for Disease Control (CDC) conducts laboratory-based passive surveillance in Puerto Rico in collaboration with the Puerto Rico Department of Health.
[0024] The reasons for the dramatic global emergence of DF/DHF as a major public health problem are complex and not well understood but several important factors can be identified. First, major global demographic changes have occurred, the most important of which have been uncontrolled urbanization and concurrent population growth. These demographic changes have resulted in substandard housing and inadequate water, sewer, and waste management systems, all of which increase Ae. aegypti population densities and facilitate transmission of Ae. aegypti -borne disease. In most countries the public health infrastructure has deteriorated. Limited financial and human resources and competing priorities have resulted in a “crisis mentality” with emphasis on implementing so-called emergency control methods in response to epidemics rather than on developing programs to prevent epidemic transmission. This approach has been particularly detrimental to dengue control because, in most countries, surveillance is, as in the U.S., passive; the system to detect increased transmission normally relies on reports by local physicians who often do not consider dengue in their differential diagnoses. An epidemic has often reached or passed its peak before it is recognized. Increased travel by airplane provides the ideal mechanism for infected human transport of dengue viruses between population centers of the tropics, resulting in a frequent exchange of dengue viruses and other pathogens.
[0025] Lastly, effective mosquito control is virtually nonexistent in most dengue-endemic countries. Considerable emphasis in the past has been placed on ultra-low-volume insecticide space sprays for adult mosquito control, a relatively ineffective approach for controlling Ae. aegypti . No dengue vaccine is yet available. While attenuated candidate vaccine viruses have been developed recently, efficacy trials in human volunteers have not been initiated. Research is also being conducted to develop second-generation recombinant vaccine viruses. Therefore, an effective dengue vaccine for public use will not be available for 5 to 10 years. Prospects for reversing the recent trend of increased epidemics and geographic expansion of dengue are not promising. New dengue virus strains and serotypes will likely continue to be introduced into many areas where the population densities of Ae. aegypti are at high levels.
[0026] Artemisinin
[0027] Artemisinin and its Chemical Derivatives Artemisinin, or (ginghaosu), a clinically useful antimalarial agent which was isolated from the plant Artemisia annua, is an unusual sesquiterpene lactone containing an epidioxide function. Dihydroartemisinin, obtained by sodium borohydride reduction of artemisinin, has been reported as more therapeutically active than its parent compound. Neither artemisinin nor dihydroartemisinin exhibit cross-resistance to chloroquine and both were proven efficacious against cerebral malaria in man. Artesunate, or sodium artesunate, the sodium salt of the succinic acid half ester derivative of dihydro-artemisinin, is water soluble and can be administered intravenously, making the compound particularly useful in the treatment of cerebral malaria where rapid administration is critical. Artesunate, however, has been shown in human clinical trials to be as effective as injectable artesunate to treat uncomplicated malaria. Alin, M H, et al, 53(6) Am J Trop Med Hyg 639-45 (1995); Luxembuger, C, et al, 53(5) Am. J. Trop Med Hyg 522-5 (1995).
[0028] Artemisinin was first isolated by the Chinese in 1972, and was soon discovered to be a fast acting, safe and effective drug against chloroquine-resistant and sensitive strains of Plasmodium falciparum , as well as cerebral malaria. No side effects, common to many synthetic anti-malarials, have been reported by the Chinese during the past 35 years of clinical use of artemisinin or artesunate. One disadvantage of artemisinin itself is that the compound is only sparingly soluble in either water or oils and thus not readily absorbable by the gastrointestinal tract. There was a long-felt need for a more ideal drug or a combination of drugs with enhanced antimalarial activity and improved physical and bioavailability properties such as artesunate for more effective oral treatment of malaria and the treatment of chloroquine-resistant malaria.
[0029] A search of the USPTO under artemisinin and malaria listed 109 patents relating to artemisinin and its chemical derivatives, novel delivery systems, treatment of a variety of protozoal and viral diseases, such as toxoplasmosis, HIV, cancer treatments, treatment of infectious diseases, and antimicrobial compositions. Romero, M R, et al 68(2) Antiviral Res 75-83 (2005); Jiao, Y, et al 28(7) Acta Pharmacol Sin 1045-56 (2007); Shoeb, H A, et al, 2(6) J Chemother 362-7 (1990); Wang, J, et al, 50(7) Antimicrob agents Chemother 2420-7 (2006).
[0030] A search of the USPTO database for dihydroartemisinin and malaria listed 46 patents for treatment of a wide variety of diseases that primarily teach new analogs of artemisinin and dihydroartemisinin and their uses.
[0031] Berberine
[0032] Berberine (5,6-Dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium) is an alkaloid present in various species of Berberis and several other plant families. Oral berberine has both anti-secretory and antimicrobial properties and is nontoxic at high oral doses.
[0033] For many centuries, berberine extract from plants has been used by traditional practitioners in both India and China to manage a variety of medical conditions, including acute diarrhea. Berberine shows in vitro activity against the protozoa Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica , several of the protozoal strains which cause leishmaniasis, as well as several types of fungi, bacteria, viruses, and the human immunodeficiency virus (HIV).
[0034] Rabbani, G H. 43(2) Dan Med Bull 173-85 (1996); Soffar, S A., et al, 31(3) J. Egypt Soc Parasitol 893-904 (2001); Hawrelak, J, 8(2) Altern Med Rev 129-42 (2003); Vennerstrom, J L, et al, 34(5) Antimoicrob Agents Chemother 918-21 (1990); Kaneda, Y, et al, 85(4) Ann Trop Med Parasitol. 417-25 (1991); Tauk, L, et al, 78(2) Fitoterapia 159-61 (2007); Sun, D., Courtney, H S, Beachey, E H, 32(9) Antimicrob Agents Chemother 1370-4 (1988); Gudima, S O Nov-Dec (6) Mol Biol 1308-14 (1994).
[0035] Berberine, purified as a hydrochloride, sulfate, or tannate salt, has been used clinically to treat bacterial, fungal and some protozoal infections. Orally administered berberine has been shown to be a safe and effective agent against acute diarrhea, such as that caused by the protozoal pathogen G. lamblia , Kaneda, Y, et al, 85(4) Ann Trop Med Parasitol. 417-25 (1991), Escherichia coli and Vibrio cholerae toxins.
[0036] Healing of sores caused by cutaneous species of leishmanial parasites has been effected by intradermal administration of berberine. Other uses of various berberine compounds are disclosed in Maroko, U.S. Pat. Nos. 5,153,178, 4,980,344, 4,749,708, and 4,761,417, each of which is incorporated herein by reference.
[0037] Berberine has shown in vitro activity against telomerase activity of the malaria plasmodium fulciparum during its erythrocyte cycle. Sriwilaijareon, N, et al, 51(1) Parasitol Int 99-103 (2002). As a major active constituent of a Vietnamese medicinal plant, berberine was found to have antiplasmodial activity by inhibiting the growth of a Plasmodium falciparium strain FCR-3 with EC(50) values of less than 10 micrograms per ml added to cell culture. Tran, Q L, et al, 86(2-3) J. Ethnopharmacol 249-52 (2003). In a human trial of 215 patients with chloroquine resistant malaria, berberine in combination with pyrimethamine, showed a clearance rate of asexual parasitaemia of 74.4%, higher than a tetracycline only group (67.2%) or a cotrimoxazole only group with a clearance rate of only 47.8%. Sheng, W D, et al, 74(5) East AFR Med J 283-4 (1997).
[0038] A search of the USPTO data base for berberine and malaria lists 13 patents that do not mention the treatment of malaria with berberine specifically. Prior to this invention, berberine has not been used in combination with artemisinin or its derivatives for the treatment of malaria in humans. Berberine and arteminisin have not been combined to treat multiple etiological agents, such as malaria, diarrhea, dysentery and other bacteria or parasites simultaneously.
[0039] Berberine and arteminisin have not previously been combined in an acute dosage regimine, nor have berberine and arteminisin been previously been combined in a blister pack to make dosing compliance simple for patients or travelers. A search of the USPTO database for berberine and diarrhea lists 25 patents, new compositions and uses for treating diverse conditions from diarrhea, circulation, Alzheimer's, depression, diaper rash, scar tissue, cancer, termite eradication and the like. No patents were revealed by searches of the USPTO database for berberine and dengue fever or travelers diarrhea and kit.
[0040] Loperamide
[0041] When a traveler is suffering from diarrhea, it is often necessary to control the symptoms of the disease while the multiple etiological agents, such as malaria, diarrhea, dysentery and other bacteria or parasites are treated, in this invention with Berberine and arteminisin have not been combined to treat. Loperamide, 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide, has well-established clinical history of use in the sympomatic control of diarrhea. It is frequently used in medicine as a hydrochloride salt, oxide, or N-oxide form.
[0042] Loperamide is considered to be an opoid agonist, Elkiweri, M S, et al, 108 Anesth Analg 149-159 (2009), though its effects on the central nervous system are not as potent as other opoids. Peripheral injection of mu-opioid agonist loperamide virtually did not modify the central compartments of the opioid system under conditions of morphine treatment. Methylnaloxone and loperamide partially prevented the development of morphine analgesia tolerance. Sudakov S K, Trigub M M, 146(6) Bull Exp Biol Med 663-6 (2008).
[0043] Japanese researchers have shown that the mechanism of action for loperamide is an effect on Peptide YY (PYY) that is produced in the lower gastrointestinal tract and has antisecretory effects in the colon and inhibition of gastrointestinal motility. Loperamide administration to rats resulted in multiple changes in plasma and intestinal mucosa PYY concentrations, along with an improvement in the diarrhea. Our research showed that the endocrine hormone PYY is involved in the onset of diarrhea, the course of the condition, and the manifestation of medicinal effects in the lower intestine. Hirotani Y, et al, 128(9) Yakugaku Zasshi 1311-6 (2008).
[0044] Several inventors hold patents relating to the use of loperamide in diarrhea, i.e., U.S. Pat. No. 6,869,602, to Ryu, et al, for diarrhea, but its combination with either berberine or artemisinin has not been heretofore disclosed. It has been used in the form of loperamide hydrochloride with saccharide selected from the group consisting of sucrose, fructose, glucose, sorbitol, xylitol, mannitol, and mixtures thereof, said saccharide being present in an amount of from 9 to about 98 wt. % of said composition and from 3,000 times to 20,000 times the weight of said loperamide hydrochloride. U.S. Pat. No. 5,182,112, to Kurazumi , et al.
SUMMARY OF INVENTION
[0045] This inventor has discovered that a composition comprising berberine, artemesinin and loperamide or their derivatives may be used to effectively treat multiple pathogens affecting humans simultaneously in a therapeutic product. Travelers and citizens of third world countries are often simultaneously exposed to, and afflicted with, a variety of pathogenic substances. An objective of this invention is to provide a single therapeutic agent designed to treat a single pathogen, such as the malaria parasite can be life-saving, but concomitant administration of other drugs to treat diarrhea, dysentery, other parasites, E. coli, Vibrio coli , fungal infections, viruses, or dengue fever may be necessary. Proper treatment is complicated by the inability of the physician or practitioner to diagnose and separately identify other pathogens, particularly in third world hospitals with limited testing abilities. The prognosis for either malaria, dengue fever, fungal infections, E. coli, Vibrio coli , or other viral infections becomes less clear when multiple pathogens are present.
[0046] Treatment is further complicated by the need to ingest multiple drugs in a complex regimen where the patient can be acutely sick or delirious and have no attending nurse or guardian present. There is a long-felt need to combine an extremely broad spectrum antibacterial, antimicrobial , antiviral, antiparasitic and antifungal agent such as berberine with its long, well-established use to treat intestinal pathogens with artemisinin or its derivatives, as effective agents for treating malaria , viruses and other blood parasites. A second objective of the invention is to provide the composition in dosage formulations that include, but are not limited to, spray bottles, fast melt pill format, bursts, gel format, adhesive bandages, skin patches, gelcaps, softgels, gelatin capsules, vegetarian capsules, hard shell gelatin capsules, injections, intravenous solutions, topical creams, topical ointments, suppositories, or sublingual methods of administration known to those versed in the art.
[0047] A third objective of the invention is to provide a compact traveler's kit consisting of a blister pack with several day's separate doses of berberine, artemisinin and loperamide in one pill or capsule and simplify compliance of afflicted persons. The method of packaging of the travelers' kit of this invention includes, but is not limited to: blister packs, zip lock packs, standup pouches, foil pouches, boxes, jars, bottles, single dose packets, one a day packs, two day packs, three day packs, and the like. Kits may contain dosages needed for any number of days, from four to thirty days, sixty days, or ninety days.
[0048] The oral dosage ranges of artemisinin or its derivatives may be from about 1 mg to about 1,500 mg per dose of artemisinin, artesunate, sodium artesunate, dihydroartemisinin or any of the artemisinin analogs described by this inventor, administered one to three times daily to a human. The oral dosage ranges are more specifically about 20 mg to about 250 mg per dose of artesunate per human taken one to three times daily, more specifically about 40 mg to about 100 mg per dose of artesunate per human taken one to three times daily and most specifically about 50 mg per dose of artesunate per human taken twice daily.
[0049] The oral dosage range of berberine, its salts or derivatives may be about 50 mg to about 1,500 mg in a single human dose administered two to three times daily, not to exceed about 4,500 mg per day. The oral dosages ranges are more specifically about 100 mg to about 1,000 mg in a single human dose not to exceed 3,000 mg per day administered one to three times daily, more specifically a single human dose of berberine at about 200 mg to about 500 mg taken one to three times daily and most specifically a single dose of berberine at about 200 mg taken twice daily.
[0050] The oral dosage of loperamide or its derivatives may be from about 0.1 mg to about 200 mg in a single human dose administered two to three times daily, not to exceed 500 mg per day. The oral dosages ranges are more specifically about 5 mg to about 10 mg in a single human does not to exceed 20 mg per day administered one to three times daily, and most specifically about 2 mg per dose of loperamide per human taken twice daily.
DETAILED DESCRIPTION OF INVENTION
[0051] In one embodiment, this invention teaches a composition for the treatment of infectious diarrhea comprised of a therapeutically effective amount of berberine, with a blood anti-parasitic antimalarial agent, artemesinin, their pharmaceutically acceptable derivatives, salts, esters, chelates. Most specifically, the artemesinin derivative is the salt of the succinic acid half ester derivative of dihydro-artemisinin known as artesunate.
[0000]
[0052] In this invention, the term berberine includes, but is not limited to, berberine alkaloid, berberine base, berberine hydrochloride, berberine, berberrubine, coreximine, tetrahydropalmatine, jatrorrhizine, 13-hydroxyberberine chloride, coralyne, coralyne chloride, 7,8-dihydro-13-methylberberine, berberine acetone, 13-allylberberine, palmatine, 13-benzylberberine, tetrahydroberberine, tetrahydroprotoberberine 8-cyanodihydroberberine, dimeric protoberberine alkaloids, demethylated protoberberine alkaloids, quataternary protoberberine alkaloids, protoberberine and protoberberine alkaloids.
[0053] In this invention, the salts of berberine, include berberine hydrochloride, berberine chloride, berberine sulfate, berberine tannate and other salts known to those versed in the art. In this invention, plant extracts containing berberine at a concentration of greater than 3%, include, but are not limited to, the Berberis family, Berberis aristata, Berberis aquifolllium, Berberis vulgaris, Berberis aetensis, Coptis chinensis, Chelidonium majus (Ukrain), goldenseal ( Hydrastis canadensis ), Rhizoma coptidis, Phellodendron chinense, Aquilegia oxysepala, Cortex phellodendra , Huanglian Jiedu decoction, San-Huang-Xie-Xin-Tang, Xietianwu, Gegen Quinlian, and Shizhu.
[0000]
[0054] In this invention, the terms ‘artemisinin’ and ‘artesunate’ will be U.S. Pat. No. ______ to include artesunate, artemisinin, dihydroartemisinin, dihydroartemisinin hemisuccinate, dihydrodroartemisinin succinate, sodium artesunate, stabilized forms of artesunate, stabilized forms of sodium artesunate, dihydroartemisitene dimers (U.S. Pat. No. 7,098,242), amino-funtionalized 1,2,4-trioxanes (U.S. Pat. No. 7,071,226), artemisinin endoperoxides (U.S. Pat. No. 6,984,640), spiro and dispiro 1,2,4-trioxolane anti-malarials (U.S. Pat. No. 6,906,205), mixed steroidal 1,2,4,5-tetraoxane compounds (U.S. Pat. No. 6,906,098), arteether (U.S. Pat. No. 6,750,356), substituted 1,2,4-trioxanes (U.S. Pat. No. 6,737,438), Artemisia annua extracts (U.S. Pat. No. 6,685,972), artemether (U.S. Pat. No. 6,683,193, trioxane derivatives based on artemisinin (U.S. Pat. No. 6,649,647), trioxane dimer compounds (U.S. Pat. No. RE38,117), conjugates of artelinic acid (U.S. Pat. No. 6,461,603.), arteethers from dihydroartemisinin (U.S. Pat. No. 6,346,631), artemisinine or artemisinene derivatives (U.S. Pat. No. 6,306,896.), C-10 carbon substituted artemisinin-like trioxane compounds (U.S. Pat. No. 6,160,004). Water-soluble trioxanes (U.S. Pat. No. 6,136,847), alpha arteether (U.S. Pat. No. 6,127,405.), artemisinin dimers (U.S. Pat. No. 5,856,351), (+)-deoxoarteminisinin and analogs of (+)-deoxoartemisinin (U.S. Pat. No. 5,225,562), and 10-substituted ether derivatives of dihydroartemisinin (U.S. Pat. No. 5,225,427).
[0055] Specifically, the berberine, its pharmaceutically acceptable derivatives, salts, chelates and esters, is present in an amount of about 50 mg to about 1500 mg; the artemisinin, its pharmaceutically acceptable derivatives, salts, chelates, and esters is present in an amount of about 1 mg to about 1500 mg; and the loperamide, its pharmaceutically acceptable derivatives, salts, chelates, and esters is present in an amount of about 0.1 mg to about 200 mg. More specifically, the berberine, its pharmaceutically acceptable derivatives, salts, chelates and esters, is present in an amount of about 100 mg to about 1000 mg; the artemisinin, its pharmaceutically acceptable derivatives, salts, chelates, and esters is present in an amount of about 20 mg to about 250 mg and the loperamide, its pharmaceutically acceptable derivatives, salts, chelates, and esters is present in an amount of about 0.5 mg to about 10 mg. More specifically, the berberine, its pharmaceutically acceptable derivatives, salts, chelates and esters, is present in an amount of about 200 mg to about 500 mg; the artemisinin, its pharmaceutically acceptable derivatives, salts, chelates, and esters is present in an amount of about 40 mg to about 100 mg and the loperamide its pharmaceutically acceptable derivatives, salts, chelates, and esters is present in an amount of about 1 mg to about 3 mg. Most specifically, berberine its pharmaceutically acceptable derivatives, salts, chelates and esters, is present in an amount of about 200 mg; the artemisinin, its pharmaceutically acceptable derivatives, salts, chelates, and esters is present in an amount of about 50 mg and loperamide is present in an amount of about 2 mg.
[0056] The composition may be present in dosage formulations selected from the group consisting of spray bottles, fast melt pill format, bursts, gel format, adhesive bandages, skin patches, gelcaps, softgels, gelatin capsules, vegetarian capsules, hard shell gelatin capsules, injections, intravenous solutions, topical creams, topical ointments, suppositories, or sublingual formulations. It may further comprise a therapeutically effective amount mefloquine for the treatment of malaria.
[0057] In a specific embodiment of the invention, the berberine, artesunate and loperamide are packaged in a daily dispenser form with daily individual doses for a number of days of one day to ninety days, and the daily dispenser may be in the form of a travelers pack.
[0058] Also taught are methods for the treatment of travelers suffering from at least one of multiple parasitic, bacterial or viral infections simultaneously by the administration to a traveler of a therapeutically effective amount of the composition of berberine, artesunate and loperamide, their pharmaceutically acceptable derivatives, salts, esters, or chelates. The administration may be performed between one and three times per day, more specifically between two and three times per day.
[0059] The method of treatment of a traveler may be fore the treatment of malaria, and the malaria may be chloroquine resistant. The same method of treatment may be used to treat mammals suffering from dysentery, diarrhea, or cholera. In another embodiment of the invention, the method of treatment is of a virus in a mammal such as dengue fever, hepatitis B, West Nile virus, or human immunodeficiency virus (HIV). In the case of human immunodeficiency virus (HIV), the treatment may be adjunctive and the human immunodeficiency virus may be anti-retroviral resistant.
[0060] In yet another embodiment of the invention, the treatment is of intestinal parasites in a mammal, including a tapeworm or tapeworms, or toxoplasmosis.
[0061] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims.
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BACKGROUND OF THE INVENTION
It is well known that the probability of surviving a heart attack often depends critically on the speed with which appropriate medical care is provided. One of the most common and life threatening consequences of a heart attack is the development of a cardiac arrhythmia such as ventricular fibrillation in which the heart is unable to pump a significant volume of blood. When such an arrhythmia occurs, serious brain damage and death will invariably result unless a normal heart rhythm can be restored within a few minutes.
The most effective treatment for ventricular fibrillation is the application of a strong electric shock to the victim. By a mechanism not fully understood, such an electric shock frequently terminates the chaotic activity characteristic of arrhythmias, and restores the normal pumping action of the heart. Defibrillators for producing and delivering such shocks have been known and successfully used for many years. However, the size and cost of prior defibrillators, coupled with the risk they pose if used improperly, have restricted the use of defibrillators to hospitals and to emergency medical facilities. Many lives would be saved each year if defibrillators could be made more immediately available to heart attack victims.
A large number of heart attacks occur to people who have a history of cardiac problems, and who are therefore known to be at risk. In recent years, many family members of high risk patients have received training in cardiopulmonary resuscitation, a technique designed to maintain some blood flow even if the heart is in fibrillation or has stopped beating altogether. Such training is helpful because a large percentage of repeat heart attacks occur in the presence of a family member. Unfortunately, it has to date not been possible to provide the family members of high risk patients with access to the generally more effective technique of defibrillation, because of the difficulty of designing a defibrillator that is portable and that can be safely and effectively used by nonmedical personnel.
SUMMARY OF THE INVENTION
The present invention provides a personal defibrillator that is portable, easy to use, and comparatively inexpensive. The defibrillator is sufficiently compact and lightweight to be kept at all times in the immediate vicinity of a person known to be at risk to heart attacks. In addition, the defibrillator is designed to be used interactively, so that a properly trained, nonmedical operator can safely and effectively operate the device.
In one embodiment, the present invention comprises an interactive, medical electronic device that is capable of obtaining information about a patient's condition, such as ECG data, directly from the patient, and information pertinent to the treatment of the patient indirectly through an operator of the device, and for producing a medically appropriate action such as a defibrillation shock in response. Sensor means are used to obtain direct information concerning the condition of the patient, and indirect information is obtained through information processing means that includes means for prompting the operator of the device, and means for receiving the operator's responses thereto. The device also includes control means for producing a control signal when the direct and indirect information indicates that the medically appropriate action should be taken, and output means responsive to the control signal for producing such action. The information processing means may also include means for communicating questions and instructions to the operator, and means for obtaining the assent of the operator before producing the control signal. In one preferred embodiment, the questions communicated to the operator are designed such that appropriate responses are either YES or NO. The indirect information obtained from the operator preferably includes information as to whether the patient is conscious, and as to whether or not cardiopulmonary resuscitation has been performed.
In a further embodiment, the present invention comprises a defibrillator having means for simultaneously obtaining electrocardiogram and transthoracic impedance data from a patient, and means for producing an indication that the electrocardiogram data is invalid if the transthoracic impedance data indicates excessive motion on the part of the patient. In a preferred embodiment, the defibrillator includes means for producing analog electrocardiogram and motion signals, the motion signal being based on transthoracic impedance, and means for alternately sampling the electrocardiogram and motion signals and providing corresponding digital samples. A processor stores the electrocardiogram samples obtained during a time interval, and examines the motion samples provided during that time interval for indications of excessive motion on the part of the patient. If excessive motion is detected, the time interval is restarted. In a further preferred embodiment, electrocardiogram and transthoracic impedance data is collected through a common pair of electrodes.
In another embodiment of the present invention, a defibrillator is provided that includes information processing means for determining whether a defibrillation shock should be delivered and for providing a first control signal if the defibrillation shock should be delivered, and defibrillation means responsive to the first control signal for producing the shock. The defibrillation means includes energy storage means and means responsive to the first control signal for charging the energy storage means up to a threshold level and then discharging it through the patient. Timing means is provided for discharging the energy storage means through the patient if the charge on the energy storage means does not reach the threshold level within a predetermined time after the first control signal is provided. In a preferred embodiment, the defibrillation means provides a second control signal whenever the storage means is discharged, and the information processing means includes means for suspending its operations from the time that the first control signal is provided until the second signal is provided only upon command from an operator of the defibrillator, and the defibrillation means then proceeds to automatically charge and discharge the energy storage means.
In another embodiment, the present invention includes means for allowing medical personnel to analyze the circumstances in which the device was used. Such means comprises a tape recorder for recording signals representing medical information on magnetic tape, a source of electrical power, and switch means for connecting the source of electrical power to the tape recorder when the tape recorder is to be operated. The tape recorder includes drive means for driving the tape past a recording means, a portion of the drive means being movable between a first position in which the drive means engages and drives the tape, and a second position in which the tape is at least partially disengaged from the drive means. The movable portion of the drive means is biased towards the first position, and the tape recorder includes a conductive fusible link positioned to hold such portion in the second position. The fusible link is connected to pass an electrical current when the switch means connects the source of electrical power to the tape recorder, the fusible link being adapted to fuse when an electrical current is passed through it. The tape recorder is used to permanently record information concerning the use of the device. The fusible link prevents damage to the tape during long periods of storage before the device is used.
In another embodiment, the device of the present invention comprises a case, a battery enclosed within the case, and testing means enclosed within a case for enabling a person to test the condition of the device without opening the case. The testing means includes means for testing the device when battery power is applied and for producing an audible tone indicating the test results, and a magnetically operated switch adapted to connect the battery to the means for testing the condition of the device when a magnet is placed in the vicinity of the switch. The device of the present invention, including the battery, may therefore be placed within a completely sealed case, while still providing a means whereby the device or battery may be tested without opening the case or breaking the seal.
In another embodiment of the present invention, a defibrillator is provided having means for detecting that a defibrillation pulse has been delivered to the patient. The defibrillator includes a conductor through which the pulse is delivered, means responsive to the presence of current in the conductor for producing a magnetic field, means for producing a sound in response to the production of the magnetic field, and means for detecting the sound. The defibrillator may also include means for recording such sound on magnetic tape.
In another embodiment of the present invention, a defibrillator is provided having electrodes for attachment to a patient, defibrillation means for providing a pulse of electrical energy, and connector means for connecting the defibrillation means to the electrodes. The connector means includes plug means adapted to permit the electrodes to be quickly disconnected from the defibrillation means. When emergency medical personnel arrive on the scene, this feature enables them to avoid delay by plugging the electrodes of the present invention directly into their own equipment.
These and other features and advantages of the invention will become apparent in the detailed description and claims to follow, taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a sealed defibrillator according to the present invention.
FIG. 2 is a perspective view of the defibrillator of FIG. 1 with the cover plate removed and the electrodes withdrawn.
FIG. 3a-3h is a series of eight views of the display of the defibrillator during different stages of defibrillator operation.
FIG. 4a-b is a block diagram of the electronic components of the defibrillator.
FIG. 5 is a circuit diagram of the processor controller.
FIG. 6 is a cross-sectional view of the wave shaping inductor and associated sound producing means of the defibrillator.
FIG. 7a-f is a flow chart of a program for operation of the data processor of the defibrillator.
DETAILED DESCRIPTION OF THE INVENTION
Referring initially to FIGS. 1 and 2, one preferred embodiment of the present invention is shown as comprising defibrillator 10 having body 12, cover plate 14, and carrying handle 16. To use the defibrillator, an operator breaks seal 18 and removes cover plate 14. The cover plate includes a pin 20 which is positioned in opening 22 of body 12 before the cover plate is removed. Removal of the cover plate withdraws pin 20 and activates the defibrillator, as described below. The underside of cover plate 14 includes printed instructions 24 for facilitating correct usage of the device.
Prior to removal of the cover plate, a pair of electrodes 30, 36 and associated cable 42 are held in the space between cover plate 14 and body 12. When the cover plate is removed, the electrodes and cable may be withdrawn for use, as indicated in FIG. 2. Electrodes 30 and 36 include adhesively surfaced outer portions 32 and 38 respectively, and respective inner portions 34 and 40 that are coated with a conductive gel for making electrical contact with a patient's body. Cable 42 includes separate cables 44 and 46 connected to electrodes 30 and 36, respectively. Cable 42 includes plug 48 which permits the electrodes to be quickly disconnected from the defibrillator, so that emergency medical personnel arriving on the scene can avoid delay by plugging electrodes 30 and 36 directly into their own equipment. Electrode 36 includes diagram 37 illustrating the correct placement of the electrodes on the patient.
The body 12 of the defibrillator includes an LCD display 50, and pushbutton switches 52, 54 and 56. Display 50 is used for prompting the operator of the defibrillator, as described in greater detail below. Switches 52 and 54 are labeled with the words YES and NO, respectively, and are used by the operator to respond to questions presented via display 50. Switch 56 is labeled "SHOCK," and is used by the operator at the appropriate time to initiate application of a defibrillation shock.
A pair of scissors 60 may also be carried in the space between body 12 and cover plate 14. The scissors are used to remove the patient's clothing, to facilitate placement of electrodes 30 and 36.
Prior to use, the defibrillator of the present invention is completely contained within the portable, compact unit illustrated in FIG. 1. This design makes it both practical and convenient to continuously keep the defibrillator in the immediate vicinity of a patient known to be at risk with respect to heart attacks. Seal 18, in combination with other features described below, helps assure the integrity of the unit during prolonged periods of storage.
GENERAL OPERATION
The general operation of the defibrillator will now be described with reference to FIGS. 3a-h. When a heart attack occurs, the operator removes the cover plate, and the defibrillator is activated electronically. The operator is immediately directed to connect the electrodes to the patient, as indicated in FIG. 3a. Diagram 37 (FIG. 1) on one of the electrodes is available to guide proper placement. When the instrument detects that the electrodes have been connected, the message indicated in FIG. 3b is displayed. This message directs the operator to perform standard CPR operations on the patient. The operator indicates that this step has been completed by pushing the YES switch. When the YES switch is pushed, or when 25 seconds has elapsed, the message shown in FIG. 3c is displayed. If the subject is not unconscious, then the operator pushes the NO switch, and the message shown in FIG. 3d will be displayed for a few seconds, after which the message in FIG. 3c will reappear. This feature allows the operator to respond appropriately if the patient later loses consciousness.
If the patient is unconscious, or becomes unconscious, then the operator pushes the YES switch (FIG. 3c), and the instrument enters a detection mode in which the message shown in FIG. 3e is displayed. In this mode, electrocardiogram (ECG) and transthoracic impedance data is obtained directly from the patient via electrodes 30 and 36 (FIG. 2). The resulting data is used, together with information supplied by the operator (e.g., subject unconscious), to determine whether a defibrillation shock is medically appropriate. During collection of data, the instrument looks for transthoracic impedance data that would indicate motion of the patient. If motion is detected, then the message shown in FIG. 3f is displayed, and the data collection is restarted.
If the ECG data indicates that a defibrillation shock is not appropriate, then the message of FIG. 3d is briefly displayed, and the defibrillator then returns to the state corresponding to FIG. 3b. If the instrument determines that a shock is medically appropriate, then the message of FIG. 3g is displayed, advising the operator to proceed by pushing the SHOCK switch. If the SHOCK switch is then pushed, the instrument displays the message shown in FIG. 3h and then delivers a defibrillation shock to the patient. After the shock has been delivered, the instrument returns to the state corresponding to FIG. 3b. The cycle beginning at FIG. 3b and ending at FIG. 3h may be repeated for a maximum of two additional times, if the patient remains unconscious.
CIRCUIT DESCRIPTION
The body 12 of the defibrillator houses the electronic components illustrated in FIGS. 4a and 4b. These components include data processor 100, analog-to-digital converter (ADC) 102, processor controller 110, defibrillation circuit 120, analog preprocessor 140, data recorder 160, battery circuit 170, and various other components described below. Electrodes 30 and 36 are connected through electromagnetic interference filter 190 to defibrillation circuit 120 and to analog preprocessor 140. During the collection of ECG and transthoracic impedance data from the patient, relay 122 is in the position shown in FIG. 4a. The analog preprocessor separates the electrode signal into ECG and transthoracic impedance components, and delivers the component signals to ADC 102 and to data recorder 160. When a shock is to be delivered, the defibrillation circuit charges capacitor 126 up to a specified value, and then switches relay 122 such that capacitor 126 discharges through the patient via electrodes 30 and 36. After the shock has been delivered, relay 122 returns to the position shown in FIG. 4a.
BATTERY CIRCUIT
The electronic circuit of the present invention is activated when cover plate 14 is removed from the unit. Removal of the cover plate causes the withdrawal of pin 20, which in turn causes switches 176 and 178 (FIG. 4b) to close, connecting recorder battery 172 to microcassette recorder 161 and system battery 174 to the other components of the circuit in FIGS. 4a and 4b. The purpose of this feature is to prevent battery drain when the instrument is stored over extended periods of time. Means are provided, however, for permitting a person to check the condition of system battery 174 without opening or unsealing the instrument. This means comprises magnetic reed switch 180 connected in parallel with switch 178. The defibrillator of the present invention includes a separate battery test card having small magnets imbedded therein. To test the condition of system battery 174, a person holds the battery test card at a designated position adjacent to the outer surface of body 12. The magnet, indicated schematically by numeral 182 in FIG. 4b, closes reed switch 180 and provides power to all components of the defibrillator with the exception of microcassette recorder 161. The closing of reed switch 180 also supplies a test signal to data processor 100 on line 184. The test signal indicates to the data processor that a test is to be performed, and directs it to the appropriate procedure for carrying out the test. If the test is successful, the data processor causes tone generator 108 to emit a prescribed sequence of audible tones, to signal that the test has been successfully completed. Diode 186 prevents a test signal from being applied to data processor 100 during normal operation of the defibrillator, i.e., when switch 178 is closed.
During operation of the defibrillator, battery level circuit 188 continuously monitors the voltage available from system battery 174. If the voltage of system battery 174 falls below the level required for operation of data processor 100, then battery level circuit 188 activates shutdown circuit 189. Shutdown circuit 189 responds by cutting off power to data processor 100, thus preventing operation of the defibrillator at a voltage which might result in unreliable operation. A back-up system for preventing defibrillator operation when the battery level is too low is provided by ADC 102. ADC 102 periodically samples the system battery voltage (B2) and provides the digitized samples to data processor 100 over bus 104. As described below, the data processor will not advise or initiate a shock if such samples indicate insufficient battery voltage.
ANALOG PREPROCESSOR
The function of the analog preprocessor is to supply a constant current signal to the electrodes and to analyze the return signal. If the return signal indicates that the electrodes are not connected to the patient, then the analog preprocessor sends a NOT CONNECTED signal to the data processor. If the electrodes are connected, then the analog preprocessor extracts ECG signals and transthoracic impedance (TTI) signals from the return signal and sends the analog ECG and transthoracic impedance signals to data recorder 160 and analog-to-digital converter (ADC) 102.
The analog preprocessor includes protection network 141, constant current source 142, synchronous demodulator 144, amplifier/filters 146 and 148, comparator 150, low pass filter 152, and amplifier/filter 154. Associated with the analog preprocessor is electromagnetic interference filter 190 consisting of inductor 192 and capacitor 194. Constant current source 142 supplies a constant (RMS) current, 12 KHz sine wave which is applied to the patient through protection network 141 and electrodes 30 and 36. The resulting signal is synchronously demodulated by synchronous demodulator 144. The synchronous demodulator provides an output signal whose amplitude is proportional to the amplitude of the 12 KHz component of the return signal, i.e., to the impedance between electrodes 30 and 36. The output signal from synchronous demodulator 144 is passed to amplifier/filter 146. Amplifier/filter 146 removes unwanted high frequency components, including any residual 12 KHz signal, and also provides a small amount of gain. The output of amplifier/filter 146 is fed to amplifier/filter 148 and to comparator 150. Amplifier/filter 148 includes a bandpass filter with a passband of approximately 1-20 Hz. This filter thus removes the DC component from the return signal, and provides an output indicative of transthoracic impedance variations over time. Comparator 150 compares the level of the output of amplifier/filter 146 with a fixed reference voltage. If the level exceeds the reference, then the comparator pulls line 158 low, signaling that the electrodes are not connected.
The signal from electrodes 30 and 36 is also input to low pass filter 152 through protection network 141. The filter removes the 12 KHz signal and other high frequency components, and passes the resulting signal to amplifier/filter 154. Amplifier/filter 154 includes a bandpass filter adapted to extract the ECG signal returned from the patient through the electrodes. As further described below, amplifier/filter 154 also provides gain to the ECG signal, the amount of gain being determined by a digital GAIN SELECT signal originating in data processor 100 and transmitted to amplifier/filter 154 over line 156.
Protection network 141 is a conventional impedance matching network that protects the analog preprocessor from the high voltage applied to the electrodes by defibrillation circuit 120 during delivery of a shock to the patient. Protection network 141 has an impedance that does not signficantly affect ECG or transthoracic impedance measurements, but that does cause the attenuation of the frequency components contained in a defibrillation pulse to a degree sufficient to prevent such a pulse from damaging any of the components of the analog preprocessor.
DATA PROCESSOR
Data processor 100 is a conventional digital computer that includes a microprocessor, read only memory (ROM) for storing a program, random access memory (RAM) for data storage, a parallel port and a timer. A suitable microprocessor for use in data processor 100 is the NSC 800 microprocessor available from the National Semiconductor Corporation.
Associated with data processor 100 are processor controller 110 and associated SHOCK pushbutton switch 56, display system 106, tone generator 108, YES and NO pushbutton switches 52 and 54, and ADC 102. Processor controller 110 coordinates the activities of data processor 100 and defibrillation circuit 120, and is described in greater detail below. Display system 106 comprises a conventional display driver and LCD display unit 50 (FIG. 2). Tone generator 108 is a conventional audio transducer used for producing audible signals. Pushbutton switches 52, 54 and 56 correspond to the pushbuttons shown in FIGS. 2 and 3, and are used by the operator to respond to prompts communicated through display system 106, and to initiate a defibrillation shock. ADC 102 is an analog-to-digital converter used for converting the analog TTI and ECG signals from analog preprocessor 140 into digital signals usable by data processor 100. ADC 102 alternately samples the TTI and ECG signals at 240 Hz, thus providing a sampling rate of 120 Hz for each signal. The digital samples are passed to the data processor over 8-bit bus 104. ADC 102 provides an interrupt signal RSTC to data processor 100 each time a digital sample is ready. In response to the RSTC interrupt, data processor 100 jumps to an interrupt service routine for inputting the sample. Through this arrangement, a uniform sampling rate is provided regardless of the timing of the program for operating data processor 100.
DEFIBRILLATION CIRCUIT
Defibrillation circuit 120 is activated by a high ENABLE signal on line 134. In response to such a signal, the defibrillation circuit begins charging capacitor 126 from system battery 174 (B2). When the charge reaches a predetermined threshold, the defibrillation circuit energizes relay 122, discharging capacitor 126 through the patient through electrodes 30 and 36.
The defibrillation circuit is activated by a high ENABLE signal momentarily appearing on line 134. In response to this signal, bistable control circuit 124 latches line 134 into a high state, and causes charge transfer circuit 128 to begin charging capacitor 126 from system battery supply B2. Bistable control circuit 124 may, by way of example, consist of two amplifiers connected in series, with positive feedback means provided to enable the circuit to be stable in either one of two states. Charge transfer circuit 128 may be any well known circuit for converting a low level DC voltage to a high voltage output by means of a flyback transformer or other conventional means.
As capacitor 126 is charged through charge transfer circuit 128, the voltage on capacitor 126 is continuously monitored by comparator/timer 130. When the capacitor voltage exceeds a threshold level, comparator/timer 130 triggers relay driver 132 which in turn energizes the coil of relay 122, switching the relay and connecting capacitor 126 to the electrodes. The capacitor then discharges through the patient via wave shaping inductor 138. At the same time that comparator/timer 130 triggers relay driver 132, it also pulls line 134 low Bistable control circuit 124 then latches line 134 into a low state, completing the defibrillation cycle. Should capacitor 126 fail to charge to the threshold level within a predetermined time interval, then a timeout circuit included within comparator/timer 130 triggers relay driver 132 and pulls line 134 low, thus delivering to the patient whatever energy is available and terminating the defibrillation cycle.
As previously described, analog preprocessor 140 pulls line 158 low when it detects that electrodes 30 and 36 are not connected to the patient. One effect of line 158 going low is that line 134 is also pulled low through diode 136. A low voltage on line 134 will cause bistable control circuit 124 to latch line 134 in its low state, terminating any defibrillation cycle that is in process. Thus the defibrillator of the present invention will not attempt to deliver a defibrillation pulse should the electrodes become disconnected. Line 134 is also connected to battery level circuit 188 through diode 137. Thus when battery level circuit 188 detects a low voltage on system battery B2, line 134 will be held low, and the delivery of a defibrillation shock will also be prevented in this circumstance.
PROCESSOR CONTROLLER
Processor controller 110 coordinates the activities of data processor 100 and defibrillation circuit 120. When the data processor determines that a shock is advised (see FIG. 3g), it sends a high SHOCK ENABLE signal to processor controller 110 on line 200. This signal activates SHOCK pushbutton switch 56, such that if switch 56 is now pushed, a high ENABLE signal will be sent to defibrillation circuit 120 on line 134, initiating a defibrillation cycle. At the same time that line 134 is driven high, processor controller 110 sends a low READY signal back to data processor 100 on line 202. A short time after the READY signal is sent, processor controller sends a low SHUT DOWN signal on line 204. The SHUT DOWN signal causes data processor 100 to go into a quiescent state in which only its timer continues to be active. The READY signal is used by data processor 100 to prepare for entering this quiescent state. The purpose of this feature is to prevent any electromagnetic interference that might accompany the delivery of a shock to interfere with the operations of the data processor. After a shock has been delivered, processor controller 110 pulls lines 202 and 204 high to restart the data processor, and then issues a high RSTA interrupt signal on line 206, causing the data processor to go back to the state corresponding to the display in FIG. 3b, starting another cycle.
The detailed construction of processor controller 110 is illustrated in FIG. 5. A high SHOCK ENABLE signal appearing on line 200 causes inverter 210 to supply a low voltage to terminal 214 of shock switch 56. When shock switch 56 is closed, terminal 216 is also driven low, enabling capacitor 218 to rapidly charge through switch 56. The resulting low voltage is input to inverter 222 through input resistor 220, driving line 134 high through resistor 224 and diode 226. When switch 56 is released, capacitor 218 discharges through resistor 228 at a rate slow enough to enable bistable control circuit 124 (FIG. 4a) to latch line 134 into a high state. After capacitor 218 discharges, diode 226 provides isolation between line 134 and inverter 222. Diode 212 prevents capacitor 218 from discharging through switch 56.
The high voltage on line 134 is sensed by inverter 232 through input resistance 234, causing inverter 232 to drive line 202 low. A low signal on line 202 causes data processor 100 to execute various housekeeping steps in preparation for line 204 going low. A low signal on line 202 also causes capacitor 236 to begin charging through resistor 238 and through resistor 240 and diode 242. The decreasing voltage at node 243 is coupled to inverter 244 through input resistor 246. When the voltage at node 243 has dropped below a certain level, a low signal appears on line 204, halting the operations of data processor 100. The delay between the SHUT DOWN and READY signals is determined by the time constant for the charge of capacitor 236.
At the time that line 204 is pulled low, node 250 goes high, and capacitor 252 begins to charge through resistor 254. The rising voltage at node 260 is coupled to inverter 256 through input resistor 258. When the voltage of node 260 has risen to a sufficient level, inverter 256 causes a low RSTA signal to appear on line 206. Since data processor 100 is shut down, the low RSTA signal has no effect at this time.
When a defibrillation cycle is completed, or when a low battery or a NOT CONNECTED signal is provided by analog preprocessor 140, line 134 is pulled low. Such a low signal initiates a sequence of events which is the reverse of that just described. In particular, a low signal on line 134 immediately drives line 202 high, and drives line 204 high a short time later, restarting the data processor. After another short time interval, processor controller 110 sends a high RSTA interrupt signal on line 206, vectoring data processor 100 to an appropriate restart point as described below.
DATA RECORDER
Data recorder 160 comprises microcassette recorder 161, multiplexer/modulator 162, audio amplifier 163, microphone 164, and coupling capacitor 165. Microcassette recorder 161 is powered by separate recorder battery (B1) 172, which is connected to the microcassette recorder through a normal conductor line 166 and through fusible link 167. Fusible link 167 consists of a piece of thin wire that melts as soon as current begins to flow through it, i.e., when cover plate 14 is removed and switch 176 closes. Prior to melting, fusible link 167 holds spring loaded pinch roller 168 out of engagement with the tape and capstan of microcassette recorder 161. This feature is provided so that the defibrillator of the present invention will be usable after an extended period of storage. During use, pinch roller 168 provides the pressure between the tape and capstan to enable the capstan to drive the tape. Prior to use, however, the fusible link holds the pinch roller disengaged from the capstan and tape to prevent it from flattening and sticking to the tape.
Microcassette recorder 161 is a two track recorder, one track for transthoracic impedance and ECG data, and the second track for voice and status information. Multiplexer/modulator 162 receives the analog transthoracic impedance and ECG signals from analog preprocessor 140, converts these analog signals to pulse-width modulation format, and multiplexes the resulting pulse streams for recording on one track of microcassette recorder 161. The other track of the microcassette recorder records voice and other audio signals picked up by microphone 164 and amplifier by audio amplifier 163. The voice track also records system status information sent by data processor 100 through line 169. The status information is coupled from line 169 to audio amplifier 163 through coupling capacitor 165.
The defibrillator of the present invention includes means by which data recorder 160 can record information confirming that a substantial amount of energy, i.e., a defibrillation pulse, has actually been delivered to the patient through electrodes 30 and 36. Referring to FIG. 6, a cross section of wave shaping inductor 138 is shown including bobbin 272 and inductor coils 270. The central portion of bobbin 272 is indented to form recess 274. Elastic cord 276 is mounted to bobbin 272 over recess 274, and mounts ferrous objects 278 thereon such that the ferrous objects are normally held over the recess spaced apart from the bobbin.
When a defibrillation pulse is delivered through wave shaping inductor 138, the current through inductor coils 270 creates a maximum magnetic field density in the direction indicated by arrow 280 that pulls ferrous objects 278 with considerable force into bobbin 272 at the base of recess 274. The unique sound caused by the objects striking the bobbin is picked up by microphone 164 and recorded on the voice track of microcassette recorder 161. These sounds can later be identified to confirm that defibrillation pulses have actually been delivered. After a defibrillation pulse, ferrous objects 278 return to the position indicated in FIG. 6, ready for a subsequent pulse to be recorded.
DATA PROCESSOR OPERATION
FIGS. 7a through 7f illustrate a flow chart for a program suitable for operation of the microprocessor of data processor 100. Block 300 represents the point at which program execution begins when power is first supplied to the microprocessor, or when line 204 (FIG. 4b) goes high. Block 302 tests the status of line 184 (FIG. 4b) to determine whether the power-on is a result of a test or actual operation of the device. If it is a test, then control passes to block 304 where appropriate tests are performed to verify that system battery 174 has sufficient voltage and that data processor 100 is capable of proper operation. In one embodiment, block 304 tests a digitized battery voltage sample provided by ADC 102 over bus 104. Block 306 determines whether the tests have been successfully passed. If they have not, then control returns to block 304 and the tests are repeated. If the tests are passed, then block 308 causes tone generator 108 to beep three times, block 310 delays program execution for three seconds, and control then returns to block 304 to repeat the tests. In the usual case, the person performing the test procedure will remove the magnet (test card) 182 when the beeps are generated, terminating the test and shutting down the system. If the three beeps are not heard, it is an indication that the tests have not been passed and that maintenance is required.
When the power-on (in block 300) is due to an actual opening of the defibrillator, then control passes from block 302 to block 312 where variable CPR is set to 1. This variable controls the number of times that the CPR sequence (FIG. 3b) is repeated, as described below. Block 316 then enables interrupts RSTA and RSTB. Interrupt RSTA is used to restart the microprocessor after a defibrillation shock has been delivered. The RSTA restart point is indicated by entry point 314, so that program execution returns at block 316 after a shock has been delivered. Referring to FIGS. 4a and 4b, interrupt RSTB is provided whenever a NOT CONNECTED signal is generated by analog preprocessor 140. In response to an RSTB interrupt, the microprocessor executes the interrupt service routine shown in FIG. 7f, and then returns control to the main program at entry point A, recommencing execution with block 312.
When the defibrillator is first opened for actual operation, electrodes 30 and 36 will not be connected, and the analog preprocessor will pull line 158 low, causing an RSTB interrupt signal to be sent to data processor 100. In this circumstance, the enabling of interrupt RSTB in block 316 will cause an immediate jump to block 452 of the interrupt service routine of FIG. 7f. Block 452 generates the display shown in FIG. 3a, and block 454 checks to see whether 20 seconds have elapsed since the defibrillator was opened. If 20 seconds have not elapsed, program execution is delayed for one second by block 456, after which program flow returns to block 312 in FIG. 7a. If the electrodes are not yet connected, interrupt RSTB will immediately vector the program back to the interrupt service routine, and this loop will continue until the electrodes are connected and interrupt RSTB is no longer present. For the first 20 seconds after the device is opened, block 454 causes a jump directly to block 456 each time the interrupt service routine is executed. Between 20-25 seconds after the device is opened, blocks 454 and 458 direct control through block 460 and a series of beeps is produced. After 25 seconds the beeps terminate and the program loops between the interrupt service routine and the main routine until the electrodes are connected.
When the electrodes are connected, interrupt RSTB is no longer present and control passes through block 316 to block 318, where the message indicated in FIG. 3b is displayed. Block 320 then causes generation of a characteristic tone sequence, and block 322 tests to see whether YES pushbutton switch 52 has been pressed. When the YES switch is pushed, or when 25 seconds have elapsed, control passes to block 324 where the number of passes through the loop consisting of blocks 316-322 is compared to variable CPR. After a poweron, this test will be satisfied after the first pass, since CPR was set to 1 in block 312. Whenever this test is not satisfied, program execution returns to block 316, and another CPR sequence is performed. When the number of CPR sequences specified by variable CPR have been completed, control passes to block 326 which checks the number of shocks that have been delivered. The defibrillator of the present invention is intended to deliver up to a maximum of three defibrillation shocks. If three shocks have already been delivered, then block 326 returns control to block 316, and the CPR sequence is continued indefinately. If three shocks have not been delivered, then control passes to block 328, where the voltage level of system battery 174 is checked by examining the battery voltage sample provided by ADC 102 over bus 104. If the battery level is too low for reliable operation, then the CPR sequence continues as indicated. If the battery level is sufficient, then control passes to block 330 (FIG. 7b).
Block 330 prompts the operator to indicate whether or not the patient is unconscious. After generating this display, block 332 directs program execution to either block 338 or 334, depending upon whether or not the operator indicated that the patient was conscious the last time the question in block 330 was answered. If the patient was not conscious in the previous pass, then block 334 outputs a characteristic tone sequence. As indicated by block 336, this tone sequence continues until the operator responds by pushing either the YES or NO pushbutton switch. When the operator does respond, control passes to block 340. When the patient was conscious in the previous pass, then control passes directly from block 332 to block 338, where the program loops until the operator responds and then continues to block 340.
Block 340 determines whether the operator of the defibrillator has indicated that the patient is unconscious. If the patient is not unconscious, then block 342 outputs the display indicated in FIG. 3d, block 344 outputs a characteristic tone sequence, block 346 causes a four second delay, and program execution returns to block 330 to again ask whether the patient is unconscious. By such means, the defibrillator will be prepared to respond in an appropriate manner should a presently conscious patient later lose consciousness.
If the patient is unconscious, control passes to block 350 (FIG. 7c), and the message indicated in FIG. 3e is displayed. Block 352 then outputs a single tone through tone generator 108, and the program commences the collection of TTI (transthoracic impedance) and ECG data from the unconscious patient. As described previously, ADC 102 alternately supplies digital TTI and ECG samples to data processor 100, issuing interrupt signal RSTC whenever a sample is ready. Block 354 enables the RSTC interrupt, and the program then waits in block 356 for TTI data to be supplied. When an RSTC interrupt is received, program control is vectored to RSTC entry point 358, the data sample is input by block 360, and block 362 determines whether the sample is TTI or ECG data. If the sample is TTI data, then execution continues with block 364.
Block 364 analyzes successive TTI values to determine whether excessive motion is present in the patient. By way of example, block 364 could detect excessive motion by determining whether the last two TTI values exceed a threshold. If excessive motion is present, then block 366 generates the display indicated in FIG. 3f, block 368 causes production of a steady tone by tone generator 108, block 370 causes a one second delay, and block 372 determines whether the excessive motion has been present for 15 seconds. If it has not been present for 15 seconds, the program returns to block 350, and the data collection sequence is begun again. If excessive motion has been present for 15 or more seconds, then the program returns to block 316 (FIG. 7a), corresponding to the display in FIG. 3b.
The defibrillator of the present invention checks the patient for excessive motion because such motion could result in invalid ECG data, and because excessive motion could indicate that the patient should not be shocked. For example, excessive motion could indicate that the patient is conscious, that the patient is being moved, or that the patient is moving internally due, for example, to cardiac output.
If excessive motion is not present, then the defibrillator waits in block 374 for ECG data. When such data is ready, it is input by block 360, and block 362 directs program flow to block 376. Block 376 attenuates 60 Hz noise in the ECG data, and block 378 then tests the amplitude of the most recent ECG data point. If the amplitude is too large, block 380 decreases the gain of the analog preprocessor 140 by modifying gain select signal 156 (FIGS. 4a and 4b), and data collection is restarted at block 350. If the ECG amplitude is not too large, then block 382 provides a second level of filtering adapted to remove rumble below the ECG frequency range. If there is more data to be collected, block 384 then returns control to block 356 for acquisition of the next TTI and ECG data samples. When a sufficient number of ECG data samples have been collected and stored, control passes to block 386 in FIG. 7d.
Block 386 disables interrupt RSTC, thereby preventing ADC 102 from subsequently interrupting program flow. Block 388 then analyzes the ECG data points to determine the repetition rate (frequency) of the dominant complex in the ECG signal (e.g., the QRS complex). If the rate is less than 2.3 Hz or greater than 12 Hz, then block 390 directs program flow to block 392, where the shock flag for this pass is set to zero, indicating that the patient is not presently in a shockable condition. If the rate is within the shockable range, then block 394 checks to see whether the frequency variance of the ECG data exceeds a maximum limit. If the variance is too large, then the shock flag is set to zero in block 392. If the frequency variance is consistent with the application of defibrillation shock, then block 396 checks the average amplitude of the ECG signal. If the average amplitude is too low, then no conclusions can be reliably drawn from the data, and the shock flag is set to zero. If the amplitude is sufficient, block 398 determines whether R waves are present in the ECG signal. If R waves are present, then the patient should not be shocked, and the shock flag is set to zero in block 392. If R waves are not present, then block 400 performs a slope histogram analysis of the ECG data. In this analysis, the differences between adjacent ECG data points are determined, and the slopes (differences) falling within a series of ranges are counted. Block 402 then checks the relative frequency of low slope values. If such relative frequency is too high to be consistent with a shockable arrhythmia, then the shock flag is set to zero in block 392. If the relative frequencies of the lower histogram ranges are within shockable limits, then block 404 sets the shock flag for this pass to one, signifying that the patient's ECG signal indicates that a defibrillation shock is medically appropriate. It is to be understood that other known tests could be used, either singly or in combination, to determine whether a shockable ECG rhythm is present, and the invention herein is not limited to any particular method of making this determination.
The defibrillator makes two or three successive passes through the data acquisition and analysis steps just described. When the first pass is complete, blocks 406 and 408 direct program flow to block 350 (FIG. 7c) to begin the second pass. When the second pass is complete, block 410 checks the shock flag for the second pass. If the second shock flag is not equal to one, then control passes to block 438 (FIG. 7e) and a SHOCK NOT REQUIRED message is displayed to the operator. If both the first and second shock flags are equal to one, then control passes to block 416 (FIG. 7e), and a shock sequence is commenced. If the second shock flag is one, but the first shock flag is zero, then control returns to block 350, and a third pass is commenced. When the third pass is complete, block 406 directs control to block 414, and the third shock flag is tested to determine whether or not a shock should be administered.
If a shock is to be administered, then block 416 causes the data processor to drive line 200 high (FIG. 4b), enabling SHOCK pushbutton switch 56. Block 418 then causes generation of the display indicated in FIG. 3g, and block 420 causes production of a characteristic tone sequence. The program then executes a loop consisting of blocks 422 and 424 until the operator pushes the shock switch, or until 30 seconds have elapsed. If the shock switch is pushed, block 426 causes generation of the display indicated in FIG. 3h, block 428 causes output of a warning tone, block 430 sets variable CPR to 2, and block 432 then waits for processor controller 110 to issue READY and SHUT DOWN signals, as previously described. If the operator does not push the SHOCK switch within 30 seconds, block 434 causes line 200 to be pulled low, disabling the SHOCK switch. Block 436 then sets variable CPR equal to 4, and returns control to the CPR sequence commencing with block 316 (FIG. 7a).
If the tests shown in FIG. 7d indicate that a shock is not to be applied, then control passes to block 438 where the indicated message is displayed. Block 440 then causes output of a characteristic tone sequence, and block 442 causes a 5 second delay. Block 436 then sets variable CPR to 4, and control returns to block 316. The values of CPR set in blocks 430 or 436 will subsequently result in block 324 causing either 2 or 4 CPR sequences to be executed, depending upon whether or not a shock was administered to the patient.
While the preferred embodiments of the invention have been illustrated and described, it should be understood that variations will become apparent to those skilled in the art. Accordingly, the invention is not to be limited to the specific embodiments illustrated and described herein, but rather the true scope and spirit of the invention are to be determined by reference to the appended claims.
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FIELD OF THE INVENTION
The present invention relates to the curling or waving of human hair. The present invention relates more particularly to chemically assisted curling or waving of human hair having a flat or oval cross sections.
BACKGROUND OF THE INVENTION
Hair which has a relatively flat or oval cross section typically has naturally tight curls of about 1/4 inch in diameter or less. Such tightly curled hair has proven difficult to safely and consistently relax and re-style into waves or looser curls typically having a diameter of 1 inch or more.
In order to change the configuration of hair from tightly curled or kinked to loosely curled or waved, it is necessary to strip the hair of its tightly curled structure and rebuild the structure of the hair into the new desired configuration. Previous methods of removing the tightly curled structure from hair often left the hair in a severly damaged condition. Often after the hair is restructured into its newly waved or loosely curled construction, the individual is reluctant to wash his or her hair for fear of removing any protective oils from the hair and cause further damage or loss of the desired loose curl or wave.
A typical process employed to re-style tightly curled hair into a new configuration involves first treating the hair with a caustic agent which is absorbed into the hair to break the internal sulfide bonds. It is the sulfide bonds which hold the hair in its tightly curled configuration. Next a test curl is made to determine whether sufficient sulfide bonds have been broken to allow the hair to be re-styled. If the results of the test curl are favorable the hair dresser quickly curls the hair on curling rods If the test curl fails, the hair dresser conducts a second test curl and continues with a series of curls until the result is favorable. Once curled on the curling rod, a neutralization composition is placed upon the hair to allow the sulfide bonds to reform, thereby retaining the hair in its newly curled configuration.
However, the use of the above method is not precise and often results in under or over processing of the hair. Under processing results in an incomplete recurling of the hair, and over processing results in substantial hair damage and breakage, and generally dull, lifeless and unmanageable hair.
Accordingly, a need exists for a process of re-curling or waving previously tightly curled hair, which significantly reduces the chance of under or over processing of the hair. Further, a need exists for a process of re-curling or waving such hair which results in substantially less damage to the hair.
SUMMARY OF THE INVENTION
The present invention provides a method by which hair which is tightly curled or kinked can be consistently relaxed and reformed into a looser curl or wave configuration, with substantially less damage to the hair. The present invention provides a process for reforming tightly curled hair into a loosely curled or waved configuration comprising the steps of: first, contacting the hair with an aqueous relaxant composition having a pH of between about 8.0 and about 11.0 and comprising at least a major proportion of water and between about 5 to 10 wt-%, based upon the aqueous relaxant composition of an alkaline thioglycolate. Second, rinsing the hair with a neutral aqueous solution so as to remove a substantial portion of the relaxant composition; third, contacting the hair with an aqueous suspending composition having a pH of between about 3.5 and 7.0, the aqueous suspending composition comprising at least a major proportion of water and about 0.0001 to 0.1 wt-% of ammonium chloride and 0.0001 to about 0.1 wt.-% of magnesium chloride, both based on the suspending composition, the suspending composition is preferably rinsed out and reapplied to the hair; fourth, the hair is wrapped onto curling rods; fifth, contacting the hair with a heat generating composition for a period of time and in an amount sufficient to increase the hair temperature to between 100° F. and 130° F. and preferably to between about 110° F. and about 120° F., the heat generating composition comprising a first solution, and a second solution, the first and second solutions are provided in separate containers until application to the hair, when combined the first and second solutions react to produce sufficient heat and provide between about 5 and about 10 wt-% unreacted ammonium thioglycolate after reaction between the first and the second solutions is complete; the hair is preferably rinsed with water to rinse most of the heat generation composition from the hair; sixth, contacting the hair with a sufficient amount of an oxidizing composition, such as sodium bromate solution, to oxidize substantially all of the remaining alkaline thioglycolate and derivatives; seventh, removing the curling rods; and eighth, contacting the hair with an acidic protein final rinse solution for a period of time and in an amount sufficient to cause the hair to reach substantially a neutral pH.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method by which hair that is tightly curled can be relaxed and reformed into looser curls or waves. Hair which in its natural state has extremely tight curls with diameters of 1/4 of an inch and less is typically relatively flat or oval in cross-section.
The process of the present invention comprises contacting the hair with a sufficient amount of an aqueous relaxant composition to relax the tight curl of the hair. The aqueous relaxant composition is believed to relax the tightly curled hair by breaking the disulfide bonds within the hair structure and removing sufficient "memory" of the hair so that the hair can be reformed into a new configuration. The relaxant composition is applied evenly throughout the subject's hair and should preferably be combed until the relaxant composition has been uniformly applied and the hair exhibits a slight residual wave. At this point a cap is preferably placed on the subject's head for roughly 5 minutes. When the subject's hair is particularly coarse or resistant to relaxation, it may be desirable to place the subject's head under a warm air conditioned dryer for the 5 minutes.
After the relaxant composition has been allowed to remain on the subject's head for the necessary duration, as described, the hair should be rinsed thoroughly with warm water to remove most of the relaxant composition from the hair.
The relaxant composition comprises an aqueous solution having a pH of between about 8.0 and about 11.0 and preferably between about 9.0 and 10.0, having about 5 to about 10 wt-% of an alkaline thioglycolate.
It is also preferred that a suitable amount of a gel forming composition such as carbopol, a polyacrylic acid commercially available from B. F. Goodrich, or its equivalent, be used to provide the relaxant composition in the form of a gel. It is advantageous to apply the relaxant composition to the hair as a gel to temper the action of the alkaline thioglycalate on the hair and to mechanically aid in application of the composition to the subject's hair by increasing lubricity. VITA-PRO CURLING GEL, commercially available from Miriam-Collins-Palm Beach Lab, Co., an ammonium thioglycolate, with aqueous free ammonia in a gel is an example of a suitable relaxant composition.
The relaxant composition of the present invention is applied to the hair of the subject by the operator in an amount which is sufficient to relax the hair to a desired state. The amount of relaxant used will be dependent on the mass of subject's hair, the coarseness of the hair and/or the resistance to relaxation exhibited by the hair. It has been found that a typical application of the relaxant composition is between about 75 and about 125 milliliters, and for a duration of about two to fifteen minutes.
After the relaxant composition has been rinsed from the subject's hair, the next step in the process of the present invention involves applying a sufficient amount of an aqueous suspending composition to the hair. The suspending composition of the present invention preferably has a pH of between about 3.5 and 7.0 and more preferably between 4.5 and 5.5. The suspending composition comprises a major portion of water and between about 0.0001 and 0.1 weight % of ammonium chloride, and between about 0.0001 to 0.1 weight % of magnesium chloride. NUCLEIC PLUS E.A.S. shampoo, commercially available from Miriam-Collins-Palm Beach Lab, Co. is an example of a suitable suspending composition.
The suspending composition is applied uniformly throughout the hair, and preferably rinsed off and applied a second time. The first application of the suspending composition removes most of the residual relaxant composition from the surface of the hair along with the gel coating which is present if the relaxant composition is in a gel form. The second application is left on the hair to perform its intended function.
After the suspending composition has been applied for the second time, the subject's hair is wrapped about a plurality of permanent wave rods having a desired diameter or diameters. Permanent wave rods are made of various materials, such as plastics, which to not react with the solutions used in the process of the present invention. In addition, permanent wave rods have fastening means that allow the hair to be secured in a desired position about the rod. Permanent wave rods typically vary in diameter from 1/4 of an inch to 3/4 of an inch in diameter. The diameter of rod is selected to give the desired curl diameter to the subject's hair.
After the subject's hair has been wrapped about the curling rods a two-part heat generating composition is applied to the hair. This heat source is intended to aid in the opening of the cuticle of the hair within the hair structure and to thereby aid in penetration. This composition is provided as two separate solutions which when combined react exothermically to provide a heated solution which raises the temperature of the hair to a desired temperature. It is desired that the temperature of the hair be raised to a temperature in the range of about 100° F. to about 130° F. and preferably in the range of between about 110° F. and about 120° F.
A suitable first solution of the heat generating composition is a solution of an alkaline thioglycolate, and water. A second solution is preferably a hydrogen peroxide solution. The ratio of the equivalents of the reactive component in the first solution, namely the ammonium thioglycolate, and the equivalents of the of the hydrogen peroxide in the second solution, should be such that the heat generating composition will provide between 5 and 10 wt-% of unreacted ammonium thioglycolate after the reaction between the first and second solutions is complete. NUCLEIC PLUS A.T.H. Automatic Timing/Heating Permanent Wave, commercially available from Miriam-Collins-Palm Beach Lab, Co. is an example of a suitable two-part heat generating composition.
The first solution of the heat generating composition preferably contains between about 10 wt-% and about 20 wt-% ammonium thioglycolate. The second solution preferably contains between about 3 wt-% and about 7 wt-% hydrogen peroxide.
The heat generating composition reaction produces a bi-product which acts to block excessive hair structure damage due to too much free thioglycolate or thioglycolic acid. It is believed that an equilibrium is reached between the thioglycolate and thioglycolic acid and dithioglycolate which prevents further decomposition of the sulfide bonds past a desired end point. Thus, the heat generating composition eliminates overprocessing of the hair's sulfide bonds and eliminates the probability of structural hair damage and depilitation.
The self-timing attribute of this composition is very important because hair has a wide range of porosity and physical geometries, and therefore, processing time for hair, even on different areas of a single hair or areas on a subject's head, may be vastly different. This self-limiting step eliminates the operator's judgment as to the proper processing time and allows for consistent curl restructuring with minimal hair damage. The heat generating composition is typically applied for about two to fifteen minutes before the next step is effected. It is desirable to rinse the heat generating composition thoroughly from the hair.
The next step in the process involves contacting the hair of the subject with an aqueous oxidizing composition, such as a hydrogen peroxide or bromate solution in a sufficient amount to oxidize substantially all of the remaining thioglycolate and thioglycolate derivatives. This step allows for the reforming of the disulfide bonds of the hair into the new configuration as determined by the configuration of the hair about the permanent wave rod. It is believed that the oxidizing composition solution allows the sulfide chain-linkages to be reassembled allowing the hair to have a new memory of its configuration about the rod.
Sodium bromate is a preferred active ingredient in the oxidizing composition because it produces a more springy and tighter curl reformation. In addition, sodium bromate is a stable oxidizing agent which will not decompose as rapidly as other oxidizing agents in storage. The aqueous oxidizing composition preferably is a 5 wt-% to 15 wt-% sodium bromate solution.
After the oxidizing composition has been allowed to soak on the subject's hair for roughly 5 to 20 minutes, preferably two to fifteen minutes the hair is typically rinsed with warm water before the curling rods are removed from the subject's hair.
A final step consists of contacting the subject's hair with an acidic aqueous solution for a period of time and in a sufficient amount to cause the hair to reach a substantially neutral pH. The acidic solution preferably has a pH in the range of between about 4.5 and about 6.5. This mild acidic solution eliminates all of the residual alkali material which may be left in the hair from the previous steps. This final acid rinse also preferably contains hair restructuring components such as proteins, vitamins, cell regenerative agents, and natural protein reconstructors. These additional hair restructuring components are physically entrapped by the hair when added in this acidic aqueous solution and the cuticle of the hair is sealed. A shiny resistant armor to the cortex of the hair fiber is produced.
The acid solution is applied to the subject's head usually after blotting excess moisture from the hair with a towel. The solution is preferably combed gently through the hair and allowed to remain for about 2 to 5 minutes before the excess is blotted from the hair and the hair is styled.
After the hair has been styled and/or cut as desired, it is preferred that a humectant spray be added to the hair to further protect the hair. A humectant spray having a high content of glycerine preferably about 2 to 15 wt-% or like material may be applied to the hair to maintain and draw moisture necessary to keep the hair in a soft and moist condition. The hydrophilic properties of this humectant spray aids in retarding natural moisture evaporation which is especially prominent in flat or oval, tightly-curled hair.
In addition, a UV light absorbing compound may be added to this final humectant spray to minimize or eliminate the oxidizing or fading effect caused by sunlight on darker hair. Dark hair is especially prone to damage by ultraviolet rays because of its high light absorbing tendencies. The final moisture retaining spray can also contain amounts of protein, quaternary detanglers cationic surfactants, and vitamins which insure that the hair has a source of enriching agents which can be absorbed from the continued exposure to the humectant spray to help maintain flexible and soft hair fibers.
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RELATED APPLICATIONS
This application claims priority under 35 U.S.C. §§ 119, 120 & 365 from, and is a continuation of, International Application No. PCT/NL97/00631, filed on Nov. 19, 1997, designating the United States of America. This application further claims benefit under 35 U.S.C. § 119 to EPO patent application 96203444.3 filed Dec. 5, 1996.
FIELD OF THE INVENTION
The present invention relates to the field of gene therapy and, more particularly, relates to DNA molecules derived from adeno-associated virus (AAV) for the genetic modification of primate hemopoietic stem cells.
BACKGROUND OF THE INVENTION
Genetic modification of pluripotent hemopoietic stem cells from primates (P-PHSC) has been an elusive goal for many years. Retrovirus vectors have been used in the past with limited success [1]. Though retroviral vector technology is still improving, progress in increasing the transduction of P-PHSC is slow. This is due to the fact that a solution is not straightforward and that the P-PHSC cannot be identified by a rapid in vitro culture method [1]. Though culture of hemopoie-tic progenitor cells is possible, the in vitro transduction levels of these cells do not reflect transduction of P-PHSC that in vivo can grow out to give long term reconstitution in multi-hemopoietic lineages [1,2,3]. Although long-term in vitro culture assays, such as, e.g., the so-called LTC-IC assay, have long been considered relevant assays for P-PHSC, it is now generally accepted that only a very minor sub-population of the cells identified in long-term in vitro culture assays are P-PHSC. Therefore, genetic modification of long-term in vitro cultured cells, even very efficient genetic modification, does not provide any relevant information on genetic modification of P-PHSC. Furthermore, although increasing knowledge is being gathered on the expression of cell surface markers on P-PHSC, P-PHSC can also not be identified by their phenotype. P-PHSC are known to express the CD34 molecule and to be negative for many other hemopoietic cell surface markers, but even the purest P-PHSC population that can currently be phenotypically characterized contains only few P-PHSC. Due to this, transduction has to be evaluated by laborious and lengthy in vivo studies using a bone marrow transplantation setting where the stem cells in the bone marrow were transduced ex vivo and subsequently transplanted back into monkey or human. Transduction of P-PUSC is verified by the long term persistence of genetically modified hemopoietic cells. Currently, the most efficient method for the transduction of P-PHSC is by means of retroviral vectors. Using such vectors, it is possible to transduce approx. up to 0.01-0.1% of the P-PHSC [3,4,5,6,7]. The limitation of retroviral transduction is most likely due to a restricted expression of the retrovirus receptor on P-PHSC, combined with the fact that P-PHSC are usually not in cell cycle, whereas retroviral vectors do not efficiently transduce non-dividing cells [8,9,10,11].
A number of methods have been devised to improve the P-PHSC transduction by retroviral vectors such as pseudotyping retroviruses using VSV (Vesicular Stomatitis Virus) envelope protein or GALV (Gibbon Ape Leukemia Virus) envelope proteins to target different and possibly more abundantly present receptors on the cell membrane. Other strategies were directed toward improving the number of cycling P-PHSC in the transplant. To date, this did not result in-a significant improvement of P-PHSC transduction.
In contrast to P-PHSC, murine PHSC are very easily transduced by the current generation of retroviral vectors. This observation, made in experiments using retroviral vectors, shows that successful gene transfer into murine PHSC is by no means indicative for successful gene transfer into P-PHSC. One can think of a number of different possible reasons for this observation. We hypothesized that it is theoretically not optimal to use a vector system that has evolved in murine animals for humans. Though the cellular processes involved in the murine retrovirus life cycle are conserved between murine mammals and primates, it is very well possible that the evolutionary divergence of the species resulted in structural differences in the related proteins that affect the functional efficiency of the murine virus proteins in human cells and, thus, affect the transduction process. To avoid these problems, we turned to a different vector system based on the human virus adeno-associated virus (AAV).
AAV is a human virus of the parvovirus family. The AAV genome is encapsidated as a linear single-stranded DNA molecule of approximately 5 kb. Both the plus and the minus strand are infectious and are packaged into virions [12,13]. Efficient AAV replication does not occur unless the cell is also infected by adenavirus or herpes virus. In the absence of helper virus, AAV establishes a latent infection in which its genome is integrated into the cellular chromosomal DNA. The AAV genome contains two large open reading frames. The left half of the genome encodes regulatory proteins, termed REP proteins, that govern replication of AAV-DNA during a lytic infection. The right half encodes the virus structural proteins VP1, VP2 and VP3 that together form the capsid of the virus. The protein coding region is flanked by inverted terminal repeats (ITRs) of 145 bp each, which appear to contain all the cis-acting sequences required for virus replication, encapsidation and integration into the host chromosome [14,15].
In an AAV-vector, the entire protein-coding domain (±4.3 kb) can be replaced by the gene(s) of interest, leaving only the flanking ITRs intact. such vectors are packaged into virions by supplying the AAV-proteins in trans. This can be achieved by a number of different methods, one of them encompassing a transfection into adenovirus infected cells of a vector plasmid carrying a sequence of interest flanked by two ITRs and a packaging plasmid carrying the in trans required AAV protein coding domains rep and cap [15,16,17,18,19]. Due to the stability of the AAV-virion, the adenovirus contamination can be cleared from the virus preparation by heat inactivation (1 hr, 56° C.). In initial studies, virus preparations were contaminated with wild-type AAV, presumably due to recombination events between the vector and the helper construct [16,17,18,19]. Currently, wild-type AAV-free recombinant AAV stocks can be generated by using packaging constructs that do not contain any sequence homology with the vector [15].
Several characteristics distinguish AAV-vectors from the classical retroviral vectors (see also table 1). AAV is a DNA virus which means that the gene of interest, within the size-constraints of AAV, can be inserted as a genomic clone [20, 21]. Some genes, most notably the human β-globin gene, require the presence of introns for efficient expression of the gene [22]. Genomic clones of genes cannot be incorporated easily in retroviral vectors, as these will splice out the introris during the RNA-stage of their life-cycle [23].
In human target cells, wild-type AAV integrates, preferentially, into a discrete region (19q13.3-qter) of chromosome 19 [24,25,26]. This activity might correlate with rep-gene expression in the target cell, since it was found that the large rep-proteins bind to, the human integration site in vitro [27]. AAV-vectors do integrate with high efficiency into the host chromosomal DNA, however, thus far, they do not share the integration site specificity of wtAAV [20]. Site-speciftc integration would be of great importance since it reduces the risks of transformation of the target cell through insertional mutagenesis. Wild-type AAV is, thus far, not associated with human disease. Evidence is accumulating that AAV infection of a cell, indeed, forms an extra barrier against its malignant transformation (reviewed in [28]). In contrast to retroviral vectors where, due to the extended packaging signal, parts of the gag-region need to be present in the vector, the entire protein coding domain of AAV can be deleted and replaced by the sequences of interest, thus totally avoiding any inTmunogenicity problem associated with viral protein expression in transduced target cells. One drawback of AAV-vectors is that they are derived from a human virus. Thus, patients treated with an AAV-vector might become exposed to wtAAV which, in the presence of a helper virus such as adeno-virus or herpes simplex virus, can supply the virus replication and packaging proteins in trans and thus induce spread of the recombinant AAV-virus into the environment. This is a feature not shared by the currently used MuLV-derived retroviral vectors; wild-type MuLV's do not normally cause infections in humans. The risk of recombinant AAV spread into the environment must, however, not be overestimated since it requires the presence of wtAAV and a helper virus. This is not a frequently occurring situation. In addition, during the integration process of AAV-vectors, often the ITRs undergo some form of recombination leading to loss of function [15]. Such proviruses cannot be rescued and, thus, provide an additional safety level of these vectors.
The first AAV-vectors were made by replacing part of the AAV-coding region with either the Chloramphenicol Acetyl-transferase (CAT) or the neon gene [16,17]. All of these vectors retained either a functional rep- or a functional cap-coding region. Recombinant virus was generated by cotransfection with a plasmid containing a complete AAV-genome. The recombinant AAV-CAT virus conferred Chloramphenicol Acetyltransferase activity to 293 cells [16] whereas the recombinant neo R virus conferred G418-resistance to Human Detroit 6 cells, KB-cells and mouse L-cells [71].
Currently, AAV-vectors are made that are totally devoid of AAV-protein coding sequences. Typically, virus is made from these vectors by complementation with a plasmid carrying the AAV-protein coding region but no ITR-sequences [15].
AAV-vector technology is under development for a number of different therapeutic purposes and target tissues. The as yet most developed system is, perhaps, AAV-vector mediated gene transfer to lung cells [29,30]. AAV-vectors carrying the neo R gene or the CAT gene were transferred and expressed efficiently in airway epithelial cells [29]. An AAV-vector carrying sequences 486-4629 of the human Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene fused to a synthetic oligonucleotide supplying the translation start site, was capable of complementing Cystic fibrosis (CF) in vitro [31]. In addition, stable gene transfer and expression was reported following infection of primary CF nasal polyp cells and after in vivo delivery of the AAV-CVTR vector to one lobe of the rabbit lung [30]. In vivo, the vector DNA could be detected in 50% of the nuclei at 3 months post-administration. Although the prevalence of the vector decreased after this time point, still ±5% of the nuclei were positive at the six months time point [30]. The presence of the vector correlated well with expression of RNA and recombinant protein which where still detectable at the six months follow up [30].
AAV-vector mediated gene transfer into murine hemopoietic cells was demonstrated by the conference of G418 resistance to murine in vitro colony forming units (CFU) following infection with a recombinant AAV-vector carrying the neo R -gene [32,33]. The presence of the vector in the progeny of CFU-GM (colony forming units-Granulocyte Macrophage) and BFU-E (burst forming units-Erythrocyte) was verified by means of PCR (Polymerase Chain Reaction). The efficiency of gene transfer varied between 0.5% and 15% [33]. Efficient gene delivery (up to 80%) into human hemopoietic progenitors and human CD34 + cells with AAV-neo R vectors has also been reported [34,35,36,37]. These studies demonstrated that rAAV vectors were able to deliver their DNA to the nucleus of the hemopoietic progenitor cells that can be cultured in vitro. Though delivery of the vector DNA to the nucleus of cells demonstrates the presence of a functional virus receptor on the surface of the target cells, delivery of rAAV to the nucleus of cells is not directly related to the integration of that DNA into the host cell genome (discussed later and presented in table 2). Recombinant adeno-associated virus DNA present as an episome in the cells is known to refrain from integration into the host cell genome in non-dividing tissue culture cells [38]. Integration of rAAV in CD34 + cells and in vitro growing colonies (CFU-C) was demonstrated in 1996 by Fischer-Adams et al. [59]. Stable transduction of P-PHSC is neither taught nor suggested in any of these prior art documents, however. None of the above mentioned studies discloses delivery and integration of rAAV to P-PHSC, the only relevant hemopoietic cell type for long term persistence of transduced cells in vivo.
We are developing rAAV gene transfer into P-PHSC for the treatment of β-thalassemia and Sickle cell anemia. Both diseases severely affect the function of erythrocytes in these patients. β-thalassemic erythrocytes contain insufficient β-globin chains, whereas mutant β-globin chains are made in sickle cell anemia (for review see [39]). Both diseases severely affect erythrocyte function which can be alleviated by persistent γ-globin gene expression in the adult patient in which case fetal hemoglobin is formed [40]. Both inherited diseases are recessive in nature which indicates that one functional intact copy of the adult β-globin gene is sufficient to ameliorate the phenotype.
Globin abnormalities were discarded as targets for gene therapy attempts in the early days of gene therapy research. This was largely due to the extremely complicated expression patterns of globin-like genes [41]. Globin-synthesis is highly regulated during development and confined to cells of the erythroid lineage. Furthermore, the expression of α- and β-globin like chains is regulated such that they are maintained at a 1 to 1 ratio in the cell. Such careful control of gene expression is not easily obtained. Expression vectors carrying the human β-globin gene with its promoter and local enhancer elements can direct erythroid specific globin RNA expression [42]. However, typically, the levels are less than 1% of the endogenous globin RNA.
Recently, sequences 50-60 kb upstream of the β-globin gene were discovered that direct the high level, tissue specific, copy number dependent and position independent expression of the β-globin gene [43]. This region, designated the Locus Control Region (LCR), is characterized by four strong erythroid-specific DNaseI hypersensitive sites (HS1-4) [44]. Fine-mapping of the active sequences in the LCR identified four fragments of ±400 bp in length that each coincide with one HS site. Walsh et al incorporated a marked γ-globin gene and the core fragment of HS2 together with the neo R gene into an AAV-vector [20]. Infected and G418 selected pools and clones of K562 cells produced the marked γ-globin RNA to 50-85% compared to the normal level expressed by one endogenous γ-globin gene [20,45]. A drawback of this vector is that the γ-globin gene and promoter used in these studies are specific for expression in fetal erythroid tissue and, thus, not ideal for use as a therapeutic agent in adult humans, tInorporation of β-LCR sites 1, 2, 3 and 4 in a vector containing the adult specific human β-globin gene resulted in a very high regulated expression in MEL (murine erythroleukemia) cells, the best in vitro marker cell line for regulated erythroid expression in adult tissue [46]. The present invention describes the use of this and similar vectors in the transduction of P-PHSC.
The term “infectious particles” is used herein to refer to AAV particles that can deliver their packaged DNA to the nucleus of cells and replicate in the presence of adenovirus and wtAAV.
The term “transducing particles” is used herein to refer to AAV particles that can deliver their packaged DNA to the nucleus of target cells where the packaged DNA is released and integrates into the chromosomal DNA of the target cells.
SUMMARY OF THE INVENTION
This invention provides a process of genetic modification of pluripotent hemopoietic stem cells of primates (P-PHSC), comprising introducing a nucleic acid molecule based on adeno-associated virus (AAV), in particular a recombinant AAV, which is derived from human AAV, into P-PHSC, preferably by transduction. The genome of the recombinant AAV comprises a DNA sequence flanked by the inverted terminal repeats (ITR) of AAV, or functional analogs or fragment thereof. Normally and preferably, but not necessarily, said DNA sequence will be a non-AAV DNA sequence, in particular a therapeutic DNA sequence,
According to a preferred embodiment of the invention, the DNA sequence comprises regulatory sequences functional in hemopoietic cells (in particular hemopoietic stem cells) and, under the control of said regulatory sequences, a sequence coding for a protein or RNA with a therapeutic property when introduced into hemopoietic (stem) cells. Preferred examples of the DNA sequence comprise the coding sequence of such genee as the human lysosomal glucocerebrosidase gene (E.C.3.2.1.45), a globin gene from the human β-globin gene cluster, a DNA sequence encoding an RNA or protein with anti-viral activity, the α1-antitrypsin gene and the human multidrug resistance gene I (MDRI).
In a particularly preferred embodiment, the DNA sequence comprises the human β-globin gene inclusive of at least one of its introns or functional analogs thereof, under transcriptional control of a functional part of the β-globin promoter or functional analogs thereof, and being operably linked to erythroid-specific DNaseI hypersensitive sites from its Locus Control Region (LCR), more particularly, the β-LCR elements HS4, HS3 and HS2 or functional analogs thereof.
The DNA sequence may also comprise a selectable marker gene useful in hemopoietic stem cells, such as a neo R gene, under transcriptional control of a herpes simplex virus (HSV) thymidine kinase (tk) promoter or functional analogs thereof or a ΔMo+PyF101 Long Terminal Repeat (LTR) promoter.
The P-PHSC may be obtained from primate bone marrow, cord blood or peripheral blood and, preferably, from a human. The P-PHSC may be exposed in vitro to proliferation stimulating compounds, such as interleukin 3 or a functional analog or fragment thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the discovery that adeno-associated virus-derived vectors efficiently transduce primate pluripotent hemopoietic stem cells. Adeno-associated virus has not been reported to transduce pluripotent hemopoietic stem cells of primates and AAV-derived vectors have not been shown to transduce hemopoietic cells with in vivo repopulating ability, In addition, it is surprising that the vector integrates with high efficiency into P-PHSC, even though most of the P-PHSC are not actively dividing at the time of infection. This is surprising, since it has been established that rAAV integration in dividing cells occurs 200 times more efficiently in dividing, as opposed to nondividing cells [38]. Also, it was reported that primary cells are much less efficiently transduced by rAAV than immortalized cell lines [47]. In addition, it was reported that orf 6 from adenovirus E4-region stimulates transduction by recombinant AAV [48]. In a gene therapy setting, it is undesirable to have functionally active adenovirus present due to toxicity problems caused by the virus directly or the immune system of the patient. At the Keystone Symposium on Molecular and Cellular Siology, Taos, N. Mex. Feb. 4-10, 1996, Prof. A. Nienhuis presented a paper stating that they transduced rhesus monkey CD34 + cells and, subsequently, autologously transplanted the infected cells [49]. Analysis of the peripheral blood cells circulating in blood with a polymerase chain reaction specific for the rAAV revealed that cells carrying the rAAV were only detected up until 7 days post transplantation [49], i.e. P-PHSC were not transduced by rAAV in their experiment. Nonetheless, the present invention demonstrates that an adeno-associated virus-derived vector may be used to deliver exogenous DNA efficiently to cells of the hemopoietic system with long term repopulating ability.
The current perception of AAV-integration into the cellular host chromosome is that the pre-integration complex is stable in cells. Although integration occurs more efficiently in dividing cells, the pre-integration complex is stable in non-dividing cells and integrates when the cell is triggered to undergo cell cycling [38,60]. The primate-derived hemopoietic stem cells and committed progenitor cells upon autologous transplantation into an irradiated recipient are triggered into cycle to repopulate the destroyed hemopoietic system. For this reason, it is generally believed that the hemopoietic cells need not be triggered in vitro. For this reason, protocols to transduce hemopoietic progenitor cells with rAAV do not involve culturing the cells in the presence of hemopoietic growth factors. Although this reasoning is very plausible with the current information, we devised experiments to investigate the effect of in vitro culture of hemopoietic stem cells and the in vitro stimulation with hemopoietic growth factors.
As used herein, the term “recombinant AAV vector” means a DNA sequence flanked at each end by an AAV-ITR or functional equivalent or part thereof. The recombinant AAV vector can be used directly or be packaged into a complex before use, As used herein, the term “complex” is defined as a combination of two or more components physically linked to each other through hydrophobic, hydrophilic or electrostatic interactions or covalent bonds, whereby one component of the complex at least is a recombinant AAV molecule. Other components of the complex can comprise, but are not limited to, one or a combination of liposomes, calcium phosphate precipitate, polylysine, Adenovirus, Adenovirus proteins, Rep78, Rep68, AAV capsids or the AAV capsid proteins VP1, VP2 or VP3. In a preferred embodiment the complex consists of the recombinant AAV vector and the AAV capsid proteins. This complex can be, but is not limited to, the form of an intact virion or particle where the recombinant AAV vector is packaged inside an AAV capsid or functional analogs thereof.
As used herein, the term “functional analogs” refers to the same activity in kind, but not in amount or degree, i.e. not quantitatively.
When the recombinant AAV is packaged into AAV particles, the size of the DNA sequence will be limited by the size constraints for packaging into AAV particles which, with the current state of the technology, is about 5 kb. The DNA fragment preferably does not contain sequences functionally analogous to the terminal resolution site in the AAV-ITR as this might interfere with the stability of the recombinant vector. The DNA sequence can be any sequence with therapeutic properties when introduced into hemopoietic stem cells, but the DNA sequence preferably encodes one or more proteins or RNA with therapeutic properties when expressed in hemopoietic cells. Non-limiting examples of such sequences are the human β-globin gene operably linked to cis-acting sequences for erythroid specific physiological expression, the human lysosomal glucocerebrosidase gene (E.C3.2.1.45), the α1-antitrypsin gene, a DNA sequence encoding an RNA or protein with anti-viral activity or the multidrug resistance gene I (MDRI). AAV-ITR sequences may be obtained from AAV serotypes 1, 2, 3, 4 or 5. Alternatively, mutant or recombinant ITR sequences can be used, which retain the essential properties of the AAV-ITR prototype, examples of which are described in Lefebvre et al, [50].
Packaging of rAAV into AAV-virions can be achieved using a variety of different methods. All methods are based on bringing the necessary proteins and rAAV-containing DNA in an environment that supports the replication and packaging of rAAV, One method relies on the transfection of adenovirus 5 infected human cells with a plasmid carrying the rAAV-DNA together with a plasmid containing expression cassettes for the AAV-genes rep and cap. Upon continued culture of the manipulated cells, rAAV is replicated and packaged. After three days, the cells are harvested and the accumulated recombinant virions are released from the cells [15-19]. A variation on the packaging system described above is the use of packaging cells that carry all or part of the relevant sequences stably integrated in their genome (i.e. the recombinant AAV vector, the rep-gene, the cap-gene, and the relevant protein coding domains of the helper virus). When only partial packaging cells are used, the missing packaging functions have to be supplied externally via transtections of plasmids carrying the functions or virus infection. The helper virus functions are required for efficient packaging of recombinant AAV. For most applications, the helper virus is inactivated or separated physically from the recombinant AAV virions before using the recombinant AAV virions for the transduction of cells [15-19]. Recombinant AAV vectors can be packaged by adding the recombinant AAV-DNA to protein extracts or mixtures of protein extracts of cells that expressed all or part of the relevant proteins for the replication and packaging of recombinant AAV. When protein extracts are used from cells expressing only some of the relevant proteins for packaging of recombinant AAV, the missing proteins can be supplied externally in purified form.
The rep-gene can be derived from AAV serotypes 1-5 or functional analogues thereof either obtained through non-essential mutations in the rep-genes or through the isolation of genes with similar capabilities such as the Human Herpesvirus 6 AAV-2 rep gene homologue [58].
The cap-gene can be derived from AAV serotypes 1-5 or functional analogues thereof obtained through non-essential mutations in the cap-genes. Alternatively, the cap-gene sequences can be altered through the replacement or addition of sequences rendering the produced virion new or altered target cell specificities.
Recombinant AAV virions produced by the methods described above can be purified and concentrated using biological, physical or chemical separation techniques such as, but not limited to, antibody affinity purification, density gradient centrifugation or ion exchange chromatography. Alternatively, the virions produced can be used in an unpurified form.
As used herein, pluripotent hemopoietic stem cells from primates (P-PHSC) are functionally defined as cells from primates with the capability to form and maintain an entire hemopoietic system, ranging from mature T-cells, B-cells, macrophages or erythrocytes to new P-PHSC. P-PHSC display this capability in unmanipulated primates or upon their autologous transplantation. Sources of P-PHSC are the bone marrow, the peripheral blood or cord blood. P-PHSC can be collected from unmanipulated primates or from primates treated with compounds such as, but not limited to, cytostatic drugs or hemopoiatic growth factors to activate, recruit or otherwise potentiate the P-PHSC.
Transduction of P-PHSC is preferably performed ex vivo, following harvesting of the P-PHSC from a suitable source, and after the transduction the transduced cells are autologously transplanted. In a preferred embodiment of the invention, the P-PHSC are cultured during their ex vivo transduction, where it is most preferred that during this culture the P-PHSC are stimulated with at least one hemopoietic growth factor, such as, e.g., interleukin-3. Alternatively, P-PHSC transduction is performed in vivo when suitable methods have been developed to target the recombinant AAV vector in vivo to P-PHSC.
BRIEF DESCRIPTION OF THE TABLES AND DRAWINGS
Table 1 Key properties of Adeno-associated virus vectors and amphotropic retrovirus vectors.
Table 2 Characterization of recombinant AAV preparations useful for the transduction of primate PHSC.
Table 3 Transduction of primate PHSC: culture and infection conditions.
IP=Infectious Particles (titrated in RCA);
TP=Transducing Particles (titrated on MEL cells).
Table 4 Transduction of primate PHSC: Hemopoietic data.
FIG. 1A Recombinant AAV-vectors useful for the transduction of primate PHSC.
ITR=Adeno-associated virus inverted terminal repeat,
LCR=Core sequences from hypersensitive sites 4, 3 and 2 from the β-globin locus control region.
−103=human β-globin gene promoter fragment extending −103 upstream of the transcription start site.
−265=human β-globin gene promoter fragment extending −265 upstream of the transcription start site.
β-globin=human β-globin gene with modified intron 2 (see text and 21).
Tkprom=Herpes Simplex Virus Thymidine kinase gene promoter (approx. 500 bp NarI-BgIII fragment)
NEO=BglII-SmaI fragment from E. coli Tn5 transposon.
pA=Polyadenylation signal from Herpes Simplex Virus Thymidine Kinase gene λapprox. 500 bp SmaI-NarI fragment).
β*-globin=human β-globin gene with in the 5′ untranslated region three point mutations that generate two restriction enzyme sites (see FIG. 1 B).
ΔMo+PyF101 a Moloney murine leukemia virus long terminal repeat fragment in which the Moloney enhancer is replaced by an enhancer from a mutant polyoma virus that was selected to grow on embryonal carcinoma cells [2,51,52,53].
FIG. 1B Nucleotide sequence of the 5′ untranslated region (UTR) of the normal (β) and the marked (β*) human β-globin gene.
FIG. 2 Detection of recombinant AAV in rhesus monkey peripheral blood cells. Blood cells were collected as described in the text. Peripheral blood mononuclear cells (WBC) were separated from the granulocytes (Gran) and a neospecific nested PCR was performed on the DNA of both cell types. DNA from the nested PCR was analyzed on agarose gels and compared to positive and negative control samples. The sensitivity of the nested PCR was such that approximately one rAAV-vector could be detected in a background of 10 5 negative cells. (+) indicates the presence of a neo-specific band and (−) the absence of a neo-specific band in the agarose gel.
FIGS. 3A-3B Graphic representation of direct and nested neo-specitic PCR data from monkeys BB94 and A94 (FIG. 3 a ) and monkeys 9128 en 9170 (FIG. 3 b ). The data on the latter two monkeys shown in FIG. 2 are included in FIG. 3 as well. For clarity, negative PCR-results were not included in the graphs. Closed circles (PBMC) and closed squares (Granulocytes) indicate the time-points after transplantation at which the vector was detected. Arrows in FIG. 3 b indicate the time-points at which docetaxel (Taxotere) was administered.
FIG. 4 Detection of neo-specific sequences in hemopoietic cells from rh BB94 at 16 months post transplantation. BM (bone marrow) , PBMC (peripheral blood mononuclear cells), Gran (granulocytes).
FIG. 5 Detection of vector specific globin sequences in rhesus monkey peripheral blood cells (samples from 2 months (A94) and 6 months (BB94) post-transplantation) With this PCR, the two vectors IG-CFT and IG-CFT* are discriminated since the size of the IG-CFT* fragment is approximately 150 pb. longer than the fragment specific for IG-CFT.
EXAMPLE 1
Ligation of Recombinant AAV Vectors Containing the Human β-globin Gene and/or the Neo R Gene
In order to determine whether recombinant AAV could transduce P-PHSC, it was necessary to generate appropriate vectors. We generated three different recombinant AAV-vectors, which are schematically represented in FIG. 1 A. The ligation of the vector IG-CFT containing a human β-globin gene together with sequences from the β-globin locus control region and the neo R -gene is described in [21], IG-CFT* differs from IG-CFT in the size of the human β-globin promoter and in the presence of three point mutations in the 5′ untranslated region (UTR) of the human β-globin gene, In IG-CFT*, the promoter driving β-globin expression extends 265 bp upstream of the transcription start site instead of the 103 bp in IG-CFT. In IG-CFT*, three point mutations in the 5′ UTR of the human β-globin gene created two new restriction sites, one for XbaI and one for HindIII, see also FIG. 1 B.
IG-ΔMoNeo (depicted in FIG. 1A) contains the rAAV-backbone (XbaI-fragment) from pSub201 [51], the NheI-SmaI promoter-fragment from the ΔMo+PyF101 LTR [53], the BglII-SmaI fragment from the Tn5-derived neo R -gene followed by the SmaI-NarI poly-adenylation signal from Herpes Simplex Virus (HSV) Thymidine Kinase (TK) gene [54]. The elements were linked together using the polylinker from pbluescript SK + (Stratagene).
EXAMPLE 2
Production of Recombinant AAV from IG-CFT, IG-CFT* and IG-ΔMoNeo
The 293 cell line [55], which is a human embryonic kidney cell line transformed with Ads DNA, the A549 cell line, which is a human bronchial carcinoma cell line, and the C88 cell line [56], which is a murine erythroleukemia (MEL) cell line, were maintained in DMEM (GIBCO-BRL) containing 10% Fetal Calf Serum (FCS), 100 μg/ml streptomycin and 100 U/ml penicillin. Recombinant AAV was produced by transfecting a rAAV packaging plasmid and a vector plasmid into approx. 90% confluent permissive 293 cells. The cells were made permissive for AAV-replication by transfecting them with a plasmid capable of expressing all the relevant early genes from adenovirus but not the late genes or by infecting them with adenovirus ts149 with a multiplicity of infection of 20. The packaging plasmid was either pAAV/Ad [15] or pIM45, which contains sequences 146 to 4493 from wtAAV2 in the polylinker of pBluescript, The ratio of vector plasmid DNA to packaging plasmid DNA was 1:10 to accommodate the fact that the recombinant AAV vector upon expression from the packaging plasmid replicates, whereas the packaging plasmid does not replicate. For crude virus stocks, the cells were harvested in their own culture medium after two to three days and subjected to three freeze/thaw cycles. The latter was performed by intermittent freezing and thawing in liquid nitrogen and a 37° C. water bath. Cell debri was subsequently pelleted. (10 min, 200 g) and the supernatant was incubated at 56° C. for 1 hour to inactivate residual adenovirus. Concentrated high titer recombinant AAV stocks were prepared by harvesting the cells in there own culture medium, and washing in PBS (max. 10 7 cells/ml). The virus was released from the cells by 3 freeze/thaw cycles and/or 30 sonication pulses of 1 second on ice to prevent warming. Cell debri was spun down and the supernatant was made a density of 1.4 by adding solid CsCl. After o/n centrifugation (50.000 r.p.m., 20° C., using a vti TI65.1 rotor in a Beckman ultracentrifuge), fractions were collected and rAAV was determined. Fractions containing rAAV were pooled and further concentrated in a centricon concentrator (Amicon) according to manufacturer's specifications. After concentration, the medium containing the virus was changed by two successive washes in the centricon concentrator, using Optimem culture medium (GIBCO-BRL).
EXAMPLE 3
Characterization of rAAV Preparations
To determine the effect of the different methods of virus preparation and the different processing steps on the quality of the various rAAV-batches, we characterized them for 5 parameters: 1) the capacity to deliver the desired DNA to the nucleus of the target cell by means of a replication center assay (RCA) described below, 2) the capacity to stably transduce cells and express the neo R -gene by means of a limiting dilution on MEL cells followed by G418 selection, 3) the wild-type AAV titer in the batches by a RCA without added wtAAV, 4) the amount of replication proficient adenovirus in each preparation, and 5) the concentration of CsCl in the rAAV preparations that were purified using CsCl radients (See Table 2).
Replication Center Assay
The replication center assay (RCA) takes advantage of the fact that in a lytic infection of AAV up to 10 6 AAV, genomes are produced inside a cell. This amount of DNA is sufficient for the radioactive detection of infected cells. To accomplish this, 293 cells were seeded in a flat bottom 96 wells plate such that they reached near confluence the following day. For a titration of recombinant AAV, the cells were infected with dilutions of recombinant virus stock, adenovirus ts149 (M.O.I. 20) and wtAAV-2 (M.O.I. 2). For a titration of the wild type AAV, the cells were infected with dilutions of recombinant virus stock and adenovirus ts149 (M.O.I. 20). The cells were subsequently incubated at 39° C. The next day, after 24 hours, the medium was replaced by ice-cold PBS containing 5 mM EDTA. After 5 to 20 min. on ice, a single cell suspension was made by rigorous pipetting. The cells were diluted in 5 ml PBS and sucked onto hybond N + filter circles (pore size 0.22 μM) of 3.6 cm diameter. Filters were incubated for 5 min in denaturation solution (0.4 M NaOH; 0.6 M NaCl) and 5 min in renaturation buffer (1,5 M NaCl; 1 M Tris-HCl, pH 7). Filters were washed and stored in 5xSSPE until hybridization. Filters were hybridized with a recombinant AAV specific probe for the determination of the recombinant AAV titer and hybridized with a wild type AAV specific probe for the determination of the wild-type AAV titer.
MEL-cell transduction
1.5×10 5 MEL cells were seeded in 2 ml culture medium per well (24 wells plate, Falcon) and the appropriate dilution of rAAV virus was added. The cells were collected the next day and reseeded in 30 ml culture medium in a 75 cm 2 flask (Falcon) . After three days, the medium was replaced by selection medium by spinning down the cells (200 g, rt) and resuspending the cells in fresh medium containing 1 mg/ml (dry weight) G418 (Gibco). Medium was replaced every three to four days. After fourteen days, the cultures were scored. When the cells had grown to confluency, the cultures were scored positive since the specific virus dilution contained rAAV capable of stably transducing MEL cells. Specific virus dilutions were scored negative when, after fourteen days, confluency had not been reached.
Adenovirus was determined by serial dilutions of the AAV virus stock on A549 (human bronchial carcinoma) cells. Dilutions were scored positive when cytopathic effect was visible after 6 days. Wild-type Adenovirus 5 stocks with a known titer were used as positive controls. CsCl concentrations in the AAV preparations were determined by flame photometry.
A summary of the characterization is given in Table 2. The infectious particle (IP) concentration, i,e. the capacity-to deliver rAAV-DNA to the nucleus of target cells determined in the PCA varied considerably among the different batches. Also the transducing particle (TP) concentration and the amount of wild-type AAV contamination varied considerably. Three batches had a IP to TP ratio of 10 4 , the 248 crude batch had a much lower ratio of 200.
EXAMPLE 4
Transduction and Autologous Transplantation of Rhesus Monkey Bone Marrow
Animal Care and Transplantation
The animals used for transplantation were 3-5 kg rhesus monkeys (Macaca mulatta), bred at the Biomedical Primate Research Centre (BPRC), Rijswijk, The Netherlands. Three weeks before transplantation, the animals were transferred to a laminar flow unit and selectively decontaminated in the digestive tract by treatment with metronidazole (40 mg/kg/day), during 5 days, followed by daily oral administration of ciprofloxacin (6.5 mg/kg/day), polymixin B (10 mg/kg/day) and nystatin (40 kU/monkey/day). A94 and BB94 received one administration of ivermectine 200 μg/kg anti-worm treatment approximately two weeks prior to transplantation. The monkeys were kept under barrier nursing and antimicrobial treatment until leukocyte counts exceeded a value of 1×10 9 /liter. The day before transplantation, the monkeys received 5 Gy total-body X-ray irradiation. For this purpose, the animals were placed in a cylindrical polycarbonate cage which rotated 6 rpm around its vertical axis during irradiation from two opposing beams (physical parameters: 300 kV, 7 mA, 0.26 Gy/min dose rate, 0.80 m average focus-to-skin distance). Bone-marrow grafts were infused into a peripheral vein in a volume of 7.5 ml 0.9% NaCl. Supportive care after transplantation included blood transfusions of 15 Gray-irradiated thrombocytes when thrombocyte counts were below 40×10 9 /liter, subcutaneous fluid upon indicationl,and red blood cell transfusions when hematocrit levels dropped below 0.2 l/l. Monkey 9128 was administered daily Baytrill s.c. for 2 weeks, 9 months after transplantation, as treatment of a Salmionella infection. Monkeys BB94 and A94 were treated for Streptococci septis and received cefamandolnafaat 50 mg/kg/day and tobramycine 3 mg/kg/day. A94 was additionally treated for Streptococci sepsis with amoxiline 9 mg/kg/day, clavulanic acid 2.5 mg/kg/day and ceftriaxone 50 mg/kg/day and with Amphotericin B 8 mg/kg/day for a yeast infection. Selective decontamination was stopped a few days after hemopoietic repopulation of the monkeys. Sepsis treatment was stopped 4 days after the body temperature had returned to normal and serum cultures were found to be sterile. Docetaxel (Taxotere®) treatment was given to monkeys rh9128 and rh9170 at indicated times (FIG. 3) at a dose of 50 mg/m 2 . In monkey rh9128, around 14 months post transplantation 4 docetaxel doses were given of 10 mg/m 2 . The appropriate amount of docetaxel was diluted in 50 ml PBS-Glucose (NPPI, The Netherlands) and was administered by IV injection at a rate of 1 ml/min.
Bone Marrow Processing and Transduction
40 ml of bone marrow aspirate was obtained by puncturing both femoral shafts under total anesthesia. Bone marrow cells were collected in Hanks' basic salt solution containing heparin at 100 units per ml and deoxyribonuclease-I and subjected to Ficoll-Hypaque (Sigma) cenitrifugation. CD34 + selection was performed using a smallscale CEPRATE LC column (CellPro, Bothell, Wash.). From 5×10 4 to 50×10 4 cells were incubated at 4° C. for 30 min in 0.1 ml PBS and 1% bovine serum albumin (BSA) with 5 ml of a phycoerythrin-conjugated anti-CD34 antibody (563.F) or unconjugated anti-CD34 antibody (566). Cells incubated with the antibody 566 were washed (PBS, 0.1* BSA) and further incubated with PerCP conjugated Rabbit anti-Mouse IgG1 (Becton-Dickinson, Cat no. 340272). After washing, cells were acquired on a FACSort (Becton-Dickinson) flow cytometer. Cells were analyzed with the Lysis II software program. The percentage of CD34 + cells was calculated as the ratio of CD34 + cells to total number of cells and multiplied by 100. For rhesus monkeys 9128 and 9170, the enriched CD34 + cells were immediately processed for transduction. For rhesus monkeys A94 and BB94 the enriched CD34 + cells were split into two equal fractions and stored in liquid nitrogen.
Transduction of CD34 + cells was done as described below. A summary of the experimental conditions is given in table 3.
Rhesus monkey 9129 and 9170: Four days prior to transplantation the CDS34 + enriched cells were split in two equal fractions and cultured at a density of 10 6 cells per ml in low density BMC culture medium supplemented with recombinant rhesus monkey interleukin-3 (RhIL-3; Burger et al., 1990) as described in [57], On day 2 and day 3, one fraction of cultured CD34 + cells was exposed to the crude rAAV preparation of IG-CFT and the other fraction was exposed to a crude rAAV-preparation of IG-ΔMoNeo by adding an equal volume of virus preparation to the medium of the cultured CD34 + cells. After three to five hours, the cells were collected by centrifugation (7 min, 200 g) and resuspended into fresh RhIL-3 supplemented low density BMC culture medium in the same volume as the culture was started in. On day four, the cells were collected by centrifugation (7 min, 200 g) and resuspended in an equal volume of 0.9% NaCl and separately transplanted into autologous rhesus monkeys by IV injection.
Rhesus monkey A94 and BB94: Four days prior to transplantation, one fraction of the frozen CD34 + enriched cells was thawed and subsequently washed with Hanks Balanced Salt solution. Live cells were collected by Ficoll-Hypaque (Sigma) centrifugation and cultured at a density of 10 6 cells per ml in Iscove's modified Eagles medium (IMDM, Gibco-BRL) supplemented with Fetal Calf's Serum (FCS, 10%) and recombinant rhesus monkey interleukin-3 (RhIL-3; Burger et al., 1990). On day 2 and day 3, cells were collected by centrifugation (7 min, 200 g) and resuspended in 10 to 200 μl of IMDM+10% FCS and RhIL-3 and subsequently exposed to a purified rAAV preparation of IG-CFT (Monkey A94) or IG-CFT* (Monkey B994). After two hours, the cells were washed with IMDM+10% FCS and reseeded in IMDM+10% FCS and Rh-IL-3. At day four, the cells were collected by centrifugation and suspended in 0.9% NaCl. Also, on day four, the other fraction of CD34 + cells was thawed and washed with Hanks Balanced Salt solution. Live cells were collected by Ficoll-Hypaque (Sigma) centrifugation, resuspended in 10 to 200 μl of IMDM+10% FCS and RhIL-3 and subsequently exposed to a purified rAAV-preparation of IG-CFT (Monkey BB94) or IG-CFT* (Monkey A94). After two hours, the cells were collected by centrifugation and suspended in 0.9% NaCl. After collection in NaCl (0.9%), the cells were separately transplanted into autologous irradiated rhesus monkeys by IV injection.
Parameter Evaluation
Daily observation of clinical signs. Weekly complete physical examination and determination of body weight. Blood chemistry analysis was performed before and after x-ray irradiation. Hematology was performed weekly. Bone marrow samples were punctured from the femoral shafts under total anesthesia. Heparine blood samples were taken weekly for PCR analysis. PBMC and granulocytes were isolated from peripheral blood samples, as described previously by Ficoll Hypaque centrifugation (Van Seusechem et al., 1992). Circulating T- and B-cells were purified from PBMC by sorting CD2 and CD20 positive cells, respectively. FITC labeled CD2 (clone S 5.2; Becton-Dickinson, California) or CD20 (clone L27; Becton-Dickinson, California) antibodies were incubated with PBMC according to the manufacturers protocols. Labeled cells were separated using the MACS® column and anti-FITC beads (Miltenyi, Germany) according to the manufacturers protocol. Re-analyses of the sorted cells on FACS® (Becton-Dickinson, USA) showed that the sorted cells were more then 95% pure populations.
Colony-Forming Cell (CFU-C) Assay
Rh912B and Rh9170 hemopoietic cells were plated in duplicate at 5×10 3 /ml (CD34 + selected) or 1×10 5 /ml (post-Ficoll) in 1 ml methylcellulose medium, as described in [57], supplemented with 30 ng/ml rhIL-3 and 25 ng/ml GM-CSF. Rh A94 and BB94 hemopoietic cells were seeded for colony formation in methylcellulose medium containing 50 ng/ml SCF, 10 ng/ml GM-CSF, 10 ng/ml IL-3 and 3 U/ml Epo (MethoCult GF H4434, StemCell Technologies Inc, Vancouver, Canada).
Polymerase Chain Reaction
For cell lysis, pellets were incubated (10 7 cells/ml) in nonionic detergent lysis buffer (0.5% NP40, 0.5% Tween 20, 10 mM Tris pH 8.3, 50 mM KCl, 0.01% gelatin, 2.5 mM MgCl 2 ) containing proteinase K (60 mg/ml) at 56° C. for 1 hour, Lysates were then heated at 95° C. for 10 min to inactivate the proteinase K. Two different PCR detections were performed. One was a nested neo R -specific PCR and one was a β-globin specific PCR. The protocol for the neo R -specifiC PCR will be described first. The first amplification was performed on 10 μl lysates in a total volume of 50 μl with 2 U of SuperTaq polymerase (HT Biotechnology, Cambridge, England) in a reaction mix (final concentration: 200 mM each of 2′-deoxyadenosine-5′-triphosphate, 2′-deoxycytidine-5′-triphosphate, 2′-deoxyguanosine-5′-triphosphate, 2′-deoxythymidine-5′-triphosphate (Pharmacia, Roosendaal, The Netherlands), 0.2 μM each of 5′ neo-1 and the antisense primer 3′ neo-2 and the reaction buffer supplied by the manufacturer (HT Biotechnology, Cambridge, England). The nested amplification was performed on 5 μl of the first reaction in a total volume of 50 μl with 2 U of SuperTaq polymerase (HT Biotechnology, Cambridge, England) in a reaction mix (final concentration; 200 mM each of 2′-deoxyadenosine-5′-triphosphate, 2′-deoxycytidine-5′-triphosphate, 2′-deoxyguanosine-5′-triphosphate, 2′-deoxythymidine-5′-triphosphate (Pharmacia, Roosendaal, The Netherlands), 0.2 μM each of 5′ neo-2 and the antisense primer 3′ neo-1 and the reaction buffer supplied by the manufacturer (HT Biotechnology, Cambridge, England). Primers were chosen to selectively amplify the neo R gene.
The primer sequences are:
5′ neo-1: 5′-GGGGTACCGCCGCCGCCACCATGATTGAACAAGATGGATTGC-3′ (SEQ ID NO.1)
5′ neo-2: 5′-TTCTCCGGCCGCTTGGGTGG-3′ (SEQ ID NO.2)
3′ neo-1: 5′-GGCAGGAGCAAGGTGAGATG-3′ (SEQ ID NO.3)
3′ neo-2: 5′-CCATGATGGATACTTTCTCG-3′ (SEQ ID NO.4)
Amplification conditions were the same for the first and the nested amplification and were performed in a TRIO thermocycler (Biometra, Göttingen, Germany) temperature cycling apparatus, The conditions chosen were: 95° C. for 5 minutes, then 30 cycles of 94° C. for 30 seconds, 55° C. for 30 seconds, 72° C. for 1 minute, followed by extension at 72° C. for 10 minutes. Five to ten microliters of the nested reaction were separated on 2% agarose gel (Pronarose, Hispanagar, Burgos, Spain). Each assay included titrations of a murine erythroid leukemia cell line C88-C1, containing a single provirus integration of IG-CFT [21] and/or a titration of a pool of G418 selected MEL cells infected with IG-CFT*. For practical reasons, we developed an alternative PCR method to detect the neo-cassette in the rAAV-vectors IG-CFT, IG-CFT* and IG-ΔMo+NEO. The sequences of the primers were as follows; NEO-1S: 5′-TAGCGTTGGCTACCCGTGAT-3′ (SEQ ID NO5), and NEO-4AS: 5′-TGCCGTCATAGCGCGGGTT-3′ (SEQ ID NO.6). Reaction mixtures were prepared as described above and the reaction temperature was 95° C. for 3 minutes followed by 30 cycles of 95° C. for 30 seconds, 65° C. for 30 seconds and 72° C. for 1 minute. The completion of the 30 cycles was followed by an extension of 5 minutes at 72° C. Five to ten microliter of the PCR-reaction was run on a 2% agarose gel, blotted and hybridized to a 157 bp. specific probe isolated from a BstBI-SmaI digest of IG-CFT.
The β-globin specific PCR was carried out in essentially the same way as the first reaction of the neo R -specific PCR. But instead of the neo R -primers, the primers listed below, specific.for the 3′ part of the HS-2 fragment and β-globin intron I, were added. The sequences of the primers are:
HS-2-S3 5′-GGAATTATTCGGATCTATCGAT-3′ (SEQ ID NO.7)
IVS-1A-A 5′-TCCTTAAACCTGTCTTGTAACC-3′ (SEQ ID NO.8)
The temperatures for the cycling were: 95° C. for 3 minutes and then 30 cycles of 95° C. for 30 seconds, 55° C. for 30 seconds, 72° C. for 30 seconds. Following the 30 cycles, an extension at 72° C. for 5 minutes was performed. Samples were run on 2% agarose gels, which were blotted and hybridized to a NcoI-ClaI β-globin promoter specific probe using standard techniques.
Hemopoietic Data of the Transplantation of Rhesus Monkeys with rAAV-Transduced BMC
The survival and the selection of the purification and transduction procedure of CD34 + rhesus monkey bone marrow cells was controlled by determining the number of CFU-C present at different stages in the procedure. The CD34 selection for Rh9128 and Rh9170resulted in a 13-19 fold enrichment of CFU-C resp. For A94 and BB94, the enrichment for CFU-C was 37-92 fold resp. (table 4). The number of CFU-C did not vary by more then a factor of 2 during culture or upon transduction, with the exception of monkey BB94 where the decrease in the number of CFU-C was considerable upon culture and infection with IG-CFT. This was due to a direct toxicity of the CsCl purified IG-CFT batch, as determined by a titration of the batch on human cord blood post ficoll bone marrow which resulted in a dilution factor dependent toxicity on CFU-C (not shown). Since it is known that CsCl is a very toxic substance, we determined the CsCl concentration in the two Cscl purified rAAV preparations. Both contained considerable amounts of CsCl, enough to account for the observed toxicity (table 2). Due to the observed toxicity on CFU-C in this experiment the two grafts that Rh-BB94 received were very different in size. Whereas the cultured graft wasostill considerable, the graft-size for the short transduction protocol was very small (table 4). However, since stem cells are not measured in a CFU-C assay and are indeed more resistant to a large variety of drugs and agents, it is possible that many of them survived the high concentration of CsCl.
Detection of rAAV Transduced Peripheral Blood Cells
To determine whether the engrafted cells had been transduced by the recombinant AAV vectors, approx. 3 ml of blood was collected each week from every monkey. Granulocytes and mononuclear cells were purified, as described in (57), and the DNA was released and analyzed by PCR for the presence of rAAV-sequences. Two different PCR reactions-were performed. On the samples from all four monkeys, PCR reactions specific for the neo R -gene were performed. The neo R -gene is present in all the vectors, so this PCR detects all recombinant AAV-genomes present in the cells. On the samples from monkeys rh-A94 and rh-BB94, also a β-globin specific PCR was performed. This PCR utilizes the size difference in the β-globin promoter in vectors IG-CFT and IG-CFT*. These vectors were used to transduce the P-PHSC via two different protocols, The effect of the two different protocols can thus be read out by the prevalence of one of the two vectors in the peripheral blood cells of the monkeys.
The results of the neo-PCR are depicted in FIGS. 2 and 3. All monkeys were negative for rAAV before transplantation and became positive for rAAV after transplantation. The presence of the vector varied from week to week. Some samples were positive for the vector, others were negative, indicating that the frequency of transduced cells averaged around the detection limit of the PCR-reaction which was determined to be at 1 copy in 10 5 nucleated cells for the neo-specific PCR. Monkey BB94 was positive in all samples immediately after transplantation and regeneration of the hemopoietic system, indicating a more efficient transduction of early progenitors during the ex vivo handling of the cells.
In monkeys BB94 and 9128, vector containing cells could be detected for at least more then one year after transplantation. Bone marrow samples taken from these animals at 2 and 6 months (9128) or 14 months (BB94) post transplantation also contained vector transduced cells. In BB94, the vector was detected in PBMC, granulocytes, bone marrow and purified populations of B- and T-cells (FIG. 4 ). This result demonstrated the transduction of stem cells which had repopulated both the myeloid lineage (granulocytes) and the lymphoid lineage (T- and B-cells). The granulocytes, T cells, and B cells were still PCR positive more than 15 months post-transplantation, indicating the transduction of cells with extensive self-renewal capacity, The transduction of primate cells with (1) an extremely long-term in vivo stability after transplantation, and (2) the capability of multiple-lineage repopulation long after transplantation, provides strong evidence for transduction of P-PHSC.
Rhesus monkey 9128 received treatments with taxotere, a cytostatic drug, to ablate the mature cells in the circulation, inducing periodic regrowth from immature hemopoietic cells residing in the bone marrow. Recombinant AAV transduced cells were detected in circulating cells fter a series of treatments with taxotere, over a period of 14 months post transplantation. The persistence of transduced cells in peripheral blood cells and the resistance to taxotere treatment provides convincing evidence of the transduction of P-PHSC.
Determination of Most Efficient Transduction Protocol
The experiment with monkeys BB94 and A94 was designed to quantify the success of two different transduction protocols. For each monkey, the transplant was split in two equal fractions and each fraction was transduced in a different way. To be able to discriminate which protocol resulted in a better transduction, we used a different vector for each transduction. We compared the efficiency of transduction of cultured P-PHSC versus that of non-cultured P-PHSC. For the transduction of P-PHSC from monkey BB94, we used the purified virus IG-GFT for the non-cultured P-PHSC and the purified virus IG-CFT* for the cultured P-PHSC. To exclude a possible role of quality differences between the virus batches, we switched the two virus batches for the transduction protocols for monkey A94; we used IG-GFT for its cultured P-PHSC and IG-GFT* for its non-cultured P-PHSC. Following transplantation and repopulation of the. hemopoietic system of the monkeys, we performed the β-globin specific PCR to determine which transduction procedure resulted in the highest frequency of gene modified circulating cells. For both monkeys, we were able to detect only the virus used to transduce the cultured P-PHSC, i.e., IG-GFT* for monkey BB94 and IG-GFT for monkey A94 (FIG. 5 ). Thus, in vitro stimulation of P-PHSC results in a more efficient transduction with recombinant AAV vectors. This result was not expected. It is generally accepted that culture of P-PHSC promotes progressive loss of the grafting potential of the P-PHSC, presumably due to differentiation. Hence, if both procedures resulted in similar P-PHSC transduction efficiencies, we would expect the progeny of the non-cultured P-PHSC co prevail among the circulating blood cells due to grafting advantages. Since we observed the opposite, the stable transduction efficiency of the cultured P-PHSC must be significantly higher than that of the noncultured P-PHSC. It is known that AAV-vectors integrate with higher efficiency in cycling cells then in non-cycling cells (38) However, in non-cycling cells the vector remains in the nucleus and retains its ability to integrate when the cell is triggered into cycle (60). Once transplanted, the P-PHSC start to divide and repopulate the ablated hemopoietic system. Considering the enormous amount of cells that need to be produced in a short time, it is presumed that the P-PHSC start to divide within a couple of days once inside the body. Therefore, a difference in transducibility of cultured versus non-cultured cells is not expected when only replication of the target cells is the enhancing factor. We infer that culture and exposure to hemopoietic growth factors such as IL-3 could in other ways potentiate the transduction with recombinant AAV. One possible explanation is the up-regulation or activation of receptors for the virus on the surface of the P-PHSC. Another is the induction of proteins inside the P-PHSC that enhance for instance nuclear transport and/or other rate limiting steps for stable transduction.
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TABLE 1
Amphotropic
AAV
Retrovirus
Vector design
Maximum insert size
4.5 kb
8 kb
Intron compatible
Yes
Poor
Vector transcription in packaging cell
Not required
Should be high
Hemopoietic host range
Murine in vitro CFU
Yes a
Yes b
Murine PHSC
Not yet reported
Yes c
Human in vitro CD34 + CFU
Yes d
Yes e
Human in vivo longlived progenitors
Not yet reported
Yes f
Provirus integrity
Point mutations per viral genome*
0.005
1
Recombination frequency
Insert-dependent
Insert-
dependent
Virus production
Crude titers
10 5 g
10 7 h
Concentrated titers
10 10 i
10 8 j
Helper free stocks
Yes
Yes
Properties of adeno-associated virus and amphotropic retrovirus vectors. *Calculated number per replication cycle. AAV is replicated via cellular DNA-polymerases which have proof reading activity. The error frequency of these polymerases is 10 −6 implying 1 point mutation per 200 recombinant AAV genomes. Retroviruses are replicated via RNA-polymerase II and reverse transcriptase (RT). The known error frequency of RT is 10 −4 . Not
# much is known about the mutation rate of RNA-polymerase II. Based on the error frequency of RT one can expect one point mutation per retroviral genome of 10 kb. a [Srivastava, 1993]; b [Joyner, 1983]; c [Einerhand, 1992 #109 ]; d [Chatteryee, 1992]; e [Nolta, 1992]; f [Brenner, 1993]; g [Walsh, 1992]; h [Miller, 1992]; i [Flotte, 1993];
# j [Kotani, 1994; Lynch, 1991].
TABLE 2
Trans-
Adeno-
Infectious
ducing
wtAAV
virus
CsCl
rAAV
Purifi-
Particles
Particles
titer
ts149
(mg/
vector
cation
(IP/ml)
(TP/ml)
(IP/ml)
pfu/ml
ml)
IG-CFT
Crude
2 × 10 6
10 4
4.5 × 10 4
<10 4
N.D.
IG-ΔMo-
Crude
2 × 10 7
10 3
<10 3
N.D.
N.D.
Neo
IG-CFT
CsCl
10 9
3.3 × 10 5
10 9
<10 4
64
IG-CFT*
CsCl
3 × 10 8
3.3 × 10 4
3 × 10 9
<10 4
44
TABLE 2
Trans-
Adeno-
Infectious
ducing
wtAAV
virus
CsCl
rAAV
Purifi-
Particles
Particles
titer
ts149
(mg/
vector
cation
(IP/ml)
(TP/ml)
(IP/ml)
pfu/ml
ml)
IG-CFT
Crude
2 × 10 6
10 4
4.5 × 10 4
<10 4
N.D.
IG-ΔMo-
Crude
2 × 10 7
10 3
<10 3
N.D.
N.D.
Neo
IG-CFT
CsCl
10 9
3.3 × 10 5
10 9
<10 4
64
IG-CFT*
CsCl
3 × 10 8
3.3 × 10 4
3 × 10 9
<10 4
44
TABLE 4
Time in
CD34 +
CFU-C
Graft-size
Reticulocyte
Rhesus
Virus
culture
Cells
per 10 5
in CFU-C
regeneration
monkey
rAAV-vector
stock
(days)
(×10 5 )
Cells
(×10 3 )
date
9170
—
—
0
100
1520
IG-ΔMo-Neo
Crude
4
50
1480
74
IG-CFT
Crude
4
50
900
45
22
9128
—
—
0
18
940
IG-ΔMo-Neo
Crude
4
9
1860
16
IG-CFT
Crude
4
9
1400
12
24
BB94
—
—
0
40
12000
IG-CFT*
CsCl
4
40
2000
75
—
—
0
20
16000
IG-CFT
CsCl
0
20
80
1.5
22
A94
—
—
0
6
12
IG-CFT
CsCl
4
6
23
130
—
—
0
2
21
IG-CFT*
CsCl
0
2
17
34
25
10
1
42
DNA
Artificial Sequence
Description of Artificial Sequenceneo specific
primer
1
ggggtaccgc cgccgccacc atgattgaac aagatggatt gc 42
2
20
DNA
Artificial Sequence
Description of Artificial Sequenceneo specific
primer
2
ttctccggcc gcttgggtgg 20
3
20
DNA
Artificial Sequence
Description of Artificial Sequenceneo specific
primer
3
ggcaggagca aggtgagatg 20
4
20
DNA
Artificial Sequence
Description of Artificial Sequenceneo specific
primer
4
ccatgatgga tactttctcg 20
5
20
DNA
Artificial Sequence
Description of Artificial Sequenceneo specific
primer
5
tagcgttggc tacccgtgat 20
6
19
DNA
Artificial Sequence
Description of Artificial Sequenceneo specific
primer
6
tgccgtcata gcgcgggtt 19
7
22
DNA
Artificial Sequence
Description of Artificial Sequencebeta-globin
specific primer
7
ggaattattc ggatctatcg at 22
8
22
DNA
Artificial Sequence
Description of Artificial Sequencebeta-globin
specific primer
8
tccttaaacc tgtcttgtaa cc 22
9
53
DNA
Homo sapiens
9
acatttgctt ctgacacaac tgtgttcact agcaacctca aacagacacc atg 53
10
55
DNA
Homo sapiens
10
acatttgctt ctagacacaa ctggtgttca ctagcaagct taaacagaca ccatg 55
| 1a
|
BACKGROUND AND SUMMARY
[0001] Blackberries are a well-known, aggregate fruit enjoyed by many throughout the world. One example of an existing blackberry variety is “APF-8”, which is marketed as “Prime Jan®”, U.S. Plant Pat. No. 15,788. Other examples of existing, patented blackberry varieties are “Navaho”, U.S. Plant Pat. No. 6,679 and “APF-12”, U.S. Plant Pat. No. 16,989 which is marketed as “Prime Jim®”.
[0002] Compared to APF-8 based on some typical results, the present cultivar, Camila (also known as “HFM-5”), and APF-8 are both primocane-fruiting blackberries, but Camila bears fruit on primocanes about one (1) week earlier than APF-8. In addition, plants of Camila have a slightly lower density of spines on the stems and the growth rate is somewhat less than that of APF-8. The fruits of Camila are much sweeter, with higher firmness, have almost no bitter aftertaste and have less acidity than APF-8. The average degrees Brix (° Bx) and percent acidity of the juice of primocane fruits of Camila is 15.1° Bx and 0.7%, respectively, versus 9.8° Bx and 1.3% for primocane fruits of APF-8. The postharvest quality of primocane fruits of Camila is also higher than that of the primocane fruits of APF-8: After seven (7) days storage at 5° C., the primocane fruits of Camila are firmer than those of APF-8 with only 27% of berries of the former showing leaking juice, versus 60% leaking fruits in the case of APF-8.
[0003] Compared to Navaho based on some typical results, the present cultivar, “Camila”, bears fruits on both floricanes and primocanes, whereas Navaho bears fruits only on floricanes. Accordingly, the following comparisons to Navaho involve floricane fruit of Camila. The vegetative growth of Camila is considerably more vigorous than that of Navaho. The canes of Camila are erect, thick and thorny, whereas those of Navaho are semi-erect, thin, and thornless. Floricane fruits of Camila are 5.9 g and 2.8 cm long versus 3.0 g and 1.5 cm for Navaho. The fruit of Camila matured four (4) weeks earlier than those of Navaho; the date of first ripening of Camila in Central Chile is week 49 versus week 1 for Navaho.
[0004] The present cultivar, Camila, provides one or more advantages compared to these and/or other blackberry varieties such as one or more of an early maturity and better blackberry fruit for at least some purposes.
BRIEF DESCRIPTION OF THE PHOTOGRAPHS
[0005] FIG. 1 is a photograph showing primocane flowers of the Blackberry cultivar “Camila”. This photograph was taken on 22 Mar. 2012 (in Chile).
[0006] FIG. 2 is a close-up photograph of a primocane shoot of the Blackberry cultivar “Camila” showing primocane color and spine density. This photograph was taken 21 Mar. 2012 (in Chile).
[0007] FIG. 3 is a close-up photograph of primocane fruits. This photograph was taken 16 Feb. 2012 (in Chile).
DETAILED DESCRIPTION
[0008] Note: statements of characteristics herein represent exemplary observations of the cultivar herein and will vary depending on time of year, location, annual weather, etc. Where dimensions, sizes, colors, and other characteristics are given, it is to be understood that such characteristics are approximations and averages. The descriptions reported herein are generally from specimen plants that were planted in August 2008 and later at Nogales, Fifth Region, Chile.
Cultivar name: “Camila” Classification:
Family.— Rosaceae. Botanical name.—Rubus subgenus Rubus. Common name.— Blackberry.
Parentage: Note: The parents and Camila have not been evaluated side-by-side. The data about Camila is from Chile and the data for the parents are from Arkansas, USA. Female parent: Name: Name: APF-77 (proprietary, and marketed under the trademark Black Magic™) U.S. Plant patent application (13/374,444) filed 29 Dec. 2011. Comparing APF-77 grown in Arkansas to Camila grown in Chile, the average floricane berry weight of APF-77 is 6 to 7 grams compared to 5.9 grams for Camila. Floricane first bloom date and first ripe date for APF-77 appear to be about a week to 10 days earlier compared to Camila: the floricane first bloom date for APF-77 is 1 April (Northern Hemisphere) versus 10 October (Southern Hemisphere) for Camila while the first ripe date for APF-77 is 2 June versus 8 December for Camila. The first primocane bloom date for APF-77 is 10 June (Northern Hemisphere) compared to 20 December for Camila (Southern Hemisphere), and the first primocane ripe fruit are 15 July (Northern Hemisphere) for APF-77 compared to 10 February (Southern Hemisphere) for Camila. Soluble solids in primocane fruit of Camila is 10.2° Brix compared to 15.1° Brix for APF-77. Male parent: Name: APF-109T. U.S. plant patent: unpatented. Comparing APF-109T grown in Arkansas to Camila grown in Chile, APF-109T is thornless and has a smaller berry than Camila: floricane berries for APF-109T average 4.4 grams versus 5.9 grams for Camila berries. The harvest window appears to be similar or perhaps Camila would be slightly earlier: the window is about 16 June (Northern Hemisphere) for APF-109T compared to about 8 December for Camila (Southern Hemisphere). The soluble solids of Camila are higher: 11.3° Brix for Camila compared to 9.2° Brix for APF-109T. The cross for Camila was made in 2006 near Clarksville, Ark., USA. It was a controlled hand pollination of the female parent (APF 77)×APF 109T (male parent). Resultant seedlings were germinated in a nursery near Hijuelas, Fifth Region of Valparaiso, Chile during the southern hemisphere summer of 2006-07. 285 individual seedlings from this cross were planted in the field near Nogales, Fifth Region of Valpariso, Chile between December 2007 and January 2008. The first evaluation of these seedlings was in early summer (November) 2008 and continued through April 2009. The selection that became Camila was selected in 2009 because the seedling stood out for its very good flavor and the early maturity on primocanes. Camila was first asexually propagated by planting root pieces horizontally in containers containing a bark/peat mix in August 2009 in a greenhouse in Macul, Santiago, Chile. Etiolated shoots that emerged from the root pieces were put in a peat/perlite mix and rooted under humid conditions (covered by clear polyethylene plastic). Camila has also been asexually reproduced using in vitro culture. Propagated plants have retained the original characteristics. Field observations were made in 2009 and later, mostly in Nogales, Chile, including evaluation over three primocane fruiting cycles and two floricane fruiting cycles between January 2009 and April 2011. Camila consistently showed above average horticultural traits and was consistently at the top for taste tests for flavor. For firmness readings, firmness was ranked by on a scale of one to five, with 1 being very firm, and 5 being very soft. General description: The Camila blackberry is characterized for its early fruit maturity, both on floricanes and on primocanes. The floricane crop begins to ripen during the first week of December (Central Chile). The primocane crop begins to ripen during the second week of February (Central Chile). The fruit has very good (sweet) flavor. The fruit is additionally quite attractive and is elongate and large. Fruit firmness is not very high, but its postharvest keeping ability is acceptable and it shows minimal color change (to red) of the drupelets when put in cold storage. The plant is healthy, moderately vigorous, and productive. Camila is a thorny variety. Average size information: in the study, plants were “pinched” during growth, so they were not allowed to grow freely. It is estimated that if not pinch-pruned, the primocanes would reach between about 1.7 and 2.2 m in height. Growth: Plants have medium vegetative vigor, and erect growth habit. Camila makes abundant canes, with primocanes emerging both from the crown of the plant as well as from the roots (as suckers). Growth rate: The growth rate is moderate, with canes reaching an average of 0.8 meters in height within one month of emergence from the soil in the spring. Productivity: High, yields average 2.0 kg and 2.9 kg of fruit per meter of row, on the floricane and on the primocane cycles, respectively. Cold hardiness: Ultimate cold hardiness is unknown, but in Chile dormant plants have resisted midwinter lows of −3° C. without damage. Branching height of the plants: Unknown (they are always pinched to induce branching and never left to grow to their own devices). Canes: General description: Erect, thorny, and medium vigor. Cane diameter (indicate point of measurement): Floricane:
Base.— 1.31 cm. Midpoint.— 1.04 cm. Terminal.— 0.45 cm.
Immature primocane:
Base.— 0.86 cm. Midpoint.— 0.67 cm. Terminal.— 0.33 cm.
Mature primocane:
Base.— 1.25 cm. Midpoint.— 0.84 cm. Terminal.— 0.40 cm.
Internode length:
Base.— 11.44 cm. Midpoint.— 7.68 cm. Terminal.— 5.01 cm.
Thorn density/30 cm:
Base.— 21. Midpoint.— 15. Terminal.— 10.
Primocane color:
Base.— Light green. Midpoint.— Light green. Terminal.— Light green.
Floricane color:
Base.— Green with brownish spots. Midpoint.— Green with brownish spots. Terminal.— Green with wine-colored spots.
Date of primocane emergence: Primocanes emerge during the first weeks of October (in Chile, at 32° 45′ S. Lat., 220 m elev.) and continue emerging until the second week of November. Date of budbreak: Vegetative budbreak occurs during the second week of September (in Chile at 32° 45′ S. Lat., 220 m elev.). Foliage: General description: Leaves are green with 3 to 5 leaflets, leaves are large with double-serrate margins. The adaxial side of each leaflet is dark green with the veins being somewhat more yellowish. The abaxial side is lighter green than the adaxial side, with soft trichomes (indumentum) over the entire surface. The petioles and petiolules of each leaflet have one rank of thorns, which extend up ¼ of the length of the central vein of each leaflet. Leaves:
Width.— 16.85 cm. Length.— 20.13 cm (including petiole). Number of leaflets.— 3 to 5 per leaf.
Leaflet:
Width.— 5.23 cm. Length.— 9.46 cm (including petiolules). Margin.— Doubly Serrate. Shape.— Cordate with acuminate tips. Color.— Base Adaxial: Green with the central vein of lighter green color. Base Abaxial: Lighter green than the adaxial side, the central vein being even lighter green with a yellowish cast. Midpoint Adaxial: Green, veins of the same color and shade. Midpoint Abaxial: Green, but of a lighter shade than the adaxial side, yellowish colored veins. Terminal Adaxial: Light green, with the veins being the same color and shade. Terminal Abaxial: Light green, but a lighter shade than the adaxial side, with the veins being the same color.
Petioles:
Length.— 10.25 cm. Color.— Light Green (with a yellowish cast).
Petiolules:
Length.— 1-4 cm. Color.— Light Green (with a slightly yellowish cast).
Flowers: Primocane:
Date of bloom.— (Central Chile). 10% bloom: 20th of December 50% bloom: 30th of December Last bloom: 2nd week of January.
Petal color: Pure White Reproductive organs:
Stamens.— The stamens are long, erect, and numerous. Pistils.— Numerous. Pollen.— Fertile and abundant. Ovary.— Superior.
Flower diameter: 3-4 cm. Petal size:
Width.— 1.2 cm. Length.— 1.8 cm.
Average number flowers per cluster: 6-7 Average number of petals per flower: 5-9 Peduncle length: 3.58 cm Peduncle color: Green Floricane: there are no material differences noted for flower dimensions and inflorescence characteristics for floricanes compared to primocanes, but bloom times for floricanes are: Date of bloom: (Central Chile)
10% bloom.— 10th of October. 50% bloom.— 20th of October. Last bloom.— Last week of October.
Fruit: General description: The fruit of Camila stands out for its good flavor, large size, and low rate of color regression (to red drupelets) in post-harvest storage. The ratio of soluble solids to acidity averages 19 on floricane fruits and for primocane fruits, the ratio averages 23 (both values on plants grown at the experimental plot at Nogales, Chile). On both the floricane and primocane fruits there is no noticeable bitter aftertaste that is typical of eastern blackberries. The level of reversion of drupelets to a red color in postharvest storage (5° C.) is low. The fruits have an attractive appearance. They are elongated in shape and large in size. The firmness is medium, but it is acceptable. Primocane: Average first ripe date: 10th of February (for plants grown under shade cloth at 50% shade) at Nogales, Fifth Region of Valparaiso, Chile. This ripening date is seven (7) days earlier than APF-8 under the same conditions. The primocane harvest lasts for approximately 50 days. Size: Large (8.4 g on average) Diameter:
Equator.— 2.05 cm. Base pole.— 2.11 cm. Terminal pole.— 1.92 cm.
Length: 3.01 cm Shape: Oblong (Elongate) Drupelet size: Medium (0.42 cm average) Seed size: Small Firmness: medium Flavor: Very good, sweet, without bitterness Soluble solids: 15.1° Bx pH: Not measured Acidity: 0.7% Processed quality: Not evaluated Uses: Fresh Market Prickles: None Floricane: Average first ripe date: 8th of December (for plants grown under shade cloth at 50% shade) at Nogales, Fifth Region of Valparaiso, Chile. This date is approximately 35 days before Navaho. The floricane harvest lasts for about 35 days. Size: Medium (5.9 g on average). Diameter:
Equator.— 2.03 cm. Base pole.— 21.4 cm. Terminal pole.— 1.84 cm.
Length: 2.85 cm Shape: Oblong (Elongate) Drupelet size: Medium, 0.39 cm Seed size: Small Firmness: Medium, similar to the blackberry cultivar APF-12 but firmer than APF-8 Flavor: Sweet and very good flavor Soluble solids: 11.3° Bx pH: Not measured Acidity: 0.6% Processed quality: Not evaluated Uses: Fresh Market Prickles: None
[0141] Thus, in some aspects, the Camila blackberry is characterized by having early ripening both on floricanes and primocanes. The fruits themselves are also distinctive in that they have excellent flavor, large size, elongated shape and are visually attractive. Furthermore, the fruits have a low rate of color reversion (to red) in cold storage. The plant has good vigor and high productivity. Fruit characteristics are similar on both primocanes and floricanes, except that primocane fruits are sweeter, have higher yields, and are larger than the floricane crop.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a corn sterilizing machine.
2. Description of Background and Relevant Information
When a farmer produces seed corn, it is usually obtained by hybridization of two varieties.
The rows of one variety are alternated with those of another variety which are to fertilize the first variety.
Therefore, it is essential to remove the male elements from the variety which is to be fertilized by the second variety. The male elements are situated in the upper part of the seedling and should be removed when they appear.
Until now, this "castration" has been performed manually. Recently, there has been use of machines comprising rotary knives with vertical axes which cut off the upper part of the plant carrying the male elements and which, therefore, work like a lawnmower.
Since the panicle that has the elements to be removed is usually interwoven with the upper leaves of the seedling, the current machines, because of the way they work, cut off an important part of the greenery, which greatly harms later development of the corn seedling.
SUMMARY OF THE INVENTION
The present invention, which presents a solution to this drawback, is noteworthy in that for each row of corn to be treated, it comprises a castrating head comprising a case open toward the front, enclosing a rotary blade whose axis is approximately perpendicular to the stem of the plant and extends toward the forward direction of the machine. The ends of the blade are bent in a right angle to form two knives which cut off the upper part of the plant in a transversal direction in the forward direction of the machine.
BRIEF DESCRIPTION OF THE DRAWINGS
Other characteristics will become clearer from the following description with reference to the attached drawings, as an example only:
FIG. 1 is an elevational view of a castrating head according to the invention;
FIG. 2 is a left-hand view of FIG. 1;
FIG. 3 is a top view of FIG. 1;
FIG. 4 is a partial view in perspective showing one embodiment of a machine according to the invention;
FIG. 5 is a view along F of FIG. 4 showing the possible use of the machine on sloping terrain;
FIG. 6 is a top view of FIG. 5;
FIG. 7 is a partial view on a larger scale and in perspective showing details of the embodiment;
FIG. 8 is a partial view in cross section on a vertical plane passing through the axis of the rotary blade and showing the setting of the case.
DESCRIPTION OF PREFERRED EMBODIMENTS
In referring to the drawings, it can be seen that in its simplest form, each castrating head comprises a case 1, presenting on its front side 2 an opening 3, and enclosing a severing device in the form of a blade 4 mounted on a shaft 5 whose axis extends to the plane of the row to be treated approximately perpendicular to the stems of the corn seedlings M.
Blade 4 is bent in a right angle at its ends to form two knives 6. Its axis extends onto the plane of the row to be treated approximately perpendicular to the stems of corn.
The vertical edges of opening 3 each present a shutter in two parts 7a and 7b, each of which is substantially planar. Part 7b is fastened onto 7a which can pivot on an approximately vertical axis 26 and can be immobilized at the required angle by mechanism 27 as shown in FIGS. 1 and 2.
Shutter 7b which is approximately shaped like a triangle is arranged so that one of its sides is approximately vertical and is journalled about a substantially vertical axis at element 28 toward the lower end of this side on shutter 7a.
In this manner, the two other sides 8 and 9 form two adjustable upper and lower ramps respectively.
The function of ramps 8 is to straighten panicle P to be cut as well as the leaf in which it is located in order to facilitate their introduction into case 1.
On the other hand, the function of ramps 9 is to bend down the underlying leaves so that they will not enter the case.
It is thus possible to cut off the panicles comprising the male elements without altering in an undesirable manner the greenery of the corn seedling.
According to an embodiment particularly applicable to machines carried by a tractor equipped with a slope correction system, the heads are affixed on bars 10 joined by journalled links 11 between them.
Each one of bars 10 is supported by the end of a pair of arms 12 journalled by its other end on an upright 13 affixed to the tractor vehicle (not shown) and which is able to pivot on an approximately vertical plane because of the action of jack 14.
Each one of bars 10 can pivot by the interposition of a shaft 15 on a plane perpendicular to that formed by arm 12 and corresponding upright 13.
Therefore, as shown in FIG. 5, if the rows of corn to be treated are located on a slope, it is possible, by careful adjustment of the angle of arms 12, to keep all castrating heads approximately equidistant from the ground. As shown in FIGS. 4 and 7, a movable parallelogram linkage connecting assembly is formed by a pair of arms 12, a respective upright 13, and a relatively short arm 12a which is movable, while remaining substantially perpendicular to the ground.
The rotary driving of blades 4 is achieved by the interposition of a hydraulic motor 16 mounted at the end of one of shafts 5. The movement is transmitted to the other blades by belts, such as 17 (FIG. 4).
Each one of cases 1 is linked to guides 18 each supported by a shank 19 that can slide and be immobilized in a catch of holder 20 affixed to the case.
The function of these guides is to straighten the seedling, which would have pushed obliquely in its row on a transversal plane. This makes it possible to guarantee that it will be possible to introduce its panicle into slot 3 of the corresponding head.
Although the supporting rods 10 can be bent horizontally, it is essential that slots 3 of the heads remain vertical.
For this purpose, a further linkage assembly is provided. Each one of cases 1 can freely pivot around the axis of shaft 5 by the driving of the blade by the interposition of link 21, journalled at one of its ends onto the end of a clamp 22 of case 1, and at the other onto axis 23 parallel to shaft 5 and affixed to mobile side 12a of the deformable parallelogram comprising corresponding arms 12.
FIG. 8 is an example of a way to link case 1 to bar 10. Thus, shaft 5 extends through bearing 24 externally comprising a shoulder on which the rear side of case 1 is engaged, which is held by plate 25.
The present invention is, of course, not limited to the embodiment described and shown, but rather extends to all varying shapes and sizes.
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FIELD OF THE INVENTION
The present invention relates to a holder for securely holding two or more cutting boards wherein the cutting boards held are all visible within the holder and may be designated for use with specific classes of food products.
BACKGROUND OF THE INVENTION
Preparation of food items often requires a preparation step in which a food item is cut using a knife or other sharpened kitchen tool. The preparation step may involve cutting a serving portion from a larger portion of a food item, such as a slice of cooked meat product. The preparation step may alternatively involve preparation of multiple smaller size pieces from a food item, such as a vegetable, by an operation such as chopping, dicing, or slicing.
These steps may be carried out on a counter top or other flat permanent surface in a kitchen or other food preparation area. These steps may also be carried out on flat temporary surfaces referred to as cutting boards. The use of cutting boards allows for the cutting, chopping, etc. to be accomplished in many areas of the kitchen while protecting permanent surfaces from disfiguration from cutting tools or from fluids released from a food item during the processing step. The use of the cutting board may also assist in the transfer of the food item to a cooking vessel. Finally, cutting boards are susceptible of being cleansed in a dishwasher allowing for convenience in cleaning after food preparation and potentially reducing risk from microbial hazards.
Despite their convenience, cutting boards may present a health risk if not properly cared for and cleansed. Raw produce may present various bacterial pathogens such as Shigella sp., E. coli sp. (including E. coli 0157H7), Salmonella sp. and viral pathogens such as Hepatitis A. The levels of these pathogens on produce can often be reduced to a level that will not affect most individuals by rinsing affected produce with fresh water shortly before serving. However, residual amounts of pathogen may be transferred to a surface where produce is placed in the food preparation process such as a cutting board. Proper cleansing of the surface can prevent any pathogen so deposited from contaminating other foods.
In the case where surfaces are not cleansed properly, pathogens may be transferred to other foods that are prepared on the same surface. This cross contamination of foods is particularly an issue where the food that is contaminated is stored in a way that allows the pathogen in the contaminated food to multiply to the point where it can cause illness in a person consuming the contaminated food.
Raw meat and processed meat products may present bacterial pathogens such as E. coli (including E. coli O157:H7), Salmonella sp., Campylobacter jejuni and Listeria monocytogenes . Careful preparation of raw meat and processed meat products can prevent these potential pathogens from causing illness as a result of eating the meat or meat product. However, it is important that cutting boards used in preparation of meat and meat products be cleansed properly between uses to prevent cross contamination of food products, thereby further reducing the risk of food-borne illness. It is especially important that pathogens present in meat products that would be killed or inactivated during normal cooking not be transferred to foods that are raw or already cooked.
To prevent this transfer, health authorities, food companies and others recommend having cutting boards dedicated for use with certain types of food products during food preparation. For example, in a kitchen a cook may prepare vegetables, breads, fruits and meats for one meal thereby requiring up to four different cutting boards in the course of preparing a meal. Increasingly, health authorities and food companies also recommend that cutting boards be permanently dedicated to one food type or at the very least food preparers should ensure that a cutting board used to for preparation of raw and processed meats only be used for such foodstuffs.
It would therefore be useful to have a cutting board kit for storage of multiple cutting boards. It would also be useful to have the various dedicated cutting boards permanently labeled to ensure consistent use by all personnel using the same kitchen facility.
SUMMARY OF THE INVENTION
The present invention relates to a cutting board kit having a cutting board holder capable of securely holding two or more cutting boards within. The cutting board holder may secure the cutting boards about the perimeter of the cutting boards and may partially or wholly enclose the cutting boards. The cutting boards may be labeled (for example, “Vegetable”, “Produce”, “Meat”, “Bread”, “Fruit” and the like) to ensure consistent usage by multiple users of the cutting boards. The boards may arranged to allow for selective storage and removal.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top perspective view of a cutting board kit of the invention with a cutting board holder securing four cutting boards in close planar proximity and with a latch on the holder in an open position allowing selective removal of one or more of the cutting boards.
FIG. 2 is a side elevation view of the cutting board kit of FIG. 1 .
FIG. 3 is a top plan view of the cutting board kit of FIG. 1 with the latch in the closed position securing the cutting boards in place.
FIG. 4 is a cutout from FIG. 3 showing the individually labeled cutting boards held within the cutting board holder.
DETAILED DESCRIPTION OF THE INVENTION
The cutting board kit of the invention includes a receiver capable of securely holding two or more cutting boards. Such secure holding allows a user to transport the cutting boards held therein as a single unit. The cutting boards are also held together as a single unit thereby allowing ease of location of cutting boards stored therein. The cutting boards may be removed from the receiver at the time desired by the user.
The receiver may include a frame with a distal wall and side walls attached to the distal wall. The side walls may include grooves to accept sides of the cutting boards and hold the cutting boards in a storage configuration until retrieved by a user of the kit. There may be disposed with the grooves one or more structures to secure the cutting boards in the receiver. These structures may include a ridge extending in a direction substantially perpendicular or perpendicular to the grooves, a rigid protrusion which may be formed during the fabrication process or a deformable protrusion which may be a malleable or a moveable structure, such as a spring loaded protrusion.
The receiver may also have a generally planar bottom surface with a receiving wall capable of contacting each of the cutting boards held within the receiver along three sides of each cutting board. The receiving wall may include two side walls attached perpendicular to the bottom surface, the side walls having proximal and distal ends, a distal wall attached at an obtuse angle to the bottom surface and attached to the distal ends of the two side walls. The bottom surface may have one or more ridges extending upwardly therefrom and running in parallel to the side walls. The one or more ridges may contact one of the cutting boards stored within the receiver. The bottom surface may also have a tab or extension, optionally defining a hole through the bottom surface, that may act as a handle or facilitate storage by hanging the cutting board kit when not in use.
The receiver may include a latch attached to the receiving wall or the frame. The latch may be capable of moving from a closed position in which the latch is capable of securing the cutting boards in the holder to an open position allowing a user to remove or replace one or more cutting boards in the holder. The latch may be pivotably attached to the side walls at or near the proximal ends of the side walls. The latch may cover at least some portion of one of the cutting boards held within the receiver when the latch is in the closed position. The latch may include protrusions capable of contacting and further securing one or more cutting boards in the holder. The latch may be secured in the closed position to prevent unintended exit of cutting boards from the receiver.
The cutting board kit of the invention includes two or more cutting boards. In some cases it may be useful to have a receiver capable of storing three, four, five, six, seven, eight, nine or ten cutting boards at once. The cutting boards may be of any shape susceptible of being held securely within a frame. The cutting boards may be rectangular and of virtually any dimension as may be convenient in food preparation. The cutting boards in any one kit may have the same dimensions or may vary slightly. In one embodiment, the distal wall of the receiver is attached at an obtuse angle with respect to the bottom surface so that cutting boards with the same length may be inserted to varying degrees thus allowing the cutting boards to present an offset configuration when inserted into the receiver. In another embodiment, cutting boards of rectangular shape have the same width, but vary slightly in length thus allowing the cutting boards to present an offset configuration when inserted the same distance into the receiver. The offset allows the user to easily determine which cutting boards are present in the receiver and further allows for selective removal of one cutting board without the need for disturbing the other cutting boards in their places.
The cutting boards may define a hole at one end of the board. The hole may be configured to allow for gripping or manipulation during removal of the cutting board from the receiver. The hole may also be configured to allow the user to grasp or secure the cutting board during use. The hole may also be configured to allow one or more cutting boards stored below the cutting board with the hole to be visible when the cutting boards are held within the receiver.
Cutting boards stored in the present kit may be uniquely identified in a way that allows each cutting board to be permanently dedicated for use with a certain food type. As noted above, permanent dedication of a cutting board to preparation of a given foodstuff may decrease risk of accidental food contamination by foodborne pathogens. For example, the cutting boards may be individually labeled with words the type of foodstuff which may be prepared on the cutting board (e.g. “Meat”, “Fruit”, “Vegetable”, “Bread”) or labeled with symbols portraying various foodstuffs or uses. Cutting boards may also be manufactured using different colors that may be suggestive of the foodstuff to be prepared thereon and that conform to a predetermined code.
Cutting boards may be made of any of number of materials, including molded polymers such as polyethylene (including high density polyethylene) and acrylics as well as wood, metal, glass or other materials. Cutting boards may also have a variety of surfaces and surface configurations that may be suited to or enhance operations in preparation of one or more foodstuffs. In the case of meats, produce and other foods in which liquids are emitted by the foodstuff during slicing or other operations, a cutting board may define a cavity on the food preparation surface to aid in collection of such liquid and preventing such liquid from spilling off of the cutting board.
A user of a cutting board holder according to the present invention may view two or more cutting boards securably stored within the holder. The user may open a latch thus allowing one or more selected cutting boards to be removed. The user may then remove one or more of the selected cutting boards and proceed with one or more food processing steps. Upon completion of the food processing steps or after food preparation is complete, the cutting boards may be cleansed in accordance with their use. For example, a cutting board used to slice bread may need only to be washed lightly with a moistened towel while a cutting board used in preparation of raw meat may be thoroughly cleansed in a dishwasher. Upon completion of the cleansing step, the one or cutting boards may be returned to the holder and securably stored once again in the holder by closing the latch.
Further understanding of the present invention may be gained by reference to the enclosed figures. FIG. 1 shows a cutting board kit of the invention ( 10 ) with four cutting boards ( 22 , 24 , 26 , 28 ) inserted into a receiver ( 12 ). Receiver ( 12 ) comprises rectangular bottom surface ( 32 ) and walls ( 14 , 16 ). Peripheral walls ( 14 ) are generally parallel to each other and contact the periphery of bottom surface ( 32 ) along most of the length of the long sides. Distal wall ( 16 ) is contiguous with distal ends of peripherals walls ( 14 ) and with distal end of bottom surface ( 32 ). Cutting boards ( 22 , 24 , 26 , 28 ) are shown inserted between peripheral walls ( 14 ) and also in contact with distal wall. Latch ( 18 ) is capable of moving from an open position to a closed position. Latch ( 18 ) is shown in an open position in FIG. 1 that allows insertion or removal of cutting boards ( 22 , 24 , 26 , 28 ) into or from receiver ( 12 ). Protrusions ( 20 ) are present on latch ( 18 ) and contact one or more cutting boards when latch ( 18 ) is in the closed position to prevent movement by the cutting boards within the receiver. Cutting boards ( 22 , 24 , 26 , 28 ) may define a cavity bounded by a peripheral wall ( 30 ) in which liquids, crumbs and small portions of food stuffs are retained during use of the cutting board. Variations in the shape of the cavity, the depth of the cavity.
FIG. 2 shows the cutting board kit ( 10 ) of FIG. 1 in a side view with latch ( 18 ) in an open position. Distal wall ( 16 ) is attached to bottom surface ( 32 ) at an obtuse angle, allowing cutting boards of the same length to be presented in a manner allowing selective removal of any of the cutting boards ( 22 , 24 , 26 , 28 ) when latch ( 18 ) is in the open position. Handle ( 34 ) is an extension or tab extending from bottom surface ( 32 ) and defines a hole therethrough.
FIG. 3 shows the cutting board kit of FIG. 1 in a top view with latch ( 18 ) in a closed position. In the present embodiment, latch ( 18 ) in the closed position engages cutting board ( 22 ) to prevent movement thereof.
FIG. 4 shows a cutout view of FIG. 3 showing word labels on four cutting boards ( 22 , 24 , 26 , 28 ) and showing one way in which a portion of each of the cutting boards is visible when the cutting boards are disposed in the receiver and the latch is in the closed position. In this embodiment, each cutting board defines a hole through which the cutting board underneath is visible. Numerous variations on the shape and placement of the hole are possible while still accomplishing the function of allowing the user to easily determine which cutting boards are still held in the receiver, even when the latch is in the closed position.
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BACKGROUND OF THE INVENTION
It is clear to the applicant that high technology is steering people toward solitary forms of entertainment; political discourse has become, in many aspects, predictable and stale; polarization between generational and demographic groups, once a temporary aberration, seems to have become such an immutable part of culture as to make discussion about generational and demographic differences futile. Thus, it is evident that there is a need for a mechanism that will encourage people to entertain in social groups, promote a dialogue about politics and economics, and foster a non confrontational exchange of views about values across generational and demographic groups.
The mechanism that is best suited for this purpose would be card game. A card game is a particularly social form of entertainment. The variation inherent in card games best captures the variation inherent in modern life. The type of card game that would meet the need described would require players to employ many of the skills gained as "players" in modern society in order to compete as players in the game. The choices available in the card game would reflect the various choices available in modern society. The game would sufficiently parody the "rules" of popular culture, economics, and politics such that the participants would have opportunity to learn about the forces and influences that shape modern society. Ideally, the card game would provide entertainment value while at the same time serving as a vehicle for social criticism and commentary. Card games are particularly well suited to fill this need since a card game relies less on chance (there being no dice to roll nor wheels to spin) and card games generally require more demanding strategies than other types of games.
Card Games in a Historic Context, Card games have long been a source of entertainment and a tool for education. Card games reportedly date as far back as the 9th Century when the Chinese Emperor Mu-tsung played a version of domino cards. It is thought that playing cards were introduced into Europe from Egypt. A card game from the region of Mameluks in Egypt, a playing card deck of 52 cards with suits of swords, polo-sticks, cups, and coins, dates to the 14th Century. Card games have not always been well-received. Town ordinances of Paris (1377) and St. Gallen (1379) reportedly prohibited card-play by members of the working class. Religious leaders of Bologna condemned card playing and, in 1423, thousands of cards were burned. This spectacle was repeated in 1452. The earliest known English card games date around 1520, and the earliest surviving English deck (French suited) dates around 1590.
A Description of the Prior Art.
Many different card games present challenges to skill and strategic thinking. Many card games have been proposed that are designed to aid the education process. Card games have been developed to provide an entertaining method for players to understand unwritten rules that govern transactions and commerce. Other card games are designed to encourage discussion of seldom discussed topics. Still other games have been proposed for the improvement of the one-card, one-value style of the standard playing card deck. Other games employ playing cards for fantasy role-playing purposes. The present invention, however, is designed to fill a need that no card game has been developed to address. Specifically, this card game has been invented to provide a means for people of different generations and demographic groups to come together to play a game that entertains; requires skillful value-based strategy decisions; educates players about the unwritten rules that govern our political, economic and political culture; encourages a discussion of issues seldom discussed across generations; and uses an innovative three-value system of cards that reflect different role-playing assignments among the players.
Games associated with the 52-card standard playing cards are those that come most readily to mind when associating card games with skill and strategic thinking. Poker, Bridge, and even such games as "Go Fish" and "Crazy Eights," long in the public domain, challenge players to plan several steps ahead of a current turn in order to succeed. Parker Brothers has marketed a French card game Mille Borne in the United States--a game that requires players to skillfully overcome "Hazard" cards in order to collect exactly 1000 points in "mileage" cards. Another card game, "UNO," requires strategic thinking by players in order to successfully match colors, numbers or words. A more recent game, U.S. Pat. No. 5,092,596, (Bucaria) challenges players to make strategic decisions as relating to owning and running a professional baseball team. Standard playing card games, and games such as UNO, however, fail to hold the public's attention because the strategies employed are designed for the accumulation of card points--points that do not correspond to appetites and wants outside the card game, i.e. the needs and wants that are a part of our everyday life. Strategy games such as that described in U.S. Pat. No. 5,092,596 are deficient because they do not reflect real-life strategies that we all employ as part of surviving in the modern world.
Many other types of card games have been proposed that are designed to aid the education process. Aside from trivia-type games that pose questions and reveal answers, many games have been developed to familiarize players with political issues. For example, United States Patent U.S. Pat. No. 816,119 (Noonan) was designed in part to educate players with about the Electoral College and the political calculus that went into electing a person as President of the United States. U.S. Pat. No. 1,357,166 (Harted) was designed to familiarize players with leaders of World War I. The limitations upon these games are that they are designed primarily to familiarize players with objective names and institutions. These games are not designed to educate players as to how these names and institutions are subjectively perceived by different generational and demographic groups.
Card games have been developed to provide an entertaining method for players to understand unwritten rules that govern various segments of our society. U.S. Pat. No. 1,146,798, (James) was designed, in part, to help educate players to the unwritten rules and procedures that govern the purchase of real estate. U.S. Pat. No. 1,553,736 (Wyle) was created to help educate players about the unwritten rules that govern the trading of stocks and bonds. U.S. Pat. No. 1,855,543 (Dalton) helps to educate players as to the unwritten rules that govern political party conventions. A recently patented game, U.S. Pat. No. 5,632,488 (Strum) is designed to familiarize players with the unwritten rules that go into creating political consensus. The short coming of these games is that they are limited to relatively narrow and specialized segments of our society. They ignore the fact that modern society itself operates by certain unwritten rules that can by captured by the dynamics of a card game.
Card games are powerful tools for communication. They are capable of serving as a mechanism for the discussion of topics that might not be raised among friends, family or strangers. For example, U.S. Pat. No. 1,314,522 (Knoos) was designed to encourage discussion between males and females at social gatherings. U.S. Pat. No. 4,635,939 (Makow), is a game that is designed to encourage the discussion of ethics as applied to various real-world scenarios. U.S. Pat. No. 5,375,846 (Smith) is a game that is designed to encourage a discussion of sexual etiquette and ethics. However, none of these games and no game known to the inventor is designed specifically to encourage members of different generational croups to discuss politics, ethics, values, economics and consumer culture.
As for the mechanics of playing card games, there have been attempts to improve the "one-card, one-value" system as typified in the standard card deck. In U.S. Pat. No. 4,588,193 (Winston) describes an alternative deck of cards that consists of three different suits with four different number values per suit such that every number value of a given suit is paired once with every number value of the other suits. This alternative to the standard card deck proved to be difficult to perfect because it was necessary to maintain a precise mathematic balance among each and every value in order to ensure that the card deck is a "fair" one. This innovation is extremely limited because in the name of preserving "fairness," U.S. Pat. No. 4,588,193 sacrifices expression and flexibility. Specifically, such a card game, determined to preserve the mathematical fairness of the card distribution, cannot reflect the fundamental unfairness, i.e. disparities that exist in our popular culture. Moreover, the system of valuation described by No. 4,588,193 cannot serve an editorial function by applying different values to an object that is featured in the center of the playing card.
Other card games employ playing cards for fantasy role-playing purposes. U.S. Pat. No. 5,092,596 (Bucaria) is a game the allows players to play the role of a major league baseball owner so as to familiarize players about the business aspects of owning and running a major league baseball team. A popular card game called "Magic," produced by Wizards of the Coast, allows players to adopt fictitious roles for battle and treasure-finding purposes. The shortcoming of these games is that the roles that are played out are so removed from the actual experience of the players that the value of these games as tools for education and understanding is speculative. U.S. Pat. No. 5,375,846 (Smith) employs role-playing by players that correspond more directly with experiences in the real world. However, this prior art utilizes real-world role-playing for the important, yet narrowly-defined, purpose of soliciting viewpoints on sexually-related issues such as sexually-related social dilemmas, sexual etiquette, and sensitivity.
Thus, a survey of the prior art reveals that no card game is adequately suited to fill the entertainment, communication, and education purposes envisioned. Thus, it would be necessary to conceive of and create a new, useful, and non-obvious card game that fills the need identified by the applicant.
BRIEF SUMMARY OF THE INVENTION
The present invention meets the need described above. It is a collectible card game that recreates the socializing dynamic of previous art forms, yet does so in a uniquely sophisticated, thought-provoking, contemporary, and dynamic manner. This card game is designed to, not only be a source of entertainment, but a catalyst for dialogue concerning the society we have created and the values that inform the public ethos. The game is designed to parody the unwritten rules that govern political, economic, and popular culture. To accomplish this, the game employs an ever-changing array of three-value cards that reflect current trends in the consumption of desired goods and services. It encourages political dialogue through the use of policy cards that conjure-up the symbols, images, and policy choices championed by elected officials, private citizens, corporations, and associations. The play of disaster cards challenge basic generational assumptions about appropriate responses to unexpected hardship. The game also challenges players with an array of strategic choices concerning how to allocate resources. Players must chose between accumulating goods and services in an Accumulated Asset Pile, devoting resources to legal processes through the Litigation Fund, donating goods and services to charity through the 501(c)(3) Pile, extending the cycle of consumption by discarding into the Recycling Bin, or disrupting another player's accumulation of three-value cards through the play of policy cards. While the object of the game is to accumulate the most value in three-value cards prior to the distribution of the last card in the Pick-Up Pile, the strategy that the winning player adopts to achieve that goal is itself the stuff of meaningful dialogue about decision-making in the modem world.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
FIG. 1--Is the front view of a typical three-value card.
FIG. 2--Is the front view of a typical policy card.
FIG. 3--Is the front view of a typical disaster card.
FIG. 4--Is a view of the card holding indicating the Pick Up Pile, the Litigation Fund, the 501(3)(3) Pile, and the Recycling Bin.
FIG. 5--Is a diagram of the lay out of playing cards among the players.
FIG. 6--Is a schematic diagram of the sequence of play.
FIG. 7--Is a schematic diagram of the sequence of possible discards available to a player to end his or her turn.
DETAILED DESCRIPTION OF THE INVENTION
Features of the Preferred Embodiment.
The game includes a deck of individually designed cards and a card holder. In the preferred embodiment, the initial "starter" deck of cards consists of 100 cards in various combinations of three-value cards, policy cards, and disaster cards. The reverse side of each type of card is like appearance, so that when viewed from the reverse a number of such cards held in a player's hand are indistinguishable one from another. However, the front side of each type of card is composed of a unique design (in the preferred embodiment using green as the background color for the three-value cards, blue as the background color for the policy cards, and red as the background color for the disaster cards) such that the three-value cards, policy cards, and disaster cards are immediately distinguishable when viewed from the front side. The "starter" deck is designed to be played by three to six players. Players may facilitate larger groups by combining multiple "starter" decks into one large deck or by collecting supplement cards. In addition, the cards will be constantly updated to reflect changes in popular, political, and economic culture and will be available for sale in collector packs. Thus, the game never goes out of date. In fact, the game is designed to be a running commentary on popular, political, and economic culture.
Three-value cards represent goods and services available in society. The three-value cards are the mechanism for keeping score and for determining the eventual winner. To accumulate three-value cards for score-keeping purposes, a player must place three-value cards in that player's "Accumulated Asset Pile" located immediately in front of that player. The "Accumulated Asset Pile" contains the cards that a player seeks to have counted toward his point total at the end of the game. In the preferred embodiment, these cards are displayed face-up so that each three-value card can be seen by the other players. Only the three-value cards in the Accumulated Asset Pile are counted towards a player's point value at the end of the game. The winner of the game is the player who has accumulated the most value in three-value cards in that person's Accumulated Asset Pile.
As shown in the embodiment pictured in FIG. 1, an three-value card has four distinctive features: (1) the text feature, (2) the graphic commentary feature, (3) the category feature, and (4) the three value feature. Text appears in the upper-center portion of the card 10. The text labels the particular good or service featured by the card. Below the text in the center of the card is a graphic commentary 11 concerning the good or service featured by the card. The graphic commentary features one or more symbols that serves to comment on the good or service identified by the text. By the particular art selected to represent the featured named by the text, the graphic commentary feature serves as a mini-editorial on the good or service featured by the card. For example, the disclosed three-value card depicted in FIG. 1 contains a graphic of a sailboat on open water as the graphic commentary for the text "Social Security Card." This graphic commentary is designed to highlight the lofty, though perhaps unrealistic view of Social Security in society. Specifically, it is designed to call to mind the myth that Social Security is established to provide the means to retire by sailing away on a blissful body of water.
The third feature of an three-value card is the category feature. Each three-value card is categorized by way of a letter 12 that appears in the lower right-hand corner of the card. In the current embodiment, there are five different categories of three-value cards: transportation ("T"), housing ("H"), insurance ("I"), employment ("E"), and general asset ("A"). The embodiment presented in FIG. 1 is titled "Social Security Card". The category of this card is "A", i.e. general asset. These categories are used in advanced levels of game-playing. Specifically, to be declared the winner of the advanced version of this game, a player must not only accumulate the most value in three-value cards, but the winner must also collect cards for each category of three-value card. In other versions of the game, the winner is the person who collects the most value in each category of three-value cards.
Different groups place different value on certain goods and services. The three value feature 13 of the three-value card captures this phenomenon. Instead of one number providing a single numerical value for a particular good or service depicted on a card, an three-value card has three values assigned to that good or service. The top number in the upper-left hand corner of the three-value card 13a provides the numerical value of the featured good or service as perceived by members of a particular demographic category (in the preferred embodiment this category is a generational group called the "World Warrior" generation, i.e. those born prior to the close of World War II). The second number from the top upper-left-hand corner of the three-value card 13b, provides the value attached to the good or service by a different category of demographic (in the preferred embodiment this category is a generational group called the "Baby Boom" generation, i.e. those born between 1945 and 1964). The bottom number of those that appear in the upper left-hand corner of the three-value card 13c provides the value of the depicted asset as seen by a third category of demographic (in the preferred embodiment this category is a generational group called the "Generation X" generation, i.e. those born between 1964 and 1980). For example, the three-value card depicted in FIG. 1 is labeled 10 "Social Security Card." Examining the valuation feature of the card, one sees that the Social Security card has a value of 1000 to those players who decided, at the beginning of the game, to compete as members of the senior citizen generation; a value of 500 to those players who had decided to compete as members of the Baby Boomer generation; and a value of zero to those players who chose to play the game as members of the Generation X generation.
The valuation feature of the three-value card introduces a unique dynamic to this game. Though players of traditional playing card games must rely, largely, on chance to acquire valuable playing cards, here attaining the highest value in three-value cards is a function of difficult strategic choices. Since the value of a particular card varies from player to player, decision to deposit a particular card into one's Accumulated Asset Pile must consider not only the value of the card to the player who holds the card, but the potential value of the card to an opposing player should the card be placed back into circulation rather than retained. Taking a card from the preferred embodiment, the Social Security Card, as an example, a player who has chosen to play as a member of Generation X would, in a traditional card game, have no incentive to retain, for his Accumulated Asset Pile, a card with zero value. Yet, because of the three value character of this game, a Generation X player would have to think long and hard about discarding back into play a card that has such high value to his competitors. The retention of the Social Security card, however, might come at the opportunity cost of retaining a card of actual value to the Generation X player.
Policy cards are cards that the players play against each other in order to slow each other's accumulation of three-value cards. In the preferred embodiment, the policy cards represent, in effect, disruptions to the process of accumulating wealth or procuring services caused by various public events. An example of a policy card taken from the preferred embodiment is depicted in FIG. 2. Policy cards have three features: (1) the title feature, (2) the instruction feature, and (3) the graphic commentary feature. This policy Card disclosed is the "Commuter Line Privatization" card. The public policy preference represented by this card is the privatization of a commuter rail line. This card represents a policy choice of requiring suburban dwellers to transfer assets into the 501(c)(3) Pile by dropping government support of mass transit. In FIG. 2, the title feature 14 names the event that will place an obstacle in the path of the player against whom it is played accumulating three-value cards--here "Commuter Rail Privatization." Next, the instruction feature 15 contains text which serves to instruct the player against whom the policy card has been played about what they must do to comply with the requirements of the card. In the policy card that has been disclosed in FIG. 2, the card states that the player against whom the card has been played must place one of the cards from her Accumulated Asset Pile into the 501(c)(3) Pile. Generally speaking, policy cards may be played by any player against any player. However, this policy card can be played only against a player who, before the initial cards were distributed at the start of the game, chose to be part of the suburban category rather than the urban category. The graphic commentary feature 16 provides an opportunity for editorial commentary on the policy instructions contained in the card. It achieves this editorial function by conjuring up many of the symbols that, in their short-hand fashion, call to mind significant events in popular and political culture, and the public ethos engendered by such symbols. In the policy card disclosed in Feature 2, the graphic commentary feature contains the image of an asphalt road running adjacent to, if not into, a building drawn to resemble a state legislature. Through these graphics, the graphic commentary feature seeks to communicate the power of the road-building (as opposed to, for example, rail-building) interests in our society. It is also drawn to communicate that the road-builders have easy access to the halls of government.
Disaster cards represent natural and man-made disasters. These cards cause a catastrophic disruption in a player's accumulation of three-value cards. Disaster cards are not distributed to the players or included in the Pick Up Pile at the start of the game. In the later part stages of the game, however, disaster cards might appear in the Pick Up Pile. Disaster cards are stored in the Recycling Bin and are entered into the game if and only if one or more cards is discarded into the Recycling Bin. If cards are discarded into the Recycling Bin, those cards are shuffled with the disaster cards that have been stored there, and are placed in the Pick Up Pile. The game is thus continued by the replenishment of the Pick Up Pile. The unfortunate player who, by chance, picks up a disaster card from the Pick Up Pile must immediately follow the instructions on the face of the card.
Disaster cards have three features: (1) the title feature, (2) the instruction feature, and (3) the graphic commentary feature. The disaster card disclosed in FIG. 3 is titled 17 "Hurricane." The instruction feature 18 tells the player against whom the card has been played that, if they have home owner's insurance (one of the three-value cards described previously), that player must wait two turns for the insurance company to process his insurance claim before that player may rejoin the game. The card states that if they player against whom this card has been played is not insured (i.e. that player does not have an "insurance" three-value card) that player must distribute all of their cards, in a clockwise direction until that player has distributed all of his cards to the other players. Then, after waiting for three turns, the player against whom the Hurricane Card was played, takes all of the cards in the 501(c)(3) Pile. The graphic commentary feature 19 presents the image of an umbrella being held up by a fist full of dollars. The editorial comment made by this feature of the Policy Card is that it takes a lot of money in order to be sheltered from the disastrous effects of a hurricane.
The card holder 20 has four separate card holders. These holders are the repositories for the Pick Up Pile 21, the Recycling Bin 22, the Litigation Fund 23, and the 501(c)(3) Pile 24.
The Pick Up Pile 21 enters the playing cards into the game. Each player initiates his turn by taking the top card from the Pick Up Pile and adding it to the six cards held in that player's hand 31.
The cards in the Recycling Pile 22 extend the duration of the game. Once all the cards have been picked up from the Pick Up Pile, the cards that have been discarded into the Recycling Bin are shuffled and placed face-down in the Pick Up Pile. The Recycling Bin is also the repository of the disaster cards. Disaster cards are not distributed with the Asset and policy cards at the beginning of the game 28. Instead, they are all placed, face-down, in the Recycling Bin. If no player discards into the Recycling Bin, the disaster cards remain, inert, in the Recycling Bin and the game concludes as soon as the last card in the Pick Up Pile is drawn. If, however, so much as one card is added to the Recycling Bin, that card will be shuffled with the disaster cards and added to the Pick Up Pile once the Pick Up Pile is depleted 33. Thus, a player who discards into the Recycling Bin makes a deliberate choice to enter all of the disaster cards into play.
The cards that are placed in the Litigation Fund 23 represents the portion of society's resources dedicated to the legal process. The cards collected in the Litigation Fund serve as a safety net for players who are victimized by certain policy or disaster cards. At the beginning of the game, there are no cards in the Litigation Fund. Contributions to the Litigation Fund are generally voluntary, though certain policy cards and disaster cards will force contributions to the Litigation Fund. Players must exercise their discretion with regard to how many cards it is appropriate to have in the Litigation Fund. Typically, there are never enough cards in the Litigation Fund when one is forced to rely upon it. However, when one's competitor collects from the Litigation Fund, there always seem to be too many cards in that pile.
The 501(c)(3) Pile 24 is the repository for cards that players seek to donate to charitable institutions. As with the Litigation Fund, the 50l(c)(3) Pile holder is empty at the start of play. The cards accumulate in the 501(c)(3) Pile by players voluntarily discarding cards into it. Some policy cards and will force contributions to the 501(c)(3) Pile. Like the Litigation Fund, various players will have to rely on the 501(c)(3) Pile when certain policy cards are played against them or when a player is unfortunate enough to have picked up a disaster card from the Pick Up Pile.
The Litigation Fund and the 501(c)(3) Pile are referred to broadly as deposit piles since cards from a player's hand are deposited into these piles. This is in contrast to discarding a card into the Recycling Bin or playing a policy card against another player.
Playing the Game
In preparation for play, each player must make an initial choice of "who" they will be for game-playing purposes by choosing from several predesignated categories 27. In the preferred embodiment, a player must first identify the generational group to which they belong. These generational groups are the World Warriors, those with birthdays in 1945 and earlier; the Baby Boomers, those with birthdays between 1946 and 1964; and the Generation X'ers, those with birth years between 1965 and 1981. The game will encompass future generation groups as they are identified. Second, each player must identify a sub-category to differentiate him or herself from the other players who may have picked the same initial cateaory. In the preferred embodiment, each player must announce whether he or she is a resident of the city or a resident of the suburbs. These identifications are critically important to the play and outcome of the game because the particular value of three-value cards and the effect of certain policy cards will vary depending upon the initial category choices of the player who holds the card.
Once the players have selected their fictitious roles, and after the Asset and policy cards are shuffled together, each player is dealt a predetermined number of cards (in the preferred embodiment, each player is dealt six cards) 29. The cards that have been dealt to each player are held in-hand, i.e. secluded from view by the other players 25. Though the composition of the cards that are held in-hand will change throughout the game, each player must hold, at the end of his turn, the pre-determined number of cards (six cards in the preferred embodiment) in order to continue in the game. If a player, for reasons described in more detail below, finishes his turn and does not have the required number of cards in-hand, that player is eliminated from the game.
After the Dealer has dealt cards to each player, the remaining cards are placed, face-down, in the Pick Up Pile 30. The Pick Up Pile enters the playing cards into the game. Each player initiates his turn by taking the top card from the Pick Up Pile and adding it to the cards held, secluded from view, in that player's hand 31, 36. A turn is complete when the player chooses an appropriate discard leaving that player with the required number of in-hand cards 37. There are five discard options available to a player. First, a player may add a card to her Accumulated Asset Pile 38. Second, a player may opt to make a contribution to the Litigation Fund 39. Third, a player may opt to make a contribution to the 501(c)(3) Pile 40. Fourth, a player may choose to discard into the Recycling Bin 41. Fifth, a player may opt to play a policy card against another player 42. Regardless of the choice that is ultimately made, a player must balance the addition of the card taken from the Pick-Up Pile with a corresponding discard to ensure that only the required number of cards are held in that player's hand by the end of that player's turn. There will be times when a player will collect a number of cards during a single turn. Such a situation will arise, for example, when a policy card or disaster card instructs a player to collect all of the cards in the Litigation Fund or the 501(c)(3) Pile. In such a situation, a player must discard however many cards is necessary to comply with the six card rule. There will also be situations in which a player finishes his turn and finds that he does not have six cards held in-hand. Such a situation arises when, for example, a player has been hit with a policy or disaster card that instructs the player to surrender in-hand cards in exchange for cards in the Litigation Fund or the 501(c)(3) Pile yet the player discovers that there are less than six cards available in those piles. In such a situation player who does not have six cards in his hand is eliminated from the game.
To play a policy card against another player, the player seeking to play the card initiates his or her turn in the usual manner, i.e. taking the top card in the Pick Up Pile. To complete his or her turn, however, the player places the selected policy card adjacent to another player's Accumulated Asset Pile. A Player who has a policy card played against him must wait until it is his turn before complying with the terms indicated on the card. When that player's turn arrives, the player who has had the policy card played against him must comply with the terms listed on the policy card before picking the top card from the Pick Up Pile as he would ordinarily do to initiate his turn.
Using FIG. 2 as an example, suppose Player A decides to play the "Commuter Line Privatization" card against Player C (who, by the terms provided on the card, must be a resident of the suburbs). Player A begins her turn as she normally would by taking the top card from the Pick Up Pile. Then, to play the policy card, Player A discards by placing the "Commuter Line Privatization" card next to the "Accumulated Asset Pile" of player C. After A has completed her turn, player B completes his turn. Next, it is player C's turn. Before picking up the top card in the Pick Up Pile, Player C must read and comply with the terms of the "Commuter Line Privatization" card. As the instructions on the Commuter Line Privatization card read, "Your commuter line has been privatized. Place one of the cards in your Accumulated Asset Pile into the 501(c)(3) Pile to cover the cost of increased fares." Once Player C complies with the terms on the policy card, he can then initiate and complete his turn as he normally would have.
Disaster cards are put into play only after there has been a discard into the Recycling Bin. Cards that are deposited into the Recycling Bin are shuffled with the disaster cards that are stored there and then placed face down in the Pick Up Pile once the cards in the Pick Up Pile have been depleted. Using FIG. 3 as an example, the player who is unfortunate enough to take the "Hurricane" card from the Pick Up Pile had better have a homeowner's insurance three-value card. If the player has a homeowner's insurance three-value card, then that player will only have to miss two turns to wait for his claim to be processed. If the player does not possess a homeowner's insurance three-value card, then that player must distribute all of the cards that are in the player's Accumulated Asset Pile, wait three turns, and then take all of the cards that are in the 501(c)(3) Pile. An encounter with such a disaster card may force a player from the game if, when it is time for that player to take "all the cards" from the 501(c)(3) Pile, there are no cards to be had. A lot can happen from the time a disaster card forces a player to surrender all of his cards, and when that player is entitled to take from the 501(c)(3) Pile. For example, other players may have to rely on the 501(c)(3) Pile leaving no cards at all. Conversely, a player might look into the 501(c)(3) Pile after being hit with a disaster cards and see no cards at all. In such a situation, it is within the power of the other players to either keep that unlucky player in the game by depositing cards into the otherwise empty 501(c)(3), or to deliberately eliminate this player from the game by leaving the 501(c)(3) Pile empty.
Play continues until the cards in the Pick Up Pile are depleted 32. When there are no more cards to be distributed, the players count the value points of all the cards in their Accumulated Asset Pile 34. The player with the most points wins.
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FIELD OF INVENTION
This invention relates to a method of reducing cardiovascular morbidity and mortality in a prediabetic or Type 2 Diabetes patient population.
BACKGROUND OF THE INVENTION
Diabetes Mellitus and Cardiovascular Disease
Patients with type 2 diabetes mellitus (DM) have an increased risk of atherosclerotic disease, including coronary heart disease, cardiovascular disease, and peripheral vascular disease. Diabetes itself 1 and not just the associated risk factors of dyslipidemia, hypertension, and obesity contributes a major portion of this risk. In particular, the level of hyperglycemia may play a key role. While the relationship of increased blood glucose to microvascular complications is well-recognized 7-9 , its relation to atherogenesis was, until recently, less well documented. A prospective, population-based study in middle-aged and elderly patients in Finland with type 2 DM has shown a linear correlation between baseline fasting blood glucose (FBG), or HbA 1c , and coronary heart disease mortality 10 . In the WESDR database, subjects diagnosed with diabetes at age 30 years or older had a statistically significant increase in mortality from vascular causes for every 1% increase in glycosylated hemoglobin, with a hazard ratio of 1.10 to 1.28 for various types of events 11 . The Islington Diabetes Survey found a linear association between 2-hour postprandial glucose or HbA 1c and coronary heart disease, with the stronger association with the 2-hour glucose test 12 . In the San Antonio Heart Study, the level of hyperglycemia was a strong, independent predictor of all-cause and cardiovascular mortality 13 .
A growing body of evidence indicates that the increased risk for macrovascular complications associated with type 2 DM extends to patients with glucose abnormalities that do not meet the criteria for frank diabetes. The Hoorn study found an increased risk of all-cause and cardiovascular mortality with higher 2-hour post-load glucose values and increasing HbA 1c in a non-diabetic general population of men and women 15 . In the EPIC study, an increase of 1% in HbA 1c was associated with a 28% increase in risk of death and an increase of approximately 40% in cardiovascular or coronary heart disease mortality in a cohort of 4,662 men 4 . Although diabetic subjects were included in this trial, and diabetes was found to be an independent predictor of cardiovascular risk when evaluated separately from HbA 1c (another independent predictor), only HbA 1c and not diabetes predicted CV death when both were included in the same analysis, further strengthening the link between glucose elevations and CV risk, versus the presence or absence of diabetes. Similarly, a study in non-diabetic elderly women found that all-cause mortality and coronary heart disease were significantly related to fasting plasma glucose 16 .
In a study from Oslo 17 , non-diabetic men aged 40-59 years had a significantly higher cardiovascular mortality rate if their FPG was >85 mg/dL. Long-term follow-up of several prospective European cohort studies has confirmed a higher risk of cardiovascular-related mortality in non-diabetic men with the highest 2.5% of values of FPG and 2-hour postprandial glucose 18 . A meta-regression analysis of data from 20 cohort studies found a progressive relationship between glucose levels and cardiovascular risk even below the cutoff points for diagnosis of DM 3 . Likewise, in the 23-year Paris Prospective Study 19 of 7,018 middle-aged nondiabetic men, increased fasting or 2-hour postprandial blood glucose was associated with increased total and coronary mortality in a graded, non-threshold relationship.
The American Diabetes Association (ADA) has recognized an intermediate category of IFG, defined as a fasting plasma glucose of 6.1-6.9 mmol/L (110-125 mg/dL) 6 , as well as the older category of IGT, defined as a 2-hour glucose level of 7.8-11.1 mmol/L (140-199 mg/dL) after a 75 gram oral glucose load, with FPG levels below 7.0 mmol/L. The European Diabetes Epidemiology Group, based on a meta-analysis of 10 prospective European cohort studies, found that IGT was associated with survival curves intermediate between those of non-diabetic and diabetic subjects, while IFG curves were similar to those of normoglycemic subjects. A direct comparison revealed that IFG had a higher specificity (79%) for predicting cardiovascular disease than IGT (57%), but IGT was a more sensitive (54%) predictor than IFG (28%) in predicting incident cardiovascular disease 20 .
In summary, the data cited above demonstrate that people with IFG and IGT (collectively referred to as “prediabetes”) have an excess risk of development of overt type 2 diabetes, coronary heart disease, cerebrovascular disease, and peripheral vascular disease compared to a population with normal fasting and 2-hour postprandial glucose levels. Further, a continuum of increasing risk appears to exist, as opposed to a threshold level of hyperglycemia below which no increased risk prevails 2-4 . IGT and IFG subjects are currently unlikely to receive glucose-lowering treatment with existing pharmacotherapies. Their under-treated dysglycemia represents a large unmet medical need, and a large public health issue.
A number of large intervention studies have been conducted over the last two decades in both type 1 and type 2 diabetic patients. The primary aim of these trials was to evaluate the impact of improved metabolic control on microvascular endpoints and the studies were designed and sized accordingly.
Macrovascular outcomes were included in these trials as secondary endpoints and although the treatment differences seen were not statistically significant, trends were evident in each trial of an association between intensified glycemic control and reduced cardiovascular mortality and morbidity.
The two principal intervention trials in recent years were the Diabetes Control and Complications Trial (DCCT) in type 1 diabetic patients 7 and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 DM 14 . In the DCCT, cardiovascular events decreased by 41% in the intensively-treated group, but this difference was not statistically significant. In the UKPDS, which compared the effects of intensive management to the effects of standard care on micro- and macrovascular complications in 3,642 type 2 diabetic subjects followed for a median of 10.4 years, a significant decrease in microvascular complications was observed in the intensive treatment group, which achieved a significantly lower median HbA 1c of 7.0% compared to the standard group (median HbA 1c 7.9%). Although strongly suggestive, the intervention data from this study failed to show a statistically significant decrease in the endpoint of myocardial infarction, which decreased by 16% with the 0.9% decrease in HbA 1c (p=0.052). However, epidemiologic analysis of the UKPDS database 2 revealed that a single percent point decrease in HbA 1c was associated with a 25% reduction in diabetes-related death, a 7% reduction in all-cause mortality, and an 18% reduction in fatal and nonfatal MI. Similar reductions in the risk for stroke, amputation and congestive heart failure were seen with decreasing HbA 1c . These associations of HbA 1c with cardiovascular risk were without threshold, i.e. they occurred across the entire study population.
In the 8-year Kumamoto study 3 of intensive multiple-dose insulin treatment of type 2 diabetic patients, half as many serious macrovascular events (MI, angina, stroke, claudication, gangrene, or amputation) occurred in the intensive treatment arm as in the conventional treatment arm. This reduction was not statistically significant, in all likelihood because of the small size of the trial (n=110). Several large prospective trials, including the ACCORD trial (NHLBI) and the VA diabetes trial, are now ongoing or planned to specifically and primarily evaluate the hypothesis that treatment of diabetes in patients with cardiovascular risk factors will reduce cardiovascular morbidity and mortality.
Recent intervention studies in IGT have focused on the reduction of rates of progression to type 2 diabetes. Lifestyle interventions (primarily institution of diet and exercise plans) have led to striking reductions in progression from IGT to diabetes in both the recently-completed NIH-sponsored DPP in North America and the Finnish DPS lifestyle study. Each trial was terminated early after independently demonstrating a 58% reduction versus controls in development of new cases of type 2 DM from IGT in the lifestyle intervention arm 21,33 . Lifestyle changes were pursued aggressively in both studies, and whether such interventions can be maintained indefinitely is an open question.
Pharmacotherapies have also been tested in delaying the development of type 2 DM:
Metformin treatment of IGT in the DPP study was associated with a statistically significant 31% reduction in the rate of progression to type 2 DM. 21 Acarbose in the STOP-NIDDM trial reduced the progression from IGT to type 2 DM from 41.8% in the placebo arm to 32.8% over 3.6 years' median duration of treatment (p<0.05) as well as reducing the risk of CV events by 49%. 40 Troglitazone in the halted TRIPOD study; 12.3% of placebo-treated subjects versus 5.4% of troglitazone-treated subjects with prior gestational diabetes developed type 2 DM over a mean of 30 months of treatment (p<0.05). 45
With the exception of the STOP-NIDDM study, cardiovascular risk reduction data from these recent diabetes prevention studies are all pending publication. At present the only other data available on CV risk reduction in the IGT/IFG population from treatment with pharmacologic antihyperglycemic agents come from a small Swedish study conducted in the 1960s which demonstrated a reduction in CV events in IGT subjects with the use of tolbutamide 22,23 . Clearly new therapies for glucose lowering must be tested for their effects on serious cardiovascular outcomes in this population.
Recent evidence has provided support for a beneficial effect of insulin treatment in improving cardiovascular outcomes in patients with diabetes. The DIGAMI study 24 , in which diabetic patients hospitalized with acute MI were allocated to receive an IV insulin-glucose infusion in-hospital followed by intensive chronic outpatient treatment with insulin, versus standard treatment, showed a significant 28% reduction of all-cause mortality in the patients who received intensive insulin treatment. Most of these deaths were cardiovascular in etiology. The most striking reductions in mortality were seen in the subset of patients without prior insulin treatment, with low cardiovascular risk pre-MI. In those subjects significant survival differences were even seen pre-discharge, while still in hospital post-MI, and enhanced survival in the same cohort was also seen in long-term followup.
Part of the benefits of insulin treatment was likely due to improved long-term glycemia post-MI, but the in-hospital results suggest that other, more acute, effects of insulin besides long-term glycemic control may have played a role, such as improved platelet function, decreased PAI-I levels, and insulin-mediated reductions in circulating free fatty acid levels with consequent improved dyslipidemia and decreased myocardial oxygen requirement. Chronic insulin therapy may thus provide a level of protection against the cumulative deleterious effect of even subacute episodes of ischemia, and on the progression of atherosclerosis.
A recent study from Belgium 25 reinforces the beneficial role of insulin treatment of critically-ill subjects. In this trial, critical-care post-surgical patients with random blood glucose values greater than 110 mg/dL were treated while in ICU either with an insulin infusion to lower blood glucose to the 80-110 mg/dL range (intervention); or to receive insulin infusions only if blood glucose exceeded 215 mg/dL, with the aim of infusion to reduce blood glucose to between 180 and 200 mg/dL (control). Twelve-month follow-up showed significantly different reductions of 8.0% and 4.6% in overall mortality in the intervention and control groups respectively, and most of the benefit was attributable to the cohort of subjects who were in ICU for 5 days or more. In-hospital mortality, septicemia, acute renal failure and hemodialysis incidence, and transfusion requirements were also significantly reduced in the intervention group versus the control group.
The use of exogenous insulin in a IGT, IFG, or diabetic population should confer several potential metabolic and cardiovascular benefits associated with insulin treatment:
1. A powerful effect to delay the exposure of target tissues to toxic levels of glycemia that is finely titratable and durable, compared to oral antidiabetic agents. 2. Suppression of circulating free fatty acids (FFA) with:
Reduced VLDL synthesis and improved lipoprotein patterns (lower triglycerides, increased HDL-C) Reduced lipotoxicity at the level of the beta cell and on insulin's target tissues Reduced obligatory oxidative metabolism in ischemic myocardium
3. Prevention of metabolic decompensation (including both glucose and FFA) due to stress, both mild and frequent (daily stresses and minor illness or injury) and severe and less common (major injury, illness, surgery, vascular events). These stress events will suppress endogenous insulin responses even when a pharmacologic secretagogue or sensitizer is present, but exogenous, injected insulin cannot be so suppressed. 4. In addition, recent work has demonstrated direct associations between insulin treatment and enhanced nitric oxide-mediated vasodilatation, which is impaired in insulin-resistant states such as IGT, IFG and diabetes 26,27 . Moreover, reductions in the endothelial dysfunction 28 and inflammation 29 that are characteristic of both diabetes and atherosclerosis have been demonstrated following insulin treatment.
Whereas insulin therapy is undoubtedly efficacious in reducing blood glucose concentrations and, as noted above, may hypothetically improve survival in individuals with dysglycemia, outcome studies using insulin in this population have not been done to date. Several reasons may account for this including a) the need for insulin to be injected as opposed to be taken orally; b) concerns regarding the side effect of hypoglycemia; (low blood glucose) c) epidemiologic evidence linking high serum insulin levels to macrovascular disease; d) the very recent recognition that glucose is a risk factor for cardiovascular outcomes across the range from normal through all stages of diabetes; e) lack of predictability in the action of long-acting insulins; and f) lack of experience in achieving near-normal glucose levels with insulin preparations available to date.
Many of these issues are, however, not relevant today. First, it is now widely recognized that the epidemiologic relationship between hyperinsulinemia and macrovascular disease is extremely unlikely to imply a cause-effect relationship. This is based on randomized controlled trial evidence from both the DCCT and the UKPDS trials that individuals who were given exogenous insulin in an effort to reduce the risk of microvascular disease had a trend towards fewer, not more, adverse cardiovascular outcomes. This conclusion is supported by other studies discussed above, including the DIGAMI study, the Kumamoto study, a meta-analysis of studies of intensified insulin therapy in type 1 diabetes, and several other analyses. It therefore appears that hyperinsulinemia as a result of exogenous administration of insulin is not a cardiovascular risk factor. Second, the potential of intensified insulin therapy has achieved new attention in light of the UKPDS and the potential benefits of tight glycemic control in people with type 2 diabetes. Third, the simplicity of glucose monitoring devices and the decreasing costs of home glucose monitoring, as well as the negligible discomfort associated with today's injection devices available today, have made injections and blood glucose monitoring more accessible and easier for patients to accomplish. Fourth, there is growing recognition of the importance of metabolic abnormalities as a cause of cardiovascular disease. Finally, there are new long acting analog insulins having properties such as a longer duration of action (up to 24 hours) and a smoother profile, with a less defined peak of action which make them viable treatment agents in the IGT, IFG early Type 2 diabetes populations.
Lantus® LANTUS (insulin glargine) is a recombinant human insulin analog that is a long-acting (up to 24-hour duration of action), parenteral blood-glucose lowering agent. 39 The post-marketing surveillance safety database experience reveals no increased incidence of hypoglycemia or unexpected adverse reactions compared to other marketed insulin preparations. In a multiple-dose pharmacokinetic study, Lantus® LANTUS (insulin glargine) levels were shown to reach steady-state after 2 doses (2 days) of treatment (Study 1020). Treatment with Lantus® insulin LANTUS (insulin glargine) offers the possibility of a smooth, daylong, blood insulin profile without a definite peak that can be finely titrated to lower subjects' FPG in a durable manner, while minimizing the risk of hypoglycemia at other times of day.
However, a central question concerns the administration of insulin to nondiabetic or early diabetic subjects and the propensity for hypoglycemia this may confer. Insulin has traditionally been reserved for treatment of more severe hyperglycemia, in established type 1, or advanced type 2, diabetes. In these patients the risk of hypoglycemia is greater the closer the achieved blood glucose is to normal. 42
For type 2 diabetic patients, as well as individuals with prediabetes, medical management begins with diet restriction and exercise as tolerated 30,31 . Even if pharmacotherapy in the form of oral antidiabetic drugs or insulin is needed later, diet and exercise are always the cornerstone of disease management. No drugs are currently approved for the treatment of prediabetes, but most of these individuals are overweight or obese, and successful lifestyle intervention has been shown to improve blood glucose levels and even delay progression to diabetes 32,33 . Exercise increases blood glucose uptake in muscle, and leads to a reduction in endogenous insulin output, as little insulin is needed to provide fuel to these tissues during exercise. 34 Exogenous, pharmacologically-provided insulin present in the circulation cannot be so modulated, and its presence can predispose to hypoglycemia.
Exercise-induced hypoglycemia in insulin-treated diabetes patients is well-described 35,41 , and is often dealt with in practice by reducing the mealtime insulin dose, or giving oral calories, prior to an exercise session. 36,37 These methods are cumbersome, and hypoglycemia is still a risk following exercise. The insulin dose that is most frequently modulated in response to upcoming exercise is the short-acting insulin given before the preceding meal, because these insulins have prominent peaks in their actions, used to target the blood glucose rise that occurs following a meal, but they place patients at increased risk for hypoglycemia if there is a mismatch between insulin availability and calories absorbed. Thus hypoglycemia is a risk e for all insulin-treated individuals, and this risk is enhanced when these individuals exercise, and the closer to normoglycemia they are treated.
The ideal basal insulin might be expected to be less worrisome from this standpoint because the circulating insulin produced would target blood glucose elevations throughout the day rather than mealtime fluctuations. It would not demonstrate notable peaks in plasma level, and in consequence the tendency to produce hypoglycemia would be less than with peaked insulins. The “Treat-to-Target” study 38 in US/Canada type 2 diabetic patients investigated whether a single bedtime dose of Lantus® LANTUS (insulin glargine) vs NPH insulin (a moderate- to long-acting insulin with a pronounced peak in plasma activity for 4 to 8 hours after injection) 39 would achieve target metabolic control without increasing nocturnal hypoglycemia. The trial was successful in demonstrating both its primary objective (more Lantus® LANTUS (insulin glargine)-treated patients than NPH-treated patients reaching target HbAlc [<=7%] without nocturnal hypoglycemia), but also showed significant reductions in nocturnal hypoglycemia vs NPH in all patients.
If peaked insulins pose a danger for hypoglycemia in advanced type 2 diabetes, they certainly do in milder forms of diabetes, and in prediabetes, where the blood glucose concentrations are only modestly elevated, especially in relation to exercise. Treatment with an insulin with notable peak effects runs a great risk of producing low blood glucose levels that will be bothersome and dangerous to people with these conditions. There exists an unmet medical need to provide insulin treatment to to individuals with milder glucose intolerance who are at high risk for CV disease. Cardiovascular disease in subjects with IGT, IFG, and early diabetes is prevalent and life-threatening. Advances have been made in recent years in treating the associated cardiovascular risk factors of hypertension and hyperlipidemia. Depended upon the results of the morbidity/mortality study association between blood glucose elevations and cardiovascular risk in these subjects is likewise continuous and progressive, treatment of this dysglycemia becomes urgent.
Insulin treatment has been demonstrated to reduce CV morbidity and mortality in a population with more advanced diabetes, and offers this prediabetic population the possibility of reducing cardiovascular risk through effective reductions in blood glucose and free fatty acid levels, and in the associated tissue damage resulting from their chronic elevations. The availability of Lantus® insulin LANTUS (insulin glargine) creates the possibility of treating subjects with widely-varying degrees of dysglycemia with the effectiveness of insulin over a 24 hour period while minimizing the risk of hypoglycemia (especially hypoglycemia seen in association with exercise) inherent in earlier insulin preparations with more distinct peak effects.
Diabetic dyslipidemia (DDL) in type 2 diabetes is another condition where there exists an unmet medical need. DDL is characterized by fasting hypertriglyceridemia, low HDL cholesterol (HDL-C), small dense (atherogenic) LDL particles, and elevated free fatty acid (FFA) concentrations. Whereas lipid disorders associated with type 1 diabetes (hypertriglyceridemia with low LDL) are simpler in etiology, and relate to insulin deficiency which, when replaced, normalizes the plasma lipid profile, the pathophysiology of lipid disturbances in type 2 diabetes is more complex, being partly related to concomitant obesity and insulin resistance. Key factors in the development of lipid abnormalities in type 2 diabetes include:
Failure of suppression of hormone-sensitive lipase in adipose tissue, which leads to increased lipolysis and increased supply of FFA from the adipocyte for, among other things, VLDL-triglyceride (TG) synthesis by the liver Reduced catabolism of TG-rich particles (such as VLDL), and reduced transfer of surface components of those particles to HDL, partly accounting for the low HDL-C levels seen in DDL. Accelerated transfer of cholesterol from HDL to other lipoproteins, also contributing to low HDL-C Reduced clearance of chylomicrons and more atherogenic chylomicron remnants, as well as reduced clearance of other remnant particles (intermediate-density lipoproteins or IDL) Decreased activity of lipoprotein lipase (LPL) and hepatic TG lipase (HTGL) which break TG down into FFA for fuel in muscle and fat cells. Overproduction of VLDL by the liver, exacerbated by elevations in glucose and FFA
Although the lipid abnormalities of type 2 diabetes are more resistant to normalization with antidiabetic treatment, even when that treatment is successful, increased insulinization has been shown to improve most of the defects above, namely, improved lipase activity with reduced lipolysis; increased clearance of chylomicrons; reduced production of VLDL from the liver, both through reduction of FFA substrate and by independent mechanisms; and increases in HDL, generally seen in association with increased LPL activity.
The treatment initially recommended for type 2 diabetes, and reinforced as the cornerstone of management even after pharmacologic treatment is initiated, is diet control and regular exercise. When these lifestyle measures are no longer successful alone in controlling blood glucose levels, pharmacologic treatment is begun, traditionally using oral antidiabetic drugs alone and in combination. Whereas there is no a priori reason why insulin cannot be used to manage mildly diabetic patients, it is usually reserved for late-stage diabetes management because:
Insulin must be given by injection and many patients find injections objectionable Insulin and injections have acquired the stigma of late-stage management—“if I'm taking insulin my diabetes must be very severe”—and to forestall insulin is a way of saying “my diabetes isn't so bad yet”
In fact insulin injections have become almost painless in recent years due to improved delivery systems. The “late-stage” stigma is based on tradition and former practice more than any real reason why insulin should be reserved for the end game of diabetes.
The one valid reason for not using insulin in patients as first pharmacotherapy is a concern over the one principal side effect of insulin—low blood glucose, or hypoglycemia. This is an important concern in using insulin to treat early type 2 diabetes primarily because most available insulins have a peak in their plasma activity at a certain time following injection. It is at these times of peak activity that the insulin-treated patient with diabetes is most vulnerable to hypoglycemia, and diets and exercise patterns must often be tailored around the prescribed insulin regimen to avoid hypoglycemia. This risk is greater the closer patients' blood glucose levels come to normal—and yet normoglycemia is the goal of diabetes management.
There is evidence that the scientific community is taking the abnormalities of DDL more seriously than it has in the past in terms of the risk they pose for atherogenesis. The Adult Treatment Panel of the NCEP on the “detection, evaluation, and treatment of cholesterol disorders in adults” authored an update of the ATP II summary in the Fall of 2002. The ATP III took hypertriglyceridemia more seriously than the predecessor ATP II Committee had as a marker for increased CV risk. The ATP III acknowledged that more recent studies, and additional analyses of older studies, have shown elevated TGs to be an independent risk factor for CHD, whereas in the past the association between TG and CHD was not independent from other confounding risk factors such as LDL and HDL abnormalities. ATP III reduced the TG concentration threshold for each degree of abnormality (normal, borderline, high, and very high) from their ATP-II levels, and offered VLDL cholesterol, and serum TG, as markers for atherogenic remnant lipoproteins, which the committee identified as a target for intervention as well as LDL-C. The committee formalized the concept of “non-HDL cholesterol” (non-HDL-C) as a target for therapy in persons with hypertriglyceridemia, perhaps more relevant than LDL-C alone in these individuals. Non-HDL-C was seen as an acceptable surrogate for apo-B in routine clinical practice.
ATP III pointed out that when fasting TG are less than 200 mg/dL, VLDL-C is not markedly elevated, and non-HDL-C correlates very well with LDL-C. As TG rises above 200 mg/dL, the relation between LDL-C and non-HDL-C is looser, and LDL-C alone “inadequately describes the CV risk associated with atherogenic lipoproteins.” When fasting TG exceed 500 m/dL, much of the cholesterol resides in nonatherogenic forms of TG-rich lipoproteins, and non-HDL-C becomes “less reliable as a predictor of CHD risk.” On the other hand, the risk of markedly elevated TG (>500 mg/dL) for pancreatitis has long been recognized, even by FDA, and here too the ability of insulin to reduce these elevations may exceed what other OADs can deliver. Thus there are two categories of elevations in fasting TG that may be amenable to insulin treatment, and for which insulin may be superior to OADs. One is elevations in the 500-1000 mg/dL range, for which hypertriglyceridemia alone is the target, being a surrogate for reduction in risk for pancreatitis. The other is elevations in the 200-500 mg/dL range, for which hypertriglyceridemia is one of a host of biomarkers associated with CHD risk; non-HDL-C, HDL-C, and remnant lipoproteins being other, perhaps more important endpoints in this regard.
SUMMARY OF THE INVENTION
The present invention provides a method of treating IGT in a patient comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of treating IFG in a patient comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of treating Type 2 diabetes, particularly early Type 2 diabetes, in a patient comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of treating diabetic dyslipidemia in a Type 2 diabetes patient comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of treating atherosclerosis in a patient with a disease or condition selected from the group of IFG, IGT or Type 2 diabetes, particularly early Type 2 diabetes, comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of improving endothelial function in a patient diagnosed with a disease or condition selected from the group of IFG, IGT or Type 2 diabetes, particularly early Type 2 diabetes, comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of preventing an increase in left ventricular mass in a patient diagnosed with a disease or condition selected from the group of IFG, IGT or Type 2 diabetes, particularly early Type 2 diabetes, comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of improving left ventricular diastolic and systolic function in a patient diagnosed with a disease or condition selected from the group of IFG, IGT or Type 2 diabetes, particularly early Type 2 diabetes, comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of preventing an increase in carotid intimal thickness in a patient diagnosed with a disease or condition selected from the group of IFG, IGT or Type 2 diabetes, particularly early Type 2 diabetes, comprising administering an effective dosage of a long acting insulin.
The present invention also provides a method of reducing blood glucose levels in a patient diagnosed with a disease or condition selected from the group of IFG, IGT or Type 2 diabetes, particularly early Type 2 diabetes, comprising administering an effective dosage of a long acting insulin.
The preferred long acting insulin for each of the above methods is insulin glargine.
DETAILED DESCRIPTION OF THE INVENTION
Study HOE901-1021 was conducted to test the safety, efficacy, and tolerability of Lantus® LANTUS (also known as HOE901 and insulin glargine) in treating individuals with IGT, IFG, and mild diabetes. As stated earlier, this patient population is at high risk for CV disease.
Study HOE901/1021 was a randomized, single-blind (pharmacist-unblinded), inpatient, dose-titration study designed to examine the safety and efficacy of HOE901 given once a day subcutaneously at bedtime in a novel population: people with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). It was conceived as a pilot study for a large international trial of HOE901 in a dysglycemic population of IGT, IFG, and early type 2 diabetes in order to investigate dosing in the prediabetic (IFG/IGT) population for the first time. Of special interest was the incidence of hypoglycemia during the study.
The study was conducted at three centers in the US. After screening tests, including fasting plasma glucose (FPG) and post prandial plasma glucose (PPG; two hours following a 75 g oral glucose load) for classification as IGT, IFG, diabetic, or normal glucose tolerance (NGT), and after satisfying other inclusion criteria including the ability to perform moderate exercise on a stationary bicycle, subjects were admitted to an inpatient study center. They were confined there for the next 15 days, during which time they were randomly assigned to receive either HOE901 once per day subcutaneously in the evening, or matching placebo (saline) injections in a 3:1 randomization (HOE901:placebo). Baseline assessments included a 5-point (before each meal, bedtime, and 3 AM) and 8-point (5-point plus readings 2 hours after each meal) blood glucose profile on separate days, and 15 minutes of exercise on a stationary bicycle at a level of exertion of “somewhat hard” on the Borg scale with blood glucose values monitored during and for 3 hours following the exercise. Each subject received a 25 kCal/kg diet while confined in the study center. Capillary whole blood glucose values were recorded on HemoCue devices. Episodes of hypoglycemia (blood glucose ≦50 mg/dL [2.8 mM] or symptoms with blood glucose ≦65 mg/dL [3.6 mM]) were recorded.
Once randomized, subjects' bedtime doses of study drug were titrated to achieve a fasting blood glucose (FBG) of 80-95 mg/dL [4.4 mM-5.3 mM]. Dose increases were based on FBG values and were performed every 2 days. Subjects remained at the site until the end of the confinement period, regardless of when target FBG levels were achieved. Five-point blood glucose profiles were performed every other day, with 8-point blood glucose profiles performed on alternate days. At endpoint all baseline procedures, including an 8-point blood glucose profile, and an exercise assessment, were repeated.
Subjects were treated from 18 Feb. 2002 to 17 Apr. 2002. Data from the study are still being analyzed, but principal results of the study are summarized below.
Twenty-one subjects were enrolled into the study. Two discontinued before completion: 1 HOE901 subject due to hypoglycemia, who however, never received study drug, and 1 subject withdrew prior to randomization. Nineteen subjects completed the study, 15 in the HOE901 group and 4 in the placebo group. The table below summarizes the demographic and baseline characteristics of these subjects.
Demography and baseline characteristics
Characteristic
Placebo
HOE901
All
Female
4 (80.0%)
6 (37.5%)
10 (47.6%)
Male
1 (20.0%)
10 (62.5%)
11 (52.4%)
Mean age (yrs)
54.6
54.8
54.7
Median age (yrs)
53.0
52.0
53.0
Mean BMI (kg/m2)
31.2
30.7
30.8
Number (%) of subjects with:
IGT/IFG
2 (40.0%)
7 (43.8%)
9 (42.9%)
Type 2 diabetes
3 (60.0%)
7 (43.8%)
10 (47.6%)
NGT
0 (0.0%)
2 (12.4%)
2 (9.5%)
Mean screening values for:
FPG (mg/dL)
114
110
111
PPG (mg/dL)
212
192
197
Although it was intended to enroll only IGT/IFG subjects, difficulties in locating enough of these subjects in the timeframe allotted for enrollment necessitated the inclusion of subjects who were found to be diabetic at screening (none were known to be diabetic prior to the study). Two subjects were enrolled with NGT (FPG and PPG of 100 and 133, and 95 and 135 mg/dL, respectively).
The starting dose following randomization for all subjects was initially set at 6 IU. Because of the occurrence of hypoglycemia in 2 subjects at this dose, the starting dose was reduced to 4 IU. The mean dose at endpoint (Day 12) was 8.4 IU for HOE901 (0.096 IU/kg), and 17.0 IU (0.195 IU/kg) for placebo.
All but 2 subjects in the HOE901 group had reached an FPG of 100 mg/dL by Day 12, and all but 4 had reached the FBG target of 95 mg/dL or less.
FIG. I displays the mean blood glucose values on the 8-point profiles at Day −1 (baseline) and on Day 12 (endpoint). As seen, there were small reductions from baseline to endpoint in mean blood glucose concentrations in the HOE901 group, ranging from 2.0 to 13.3 mg/dL at different timepoints. Mean FBG was reduced from 98.1 to 85.6 mg/dL, and mean daylong blood glucose was reduced by 8.8 mg/dL, in the HOE901 group. In the HOE901 group the lowering of blood glucose from Day −1 to Day 12 was not confined to the fasting timepoint, but occurred daylong, at each timepoint.
In contrast, in the placebo group mean blood glucose values increased at most timepoints, with a mean FPG increase from 103.8 to 111.3 mg/dL and a mean daylong blood glucose increase of 8.2 mg/dL. The placebo group mean response was heavily influenced by 1 of the 4 subjects who had large increases in 8-point blood glucose over the course of the study, for unclear reasons.
It is clear from these data and the mean screening values in the table above that there was a drop in mean fasting glucose in the HOE901 group between screening and Day −1 (baseline). Differences in blood glucose measurements (plasma at screening, whole blood at Day−1) contributed to the observed drop in blood glucose between-these two timepoints, however, the likely reason for most of this difference was the institution of a diet policy in both groups (in this study a diet similar to what would be prescribed in these subjects in practice (25 Kcal/kg) was used). Diet compliance in subjects with dysglycemia is classically poor, but because the subjects were confined in this study, they were perforce adherent to the diet regimen, and it was effective in lowering their blood glucose levels. No such decrease in mean FBG occurred between screening and Day −1 in the 5 subjects taking placebo. Mean body weight was reduced in both the placebo group and HOE 901 over the course of the study, by 0.25 and 0.44 kg respectively.
FIG. II illustrates mean blood glucose responses before (−0.25 hr ) and for 3 hours following the 15-minute stationary bicycle exercise period. As can be seen, mean blood glucose was similar before and after treatment with HOE901, and did not approach the hypoglycemic range. In the placebo group mean blood glucose showed a notable increase from Day −1 to Day 12, due to 2 of the 4 subjects in that group who demonstrated large increases over baseline by Day 12, for reasons which are unclear but are possibly related to relative physical inactivity over the 2 weeks of confinement, with resultant decreased insulin sensitivity at the time of the assessment on Day 12. It is noteworthy that no hypoglycemic events were reported during exercise for any subject.
Treatment-emergent adverse events (TEAEs) occurred in 10 subjects in the HOE901 group (16 events) vs. 2 in the placebo group (5 events). Each event occurred in only 1 individual except for headache, which occurred in 3 HOE901 subjects. Only 2 HOE901 subjects and 1 placebo subject had events that were considered by investigators as possibly related to study drug. The HOE901 events were 2 episodes of headache, and one of hypoglycemia. The two headaches occurred in subjects who had hypoglycemic events on the same days and at approximately the same time as the headaches. There were no serious adverse events during the study. Subject 3011 (who reported dizziness as an adverse event during screening) was removed from the study by the sponsor prior to receiving any study drug dose because of hypoglycemia that occurred during screening.
HOE901 treatment plus modest calorie restriction was effective in lowering blood glucose values in these dysglycemic individuals to target FBG levels. Daylong (8-point) blood glucose profiles were lowered in parallel to FPG in the HOE901 group. A relatively low dose of HOE901 (mean of only 8.4 IU) was required to achieve the glucose goals under these test conditions. Blood glucose profiles in response to exercise fell only modestly over the course of the study in the HOE901 group. Blood glucose responses in the placebo group increased over the course of the study in both 8-point and exercise assessments, but the small size of this group and the atypical responses of 1 or 2 subjects makes drawing conclusions from the placebo responses difficult.
Only mild hypoglycemia occurred in 4 out of 16 subjects treated with HOE901 in this study. These hypoglycemic events generally occurred before lunch or supper, and resolved promptly with oral caloric intake. No episodes of hypoglycemia occurred in relation to exercise. Although the calorie-restricted diet subjects consumed during this study doubtless played a role in the occurrence of these events, the diet was typical in size for what is recommended to these frequently overweight individuals. Based on this study in individuals with IGT, IFG, or mild untreated type 2 diabetes, the adminstration of HOE 901 seems safe and well tolerated. Hypoglycemia can occur, but is manageable not related to exercise, and detectable with the aid of home glucose monitoring.
Thus in this study it was possible to use Lantus® LANTUS (insulin glargine) to treat the mildly hyperglycemic subjects to normoglycemic levels without hypoglycemia in relation to exercise. These data have prompted the undertaking of a large intervention trial, the ORIGIN study, wherein it is expected that Lantus® LANTUS (insulin glargine) will be shown to be efficacious in reducing CV disease, with low risk for producing hypoglycemic side effects in relation to the exercise which forms a cornerstone of the glucose management of these individuals. The ORIGIN study will randomly allocate approximately 10,000 subjects with IGT, IFG, or early type 2 diabetes at risk for cardiovascular morbidity (because of a history of previous serious cardiovascular events, or because of significant cardiovascular risk factors) either to treatment with a single injection of Lantus® LANTUS (insulin glargine) per day, titrated to produce a FPG of 95 mg/dL or less without hypoglycemia, or to standard treatment of each condition. Examples of serious cardiovascular events include, but are not limited to, previous myocardial infarction, stroke, angina with documented ischemic changes, previous coronary, carotid or peripheral arterial revascularization, or left ventricular hypertrophy by electrocardiogram or echocardiogram. Examples of significant cardiovascular risk factors include, but are not limited to, previous myocardial infarction, stroke, angina with documented ischemic changes, previous coronary, carotid or peripheral arterial revascularization, or left ventricular hypertrophy by electrocardiogram or echocardiogram. This standard treatment plan includes a stepped-care algorithm for the institution of therapy in subjects who are either diabetic at baseline, or who become so during the trial. Monitoring of, and treatment intervention in, these control subjects will occur in a manner that is at least as aggressive as that recommended by currently-accepted standards of care (e.g. ADA guidelines). The morbidity/mortality study will be multicenter, international, randomized, and open-label, with a mean treatment duration of 5 years. The primary outcome variable is a composite cardiovascular endpoint of cardiovascular deaths, nonfatal MI and stroke, revascularization, hospitalization for heart failure CHF, and unstable angina. Secondary variables include all-cause mortality and rates of development or progression of microvascular disease. A separate investigation will examine the progression to type 2 diabetes in the IGT and IFG subjects treated with Lantus® LANTUS (insulin glargine) versus usual care.
Despite the novelty of the treatment paradigm proposed for the ORIGIN study, it is believed that hypoglycemia will be minimal based on several factors:
1. The 24-hour plasma insulin profile without a definite peak resulting from Lantus® LANTUS (insulin glargine) administration, decreasing the vulnerability of patients to excessive insulin concentrations which have historically occurred at unpredictable times during the day, and to unpredictable degrees, with other insulin preparations. 2. The gradual dose titration scheme proposed for the study. Lantus® LANTUS (insulin glargine) doses will start low, from 2-6 IU per day and the insulin administered will be distributed over a 24-hour period. Dose increases will be small, and made only after FPG levels from previous doses have reached steady-state. 3. The goal of Lantus® LANTUS (insulin glargine) titration is a target FPG of 95 mg/dL. This is at the upper end of the normal range for subjects without diabetes. Many IGT subjects in this trial will have an FPG in the target range from the start of the study, and if assigned to receive Lantus® LANTUS (insulin glargine) will consequently receive the starting dose only. In any case, the risk of nocturnal hypoglycemia resulting from Lantus® LANTUS (insulin glargine) administration which has reduced FPG to the vicinity of 95 mg/dL should be minimal, especially since most of these subjects will exhibit a degree of decreased insulin sensitivity. 4. Subjects will be asked to monitor their blood glucose at home especially during titration, to detect any tendency to hypoglycemia in that setting (pen-exercise, after missed meals, overnight).
The results of the 1021 Study which confirmed the safety and tolerability of Lantus® LANTUS (insulin glargine) in drug-naïve type 2 diabetes patients as well as in prediabetic individuals, also support Lantus' LANTUS' (insulin glargine) special usefulness in patients with moderate to severe DDL.
Insulin has features that make it especially useful in the patient with pronounced diabetic dyslipidemia, as compared to the oral antidiabetic agents usually used as initial pharmacotherapy. The “Treat-to-Target” study (HOE901/4002) of Lantus® LANTUS (insulin glargine) in a type 2 diabetic population inadequately treated with oral drugs was notable in demonstrating the success of Lantus® LANTUS (insulin glargine) and its comparator, NPH insulin, in reducing blood glucose levels to target levels in the majority of randomized patients. NPH insulin despite having a prolonged duration of action, has a pronounced peak effect from 3-6 hours after injection, rendering it less suitable in the management of the patient with milder diabetes due to the risk for hypoglycemia. Indeed even in this more severely diabetic population Lantus LANTUS (insulin glargine) demonstrated significant advantages over NPH in hypoglycemia, especially nocturnal hypoglycemia.
As a consequence of the excellent glycemic control attained, which set the standard for glycemic control in future trials, the 4002 study results are especially useful as an assessment of Lantus' s LANTUS' (insulin glargine) effects on lipids. The effects of Lantus LANTUS (insulin glargine) in the population of the “treat-to-target” 4002 study on fasting TG levels increased with the magnitude of baseline TG elevations: reductions of 24%, 34%, and 38% were seen in fasting TG levels with, respectively, all patients; those with fasting TG in the 300-499 mg/dL range (13% of the 4002 population); and those with elevations of 500 mg/dL or more (another 8% of the 4002 population). It is also notable that highly statistically significant reductions in non-HDL-cholesterol (see below) were seen in the two pooled treatments in the 4002 study, greater in magnitude the higher the baseline level of TG.
There is evidence from the literature that use of sulfonylurea (SU) as initial drug treatment of the type 2 patient with DDL exerts a weaker effect on reduction of hypertriglyceridemia, or on increasing HDL-C, than is seen with insulin, and/or that the effects are less durable. In order to compare the effects of Lantus LANTUS (insulin glargine) on fasting TG and non-HDL-C levels with oral agents from the sulfonylurea class, the glimepiride (Amaryl® AMARYL) database at Aventis was examined. Both multicenter placebo-controlled studies in the Amaryl® AMARYL (glimepiride) registration database demonstrated a more modest effect of Amaryl® AMARYL (glimepiride) on both TG and non-HDL-C concentrations than Lantus LANTUS (insulin glargine) demonstrated in the 4002 study, despite a prominent effect of Amaryl® AMARYL (glimepiride) to lower blood glucose. These results are shown in Table 1 below for patients with various levels of fasting hypertriglyceridemia.
TABLE 1
Summary of lipid data for LANTUS (from 4002 Study) and AMARYL (from two AMARYL studies with placebo control)
Subgroup by TG
Sample
Change at Endpoint
% reduction
LANTUS -
Variable
baseline range
size
Treatment
Baseline
Endpoint
(Mean/SD)
from baseline
AMARYL
Triglycerides
300-500
44
LANTUS
362
240
−122.5/102
34%
16%
52.5
50
AMARYL
390
321
−70.0/111
18%
500-1000
25
LANTUS
661
409
−252.0/208
38%
5%
34.4
16
AMARYL
662
445
−217.6/188
33%
300-1000
69
LANTUS
470
301
−169.4/160
36%
13%
63.6
66
AMARYL
459
350
−105.8/147
23%
200-500
124
LANTUS
288
232
−56.3/117
25%
13%
21.7
129
AMARYL
299
265
−34.6/107
12%
Non-HDL
300-500
44
LANTUS
180
152
−27.6/36
15%
12%
21.9
Cholesterol
50
AMARYL
203
198
−5.7/32
3%
Total
500-1000
25
LANTUS
186
171
−14.1/35
8%
−2%
−9.0
16
AMARYL
224
200
−23.1/35
10%
300-1000
69
LANTUS
181
163
−18.5/40
10%
5%
8.6
66
AMARYL
209
198
−9.9/33
5%
200-500
124
LANTUS
167
155
−12.5/33
7%
4%
5.8
129
AMARYL
197
191
−6.7/30
3%
HDL
300-500
44
LANTUS
40
40
0.1/6
50
AMARYL
36
37
1.2/6
500-1000
25
LANTUS
33
36
3.1/7
16
AMARYL
37
39
1.6/6
300-1000
69
LANTUS
37
38
1.2/7
66
AMARYL
36
37
1.3/6
200-500
124
LANTUS
42
41
−0.6/8
129
AMARYL
38
39
1.2/5
LDL
All
306
LANTUS
113
110
−3.3/27
272
AMARYL
142
140
−1.5/23
The lipid-lowering effects of metformin are variable depending on the study and clinical setting, but while the TG-lowering and HDL-increasing effects of metformin are generally superior to SU, they do not exceed the effects of insulin quoted above. Thiazolidinediones (TZDs) differ in their effects—pioglitazone is associated with notable beneficial effects on the abnormalities of DDL, whereas rosiglitazone seems to have almost no effect on these parameters (confirmed significantly inferior to Lantus LANTUS (insulin glargine) in Study 4014, which compared Lantus® LANTUS (insulin glargine) and rosiglitazone in type 2 diabetic patients already treated with other oral antidiabetic drugs—see Table 2 below).
TABLE 2
Summary of lipid data for LANTUS and AVANDIA from Study 4014
Subgroup by TG
Sample
Change at Endpoint
% reduction
LANTUS -
Variable
baseline range
size
Treatment
Baseline
Endpoint
(Mean/SD)
from baseline
AVANDIA
Triglycerides
300-500
11
LANTUS
380
277
−102.8/130
27%
18%
68.5
18
AVANDIA
376
341
−34.3/159
9%
500-1000
4
LANTUS
817
494
−323.3/268
3
AVANDIA
572
649
77.0/548
200-500
37
LANTUS
285
234
−50.2/101
18%
18%
47.7
51
AVANDIA
294
291
−2.5/133
0.1%
Non-HDL
300-500
11
LANTUS
156
150
−5.9/22
4%
Cholesterol
18
AVANDIA
177
207
29.8/47
−17%
Total
500-1000
4
LANTUS
178
153
−25.3/25
3
AVANDIA
231
261
30.0/48
200-500
37
LANTUS
168
152
−15.5/32
51
AVANDIA
41
59
29.2/48
HDL
300-500
11
LANTUS
32
34
2.2/4
18
AVANDIA
38
41
3.8/6
500-1000
4
LANTUS
28
29
1.0/3
3
AVANDIA
39
38
−1.0/8
200-500
37
LANTUS
38
40
1.2/5
51
AVANDIA
38
40
2.6/6
LDL
200-500
34
LANTUS
115
111
−4.3/34
46
AVANDIA
99
129
29.7/36
The special advantages of insulin in the treatment of diabetic dyslipidemia, which along with insulin's established effectiveness in blood glucose control, suggest that it is a preferred treatment compared to available oral antidiabetic drugs. Until recently, the drug treatment of blood glucose elevations in drug-naïve diabetic patients has consisted of oral antidiabetic agents because of a fear of hypoglycemia from the use of insulin in this population. The novel development is the availability of Lantus® LANTUS (insulin glargine), the first truly basal insulin, which by virtue of its flat pharmacokinetic profile and 24-hour duration of action, can supply a steady insulin effect with low risk for hypoglycemia due to the lack of a pronounced peak effect. Because of this, insulin treatment of the diabetic patient previously treated with lifestyle measures only, is possible, and thus insulin treatment of patients in this category with pronounced diabetic dyslipidemia is possible, to reduce their elevated blood lipid values as well as their elevated blood glucose values.
In view of the data described above, treatment with long acting insulin, particularly insulin glargine, is expected to safely and effectively retard atherosclerosis progression in patients with IGF, IFG or Type 2 diabetes, particularly early Type 2 diabetes by improving glycemic control and by additional mechanisms including decreased free fatty acid production, improved control of dyslipidemia, decreased oxidative stress and increased endothelial nitric oxide availability.
Treatment with long acting insulin, particularly insulin glargine, is also expected to safely and effectively improve vascular function in patients with IGT, IFG or Type 2 diabetes, particularly early Type 2 diabetes. Long acting insulin, particularly insulin glargine, is expected to improve endothelial function based on its effects on smooth muscle cells, endothelial cells, suppression of cytokines, coagulants and increased endothelial nitric oxide synthase. Coronary endothelial dysfunction is defined as an impaired vasodilatory response to intracoronary infusion of acetylcholine (Ach) and is predictive of vascular events. Acute studies have shown that a physiological increase in the circulating insulin concentration potentiates Ach-induced vasodilation. 43 In another study, after two months of insulin therapy, patients with type 2 diabetes saw an increase in the blood flow response to Ach and restored the ability of insulin to acutely potentiate Ach-induced vasodilation. 44
Finally, patients with diabetes have been shown to have increased left ventricular mass and abnormalities in left ventricular (LV) diastolic and systolic function, often referred to as diabetic cardiomyopathy. These abnormalities may extend also to patients with “mild” prediabetic hyperglycemic disorders. Treatment with long acting insulin, particularly insulin glargine, is expected to prevent an increase in LV mass and improve or prevent an increase in both LV diastolic and systolic function in patients with IGT, IFG or Type 2 diabetes, particularly early Type 2 diabetes.
Treatment with long acting insulin, particularly glargine, is expected to prevent an increase in carotid intimal thickness of the extracranial carotid artery. Measurement of carotid intimal thickness is a highly reproducible technique, which correlates with risk factors for atheosclerosis progression in coronary disease and stroke (N Engl J. Med. 1999; 340:14-22). Angiotensin-converting enzme inhibitors and the insulin sensitizing thiazolidinediones are all agents which have been shown to reduce carotid intimal thickness in placebo controlled trials (Circulation. 2001; 103:919-925; J Clin Endocrinol Metab 1998; 83:1818-1820; J Clin Endocrinol Metab 2001;86:34552-3456).
The amount of long acting insulin necessary to achieve the desired biological effect depends on a number of factors, for example the specific long acting insulin chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose of insulin glargine is generally in the range from 2 to about 150 IU per day. More preferred is a daily dose in range in the range of 2 to about 80 IU per day. Even more preferred is a daily dose in the range of about 2 to about 40 IU per day.
As used herein, the term “patient” means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.
As used herein, the term “treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
As used herein, the term “effective dosage” means a quantity of the compound which is effective in treating the named disorder or condition.
As used herein, the term “long acting insulin” is an insulin analog that is a long acting (up to 24-hour duration of action) blood glucose lowering agent. Such long acting insulins include, but are not limited to, Lantus®, NPH, Lente®, Ultralente®, and Semilente®.
As used herein, the term “long acting insulin” is an insulin analog that is a long acting (up to 24-hour duration of action) blood glucose lowering agent. Such long acting insulins include, but are not limited to, Lantus® LANTUS (insulin glargine), NPH, Lente® LENTE human insulin zinc suspension [rDNA origin], Ultralente®ULTRALENTE human insulin extended zinc suspension [rDNA origin], and Semilente® SEMILENTE (prompt insulin zinc suspension).
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I depicts mean blood glucose values on the 8-point profiles at Day 1 (baseline) and Day 12 (endpoint).
FIG. II illustrates mean blood glucose responses before (0.25 hr) and for 3 hours following the 15 minute stationary bicycle exercise period.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part patent application of U.S. application having Ser. No. 10/928,901 filed on Aug. 27, 2004 now U.S. Pat. No. 7,204,262 and also claims priority to the PCT patent application No. PCT/US2006/004997 filed on Feb. 14, 2006.
BACKGROUND OF INVENTION
This invention relates generally to padded cane or crutch coverings and cushions. More specifically, this invention relates to a padded cover or cushion for a forearm cane or crutch. A typical forearm cane or crutch consists of an adjustable length pole with a forearm cradle pivotally attached at or near the top of the pole. The cane or crutch is typically made of metal or some other sturdy material for support and durability.
During normal activities, the user can develop sores on the forearm due to pressure or pinching of the arm in the forearm cradle. In addition, the junction where the forearm cradle attaches to the crutch pole can often create discomfort and pain. For example, the user may pinch his arm between the forearm cradle and pole as the forearm cradle pivots at its hinge through a range of positions. The attachment junction can also pinch or catch on materials near it and cause damage to clothing, coats, upholstery or other materials it contacts. Further, the attachment junction can scratch or mar walls, doors, trim, furniture, vehicles or the like.
Holding a forearm crutch limits the availability of the user's hands for everyday tasks and creates safety issues for the user. For example, the user may let go of one crutch hand grip and transfer the crutch to the other hand in order to open a door. The user must open the door, hold it open and walk through the doorway while maintaining control over the free crutch. All of this activity is done while the user is balancing on the remaining crutch. If the user drops the free crutch, he must bend down and pick it up while balancing on the remaining crutch. Another similar problem occurs when pushing a shopping cart. While the user use the shopping cart to help balance while walking on one crutch, any movement away from the cart to remove anitem from the shelf requires balancing on one crutch and creates a safety concern for the user.
What is needed, therefore, is a forearm cane or crutch covering or cushioning that makes the crutch more comfortable for the user while at the same time it helps protect the user and his surroundings from injury or damage related to relative movement between the forearm cradle and the pole on which it is mounted or injury resulting from the need to let go of the hand grip and perform everyday tasks.
It is an object of this invention to make the forearm cradle of a forearm cane or crutch more comfortable and to minimize or eliminate pinching, scratching or other damage caused by the pivotable connection of the forearm cradle to the pole.
It is feature of this invention that the forearm cane or crutch cover will fit the forearm cane or crutch when it is adjusted to fit the height and arm length of a user.
It is another feature of the invention to make it more comfortable and to make it easier to control the operation of a cane or crutch.
It is another feature of the invention to make it safer to for user to let go of the crutch and use his hand, by preventing the crutch from slipping off the forearm when the user lets go of the handgrip.
It is yet another feature of the invention to make it possible to apply the teachings of the present invention to known canes or crutches to increase their comfort and to make them better able to be used.
Another feature of the invention is to make better use of commercially available canes and crutches.
Still other objects, advantages, distinctions and alternative constructions and/or combinations of the invention will become more apparent from the following description with respect to the appended drawings. Similar components and assemblies are referred to in the various drawings with similar alphanumeric reference characters. This description should not be literally construed in limitation of the invention. Rather, the invention should be interpreted within the broad scope of the further appended claims.
SUMMARY OF THE INVENTION
The present invention is directed to a forearm cane cover or cushion or a forearm crutch cover or cushion that makes the forearm cradle more comfortable for the user and helps prevent injury or damage caused by contact with the sharp edges of the pivoting attachment junction and by the resultant gap created and closed between the forearm cradle and pole when the forearm cradle pivots around the pole of the cane or crutch. In addition, the forearm cane cover will prevent slippage or the forearm cane from the user's arm when the user lets go of the handgrip to use his hands.
The cover may include an at least partially padded covering for the forearm cradle with pieces that may extend from the forearm cradle and may cover at least some portion of the pivoting attachment junction that connects the forearm cradle to the pole. Preferably the cover may provide padding on the inside of the forearm cradle to make the forearm cradle more comfortable to the user. Then extensions from the forearm cradle area may cover the pivoting attachment junction that connects the forearm cradle to the pole. These extensions may essentially enclose the pivoting attachment junction and the gap between the forearm cradle and pole created and closed as the forearm cradle pivots from a backward position to a forward position.
An optional feature of the present device is the use of an expandable portion in the extensions or pieces that cover at least some portion of the pivoting attachment junction. Thus when the forearm cradle pivots through its range of positions, the expansion of the expandable portion may reduce gaping or bunching in the pieces that cover at least some portion of the pivoting attachment. In addition, the expandable portion may allow a forearm crutch cover to fit a forearm crutch when adjusted to various users' heights and arm lengths.
A further significant advantage of the current invention is that the inclusion of a resilient portion that spans between the crutch cover and the crutch pole, particularly when oriented at the front of the crutch, when the cradle is bent rearwardly, as during usage, under pressure of the user, once that pressure is released, the cradle will be pulled back into alignment, and ready for use and application by the invalid, because of the resilience of the expandable portion.
A further advantage of the concept of this invention is the usage and application of the safety strap, that extends from the cradle cover, and which can span across the front opening of the cradle, in order to add to the safety of retention of the invalid's arm therein, during usage and application of the crutch. This provides greater safety during usage of this inventive device.
In addition, other hook and loop straps may extend downwardly from one edge of the cradle cover, extend underneath of the same, and be fastened to the other side of the cover, in order to assure that the cradle cover remains in place, during usage, and can not slip from the crutch during its application.
Another optional feature includes an opening on the front extension of the cover that encompasses the handgrip. This opening may help secure the cover's attachment to the cane or crutch. Alternatively, the crutch cover may include a portion that covers the handgrip of the cane or the crutch. This opening may help secure the cover's attachment to the cane or crutch as well as increase the comfort of the handgrip. It also resets the cradle after usage.
Another preferred embodiment of the forearm crutch cover includes a pleated covering for the hinge, and a height adjustment portion that attaches along the pole extension and attaches the cradle portion of the cover to the handgrip. In adition, this embodiment include a safety strap to help the forearm crutch dangle from the user's arm when the crutch is not in use. The forearm cradle portion may also be made of non-allergenic material and include a permanent or removable breathable pad to help eliminate sores and irritation on the user's arm. If removable, the breathable pad may be disposable or washable for reuse.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a preferred embodiment of the forearm crutch cover as used on a forearm crutch, and a cut away perspective view of the pivoting connection junction that connects the forearm cradle to the pole of the forearm crutch;
FIG. 2 is a cross-sectional view of FIG. 1 taken along the line 2 - 2 ;
FIG. 3 is a plan view of the preferred embodiment of the forearm crutch cover as seen from the front;
FIG. 4 is a plan view of the preferred embodiment of the forearm crutch cover as seen from the rear;
FIG. 5 is a side view of a preferred embodiment of the invention as shown on a forearm crutch with the forearm cradle rotated forward, or in a weight bearing position typically associated with walking;
FIG. 6 is a side view of a preferred embodiment of the invention as shown on a forearm crutch with the forearm cradle rotated backward, or in a hands free position typically associated with resting;
FIG. 7 is a perspective view of another preferred embodiment of the forearm crutch cover as used on a forearm crutch;
FIG. 8 is a plan view of the preferred embodiment of the forearm crutch cover of FIG. 7 as seen from the front;
FIG. 9 is a plan view of the preferred embodiment of the forearm crutch cover of FIG. 7 as seen from the front with the optional removable handgrip attachment;
FIG. 10 is a plan view of the removable handgrip attachment for use with the forearm crutch cover of FIG. 9 ; and
FIG. 11 is a rear elevated view of the preferred embodiment of the forearm crutch cover of FIG. 7 .
DETAILED DESCRIPTION OF THE INVENTION
The apparatus described herein covers the top portion of a forearm cane or crutch to provide a padded forearm cradle and at least a partial enclosure for the pivoting connection junction that attaches the forearm cradle to the pole.
FIG. 1 depicts a preferred embodiment of a cover 10 for a forearm cane or forearm crutch as shown on a forearm crutch having a forearm cradle 14 , a pole 18 and a handgrip 20 . The pivoting attachment 16 of the forearm cradle 14 to the pole 18 is shown in the encircled portion of FIG. 1 without the cover 10 . This pivoting connection 16 , shown as a yoke and bolt attachment in this embodiment, could be a collar and pin joint, a hinge, a swivel, a ball and socket assembly, or the like, depending upon the particular design and construction of the forearm cane or crutch. The pivoting connection 16 allows the forearm cradle 14 to rotate about an axis A through a range of positions. When utilized, the cover 10 may fit over the forearm cradle 14 , extend down the pole 18 and may cover at least a portion of the yoke and bolt attachment 16 that pivotally attaches the forearm cradle 14 to the pole 18 . The front 22 of the cover 10 may be situated inside the forearm cradle 14 and may extend down the pole 18 towards the sidewardly extending handgrip 20 . The back 24 of the cover 10 may be situated around the back or outside of the forearm cradle 14 and may extend down the pole 18 and may cover at least a portion of the yoke and bolt attachment 16 that attaches the forearm cradle 14 to the pole 18 .
The forearm cane or crutch cover 10 may be described in four portions—the inner or front forearm cradle portion 26 , the outer or back forearm cradle portion 28 , the front pole portion 30 and the back pole portion 36 as seen in FIGS. 2 , 3 and 4 . FIG. 2 is a cross-sectional view of the cover 10 shown in FIG. 1 taken along the line 2 - 2 . The front forearm cradle portion 26 and the back forearm cradle portion 28 are shown on either side of the forearm cradle 14 .
The front and back forearm cradle portions 26 , 28 may form a flexible covering sized to fit over the U-shaped C-shaped forearm cradle 14 . The flexible covering may be constructed in a number of ways that include, but are not limited to, sewing, hook and loop closures, mechanical fasteners, adhesives, or the like. The front and back pole portions 30 , 36 may extend from the front and back forearm cradle portions 26 , 28 . An alternate construction of the cover may include a cushioning material applied directly to the inner or front forearm cradle portion and one or more pole portions may extend from the inner or front forearm cradle portion.
FIG. 3 shows a plan view of the front 22 of the forearm crutch cover 10 . The inner or front cradle portion 26 is usually the portion in contact with the user's arm. The padding on the front cradle portion 26 may cushion the user's arm, and it may be made from natural materials or man-made materials, such as soft plastic or rubber, leather, fur or fur-like materials, or the like. The front pole portion 30 may extend from the front forearm cradle portion 26 , and it may cover at least some portion of the yoke and bolt attachment 16 that connects the forearm cradle 14 to the pole 18 .
FIG. 4 depicts the back 24 of the forearm crutch cover 10 . The back forearm cradle portion 28 may cover the back or the outside of the forearm cradle, as at 14 . The back cradle portion 28 may be made of natural materials or man-made materials. The back pole portion 36 may extend from the back forearm cradle portion 28 , and it may cover at least some portion of the yoke and bolt attachment 16 that connects the forearm cradle 14 to the pole 18 . In addition, the back pole portion 36 may have cooperatively engaging elements 32 , 38 to help the forearm crutch cover 10 remain on the forearm crutch 12 . The cooperatively engaging elements 32 , 38 may be, but are not limited to, hook and loop closure as shown in FIG. 4 , or any number of methods, such as mechanical fasteners, buckles, slide fasteners, adhesives or the like.
The front pole portion 30 shown in FIG. 3 may include an opening 34 sized to encircle the base of the handgrip 20 that may serve as an additional method to secure the forearm crutch cover 10 to the forearm crutch 12 . Alternatively the front pole portion 30 may include a portion that may encase at least some portion of the handgrip 20 that may serve as an additional method to secure the forearm crutch cover 10 to the forearm crutch 12 . This covering may provide a better grip for the user and it may be padded to increase the user's comfort.
The front and back pole portions 30 , 36 may have an expandable portion 40 , 42 at or near their connection to the front and rear cradle portions 26 , 28 to provide for the increase in length that may be required in the front and back pole portions 30 , 36 as the forearm cradle 14 is rotated about axis A through its range of positions. FIGS. 5 and 6 show the increase in length that may be required of the expandable portions 40 , 42 when the forearm cradle 14 is rotated from a forward position as shown in FIG. 5 , around axis A, to a more backward position as shown in FIG. 6 . In FIG. 5 , when the forearm cradle is in its generally forward or weight bearing position associated with using the forearm crutch to walk, the expandable portion 40 is shown to have length L, and the expandable portion 42 is shown to have length M. In FIG. 6 , when the forearm cradle is in its generally backward or hands free position associated with using the forearm crutch at rest, the expandable portion 40 is shown to have length X+L, and the expandable portion 42 is shown to have length Y+M to accommodate the increased length that may be required in the front and back pole portions 30 , 36 . In addition, because the typical forearm crutch is adjustable for users of various heights and arm lengths, the expandable portions 40 , 42 may allow the same forearm crutch cover 10 to fit a forearm crutch at a variety of adjusted sizes.
The forearm crutch cover 10 may be made entirely of soft, flexible natural or man-made material. The use of an expandable portion 40 , 42 , however, allows for more freedom in selecting the material that may be used for the cover 10 . With the exception of the padding for the front cradle portion 26 , the forearm crutch cover 10 may be made of a harder, more durable material such as plastic, vinyl, metal or the like, or a combination of hard and soft materials, provided an expandable portion is used at some location along the forearm crutch cover 10 to allow for movement of the forearm cradle 14 .
The advantage of having an expandable portion, as at 40 , along the front or inside part of the crutch, below its cradle, is that furnishing and expandable portion at this location allows for the cradle to be biased back into its aligned position, ready for usage, in the event that the cradle may have been tilted or pivoted rearwardly, during usage. Thus, the use of an expandable portion at this location helps maintain the forearm crutch in proper alignment, ready for usage, whenever it is applied.
Another alternative for this invention includes a forearm crutch or cane having a forearm cradle constructed with a padded material attached to the inside of the forearm cradle. The invention could further include one or more pole portions covering at least part of the pivoting attachment junction of the forearm cradle and the pole.
A second preferred embodiment of the forearm crutch cover is shown in FIG. 7 . In this embodiment, cover 50 for a forearm cane or a forearm crutch as shown on a forearm crutch of in FIG. 1 having forearm cradle 14 , pole 18 and handgrip 20 . Pivoting attachment 16 of forearm cradle 14 to pole 18 is shown in the encircled portion of FIG. 1 without cover 50 . Again, pivoting connection 16 , shown as a yoke and bolt attachment in this embodiment, could be a collar and pin joint, a hinge, a swivel, a ball and socket assembly, or the like, depending upon the particular design and construction of the forearm cane or crutch. Pivoting connection 16 allows forearm cradle 14 to rotate about axis A through a range of positions. When utilized, cover 50 may fit over forearm cradle 14 and may cover at least a portion of yoke and bolt attachment 16 that pivotally attaches forearm cradle 14 to pole 18 . The front 52 of cover 50 may be situated inside forearm cradle 14 and may extend down pole 18 towards sidewardly extending handgrip 20 . The back 54 of cover 50 may be situated around the back or outside of forearm cradle 14 and may extend down pole 18 and may cover at least a portion of yoke and bolt attachment 16 that attaches forearm cradle 14 to pole 18 . In this embodiment, cover 50 is made from a flexible or nonflexible material that envelopes forearm cradle 14 . The back of 54 of cover 50 may include pleat 60 , which may be expandable to cover attachment 16 of forearm cradle 14 to pole 18 . This embodiment also includes optional safety strap 62 that covers the forearm when inside forearm cradle 14 . Safety strap 62 may be attached to the back 54 of cover 50 by hook and loop, or any suitable attachment method as described above. When the forearm crutch is used with cover 50 , the user positions safety strap 62 across the forearm, enclosing the U-shaped or C-shaped forearm cradle 14 . When the user releases handgrip 20 , safety strap 62 may allow the forearm crutch to hang or dangle from the user's arm and may prevent the forearm crutch from falling to the ground.
FIGS. 8 and 9 show an embodiment for the front 52 of forearm crutch cover 50 including front cradle portion 56 , pole extension 70 , and handgrip loop portion 72 , Front cradle portion 56 of cover 50 is situated inside forearm cradle 14 and comes directly in contact with the user's arm. Front cradle portion 56 may be padded with a breathable padding and made of non-allergenic material for the comfort of the user. Front cradle portion 56 may include a breathable pad or be constructed from material that minimizes or helps eliminate perspiration. Suggested materials for the cover include, but are not limited to, 1000 denier nylon for the outside and COOLMAX® for the breathable pad. As an option, front cradle portion 56 may include a removable pad that can be removed and discarded or removed and washed for reuse. Pole extension 70 attaches to front cradle portion 56 and extends down pole 18 towards handgrip 20 . Handgrip portion 72 includes handgrip loop 74 that may be placed around handgrip 20 as shown in FIG. 7 to help secure cover 50 to the forearm crutch. Handgrip loop portion 72 may include hook and loop attachment system, or some other suitable attachment system, to pole extension 70 . Pole extension 70 may be constructed of a stretchable or nonstretchable material such as elastic, or it may include a stretchable portion to accommodate the variation of lengths of poles 18 and to allow forearm cradle 14 to rotate through its range of positions as described hereinabove in a discussion of FIGS. 5 and 6 . Handgrip loop portion 72 may also adjust the length of pole extension 70 . As previously reviewed, the pole extension 70 may include a resilient portion, that continuously biases the cradle into proper alignment upon the forearm crutch, and to maintain it prepared for ready usage when applied. In other words, the user need not be continuously pivoting the cradle into a usable position, every time he/she wishes to make use of the same. Increasing and decreasing the amount of overlap between handgrip loop portion 72 and pole extension 70 , may allow cover 50 to be used with varying pole 18 lengths.
FIG. 10 depicts an option to the embodiment of cover 50 shown in FIG. 7 . In this option handgrip loop portion 72 is basically eliminated and handgrip loop 84 is attached directly to pole extension 70 . Pole extension 70 attaches to front cradle portion 56 and extends down pole 18 and attaches to handgrip 20 using handgrip loop 84 that may be placed around handgrip 20 . Another option shown in FIG. 10 includes the use of hook and loop straps 78 or any suitable attachment method as described above to secure front cradle portion 56 to forearm cradle 14 .
During normal operation, without forearm crutch cover 10 , forearm cradle 14 can pivot from its forward position desired during use by the user to a backwards position. When pivoted backwards, the user must first rotate forearm cradle 14 forward while balancing without the use of the crutch before placing an arm inside forearm cradle 14 for use. When forearm crutch cover 10 is attached to the forearm crutch with pole extension 70 engaging handgrip 20 by either option depicted in FIGS. 8 to 10 , cover 10 may help maintain forearm cradle 14 in a relative forward position. Therefore pole extension 70 may act as a forearm cradle 14 reset by resisting the tendency of forearm cradle 14 to fall backward out of the desired position of the forearm crutch user. Thus the need to find a place to balance while readying the forearm crutch for use may be minimized or eliminated.
FIG. 11 depicts the back 54 of cover 50 shown in FIG. 7 . Forearm cradle 14 fits inside 65 cover 50 , and hinged attachment 16 of forearm cradle 14 to pole 18 sits under or inside pleat 60 . Pleat 60 may be made of a durable material that generally holds its shape as described above. Pleat 60 may include a portion sized to enclosed is most or all of attachment 16 .
This description does not intend to limit the performance of these processes and functions to only the methods described herein. Many processes can be performed in a different, but equivalent manner or order than described herein without exceeding the scope of this invention.
Although the invention has been described in terms of specific embodiments and applications, persons skilled in the art can, in light of this teaching, generate additional embodiments without exceeding the scope or departing from the spirit of the claimed invention. In addition, specific features of the invention are shown in some drawings and not in others for convenience only, as each feature may be combined with any or all of the other features in accordance with the invention. Accordingly, it is to be understood that the drawings and description in this disclosure are proffered to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of application Ser. No. 07/950,294, filed Sep. 24, 1992, now U.S. Pat. No. 5,407,811, which is a division of application Ser. No. 07/647,209, filed Jan. 28, 1991, now abandoned, which is a continuation of application Ser. No. 07/494,858, filed Mar. 14, 1990, which is a continuation of application Ser. No. 07/279,280, filed Dec. 2, 1988, now abandoned, which is a continuation of application Ser. No. 06/771,247, filed Sep. 30, 1985, now abandoned, which is a continuation-in-part of 06/771,230, filed Aug. 30, 1985, which is a continuation-in-part of application Ser. No. 06/706,562, filed Feb. 28, 1985, now abandoned, which is a continuation-in-part of application Ser. No. 06/558,109, filed Dec. 5, 1983, now abandoned.
The present invention relates to a purified virus of Lymphadenopathy (denoted below by the abbreviation LAS) and of Acquired Immunodeficiency Syndrome (denoted below by the abbreviation AIDS), to a process for producing antigens of the envelopes of these viruses, and their use in the preparation of immunogenic compositions for the diagnosis of LAS and AIDS.
BACKGROUND OF THE INVENTION
A retrovirus showing characterizations of the etiological agent of AIDS has been identified. It was first described in an article of Barre-Sinoussi et al., Science, 220, 868 (1983).
This retrovirus has the following characteristics. It is T-lymphotropic; its preferred target is constituted by Leu 3 cells (or T4 lymphocytes); it has reverse transcriptase activity requiring the presence of Mg 2+ and exhibits strong affinity for poly(adenylate-oligodeoxy-thynidylate) [poly(A)-oligo(dT) 12-18]; it has a density of 1.16-1.17 in a sucrose gradient, an average diameter of 139 nanometers; and a nucleus having an average diameter of 41 nanometers; the lysates of this virus are recognized immunologically, these lysates contain a protein p25 recognized by the same sera but which is not recognized immunologically by the p24 protein of the HTLVI and II viruses.
Retroviruses of this type (sometimes denoted by the genetic abbreviation LAV) have been deposited in the National Collection of Micro-organism Cultures of the INSTITUT PASTEUR of Paris 28 rue du Docteur Roux, 75724 Paris Cedex 15, under numbers I-232, I-240 and I-241. Morphologically and immunologically similar virus strains have been isolated in other laboratories; the retrovirus strain HTLV-III (Gallo et al., Science, 224, 500 (1984); Sarngadharan et al., Science 224, 506 (1984); and ARV, isolated by Levy et al., Science, 225, 840-842 (1984). Reference is also made to European patent application filed Sep. 14, 1984, with the priority of British patent application No. 83 24800, filed Sep. 15, 1983, which corresponds to U.S. Ser. No. 06/558,109, filed Dec. 5, 1983, now abandoned, as regards a more derailed description of the LAV retroviruses and uses of extracts of these viruses.
Only the core antigens of the virus could be recognized, alter lysis of the virus, by sera of patients infected with AIDS or LAS. A protein p41 has been described in the above articles on HTLV3 as a possible component of the envelope of the virus. However, formal proof that p41 was a protein of the envelope has not been forthcoming.
Processes for obtaining a LAV virus or a related virus have also been described. Barre-Sinoussi et al., cited above describes the preparation of the virus in T lymphocyte cultures derived either from blood, or from the umbilical cord, or from bone marrow cells of adult donors in good health. This process comprises particularly the following essential steps:
viral infection of the T lymphocytes, after activation by a mitogenic lectin, with a viral suspension derived from a crude supernatant liquor of lymphocytes producing the virus (initially obtained from a patient infected with AIDS or LAS),
culturing of cells infected with TCGF, in the presence of anti-α-interferon sheep serum,
purification of the virus produced (production commences generally the 9th and the 15th day following the infection and lasts 10 to 15 days) by precipitation of the virus in polyethyleneglycol to produce a concentrated sample of the virus, then centrifuging the preparation in a sucrose gradient of 20 to 60% or in isotonic gradient of metrozanide (sold under the trade mark NYEGAARD™ by NYEGAARD™, Oslo). The virus is then recovered with a strip of suitable density 1.16-1.17 in the case of the sucrose gradient or 1.10-1.11 in a NYCODENZ™ gradient.
The LAV virus may also be produced from continuous cell lines of type T, such as the CEM cell line, or from B lymphoblastoid cell lines, such as obtained by the transformation of the lymphocytes derived from a healthy donor with the Epstein-Barr virus. The cell lines obtained continuously produce a virus (LAV-B) which possesses the essential antigenic and morphological lines of the LAV viruses (except that it is collected in a strip of density sometimes slightly higher than in the preceding case, particularly 1.18) in sucrose. The final purification of the virus can also be carried out in a NYCODENZ™ gradient. Reference can also be made to general techniques of producing virus type B-LAV, French patent application, 84 07151, filed May 9, 1984.
DESCRIPTION OF THE FIGURES
FIG. 1 is a photographic reproduction of gel strips used in the electrophoresis of lysate extracts of T lymphocytes infected with LAV, and uninfected T lymphocytes (controls).
FIG. 2 shows the restriction charts of several cloned plasmids comprising the genome of LAV. The cDNAs comprise a total of 9.1 to 9.2 kb.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention relates to a novel variety of purified retroviruses, related to the retrovirus defined above, but which are distinguished therefrom (or which is characterized) in that these viruses include one or several antigens having the characteristics of a glycoprotein in the tests which are described below. These antigens can be detected by labeling the virus with labeled cysteine, particularly 35 S-cysteine, in sufficiently high concentration in the culture medium of the virus, particularly 200 microcuries per ml of medium; wherein the culture medium is devoid of unmarked cysteine. These antigens are selectively recognized by sera of patients afflicted with AIDS or LAS or by the sera of asymptomatic carriers of the virus.
A preferred antigen, according to the preceding definition, obtained from a lysate of this virus (or by gentle scouring of the envelopes of the virus), has a molecular weight of about 110,000 daltons. This molecular weight can be compared with known molecular weight (MW) standards in a comparison of migration distances employing gel electrophoresis. In particular, the following proteins (marketed by AMERSHAM™) are employed:
lysozyme-( 14 C)-methyl(MW: 14,300),
carbon dioxide-( 14 C)-methyl (MW: 30,000),
ovalbumin-( 14 C)-methyl (MW: 46,000),
bovine albumin serum (14C)-methyl (MW: 69,000),
phosphorylase b-( 14 C)-methyl (MW: 92,500),
myosin-( 14 C)-methyl (MW: 200,000).
The gel electrophoresis was carried out on a 12.5% gel, then under a voltage of 35 V for 18 hours.
The invention also relates to antigens of the retrovirus, particularly antigens having a molecular weight of about 100,000. The antigens are recognized by sera of patients infected with AIDS or LAS or by sera of persons who have been exposed to LAV viruses, or viruses analogous with the latter. These antigens also form complexes with concanavalin A, said complex being dissociatable in the presence of O-methyl-α-D-mannopyranoside. The antigens according to the invention can also form complexes with other lectins. For example, those known as LENTYL-LECTIN. The preferred antigen according to the invention, having a molecular weight of about 100,000, is also sensitive to the action of endoglycosidases. On exposure to an endoglycosidase, the antigen having a molecular weight of about 100,000 produces a protein having a molecular weight of about 90,000, the latter being separable by, for example, immunoprecipitation or gel electrophoresis.
The preferred antigens of the invention are constituted by glycoproteins.
The invention also relates to the process for producing the viruses according to the invention. This process is distinguished from the processes described above in the method of final purification. In particular, the purification step of the process according to the invention does not employ gradients but involves performing differential centrifugations on the supernatants of the culture media of the producing cells. This process comprises a first centrifugation at an angular centrifugation velocity, particularly of about 10,000 rpm, enabling the removal of non-viral constituents, more particularly of cellular constituents, followed by a second centrifugation at a higher angular velocity, particularly at about 45,000 rpm, to precipitate the virus itself. In preferred embodiments, the first centrifugation, at 10,000 rpm, is maintained for 10 minutes and the second at 45,000 rpm, for 20 minutes. These are only indicative values, and it is within the ability of the specialist to modify the centrifugation conditions to ensure the separation of the cellular constituents and the viral constituents.
This modification of the purification process results in the production of viral preparations from which the characterized antigen can be isolated. This antigen has not been obtained from virus preparations purified by the previous methods. The viruses obtained by the process of the present invention are distinguished from the preceding viral preparations, in that they are recognized by sera of patients or of persons who have been exposed to the LAV virus or to morphologically and antigenically similar strains.
The antigen according to the invention can be obtained from these viruses by lysis (or other suitable processing) of the viruses in the presence of any suitable detergent and by recovery and separation of the liberated antigens. Advantageously, the lysis of the virus is effected in the presence of aprotinin or any other agent suitable for inhibiting the action of proteases. The separation of the antigens according to the invention can then be carried out by any method known: for example, it is possible to separate the proteins by employing their different migration distances in a predetermined gel, the desired protein is then isolated from the band of the gel in which it would normally be found in an electrophoresis process under determined conditions, having regard to its molecular weight. The antigen according to the invention can be separated from the lysate of the above viruses, due to their affinity for lectins, in particular, concanavalin A or lentyl-lectine. The lectin used is preferably immobilized on a solid support, such as the agarose-based cross-linked polymer marketed under the trade mark SEPHAROSE®. After contacting the lysate with a suitable buffer, the antigen retained can be eluted in any suitable manner, particularly by employing O-methyl-α-mannopyranoside in solution.
A more thorough purification of these antigens can be performed by immuno-precipitation with sera of patients known to possess antibodies against this protein, with concentrated antibody preparations (polyclonal antibodies) or with monoclonal antibodies, more particularly directed against the antigen of the invention, in particular, the antigen having a molecular weight of about 110,000, denoted below by the abbreviation gp110.
Additional characteristics of the invention appear in the following description of the isolation of a virus according to the invention, and of an envelope antigen of the virus. Reference is also made to FIG. 1, which is a photographic reproduction of gel strips which been used to carry out electrophoresis of lysate extracts of T lymphocytes, respectively infected and uninfected (controls) by a LAV suspension.
T lymphocytes derived from a healthy donor and infected with LAV1, under the conditions described by Barre-Sinoussi et al., or CEM cells derived from a patient afflicted with leukemia and infected in vitro with LAV1, were cultured in a medium containing 200 microcuries of 35 S-cysteine and devoid of marked cysteine. The infected lymphocytes were cultured in a non-denaturing medium to prevent the degradation of the antigen sought. The supernatant liquor from the culture medium is then centrifuged at 10,000 rpm for 10 minutes to remove the non-viral constituents, followed by a second centrifugation at 45,000 rpm for 20 minutes, to produce the sedimentation of the virus. The virus is then lysed with a detergent in the presence of aprotenin (5%), particularly under the conditions described by Barre-Sinoussi et al.
The same process is repeated on lymphocytes coming from a healthy donor as a control.
The various lysates were then immuno-precipitated by sera of patients infected with AIDS or with SLA, as well as from healthy donors or donors only infected with other diseases. The media were then electrophoresed in a SDS-polyacrylamide gel.
The results are shown in FIG. 1. The gel strips numbered from 1 to 6 were obtained from preparations labeled with 35 S-cysteine. The strips numbered 7 to 10 correspond to the results observed on infected or uninfected lymphocyte preparations labeled with 35 S-methionine. Finally, the strip M corresponds to the migration distances of the reference proteins identified above. The molecular weights of the reference proteins are recited in the right hand portion of the figure. To the left of the figure are referenced the labeled viral proteins.
It is noted that columns 7 to 10 show protein p25 of LAV, marked with 35 S-methionine. This protein is absent from the columns 8 to 10 corresponding to results obtained from healthy lymphocytes.
The columns 3 and 5 correspond to the results observed on preparations obtained from lymphocytes infected and marked with 35 S-cysteine. The proteins p25 and p18 were characteristic of proteins of the nucleotide of LAV and the glycoprotein gp110, also specific of LAV. There also appear in the various preparations, although less distinctly, images corresponding to a protein p41 (molecular weight of the order of 41,000), non-specific to the LAV virus. This protein is also observed in the controls.
The virus according to the invention and the antigen according to the invention can be either precipitated by lectins, particularly concanavalin A, or fixed to a SEPHAROSE®-concanavalin A column. This fixation comprises contacting the lysate of the above virus in a buffer to form the following composition:
______________________________________ Tris 10 mM NaCl 0.15 M CaCl 1 mM MgCl 1 mMDetergent marketed under the trademark TRITON ™ 1% pH 7.4______________________________________
Once the fixation has been effected, the SEPHROSE®-concanavalin A is washed with a buffer of the same composition, except that the TRITON™ is lowered to 0.1%. The elution is then effected with an 0.2M o-methyl-α-D-mannopyranoside solution in the washing buffer.
The protein may be further concentrated by immuno-precipitation with antibodies contained in the sera of patients infected with AIDS, or with polyclonal antibodies obtained from a serum derived from an animal previously immunized against the virus of the invention, or the above glycoprotein. The protein can then be recovered by dissociation of the complex employing a solution having an adequate content of ionic salt.
Preferably the above antibody preparation have been previously immobilized on an insoluble support of the SEPHAROSE® B type.
It is also possible to employ monoclonal antibodies secreted by hybridomas previously prepared against gp110. These monoclonal antibodies, as well as the hybridomas which produce them, also form part of the invention.
Below are described the conditions under which the monoclonal antibodies according to the invention can be prepared.
Immunization of the Mice
Groups of Balb/c mice aged from 6 to 8 weeks were used. One group received the virus containing the above glycoprotein, another the glycoprotein gp110. The immunization procedure, identical for the 4 mice, consisted of an injection, intraperitoneally, with three repeats, followed by one injection intravenously of 10 mg of the antigenic preparation, in the presence of Freund complete adjuvant at day 0, Freund incomplete adjuvant at day 0, Freund incomplete adjuvant at day 14, and without adjuvant at days 28 and 42.
Fusion and Culture of the Hybrids
The variant 6.53 which does not secrete myeloma P3×63 Ag8, is resistant to azaguanine, and which is derived from the cell line MOPC-21, was used. Fusion with immunized mouse splenocytes was carded out in the presence of polyethylene-glycol 4000 by the technique of FASEKAS DE ST-GROTH and SCHEIDEGGER on the 45th day (8). The selection of the hybrids in RPMI 16-40 "HAT" medium was carded out by the same culture in 24 plates (Costar).
The hybridomas producing antibodies of adequate specificity were then cloned in plates of 96 cups, in the presence of a "feeder" layer of syngenic thymocytes. The producing clones selected were then expanded in 24 cup plates, still in the presence of thymocytes. When the confluence appeared in one of the cups, the clone was injected intraperitoneally into a BALB/c mouse which had received an injection of Pristane 8 days previously, and/or kept in liquid culture.
Demonstration of the Anti-LAV Antibodies
Five different techniques enabled the characterization of the clones which produced antibodies of interesting specificity. In a first stage, the hybrids producing antibodies were determined by an ELISA test revealing mouse immunoglobulins in the supernatant liquors. From this first selection, supernatants were selected which had antibodies directed against viral constituents as shown by an ELISA test revealing anti-LAV antibodies (9), or by immunofluorescence on the virus producing human cells. Finally, the supernatant liqours were analyzed by radioimmunoprecipitation of virus labeled with cysteine and by the technique of Western-Blot on viral preparation (10), which permitted the determination of the specificities of these anti-LAV antibodies.
RESULTS
Cells obtained from the various fusions were cultured in 648 cups. Their microscopic examination has shown that the majority of these cups contained a single hybrid clone capable of growing in a "HAT" selective medium. More than 50% of the samples produced antibodies giving rise to a positive response on ELISA antivirus examination. The most representative fusions were tested by the Western-Blot technique and several of the fusions were subcloned, taking into account their specificity, their reactivity in antivirus ELISA and their behavior in cultivation. The hybrids which produced antibodies which recognized gp110 were preferably selected. All of the subclones produced antibodies which, after expression, were injected into syngenic mice. Analysis of the specificities of the antibodies present in the different ascites liquids confirm the specificity of the antibodies of said ascites with respect to gp110.
The monoclonal antibodies obtained can be employed to purify proteins containing an antigenic site also contained in gp110. The invention relates therefore, to these processes of purification. This process is advantageously applied to virus lysates, or T lymphocytes lysates, or other cells producing LAV or the like, when before the lysis is performed care is taken to avoid the uncontrolled separation of gp110 (this process can also be applied to any solution containing gp110 or a protein, polypeptide or glycoprotein comprising an antigenic site of an envelope protein recognized by the monoclonal antibody, whatever the nature of this solution). For practicing this process, the monoclonal antibodies are advantageously immobilized on a solid support, preferably adapted to affinity chromatography operations. For example, these monoclonal antibodies are fixed on an agarose lattice with three-dimensional cross-linking, marketed under the trade mark SEPHAROSE® by the Swedish company PHARMACIA A.G., for example, by the cyanogen bromide method.
The invention therefore relates more particularly to a process for separating the antigens characterized by processes comprising contacting the culture medium which may contain the antigens with an affinity column having the above monoclonal antibodies, to selectively fix said polypeptides, proteins or glycoproteins, and then to recover the latter by dissociating the antigen-antibody complex formed by employing a suitable buffer, particularly a solution of adequate ionic strength, for example, of a salt, preferably ammonium acetate (which does not leave a residue when freeze drying of the preparation is then carried out). It is also possible to employ a solution acidified to pH 2-4 or to a glycine buffer at the same pH.
These antigens can be employed as reagent or as in vitro diagnostic agents for the detection of anti-LAV antibodies. It is self-evident that the invention relates also to polypeptide fractions which can have lower molecular weights, when the polypeptide fractions carry antigenic sites recognizable by the same monoclonal antibodies. It will be clear to the specialist that the monoclonal antibodies of the invention enable the isolation, from the above-indicated antigens, of smaller peptide sequences containing the same antigenic sites, for example, by using known techniques of cutting up the original polypeptide employing enzymes capable of cleaving the larger polypeptides at specific sites. As an example, the enzyme of Staphilococcus aureus V8, alpha-chymotrypsine; "mouse sub-maxilllary gland protease" marketed by the BOEHRINGER™ company, Vibrio alginolyticus chemovar iophagus collagenase, specifically recognizes the peptides Gly-Pro and Gly-Ala, etc.
It is also possible to isolate polypeptides or fragments of antigens of envelopes of the virus, by cloning fragments excised from a cDNA constructed from genomes of the various varieties of LAV viruses and the like.
FIG. 2 is representative of restriction charts of several of these cDNAs comprising a total of 9.1 to 9.2 kb. More particularly, the polypeptides coded by cDNA fragments located in the region extending between the site KpnI (position 6100) with respect to restriction charts of FIG. 2 and site BglII (position 9150). The presence of a site characteristic of an antigen of the envelope of LAV or the like in the polypeptide which can be expressed (in a suitable host cell previously transformed by such a fragment or by a vector containing this fragment) can be detected by any suitable immunochemical means.
The antigens can also be used to separate antibodies having the above indicated characteristics from the polyclonal antibody mixture. In this case, the polypeptides can also be immobilized on an affinity chromatography support., for example, of the type indicated above. The process of separation will comprise contacting a solution containing the polyclonal antibodies with immobilized polypeptides, followed by recovering the antibodies retained by employing a solution or a buffer similar to that described above.
Finally, the invention relates to immunogenic composition characterized by the association of an antigen of the invention, and an immunogenic particle particularly in the proportion of 10 to 500, more particularly from 50 to 100 micrograms/kg, with a physiologically acceptable excipient permitting its administration to a living host, more particularly man, to confer on the host immunity with respect to said antigens, including the LAV viruses or entire analogs. These antigens comprise active principles whose immunogenicity can be employed any time that protection is sought in vivo against LAV viruses which are related to the immunogenic particles.
The invention also relates also to a process using the antigens of the invention for the detection of the presence of anti-LAV antibodies, particularly in blood specimens derived from man or from an animal, indicating the presence of AIDS or of LAS.
Finally, the invention relates to an in vitro process of diagnosis employing an envelope antigen of the invention for the detection of anti-LAV antibodies in the sera of patients afflicted with the disease or persons immunized against the virus. More particularly, the invention relates to a "kit" comprising this antigen.
The diagnostic method comprises:
depositing predetermined amounts of an antigen of the invention in the cup of a titration microplate:
adding increasing dilutions of the serum to be diagnosed into the cups;
incubating the microplate;
washing the microplate;
introducing into the cups of the microplate labeled antibodies of immunoglobulins of the blood, the label being an enzyme selected from enzymes capable of hydrolysing a substrate such that the substrate undergoes a modification of its absorption of radiations, at least within a predetermined band of wavelengths, and
detecting, preferably comparatively with respect to a control, the amount of hydrolysis of the substrate as a measure of the potential risks or of the effective presence of the disease.
Of course, it is possible to carry out quantitative titrations of antibodies on the sera studied.
Preferred methods employ immuno-enzymatic or immunofluorescent titrations, in particular, employing the ELISA technique. Titrations may be determinations by immunofluorescence or direct or indirect immuno-enzymatic determinations.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a perfusion apparatus (heart/lung machine) used during open heart surgery, liver transplants, repairs of the aorta, and other surgical or emergency procedures that require the use of an extra corporeal device. More particularly, the present invention relates to a semi-automatic perfusion machine.
2. Description of Related Art
In many surgical procedures, the functions of the heart and lungs are performed outside of the body by specialized devices such as membrane oxygenators, cardiac assist pumps and heat exchangers. This array of equipment is operated by a perfusionist who supervises the removal and return of the patient's blood during the procedure.
Prior art devices used for regulating and processing blood taken from a patient have had a number of disadvantages. Historically, gravity has been used for drawing blood from the patient into a storage container, said storage container being either a hard or soft-shelled reservoir. Gravity procedures require that the reservoir be placed below the level of the patient near the floor. This is done to facilitate the siphoning of blood from the patient to the reservoir. Thus, increasing venous return (de-oxygenated blood leaving the patient) may require raising the patient and operating table, resulting in a need to lengthen the perfusion circuit and add prime volume for the conduits that lead from the operating table down to the reservoir and back to the patient. With prior art systems, the pump was required to generate incremental pumping energy to overcome the hydrostatic head of at least three feet, in addition to energy needed for the rest of the extracorporeal circuit resistance and patient pressure.
An additional disadvantage of the prior art devices just discussed is that the priming volume for the conduits from the table down to the heart/lung machine and back, along with the volumes required for the separate reservoirs, pumps, and interconnecting tubing can end up being a large volume, sometimes two to two and a half liters. Such volume acts to dilute the patient's own blood supply. As such, hemoconcentration of the patient and a significant amount of additional blood, or both, may be required to support the patient. In addition, all the additional conduit material increases the foreign surface area that the blood comes in contact with. Such contact with foreign surface area has been reported to cause damage to the complement, coagulation, and immune system of the patient.
During surgical procedures a significant amount of the patient's blood is lost as a result of bleeding into the chest cavity. The prior art perfusion devices used separate suction devices for recovery of this blood from the operative field, i.e., cardiotomy suction. Blood recovered from cardiotomy suction was in some prior art devices fed into the reservoir. These separate suction devices have been unable to recover and process the shed blood without causing irreversible damage to the formed and unformed elements of the blood.
After blood has been removed from the patient, either through the venous return line, cardiotomy suction or otherwise, it must be directed to an oxygenator, heat exchanger, and filter before being returned to the patient. Bubbles and gross air may be entrapped in the blood that comes from cardiotomy suction and from the venous return line. Such air must be removed before the blood can be safely returned to the patient. A particular problem encountered with past systems that have utilized unsealed reservoirs or, in other words, reservoirs that are open to atmospheric pressure, is that the perfusionist must ensure a minimal blood level in the reservoir in order to prevent gross air from entering the arterial circuit.
In the unsealed reservoir prior-art systems, the mechanism for bringing blood into the reservoir, i.e, either cardiotomy suction or the gravity fed venous return line is completely separate from the mechanism that drains blood from the reservoir, i.e, the pump. It was therefore the perfusionist's job to ensure that in-flow met out-flow in such a way that the blood level in the reservoir did not completely empty, thereby allowing gross air to enter the pump. Therefore, the perfusionist had to constantly increase or decrease the pump output, or increase or decrease the flow from the patient by opening or closing clamps to the venous return line, to maintain a minimum blood level in the reservoir. If gross air entered the pump from an empty reservoir, the perfusionist had to stop the pump and then reprime the system to force the air back into the reservoir before restarting pumping.
In prior art systems, the perfusionist was usually required to use manually operated clamps to control the perfusion circuit along with a pump controller that controlled the output of the reservoir through the pump. Because prior art unsealed reservoirs required constant monitoring, an undesirable situation was created when the perfusionist must perform sampling and other duties throughout the procedure which necessarily diverted the perfusionist's attention away from the perfusion circuit.
The objective of all perfusion apparatus is to ensure that the patient's blood supply is removed, oxygenated, cooled and/or heated and pumped back into the patient in the least traumatic and safest way possible. Therefore, it is evident that there exists a need for a perfusion system that requires a small priming volume, utilizes less foreign surface area, provides fail-safe protection from air being returned to the patient and requires relatively less attention from the perfusionist.
SUMMARY OF THE INVENTION
The present invention provides a perfusion apparatus that improves the regulation of blood flow during surgery or emergency procedures, minimizes priming volume, minimizes foreign surface contact, minimizes pumping pressure requirements and is safe and easier to use. In one embodiment, the invention includes a sealed reservoir that allows air entrapped within the blood supply from a patient to separate from the blood and thereafter by prevented from returning up the venous return line or out-flowing from the reservoir itself into a patient's vascular system. In a further embodiment, the reservoir can be connected to or made integral with a pump. These embodiments are not mutually exclusive and may be incorporated together into a single unit.
In a preferred embodiment, the reservoir incorporates a sealed hard shell reservoir with an integral blood pump mounted vertically below the reservoir. The blood pump may be of any variety. However, a centrifugal is preferably used as the pump.
The term "sealed reservoir" as used in the context of the present invention means that the reservoir is sealed airtight in such a way that any negative pressure created at the inlet of the pump is and can be communicated directly to the reservoir, distributed there throughout and therefore communicated through any conduits connected to the reservoir. The perfusionist may, for reasons to be discussed later, increase the pressure in the reservoir above the negative pressure created by the pump by opening the reservoir to atmospheric pressure or decrease the pressure in the reservoir below that of the negative pressure created by the inlet of the pump by opening the reservoir to a vacuum source. Because of the sealed nature of the reservoir, the pressure within the reservoir may be controlled at all times by the perfusionist.
The reservoir is filled from a primary venous return line that brings unoxygenated blood from the patient. The venous return line in the preferred embodiment enters the top of the reservoir. Such entry conduit is connected to a one-way valve at its distal end to prevent retrograde flow of venous blood and preclude the passage of air from the reservoir to the patient through the venous return line if the reservoir were to be brought to a pressure greater than that of a patient's own venous pressure. Throughout this disclosure, distal means furthest from the point of reference and proximal means closest to the point of reference.
The reservoir, at its exit, has a floating ball valve that is designed so that the ball will seat if there is insufficient fluid in the reservoir to maintain the ball's buoyancy. Therefore, air will be prevented from leaving the reservoir and entering the pump where it could be passed on toward the patient. As will be apparent to those skilled in the art, any valve that will remain open when substantial fluid exists in the reservoir and close when a minimum amount of fluid is left in the reservoir would suffice. As further protection against air entering the patient's blood stream, during normal operation, any gross air or entrained air that may enter or be contained in the pump may be eliminated by stopping the pump so that the air in the pump can flow up toward the reservoir.
By design, pumps create positive pressure on the outlet and negative pressure on the inlet to the pump. This negative pressure is transferred to the perfusion circuit through the fluid in the reservoir and the venous line. In the preferred embodiment, with the pump directly connected to or integral with the reservoir, the negative pressure of the pump is contained in the sealed reservoir and that negative pressure is then used to facilitate venous flow without hydrostatic or syphon requirements.
The blood may be removed from the patient through one or more cannulae inserted into blood vessels or chambers of the heart of the patient. This blood is free of debris from bone or tissue that is often present in, for example, a patient's chest cavity during surgery. The blood passes from the cannula into the venous return line to the sealed reservoir because of the small amount of suction the pump creates within the reservoir while it is pumping. It is because of this feature that the device can be placed near the patient and at his or her level, thus eliminating the long lines of tubing necessary for prior art devices. Eliminating the long lines of tubing reduces the foreign surface area that the blood necessarily contacts, as well as reduces the necessary priming volume.
The sustained negative pressure within the reservoir created via the pump is communicated to the venous return line via an unfiltered connection site to which the tubing of the venous return line is connected. An unfiltered connection site is one where the connection feeds fluid directly into the mixing chamber where the fluid mixes with blood from the various return lines. This connection site is unfiltered because the blood is free from debris. The negative pressure in the reservoir causes the movement of blood from the cannula (high pressure) to the reservoir (low pressure).
Other connection sites are preferably filtered connections because fluid entering these sites may come from areas where debris may mix with the blood. One example of such an area is the chest cavity where the blood may be contaminated by bone fragments or other tissue as a result of the process of opening the patient's chest for surgery. This blood is brought through filter and defoamer materials before mixing with the blood coming from the venous return line. Such filtered connection sites remove bubbles and debris in the blood. Consequently, such sites are particularly well adapted for use in left ventricular sumps or for cardiotomy suction, as well as for other means.
Traditionally, cardiotomy suction has been separately provided by roller pumps that potentially pull a strong vacuum. This not only introduces additional pumps into the system, but involves the use of a more blood-destructive roller pump. The present system using a centrifugal pump or other pump with less negative pressure at the inlet than a roller pump will provide a more gentle suction action to be used with cardiotomy suction. This is desirable because the gentle suction will provide less velocity and turbulence of the blood than does a relatively stronger suction. Such a system also reduces the number of pumps needed to effect the extracorporeal circulation from two to one.
Blood retrieved by cardiotomy suction from the patient's chest cavity or heart or both enters the reservoir through the connection sites that may or may not be filtered sites depending on the cleanliness of the blood. If the blood needs to be filtered, the blood passes through a filter and a defoamer before entering the main mixing cavity of the reservoir. In the main cavity, venous blood is mixed with cardiotomy blood sources and other miscellaneous blood sources. The mixture is then passed through defoamers before passing on to the outlet of the reservoir. In addition, simply by having a reservoir with slightly negative pressure, entrained air and gross air tend to be removed out of the blood and moved upward into the upper parts of the reservoir.
A variable pressure source can be connected to a port on the sealed reservoir. If the need arises, the pressure within the reservoir can be brought to a value lower than that provided from the suction of the pump. This can be done by opening the reservoir to a vacuum source. As a result of increasing the negative pressure in the reservoir, the rate of drawing blood from the patient will be higher than the rate resulting from just the negative pressure generated by the pump. As a result of the greater negative pressure, the level of blood in the reservoir will increase resulting in a net removal and sequestration of blood from the patient.
When the volume of blood removed, or any volume including the blood removed from the patient and additional fluids added to the reservoir, needs to be given back to the patient, the pressure within the reservoir can be brought to a value higher than the suction of the pump. This can be done by opening the reservoir to the atmospheric pressure. With the relatively higher air pressure in the reservoir, relatively more blood will be taken from the reservoir through the pump and on to the patient than is being brought into the reservoir. This will cause the fluid level in the reservoir to drop.
Finally, an extra volume of blood or balanced electrolyte solutions may be given to the patient from outside sources by connecting the source fluid to a filtered or unfiltered connector on the reservoir. This puts the added fluid in communication with the suction created in the reservoir by the pump.
While the blood passes through the reservoir, any air that is entrained in the venous return line from cardiotomy suction, left ventricular suction, outside fluid source or by other means will be eliminated from the blood in the relatively large, i.e., large relative to the area of the tubing, expanse of the reservoir.
Another embodiment of the present invention includes the use of the hard-shelled reservoir as an unsealed reservoir but still incorporates the floating ball valve at the bottom. As such, when the volume of fluid in the reservoir is depleted, the ball valve will seat, and no air from the reservoir will enter the pump. The pump may continue to pump thereby pulling a gentle vacuum against the ball valve until fluid refills the reservoir. At that point, a brief stoppage of the pump will release the ball to float up with the buoyancy of the fluid and the pump may be simply restarted because there will be no air in the system. In prior systems, the perfusionist would have had to back-fill the pump, the tubing, and the reservoir prior to restarting the system to eliminate any air that had exited from the reservoir once the fluid level was depleted.
In a further preferred embodiment of the present invention, an electronic control panel is utilized to operate electrically or pneumatically controlled clamps can be placed on critical tubes throughout the perfusion system to control the entire perfusion system. In addition to the remotely controlled clamps, the control panel utilizes sensors such as pressure, temperature, fluid level, etc., to feed back information to the control panel for display to the operator. As will be apparent to those skilled in the art, some aspects of control may then be made automatic.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram of the perfusion system of the invention.
FIG. 2 is a cross-section view of a preferred embodiment of the sealed reservoir and attached pump of the present perfusion system;
FIG. 3 is a block diagram of a preferred embodiment of the control system of the present invention; and
FIG. 4 is a cross-section view of the preferred embodiment of FIG. 2 with the addition of a bypass apparatus.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention relates to a perfusion system used in performing surgeries or procedures when blood is removed from and returned to the patient. Throughout this description, like elements are referred to by like reference numbers. In a preferred embodiment, shown in FIG. 1, a perfusion circuit 10 is shown having a sealed reservoir 12, a pump 14, an oxygenator 16 and a heat exchanger 18. Blood passes from a cannula 20 in a patient's vein or heart to a cannula 22 in an artery or aorta through reservoir 12, pump 14, oxygenator 16 and heat exchanger 18.
Referring now to FIG. 2, a sealed reservoir 12 and centrifugal pump 14 of the preferred embodiment of the present invention is shown.
A cannula 20 is generally inserted into a vein or chamber of the heart so that blood flows to the perfusion reservoir 12 through the venous return line 24. The blood passes from venous return line 24 into the mixing chamber 26 through a one-way valve 28 at the end of venous return line 24. One-way valve 28, in the preferred embodiment, is a duck-bill valve such as is manufactured and distributed by American Omni, Inc. of Irvine, Calif. Although one-way valve 28 is preferable a duck-bill valve, any type of one-way valve may be used. An example of another such one-way valves is, but is not limited to a spring loaded seating valve. One-way valve 28 prevents retrograde flow of blood from reservoir 12 back toward the patient. Additionally, one-way valve 28 prevents air within reservoir 12 from flowing in a retrograde direction to the patient should pressure within reservoir 12 ever exceeds patient venous pressure. Air that may enter the mixing chamber 26 from the venous return line 24 will be dissipated to the top of reservoir 12. The dissipation of the air in reservoir 12 is enhanced by the sub-ambient pressure in reservoir 12 compared to the pressure in the blood.
Blood passes from the mixing chamber 26 through a defoamer 30 and filter screen 34 before being passed through a mixed chamber 32. Defoamer 30 is preferable a polyurethane open cell silicone antifoam although defoamer 30 may also be any biocompatible material with a large surface area. Filter screen 34 is preferably a sock-like enclosure made of a nylon trico material.
Blood, having previously had any air present removed in chamber 26, leaves the mixed chamber 32, and therefore reservoir 12, through a floating ball valve 36. Ball valve 36 may be of the type manufactured by Healthdyne Cardiovascular, Inc. of Costa Mesa, Calif. Blood leaves ball valve 36 through line 38 and passes to centrifugal pump 14. In ball valve 36, an opening 40 allows blood in mixed chamber 32 to pass into ball valve 36. Ball valve 36 includes a ball 42 designed to float or be buoyant in blood or blood products and will seat on site 44 if insufficient blood remains in ball valve 36 to continue to float the ball 42. Ball 42 will seat on site 44 only after virtually all the blood has been removed from chamber 26. Site 44 is preferably an O-ring to provide a sealed seat for ball 42 to rest on. When ball 42 is seated on O-ring 44, no air may pass from reservoir 12 into pump 14 through line 38.
In the preferred embodiment, pump 14 is a centrifugal pump that utilizes smooth conical impellers. Such a pump is manufactured and distributed as a Biopump BP-80 by Medtronic Bio-Medicus, Inc., 9600 W. 76th Street, Eden Prairie, Minn. While a centrifugal pump is preferred for pump 14, any pump that pulls a suction at its inlet could be used with the present invention. Examples of such pumps include, but are not limited to peristaltic or "roller" pumps. With the preferred centrifugal pump 14, air that gets into pump 14 may be eliminated from pump 14 by stopping pump 14, thereby allowing the air to rise from pump 14 through line 38 into ball valve 36 and into reservoir 12 where it will separate from the blood contained therein.
Not shown is the controller that controls pump 14. Such a controller, with a centrifugal pump, provides the turning power and RPM control for pump 14. Furthermore, to enhance the buoyancy effects of the floating ball valve 36, the external dimensions of reservoir 12 are preferably approximately four inches in diameter and eighteen inches high for a reservoir 12 to be used on an adult. As will be clear to those skilled in the art, these dimensions are approximate and may be varied as needed or desired. In addition, these dimensions will be smaller for a reservoir 12 to be used on a pediatric patient.
Reservoir 12 is preferably sealed and requires all ports to be actively occluded or connected to the patient in order to maintain the desired pressure inside reservoir 12. The pressure in mixing chamber 26 is in complete communication with mixed chamber 32. Therefore, the pressure everywhere within reservoir 12 is the same. The fluid level in the mixed chamber 32 is held constant, or nearly so, as long as reservoir 12 is sealed and the subambient pressure generated by pump 14 is maintained. However, the fluid level within reservoir 12 can be altered by using pressure differentials between site 46 and the suction pressure generated by pump 14 at ball valve 36. The pressure differentials can be used to add volume to the chamber 32 by taking volume from the patient, or they can be used to remove volume from the chamber 32 and thereby give volume back to the patient.
A vacuum source 48 attached to reservoir 12 may be controlled so that the pressure in line 50 is lower than in reservoir 12. The reservoir pressure can be measured anywhere within mixing chamber 26 or mixed chamber 32. When the greater negative pressure in line 50 is communicated via site 46 to reservoir 12, volume from the patient will be added to reservoir 12.
If volume in reservoir 12 is to be given back to the patient, site 46 is communicated to atmospheric pressure via line 52. The pressure in reservoir 12 is then greater than the pressure in pump 14. This causes volume to leave reservoir 12 through the oxygenator 16, heat exchanger 18 and cannula 22.
Blood spilled into the operative site in the patient's body during the operation is brought back to reservoir 12 by way of cardiotomy suction. This is done by connecting a suction line 54 ending in a sucker tip 56 to site 58. The sucker tip 56 at the end of suction line 54 is placed below the level of blood in the operative field. Suction line 54 is thereby exposed to the gentle suction contained within the sealed reservoir 12. The blood passes through sucker tip 56 and suction line 54 to site 58 through filter 60 and defoamer 62 and enters mixing chamber 26 through opening 64. Defoamer 62 is preferably a polyurethane open cell antifoam material but may also be any other type of defoamer as will be well understood by those skilled in the art. Filter 60 is preferably a forty micron filter made of a non-woven felt material but may also be any other type of filter for removing debris from blood as will be well understood in the art. Site 58 is a filtered connection because fluid entering there is filtered before mixing with the venous return blood in chamber 26. In the mixing chamber 26, the cardiotomy blood is mixed with the blood and fluids in chamber 26 before being passed through defoamer 30 into the mixed chamber 32. Air that may be brought back with the cardiotomy blood through line 54 or through the venous return line 24 is separated from the blood in reservoir 12 by allowing the air to dissipate to the top of reservoir 12.
In a preferred embodiment the defoamer foam material of 30 and 62 are sprayed with a silicon antifoam such as Antifoam A®, made by Dow Corning, to enhance defoaming capability. In addition, all surfaces in perfusion circuit 10 that will contact blood are preferably coated with a covalent heparin bonding material such as CARMEDA® Bioactive Surface Material sold by Medtronic, Inc. of Minneapolis, Minn. The covalent heparin bonding material increases the biocompatability of any surface of perfusion circuit 10 that may come into contact with blood, thereby reducing clotting.
Often blood lost during surgery cannot be recovered. Balanced electrolyte solution or an outside supply of blood is used to make up for the blood lost. When additional fluids are required, they are added via conduit tubing that delivers the fluid into an unfiltered site 66 of reservoir 12 that empties into mixed chamber 32. The added fluid is then mixed with the patient's blood and is delivered to the patient.
In the preferred embodiment, centrifugal pump 14 is located below reservoir 12 so that blood from reservoir 12 is supplied to centrifugal pump 14 under hydrostatic pressure during surgery as long as the volume in mixed chamber 32 is great enough to float ball 42. This centrifugal pump 14 creates positive pressure at its outlet site 68 and simultaneously creates a negative pressure at inlet line 38.
Pump 14 is also preferably made integrally with reservoir 12 so that the length of inlet line 38 is minimized. In another preferred embodiment, pump 14, though attached to reservoir 12, is not made integrally with reservoir 12. Pump 14 may also be located a distance from reservoir 12 so that inlet line 38 may have a significant length. The negative pressure, or suction, created by pump 14 is communicated equally throughout reservoir 12 because reservoir 12 is sealed. The suction contained in reservoir 12 causes venous blood flow through venous return line 24 without having to lower reservoir 12 below the patient to create a syphon effect. Since reservoir 12 can now be placed at the level of the patient, shorter lines can be used between cannula 20 and the patient and reservoir 12. This reduces both the prime volume needed to get the perfusion circuit 10 started and also reduces the foreign surfaces that the blood must contact throughout the extracorporeal circuit.
Additional unfiltered ports, such as 70 and 72, may communicate directly with the mixing chamber 26. Additional filtered ports, such as 74, may also exist that allow fluids added to reservoir 12 to pass through defoamer 62 and then through filter 60 before entering mixing chamber 26. These filtered ports 74 could be utilized for additional cardiotomy lines.
Ventricular sumping is achieved by way of connecting a ventricular sumping line 75 to port 76 that provides a gentle suction to cannula 20 placed into the left ventricle of a heart to keep the left ventricle empty. Blood entering reservoir 12 through port 76 bypasses filter 60 and defoamer 62 and passes directly into mixed chamber 32 through opening 78. This system brings the blood back to the unfiltered mixed chamber 32 for re-introduction into the extracorporeal circuit.
As shown in FIG. 1, the output from pump 14 is processed through an oxygenator 16 and a heat exchanger 18. The oxygenator 16 and heat exchanger 18 may be provided integrally with pump 14 and reservoir 12. Alternately, either oxygenator 16 or heat exchanger 18 may be made integrally with pump 14 with or without an integral reservoir 12. In another alternate embodiment, oxygenator 16 or heat exchanger 18 may be made integrally with reservoir 12 regardless of whether pump 14 is integral with reservoir 12.
The perfusion circuit 10 of the present invention can also be used for procedures such as thoracic aneurysms and liver transplants. These procedures do not utilize an oxygenator 16 but could benefit from the use of the combined reservoir 12 and pump 14 of the present invention. Because the fluid level in reservoir 12 is essentially constant once established, the use of the combined reservoir 12 and pump 14 of the present invention will provide additional safety beyond simply using a pump system to pull blood from the body and return it back to the patient. In addition, because the perfusion circuit 10 of the present invention can be primed quickly and easily and be ready to apply to the patient in very short order, perfusion circuit 10 may be used for urgent or emergency situations in the cath lab, emergency room, ICU, CCU or hospital room. To prime the perfusion circuit 10 requires simply supplying some prime fluid to the sealed reservoir 12 to establish a minimum fluid level thereby opening ball valve 36. Pump 14 is then turned on and the system, including oxygenator 16, heat exchanger 18 and the rest of perfusion circuit 10 primes itself by movement of fluid from pump 14 through perfusion circuit 10.
The present invention provides a perfusion circuit 10 that may be primed with approximately half the amount of prime volume currently required for prior art systems. In addition, because perfusion circuit 10 can be placed close to the patient thereby reducing the lengths of tubing needed, the amount of foreign surface level contacted during perfusion activities is substantially reduced. Reducing the length of foreign surface contacted by the blood provides less trauma to the blood and reduces clotting.
Finally, because the outlet flow and the inlet flow of reservoir 12 may be made to be the same due to the sealed nature of reservoir 12, the fluid level within reservoir 12 remains virtually constant. Because of the sealed nature of the reservoir 12 and pump 14 system, the fluid level in reservoir 12 is virtually constant and therefore no gross air may enter perfusion circuit 10. This reduces the burden on the perfusionist to try to constantly match in-flow and out-flow to and from reservoir 12. In addition, the perfusion circuit 10 can be set to provide a more constant rate of blood withdrawal and return to the patient, rather than having to fluctuate the output of pump 14 to prevent gross air from entering perfusion circuit 10. Such fluctuation of the flow from pump 14 varies the amount of blood returning to the patient.
Referring to FIG. 3, a preferred embodiment of the control system of the perfusion circuit 10 is shown generally labelled 80. The preferred embodiment of control system 80 includes pneumatically or electrically operated clamps. The first clamp 82 is placed on the venous return line 24. The second clamp 84 is placed on a by-pass line 86 going directly from the oxygenator 18 back to reservoir 12. The third clamp 88 is placed on the atmospheric vent line 52. The fourth clamp 90 is placed on an IV line entering unfiltered site 66 for providing either a balanced electrolyte solution or blood from an outside source. The fifth clamp 92 is placed on the line 50 from vacuum source 48. The sixth clamp 94 is placed on the outlet from pump 14 to oxygenator 16. The seventh clamp 96 is placed on the line 54 used for cardiotomy suction. Although specific arrangements of clamps 82, 84, 86, 88, 90, 92, 94 and 96 have been shown, it is to be understood that other arrangements of these or additional clamps may be used and still be within the intended scope of the disclosed invention.
Pressure transducers 98a-e are used to measure the pressure of the vacuum source 48 and the pressure of reservoir 12, pump 14, oxygenator 16 and atmospheric pressure, respectively. Additionally, transducers 99a-d can also be used to monitor fluid level in reservoir 12, the flow rate and possibly even detect air or bubbles in either the in-flow or outflow of the perfusion circuit 10, respectively.
A console 100 is designed to display the various data retrieved by transducers 98 and to provide control buttons 102 for the various clamps 82, 84, 86, 88, 90, 92, 94 and 96 as well as some standardized control buttons. For example, there may be a button 104 that, when activated, will control clamps that add volume to the patient to return volume to the patient. In this instance, opening clamp 88 will open reservoir 12 to atmosphere, thereby increasing the pressure within reservoir 12 and forcing more fluid to pump 14.
There could also be a button 106 to initiate a procedure to add volume to reservoir 12 from the patient. This would be accomplished by opening clamp 92 to vacuum source 48 and adding additional negative pressure into reservoir 12, thereby pulling more fluid from the patient.
There could also be a button 108 to initiate a procedure to add prime volume to reservoir 12 from an external source. This would be accomplished by operating clamp 90 to release an IV line so that blood or balanced electrolyte solutions or other medicines or other external fluids may be added to the blood contained in reservoir 12.
Another button 110 may be provided to turn off and on cardiotomy suction. This may be accomplished by pressing button 110 that would cause clamp 96 to open thereby applying suction to sucker tip 56.
Another button 112 may provide cardiotomy suction boost by opening cardiotomy suction clamp 96 to the negative pressure already contained in reservoir 12 by the operation of pump 14 and then boosting or increasing that negative pressure by opening clamp 92 to vacuum source 48. Other preset buttons may be provided in addition to other various displays. The general concept is to provide monitoring of pressures and fluid levels and provide remotely controlled clamps that may be opened and closed in response to control signals from the control system 80 to provide for certain desired results within perfusion circuit 10. The control system 80 of the present invention would also be useful with prior art perfusion systems.
As will be appreciated by those skilled in the art, the use of a reservoir 12 that is not sealed but that still has a ball valve 36 at the base of reservoir 12, between reservoir 12 and pump 14, will provide protection from gross air entering the perfusion circuit. With such a system, precious time may be saved during an operation when reservoir 12 empties of fluid by not allowing air to pass out of reservoir 12 into the perfusion circuit. As such, pump 14 may be restarted as soon as reservoir 12 refills or is refilled with fluid rather than having to purge the system of air and then restart pump 14.
A further embodiment of the present invention that is directed to further reducing the foreign surface area of the perfusion circuit 10 that the blood must contact provides a bypass around sealed reservoir 12. Referring to FIG. 4, the device shown in FIG. 2 is modified by adding a bypass line 114 that feeds directly from venous return line 24 to a pump intake 116 on pump 14. Bypass line 114 includes a bypass valve 118 at or near venous return line 24 before venous return line 24 connects to reservoir 12. Bypass valve 118 may be operated either manually or automatically. When bypass valve 118 is activated, blood in venous return line 24 is directed through bypass line 114 directly to pump 14 without first entering reservoir 12.
In an embodiment where bypass valve 118 is automatically controlled, an air or bubble sensor 120 may be attached to the venous return line 24. When air or bubble sensor 120 indicates that no air is contained in the venous blood in venous return line 24, the blood is bypassed from venous return line 24 around reservoir 12 and sent directly to pump 14. When the air or bubble sensor 120 indicates that air or bubbles exist in the venous blood in venous return line 24, bypass valve 118 is activated so that the venous blood will enter sealed reservoir 12 from venous return line 24 and go through defoamer 30 and filter 34 and the settling process of sealed reservoir 12 as described above. Such a modification would ensure that during standard operation when no air is included with the venous blood supply in venous return line 24, the blood need only come in contact with the bypass line 114 and not all of the various elements of sealed reservoir 12. In such an embodiment, either when bypassing or when going through sealed reservoir 12, venous return line 24 will always be subject to the suction pressure at the inlet of pump 14, and therefore, perfusion system 10 may still be placed at or near the patient. Therefore, the bypass embodiment also achieves the benefits of reducing priming volume and further reducing foreign surface contact.
The present invention as described provides a safe, easy to use perfusion system that is easier to prime and provides less trauma for blood products than previously known perfusion systems. Although the present invention has been described in connection with several specific embodiments of the invention, it is to be understood that the specific embodiments disclosed have been for the purpose of illustrating the invention. However, the invention is not intended to be limited to the embodiments disclosed. It is clear that changes and improvements to the invention disclosed will occur to those skilled in the art and will still be within the scope of the claims that appear hereafter.
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RELATED APPLICATIONS
This application is the U.S. National Phase filing under 35 U.S.C. §371 of PCT/EP2007/058418, filed Aug. 14, 2007, entitled “Method of Preparing a Cake Using Phospholipase”, which designated the United States and was published in English on Mar. 6, 2008, which claims priority under 35 U.S.C. §119(a)-(d) to European Patent Application No. 06119649.9, filed Aug. 28, 2006.
FIELD OF THE INVENTION
The present invention relates to a method of preparing a cake.
BACKGROUND OF THE INVENTION
Basic cake ingredients are usually flour, sugar, fats (from animal or vegetal origin), eggs and leaveners. Additional ingredients may be for example milk or milk fractions, flavorings or salt (in Pyler, E. J., 1988, Baking Science and Technology, Sosland Publishing, pp. 979-981). Eggs are commonly used in the preparation of various cakes. A certain amount of eggs is generally required to obtain a good cake quality, but eggs are an expensive ingredient, so it is desirable to reduce the amount of eggs and still achieve a satisfactory cake quality.
JP 63-258528A is directed to a method for producing a sponge cake by using egg liquid treated with phospholipase.
JP 10-191871A is directed to a method for producing baked confectionery by treating a mixture with phospholipase before baking.
EP 0 426 211 A1 is directed to a method of preparing a food product containing dried lysophospholipoprotein or dried lysophospholipoprotein containing material. In this invention egg yolk is treated during 4.5 hours at 54° C., the modified egg yolk is spray dried and the dried lysophospholipoprotein is added to dry cake mix, that after reconstitution with water and baking, results in a cake with an open and moist texture.
US 2003/0175383 A1 is directed to a method of preparing a flour dough, said method comprising adding to the dough components an enzyme that under dough conditions is capable of hydrolysing a glycolipid and a phospholipid, wherein said enzyme is incapable, or substantially incapable, of hydrolyzing a triglyceride and/or a 1-monoglyceride, or a composition comprising said enzyme, and mixing the dough components to obtain a dough and to improve the strength and machinability of doughs and the volume, softness and crumb structure of bread and other baked products.
US 2003/0124647 A1 is directed to a method of modifying whey protein in an aqueous solution by treating it with phospholipase. The modified whey protein shows to have improved foaming overrun and foam stability when whipped, as compared to whey protein preparation that is not treated with a phospholipase.
SUMMARY OF THE INVENTION
The inventors confirmed that the volume and properties of a cake tend to deteriorate when the amount of eggs in the cake recipe is reduced.
They found that this deterioration can be counteracted by adding a phospholipase to the cake batter, as seen by an increased cake volume and improved cake properties, including the properties (of the fresh cake and also after storage), e.g. increased cohesiveness, increased springiness, and increased elasticity.
They found that the cake quality (as measured by these parameters) can be further improved, even up to the level of the original cake, by adding a non-egg protein together with the phospholipase.
Accordingly, in a first aspect the invention provides a method of preparing a cake, said method comprising preparing a cake batter by mixing cake batter ingredients, said ingredients comprising non-phospholipase treated egg lecithin and phospholipase, and baking the cake batter to make the cake.
Accordingly, the invention provides a method of preparing a cake, comprising:
a) preparing a cake batter comprising egg yolk lecithin,
b) adding a phospholipase to the cake batter, and
c) baking the cake batter to make the cake.
The method may further comprise adding a non-egg protein to the cake batter.
In another embodiment of the present invention the phospholipase is added to the mix of dry ingredient that is further mixed with other ingredients such as liquid eggs, oil, and water to prepare the batter.
DETAILED DESCRIPTION OF THE INVENTION
Phospholipase
The phospholipase is an enzyme that catalyzes the release of fatty acyl groups from a phospholipid. It may be a phospholipase A2 (PLA2, EC 3.1.1.4) or a phospholipase A1 (EC 3.1.1.32). It may or may not have other activities such as triacylglycerol lipase (EC 3.1.1.3) and/or galactolipase (EC 3.1.1.26).
The phospholipase may be a native enzyme derived from mammalian or microbial sources.
An example of a mammalian phospholipase is pancreatic PLA2, e.g. bovine or porcine PLA2 such as the commercial product Lecitase® 10 L (porcine PLA2, product of Novozymes A/S).
Microbial phospholipases may be derived from Fusarium , e.g. F. oxysporum phospholipase A1 (WO 1998/026057), F. venenatum phospholipase A1 (described in WO 2004/097012 as a phospholipase A2 called FvPLA2), from Tuber , e.g. T. borchii phospholipase A2 (called TbPLA2, WO 2004/097012).
The phospholipase may also be a lipolytic enzyme variant with phospholipase activity, e.g. as described in WO 2000/032758 or WO 2003/060112.
The phospholipase may be added in an amount of 500-20,000 units (LEU) per kg of batter, e.g. 1000-10,000 units (LEU) per kg.
The phospholipase may also catalyze the release of fatty acyl groups from other lipids present in the batter, particularly wheat lipids. Thus, the phospholipase may have triacylglycerol lipase activity (EC 3.1.1.3) and/or galactolipase activity (EC 3.1.1.26).
Protein
Compared to a conventional cake recipe the amount of egg protein may be reduced and may be replaced by non-egg-protein. For example, compared to a conventional cake recipe, the amount of egg white protein may be reduced and may be replaced by non-egg protein.
Thus, the batter used in the invention may contain 0.5-3.0% by weight of egg protein, and may contain 0.1-6% (particularly 0.5-2%) by weight of non-egg protein. For example, the batter used in the invention may contain 0.5-2.5% by weight of egg white protein, and may contain 0.1-6% (particularly 0.5-2%) by weight of non-egg protein.
The non-egg protein may particularly be a water-soluble, globular protein. The non-egg protein may particularly be partially or fully purified or isolated protein, such as, a water-soluble, globular protein. The non-egg protein may be denatured, and it may be one that partially unfolds to a rod-shaped or flexible molecule under the interaction of lyso-lecithin formed by the action of the phospholipase on the egg yolk lecithin.
Protein sources with a good waterbinding, emulsifying and gelling properties in presence of lysophospholecithin are considered especially suitable
Examples of non-egg proteins are wheat proteins. Further examples of non-egg proteins are casein, whey protein, wheat gluten, legume protein (e.g. from soy bean, pea or lupine).
The non-egg protein may be subjected to a limited hydrolysis, e.g. enzymatic hydrolysis to 0-6% hydrolysis. The enzymatic hydrolysis may be carried out with an amino-acid specific protease, e.g. one which is specific for Arg, Lys, Glu, Asp and/or Pro, such as the protease described in WO 91/13554.
The modification may include steps of shear treatment and acidic or alkaline pH, e.g. as described in WO2003/13266, increased temperature to denature partially or completely, protein deamidation, and separation steps including centrifugation, decanting and ultracentrifugation.
The protein (or hydrolyzed) protein may be enzymatically modified, e.g. with a cross-linking enzyme like transglutaminase or another protein modifying enzyme like protein-glutaminase. Furthermore the protein may be modified physically or chemically, e.g. through denaturation and deamidation.
Egg Yolk Lecithin
The cake batter comprises egg yolk lecithin, e.g. in the form of whole eggs, egg yolks, or egg powder.
The invention makes it possible to reduce the amount of egg material, e.g. to about half of a conventional cake. Thus, the batter may contain 0.3-1.5% by weight of egg lecithin or 5-25% (particularly 7-20, or 8-15) by weight of whole eggs.
Advantageously, the batter may contain 0.1-1.5%, such as 0.1-1.2%, or 0.1-0.9%, or 0.2-1.5%, or 0.2-1.2%, or 0.2-0.9%, or 0.3-1.5%, or 0.3-1.2%, or 0.3-0.9% by weight of egg lecithin or 5-25% (particularly 7-20, or 8-15) by weight of whole eggs.
Other Ingredients
The cake batter may comprise other conventional ingredients, typically in the following amounts (in % by weight of the batter):
Flour (untreated, heat treated, chlorinated): 15-30% Starch (modified, native): 0-10% Sugar: 15-25% Emulsifier (mono and diglycerides of fatty acids, propylene glycol esters of fatty acids, lactic acid esters of mono and diglycerides of fatty acids, sodium stearoyl-2-lactylate): 0.1-1% Baking powder (containing soda and acid or acidic salts): 0.5-1% Hydrocolloids (Locust bean gum, guar gum, tara gum, xanthan gum, carrageenan, acacia gum, cellulose, modified cellulose, pectin): 0-1% Vegetable fat (ex. oil, margarine, shortening, fat paste, powdered fat): 5-30% Water: up to 100%
Butter may advantageously replace part or all of the fat.
An example of cake is a cake prepared with eggs-sugar-wheat flour-vegetable oil-starch-baking powder: sodium bicarbonate (E500ii), sodium acid pyrophosphate (E450i)-emulsifier: mono and diglycerides of fatty acids (E471), lactic acid esters of mono and diglycerides of fatty acids (E472b), sodium stearoyl-2-lactylate (E481)-hydrocolloid: xanthan gum.
Another example of cake is a cake prepared with eggs-sugar-wheat flour-starch-margarine-baking powder: sodium bicarbonate (E500ii), sodium acid pyrophosphate (E450i)-emulsifier: mono and diglycerides of fatty acids (E471)-propylene glycol esters of fatty acids (E477)-lactic acid esters of mono and diglycerides of fatty acids (E472b), sodium stearoyl-2-lactylate (E481)-hydrocolloid: carrageenan
A further example of cake is a cake prepared with eggs-sugar-wheat flour-starch-margarine-baking powder: sodium bicarbonate (E500ii), sodium acid pyrophosphate (E450i)-emulsifier: mono and diglycerides of fatty acids (E471)-propylene glycol esters of fatty acids (E477)-lactic acid esters of mono and diglycerides of fatty acids (E472b)-hydrocolloid: carrageenan
Assay Methods
Phospholipase Activity (LEU)
Lecithin is hydrolyzed under constant pH and temperature, and the phospholipase activity is determined as the rate of titrant (0.1N NaOH) consumption during neutralization of the liberated fatty acid. The substrate is soy lecithin (L-α-Phosphotidyl-Choline), and the conditions are pH 8.00, 40.0° C., reaction time 2 min. The method is further described in DK 99/00664 (Novo Nordisk A/S, Denmark). The phospholipase from porcine pancreas has an activity of 510 LEU/mg and is taken as standard.
Texture Profile Analysis (TPA) for Determination of Cohesiveness and Springiness
Two consecutive deformations of a cylindrical crumb sample (φ=45 mm) performed with a cylindrical probe (φ=100 mm) with a maximum deformation of 50% of the initial height of the product are performed at a deformation speed of 2 mm/s and waiting time between consecutive deformations of 3 s. Force is recorded as a function of time.
Cohesiveness is calculated as the ratio (expressed in percent) between the surface under the second deformation curve (downwards+upwards) and the surface under the first deformation curve (downwards+upwards).
Springiness is calculated as the ratio between the height of the sample after the first deformation and 3 seconds waiting time and the initial height of the product.
Penetration Test for Determination of Elasticity
Penetration of cake crumb with a cylindrical probe (φ=25 mm) until a total deformation of 25% of the initial height of the sample, at a deformation speed of 2 mm/s and keeping the target deformation constant during 20 s. Force is registered as a function of time. Elasticity is the ratio (expressed in percent) between the force measured after 20 s at constant deformation to the force applied to obtain the target deformation.
EXAMPLES
Example 1: Effect of Phospholipase
Cakes were made using a typical batter cake recipe. 15-25% eggs, 20-30% flour, 0-10% starch, vegetable fat 15-20%, 20-25% sugar, 0.1-1% emulsifier (mono and diglycerides of fatty acids, propylene glycol esters of fatty acids, lactic acid esters of mono and diglycerides of fatty acids, Sodium Stearoyl-2-lactylate), baking powder 0.8% (soda and SAPP (Sodium acid PyroPhosphate)), 0-1% hydrocolloids, 0-1% protein and water to 100% were mixed for 2 minutes at speed 2 (low) and 2 minutes at speed 5 (medium) in a Hobart mixer.
Phospholipase was added directly to the dry mix, and finally eggs and oil and water were added to form the batter. A total of 1.875 kg cake batter was prepared per trial. 300 g cake batter was weighed into aluminium pans.
The cakes were baked at a temperature of 180° C. for 45 minutes. 6 cakes with a total weight of 1.66 kg were made from each batter. Afterwards the cakes were cooled and packed in a plastic bag.
Textural properties were measured on day 1 and day after baking using the method described above. Cohesiveness, springiness and elasticity as well as volume of the cakes were evaluated.
In the first example 1500 LEU/kg or 3750 LEU/kg was added to the batter where 50% of the eggs (corresponding to 7.5-12.5% by weight of the batter) were replaced by flour and water. A control was made with 100% egg (corresponding to 15-25% by weight of the batter); the volume and textural properties were taken as 100%.
The following results show the effect of phospholipase on volume and texture of cake with 50% egg reduction and a comparison between microbial phospholipases and pancreatic phospholipase (Table 1).
TABLE 1
Amount of
egg g/kg
Type of
Enzyme dosage
Cake
cohesiveness
elasticity
batter
enzyme
(LEU/kg batter)
volume
Day 1
Day 14
Day 1
Day 14
190
0
100
100
100
100
100
95
0
90
68
70
90
89
95
Lecitase
1500
94
82
95
93
99
10L
95
Lecitase
3750
97
84
98
93
97
10L
95
TbPLA2
1500
94
79
92
87
97
95
TbPLA2
3750
94
82
93
91
95
95
FvPLA2
1500
94
75
82
90
91
95
FvPLA2
3750
94
81
92
91
98
The results show that for 50% egg replaced by flour, the volume of the cake was only 90%, the cohesiveness on day was only 70%, and the elasticity on day 14 was 90% compared to the Control.
By the addition of TbPLA2, Lecitase 10 L, and FvPLA2 the volume of the 50% egg cakes was improved by 4-7%. 7% volume increase was achieved for 3750 LEU/kg batter Lecitase 10 L.
The cohesiveness on day 14 was improved by 12-28%. Highest increase in cohesiveness was achieved by 3750 LEU/kg batter Lecitase 10 L.
The elasticities of the resulting cakes were increased by 2-10% on day 14. Highest increase was measured for Lecitase 10 L (1500 LEU/kg batter and 3750 LEU/kg batter), FvPLA2 (3750 LEU/kg batter) and TbPLA2 (1500 LEU/kg batter).
Cake texture and cake volume were improved by all 3 phospholipases. Lecitase 10 L gave, with only 3% difference in volume, an elasticity and a cohesiveness on day 14 comparable to a Control cake with 100% egg.
Example 2: Effect of Combination of Phospholipase and Non-Egg Protein
Cakes were prepared as in Example 1, but with phospholipase (Lecitase 10 L) and various non-egg proteins.
The following results show the effect of a combination of phospholipase and non-egg protein on volume and texture of cake prepared with 50% egg reduction (Table 2). Provabis is a soy protein; the other proteins tested are all whey proteins.
The amount of protein (dry material) added in % by weight of the batter was 1.87-2.35% for soy protein (corresponding to all dry material of the replaced egg) and 0.935-1.175% for the other proteins (corresponding to 50% of the dry material of the replaced egg).
The non-egg proteins were commercial products from the following suppliers:
Foamalac, Probake M, Carbelac 80 UHG: Carberry Group, Cork, Ireland Hiprotal 45: Borculo Domo Ingredients, The Netherlands Lacprodan, Nutrilac BE-7602, Nutrilac BK-8310: Arla Foods Ingredients, Denmark Provabis: Cargill N V, Belgium Hygel 8293, Hyfoama DSN: Kerry Bio-Science, The Netherlands
TABLE 2
Amount
Enzyme
of egg g/kg
dosage
cake
Type of
(Lecitase 10L,
Cake
cohesiveness
springiness
elasticity
batter
protein source
LEU/kg batter)
volume
Day 1
Day 14
Day 1
Day 14
Day 1
Day 14
190
0
100
100
100
100
100
100
100
95
0
85
69
68
74
81
91
86
95
3750
94
82
97
82
88
91
98
95
Whey protein
3750
97
101
94
94
95
100
103
(Foamalac)
95
Whey protein
3750
103
94
102
93
94
99
105
(Probake M)
95
Whey protein
3750
103
93
105
92
93
98
104
(Carbelac 80
UHG)
95
Na-caseinate
3750
103
86
105
89
95
92
100
95
Whey protein
3750
100
87
100
88
90
96
94
(Lacprodan)
95
Whey protein
3750
107
89
103
87
88
95
101
(Hygel 8293)
95
Whey protein
3750
103
86
100
86
91
95
96
(Hiprotal 45)
95
Whey protein
3750
97
87
95
88
90
97
101
(Nutrilac BE-
7602)
95
Whey protein
3750
94
84
87
88
88
99
103
(Nutrilac BK-
8310)
95
Soy protein
3750
95
87
101
91
93
95
98
(Provabis)
The results (Table 2) show that by replacing 50% of the eggs and adding a non-egg protein together and a phospholipase it was possible to reach the same cake volume and/or the same level of cohesiveness and/or elasticity after 14 days as the control.
50% egg replaced by flour resulted in a volume loss of 15% compared to the Control.
By the addition of Lecitase 10 L the volume was increased again by 9%. With some of the non-egg proteins the volume of the 50% egg cake was improved to above the volume of the Control cake, while other proteins also showed an increase of the volume, but not up to the level of the control.
Cohesiveness and elasticity were generally comparable or even above the values measured for the Control.
Springiness was improved by the non-egg proteins, but remained below the values measured for the Control on day 14.
Thus, the addition of non-egg protein together with a phospholipase can improve the volume, elasticity and cohesiveness of a 50% egg cake and make it comparable to the Control.
Example 3: Effect of Combination of Phospholipase and Non-Egg Protein
Cakes were prepared as in Example 1, but with addition of phospholipase and non-egg protein, alone or in combination (Table 3).
TABLE 3
Enzyme
dosage
Amount of
Type of
(Lecitase
egg g/kg
protein
10L, LEU/
Cake
cohesiveness
springiness
elasticity
batter cake
source
kg batter)
volume
Day 1
Day 14
Day 1
Day 14
Day 1
Day 14
190
0
100
100
100
100
100
100
100
95
0
91
69
68
78
83
90
87
95
3750
100
82
94
80
88
89
95
95
Whey protein
0
91
74
77
83
89
91
86
(Hiprotal 45)
95
Whey protein
3750
103
86
100
86
91
95
97
(Hiprotal 45)
95
Whey protein
0
94
86
87
94
93
94
90
(Carbelac
80UHG)
95
Whey protein
3750
103
92
107
92
92
96
104
(Carbelac
80UHG)
95
Whey protein
0
94
86
86
95
93
94
93
(Foamalac)
95
Whey protein
3750
103
96
106
96
95
97
101
(Foamalac)
The effect of the non-egg protein is illustrated in the data where the addition of non-egg protein alone and in combination with phospholipase is compared to 50% egg where egg has been replaced by flour and to 100% egg cakes (=Control).
It can be clearly seen that the addition of non-egg protein alone only gives slight improvement on the volume, while when combined with the Lecitase 10 L the volume is superior to the Control.
Here also the cohesiveness and the elasticity were comparable or above the values measured for the Control on day 14.
Springiness remains below the control on day 14.
Example 4: Effect of Combination of Phospholipase and Non-Egg Protein: Wheat Protein
Cakes were prepared as in Example 1, but with phospholipase (Lecitase 10 L) and various non-egg proteins, i.e. wheat proteins (Tables 4a to 4d). A substantial amount of wheat proteins have been added such that the quantity of wheat protein is increased by at least 30% compared to the quantity originally present in the flour.
The following results show the effect of a combination of phospholipase and non-egg protein on volume and texture of cake prepared with 50% egg reduction.
The amount of protein (dry material) added in % by weight of the batter was 0.9067% and 1.813% (corresponding to respectively 50% and 100% of the dry material of the replaced egg).
The non-egg proteins were commercial products from the following suppliers:
Prolite 100 and Prolite 200, ADM Speciality Food Ingredients, Keokuk, USA
Meripro 420, Tate & Lyle Europe N.V., Belgium
Gemtec 2170, Manildra Group, Auburn, Australia
HWG 2009, Loryma, Zwingenberg, Germany
Arise 5000, Midwest Grain Proteins, Atchison, Kans., USA
Amygluten 110, Tate & Lyle Europe N.V., Belgium
Super Gluten 75 and Super Gluten 80, ADM
Glutastar EC75 and Glutastar EC80, Fiske Food Ingredients
TABLE 4a
Amount
Enzyme
Amount
of wheat
dosage
of egg g/
Type of
protein
(Lecitase
kg cake
wheat
g/kg
10L, LEU/
Cake
cohesiveness
springiness
elasticity
batter
protein
batter
kg batter)
volume
Day 1
Day 14
Day 1
Day 14
Day 1
Day 14
190
100
100
100
100
100
100
100
95
88
73
70
74
74
90
91
95
3750
97
87
96
78
82
92
101
95
Prolite
9
3750
97
95
102
84
88
92
104
100
95
Prolite
18
3750
100
98
110
88
92
94
103
100
95
Prolite
9
3750
100
92
102
83
87
94
103
200
95
Prolite
18
3750
100
100
109
88
91
96
107
200
95
Meripro
9
3750
97
90
98
81
86
91
103
420
TABLE 4b
Enzyme
Amount
dosage
Amount
of wheat
(Lecitase
of egg g/kg
Type of
protein
10L, LEU/
cake
wheat
g/kg
kg
Cake
cohesiveness
springiness
elasticity
batter
protein
batter
batter)
volume
Day 1
Day 14
Day 1
Day 14
Day 1
Day 14
190
100
100
100
100
100
100
100
95
90
69
63
77
74
91
90
95
3750
97
81
96
81
87
91
96
95
Meripro
9
93
80
75
87
86
92
91
420
95
Meripro
9
3750
100
89
101
85
89
94
98
420
95
Meripro
18
93
87
85
91
90
95
98
420
95
Meripro
18
3750
100
91
107
90
92
97
99
420
TABLE 4c
Enzyme
Amount
dosage
Amount
of wheat
(Lecitase
of egg g/kg
Type of
protein
10L, LEU/
cake
wheat
g/kg
kg
Cake
cohesiveness
springiness
elasticity
batter
protein
batter
batter)
volume
Day 1
Day 14
Day 1
Day 14
Day 1
Day 14
190
100
100
100
100
100
100
100
95
85
73
70
74
74
90
91
95
3750
94
87
96
78
82
92
101
95
HWG
9
87
64
63
68
75
90
87
2009
95
HWG
9
3750
99
81
92
72
79
93
94
2009
95
HWG
18
87
64
61
66
73
90
90
2009
95
HWG
18
3750
97
83
95
73
82
92
93
2009
95
Gemtec
9
85
69
71
75
76
88
94
2170
95
Gemtec
9
3750
93
79
98
73
81
90
101
2170
95
Gemtec
18
90
77
75
83
81
89
94
2170
95
Gemtec
18
3750
93
89
103
86
86
95
101
2170
95
Arise
9
90
72
73
74
79
91
89
5000
95
Arise
9
3750
101
90
100
77
85
94
98
5000
95
Arise
18
92
82
79
81
85
92
92
5000
95
Arise
18
3750
100
95
107
87
91
97
98
5000
TABLE 4d
Enzyme
Amount
dosage
Amount
of wheat
(Lecitase
of egg g/kg
Type of
protein
10L, LEU/
cake
wheat
g/kg
kg
Cake
cohesiveness
springiness
elasticity
batter
protein
batter
batter)
volume
Day 1
Day 7
Day 1
Day 7
Day 1
Day 7
190
100
100
100
100
100
100
100
95
90
81
85
90
87
66
78
95
2667
100
86
91
88
88
72
82
95
Super
9
2667
102
85
98
87
85
70
89
Gluten
75
95
Super
9
2667
101
86
98
86
86
71
88
Gluten
80
95
Meripro
9
2667
99
88
98
89
87
76
90
420
95
Glutastar
9
2667
98
88
100
87
85
74
91
EC75
95
Glutastar
9
2667
99
89
100
87
84
75
91
EC80
The effect of the non-egg protein(s) is illustrated in the data presented on the tables 4a to 4d where the addition of non-egg protein(s) alone or in combination with phospholipase is compared to 50% egg formulations where egg has been replaced by flour and to 100% egg cakes (=Control).
Table 4a. When combining wheat protein and phospholipase (Lecitase 10 L) in cake prepared with 50% less egg, volume of cake prepared with 100% egg can be completely recovered. When adding Prolite 100 or Prolite 200 in combination with phospholipase to 50% egg formulations cohesiveness and elasticity of crumb 14 days after baking can be recovered or even increased and springiness is improved.
Table 4b. Meripro 420, when added alone, has only a slight positive effect on volume of cake prepared with 50% less egg. Volume of cake prepared with 100% egg can be completely recovered by adding a combination of phospholipase and Meripro 420 to a 50% egg formulation. Cohesiveness is highly improved when adding both phospholipase and Meripro 420.
Table 4c. Wheat proteins tested, when added alone, have only a slight positive effect on volume. HWG2009 has a positive effect on volume but not on texture properties of cake prepared with 50% egg and phospholipase. Gemtec 2170 has no effect on volume of cake prepared with 50% egg and phospholipase but a positive effect on cohesiveness 14 days after baking and springiness 1 and 14 days after baking. Arise 5000 in combination with phospholipase has a positive effect on volume and cohesiveness of 50% egg cake.
Table 4d. When adding wheat proteins: Meripro 420, Super Gluten 75, Super Gluten 80, Glutastar EC75 or Glutastar EC80 to a 50% egg cake recipe containing Lecitase 10 L, cohesiveness and resiliency measured 7 days after baking are significantly increased (between 7 and 9%) when comparing these parameters measured 7 days after baking on 50% egg cake only containing Lecitase 10 L.
Example 5: Effect of Combination of Phospholipase and Non-Egg Proteins: Sensorial Analysis
Cakes were prepared as in Example 1, but without hydrocolloids and with phospholipase (Lecitase 10 L) and two different non-egg proteins: Prolite 100 (ADM Speciality Food Ingredients, Keokuk, USA) and Meripro 420 (Tate & Lyle Europe N.V., Aalst, Belgium).
Five different cake samples have been subjected to sensorial analysis by 29 subjects.
1. reference cake with 100% egg.
2. reference cake with 50% egg and replacement of egg by flour and water.
3. reference cake with 50% egg and replacement of egg by 3750 LEU lecitase 10 L/kg batter+9 g/kg batter Meripro 420+9 g/kg batter of flour+water.
4. reference cake with 50% egg and replacement of egg by 3750 LEU lecitase 10 L/kg batter+9 g/kg batter Prolite 100+9 g/kg batter of flour+water.
5. reference cake with 50% egg and replacement of egg by 3750 LEU lecitase 10 L/kg batter+18 g/kg batter Meripro 420.
Subjects have been asked to rank the different cakes according to their preference with the highest value for the highest appreciated cake and the lowest value for the less appreciated cake (Table 5).
TABLE 5
Cake
Sum of rankings
1
Reference 100% egg
90.0
2
Reference 50% egg
64.5
2
50% egg + lecitase + 9 g Meripro 420/kg batter
91.0
4
50% egg + lecitase + 9 g Prolite 100/kg batter
96.0
5
50% egg + lecitase + 18 g Meripro 420/kg batter
93.5
The sum of rankings indicates that cake prepared with only 50% egg is less appreciated and that the four other types of cake are equally appreciated.
Example 6: Effect of Combination of Phospholipase and Non-Egg Protein: Different Types of Cakes
Cakes were prepared with two different types of commercial dry mixes from Puratos (Brussels, Belgium): Tegral Satin Cream Cake and Tegral Allegro Cake and with phospholipase (Lecitase 10 L) and Meripro 420 (Tate & Lyle Europe N.V., Aalst, Belgium). The margarine added is Aristo Cake (Puratos, Brussels, Belgium). The oil added is rapeseed oil. Batter is prepared and cakes are baked as described in example 1. The regular composition of the batters is given in table 6.
TABLE 6
Regular Batter composition
Liquid
Dry mix
pasteurized
Water
Type of dry mix
(g)
egg (g)
Fat (g)
(g)
Tegral Satin Cream
1000
350
300 rapeseed oil
225
Cake
Tegral Allegro Cake
1000
500
500 margarine
0
The following results show the effect of a combination of phospholipase and non-egg protein(s) on volume and texture of cake prepared with 50% egg reduction (Table 7).
TABLE 7
Amount
Enzyme
Amount
of
dosage
of egg g/kg
Meripro
(Lecitase
cake
Type of
420 g/kg
10L, LEU/
Cake
cohesiveness
springiness
elasticity
batter
cake
batter
kg batter)
volume
Day 1
Day 14
Day 1
Day 14
Day 1
Day 14
190
Tegral
100
100
100
100
100
100
100
Satin
Cream
Cake
95
Tegral
88
73
70
74
74
90
91
Satin
Cream
Cake
95
Tegral
9
3750
97
89
101
85
89
94
98
Satin
Cream
Cake
250
Tegral
100
100
100
100
100
100
100
Allegro
Cake
125
Tegral
80
65
63
78
82
93
92
Allegro
Cake
125
Tegral
12.5
3500
85
94
123
93
100
95
91
Allegro
Cake
Cake volume and texture were improved in recipe with 50% egg reduction by the use of a combination of non-egg protein(s) and phospholipase.
| 1a
|
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the field of pumice stones which are used to peel calluses from the back or from the underside of a person's toes. The present invention also relates to the field of motorized devices which are used to peel calluses in a more rapid and efficient way as opposed to a hand held pumice stone which is rubbed against the calluses by a back and forth motion from a user's hand.
2. Description of the Prior Art
The following 20 patents are relevant to the field of the present invention:
1. U.S. Pat. No. 4,061,136 issued to Giuseppe Vaniglia on Dec. 6, 1977 for “Portable Washer And Massager Apparatus For Bathtubs” (hereafter the “Vaniglia Patent”);
2. U.S. Pat. No. 5,345,640 issued to Mary A. Goss on Sep. 13, 1994 for “Motorized Back Scrubber” (hereafter the “Goss Patent”);
3. U.S. Pat. No. 5,784,722 issued to Luis A. Ureta et al. on Jul. 28, 1998 for “Shower Back Scrubber” (hereafter the “Ureta Patent”);
4. U.S. Pat. No. 6,178,970 issued to Veena E. Purifoy et al. on Jan. 30, 2001 for “Foot Sander” (hereafter the “Purifoy Patent”);
5. U.S. Pat. No. 6,210,350 issued to Mark K. Finch on Apr. 3, 2001 for “Device And Method For Removing In A Shower Or Bath Area Selected Skin Areas From A Bottom Foot Portion Of A Person” (hereafter the “Finch Patent”);
6. U.S. Pat. No. 6,523,546 issued to Jeom-Sup Jo et al. on Feb. 25, 2003 for “Pedicure Sander Having Shock-Absorbing Unit” (hereafter the “Jo Patent”);
7. U.S. Pat. No. 6,684,444 issued to Todd Wheeler et al. and assigned to Accurva, LLC on Feb. 3, 2004 for “Foot Scrubbing Device And Massaging Device” (hereafter the “Wheeler Patent”);
8. U.S. Pat. No. 6,708,351 issued to Kelly Sullinger on Mar. 23, 2004 for “Dry Skin And Callus Removal Device” (hereafter the “Sullinger Patent”);
9. U.S. Pat. No. 6,779,218 issued to Robert Jusinski on Aug. 24, 2004 for “Apparatus And Method For Ergonomic Basic Chiropody” (hereafter the “Jusinski Patent”);
10. U.S. Pat. No. 6,848,451 issued to Robert T. Postal et al. and assigned to Twist2It, Inc. on Feb. 1, 2005 for “Drive Mechanism For Oscillatory Abrasion And Polishing Tool” (hereafter the “Postal Patent”);
11. U.S. Pat. No. 7,278,431 issued to Paul M. Anderson et al. and assigned to Revlon Consumer Products Corporation on Oct. 9, 2007 for “Device for Smoothing Keratinous Surfaces” (hereafter the “Anderson Patent”);
12. U.S. Pat. No. 7,347,211 issued to Elizabeth Macklin on Mar. 25, 2008 for “Electrically Operated Sander For Removing Calluses And Increasing Circulation” (hereafter the “Macklin Patent”).
13. U.S. Pat. No. 5,913,313 issued to Pamela Jean Brunderman on Jun. 22, 1999 for “Footcare device And Method Of Using Same” (hereafter the “'313 Brunderman Patent”);
14. U.S. Pat. No. 6,142,156 issued to Pamela Jean Brunderman on Nov. 7, 2000 for “Footcare device And Method Of Using Same” (hereafter the “'156 Brunderman Patent”);
15. United States Published Patent Application No. 2005/0103357 to Jeom-Sup Jo et al. on May 19, 2005 for “Disposable Sand Cap For Removing Calluses And Callus Removal Device Having The Same” (hereafter the “Jo Published Patent Application”);
16. U.S. Pat. No. 7,267,125 issued to Michael G. Nevakshonoff on Sep. 11, 2007 for “Device For Sanding Buffing or Grinding Elongate Objects” (hereafter the “Nevakshonoff Patent”);
17. United States Published Patent Application No. 2009/0004953 to Verla M. Kinsey on Jan. 1, 2009 for “Skin Sander” (hereafter the “Kinsey Published Patent Application”);
18. U.S. Pat. No. 7,568,451 issued to Jay Drelinger on Aug. 4, 2009 for “Rotary Nail Filing Apparatus For Animals” (hereafter the “Drelinger Patent”);
19. U.S. Pat. No. 7,578,300 issued to Jeff G. Ryder on Aug. 25, 2009 for “Motorized Foot Sander” (hereafter the “Ryder Patent”);
20. U.S. Pat. No. 7,581,545 issued to Clerice Moldawski et al. on Sep. 1, 2009 for “Dermabrasive Device” (hereafter the “Moldawski Patent”).
The Vaniglia Patent is a portable power driven washer and massager apparatus for use in bathtubs. It includes a pair of roller brushes which are rotary driven by an electric motor, a heater and blower apparatus for directing hot air to the user, and means for readily mounting and dismounting the apparatus to a bathtub including adjustable locking means with suction cups. The device is intended to massage the back of a person.
The Goss Patent discloses a motorized scrubber for cleaning the back of a person. It has several rotating brushes and can be retained on the wall of a shower by suction cups. A soap dispenser provides soap to the center area of each of the brushes and another embodiment includes a water supply assembly for rinsing the user's back.
The Ureta Patent discloses a back scrubber for removable installation in a shower. A sponge is releasably held by a housing and has a thickness greater than the depths of the sidewall of the housing which retains it so that it can be used to sponge a person's back. The device discloses a back scrubber which is used to scrub a person's back and can be retained to the wall of a shower by suction cups and a sponge is used to scrub the person's back.
The Purifoy Patent discloses the concept of having a device for removing calluses from the underside of the foot by an orbital motion of a sander. It is a device that is held in the hand and is driven by a motor. A sheet of sandpaper or massaging pad is adopted to be removably attach to an orbital motion disc for foot sanding or massaging when applied thereto. The appliance body is orthopedically engineered to fit the palm of a user to enhance gripping. This is a device that is not intended to be used in a shower but is instead intended to be a personal grooming device to remove calluses from the back of the feet presumably when the person may be in the bathroom but not necessarily in a water environment such as a shower or bathtub.
The Finch Patent discloses a foot device that is retained on the bottom of a shower floor by suction cups and has a device which essentially is depicted in FIGS. 1 through 5 and is generally arch shaped and has abrasive material on it so that a person can rub each foot on the respective side of the abrasive material to remove calluses from the bottom of the feet. The device itself is stationary and the person has to move back and forth to remove the calluses from the bottom of the feet.
The Jo Patent discloses a handheld pedicure sander which is used to remove calluses from the bottom of the feet but it is not a device that is used in a shower or a water environment but instead is a handheld device. Specifically, referring to the patent text beginning on Column 3 Line 8, the patent states:
“As shown in the drawings, the pedicure sander 1 of this invention has cylindrical rotary body 10, rotatably held by a bracket 50 at its drive shaft 32 and covered with a safety housing 16 at its top. In the present invention, the rotary body 10 may be preferably formed of a pumice stone or a float stone. However, it is more preferable to make the body 10 using a plastic material or metal. The drive shaft 32 is fixedly set along the central axis of the body 10. The rotary body 10 also has two axial fixing grooves 12 and 12a on its external surface such that the two grooves 12 and 12a are arranged in a line. Each of the two fixing grooves 12 and 12a firmly hold opposite ends of an associated one of two abrasive sheets 20 and 20a, thus allowing the two sheets 20 and 20a to closely and firmly cover desired parts of the external surface of the body 10 without being undesirably removed from the body 10. The rotary body 10 is a cylindrical body, stepped on its external surface at a predetermined portion to form two large diameter annular parts at opposite end portions and a small diameter part 26 defined between the two large diameter annular parts. Of the two large diameter annular parts, one has a large width, while the other has a small width. The two fixing grooves 12 and 12a are formed on the two large diameter annular parts, with the two abrasive sheets 20 and 20a covering the two large diameter annular parts to form a wide abrasive part 22 and a narrow abrasive part 22a.”
The Wheeler Patent discloses a foot scrubbing and massaging device. The patent discloses a foot scrubber and massager formed of modular parts. The broadest claim is Claim 1 which reads as follows:
“A foot scrubber comprising: a base module having an upper and a lower surface, wherein said base module is configured to cradle and substantially conform to a foot; and a customizable bristle module, said bristle module capable of being secured to said upper surface of said base module and said bristle module having a plurality of bristles extending outward from said bristle module, wherein said customizable bristle module may be customized to accommodate at least one plurality of interchangeable attachments.”
The Sullinger Patent discloses a dry skin and callus removal device. The device for removing calluses and dry skin includes a base 2 with a rim 24 and a support 30 for a block of pumice 15. The base 2 has a keyhole 8 and the pumice block 15 has a receiving hole 16 to accommodate suction cups 20. Specifically, Claim 1 of the patent reads as follows:
“A non-hand held device for the removal of dry skin and calluses from the human body comprising: (a) a planar base; (b) a block formed entirely of abrasive material supported by said base, said block of abrasive material having a planar lower surface and an upper surface, the entirety of which is concave, for abrasion; and (c) a plurality of suction cups attachable to said base.”
The Jusinski Patent discloses an apparatus and method for ergonomic basic chiropody. It discloses a device which apparently needs to be positioned in a corner portion of the location so it is parallel to two perpendicular walls and the device operates to remove calluses from the feet.
The Postal Patent discloses a drive mechanism for oscillatory abrasion and polishing. It is a handheld tool which can be connected to a power source and which can be used for various abrading applications including manicuring, polishing and dermabrasion.
The Anderson Patent discloses a device for abrading the underside of a foot for removing calluses, corns, etc. The device has a concave and a convex surface so that the different locations of the foot can be massaged and calluses abraded away as illustrated in FIGS. 1 through 3. The claims require the device to be in a figure 8 configuration with a concave portion on one side and a convex portion on the other side.
The Macklin Patent discloses:
“An electrically operated sander for removing calluses and increasing circulation, having a rectangular base unit for insertion into a docking unit. The base unit has a rear end, and includes a movable base plate having rounded edges and a grainy surface area and a gripping handle. The gripping handle extends outwardly from the base unit and defines a curved junction before extending horizontally toward the rear end of the base unit. The base unit houses a motor having a drive shaft mechanically linked to the base plate. A rotating two position on-off switch actuates the motor, causing the base plate to vibrate. A rectangular docking unit has a hollow cavity for accepting the gripping handle of the base unit therein for allowing users a hands free method of removing calluses.”
The only independent claim of invention which is Claim 1 reads as follows:
“A hands free method of removing calluses from hands or feet using an electrically operated sander, having a base unit having an on-off switch having an on position and an off position, a motor, a base plate having a grainy surface area, and having a docking unit, the steps comprising: positioning the base unit into the docking unit; vibrating the grainy surface of the base plate by actuating the on-off switch to the on position; and positioning calluses against the grainy surface and applying slight pressure while calluses are slowly removed.”
The '313 Brunderman Patent contains essentially two solid objects which contain abrading material on it. There is a mound 34 on which you can rub the foot against and there is also a toe stick 32 with an abrasive surface 36 which fits within the mound so that it can be used to remove calluses from the toes.
The '156 Brunderman Patent issued in 2000 and is a continuation application of the previous Brunderman Patent.
In each of these Brunderman Patents, we are dealing with a solid object and are not dealing with anything providing rotary motion.
The Jo Published Patent Application discloses:
“The present invention provides a disposable sand cap for removing calluses and a callus removal device having the same. The disposable sand cap for removing calluses includes a cap body which has a “ ”-shaped cross-section and is made of a synthetic resin, and an abrasive sand which has a 60.about.90 mesh particle size and is attached on a lower end surface of the cap body with a bonding agent. The callus removal device has the disposable sand cap with the abrasive sand. The callus removal device includes a grip part having an elliptical shape, with a plurality of finger grooves provided at several predetermined positions around a circumferential outer surface of the grip part, thus allowing fingers of a user to be placed on finger grooves. The callus removal device further includes a sand cap support part extending downwards from a lower portion of the grip part, with an insert ring provided around a circumferential outer surface of the sand cap support part. The callus removal device further includes an intermediate depression part provided between the grip part and the sand cap support part while being depressed inwards.”
The Nevakshonoff Patent discloses a device for sanding and buffing objects which has a rotary device on top of an elongated shaft.
The Kinsey Published Patent Application discloses:
“A skin sander for removing dead skin such as calluses and rough dry skin, including a housing, electric motor, and an oscillating sanding surface. The skin sander is ergonomically designed for use by various sized hands with minimal effort.”
The Drelinger Patent discloses:
“A rotary nail filing apparatus for animals is described that includes a shroud or housing, an opening in the shroud that is suitable sized and shaped to allow an end portion of an animal's nail to be put through the opening, and a suitably shaped and oriented rotary grinder that is contained within the shroud grinding at least a portion of an animal's nail when put through the opening, where at least a portion of the nail particles that are grinded away by the rotary grinder are contained in a portion of the shroud. In some embodiments, the rotary grinder position/orientation and/or its surface are adjustable and/or replaceable.”
This patent discloses an object having a rotary motion for the purpose of sanding down an animal's nails.
The Ryder Patent discloses a hand sander where there is an abrasive method on the bottom of the device and it can be rubbed against the skin to abrade calluses, etc.
The Moldawski Patent discloses:
“A lightweight, portable, electrically-powered dermabrasive device adapted to gently and painlessly remove keratinized epidermal portions of the hands and feet. The dermabrasive device includes a protective shield which shields user against contact from flakes of flying or ejected epidermis or other detritus.”
There is a significant need for an improved dermabrasion device to remove calluses which can be operated in a water environment such as a shower or bathtub and is operated so that a person does not need to use the person's hands to operate the pumice stone when removing calluses from the underside of a person's feet.
SUMMARY OF THE INVENTION
The present invention is a device including a body having a bottom wall and a cover including a top wall and a sidewall which enclose an interior chamber so that the interior chamber is waterproof to enable the device to be placed in an enclosure where water comes in contact with the device, the interior chamber housing a mechanism by which a shaft or axle supporting a dermabrasion wheel is caused to rotate, the body further comprising an activation member which when activated causes the shaft and the dermabrasion wheel to rotate in either a counterclockwise direction or a clockwise direction, so that the dermabrasion wheel will peel hardened skin cells from a location on a foot when the location on the foot is placed against the dermabrasion wheel while the dermabrasion apparatus is rotating.
The present invention is a waterproof motorized pumice stone described more broadly as a dermabrasion apparatus used to peel calluses from the a person's foot. The most common location from which calluses are removed are the underside of the foot at the location of the back of the heel and the underside of the foot below the toes. It is within the spirit and scope of the present invention to provide a device which can remove calluses from any location on a person's foot.
A key object of the present invention is to provide a device to remove calluses which is operated in a water environment. The device is operated while the person is in water so that the person's skin and calluses are softened by the water to facilitate the removal of calluses. The most common use is in a shower, however the present invention can also be used in a bathtub or spa, or other water environment while a person is taking shower or bath or soaking in hot water so that the skin and calluses on the person's foot are softened so that the removal of calluses is achieved more readily than an environment where the skin is dry and the calluses are hard. The device can be used while the shower head is spraying water onto the person or while the person is sitting in a bathtub or spa and after the calluses have been softened by the moisture so that callus removal is facilitated. The device can also be used in a dry environment.
It is another object of the present invention to provide a waterproof device which is operated in a hands free manner so that person does not have to hold the device while the device is being operated to remove calluses and other dead skin from a person's foot.
It is an additional object of the present invention to provide a device which enables calluses and other dead skin to be removed from a person's foot while a person is standing in a shower (or seated in the shower) or resting in a bathtub or hot tub so that the person can place the location of the person's foot where the calluses and dead skin are to be removed directly against the device.
It is a further object of the present invention to provide a waterproof device which has a rotating pumice stone which is balanced in the center of the device so that the device will not tip over as pressure form a foot is placed against the rotating pumice stone.
It is also an object of the present invention to provide a device which has a waterproof motorized enclosure which has a switch in the middle of the device and which can be activated by pressing on the switch with a person's foot. The device is normally off and a battery circuit is turned on when the switch is pressed and the circuit can be turned on and off by subsequent pressing action against the switch.
It is additionally an object of the present invention to provide a device having a rotatable shaft which contains a rotating pumice stone. When the activation switch is pressed or activated once, the pumice stone rotates in the counterclockwise direction or clockwise direction. When the switch activated again, the device is turned off.
It is a further object of the present invention to enable the device to be operated in a water environment so that when the pumice stone is rotating, foot can be placed on the pumice stone so that the back portion of the heel is polished and calluses, corns and hardened skin on the heel are removed. In addition, a person can place the back of their toes such as the underside of the ball of their big toe and underside of the front portion of their foot against the rotating pumice stone so that calluses, corns and other hardened skin can be removed.
It is additionally an object of the present invention for the device to have suction cups so that it can be affixed to the floor or a shower or bathtub so that the body of the apparatus will not move while it is being operated to remove calluses, etc. In this way, a person will not slip or fall while the pumice stones are rotating since the device itself will not move from its location where it is affixed to the floor by the suction cups.
It is also an object of the present invention to have warning means such as bright colors, a reflector, or other visible indicia on the device or molded into the device so that the device is visible and a person will not inadvertently step on the device or trip over the device and hurt themselves.
Further novel features and other objects of the present invention will become apparent from the following detailed description, discussion and the appended claims, taken in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Referring particularly to the drawings for the purpose of illustration only and not limitation, there is illustrated:
FIG. 1 is a perspective view of the present invention waterproof motorized device having a rotating dermabrasion apparatus, also illustrated in broken lines is a foot in a position to facilitate removal of dead skin cells from beneath toes;
FIG. 2 is a top plan view of the present invention waterproof motorized device having a rotating dermabrasion apparatus, with a foot illustrated in broken lines;
FIG. 3 is a bottom plan view of the present invention waterproof motorized rotating device having a rotating dermabrasion apparatus with suction cups affixed to the bottom of the device;
FIG. 4 is an interior view of the present invention waterproof motorized device having a rotating dermabrasion apparatus illustrating the electrical wiring of the device;
FIG. 5 is a side elevational view of the present invention waterproof motorized device having a rotating dermabrasion apparatus illustrating a foot shown in broken lines and positioned to enable the rotating pumice stone to be used to remove calluses, corns, and hardened skin from location below a person's heel;
FIG. 6 is a front view of the present invention waterproof motorized device having a rotating dermabrasion apparatuses; and
FIG. 7 is a perspective view showing the interconnection of the shaft from the motor and the shaft on which the pumice stone rotates.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Although specific embodiments of the present invention will now be described with reference to the drawings, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present invention. Various changes and modifications obvious to one skilled in the art to which the present invention pertains are deemed to be within the spirit, scope and contemplation of the present invention as further defined in the appended claims.
Referring to FIGS. 1 through 6 , there is illustrated a preferred embodiment of the present invention waterproof motorized rotating dermabrasion device 10 which comprises a bottom wall 20 having an exterior surface 22 and an interior surface 24 . The bottom wall 20 is enclosed by a cover 30 . The cover 30 has a top wall 40 with an exterior surface 42 and an interior surface 44 with a central opening 46 extending through the top wall 40 . The exterior surface 42 and a pair of oppositely disposed depressions 52 and 62 respectively accommodate a resistance pad 54 and 64 . The cover 30 includes a sidewall 70 which includes a side opening 72 to accommodate an on-off switch 74 . The side opening 72 is shielded by a portion of sidewall 70 A. The sidewall 70 has an exterior surface 76 and an interior surface 78 . The cover 30 fits over the bottom wall 20 to create an interior chamber 80 surrounded by the interior surface 24 of bottom wall 20 , the interior surface 44 of top wall 40 and the interior surface 78 of sidewall 70 .
A key innovation of the present invention is a central rotating pumice stone 90 which is a wheel 92 having an interior body 94 supporting an axle 96 extending transversely from either transverse side 94 A and 94 B of the body 94 , the exterior rim 94 C of the body covered by abrasive material 98 .
Referring to FIG. 4 , the rotating pumice stone 90 is driven by a DC motor 100 which is connected to wires 102 and 104 . Wire 102 is connected to a pole of the on-off switch 72 and wire 104 is connected to power pack 120 which can be a gang of batteries such as 4 AA batteries. Wire 106 connects the on-off switch 72 to the power pack 120 and wire 108 connects the on-off switch 72 to ground 110 . Access door 26 is retained on bottom wall 20 by retaining means such as screws 28 A, 28 B, 28 C and 28 D. With the retaining means 28 A, 28 B, 28 C and 28 D removed, the access door 26 is opened to gain access to the power pack 120 to change batteries 122 QA, 122 B, 122 C and 122 D. The interior chamber 80 is entirely sealed so that it is waterproof.
An interior shield 130 surrounds the opening 46 so that the interior chamber 80 is waterproof. The motor 100 , wires 102 , 104 , 106 and 108 and power pack 120 are retained within chamber 80 .
Referring to FIG. 7 , the motor 100 is connected to a shaft 102 which at the end 104 distal from the motor has an offset gear 106 formed to rotate in a given direction such as counter-clockwise. The axle 96 of the wheel 90 has a distal end 97 which is connected to an offset gear 99 which is formed to rotate in a direction opposite from the direction of the gear 106 on the motor shaft 102 . The gear 99 can be formed to rotate in the clockwise direction. The gears 106 and 99 are intermeshed and when caused to rotate, because of the opposite orientation, the gears 106 and 99 remain together and will not separate.
The cover 30 has a central slot 140 extending into the shield 130 which surrounds the opening 46 . The axle 96 has a short section 96 A which extends transversely to face 94 B of wheel body 94 and a long section 96 B which extends transversely to face 94 A of wheel body 94 . The wheel 90 is retained within opening 46 of the cover, with the short section 96 A of axle 96 retained in short slot section 140 A while the long section 96 B extends past slot section 140 B to be engaged with the motor as illustrated in FIG. 7 . The wheel 90 extends above the top surface 42 of cover 40 and when the switch 74 is moved or pushed to the “on” condition, the motor 100 causes its shaft 96 to rotate so that the intermeshed gears 99 and 106 cause the wheel 90 to rotate. The direction of rotation is either clockwise or counter-clockwise.
Movement retardation means such as suction cups 150 are placed on the exterior surface 22 of bottom wall 20 to help prevent the dermabrasion device from moving on the surface onto which it is placed.
The dermabrasion device 10 is placed on a surface such a bathroom floor or a shower floor. As illustrated in FIG. 1 with a foot 200 illustrated in broken lines, a person places his/her 210 heel of a foot 200 onto a resistance pad 54 or 64 so that a portion 220 of the foot from which calluses or other dead skin is to be removed are aligned with the wheel 90 and with the abrasive material 98 of the wheel. When the switch 74 is activated, the wheel 98 rotates and the abrasive material rotates. The portion of the foot 220 placed against the abrasive material has calluses, dead skin cells, etc. removed by the rotating action of the wheel 96 and the abrasive material 98 peeling off the calluses and other dead skin. To remove calluses and other dead skin from other portions of the same foot or the opposite foot, the heel can be placed in the same resistance pad 54 or the opposite resistance pad 64 so that the proper area of the foot is aligned with the abrasive material 98 on wheel 96 . The dermabrasion device 10 can be rotated 180 degrees if necessary for proper alignment of the specific area of the foot to be treated. As illustrated in FIG. 5 , the foot portion 220 can be placed on a resistance pad 54 and the heel 210 can be placed against the dermabrasion wheel 98 to remove dead skin cells from that location of the foot.
The present invention wheel 96 is in the center of the dermabrasion device 10 so that it is properly balanced and will not tilt to one side as pressure from a foot is applied against the wheel 96 . The waterproof enclosure enables the dermabrasion device 10 to be used in a shower while it is running. The movement retardation means 150 assists in preventing the device 10 from moving while in operation.
As an additional safety measure, warning means 170 such as florescent or other light reflecting material can be on the top surface 42 of cover 40 so that the device 10 is more visible to avoid a person accidentally tripping over the device 10 , either in the bathroom or in a shower.
The fact that at least a portion of the axle 94 A is within the shield 130 and the addition of the nature of the intermeshing gears 99 and 106 prevents the wheel 96 from flying out of the device 10 while it is in operation.
It will be appreciated that the device 10 can be used to remove dead skin cells from any location of the body but it is primary desired to remove dead skin cells from hard-to-reach locations on the foot. The device 10 is waterproof so it can be run while the source of water from a shower is running or after the source of water is turned off.
The motor 100 is preferably a battery operated DC motor.
The device 10 and its walls are preferably made of molded plastic but may be made of any rustproof and waterproof material.
Of course the present invention is not intended to be restricted to any particular form or arrangement, or any specific embodiment, or any specific use, disclosed herein, since the same may be modified in various particulars or relations without departing from the spirit or scope of the claimed invention hereinabove shown and described of which the apparatus or method shown is intended only for illustration and disclosure of an operative embodiment and not to show all of the various forms or modifications in which this invention might be embodied or operated.
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FIELD OF THE INVENTION
A new and distinctive short-day type strawberry cultivar designated ‘Camino Real’ is provided that resulted from a cross performed in 1994 between advanced selections Cal 89.230-7 (non-patented in the United States) and Cal 90.253-3 (non-patented in the United States). The cultivar is botanically identified as Fragaria×ananassa Duch. The parentage of the new cultivar can be summarized as follows:
Cal 89.230-7×Cal 90.253-3.
‘Camino Real’ was first fruited at the University of California, Wolfskill Experimental Orchard, near Winters, Calif., U.S.A., in 1995, where it was selected, was originally designated Cal 94.3-11, and was propagated asexually by runners. The characteristics of the new cultivar have been found to be fully transmissible by such asexual propagation. Following selection and during testing the plant was designated ‘C213’, and subsequently has been named ‘Camino Real’ for introduction. Asexual propagules from this original source have been tested at the Watsonville Strawberry Research Facility, the South Coast Research and Extension Center of the University of California, and to a limited extent in grower test fields starting in 1996.
It was found that the new cultivar of the present invention exhibits the following combination of characteristics:
(a) Exhibits a very compact growth habit,
(b) Typically forms attractive mostly symmetrical-conic fruit of very good quality in a good yield, and
(c) Forms relatively small broad concave leaflets having semi-pointed serrations.
BRIEF DESCRIPTION OF THE PHOTOGRAPHS
The depicted plants and plant parts of the ‘Camino Real’ cultivar were grown at Watsonville, Calif., U.S.A.
FIG. 1 —shows rows of typical fruiting plants during early May, 2000;
FIG. 2 —shows a close view of a representative individual fruiting plant during early May, 2000;
FIG. 3 —shows a one-half crate of representative fruit during early May, 2000;
FIG. 4 —shows representative mature fruit externally on the upper row and internally on the lower row with dimensions in centimeters being shown at the left; and
FIG. 5 —shows a typical mature leaf during late spring.
DETAILED DESCRIPTION
‘Camino Real’ as other short-day strawberry cultivars produces fruit over an extended period when treated appropriately in arid, subtropical climates. The production pattern for ‘Camino Real’ is similar to that of the ‘Camarosa’ cultivar U.S. Plant Pat. No. 8,708), although it is somewhat later to initiate fruiting with most cultural treatments. ‘Camino Real’ will be of special interest for winter plantings where the ‘Camarosa’ cultivar has been successful, and in summer plantings where the ‘Pajaro’ cultivar (U.S. Plant Pat. No. 4,538) and the ‘Chandler’ cultivar (U.S. Plant Pat. No. 5,262) have been successful.
Plants and Foliage
Fruiting plants of ‘Camino Real’ are smaller and more compact, more open, more erect, and less vigorous than plants of the ‘Camarosa’ cultivar. The ‘Camino Real’ plants are more compact but less erect than those of the ‘Gaviota’ cultivar (U.S. Plant Pat. No. 10,461). Comparative statistics for foliar characters near mid-season are given for the three cultivars in Table 1 that follows. Individual leaflets of ‘Camino Real’ are smaller than those of the ‘Gaviota’ and ‘Camarosa’ cultivars, and are somewhat more rounded than those of the ‘Camarosa’ cultivar. Leaves (including petioles) are similar in length to those of the ‘Gaviota’ cultivar, but are much broader. The leaves of ‘Camino Real’ are shorter and broader than those of the ‘Camarosa’ cultivar. Petioles are similar in thickness to those of ‘Gaviota’ cultivar. Leaves on vigorous plants of ‘Camino Real’ occasionally have 4 or 5 leaflets. ‘Camino Real’ has a consistently concave leaf form, generally much more concave than leaves of the ‘Gaviota’ and ‘Camarosa’ cultivars, and has more and usually more pointed serrations than these comparison cultivars. Plant height and width values were obtained for established plants growing at Watsonville, Calif. that were established on October 23rd and were measured on January 21st. This is the industry standard for planting these cultivars at this location. The typical length and color of the stipule is provided. The stipule color varies somewhat depending on age and stage of development. Individual stipules commonly display a green interior and reddish margins. The stipules are substantially the same for all three varieties. Strawberry plants do not commonly produce stolons during the fruiting period in annual planted systems such as those used in California. The stolon information included in Table 1 is estimated from the initial stolon production in a foundation nursery located near Redding, Calif.
TABLE 1
Cultivar
Foliar Character
‘Camarosa’
‘Gaviota’
‘Camino Real’
Plant height (mm)
mean
56
54
62
range
40-70
50-50
50-70
Plant spread (mm)
mean
167
143
193
range
150-200
130-155
165-220
Mid-Tier Leaflet
Length (mm)
mean
91
95
81
range
80 to 100
83 to 109
64 to 90
Width (mm)
mean
83
95
82
range
68 to 104
71 to 105
62 to 95
Mid-Tier Leaf
Length (mm)
mean
313
254
252
range
256 to 426
201 to 314
199 to 314
Width (mm)
mean
161
182
150
range
130 to 183
146 to 205
125 to 173
Leaf components
Petiole length (mm)
mean
209
168
170
range
171-285
133-208
135-212
Petiole diameter
(mm)
mean
3.0
3.2
3.1
range
2.9-3.1
3.1-3.4
2.9-3.3
Petiolule length
(mm)
mean
11
11
11
range
9-16
9-14
9-14
Number of
3
3
3, rarely 4 or 5
Leaflets/Leaf
Leaf Convexity
flat-convex, most
most are
very concave
are slightly
concave, some
concave
flat
Serrations
number/leaf (mean)
19.4
17.8
17.8
range
18-21
16-19
17-20
shape
rounded, some
rounded to
semi-pointed
semi-pointed
semi-pointed
Leaf Pubescence
light-moderate
light-moderate
light
Petiole Pubescence
density
moderate to
heavy
moderate
heavy
direction
perpendicular to
perpendicular
perpendicular
acropetal
Petiole color
2.5 GY 5/5
2.5 GY 6/8
2.5 GY 6/8
(Munsell)
Stipule length (mm)
mean
22
21.8
26.2
range
20-23
21-23
23-30
Stipule color
core
2.5 GY 6/8
2.5 GY 6/8
2.5 GY 6/8
margins
2.5 R 6/11
2.5 R 6/11
2.5 R 6/11
Stolons per nursery
215
194
184
mother plant
Venation pattern
pinnate
pinnate
pinnate
Color (Munsell)
2.5 GY 6/8
2.5 GY 6/8
2.5 GY 6/8
The adaxial (upper) surfaces of leaves of ‘Camino Real’ are darker than those of the ‘Gaviota’ cultivar and the ‘Camarosa’ cultivar, and the abaxial (lower) leaf surface colors are similar. See Table 2 that follows.
TABLE 2
Cultivar
Color Character
‘Camarosa’
‘Gaviota’
‘Camino Real’
Leaf Color (CIELAB)*
Adaxial
L*
mean
32.3
29.0
27.4
range
30.8 to 34.6
27.4 to 30.0
26.1 to 28.5
a*
mean
−7.0
−7.0
−6.4
range
−4.8 to −8.2
−6.1 to −7.7
−5.3 to −8.0
b*
mean
14.0
11.5
11.1
range
9.4 to 18.4
9.7 to 13.7
9.4 to 14.3
Munsell
5GY 4/3
5GY 4/3
5GY 4/3
Abaxial
L*
mean
46.1
47.5
45.7
range
43.9 to 49.2
46.4 to 48.7
44.0 to 47.5
a*
mean
−7.6
−7.6
−7.5
range
−6.8 to −8.0
−6.7 to −8.5
−6.6 to −8.3
b*
mean
21.8
20.4
19.8
range
20.1 to 25.0
17.2 to 24.5
18.4 to 20.7
Munsell
2.5GY 5/5
2.5GY 5/5
2.5GY 4/3
*CIELAB is the abbreviation of the international color system known as “Commission Internationale De L' Eclairage” 1978. For recommendations concerning uniform color spaces, color difference equations, and psychometric color terms see Supplement No. 2 of CIE Publication No. 15, Paris.
Isozymes in Leaf Extracts
‘Camino Real’ has been classified for three isozyme systems using Starch Gel Electrophoresis: Phosophoglucoisomerase (PGI), Leucine Aminopeptidase (LAP), and Phosphoglucomutase (PGM). It is distinguishable from the ‘Gaviota’ and ‘Camarosa’ cultivars using this methodology. See Table 3 that follows.
TABLE 3
Cultivar
Locus
‘Camarosa’
‘Gaviota’
‘Camino Real’
PGI
A2
A2
A2
LAP
B3
B3
B3
PGM
C1
C1
C3
For electrophoretic procedures see: J. Amer. Soc. Hort. Sci. 106:684 to 687.
Disease and Pest Reactions
‘Camino Real’ is moderately susceptible to common leaf spot ( Ramularia tulasnei ) and somewhat sensitive to powdery mildew ( Sphaerotheca macularis ). It is quite resistant to Verticillium wilt ( Verticillium dahliae ) and Phytophthora crown rot ( Phytophthora cactorum ), and relatively resistant to Anthracnose crown rot ( Colletotrichum acutatum ). When treated properly, it has tolerance to two-spotted spidermites ( Tetranychus urticae ) equal or greater than ‘Gaviota’ and ‘Camarosa’. ‘Camino Real’ is tolerant to strawberry viruses encountered in California.
Flowering, Fruiting, Fruit and Production Characteristics
Comparative statistics for flower and fruit characters near mid-season are given for ‘Camarosa’, ‘Gaviota’ and ‘Camino Real’ in Table 4 that follows. The primary flowers for ‘Camino Real’ are similar in size to those of the ‘Gaviota’ and ‘Camarosa’ cultivars. The petals for all three cultivars are white on both surfaces. The petal apex for all three cultivars is flat across the top with slightly rounded edges to slightly rounded across the top. The sepals are somewhat larger than those of the ‘Gaviota’ cultivar and are similar to those of the ‘Camarosa’ cultivar. The number of sepals equals the number of petals for all three cultivars. The calyx for ‘Camino Real’ varies from slightly indented to slightly necked, and each primary flower has 5 to 8 petals. The fruit shape for ‘Camino Real’ can vary but is typically rounded or symmetrical conic, and is easily distinguishable from that of the ‘Camarosa’ cultivar that is shortened flat conic. ‘Camino Real’ commonly has a greater proportion of symmetrical fruit than the ‘Gaviota’ cultivar. The fruit color information included in Table 4 was obtained using a reflectance spectrophotometer that integrates color over a 1.5 cm diameter circle. As indicated in FIG. 4, the internal fruit coloration is variable over a wide range and is lighter in the center than at the margin. This wide color variation is present in almost all strawberry cultivars. Achenes vary from yellow to dark red, and are generally even with the fruit surface or slightly indented. The pedicel information included in Table 4 was obtained on Jan. 21, 2002.
TABLE 4
Cultivar
Character
‘Camarosa’
‘Gaviota’
‘Camino Real’
Number of Petals
mean
6.3
5.9
5.8
range
5 to 8
5 to 8
5 to 8
Petal shape
apex
truncate to
truncate to
truncate to
slightly obtuse
slightly obtuse
slightly obtuse
base
attenuate
attenuate
attenuate
margin
entire
entire
entire
Petal length (mm)
mean
14.4
14.4
17.4
range
14-15
13-15
16-19
Petal width (mm)
mean
14.2
15.7
17.4
range
14-15
14-17
17-18
Flower Position
mostly even
exposed
exposed
(relative to
some exposed
foliage)
Calyx Diam.
(mm)
mean
48.1
41.7
47.1
range
32 to 58
30 to 58
37 to 57
Corolla Diam.
(mm)
mean
35.6
37.9
26.8
range
30 to 47
32 to 48
32 to 42
Sepal length
(mm)
mean
17.8
16.2
19.8
range
17-20
15-17
19-20
Sepal width
(mm)
mean
6.4
9.6
6-8
range
6-7
9-11
6-7
Sepal color
7.5 GY 4/4
5 GY 4/3
5 GY 4/3
(Munsell)
Pedicel length
(mm)
mean
93.2
72.8
76.0
range
85-112
62-87
72-80
Pedicel diameter
(mm)
mean
2.4
2.6
2.8
range
2.2-2.5
2.5-2.9
2.7-2.9
Pedicel color
5 GY 6/8
2.5 GY 6/8
5 GY 6/8
(Munsell)
Fruit Shape
Fruit length (mm)
mean
54
54
56
range
42-63
45-70
48-68
Fruit width (mm)
mean
49
44
50
range
39-72
37-51
43-62
length/width
ratio
1.13
1.22
1.14
range
0.61 to 1.51
1.02 to 1.45
0.92 to 1.28
subjective
short flat conic
mostly rounded
mostly
conic, some flat
symmetrical
conic
conic, some flat
conic
Calyx Position
even to
even to
even to
slightly necked
slightly indented
slightly indented
Seed Position
even to
even
even
slightly
indented
External and internal fruit color for ‘Camino Real’ is darker than that of the ‘Camarosa’ cultivar, and slightly darker than that of the ‘Gaviota’ cultivar. See Table 5 that follows where CIELAB fruit color information is presented.
TABLE 5
Cultivar
‘Camarosa’
‘Gaviota’
‘Camino Real’
External
L*
mean
23.3
22.4
20.1
range
20.7 to 27.0
20.3 to 24.5
15.6 to 22.9
a*
mean
26.6
28.2
26.3
range
21.6 to 29.5
25.3 to 31.4
21.6 to 29.4
b*
mean
12.8
14.8
13.6
range
9.9 to 14.6
12.0 to 17.7
7.8 to 20.3
Munsell
2.5R 3/7
5R 3/7
5R 3/7
Internal
L*
mean
44.0
48.1
40.2
range
40.7 to 46.9
44.3 to 53.9
26.3 to 45.4
a*
mean
41.4
37.2
39.2
range
35.0 to 45.1
26.1 to 41.3
31.8 to 43.6
b*
mean
29.9
28.6
28.8
range
24.1 to 35.3
19.9 to 32.6
19.8 to 35.5
Munsell
5R 4/12
5R 5/13
5R 5/13
Performance
‘Camino Real’ has been tested under a variety of cultural regimes, and optimal performance is obtained when nursery treatments and nutritional programs similar to those used with the ‘Gaviota’ and ‘Camarosa’ cultivars are employed. In general, ‘Camino Real’ is less adapted to very early season planting but less sensitive to excess chilling than the ‘Camarosa’ cultivar. ‘Camino Real’ retains excellent fruit quality in summer planting systems.
When treated with appropriate planting regimes, ‘Camino Real’ has larger fruit and produces greater individual-plant yields than the ‘Gaviota’ or ‘Camarosa’ cultivars. ‘Camino Real’ is intermediate to the ‘Gaviota’ and ‘Camarosa’ cultivars in its production pattern. It is somewhat later to initiate production than the ‘Camarosa’ cultivar, with conventional winter planting in central California but has earlier average production than the ‘Gaviota’ cultivar. Commercial appearance ratings have been better than those for the ‘Gaviota’ and ‘Camarosa’ cultivars and trials conducted at Santa Maria, Calif., U.S.A. in 1998 to 1999 have indicated that the fraction of non-marketable fruit is approximately one-half that produced by the ‘Camarosa’ cultivar. Fruit for ‘Camino Real’ is substantially firmer than the fruit of the ‘Gaviota’ cultivar, and is similar in firmness to that of the ‘Camarosa’ cultivar. Subjectively, the ‘Camino Real’ fruit has very good flavor. The fruit will be outstanding for both the fresh market and for processing, and will be useful for home garden purposes as well. See the comparative data presented in Table 6 that follows. There information is provided for plants that were evaluated during 1998 and 1999 at the Watsonville, Calif., U.S.A., Research Faculty of the University of California. Such plants had been asexually reproduced by the use of runners at Macdoel, Calif., U.S.A., were harvested on October 15 th , and were subjected to supplemental storage for approximately 7 to 10 days prior to being transplanted. The test planting consisted of 52 inch two-row beds, 17,300 plants/acre. Harvest was initiated in early April and continued through the last week of August.
TABLE 6
Yield
Appearance
Size
Cultivar
(g/plant)
Score
(g/fruit)
Firmness
‘Camarosa’
1,783
3.3
27.2
7.7
‘Gaviota’
1,437
3.5
27.8
7.1
‘Camino Real’
1,813
3.8
31.1
7.6
‘Camino Real’ has not been observed under all possible environmental conditions to date. Accordingly, it is possible that the phenotype may vary somewhat with variations in the environment.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application takes benefit of U.S. Prov. App. 61/877,250 filed 12 Sep. 2013 which is hereby incorporated in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to devices for the administration of fluid therapy and chromotherapy to the head for stimulatory purposes. Particularly, the invention comprises a portable device for administering fluid therapy using pressurized water and/or other therapeutic fluids and/or substances to massage and relax the head and scalp of the user while simultaneously allowing the use of craniofacial chromotherapy thus providing a generally relaxing and refreshing stimulative experience for the head.
BACKGROUND OF THE INVENTION
[0003] It is well known that merely standing in a shower with a stream of water directed at one's body results in a stimulating and relaxing effect in and about the area on which the water impinges. Many inventions for applying one or more streams of water to the body are well known in the prior art. Such devices range from mere handheld devices (e.g. a handheld shower massager) through more complex devices that subject the user's entire body to a multiplicity of streams of water and/or steam and/or entrained air (e.g. a therapeutic shower cabinet or whirlpool bath). Moreover, it is well known that variations in the temperature of the impinging water act to vary the stimulative or relaxing effect. Cold water causes one set of sensations, hot water causes another.
[0004] These effects are equally effective when applied directly to the head, particularly as a means of decreasing or eliminating head and neck pain and discomfort. A stream of water naturally acts to decrease tension in the muscles of the head and face, thus lessening stress related headaches. Some people report that a hot or warm water spray applied to the head lessens headaches. By the same token, a stream of cold water applied to a greater area of the scalp lowers the temperature of the scalp, thus causing the vasculature of the scalp to constrict slightly. Some people feel this helps alleviate headaches. Other therapeutic effects may be obtained by means of decreasing intra-cranial blood pressure thus preventing and/or treating some forms of stroke and/or facilitating more rapid recovery from cranial concussion. To achieve these effects water and/or other therapeutic fluids and/or substances may be sprayed or misted onto the scalp in a variety of temperatures, from cold to hot. Therapeutic fluids include, but are not limited to, carbonated water, tonic water, and astringent liquids. Therapeutic substances include, but are not limited to ice, bathing salts, and sea salt.
[0005] However, no such device exists in the prior art to apply one or more flowing sources of water and/or other therapeutic fluids and/or substances to the head, and only the head of the user. If one wishes to partake of such therapy using devices presently extant in the prior art, one must either take a shower or bath. Obviously, the necessity of disrobing to enjoy these existing therapies adds to their inconvenience.
[0006] Similarly, the use of colored light (chromotherapy or light therapy) as a therapeutic regimen is well known in the prior art both to practitioners of Ayurvedic medicine and photobiology. Chromotherapy is variously believed to induce feelings of well-being or “balance” various “energies” in the body (i.e. physical, emotional, spiritual, or mental) and/or treat specific sleep, skin, and mood disorders. While various devices are known in the prior art that combine shower heads, full sized bathtubs, and full-sized shower cabinets with chromotherapeutic devices, none are known that allow selective chromotherapy in the region of the face and neck. Thus, to the extent phototherapy is effective solely when administered through the eyes and the skin of the head and scalp, an apparatus that administers such therapy either independently or in concert with the fluid therapy described above would be advantageous.
[0007] By the same token, the use of aromatic substances as a therapeutic regimen is also well known in the prior art. Aromatherapy is variously believed to alter the user's mood or cognitive state, or physical well-being. While various devices are known in the prior art that combine shower, bathtubs, and shower cabinets with aromatherapeutic, none are known that allow selective aromatherapy in the region of the face and neck. Thus, to the extent aromatherapy is effective an apparatus that administers such therapy either independently or in concert with the therapies described above would be advantageous.
[0008] Further, to improve the relaxatory effect of the fluid therapy, chromotherapy, and aromatherapy described above, it would be advantageous to use the device in conjunction with a table also equipped with chromotherapeutic light sources.
[0009] Thus, it is a first object of the present invention to provide a device that can be used to administer fluid therapy by applying a multiplicity of streams of water and/or other therapeutic fluids and/or substances onto the head, and only the head, of the user. These streams of water and/or other therapeutic fluids and/or substances may be deposited on the scalp and face in any one of a variety of temperatures ranging from hot to cold, or any combination in between. Therapeutic fluids include, but are not limited to, carbonated water, tonic water, and astringent liquids. Therapeutic substances include, but are not limited to, ice, bathing salts, and sea salt.
[0010] It is a second object of the present invention to provide a device that can be used to administer chromotherapy to the head of the user. Such chromotherapy is administrable in a variety of colors and intensities—from individual single color therapy to variable color therapy, such colors being derived by varying the intensity of independent red, green, and blue light sources.
[0011] It is a third object of the present invention to provide a device that can be used to administer aromatherapy.
[0012] It is a fourth object of the present invention to provide a table equipped with chromotherapeutic light sources to enhance the chromotherapeutic effect of the device.
[0013] It is a fifth object of the present invention to allow the user to undergo stone or crystal therapy simultaneously while enjoying therapeutic fluid and/or chromotherapy and/or aromatherapy.
SUMMARY OF THE INVENTION
[0014] The device is comprised of a cabinet which loosely surrounds the head. The cabinet comprises a top support with a substantially transparent Plexiglas or glass insert and substantially transparent left and right side panels also preferably constructed primarily of Plexiglas or glass. Lamps or LEDs that allow for the administration of chromotherapy are embedded in the edges of the Plexiglas or glass panels comprising the top support and in the rear edges of the left and right side panels such that when activated the Plexiglas or glass insert of the top support and the left and right side panels act as light guides causing the Plexiglas or glass insert of the top support and the left and right side panels to simultaneously glow with the desired color. The base and rear structure of the cabinet rectangular, with the base serving as the repository for water and/or therapeutic substances when the device is used.
[0015] The device further comprises a pump to continuously circulate the water and/or therapeutic substances held in the base of the unit up through the rear structure of the unit where they exit through a waterfall spigot onto the forehead of the user and through two adjustable flow lines onto areas of the face chosen by the user.
[0016] Constructed into the rear structure of the device is a cavity for containing stones or crystals as might be used in stone therapy. Attached to the rear of the rear structure is a support and cover for an aromatherapy generator unit. Aroma lines duct the generated aromatherapy through the rear structure into the cabinet. Also, the Plexiglas or glass insert mounted in the top support has multiple perforations allowing the placement of another aromatherapy generator on the top support. A pyramidal structure surmounts the top support enclosing this second aromatherapy generator. Installed to the sides and front of the top support is a holder into which a tablet computer may be placed, such that the tablet computer may be used while the user receives fluid and/or chromotherapy and/or aromatherapy. Also installed through the top support is a wireless or wired speaker, preferably a wireless Bluetooth speaker, such that sound from the tablet computer or a cell phone or wireless media steamer may be audibly reproduced.
[0017] Since the user must necessarily lay horizontally while using the device, a table is provided. The table comprises a support stand, a reservoir for containing several air-filled or foam cushions or water. Affixed to the inner aspects of the sides of the reservoir are waterproof light strips, preferably LEDs that glow with the desired color. The reservoir may be optionally lined with a colored or colorless transparent or translucent light guide liner to act as a light guide and further enhance the chromotherapeutic effect of the waterproof light strips.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a right perspective view of an improved portable relaxation therapy massage device for the head.
[0019] FIG. 2 is a rear-right perspective view of an improved portable relaxation therapy massage device for the head.
[0020] FIG. 3 is a front perspective view of an improved portable relaxation therapy massage device for the head.
[0021] FIG. 4 is a right detail view of the upper aspect of an improved portable relaxation therapy massage device for the head.
[0022] FIG. 5 is a top oblique perspective view of a table for use with an improved portable relaxation therapy massage device for the head.
[0023] FIG. 6 is a partially schematic view of an improved portable relaxation therapy massage device for the head showing typical electrical and fluid handling components.
DETAILED DESCRIPTION OF THE INVENTION
[0024] Referring now to FIGS. 1 through 6 , the device is comprised of a cabinet 10 which loosely surrounds the entire head. Cabinet 10 generally comprised of substantially opaque fluid reservoir 11 , rear structure 13 , and top support 15 and substantially transparent Plexiglas or glass insert 16 installed in top support 15 , left side panel 17 , and right side panel 18 . A multiplicity of lamps or LEDs 19 that allow for the administration of chromotherapy are installed in the supporting edges of Plexiglas or glass insert 16 and the rear and bottom edges of left and right side panels, 17 and 18 respectively, such that when activated the Plexiglas or glass insert 16 in top support 15 , left side panel 17 , and right side panel 18 act as light guides causing Plexiglas or glass insert 16 of top support 15 , left side panel 17 , and right side panel 18 to simultaneously glow with the desired color. Rear structure 13 of cabinet 10 is generally rectangular, substantially hollow prism, containing various aromatherapy and fluid therapy distribution passages. The interior of rear structure 13 is accessible by means of hinged door 14 .
[0025] On the bottom of the inside aspect of cabinet 10 is drain grate 12 which is ordinarily equipped with a waterproof cushion. Drain grate 12 lets fluid drain into fluid reservoir 11 , which then flows by means of gravity through a filter mat into suction feed line 22 . The upper part of the inside aspect of rear structure 13 is equipped on the left and right sides by directionally adjustable left flow line 26 and right flow line 27 whereby the user can adjustably direct individual streams of water to different points on the head. Ordinarily two flow lines are sufficient, but those having skill in the art will recognize that more than two may be supplied. Similarly, at the level of left and right flow lines, 26 and 27 , respectively, and preferably between them, is waterfall spigot 25 . Waterfall spigot 25 is designed so that a nearly continuous sheet of water falls vertically in a plane onto the forehead of the user. This is of course not the only design conceivable. It would be useful to have alternative designs. For example, a waterfall spigot arranged to direct water backwards at an angle towards rear structure 13 and the forehead of the user is helpful to limit splashing in high water volume applications. It will be readily appreciated that other spray/flow patterns are conceivable. All such combinations that produce sprays, drips, mists, and streams are implicitly included in the present disclosure. Left flow line 26 , right flow line 27 , and waterfall spigot 25 are each in turn connected to a distribution manifold, internally housed in the upper aspect of rear structure 13 . The distribution manifold is in turn connected to pressurized feed line 20 which is in turn attached to the output of pump 21 .
[0026] Constructed into rear structure 13 is stone receptacle 28 for stones or crystals as might be used in stone therapy. Stone receptacle 28 is located adjacent to seventh primary chakra, the Sahasrara, when the user's head is inserted into cabinet 10 . By placing the appropriate stones or crystals in stone receptacle 28 , the user can enjoy stone therapy.
[0027] Attached to the rear of rear structure 13 is support 50 and cover 51 . The cavity formed inside cover 51 may be used to enclose a source of aromatherapy such as aromatherapy generator unit 52 . Left and right aroma lines, 53 and 54 , respectively, duct generated aromatherapy through rear structure 13 and into cabinet 10 .
[0028] Plexiglas or glass insert 16 mounted in top support 15 has multiple perforations 16 a allowing the placement of another aromatherapy generator on top support 15 . Pyramidal structure 61 surmounts top support 15 enclosing this second aromatherapy generator. Perforations 16 a duct generated aromatherapy through Plexiglas or glass insert 16 and into cabinet 10 .
[0029] Installed to the sides and front of top support 15 is tablet computer holder 62 . Tablet computer 63 may be placed in tablet computer holder 62 , such that tablet computer 63 may be used while the user receives fluid and/or chromotherapy and/or aromatherapy.
[0030] Also installed through top support 15 is wireless or wired speaker fluid resistant speaker 64 , preferably a wireless Bluetooth speaker, such that sound from the tablet computer 63 may be audibly reproduced.
[0031] Framework 30 supports cabinet 10 on table top 31 . Table top 31 has a drain hole providing a passage for suction feed line 22 such that when fluid is sprayed on the user's head it drains through drain grate 12 , into fluid reservoir 11 , through a filter mat and into suction feed line 22 and thence to the input of pump 21 . Installed in suction feed line 22 is valve 23 used to control the flow of drain water to pump 21 . Also, installed in suction feed line 22 is drain cock 24 used to drain used water from fluid reservoir 11 .
[0032] Pump 21 is electrically wired to power supply 40 operated by means of a pump switch 41 . When the user actuates pump switch 41 pump 21 is energized and begins to pump, drawing water and/or other therapeutic fluids and/or substances from the bottom of the fluid reservoir 11 by means of suction feed line 22 , through pump 21 and into pressurized feed line 20 , into the distribution manifold, and finally out of left and right flow lines, 26 and 27 , respectively, and waterfall spigot 25 . The water and/or other therapeutic fluids and/or substances fall onto the user's head, flow down through drain grate 12 and into fluid reservoir 11 .
[0033] LEDs 19 in cabinet 10 can be monochromatic (i.e. all constituent LEDs are the same color) or multi-colored (i.e. each LED can generate a range of colors). LEDs 19 are wired to light control unit 42 that is, in turn, wired to power supply 40 and two controls: 1) Intensity control 43 ; and, 2) Color control 44 . In the case of monochromatic LEDs 19 , the user operates intensity control 43 to simultaneously vary the intensity of the light emitted by LEDs 19 , thus varying the intensity of the monochromatic light generated inside cabinet 10 . In the case of multi-colored LEDs 19 , the user operates color control 44 to cause the light control unit 42 to vary the color of LEDs 19 to create a color inside cabinet 10 ranging from no light (black) to red to green to violet to white. If the user selects a color of light, the user then operates intensity control 43 to vary the intensity of the light from dim to bright.
[0034] When top support 15 with Plexiglas or glass insert 16 is equipped with Plexiglas or glass pyramidal structure 61 , pyramidal structure 61 serves as a light guide and glows with the same color and intensity as Plexiglas or glass insert 16 when illuminated.
[0035] Since the user must necessarily lay horizontally while using the device, table 70 is provided. Table 70 generally comprises support stand 71 and table reservoir 72 for containing several cushions 75 or water and/or therapeutic substances. When used with water and/or therapeutic substances, drain 73 is used to drain table reservoir 72 when therapy has been concluded. Drain 73 may be closed by a conventional stopper or valve. Those having skill in the art will recognize that cushions 75 may be air-filled or vinyl encapsulated foam. Affixed to the inner aspects of table reservoir 72 are waterproof light strips 74 , preferably comprising LEDs, that glow with the desired color. As before, the LEDs that comprise light strips 74 can be monochromatic (i.e. all constituent LEDs are the same color) or multi-colored (i.e. each LED can generate a range of colors). Also as discussed before, the LEDs comprising light strips 74 are wired to light control unit 42 and operated in tandem with LEDs 19 in cabinet 10 . By this means, all LEDs 19 in cabinet 10 the LEDs that comprise light strips 74 in table reservoir 72 may be coordinated to generate chromotherapeutic light as desired. Table reservoir 72 may be optionally lined with a transparent or translucent light guide liner 76 to act as a light guide and further enhance the chromotherapeutic effect of waterproof light strips 74 . Light guide liner 76 may be constructed of any suitable glass or plastic material, preferably Plexiglas or styrene, and may be any color including colorless. Further, light guide liner 76 may only cover the inner aspects of the sides of table reservoir 72 or it may cover the entirety of the inner aspect of table reservoir 72 .
[0036] To operate the device to administer fluid therapy, the user pours water and/or therapeutic fluids and/or substances into fluid reservoir 11 . Next, the user places cushions 75 in table reservoir 72 . The user then lies on adjoining table 70 and inserts his head, face up, into cabinet 10 . The user then rests his head on the waterproof cushion and activates pump 21 via pump switch 41 and enjoys the stimulating and refreshing flow of the water and/or therapeutic fluids and/or other substances present in fluid reservoir 11 as they are expelled onto the user's scalp and face through left and right flow lines, 26 and 27 , respectively, and waterfall spigot 25 . The water and/or therapeutic fluids and/or substances then drain through drain grate 12 , into fluid reservoir 11 and through a filter mat where they travel by means of gravity into suction feed line 22 to pump 21 . Pump 21 pressurizes the water and/or therapeutic fluids and/or other substances through pressurized feed line 20 , into an internally mounted distribution manifold and thence through left and right flow lines, 26 and 27 , respectively, and waterfall spigot 25 to repeat the process.
[0037] To operate the device to administer chromotherapy (when the device is equipped with multi-colored LEDs 19 and light strips 74 ), the user lies on table 70 and inserts his head, face up, into cabinet 10 . The user then rests his head on the waterproof cushion and activates light control unit 42 by actuating color control 44 and intensity control 43 to create a colored light inside cabinet 10 and table reservoir 72 of the desired color and intensity.
[0038] To operate the device to administer fluid therapy, the user pours water and/or therapeutic fluids and/or substances into fluid reservoir 11 . Next, the user places cushions 75 in table reservoir 72 . The user then lies on adjoining table 70 and inserts his head, face up, into cabinet 10 . The user then rests his head on the waterproof cushion and activates pump 21 via pump switch 41 and enjoys the stimulating and refreshing flow of the water and/or therapeutic fluids and/or other substances present in fluid reservoir 11 as they are expelled onto the user's scalp and face through left and right flow lines, 26 and 27 , respectively, and waterfall spigot 25 . The water and/or therapeutic fluids and/or substances then drain through drain grate 12 , into fluid reservoir 11 and through a filter mat where they travel by means of gravity into suction feed line 22 to pump 21 . Pump 21 pressurizes the water and/or therapeutic fluids and/or other substances through pressurized feed line 20 , into an internally mounted distribution manifold and thence through left and right flow lines, 26 and 27 , respectively, and waterfall spigot 25 to repeat the process. Simultaneously, to operate the device to administer chromotherapy (when the device is equipped with multi-colored LEDs 19 and light strips 74 ) the user activates light control unit 42 by actuating color control 44 and intensity control 43 to create a colored light inside cabinet 10 and table reservoir 72 of the desired color and intensity.
[0039] In another embodiment an electrical device to heat and/or cool the water and/or therapeutic fluids and/or substances in fluid reservoir 11 may be installed in fluid reservoir 11 , suction feed line 22 , or pressurized feed line 20 .
[0040] In another embodiment an ultraviolet lamp, or some other means of sterilizing the water and/or therapeutic fluids and/or substances in fluid reservoir 11 may be installed in fluid reservoir 11 , suction feed line 22 , or pressurized feed line 20 .
[0041] In another embodiment, a ventilation port for admitting air or other gasses into cabinet 10 is provided. Air may be provided by any of the conventional means, i.e. by a fan or blower and may be warmed by an electrical heating element or cooled by a refrigerated air system. Further, ventilating air may be admixed with oxygen or other compressed gasses to provide an altered atmospheric environment inside cabinet 10 .
[0042] In another embodiment fluid reservoir 11 may be externally removed from the device and interconnected with cabinet 10 by means of a feed line such that water and/or other therapeutic fluids and/or substances in fluid reservoir 11 are expelled over the head of the user by gravity. In this embodiment, the water and/or other therapeutic fluids and/or substances expelled over the user's head drain directly from the device and into a suitable floor drain.
[0043] While the invention has been described in connection with what are considered to be the most practical and preferred embodiments, it is to be understood that the invention is not to be limited to the disclosed embodiments, variants, and sub-variants, but on the contrary is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the disclosure. For example, Plexiglas or glass insert 16 in top support 15 may be an “infinity mirror” such that multiple reflections of LEDs 19 installed at the edge of Plexiglas or glass insert 16 in top support 15 may be perceived. Similarly, it will be readily apparent the phototherapeutic effect of the LEDs 19 and light strips 74 may be enhanced by including one or more effects machines inside or used in conjunction with cabinet 10 . For example, a bubble generator or a vapor generator equipped with user selectable or externally controllable sources of colored light may be used to amplify the phototherapeutic effect.
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FIELD OF THE INVENTION
This application relates to a laryngoscope and more particularly to a laryngoscope with a releasable blade.
BACKGROUND OF THE INVENTION
A laryngoscope is a device, typically comprising a handle and a blade, which is used by clinicians during tracheal intubation and that assists with intubation by allowing the clinician to visualise the path of the endotracheal tube as it passes through the glottis towards the trachea.
Typically, tracheal intubation begins with the blade inserted into the corner of the patient's mouth. The blade is shaped such that a flange will push the tongue to the left side of the oropharynx to create space in the oropharynx through which a view of the larynx will be sought. The epiglottis is visualised. The laryngoscope handle is manipulated so that the blade lifts the epiglottis directly with the blade or indirectly with the curved blade thereby exposing the laryngeal inlet in normal patients. The endotracheal tube is then advanced past the vocal cords into the trachea.
Due to the contact of the laryngoscope blade with bodily fluids, the equipment must be thoroughly sterilized between uses and sterilization procedures are time-consuming and costly. Alternatively, in order to eliminate cross-contamination between patients, the blade may be covered during use with a disposable sleeve as described in U.S. Pat. No. 5,347,995. However, the sleeve can become easily detached from the blade and prevent the clinician from properly performing the intubation. Another option is to use a detachable blade which is disposed of after each use. The proximal part of the blade is typically attached to the handle by means of pins, screws or bolts.
During intubation, the clinician will direct the laryngoscope with one hand and introduce the tracheal tube with the other and it is essential that the laryngoscope is easy to handle. In addition, the presence of protruding connecting parts can potentially injure or scratch the patient's anatomy both during intubation and removal of the laryngoscope. The removal of small parts such as bolts, pins or screws is fiddly and such small parts can easily be lost. Moreover, the connecting parts themselves may retain impurities such as blood and other bodily fluids that can harden and become increasingly difficult to remove and sterilisation becomes necessary.
It is an object of this invention to mitigate problems such as those described above.
SUMMARY OF THE INVENTION
According to a first aspect of the invention, there is provided a laryngoscope comprising a handle, a blade holding element, a releasable blade and releasable attachment means to attach the blade to the blade holding element.
The blade holding element may be pivotally attached to the handle, so that the blade may be arranged in a first operative position and a second inoperative position. Preferably, the blade is shaped so that it is releasable when in the second inoperative position. The blade may also be shaped so that it is not detachable when in the first operative position. These features ensure that the blade does not become detached during use when the clinician is performing the intubation. The invention is intended to improve the ease of connection and removal of the detachable blade.
The blade and the blade holding element may comprise mutually cooperative releasable attachment means and preferably at least one of the releasable attachment means comprises a resiliently deformable element. Most preferably, the releasable attachment means is a snap clip system.
The snap clip means may comprise at least one tooth and a corresponding groove for receiving the tooth. The blade holding element may comprise a tooth and the blade comprises a corresponding groove; or the blade may comprise a tooth and the blade holding element comprises a corresponding groove.
The use of a snap clip has the advantage that the connection mechanism does not have loose parts that can become lost when the blade is detached. In addition, it minimises the risk of injury to the patient during use.
Preferably, the blade is slidable onto the blade holding element. The blade may be made partially or wholly of a flexible thermoplastic or metal material.
The laryngoscope may further comprise a light source and/or vizualisation means in order to enable the clinician to clearly view the laryngeal inlet of the patient.
According to a second aspect of the invention, there is provided a blade for use with a laryngoscope as described above.
According to a third aspect of the invention, there is provided a handle for use with a laryngoscope as described above.
The invention will be further described with reference to the drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a laryngoscope according to an embodiment of the invention;
FIG. 2 is a side view of a laryngoscope according to an embodiment of the invention wherein the blade is detached;
FIG. 3 is a side view of the laryngoscope of FIG. 2 wherein the blade is sliding onto the blade holding element;
FIG. 4 is a partial side view of the laryngoscope of FIG. 2 showing a snap clip system used in the invention;
FIG. 5 is a side view of the laryngoscope of FIG. 2 wherein the blade is connected;
FIG. 6 is a partial perspective view of the laryngoscope of FIG. 2 wherein the blade is connected;
FIG. 7 is a side view of the laryngoscope of FIG. 2 in an inoperative position; and
FIGS. 8 and 9 are perspective views of the laryngoscope of FIG. 2 wherein the blade is being detached from the blade holding element.
DESCRIPTION OF PREFERRED EMBODIMENTS
In this application, the terms “distal part” and “proximal part” are used relative to the medical professional, i.e. the “distal part” is used to describe the part of the device that is inserted first into the patient.
The laryngoscope ( 1 ) of FIG. 1 comprises a handle ( 2 ) for holding and manoeuvring the laryngoscope, a blade holding element ( 3 ) that is pivotally attached to the handle ( 2 ) and a blade ( 4 ) that is attached to the blade holding element ( 3 ). The laryngoscope ( 1 ) further comprises means of visualisation including a display screen ( 5 ) to visualise the area captured, for example, by a camera (not shown). This embodiment has a viewing means comprising a fibre optic viewing device but within the context of the invention, the viewing means may include any of a fibre optic device, camera, viewing screen and/or other viewing means. The laryngoscope may be used without a visualisation means such as camera, viewer and/or fibre optics for straightforward cases but the use of a visualisation means is recommended in more complex and difficult intubation situations.
The handle ( 2 ) is preferably made of stainless steel for robustness, although other materials such as metals or plastics may be used. In the embodiment of FIG. 1 a detachable display screen ( 5 ) is connected at the proximal end of the handle ( 2 ). At the proximal end, the blade holding element ( 3 ) is pivotally connected to the heel of the handle ( 2 ).
The blade ( 4 ) may be hollow so that it can be fitted onto the blade holding element by sliding as can be seen in FIGS. 2 and 3 (described in more detail below). Preferably, the blade holding element ( 3 ) is elongated in shape and its outer contour corresponds substantially to the inner shape of the blade ( 4 ). In a preferred embodiment, the blade ( 4 ) may comprise a pair of wings ( 6 ) that fit the contour of the heel of the handle ( 2 ).
As can be seen in FIG. 4 , the proximal end of the blade ( 4 ) is connected to the proximal end of the blade holding element ( 3 ) by means of a snap clip. In this embodiment, the blade holding element ( 3 ) comprises a tooth ( 7 ) that can snap into a corresponding groove ( 8 ) in the blade ( 4 ). It can be envisaged a construction in which the blade ( 4 ) comprises a tooth ( 7 ) and the blade holding element ( 2 ), the corresponding groove ( 8 ). The tooth ( 7 ) is shaped to allow the blade ( 4 ) to slide on easily, but prevent its accidental removal. Preferably, the height of the tooth ( 7 ) is less than the depth of the groove ( 8 ) so that there are substantially no protruding parts.
The blade ( 4 ) is preferably integrally constructed and is for example produced by injection moulding so that the cost of production is relatively affordable. However, two-part blades may also be used, where the components are joined together by welding, gluing or clipping. The blade is preferably disposable to minimise or eliminate any risk of cross-contamination between patients. Preferably the blade ( 4 ) is partially or wholly made of a flexible material, such as a flexible thermoplastic material. Most preferably, the blade wings ( 6 ) are made of a flexible material, such as a flexible thermoplastic material. Also, the blade or part of the blade may be flexible due to its shape, design or dimension (e.g. thickness).
The blade ( 4 ) may be straight, e.g. a Miller laryngoscope blade. Preferably, a curved blade may be used, e.g. a Macintosh blade, because a curved blade can be dimensioned to conform to the anatomical curve of the patient's throat.
The laryngoscope ( 1 ) may comprise a light source and/or visualisation means such as fibreoptics, camera, display screen or other technology that enable external indirect visualisation of the laryngeal inlet.
A light source may be provided so that the distal tip of the blade is illuminated. This can be achieved for example by providing the handle with electrical power, such as a battery supply, which is electrically connected to a light source preferably located at the distal end of the blade holding element so that light exits through an opening in the distal part of the blade ( 4 ). Alternatively, electrical power may be provided by the viewer where a viewer is provided.
Similarly, visualisation means may be provided to view the distal tip of the blade ( 4 ) and the laryngeal inlet. For example, a fibre optic viewing means may be mounted in the blade holding element and comprise optical fibres. The fibres may be arranged so that their proximal end is attached to a screen ( 5 ). The screen is preferably detachable so that the equipment can be easily cleaned after use. The fibres exit from the distal end of the blade holding element ( 3 ) and through an opening in the distal part of the blade ( 4 ) to view the laryngeal inlet. Alternatively, the material of the blade may be wholly or partly transparent so as to allow visualisation instead of using an opening which could be considered to be prone to contamination. In another preferred embodiment, a camera is located at the distal end of the blade holding element.
The blade ( 4 ) is attached to the blade holding element ( 3 ) by means of a snap clip ( 7 , 8 ). In this embodiment, and as can be seen on FIGS. 2 and 3 , the blade holding element ( 3 ) is placed in the operative position (i.e. substantially perpendicular to the handle). The user can slide the hollow blade ( 4 ) onto the blade holding element ( 3 )—in a direction from the distal end to the proximal end of the element ( 4 ). Preferably, the outer contour of the blade holding element ( 3 ) corresponds substantially to the inner shape of the blade ( 4 ) to minimise or eliminate any movement of blade ( 4 ) relative to the blade holding element ( 3 ) in use.
As can be seen in FIGS. 4 to 6 , when the limit of travel is reached, the tooth ( 7 ) of the blade holding element ( 3 ) snaps into the groove ( 8 ) of the blade ( 4 ). A correct fit is indicated by audible feedback of the tooth ( 7 ) snapping into place. The blade ( 4 ) is held in place by a tooth ( 7 ) which is shaped to allow the blade ( 4 ) to slide on easily, but prevent its accidental removal.
In this embodiment, the blade ( 4 ) is detached from the blade holding element ( 3 ) by setting the laryngoscope ( 1 ) to its inoperative position by folding up the blade holding element ( 3 ) as shown for example in FIG. 7 .
As can be seen in FIG. 8 , the blade ( 4 ) may be removed by applying pressure onto the blade wings ( 6 ). The flexibility of the wings material deforms the area around the tooth catch ( 7 ), sending it away from the blade holding element and allowing the blade to clear the tooth ( 7 ) and slide away from it. The fit between the blade ( 4 ) and the heel of the handle ( 2 ) prevents the blade ( 4 ) from being removed whilst the laryngoscope ( 1 ) is in use since it is difficult to deform the blade ( 4 ) by pinching because of the presence of the handle ( 2 ).
In operation, the laryngoscope ( 1 ) is inserted into the mouth of the patient. The blade ( 4 ) will push the tongue of the patient to the side of the oropharynx to create space through which the larynx and the epiglottis can be viewed. The blade ( 4 ) is manipulated to lift the epiglottis thereby exposing the laryngeal inlet. An endotracheal tube can then be introduced and advanced past the vocal cords into the trachea. The user can visualise the distal end of the blade ( 4 ) for example on the display screen and manipulate the laryngoscope ( 1 ) accordingly. Once the tube is correctly positioned, the laryngoscope ( 1 ) is removed.
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BACKGROUND OF THE INVENTION
Caskets are fundamentally bulky items and are thus expensive to ship. Modularity of casket design enhances shipment by breaking down the otherwise bulky casket into a plurality of easily transportable boxes. However, modularity necessitates assembly that may prove too time-consuming or too complex for many end point users. There is thus a need in the casket market for a modular design that can be quickly and easily assembled and preferably without the use of tools.
Efforts to design modular and/or collapsible caskets date back nearly a century. For instance, U.S. Pat. No. 1,349,799 provides a collapsible design and U.S. Pat. No. 1,373,730 provides for separable connected members. A more modern design, see U.S. Pat. No. 3,924,309, divides a casket into its upper, middle and lower bands and allows for relatively quick reassembly. This succeeds at decreasing the weight of any one parcel, but still yields three parcels that are still as long as a casket and thus quite unwieldy. Other efforts succeed at breaking casket members down to smaller sizes, but make assembly too cumbersome. See, for example, U.S. Pat. Nos. 4,800,631; 6,269,526; 7,222,400; 7,614,131; and 7,730,595.
SUMMARY OF THE INVENTION
The object of this invention is to provide a practical and sleek casket design that can be easily shipped and quickly assembled by any user without the use of tools. This is achieved by the provision of a modular casket comprised of 16 roughly planar pieces that adhere together through the controlled actuation of magnetic force. Upon proper alignment of the side panels within a groove around the periphery of the base, removal of support pins from the interior side of the side panels forces a magnetic plate downward to mate with a large ferromagnetic strip at the bottom of the base groove. The upper portions of the side panels are aligned and held together through the use of magnetic dowels that mate with permanent magnets embedded within the side panels. The lid pieces are also held in place through a direct and less powerful magnetic force.
BRIEF DESCRIPTION OF THE DRAWINGS
An embodiment of the present invention will now be described by the way of an example and with references to the accompanying drawings, in which:
FIG. 1 illustrates a perspective view of the modular casket.
FIG. 2 illustrates a perspective view of the casket base with one end exploded.
FIG. 3 illustrates a perspective view of the side panels placed in the base groove.
FIG. 4 illustrates an exterior view of a flanking panel with a handle.
FIG. 5 illustrates the interior view of an end panel.
FIG. 6 illustrates the interior view of a flanking panel.
FIG. 7 illustrates a perspective view of a magnetic dowel.
FIG. 8 illustrates the internal view of a side panel.
FIG. 9 illustrates the interior view of a side panel post-actuation.
FIG. 10 illustrates the interior view of the casket lid.
DETAILED DESCRIPTION OF THE INVENTION
The preferred embodiment is a modular casket as shown in FIG. 1 . It is generally rectangular and consists of a base 1 that is partitioned into four parts of equal dimension. Attaching to the base 1 are six equivalent side panels 2 , three to each long side, and two equivalent end panels 3 , one to each short side. The lid of the casket 4 , like the base, is also partitioned into four parts of equal dimension.
FIG. 2 is the base with one end exploded to reveal how the four parts 5 align with one another with the use of dowels 6 . There is a groove 7 that runs along the outer portion of each part of the base. This groove 7 is partly filled in with a ferromagnetic strip 8 , preferably steel, and this ferromagnetic strip 8 is attached to the bottom of the groove with screws 9 . The portion of the groove 7 above the magnetic strip 8 is used for receiving and aligning the side panels.
FIG. 3 shows how the side panels align within the base groove 7 . The side panels are comprised of two different types of panels: there are two equivalent ends panels 10 and six equivalent flanking panels 11 .
FIG. 4 is the exterior view of a flanking panel. It contains a centered handle portion 12 that is used for lifting the casket. The handle portion 12 is attached to the side panel via dowels, screws, nails, glue or some combination thereof. The exterior of the end panel is equivalent except for the absence of a handle. Typically handle portions are placed to the side of caskets.
FIG. 5 is the interior view of an end panel. The end panel mates with the ends of the flanking panels via magnetic dowels inserted into holes 13 near the top of each panel type. Use of dowels provides for proper alignment as well as rigidity at the top of the casket. The dowel holes 13 are partly filled with a permanent magnet 14 that is glued or otherwise mounted to the bottom of the hole. This permanent magnet 14 is properly oriented to attract the magnetic dowel. This view, like interior view of all side panels, shows the access to the support pin 15 . The support pin holds up the magnetic plate nestled inside the side panels and it is preferably a ball locking pin with a ring handle. After all side panels are properly aligned, the support pins 15 are pulled out to actuate the magnetic force between the side panels and the base. Once the force is actuated, the support pins 15 can either be discarded or placed back in the original position.
FIG. 6 is the interior view of a flanking panel. Like the end panel of FIG. 5 , it has support pins 15 , but the holes for receiving the magnetic dowels are to the sides and thus are not visible in this view.
FIG. 7 is the dowel 16 with permanent magnets 17 attached to the ends. These permanents magnets 17 are preferably attached to the dowel ends with a screw 18 .
FIG. 8 is the equivalent internal view of all side panels. It demonstrates the entire mechanism for attaching the side panels to the base. It also reveals the mechanics of lateral attachment to other side panels and attachment of the lid. There is a magnetic plate 19 that houses an array of permanent disc magnets 20 . Prior to attachment, the magnetic plate 19 is held several inches above the bottom of the side panel and is held in place with a support pin 15 . After the support pin 15 is removed, the magnetic plate 19 falls to the bottom with the assistance of springs 21 and mates with the ferromagnetic strip in the base. This action is hereafter referred to as actuation. To enhance the force of attraction between the magnetic plates 19 and the base, the ferromagnetic strip within the base can be replaced by disc magnets mounted within the groove of the base. However, since this introduces additional costs and complexity with respect to alignment, the use of high flux rare-earth magnets, such as neodymium-iron-boron or samarium-cobalt along with a robust ferromagnetic strip is preferred. It is ideal for the support pin 15 to possess a rectangular cross-section. A rectangular cross-section, as opposed to the more common circular design, assists in preventing the magnetic plate from pivoting clockwise or counterclockwise around the support pin pre-actuation. Inhibiting said rotation should assure proper alignment within the side panel and prevent malfunction.
Upon actuation, the maximum distance traveled by the magnetic plate is limited by three separate components: the length of the guide posts 22 which attach to the magnetic plate 19 at one end and possess flange cap nuts at the other end, the side support lips 23 , and the magnetic strip in the base with which the magnetic plate mates. It is critical to maintain a high degree of precision amongst these three components. The magnetic plates must contact or come in very close contact with the magnetic strip in the base in order to maximize the force of attraction and thus the lift capacity of the casket. Additionally, this force must be counteracted by components within the side panels so that when the casket is lifted from the handles it carries the magnetic plates and the mated base along with them. The force transferring components are both the flange nut caps at the end of the guide posts 22 and the side support lips 22 . In order for both of these components to contribute to the lifting of the magnetic plate, the flange of the cap nuts must contact the weight support boards 24 just as the sides of the magnetic plate contact the support lips 23 . Either method may prove sufficient on its own to support the weight held up by the magnetic plate 19 . Since both are easily employed, the preferred embodiment incorporates both.
The side ends of the side panels mate with the dowels 16 possessing ends of opposite polarity to the magnets 14 nestled inside the dowel holes 13 . The dowels 16 provide a means to align the panels as well as provide lateral strength. With ends of opposite polarity to the magnets 14 within the dowel holes, the dowels 16 not only provide rigidity but draw the side panels tightly together. This closeness helps to assure proper alignment prior to actuation. After actuation, any adjustments to alignment will require special levers or other means that will be impractical to the average consumer. It is therefore imperative that proper alignment be assured prior to actuation. There is also an array of permanent disc magnets 25 nestled into the top of each side panel. These magnets 25 are used to attract the magnetic strip within the lid groove.
FIG. 9 provides an internal view post-actuation. After removal of the support pin 15 , the force of gravity, the tension of the springs 21 , and some very slight magnetic force draws the magnetic plate 19 to the bottom of the side panel and towards the ferromagnetic strip within the base.
FIG. 10 is the bottom view of the lid with a groove 26 cut along the interior periphery of each lid portion with dimensions complementary to the side panels enabling alignment and seating over the same. The groove 26 is partially filled with a flexible ferromagnetic strip that is glued or otherwise attached to the bottom of the groove. The flexible ferromagnetic strip is used for sealing the lid portions to the tops of the end panels but not with so much force as to inhibit easy removal of said lid portions. This easy removal will facilitate viewing of the body. Furthermore, a weaker magnetic force will enable fine adjustments to the alignment of the individual lid portions. The necessary play between the lid groove 26 and the tops of the side panels may require these fine adjustments for aesthetic purposes.
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