A method for stabilizing a charge director solution, and a charge director composition made by this method, whereby a charge director is mixed with a solvent and a polar monomer species and a polymerization reaction is initiated and allowed to progress to completion.

The present invention relates to liquid developer electrostatic photocopying and more particularly to a method of stabilizing charge director solutions and a new stabilized charge director composition.
Processes for forming electrostatic images, existing as electrostatic charge patterns upon a substrate, are well known. In electrostatic printing or copying, a photoconductive imaging surface is first provided with a uniform electrostatic charge, typically by moving the imaging surface past a charge corona at a uniform velocity. The imaging surface is then exposed to an optical image of an original to be copied. This optical image selectively discharges the imaging surface in a pattern to form a latent electrostatic image. In the case of an original bearing dark print on a light background, this latent image consists of substantially undischarged "print" portions corresponding to the graphic matter on the original, amidst a "background" portion that has been substantially discharged by exposure to light. The latent image is developed by exposure to oppositely charged, pigmented, toner particles, which deposit on the print portions of the latent image in a pattern corresponding to that of the original.
In liquid developer photocopiers, these charged toner particles are suspended in a liquid developer comprising a carrier liquid, toner particles and charge directors. The entire latent electrostatic image is covered with a thin film of liquid developer from a liquid developer reservoir. The charged toner particles in the liquid developer migrate to the oppositely charged "print" portions of the latent image to form a pattern on the photoconductive surface. This pattern, and the corresponding toner particles, are then transferred to a sheet to produce a visible image. Any liquid developer remaining on the photoconductive surface after this process is recycled back into the liquid developer reservoir.
Charge director plays an important role in the developing process described above. The charge director is a chemical species, either molecular or ionic, which acts to control the polarity and charge on the toner particles. The charge director creates charged species causing charging of the imaging material to ensure that the toner particles will be deposited and migrate in such a way as to form the desired image, on the imaging surface. Counter ions are also created to keep the liquid developer substantially electrically neutral overall. The present invention may be practiced with any number of charger directors, of which lecithin and barium petronate are examples.
One of the major problems concerning the material used as charge directors is the degradation of the charge carrying species under the application of the electric field created during the electrophoretic development process. Degradation of the charge carrying species also occurs during replenishment of developer with carrier liquid due to dilution of the charge director. Degradation of the charge carrying species destabilizes the liquid developer electrically. Since stable electrical characteristics of the liquid developer are important to achieve a high quality image, particularly when a large number of impressions are to be produced without changing the liquid developer dispersion, degradation of the charge carrying species results in poor copy quality.
It is believed that in many liquid developers the charge director molecules form inverse micelles. An example of these micelles is shown in FIG. 1. The micelles are formed by aggregation such that the polar portions of the charge director molecules point inside, and the nonpolar portions point outside to decrease the overall surface energy of the system. These micelles may solubilize ions generated by the dissociation of the charge director molecules. It is believed that the solubilization of ions by the charge director micelles is due to the formation within and around the micelles, of a microenvironment having a higher dielectric constant. The solubilization of ions by the charge director micelles results in micelles containing a charged species in their center. Some of the micelles have a positive species in the center and others have a negative species in the center. We believe that during the electrophoretic developing process these micelles rupture under the influence of the electric field created by the charged; photoconductive surface. The exact mechanism of the rupturing is not known. The rupture of the micelles changes the electrical properties of the liquid developer solution by freeing the charged species in the center of the micelles which, due to their relatively strong positive and negative charges and the low dielectric constant of the carrier liquid, tend to reassociate with each other to form electrically neutral compounds. The formation of these electrically neutral compounds changes the overall electrical properties of the liquid developer. The change in electrical properties of the liquid developer changes the toner particle dispersion in the liquid developer and the number of the charge-carrying species resulting in a degradation in copy quality.
We also believe that the micelles rupture when the liquid developer dispersion in a photocopier is replenished by the addition of new carrier liquid. Again, the exact mechanism is not known. The effect of this rupturing is manifested in an instability of the charge-carrying species in the system. Again, the overall result is a degradation in copy quality.
Accordingly, one object of the present invention is a charge director composition which will resist degradation under the influence of an electric field.
Another object of the present invention is a charge director composition which will resist degradation during the replenishment of carrier liquid in a liquid developer dispersion.
A further object of the present invention is a charge director solution which will resist destabilization.

Liquid developer containing stabilized charge director composition


A method of moving a door of a well for an aircraft undercarriage during sequences of deploying or retracting the undercarriage includes: using a temporary mechanical connection between the door and the undercarriage that is effective when the undercarriage is close to its retracted position, causing the door to be opened by the undercarriage while the undercarriage is being deployed and causing the door to be closed by the undercarriage while the undercarriage is being retracted, but releasing the door from the undercarriage when the undercarriage is close to its deployed position, and using a door actuator acting on the door to close and open the door when the undercarriage is in its deployed position and the temporary mechanical connection is interrupted.

The present disclosure generally relates to methods of moving a door of a well for an aircraft undercarriage. Generally, aircraft undercarriages are retractable into wheel wells in flight. Such a well is generally closed both by a leg fairing connected to the undercarriage and it remains open when the undercarriage is deployed so that it projects from the well, and also by at least one door that closes a zone of the well that receives the wheels, and that is often closed again once the undercarriage has been deployed.
On aircraft of a certain size, such as commercial transport airplanes, each door is associated with an actuator for moving the door between a closed position and an open position, and with a locking member for holding the door closed in flight. The sequence for deploying the undercarriage is generally as follows:                unlock the doors;        open the doors;        unlock the undercarriage;        move the undercarriage towards its deployed position;        lock the undercarriage in the deployed position;        close the doors; and        lock the doors.
The sequence for retracting the undercarriage is generally as follows:                unlock the doors;        open the doors;        unlock the undercarriage;        move the undercarriage towards its retracted position;        lock the undercarriage in the retracted position;        close the doors; and        lock the doors.
In general, each door has its own actuator and its own locking member, thereby leading to hydraulic installations that are complex, having multiple valves that need to be controlled with the above-mentioned sequences.
In certain aircraft that are simpler, a temporary mechanical link between the door and the undercarriage enables the door to be moved while the undercarriage is being deployed. More precisely, a roller secured to the undercarriage engages in a fork pivotally mounted on the structure of the aircraft and connected by a connecting rod to the door so that lowering the undercarriage causes the door to open. At a given position in the travel of the undercarriage, the door reaches an open position abutment, and the roller moves away from the fork as the undercarriage continues to move towards its deployed position. A resilient member holds the door in abutment in the open position. When the undercarriage moves back up, the roller docks with the fork and then causes it to pivot, thereby causing the door to be closed against the resilient member when the undercarriage terminates its travel towards the retracted position. The door is then prestressed in the closed position by the actuator for moving the undercarriage, and it is held in the locked position by the undercarriage being locked. Such a disposition makes it possible to omit an actuator for moving the doors and the associated locking members, but it does not allow the doors to be closed when the undercarriage is in the deployed position.
Unfortunately, closing the doors while the undercarriage is in the deployed position is advantageous, since it serves to reduce the aerodynamic turbulence caused by the well being fully open, it reduces the noise due to that turbulence, and it improves the appearance of the aircraft, in particular on the ground.
In order to mitigate that absence of the well closing when the undercarriage is deployed, proposals are made in Document FR 2,947,526 to associate the doors with the undercarriage by a permanent mechanical connection linking the movement of the doors with the movement of the undercarriage, and arranged to cause the doors to perform a go-and-return movement between the closed and open positions whenever the undercarriage is deployed or retracted. However, that provision is not always possible. Certain well shapes and/or certain linkages for moving the undercarriage do not enable the doors to be caused to open and close by means of a permanent mechanical connection with the undercarriage. In addition, such a permanent mechanical connection makes it necessary to provide disconnection means in order to be able to open the doors and access the wheel well on the ground.

Method of moving doors of a well for an aircraft undercarriage


A cover assembly for concealing an automotive vehicle air bag restraint assembly with an air bag, an air bag housing and a gas generator located in the housing for supplying gas to the air bag in response to vehicle impact. The cover assembly includes an inner retainer panel secured between the air bag and a vehicle passenger compartment. An air bag door is mounted within an opening in the retainer panel. A hinge connects the door to the retainer panel and allows the door to swing open under the force of an inflating air bag. A foam layer is sandwiched between an outer skin and the retainer panel and extends across both the retainer panel and the air bag door. A weakened tear-seam is formed in an outer surface of the outer skin and runs parallel to and adjacent an edge of the door opposite the hinge. A rigid applique is supported in a layered disposition over the outer skin to conceal the weakened tear-seam from passenger compartment occupants.

Many passenger vehicles are equipped with supplemental inflatable restraints, i.e., air bags, for vehicle occupants. Many of these air-bag-equipped vehicles also include cover assemblies that conceal the supplemental restraints. For primarily aesthetic reasons, it is desirable for such cover assemblies to include continuously formed outer skins or covers that provide no outward indication that an air bag assembly is concealed beneath or behind.
When an air bag inflates in response to a vehicle collision, a continuously-formed outer skin must tear open through a wide range of temperatures to allow the inflating bag to expand into the passenger compartment in a predictable manner.
One such method of controlling outer skin tearing is to create a weakened tear seam by weakening a linear portion of the outer skin so that tearing will occur along that weakened line when the air bag inflates. Weakening is sometimes accomplished by such means as perforating, cutting or melting the outer skin prior to assembling the cover assembly. For example, U.S. Pat. No. 5,131,678, assigned to the assignee of the present application, discloses an air bag cover assembly that includes a weakened tear-seam formed in the outer surface of an outer skin prior to assembly by cutting. The '678 patent does not, however, provide for concealment of the weakened tear-seam from passenger compartment occupants.
Another method of controlling outer-skin tearing is to use one or more pressure-assist members such as cutters or tear edges. For example, U.S. Pat. No. 4,097,064 discloses a cover assembly with a rigid applique in the form of a semi-rigid pad that is supported in a layered disposition over an outer skin. A cutter is mounted on the inner surface of the semi-rigid pad with a sharp cutting edge extended inward toward the outer skin. Air bag inflation forces the outer skin outward into contact with the inwardly-directed cutter, cutting the outer skin and releasing the inflating air bag. The position of the cutter on the inner surface of the pad also serves to conceal the cutter from vehicle occupants.
The prior art also includes an air bag cover assembly that employs both outer-skin weakening and a tear edge positioned along the weakened tear seam. U.S. Pat. No. 5,375,875 discloses a cover assembly with a weakened tear-seam formed in the inner surface of an outer skin, and a tear edge on a cutter panel that swings outwardly under the force of air bag inflation to cut the outer skin along the weakened tear-seam. The weakened tear seam is concealed from passenger compartment occupants by positioning it on the inner surface of the outer skin.
It would be desirable to provide an air bag cover assembly that controls the tearing of a continuously-formed outer skin by weakening a tear seam in the outer surface of the skin while concealing the weakened seam from passenger compartment occupants.

Frontal weakening of invisible air bag door cover


A method for making a semiconductor die package is disclosed. In some embodiments, the method includes using a leadframe structure including at least one lead structure having a lead surface. A semiconductor die having a first surface and a second surface is attached to the leadframe structure. The first surface of the semiconductor die is substantially planar to the lead surface and the second surface of the semiconductor die is coupled to the leadframe structure. A layer of conductive material is formed on the lead surface and the first surface of the semiconductor die to electrically couple the at least one lead structure to the semiconductor die.

There are a number of semiconductor die packages. Many semiconductor packages use wires to electrically connect source and gate regions on a semiconductor die to the source and gate leads on a leadframe. Many other semiconductor packages use clips instead of wires to form the external connections to external terminals. Such semiconductor die packages are sometimes referred to as "wireless" packages. A typical wireless package includes a clip that is attached to a semiconductor die. Wireless semiconductor die packages are generally preferred because they have better thermal and electrical properties than semiconductor die packages that use wires for terminal connections.
While clip bonded semiconductor packages are useful, improvements could be made. For example, one problem is the high cost of semiconductor package platforms that require clip bonding. The cost of a clip can be as high as the cost of the leadframe. Moreover, clip bonding requires expensive customized clip bonders and paste dispenser systems. Clip bonded packages thus have very high material and manufacturing costs.
Another problem that exists with clip bonding is the problem of applying inconsistent or uneven amounts of solder between the clip and the semiconductor die. When inconsistent or uneven amounts of solder are used between a die and a clip, the resulting packages may exhibit poor performance. And, as the feature sizes of microlead package (MLP) components get increasingly smaller, designs are constrained by the metal-to metal clearance and dimensional tolerance capabilities of etched and half-etched frame technology.
Embodiments of the invention address the above problems and other problems individually and collectively.

Clipless and wireless semiconductor die package and method for making the same


A packaged semiconductor device uses built-in self test to characterize voltage between points within the semiconductor die during a current discontinuity generated in the semiconductor die. The semiconductor die is operated to generate a current discontinuity, or several sequential current discontinuities, and the voltage is measured with an on-chip ADC. Measuring the voltage within the semiconductor die, rather than measuring at external test points, provides a more accurate prediction of device operation. Multiple test points are measured using a multiplexer, multiple ADCs, or by reconfiguring an FPGA. Impedance versus frequency information of the greater power distribution system connected to the semiconductor die is obtained by transforming the voltage and current through the semiconductor die measured during a current discontinuity.

Electrical systems often include semiconductor devices with very demanding power requirements (e.g. providing for high current transients with stable voltage over a wide frequency range). It is desirable to know information about the electrical characteristics of the power distribution system ("PDS") that provides electrical power to the semiconductor device. For purposes of discussion, the term "device" refers to a packaged semiconductor device, and "die" refers to the semiconductor die ("chip") within the packaged device. "PDS" refers to the greater PDS, which includes not only the output ports of power supply, but also the printed circuit board ("PCB"), additional components mounted on the PCB, and the package of the semiconductor device. Factors that can affect the performance of the PDS include voltage regulators, decoupling capacitors, power planes and sandwiches, power vias, solder lands, device package balls, package substrate planes and vias, and similar elements. The impedance of the PDS over all frequencies of interest (i.e. the frequencies at which the semiconductor device requires transient current, such as when several switching operations simultaneously occur in the semiconductor device, as well as steady-state direct current ("DC")) is frequently used as a figure of merit of the PDS.
Conventional techniques for accurately determining the relevant impedance have several drawbacks. One technique uses a network analyzer in either a 1-port or 2-port configuration to measure the impedance of a portion of the PDS. The network analyzer injects a stimulus into the network under test (i.e. the PDS) that sweeps all frequencies of interest while simultaneously measuring the reflected and/or transmitted energy. The PDS impedance can be derived from the reflected and/or transmitted energy.
This method uses test points on the PCB, whether built into the PCB solely for that purpose, or whether retrofitted to the PCB, such as when measurements are made through a pair of decoupling capacitor lands with the capacitor removed. However, even with the best of test points, this method does not provide an accurate measurement of the PDS impedance seen by the semiconductor die (i.e. at the chip) because it does not measure the portion of the PDS between the voltage present at the chip and the external test points. In particular, it does not measure parasitic contributions of the package and the portion of the PCB between the semiconductor device and the test points. Removing the lid of a packaged semiconductor device to expose interior test points on the die is impractical because it destroys the packaged device.
Another limitation of this method is that network analyzers are typically designed to measure impedance in the range of 50 ohms. A good PDS often has impedance in the range of tens or hundreds of milliohms, and sometimes much lower. It is difficult for a network analyzer designed to measure a 50-ohm system to accurately measure impedances orders of magnitude smaller.
Another technique measured high-frequency impedance of a power supply loop for a microprocessor using current switching in the microprocessor. The microprocessor was programmed to generate periodic, changing current draw containing relatively long DC fractions, one portion having low current draw ("cold"), and another portion having high current draw ("hot"). The hot portion contained four integer additions, and the cold portion had four integer no-ops per cycle. Test pads were provided on the package of the microprocessor to provide Vdd–Vss sensing. Calibrated sense resistors were used in series between the voltage regulation modules and the microprocessor to extract quiescent hot and cold Idd values. A digital oscilloscope was used to measure the voltages and process the data to provide impedance information. Many thousands of sweeps were taken with the oscilloscope and averaged to filter random noise.
While this approach avoids the limitations of measuring the PDS in a 50-ohm test system, it still does not account for the impedance of the PDS generated by the portion of the network between the test pads and the point(s) of interest in the microprocessor, such as the package impedance. The package impedance is particularly relevant for devices that are provided in a variety of package types.
Another limitation of this technique is that the data obtained is only relevant for the PCB that the microprocessor is loaded onto. Another PCB for the same electronic system might have different impedance due to manufacturing tolerances and variance in the loaded components. A PCB having a different layout and different components (such as different power supplies) would almost certainly have different impedance.
Therefore, it is desirable to more accurately characterize PDSs. It is further desirable to characterize PDSs for use with semiconductor devices in a variety of electronic systems and semiconductor dice in a variety of device packages, and to characterize the expected operation of a semiconductor device in an electronic system.

Power distribution system built-in self test using on-chip data converter


An optical scanning device includes a mirror adjusting mechanism which includes an abutting surface and a mirror holding member. The abutting surface is provided with one or more first support protrusions making point contact or line contact with a reflecting surface of a planar mirror on the same straight line. The mirror holding member includes a mirror receiving part provided with one second support protrusion making point contact with the reflecting surface of the planar mirror. The mirror holding member is rotated while maintaining a contact state between the planar mirror and the first support protrusions and a contact state between the mirror receiving part and the abutting surface, so that an angle of the planar mirror is adjustable only in one direction by employing a straight line, which connects contact points between the plurality of first support protrusions and the planar mirror to each other, as a swing axis.

The technology of the present disclosure relates to an optical scanning device that forms a latent image on a surface to be scanned by exposure scanning, and an image forming apparatus including the same such as a copy machine, a printer, a facsimile, and a multifunctional peripheral thereof.
Conventionally, in an optical scanning device used in an image forming apparatus, beam light emitted from a light source is deflected in a deflector such as a polygon mirror, is led to a photosensitive drum (an image carrying member) by passing through an optical member such as a lens, exposes and scans a surface of the photosensitive drum, and forms an electrostatic latent image thereon.
In such an optical scanning device, a sensor for detecting writing light is arranged in order to decide a writing position (a writing timing) of an image. A writing position is controlled such that after the writing light is incident into the detection sensor, an image is written after a predetermined time (several μseconds) passes. The writing light is reflected toward the detection sensor by a mirror. However, at this time, when an angle of the mirror in a sub-scanning direction is shifted, since the writing light is deviated in a vertical direction (the sub-scanning direction) of the detection sensor and is not detected, drawing is not started.
Conventionally, in order to correct a position of the writing light in the sub-scanning direction, a correcting lens is mounted. However, since the correcting lens is expensive as compared with general resin parts, it is preferable to employ a configuration with no correcting lens in order to enhance a cost-down effect by reducing parts. Therefore, particularly, when an optical path length from the mirror to the detection sensor is long, since the accuracy of a mirror angle has a large influence on shift of the writing light in the sub-scanning direction, there is a case in which a means for adjusting the mirror angle is necessary.
In this regard, there has been known various technologies for adjusting the mirror angle with a simple configuration. For example, there has been proposed a configuration for adjusting the mirror angle by allowing one end of the mirror to be brought into press-contact with a support point of a housing side by an elastic member and to directly press the other end of the mirror by an adjusting screw.
Furthermore, for example, there has been proposed a configuration for adjusting the mirror angle by mounting the mirror in a wedge-shaped mirror holding member and rotating the mirror holding member.

Optical scanning device and image forming apparatus including the same


A free standing film includes: i. a matrix layer having opposing surfaces, and ii. an array of nanorods, where the nanorods are oriented to pass through the matrix layer and protrude an average distance of at least 1 micrometer through one or both surfaces of the matrix layer. A method for preparing the free standing film includes (a) providing an array of nanorods on a substrate, optionally (b) infiltrating the array with a sacrificial layer, (c) infiltrating the array with a matrix layer, thereby producing an infiltrated array, optionally (d) removing the sacrificial layer without removing the matrix layer, when step (b) is present, and (e) removing the infiltrated array from the substrate to form the free standing film. The free standing film is useful as an optical filter, ACF, or TIM, depending on the type and density of nanorods selected.

1. Technical Field
A free standing film containing nanotubes is prepared by the process described herein. Depending on the type of nanotubes, the free standing film is useful as an optical filter, as an anisotropically electrically conductive film (ACF), or as a thermal interface material (TIM).
2. Problems to be Solved
Electronic components such as semiconductors, transistors, integrated circuits (ICs), discrete devices, and others known in the art are designed to operate at a normal operating temperature or within a normal operating temperature range. However, the operation of an electronic component generates heat. If sufficient heat is not removed, the electronic component will operate at a temperature significantly above its normal operating temperature. Excessive temperatures can adversely affect performance of the electronic component and operation of the device associated therewith and negatively impact mean time between failures.
To avoid these problems, heat can be removed by thermal conduction from the electronic component to a thermal management aid such as a heat sink. The heat sink can then be cooled by any convenient means such as convection or radiation techniques. During thermal conduction, heat can be transferred from the electronic component to the heat sink by surface contact between the electronic component and the heat sink or by contact of the electronic component and heat sink with a TIM. The lower the thermal impedance of the TIM, the greater the flow of heat from the electronic component to the heat sink.
Surfaces of the electronic component and the heat sink are typically not completely smooth; therefore, it is difficult to achieve full contact between the surfaces. Air spaces, which are poor thermal conductors, appear between the surfaces and increase impedance. These spaces can be filled by inserting a TIM between the surfaces. As manufacturers make smaller and smaller devices, there is a continuing need for TIMs which are thin and have improved thermal conductivity to efficiently transfer heat from electronic components to thermal management aids.
Composites containing nanotubes randomly distributed in a matrix are known for use as TIMs in the art. However, when nanotubes are oriented in an array instead of being randomly distributed, the array may exhibit improved properties, such as thermal conductivity. It is difficult to produce TIMs containing such arrays.

Process for preparing conductive films and articles prepared using the process


The present invention relates to compositions and methods for the treatment of traumatic conditions of the skin including radiation dermatitis, thermal burn, sunburn, dermatomyo-fibromas, and exposure-induced wrinkles, comprising omega-3 fish oils, tocopherols, lavender oil and a suitable amount of a pharmaceutically acceptable carrier, and optionally, one or more of the following: Sodium PCA, or MSM.

Fatty acids are essential for life. Besides storing energy, these fats are part of our makeup; they are formed in our healthy cells, muscles, nerves, and organs. The omega-3 polyunsaturated fatty acids are found in marine oils and are well known for their benefit as orally administered supplements for the maintenance of healthy arteries. A multitude of research has underscored the major role of essential fatty acids play as a defense against disease and age-related disorders. Gamma-linolenic acid (GHA) and docosahexaenoic acid (DHA) have been shown to protect against age related disorders such as heart disease, hypertension, elevated cholesterol, insulin resistance, dementia, memory loss, and atherosclerosis that can lead to heart disease, stroke, and elevated cholesterol levels. In youth, the fatty acids GLA, DHA, and eicosapentaenoic acid (EPA) are produced through metabolic processes involving the enzyme delta-6 desaturase. Unfortunately, this enzyme diminishes with age, leading to a deficiency of essential fatty acids that are needed to respond optimally to trauma.
In general, the "good" fats are unsaturated fats from oils of vegetables, nuts, and some fish. "Bad" fats are saturated fats, typically from animal fats, dairy products, etc. Without adequate levels of good fats, dangerous saturated fats will replace the essential fatty acids in our cells, reducing membrane fluidity and efficiency, starting the process of premature aging, and lessening the ability of the body to appropriately respond to trauma. Supplementation with the right proportions of fatty acids can maximize the production of anti-inflammatory prostaglandins (E1 and E3), while suppressing pro-inflammatory prostaglandin E2.
In addition, omega-3 fatty acids have been used as emulsion vehicles for the oral administration of poorly water-soluble therapeutic agents, as taught in U.S. Pat. No. 6,284,268, to Mishra. Their derivatives have been used to prevent a psychiatric, neurological or other central or peripheral nervous system disease, according to Horrobin, U.S. Pat. No. 6,479,544, who teaches a composition comprising EPA in combination with arachidonic acid or an arachidonic acid precursor such as dihomo-gammalinolenic (DGLA) or GLA. U.S. Pat. No. 6,361,806, to Allen, teaches the topical application of the linoleic acids, including gamma-linoleic acid, to the skin to effect changes in subcutaneous adipose tissue, and methods for ameliorating diseases of the subcutaneous tissue, primarily fibrocystic disease of the breast.
The variety of substances used to sooth irritated skin is limited only by the imagination of the formulator. Natural oils, such as aloe vera, are used extensively and several U.S. Patents are issued for specific formulas such as U.S. Pat. No. 6,193,987, to Harbeck, which teaches a lubricating composition for hands and skin comprised of organic safflower oil, flaxseed oil, tincture of benzoin, and organic beeswax blended in a cream-like base. U.S. Pat. No. 5,244,679, to Freston, teaches the alleviation of minor human skin irritations with topical application of glycerin, stearic acid, cocoa butter and boric acid blended together in a creamy base.
The omega-3 polyunsaturated fatty acids have also been sought as topical preparations, but technology in the field has had poor success in topical pharmaceutical formulations of fish oil-derived DHA and EPA. One of the main technical obstacles that has heretofore prevented their effective topical use is their very unpleasant smell, generated after application, and caused by oxidization of marine lipids from atmospheric oxygen and/or cutaneous enzymes.
The "off" or "rancid" odor associated with these oils is produced, in part, by oxidation of polyunsaturated fatty acids. Since highly unsaturated fatty acids occur in greater proportion in marine oils than in land animal- and vegetable-derived oils, rancidity is a greater problem when using marine sources. Oxidation of polyunsaturated fatty acids leads to the formation of hydroperoxides. The decomposition products of these hydroperoxides, such as aldehydes resulting from oxidation of marine animal oils, exhibit the unpleasant odors characteristic of rancid oils. Certain decomposition intermediates may also contribute to the problem.
Hence, the use of creams, lotions or gels containing omega-3 polyunsaturated fatty acids, which are initially odorless or pleasantly perfumed, is limited by their very unpleasant and repellent smell after application, which emanate from application sites and adhere to clothes that come into contact with them. As a result, consumer acceptability of topical compositions is low.
These odors appear to be characteristic of the fatty acids or long-chain hydrocarbons associated with natural oil compositions. In fish oils, for example, the "fishy" odor is postulated to be the result of interaction during oxidation between nitrogenous moieties and unsaturated glycerides present in the oil composition. Another theory regarding the source of the odor is that the unsaponifiable fraction (i.e., 5-hydrocarbon, sterol, methyl-sterol, long-chain alcohol, triterpene alcohol, pigment, trace materials and the like) of the oil composition is the component with which the "fishy" odor is associated.
In any event, this odor is not permanently removable even by drastic steam deodorization procedures (i.e., prolonged vacuum treatment at elevated temperatures, such as from about 230 degree to 260 degree. C.). The odor returns upon exposure of the "deodorized" oil to oxygen.
Since marine oils are capable of imparting advantageous properties to topical compositions, efforts have been made to overcome the aroma problem. These efforts were complicated by the fact that many processes alter the composition of fats and fatty acids. Exemplary processing techniques are refining, high temperature clay bleaching, high temperature-high pressure fat splitting, transesterification reactions and partial hydrogenation. Alterations arising from processing include cis-trans isomerization, conjugation of polyunsaturates, polymerization, dehydrogenation and the like.
Several strategies have emerged for using malodorous oils in topical compositions. In the first, only amounts of oil small enough not to adversely impact the odor of the complete topical composition were used. This strategy is not effective when higher concentrations of oil are required or desirable. The use of perfumes or any other deodorizing agent, even if intense and strong, is useless. In fact, upon application of the cream or of any other topical form to the skin, the perfume volatile components evaporate faster than the higher boiling esters of polyunsaturated fatty acids, which assume, in a very short time, a very unpleasant smell.
U.S. Pat. No. 5,472,705, to Bruzzese, teaches the addition of phenolic antioxidants to topical compositions of the esters of omega-3 polyunsaturated fatty acids to hinder the decomposition and the generation of very unpleasant and repellent smells. Horrobin, in U.S. Pat. No. 6,479,544, provides an example for topical use of EPA with GLA, but neither addresses the problem of odor in a topical composition, discloses the addition of DHA or lavender oil to the EPA-GLA composition, nor teaches the need to use molecularly distilled fish oils in the specific proportions with GLA that are appropriate for topical administration.
U.S. Pat. No. 5,650,157, to Bockow, teaches a method to prepare stable, deodorized oils by adding an amount of a deodorizing agent effective to substantially reduce the odor of the derived oil composition, fraction or combination thereof. Bockow teaches a multi-step process for the deodorization of marine oils wherein warm water is added to ground raw marine product, the pH is adjusted by the addition of acid to between 2.0 and 3.5, preferably about 2.8, the solution is mixed gently and allowed to stand at room temperature for approximately 24 hours to allow the oil to separate. Following this, the solution is mixed and allowed to stand again two or three times, requiring several days for the preparation of the deodorized oils. After the oil is drawn off, particles are removed, and the oil is filtered, heated, and allowed to cool gradually.
U.S. Pat. No. 6,551,602, to Barrett teaches a conjugated linoleic acid composition containing a phenolic compound selected from the group consisting of epigallocatechin gallate, genistein, green tea extract and soy extract as a treatment for wrinkles.
Unexpectedly, this inventor has discovered that the use of molecularly distilled fish oils to supply EPA and DHA diminishes the generation of unpleasant smells and the need for phenolic antioxidants as taught by Bruzzese. The molecularly distilled fish oils, in a specific proportion of fish oils with GLA, mixed tocopherols, and lavender oil, were found to have remarkable success in treating traumatic conditions of the skin.
Radiation Dermatitis
Radiation therapy has traditionally been the treatment of choice for locally or regionally advanced cancer, but its therapeutic efficacy is often hindered by limited tolerance of normal tissues and by tumor radio resistance. To improve therapeutic outcome, radiotherapy is frequently combined with chemotherapeutic drugs that are themselves cytotoxic and may sensitize cells to radiation. Milas L, et al, 17 (5 Suppl 5) ONCOLOGY (Hunting) 15-24 (2003). Radiation may cause severe burns of the skin and surrounding tissue as well as permanent changes in pigmentation. As many as 95% of patients treated with radiation therapy for cancer will experience a skin reaction. Porock D, Nikoletti S, Kristjanson L 19(4) PLAST SURG NURS. 185-92 (1999).
Some patients suffer radiation-induced skin injuries and younger patients may face an increased risk of future cancer. Davis MM, et al 20(4) J AM ACAD DERMATOL 608-16 (1989). Interventionists are suffering injury and are exposing their staff to high doses of radiation. In some interventional procedures, skin doses to staff approach those experienced in some cancer radiotherapy fractions. Radiation-induced skin injuries occur in patients due to the use of inappropriate equipment and, more often, poor operational technique. Valentin, 30(2) J. ANN ICRP, 7-67 (2000). Others report that such burns, when experienced in the hand, require aggressive debridement and immediate coverage with well-vascularized flaps, either regional or free-tissue transfers to achieve adequate wound healing and the most rapid, effective return of function with rapid institution of therapeutic modalities. Milanov NO, Shilov BL, Tjulenev AV 92(2) PLAST RECONSTR SURG. 294-300(1993).
Aloe vera has been tried without improvement in the results of irradiated breast tissue, Heggie S, et al, 25(6) CANCER NURS. 442-51 (2002), as has topical Vitamin C, Halperin EC, et al, 26(3) INT J RADIAT ONCOL. BIOL. PHYS 413-6 (1993). Other groups report that prophylactic and ongoing use of topical therapy with either topical corticosteroid or a dexpanthenol-containing emollient ameliorates, but does not prevent, radiation dermatitis. Schmuth, M, et al 146(6) BR J DERMATOL. 983-91(2002). Similarly, the increased effectiveness produced by the addition of a potent topical corticosteroid to an emollient cream is statistically significant as compared to the emollient cream itself in reducing acute radiation dermatitis but had no effect on pigmentation changes. Bostrom, A, et al, 59(3) RADIOTHER ONCOL. 257-65 (2001). Authors report that moist skin care with 3% urea lotion delays the occurrence and reduces the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors. Momm, F, et al, 179(10) STRAHLENTHER ONKOL. 708-12 (2003).
Biafine and Lipiderm had no radioprotective effect, Fenig E, 8(2) ONCOL. REP 305-9 (2001), while another group reported a significant dermato-cytoprotective effect of amifostine in its retrospective analysis. Kouvaris, J, 12(5) EUR J DERMATOL. 458-62 (2002).
Misoprostol, a prostaglandin E(1) analog, has been found to be an effective radioprotector in animal studies. It was shown to prevent to oncogenic transformation of Syrian hamster embryos exposed to radiation in utero. LaNasa P, 29(2) INT J RADIAT ONCOL. BIOL. PHYS. 273-5 (1994). However, results in humans were disappointing. Oral complications of radiation therapy seriously impact quality of life because of changes in taste, saliva, mucous, and eating. Johnson D J, et al, 54(5) INT J RADIAT ONCOL. BIOL. PHYS 1455-9 (2002). Oral administration of misoprostol produced inconsistent results in the prevention of oral mucositis in head and neck cancer patients treated with radiation. Hanson W R, et al 2(11) AM J THER. 850-857 (1995).
Recent advances in molecular biology have discovered many cellular molecules, including the cyclooxygenase-2 (COX-2) enzyme, which promote tumor cell survival and are responsible for tumor resistance to cytotoxic agents, that are being studied as potential targets for augmentation of response to radiation or chemotherapy. Milas L, et al, 17 (5 Suppl 5) ONCOLOGY (Hunting) 15-24 (2003)
None of the attempted treatments is completely successful and there is no "gold standard" in the prophylaxis and treatment of radiation dermatitis, creating a long-felt need to treat the dermatologic effects of radiation.
Burns
Usually the result of trauma, but occasionally due to self mutilation, burns are amongst the most serious conditions seen by medical personnel. Treatment is supportive, with antibiotics and fluid replacement followed by multiple skin grafting to restore the appearance as best as can be accomplished. The hypermetabolic response, which is mediated by hugely increased levels of circulating catecholamines, prostaglandins, glucagon and cortisol, causes profound skeletal muscle catabolism, immune deficiency, peripheral lipolysis, reduced bone mineralization, reduced linear growth, and increased energy expenditure. Murphy K D, Lee J O, and Herndon D N, 4(3) EXPERT OPIN PHARMACOTHER. 369-84 (2003). Burn-related immune disturbances, specifically the burn-related suppression of mesenteric lymph node T-cell proliferation and interleukin-2 production, were studied in rats and prevented when the rats were fed on a high-protein diet rich in glutamine, arginine, fish oil, and nucleotides. Choudhry, M A, 31(6) CRIT CARE MED 1764-70 (2003)
Topical treatments for the traumatic conditions produced by burns has not been remarkable. Jandera, et al, 26(3) BURNS 265-70 (2000) reported more rapid healing in both the Melaleuca alternifolia Hydrogel and water-cooled burns compared with the untreated controls. Tea tree oil, a known antiseptic, was ineffective in inhibiting bacterial growth in burns and therefore not recommended after clinical trial. Faoagali J, George N, Leditschke J F. 23(4) BURNS 349-51 (1997).
Sunburn
Sunburn is produced by the ultraviolet (UV) radiation of the sun and is mediated by inflammatory substance cyclooxygenase-2 and prostaglandins. Cyclooxygenase-2 expression is induced by ultraviolet irradiation; data suggest that tyrosine kinases and reactive oxygen intermediates are involved in this induction. Isoherranen, K, et al, 140(6) BR J DERMATOL 1017-22 (1999). The effects of ultra-violet radiation of the sun can be mitigated by oral supplementation with dietary fish oils. Following 3 months of fish oil, prostaglandin E2 decreased in both control and irradiated skin. Reduction of UV-induced trauma by fish oil may be due, at least partially, to lowered prostaglandin E2 levels. The photoprotection against UVA-provocation of a papular response suggests a clinical application for fish oil in polymorphic light eruption. Rhodes, L E, et al 105(4) J INVEST DERMATOL 532-5 (1995).
Exposure-Induced Wrinkles
Numerous measures have been attempted to retard the natural aging process of the human skin, which is greatly exacerbated by trauma, e.g. sunburn and windburn. The fashionable treatment of the day is the injection of Botulinum toxin to weaken the smooth muscle around the wrinkle and cause it to collapse, popularized as "Botox." Redaelli, A, Forte, R, 5(3-4) J COSMET LASER THER 220-2 (2003). But other aggressive therapies are readily available, limited only by the courage of the recipient. Pyruvic acid peels, Ghersetich, I, 30(1) DERMATOL SURG 32-6 (2004), injectable collagen, Galadari H, Lebwohl M, 49(5 Suppl) J AM ACAD DERMATOL. S265-6 (2003), and laser skin resurfacing, Batra R S, 139(10) ARCH DERMATOL 1295-9 (2003), have all been used with mixed success and obvious risks.
There is a suggestion that gentler methodology may be as effective as injections and chemical peels. French researchers reported some success in the use of a preparation containing a fucose-rich polysaccharide as an active principle on the microdepressionary skin surface. In 17 out of 20 female volunteers, aged from 39 to 71 years, exhibited significant improvement of the skin surface relief after 4 weeks of treatment, as shown by the displacement of geometrical characteristics, towards a "younger" pattern, corresponding to a decrease of apparent age by 10-15 years. Robert C, Robert A, and Robert L, 51(10) PATHOL BIOL(PARIS) 586-90 (2003). Alpha-Lipoic Acid has also been demonstrated to have some effect, Beinter, H, 149(4) BR J DERMATOL 841-9 (2003), and is now found in a multitude of preparations available at any local pharmacy or supermarket.
Dermatomyfibroma
Dermatomyofibroma is a recently described, rare, benign proliferation of myofibroblasts of the skin, often as a reaction to minor trauma such as scratches and insect bites, mainly found in young women. Only a few cases have been reported in males, but a case was reported in a four year old boy. Rose C, Brocker E B, 16(6) PEDIATR DERMATOL 456-9 (1999). Treatment is generally by conservative excision; follow-up information revealed no evidence of recurrence. Kamino, H, 19(2) J CUTAN PATHOL 85-93 (1992). Occasionally, lesions can be resolved through prompt and frequent topical application of steroid cream or diphenhydramine.

Compositions and methods for the treatment of radiation burns and other traumatic skin conditions


Disclosed are an optical test apparatus, related test method and method of operation, and related probe card adapted to optically test an image sensor. An illumination source of the optical test apparatus provides an optical test signal to the image sensor through the probe card. The optical test signal has a property variably defined by a feedback loop formed between a reference image sensor associated with the probe card and a control unit connected between the reference image sensor and the illumination source.

1. Field of the Disclosure
Embodiments of the invention relate generally to image sensor testing methods and related testing apparatuses. More particularly, embodiments of the invention relate to automated test methods for image sensors and related test apparatuses providing improved testing uniformity.
This application claims the priority of Korean Patent Application Nos. 2006-0002296, filed Jan. 9, 2006, and 2006-0022314, filed Mar. 9, 2006, the disclosures of which are hereby incorporated by reference in their entirety.
2. Description of the Related Art
Improved semiconductor fabrication technology has resulted in semiconductor image sensors characterized by smaller size, high quality performance, and lower manufacturing costs. As a result, image sensors are now used in a wide variety of commercial devices, such as digital cameras, camcorders, printers, scanners, and certain cellular telephones. In general operation, image sensors are adapted to capture optical energy (e.g., visible light), convert the optical energy into coherent electrical signals, and subsequently process the electrical signals into digital data that may be easily stored, transferred, and manipulated. The end result of this remarkable sequence of processes is the generation of image data that may be visually displayed or recorded in a number of different forms using conventionally available digital media.
The two most widely used types of semiconductor image sensors are the charge coupled device (CCD) and the CMOS image sensor (CIS). CCD sensors generally provide higher performance than CIS sensors. CCD sensors operate with comparatively lower noise and higher device uniformity. However, CIS sensors operate with comparatively lower power consumption and at higher operating speeds. The lower power consumption and higher operating speed provided by CIS sensors make CIS sensors the image sensor of choice for many portable electronic devices. That is, for many portable electronic devices constrained in their design and operating characteristics by a limited battery life, the reduced power consumption is an acceptable trade-off with the inferior performance of CIS sensors relative to CCD sensors. Cellular telephones having an integrated camera are one example of this type of portable electronic device.
This current design preference related to portable electronic devises raises some difficult challenges in the context of the constituent image sensors. For example, given the inherent weaknesses associated with CIS sensors (e.g., high noise and less uniformity between individual sensor operations), the quality control and testing processes within the lengthy sequence of fabrication processes necessary to manufacture CIS sensors become increasingly important.
Regardless of whether CCD or CIS technology is used, most image sensor manufacturers begin quality control testing at the wafer level to avoid the expense of continued fabrication of failed image sensor elements, and to reduce the possibility of producing non-functional or substandard products. The term "wafer level" refers to any fabrication process, including testing and quality control processes, performed on a wafer substrate containing many individual semiconductor image sensors. (See, Figure (FIG.) 1). Wafer level testing is performed before individual devices are cut from the wafer and packaged or connected to other host device components.
Given the optical-to-electrical conversion functionality provided by image sensors, it is not surprising that optical testing (e.g., a test associated with the optical illumination of the image sensor) is an important part of the overall quality control process. A great deal of optical testing is performed at the wafer level. Such testing directly implicates the quality of the optical test equipment and, more particularly, the quality of the illumination source within the optical test equipment. Indeed, the reliability of the optical test equipment should at all times exceed the performance specifications of the image sensors being tested. A consequence of this conclusion requires that the illumination source within optical test equipment be precisely controlled in its characteristics (e.g., intensity, wavelength, etc.), highly uniform in its application across a wafer, and very reliable. Without such qualities in an illumination source, it is impossible to distinguish performance variations between individual image sensors formed on the wafer.
As currently used in the fabrication of image sensors, conventional illumination sources are manually calibrated according to a periodic maintenance schedule (e.g., every 1000 to 2000 hours of operation). Such an approach requires interruptions of the fabrication process, as test equipment is taken off-line for maintenance. Further, the manual calibration process is subject to qualitative variations due to its inherent "human factors" (e.g., variations in the training of technicians, etc.).
Additionally, the mass production capabilities provided by modern semiconductor fabrication facilities mandates the use of multiple optical testing stations, each having an illumination source. Ideally, the illumination source used in each fabrication line should produce an identical output so that image sensor testing across multiple fabrication lines is consistent. Unfortunately, this is almost never the case. As presently instituted, each illumination source is merely tested (or compared) to a "standard" illumination source, and this process is inherently variable in its outcome.
The difficulty of consistently providing uniform, high quality illumination sources is compounded by the fact that the performance of all illumination sources tends to degrade over time. As a result, illumination source manufacturers provide expected performance profiles that characterize "typical" illumination performance over time. These performance profiles suggest voltage bias adjustments or operating voltage offset values for an illumination source during different periods of its life span. However, such performance profiles and the corresponding voltage offsets are merely "average" adjustments defined in relation to modeled outcomes. They do not accurately take into consideration the actual performance of individual illumination sources.
All of the foregoing results in an unacceptably high level of variation in the performance quality of illumination sources. Absent a reliable and clearly defined optical reference signal (e.g., uniform optical energy having a well controlled intensity) it is not possible to accurately characterize the performance of individual image sensors formed on a wafer. More critically, it is well understood that semiconductor fabrication processes frequently produce variable results across the surface area of a wafer (e.g., material layer characteristics on edge portions of the wafer verses center portions of the wafer). Such fabrication process variations must be identified, carefully quantified, and controlled in order to improve image sensor yield. It is nearly impossible to identify such process variations during wafer level optical testing of image sensors if the characteristics of the illumination source in the optical test equipment also vary across the surface of the wafer.

Image sensor testing method and apparatus


An optical device includes an echelle grating and input waveguide arranged such that the echelle grating receives an input signal that exits from a port of the input waveguide. The echelle grating is configured to reflect the input signal such that when the input signal has a plurality of channels, the input signal separates into output signals that each includes a different one of the channels. The device also includes a plurality of output waveguides that each includes a port positioned to receive one of the output signals. The output waveguides include central waveguides. The central waveguides are the three centermost output waveguides when the total number of output waveguides is odd and the two centermost output waveguides when the total number of output waveguides is even. The central waveguides are positioned such that the grating axis passes through the port associated with one of the central waveguides or passes between the ports associated with the central waveguides.

A variety of optical devices make use of optical gratings such as Echelle gratings. In addition to the gratings, these devices typically include an input waveguide and a plurality of output waveguides. During operation of the device, a multi-channel light signal travels from the input waveguide to the grating and is reflected off the grating toward the output waveguides. The reflected light signal separates into output signals that each carries one of the channels. Each of the output waveguides is positioned to receive one of the output signals. Accordingly, each output waveguide is associated with a particular one of the output signals.
The reflection of the light signals off of a grating with non-ideal facet verticality excites higher order modes that disperse as they travel from the grating to the output waveguides. The dispersion of these higher order modes can cause a portion of the light from one of the output signals to be received at an output waveguide that is not associated with that output signal. Accordingly, the dispersion can be a source of cross talk and loss at the output waveguides. One method of dealing with this dispersion has been to improve the verticality of grating facet or make the device support only a single mode. However, the vertically of grating facet is limited by fabrication capability and single mode devices are often not desirable especially for Silicon on Insulator (SOI) waveguide.
Accordingly, there is a need for an optical device that includes an optical grating with reduced mode dispersion.


A network usage management system comprises at least one collector adapted to collect network usage data associated with a data source using a network, the at least one collector adapted to generate log data associated with the at least one collector. The network usage management system also comprises at least one log collector adapted to retrieve the log data from the at least one collector.

Internet usage management (IUM) systems generally comprise a plurality of distributed resources (e.g., "collectors") used to collect, transform and store data corresponding to a variety of types of network data sources (e.g., information associated with telephone usage, web access monitoring and data upload/download transfers). In some instances, the collected data is used to support billing and other business-based applications. However, because of the distributed nature of the data-collecting resources, troubleshooting, debugging and/or other types of management operations corresponding to such resources is time-consuming and troublesome.

Network usage management system and method

Hewlett-Packard Development Company, L.P.


A shipping method includes the steps of receiving stacks of flat die cut corrugated paperboard blanks from a corrugator or sheet plant; loading the stacks of blanks into a pallet assembly machine; folding the blanks together in the assembly machine to produce a corrugated paperboard pallet; and providing the pallets for shipping items to a receiver. The assembly machine folds the blanks using intermittent motion of the blanks through multiple folding sections in the assembly machine. The sections operate by positioning, clamping and folding the blanks using levers that are supported by rotary bearings and driven by pinned end mounted pneumatic cylinders. The assembly machine overcomes misalignment and shifting of the stacks of blanks by picking up single blanks from the top of the stacks using vacuum, and adjusting alignment of the blanks after being picked up but prior to being fed into the first folding section of the assembly machine.

Shipping pallets are said to move the world. Eighty percent of commerce ships on shipping pallets. They are estimated at greater than a $30 B industry worldwide. More than 500 million pallets are manufactured in the US each year, with 1.8 billion pallets in service in the US alone.
Pallets can be made from various materials, however wood pallets currently comprise about 80% of the market. More than 40% of worldwide hardwood lumber currently goes to manufacture of wood pallets. Other materials used for pallet manufacture include plastic, metal and corrugated paperboard.
Recent regulations regarding infestation and contamination are creating a surge in interest and use of non-wood pallet alternatives. A small, but the fastest growing segment, is the use of corrugated paperboard pallets. There is a desire by many to replace conventional wooden pallets with corrugated pallets for increasing recyclability, lowering pallet weight, eliminating product contamination and reducing injuries. Despite the potential advantages of corrugated pallets, their use has not yet become mainstream. Significant deficiencies holding back their use have been too high costs and an inherent inability to be able to readily produce and distribute them in sufficiently high volume.
In both private and public industries, it is desirable to be able to ship items with reduced total costs. Currently, shipping pallets require extensive storage space, significant logistical costs as well as injury and product damage uncertainty costs. A new shipping method is needed to facilitate shippers to easily and reliably ship items in high volume and with the lowest possible total cost.


Soluble alkali metal silicates combined with antiredeposition agents can actually have a beneficial effect on bleach stabilisation if said antiredeposition agents are intimately mixed with an alkali metal silicate solution, the resulting product being then dried (spray drying, turbo drying, etc . . . ) into granules.

Alkali metal silicates, and more particularly sodium silicates, are commonly used in detergents compositions such as washing and dishwashing compositions.
Dishwashing powders generally consist of dry mixed granular components having a particle size between 200 and 2000 micrometers, preferably between 300 and 1000 micrometers. Although most fabric washing powders were produced by spray-drying a liquid mixture (slurry), including alkali metal silicate in liquid form, developments towards phosphate-free- and higher density powders have increasingly led to a change in processing to produce these fabric washing detergent powders, i.e.: Either towards a complete dry-mixing of all components in granular form or by spray drying only part of the components followed by post-dosing of the remaining components in granular form. The alkali metal silicate is preferably post-dosed in granular form in this process as well.
Alkali metal silicates used in detergents are preferably sodiumsilicates having molar ratios SiO.sub.2 /Na.sub.2 O varying between 1.0 (Sodium metasilicate used in machine dishwashing products) and 3.4. Generally preferred molar ratios (SiO.sub.2 /Na.sub.2 O) for modern machine dish washing and fabric washing powders being between 2.0 and 2.4.
Many formulations for dishwashing as well as for fabric washing contain bleach components which are based on peroxide. For detergent powder formulations, alkalimetal salts of perborate and percarbonate are generally preferred either alone or in combination with bleach promoters (e.g.: TAED, i.e.: tetraacetylethylenediamine).
In washing compositions, it is known, for example from WO92/03525, that heavy metals present can catalytically decompose peroxide bleach systems in the presence of water, e.g.: during the washing process. The heavy metal ions are either present in the washgoods (dirt/stains) or in the raw materials used for the detergent powder. It is also known that alkali metal silicates can bind heavy metals and have thus a positive effect on bleach stabilisation. However, during each washing cycle, part of said alkali metal silicates which have absorbed heavy metals, precipitates on the textile fibres, leading to a deposit on the cloth, which increases during each subsequent wash cycle. This heavy metal silicate gives rise to local decomposition of the bleach and to textile strength loss as well as to dye damage. This phenomenon has been for example disclosed in WO92/03525 pages 38-39. It is known that antiredeposition agents, such as certain polymers or copolymers, can in some circumstances prevent deposition of metal silicates.
Nevertheless, WO92/03525 has shown that adding such polymers has little effect on bleach stability and textile strength in presence of silicates (comparative example E).
Thus there is a need for a soluble alkali metal silicate in a granular form which can be added to bleach containing detergent compositions for its heavy metals sequestering capacity and which does not cause deposition of silicates onto the fabrics.
Turning to dishwashing compositions silicate compounds inhibit corrosion on glass while acting as alkali generating agents. Now, while being very active in such compositions, said compounds, specifically metasilicates, can be particularly dangerous when ingested by young children. Less alkalinity with a comparable level of protection against corrosion can be achieved by using sodium silicates with higher SiO.sub.2 :Na.sub.2 O molar ratios, e.g. disilicates (SiO.sub.2 /Na.sub.2 O molar ratio: 2.0). Nevertheless such products are still hazardous and more and more national legislations are requiring to further limit the alkalinity of the mechanical dishwashing compositions, something which is normally achieved by decreasing the volume of alkali metal silicate in the composition since the alternative of using alkali metal silicates with a molar ratio of more than 2.4 is not practical due to the poor dissolution properties of such a product.
In fabric washing powders, soluble alkali metal silicate with a molar ratio (SiO.sub.2 /Na.sub.2 O) of 2.0 is generally used and although the quantity of silicate used in fabric washing powders is generally much lower (e.g.: 2-7%) alkalinity is also becoming an issue in these products, also containing other alkaline components.
There is therefore a need for a soluble alkali metal silicate in a granular form which can be added in increasing amounts to detergent compositions without increasing the pH.

Granules based on silicate antiredeposition agent mixtures and method for manufacturing same


A bistable nematic liquid crystal display device includes two cell walls enclosing a layer of a nematic liquid crystal material, means for applying an electric field across at least some of the layer, and means for inducing local planar alignments of said liquid crystal material at an inner surface of each cell wall. The local planar alignments are oriented to each other at an angle greater than 0° and less than 90°. The device also includes means for selectively masking an alignment effect of either of the local planar alignments by applying a unidirectional electric field pulse of suitable magnitude and duration to stabilise the device in one of two different homeoplanar configurations determined by the polarity of the pulse.

Pixel bistability is a desirable attribute for a liquid crystal display ('LCD') because this eliminates the need constantly to refresh the display or to employ a silicon memory device behind each pixel, which becomes prohibitively expensive as the number of pixels increases. With bistability, only pixels that need to be changed need addressing, and simple matrix addressing may be employed. If the liquid crystal ('LC') can switch at video frame rates, the device may be used as an LCD TV or monitor. For other applications such as 'digital paper', where the device is used as a permanent or semi-permanent display for information which can be changed or updated from time to time, slower switching times are acceptable.
In co-pending U.S. patent application Ser. No. 10/698,028, electrophoretically-controlled nematic (EPCN) bistable devices are presented in which a 'hidden' electrophoretic effect is used to stabilise the LC in one of two stable states. The nematic LC is doped with nanoparticles carrying either a positive or a negative charge. An optical effect is observed by using a homeoplanar or 90° twist cell. The homeoplanar cell has a homeotropic alignment on one substrate and a planar alignment on an opposed substrate. The alignments are provided using different materials and different fabrication techniques, requiring some complexity in the process for fabricating the device. The 90° twisted cell switches between twist and homeoplanar states, and requires electrical pulses that control switching close to one surface. Such switching may, however, require very precise control of the electrical pulses.


The present invention relates to processes and reagents for oligonucleotide synthesis and purification. One aspect of the present invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention. Another aspect of the present invention relates to sulfur-transfer agents. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to a method of preparing a phosphorothioate by treating a phosphite with a sulfur-transfer reagent of the invention. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to compounds that scavenge acrylonitrile produced during the deprotection of phosphate groups bearing ethylnitrile protecting groups. In a preferred embodiment, the acrylonitrile scavenger is a polymer-bound thiol. Another aspect of the present invention relates to agents used to oxidize a phosphite to a phosphate. In a preferred embodiment, the oxidizing agent is sodium chlorite, chloroamine, or pyridine-N-oxide. Another aspect of the present invention relates to methods of purifying an oligonucleotide by annealing a first single-stranded oligonucleotide and second single-stranded oligonucleotide to form a double-stranded oligonucleotide; and subjecting the double-stranded oligonucleotide to chromatographic purification. In a preferred embodiment, the chromatographic purification is high-performance liquid chromatography.

The study of oligonucleotides is a key area of research for many academic and industrial laboratories. See S. Agrawal Trends in Biotechnology 1996, 14, 375-382; J. Marr Drug Discovery Today 1996, 1, 94-102; and W. Rush Science 1997, 276, 1192-1193. The therapeutic and diagnostic potential of oligonucleotides has sparked a substantial amount of research activity. One important application of oligonucleotides is the ability to modulate gene and protein function in a sequence-specific manner. However, many research efforts are hampered by the small quantities of oligonucleotides that are available for study. A method to produce large quantities of oligonucleotide compounds having high purity would greatly facilitate oligonucleotide research. Furthermore, it would be highly useful to be able to prepare derivatives of certain oligonucleotides. However, the synthesis of oligonucleotides and their analogs is often a tedious and costly process.
RNA is generally synthesized and purified by methodologies based on the following steps: phosphoramidite coupling using tetrazole as the activating agent, oxidation of the phosphorus linker to the diester, deprotection of exocyclic amino protecting groups using NH4OH, removal of 2′-OH alkylsilyl protecting groups using tetra-n-butylammonium fluoride (TBAF), and gel purification and analysis of the deprotected RNA. Examples of chemical synthesis, deprotection, purification and analysis procedures are provided by Usman et al. in J. Am. Chem. Soc. 1987, 109, 7845; Scaringe et al. in Nucleic Acids Res. 1990, 18, 5433-5341; Perreault et al. in Biochemistry 1991, 30, 4020-4025; and Slim and Gait in Nucleic Acids Res. 1991, 19, 1183-1188. Odai and coworkers describe reverse-phase chromatographic purification of RNA fragments used to form a ribozyme. See Odai et al. FEBS Lett. 1990, 267, 150-152. Unfortunately, the aforementioned chemical synthesis, deprotection, purification and analysis procedures are time consuming (10-15 min. coupling times), subject to inefficient activation of the RNA amidites by tetrazole, incomplete deprotection of the exocyclic amino protecting groups by NH4OH, limited by the low capacity of RNA purification using gel electrophoresis, and further limited by low resolution analysis of the RNA by gel electrophoresis. Therefore, the need exists for improved synthetic processes for the synthesis of oligonucleotides.
One important class of oligonucleotide analogues are compounds that have a phosphorothioate in place of the phosphodiester linkage. Phosphorothioate analogues are important compounds in nucleic acid research and protein research. For example, phosphorothioate-containing antisense oligonucleotides have been used in vitro and in vivo as inhibitors of gene expression. Site-specific attachment of reporter groups onto the DNA or RNA backbone is facilitated by incorporation of single phosphorothioate linkages. Phosphorothioates have also been introduced into oligonucleotides for mechanistic studies on DNA-protein and RNA-protein interactions, as well as catalytic RNAs.
Introduction of phosphorothioate linkages into oligonucleotides, assembled by solid-phase synthesis, can be achieved using either an H-phosphonate approach or a phosphoramidite approach. The H-phosphonate approach involves a single sulfur-transfer step, carried out after the desired sequence has been assembled, to convert all of the internucleotide linkages to phosphorothioates. Alternatively, the phosphoramidite approach features a choice at each synthetic cycle: a standard oxidation provides the normal phosphodiester internucleotide linkage, whereas a sulfurization step introduces a phosphorothioate at that specific position in the sequence. An advantage of using phosphoramidite chemistry is the capability to control the state of each linkage, P═O vs. P═S, in a site-specific manner. The earliest studies to create phosphorothioates used elemental sulfur, but the success of the phosphoramidite approach is dependent on the availability and application of more efficient, more soluble sulfur-transfer reagents that are compatible with automated synthesis. Therefore, the need exists for novel sulfur-transfer reagents that are compatible with automated oligonucleotide synthesis.
Another important class of oligonucleotides is double-stranded RNA which can be used to initiate a type of gene silencing known as RNA interference (RNAi). RNA interference is an evolutionarily conserved gene-silencing mechanism, originally discovered in studies of the nematode Caenorhabditis elegans (Lee et al, Cell 75:843 (1993); Reinhart et al., Nature 403:901 (2000)). It is triggered by introducing dsRNA into cells expressing the appropriate molecular machinery, which then degrades the corresponding endogenous mRNA. The mechanism involves conversion of dsRNA into short RNAs that direct ribonucleases to homologous mRNA targets (summarized, Ruvkun, Science 2294:797 (2001)). This process is related to normal defenses against viruses and the mobilization of transposons.
Double-stranded ribonucleic acids (dsRNAs) are naturally rare and have been found only in certain microorganisms, such as yeasts or viruses. Recent reports indicate that dsRNAs are involved in phenomena of regulation of expression, as well as in the initiation of the synthesis of interferon by cells (Declerq et al., Meth. Enzymol. 78:291 (1981); Wu-Li, Biol. Chem. 265:5470 (1990)). In addition, dsRNA has been reported to have anti-proliferative properties, which makes it possible also to envisage therapeutic applications (Aubel et al., Proc. Natl. Acad. Sci., USA 88:906 (1991)). For example, synthetic dsRNA has been shown to inhibit tumor growth in mice (Levy et al. Proc. Nat. Acad. Sci. USA, 62:357-361 (1969)), is active in the treatment of leukemic mice (Zeleznick et al., Proc. Soc. Exp. Biol. Med. 130:126-128 (1969)); and inhibits chemically-induced tumorigenesis in mouse skin (Gelboin et al., Science 167:205-207 (1970)).
Treatment with dsRNA has become an important method for analyzing gene functions in invertebrate organisms. For example, Dzitoveva et al. showed for the first time, that RNAi can be induced in adult fruit flies by injecting dsRNA into the abdomen of anesthetized Drosophila, and that this method can also target genes expressed in the central nervous system (Mol. Psychiatry 6(6):665-670 (2001)). Both transgenes and endogenous genes were successfully silenced in adult Drosophila by intra-abdominal injection of their respective dsRNA. Moreover, Elbashir et al., provided evidence that the direction of dsRNA processing determines whether sense or antisense target RNA can be cleaved by a small interfering RNA (siRNA)-protein complex (Genes Dev. 15(2): 188-200 (2001)).
Two recent reports reveal that RNAi provides a rapid method to test the function of genes in the nematode Caenorhabditis elegans; and most of the genes on C. elegans chromosome I and III have now been tested for RNAi phenotypes (Barstead, Curr. Opin. Chem. Biol. 5(1):63-66 (2001); Tavernarakis, Nat. Genet. 24(2):180-183 (2000); Zamore, Nat. Struct. Biol. 8(9):746-750 (2001).). When used as a rapid approach to obtain loss-of-function information, RNAi was used to analyze a random set of ovarian transcripts and have identified 81 genes with essential roles in C. elegans embryogenesis (Piano et al., Curr. Biol. 10(24):1619-1622 (2000). RNAi has also been used to disrupt the pupal hemocyte protein of Sarcophaga (Nishikawa et al., Eur. J. Biochem. 268(20):5295-5299 (2001)).
Like RNAi in invertebrate animals, post-transcriptional gene silencing (PTGS) in plants is an RNA-degradation mechanism. In plants, this can occur at both the transcriptional and the post-transcriptional levels; however, in invertebrates only post-transcriptional RNAi has been reported to date (Bernstein et al., Nature 409(6818):295-296 (2001). Indeed, both involve double-stranded RNA (dsRNA), spread within the organism from a localized initiating area, to correlate with the accumulation of small interfering RNA (siRNA) and require putative RNA-dependent RNA polymerases, RNA helicases and proteins of unknown functions containing PAZ and Piwi domains.
Some differences are evident between RNAi and PTGS were reported by Vaucheret et al., J. Cell Sci. 114(Pt 17):3083-3091 (2001). First, PTGS in plants requires at least two genes—SGS3 (which encodes a protein of unknown function containing a coil-coiled domain) and MET1 (which encodes a DNA-methyltransferase)—that are absent in C. elegans, and thus are not required for RNAi. Second, all of the Arabidopsis mutants that exhibit impaired PTGS are hyper-susceptible to infection by the cucumovirus CMV, indicating that PTGS participates in a mechanism for plant resistance to viruses. RNAi-mediated oncogene silencing has also been reported to confer resistance to crown gall tumorigenesis (Escobar et al., Proc. Natl. Acad. Sci. USA, 98(23):13437-13442 (2001)).
RNAi is mediated by RNA-induced silencing complex (RISC), a sequence-specific, multicomponent nuclease that destroys messenger RNAs homologous to the silencing trigger. RISC is known to contain short RNAs (approximately 22 nucleotides) derived from the double-stranded RNA trigger, but the protein components of this activity remained unknown. Hammond et al. (Science 293(5532):1146-1150 (August 2001)) reported biochemical purification of the RNAi effector nuclease from cultured Drosophila cells, and protein microsequencing of a ribonucleoprotein complex of the active fraction showed that one constituent of this complex is a member of the Argonaute family of proteins, which are essential for gene silencing in Caenorhabditis elegans, Neurospora, and Arabidopsis. This observation suggests links between the genetic analysis of RNAi from diverse organisms and the biochemical model of RNAi that is emerging from Drosophila in vitro systems.
Svoboda et al. reported in Development 127(19):4147-4156 (2000) that RNAi provides a suitable and robust approach to study the function of dormant maternal mRNAs in mouse oocytes. Mos (originally known as c-mos) and tissue plasminogen activator mRNAs are dormant maternal mRNAs that are recruited during oocyte maturation, and translation of Mos mRNA results in the activation of MAP kinase. The dsRNA directed towards Mos or TPA mRNAs in mouse oocytes specifically reduced the targeted mRNA in both a time- and concentration-dependent manner, and inhibited the appearance of MAP kinase activity. See also, Svoboda et al. Biochem. Biophys. Res. Commun. 287(5):1099-1104 (2001).
The need exists for small interfering RNA (siRNA) conjugates having improved pharmacologic properties. In particular, the oligonucleotide sequences have poor serum solubility, poor cellular distribution and uptake, and are rapidly excreted through the kidneys. It is known that oligonucleotides bearing the native phosphodiester (P═O) backbone are susceptable to nuclease-mediated degradation. See L. L. Cummins et al. Nucleic Acids Res. 1995, 23, 2019. The stability of oligonucleotides has been increased by converting the P═O linkages to P═S linkages which are less susceptible to degradation by nucleases in vivo. Alternatively, the phosphate group can be converted to a phosphoramidate or alkyl phosphonate, both of which are less prone to enzymatic degradation than the native phosphate. See Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 544. Modifications to the sugar groups of the oligonucleotide can confer stability to enzymatic degradation. For example, oligonucleotides comprising ribonucleic acids are less prone to nucleolytic degradation if the 2′-OH group of the sugar is converted to a methoxyethoxy group. See M. Manoharan ChemBioChem. 2002, 3, 1257 and references therein.
Therefore, the need exists for improved synthetic processes that facilitate the synthesis of oligonucleotides. Representative examples of needed improvements are better activating agents for phosphoramidite coupling of nucleotides, better sulfur-transfer reagents for preparing phosphorothioate-containing oligonucleotides, and improved procedures for purifying oligonucleotides.

Processes and reagents for desilylation of oligonucleotides


An improved multi-polar feedthrough assembly employs a particular metallic ferrule material for improved dimensional stability during initial fabrication and sustained hermetic operation. In one aspect, the disclosure relates to implantable medical devices (IMDs) including an IMD enclosure fabricated with grade 2 titanium and having a ferrule material fabricated with grade 4 titanium or grade 5 titanium. In one form, the multi-polar feedthrough assembly includes a filtered feedthrough array (e.g., employing capacitive filters coupled to the electrically conductive pins or serpentine conductors of the array). According to another aspect, the improved multi-polar feedthrough assembly incorporates additional pins, thus increasing the footprint of the assembly, and the additional pins provide analog electrical communication between operative circuitry inside an IMD and analog components external to the IMD.

Electrical feedthroughs serve the purpose of providing an electrical circuit path extending from the interior of a hermetically sealed enclosure or housing to an external point outside the enclosure. Implantable medical devices (IMDs) such as implantable pulse generators (IPGs) for cardiac pacemakers, implantable cardioverter defibrillators (ICDs), nerve, brain, organ and muscle stimulators and implantable gastric monitors, or the like, employ such electrical feedthroughs through a hermetically-sealed enclosure that surrounds operative internal circuitry and electrically couples said circuitry with external medical electrical leads and associated electrodes.
Such feedthroughs typically include a ferrule adapted to fit within an opening in the enclosure, one or more conductor and a non-conductive hermetic glass or ceramic seal which supports and electrically isolates each such conductor from the other conductors passing through it and from the ferrule. The IMD enclosure is formed of a biocompatible metal such as titanium, although non-conductive ceramic materials have been proposed for forming the enclosure. The ferrule is typically of a metal that can be welded or otherwise mechanically coupled to the enclosure in a hermetically sealed manner.
Initially, single pin feedthroughs supported by glass, sapphire and ceramic were used with hermetically sealed IPGs. As time has passed, the volume and, consequently the surface area, of enclosures for IMDs has dramatically decreased and the number of medical electrical leads and associated electrodes coupled with the internal circuitry of an IMD has increased. Consequently, use of the relatively large single pin feedthroughs was no longer feasible, and numerous multiple conductor feedthroughs have been used or proposed for use that fit within the smaller sized opening and provide two, three, four or more conductors. Examples include those depicted and described in U.S. Pat. Nos. 6,660,116; 6,414,835; and 5,870,272 the contents of which are hereby incorporated herein by reference.
Many different insulator structures and conductor structures are known in the art of multiple conductor feedthroughs wherein the insulator structure also provides a hermetic seal to prevent entry of body fluids through the feedthrough and into the housing of the medical device. The conductors typically comprise electrical wires or pins that extend through a glass and/or ceramic layer within a metal ferrule opening as shown, for example, in commonly assigned U.S. Pat. Nos. 4,991,582; 5,782,891; and 5,866,851 or through a ceramic enclosure as shown in the commonly assigned '891 patent and in U.S. Pat. No. 5,470,345.
Such multi-conductor feedthroughs have an internally disposed portion configured to be disposed inside the enclosure for connection with electrical circuitry and an externally disposed portion configured to be disposed outside the enclosure that is typically coupled electrically with connector elements for making connection with the leads, electrodes or sensors. The elongated lead conductors extending from the connector elements effectively act as antennae that tend to collect stray electromagnetic interference (EMI) signals that may interfere with normal IMD operations. At certain frequencies, for example, EMI can be mistaken for programming signals from an external programming device that can then cause an IMD to change operating mode.
This problem has been addressed in certain of the above-referenced patents by incorporating a capacitor structure upon the internally facing portion of the feedthrough ferrule coupled between each feedthrough conductor and a common ground, the ferrule, to filter out any high frequency EMI transmitted from the external lead conductor through the feedthrough conductor. The feedthrough capacitors originally were discrete capacitors but presently can take the form of chip capacitors that are mounted as shown in the above-referenced '891, '435, '476, and '906 patents and in further U.S. Pat. Nos. 5,650,759; 5,896,267; and 5,959,829, for example. Or, the feedthrough capacitors can take the form of discrete discoidal capacitive filters or discoidal capacitive filter arrays as shown in commonly assigned U.S. Pat. Nos. 5,735,884; 5,759,197; 5,836,992; 5,867,361; and 5,870,272 and further U.S. Pat. Nos. 5,287,076; 5,333,095; 5,905,627 and 5,999,398. These patents disclose use of discoidal filters and filter arrays in association with conductive pins which are of relatively large scale and difficult to miniaturize without complicating manufacture. It is desirable to further miniaturize and simplify the fabrication of the multi-conductor feedthrough assembly.
A high integrity hermetic seal for medical implant applications is very critical to prevent the ingress of body fluids into the IMD. Even a small leak rate of such body fluid penetration can, over a period of many years, build up and damage sensitive internal electronic components. This can cause catastrophic failure of an IMD. The ferrule of a feedthrough for an IMD typically is selected from a material having physical properties that match the properties of the surrounding IMD enclosure. For example, if an IMD enclosure is constructed from grade 2 titanium, a feedthrough ferrule of grade 2 titanium is implemented. However, as the dimensions of such prior art feedthroughs have expanded, combined with the high temperature they are typically subjected to during fabrication the inventors found that the grade 2 titanium oftentimes fails to maintain the close dimensional tolerance required to guarantee long-term hermeticity. That is, the grade 2 titanium metal component of the ferrule changes shape which potentially undermines the close fit of the ferrule in the corresponding aperture of the enclosure thereby negatively effecting the ability to repeatably join the feedthrough to the enclosure via welding. Furthermore, the inventors posit that when subjected to high temperature brazing to seal the interface between a ferrule and an insulator member such relatively high-grade titanium undergoes random dimensional distortion. This random distortion can depend upon such factors as the manner of fabrication of the high grade titanium (e.g., how it was initially forged, drawn into sheet form, etc.) and thus is essentially unpredictable. Furthermore, the inventors suggest that at least part of the reason that grade 2 titanium distorts relates to the physical composition thereof. That is, grade 2 titanium comprises relatively small sized grains and when heated up to or in excess of the phase transition temperature (approximately 850 degrees Celsius) the coupling between the grade 2 titanium grains changes and such changes can lead to a loss of the originally specified dimensions of grade 2 titanium components. The phase transition temperature increases with increasing impurity content, (e.g., grade 4 has a transition temperature of approximately 950 degrees Celsius).
Thus, the inventors have recognized a need in the art to fabricate highly accurately dimensioned components that are integral to high-grade titanium IMD enclosures so that long-term hermeticity is maintained. In particular, the inventors have discovered that as the overall surface area of diverse IMDs has decreased relative to the size of certain integral IMD-surface components (e.g., multi-polar feedthrough assemblies), maintaining dimensional is critical to maintaining long-term hermeticity and to the ability to mount accessories directly to the feedthrough, such as, but not limited to modules for electronic assembly or multi-hole EMI filter capacitors contained in a single dielectric structure. In addition, the inventors has discovered that, in addition to the potential negative impact to long-term fit issue with the enclosure & with components added to the feedthrough, the traditional grade-matching (i.e., grade 2 titanium enclosure and grade 2 titanium ferrule) reduces manufacturing yield of acceptable feedthrough (and ferrule) components and finally assembled IMDs.
Moreover, highly accurately dimensioned ferrules lead to robust feedthrough arrays of simplified construction, utilizing straightforward and uncomplicated assembly, thus resulting in overall manufacturing cost reductions. The inventors contemplate applying the present invention to myriad multi-polar feedthrough assemblies, including those designed for effectively filtering out undesirable EMI. The present invention fulfills these needs and provides other related advantages which will be appreciated by those skilled in the art as defined by the appended claims.

Multi-polar feedthrough array for analog communication with implantable medical device circuitry