text:
Microneedle devices are provided for controlled sampling of biological fluids in a minimally-invasive, painless, and convenient manner. The microneedle devices permit in vivo sensing or withdrawal of biological fluids from the body, particularly from or through the skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue. The microneedle device includes one or more microneedles, preferably in a three-dimensional array, a substrate to which the microneedles are connected, and at least one collection chamber and/or sensor in communication with the microneedles. Preferred embodiments further include a means for inducing biological fluid to be drawn through the microneedles and into the collection chamber for analysis. In a preferred embodiment, this induction is accomplished by use of a pressure gradient, which can be created for example by selectively increasing the interior volume of the collection chamber, which includes an elastic or movable portion engaged to a rigid base. Preferred biological fluids for withdrawal and/or sensing include blood, lymph, interstitial fluid, and intracellular fluid. Examples of analytes in the biological fluid to be measured include glucose, cholesterol, bilirubin, creatine, metabolic enzymes, hemoglobin, heparin, clotting factors, uric acid, carcinoembryonic antigen or other tumor antigens, reproductive hormones, oxygen, pH, alcohol, tobacco metabolites, and illegal drugs.
1. A device for collecting a sample of a biological fluid comprising:
one or more hollow or porous microneedles, each having a base end and a tip;
a substrate to which the base end is attached or integrated; and
at least one collection chamber suitable for collecting said sample of said biological fluid, said collection chamber selectably in fluid communication with the base end, and wherein said collection chamber comprises a one-way valve and an upper portion which is formed of a deformable material.
2. A device for collecting a sample of a biological fluid comprising:
one or more hollow or porous microneedles, each having a base end and a tip;
a substrate to which the base end is attached or integrated; and
at least one collection chamber suitable for collecting said sample of said biological fluid, wherein said collection chamber is selectably in fluid communication with the base end, and comprises a plurality of compartments.
3. The device of
4. The device of
5. The device of
6. The device of
7. The device of
8. The device of
9. The device of
10. The device of
11. The device of
12. The device of
13. The device of
14. The device of
15. The device of
16. The device of
17. The device of
18. The device of
19. The device of
20. The device of
21. A device for collecting a sample of a biological fluid comprising:
one or more hollow or porous microneedles, each having a base end and a tip;
a substrate to which the base end is attached or integrated;
at least one collection chamber suitable for collecting said sample of said biological fluid, said collection chamber selectably in fluid communication with the base end; and
a fracturable or removable barrier for controlling flow through the microneedle, said barrier interposed between the collection chamber and base of the microneedle.
22. A device for collecting a sample of a biological fluid comprising:
one or more hollow or porous microneedles, each having a base end and a tip;
a substrate to which the base end is attached or integrated; and
at least one collection chamber suitable for collecting said sample of said biological fluid, said collection chamber selectably in fluid communication with the base end,
wherein the one or more microneedles has a hollow bore containing a material to modulate the flow of biological fluid through the microneedles into the collection chamber.
23. The device of any one of
24. A device for collecting a sample of a biological fluid comprising:
one or more hollow or porous microneedles, each having a base end and a tip, a length between 500 μm and 1 mm and a width between about 1 μm and 500 μm, and comprising a metal;
a substrate to which the base end is attached or integrated; and
at least one collection chamber suitable for collecting said sample of said biological fluid, said collection chamber selectably in fluid communication with the base end.
25. A method for collecting a sample of a biological fluid or analyte therein, comprising the steps:
providing the device of any one of
inserting said one or more microneedles of the device into a biological barrier comprising biological fluid; and
triggering the transport of a quantity of the biological fluid or analyte therein through said one or more microneedles and into the collection chamber.
26. The method of
27. The method of
28. The method of
29. The method of
30. The device of
31. A device for sensing an analyte in a biological fluid comprising:
one or more microneedles, each having a base end and a tip, a length between about 500 μm and 1 mm and a width between about 1 μm and 500 μm, and comprising a metal;
a substrate to which the base of the microneedle is attached or integrated; and
at least one sensor which is selectably in fluid communication with the microneedle.
32. A device for sensing an analyte in a biological fluid comprising:
one or more microneedles, each having a base end and a tip;
a substrate to which the base of the microneedle is attached or integrated; and
at least one sensor which is selectably in fluid communication with the microneedle,
wherein the one or more microneedles has a hollow bore containing a material to modulate the flow of biological fluid through the microneedles into a collection chamber.
33. The device of
a chemical or biochemical agent that react with the analyte, and
electrochemical or optical transducers which measure the reaction of the agent and the analyte.
34. The device of
35. The device of
36. The device of
37. The device of
38. The device of
39. The device of
40. A device for sensing an analyte in a biological fluid comprising:
one or more microneedles, each having a base end and a tip; and
a substrate to which the base of the microneedle is attached or integrated, wherein at least one of the microneedles is or comprises a sensor, and wherein the one or more microneedles has a hollow bore containing a material to modulate the flow of biological fluid through the microneedles into a collection chamber.
41. The device of
a chemical or biochemical agent that reacts with the analyte, and
electrochemical or optical transducers which measure the reaction of the agent and the analyte.
42. The device of
43. A method for sensing an analyte in a biological fluid, comprising the steps:
providing the device of
inserting said one or more microneedles into a biological barrier comprising said biological fluid which contains said analyte; and
contacting the sensor with the biological fluid, thereby sensing the analyte.
44. The method of
at least one collection chamber which is selectably in fluid connection with the base end of the microneedle, and
a means for inducing transport of the biological fluid or the analyte therein into the collection chamber,
wherein, after the microneedles are inserted, the means for inducing is triggered to draw the biological fluid or the analyte therein through the microneedles and into the collection chamber.
45. The method of
46. The method of
47. The method of
48. The method of
This application is a continuation-in-part of U.S. patent application Ser. No. 09/316,229, now U.S. Pat. No. 6,334,856, filed May 21, 1999, which is a continuation-in-part of U.S. patent application Ser. No. 09/095,221, now U.S. Pat. No. 6,503,231, filed Jun. 10, 1998. This application claims the benefit of the filing date of U.S. provisional application Ser. No. 60/146,200, filed Jul. 29, 1999.
This invention was made with government support under Contract Number BES-9813321 awarded by the U.S. National Science Foundation. The government has certain rights in the invention.
This invention is generally in the field of devices for the withdrawal and sensing of biological fluids, such as in the analysis of blood glucose levels.
The extraction of analytes through the skin is critical to diabetic patients, who typically must measure blood glucose several times per day in order to optimize insulin treatment and thereby reduce the severe long-term complications of the disease. Currently, diabetics do this by pricking the highly vascularized fingertips with a lancet to perforate the skin, then milking the skin with manual pressure to produce a drop of blood, which is then assayed for glucose using a disposable diagnostic strip and a meter into which the strip fits. This method of glucose measurement has the major disadvantage that it is painful, so diabetics do not like to obtain a glucose measurement as often as is medically indicated. It would therefore be highly useful to be able to obtain a sample of blood, lymph, or interstitial fluid more quickly, using an easier procedure, and relatively noninvasively. It also would be advantageous to be able to repeatedly or continually extract analyte transdermally over a period of time.
Another common technique for withdrawal of bodily fluids, such as for diagnostic purposes, is the use of a needle, such as those used with standard syringes or catheters. While effective for this purpose, needles are invasive and generally cause pain; local damage to the skin at the site of insertion; and bleeding, which can increase the risk of disease transmission. Needle techniques also generally require administration by one trained in its use, and are not preferred for frequent routine use due to the vascular damage caused by repeated punctures. Some proposed alternatives to the needle require the use of (1) lasers or heat to create a hole in the skin, which is inconvenient, expensive, or undesirable for repeated use; (2) electric fields or ultrasound, which also is inconvenient and expensive; or (3) chemical or biological penetration enhancing agents, which can be irritating to the tissue and undesirable for repeated use.
It is therefore an object of the present invention to provide a device for controlled sampling of biological fluids in a minimally-invasive, painless, and convenient manner.
It is another object of the present invention to provide a device for sensing of biological fluids in a minimally-invasive, painless, and convenient manner.
Microneedle devices for controlled sampling of biological fluids in a minimally-invasive, painless, and convenient manner, are provided. The microneedle devices permit in vivo sensing or withdrawal of biological fluids from the body, particularly from or through the skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.
The microneedle device includes one or more microneedles, preferably in a three-dimensional array, a substrate to which the microneedles are connected, and at least one collection chamber and/or sensor in communication with the microneedles. Preferred embodiments further include a means for inducing biological fluid to be drawn through the microneedles and into the collection chamber for analysis. In a preferred embodiment, this induction is accomplished by use of a pressure gradient, which can be created for example by selectively increasing the interior volume of the collection chamber, which includes an elastic or movable portion engaged to a rigid base.
In a preferred embodiment, the microneedle device further comprises means for transduction, storage, transmission, and display of measured values. The microneedle device also preferably includes means for securing the device to a biological barrier during withdrawal or sensing.
Preferred biological fluids for withdrawal and/or sensing include blood, lymph, interstitial fluid, and intracellular fluid. Examples of analytes in the biological fluid to be measured include glucose, cholesterol, bilirubin, creatine, metabolic enzymes, hemoglobin, heparin, clotting factors, uric acid, carcinoembryonic antigen or other tumor antigens, reproductive hormones, oxygen, pH, alcohol, tobacco metabolites, and illegal drugs.
1. The Microneedle Device
The microneedle devices include at least three components: at least one, preferably more, microneedle(s), a substrate to which the base of the microneedle(s) is secured or integrated, and at least one fluid collection chamber and/or sensor that is selectably in communication with at least one microneedle. Typically, the microneedles are provided as a three-dimensional array, in contrast to a device with a single needle or row of needles. The microneedle device can be adapted to be a single-use, disposable device, or can be adapted to be fully or partially reusable.
a. Substrate
The substrate of the device can be constructed from a variety of materials, including metals, ceramics, semiconductors, organics, polymers, and composites. The substrate includes the base to which the microneedles are attached or integrally formed. A fluid collection chamber and/or sensor can be attached to the substrate or formed (e.g., as part of the substrate) to communicate directly with the base of the microneedles.
b. Microneedles
The microneedles function either as a conduit, a sensing element, or a combination thereof. Conduit microneedles can have a porous or hollow shaft. As used herein, the term "porous" means having pores or voids throughout at least a portion of the microneedle structure, sufficiently large and sufficiently interconnected to permit passage of fluid and/or solid materials through the microneedle. As used herein, the term "hollow" means having one or more substantially annular bores or channels through the interior of the microneedle structure, which have a diameter sufficiently large to permit passage of fluid and/or solid materials through the microneedle. The annular bores may extend throughout all or a portion of the needle in the direction of the tip to the base, extending parallel to the direction of the needle or branching or exiting at a side of the needle, as appropriate. A solid or porous microneedle can be hollow. One of skill in the art can select the appropriate porosity and/or bore features required for specific applications. For example, one can adjust the pore size or bore diameter to permit or regulate passage of the particular material to be transported through the microneedle device.
In one embodiment, one or more of the microneedles are coated (if solid, porous, or hollow) and/or at least partially filled (if porous or hollow) with a sensing or diffusion-modifying material.
The microneedles of the device can be constructed from a variety of materials, including metals, ceramics, semiconductors, organics, polymers, and composites. Preferred materials of construction include pharmaceutical grade stainless steel, gold, titanium, nickel, iron, tin, chromium, copper, palladium, platinum, alloys of these or other metals, silicon, silicon dioxide, and polymers. Representative biodegradable polymers include polymers of hydroxy acids such as lactic acid and glycolic acid polylactide, polyglycolide, polylactide-co-glycolide, and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone). Representative non-biodegradable polymers include polycarbonate, polymethacrylic acid, ethylenevinyl acetate, polytetrafluoroethylene (TEFLON™), and polyesters.
The microneedles should have the mechanical strength to remain intact for sensing analyte and/or for serving as a conduit for the collection of biological fluid, while being inserted into the skin, while remaining in place for up to a number of days, and while being removed. In embodiments where the microneedles are formed of biodegradable polymers, the microneedle must remain intact at least long enough for the microneedle to serve its intended purpose (e.g., its conduit function). The microneedles should be sterilizable using standard methods, such as ethylene oxide treatment or gamma irradiation. The microneedles can have straight or tapered shafts. A hollow microneedle that has a substantially uniform diameter, which needle does not taper to a point, is referred to herein as a "microtube." As used herein, the term "microneedle" includes both microtubes and tapered needles unless otherwise indicated. In a preferred embodiment, the diameter of the microneedle is greatest at the base end of the microneedle and tapers to a point at the end distal the base. The microneedle can also be fabricated to have a shaft that includes both a straight (untapered) portion and a tapered portion.
The microneedles can be formed with shafts that have a circular cross-section in the perpendicular, or the cross-section can be non-circular. For example, the cross-section of the microneedle can be polygonal (e.g. star-shaped, square, triangular), oblong, or another shape. The shaft can have one or more bores. The cross-sectional dimensions typically are between about 1 μm and 500 μm, and preferably between 10 μm and 100 μm. The outer diameter is typically between about 10 μm and about 100 μm, and the inner diameter is typically between about 3 μm and about 80 μm.
The length of the microneedles typically is between about 10 μm and 1 mm, preferably between 100 μm and 500 μm, and more preferably between 150 μm and 350 μm. The length is selected for the particular application, accounting for both an inserted and uninserted portion. An array of microneedles can include a mixture of microneedles having, for example, various lengths, outer diameters, inner diameters, cross-sectional shapes, and spacings between the microneedles. Preferably, the microneedles are sized to avoid or minimize contact with nerve endings in the biological tissue, such as the dermis, thereby eliminating or reducing pain when the microneedles are inserted, for example into the skin.
The microneedles can be oriented perpendicular or at an angle to the substrate. Preferably, the microneedles are oriented perpendicular to the substrate to provide structural strength and to permit ease of insertion into the tissue. An array of microneedles can include a mixture of microneedle orientations, heights, spacings, or other parameters. This variation in an array can be useful, for example, if different microneedles are to provide different sensing or insertion functions.
In one embodiment, the microneedle has one or more holes (ports) or slits positioned on the sides of the shaft of a hollow microneedle having a blunt, open, or closed tip. This design may reduce blockage of the conduit, for example, due to tissue or cells when the microneedles are inserted.
In a preferred embodiment of the device, the substrate and/or microneedles, as well as other components, are formed from flexible materials, or have appropriate materials so as to be flexible, to allow the device to fit the contours of the biological barrier, such as the skin, vessel walls, or the eye, to which the device is applied. A flexible device facilitates more consistent penetration during use, since penetration can be limited by deviations in the attachment surface. For example, the surface of human skin is not flat due to dermatoglyphics (i.e. tiny wrinkles) and hair. Conformality of the flexible device to the skin can be further enhanced by using an external force, such as a uniform pressure, to aid insertion of the microneedles into the biological barrier.
c. Collection Chamber
The fluid collection chamber is selectably in connection with the microneedle bores or pores, such that a biological fluid can flow from the tissue surrounding the microneedle, through the microneedle, and into the collection chamber. Typically, the collection chamber is attached to, or integrated into, the substrate. The chamber should function to contain a biological fluid sample so as to permit analysis within the microneedle device or following transfer to a separate analytical device.
The collection chamber can be substantially rigid or readily deformable. The collection chamber can be formed from one or more polymers, metals, ceramics, semiconductor, or combinations thereof. In a preferred embodiment, the collection chamber contains a porous or absorbent material, such as a sponge, gel, or paper or polymeric strip. The material can be permanently contained or removable, and can function as a diagnostic element or substrate for use in analytical devices. The chamber can initially be empty or can contain a gas or one or more reagents in any form (e.g., liquid or solid particles). In one embodiment, at least a portion of the interior walls of the chamber are coated with a reagent for assaying the biological fluid.
In a preferred embodiment, the collection chamber is formed of an elastic material, such as an elastomeric polymer or rubber. For example, the collection chamber can be a collapsed balloon-like pouch that expands when the biological fluid is drawn into the collection chamber.
The collection chamber of a microneedle device can include a plurality of compartments that are temporarily or permanently isolated from one another and/or from a portion of the microneedles in an array. The device can, for example, be provided to collect or sense through different needles at different rates or at different times into the different compartments. Alternatively, some of the different compartments can contain analytical reagents which can be combined with the biological fluid sample, for example, by piercing, or otherwise removing, a barrier between the compartments, so as to allow the materials to mix for analysis.
In a preferred embodiment, the collection chamber is a standard or Luer-Lock syringe adapted to be connected to a microneedle array. See
In another preferred embodiment, the collection chamber is adapted to receive and use standard glucose sensing strips, which can be loaded into the microneedle device before, during, or after the biological fluid is extracted.
Preferred embodiments of the microneedle device are shown in
d. Sensors
The sensing/analyzing function can occur in the microneedle or body of the device (e.g., in the fluid collection chamber), or external to the device following removal of a sample. The sensing device can be in or attached to one or more microneedles, integrated into the substrate, or within or in communication with the fluid collection chamber. Biosensors can be located on the microneedle surface, inside a hollow or porous microneedle, or inside a device in communication with the body tissue via the microneedle (solid, hollow, or porous).
In a preferred embodiment, the microneedle device provides a single-use collection means. In this design, the microneedle array is used to extract a single measurement and then is detached from a reusable base portion, if any, and disposed.
In one embodiment, the microneedle device is adapted to work with "laboratory-on-a-chip" devices, such as manufactured by Caliper Technologies, Palo Alto, Calif. (see, e.g., U.S. Pat. No. 5,852,495 to Parce and U.S. Pat. No. 5,876,675 to Kennedy); Aclara Biosciences, Hayward, Calif. (see, e.g., U.S. Pat. No. 5,858,188 to Soane et al. and U.S. Pat. No. 5,883,211 to Sassi et al.); and Nanogen, San Diego, Calif. (see, e.g., U.S. Pat. Nos. 5,605,662 and 5,632,957 to Heller et al.).
(i). Tapes of Sensors
Useful sensors may include sensors of pressure, temperature, chemicals, pH, and/or electro-magnetic fields. These microneedle biosensors can include four classes of principal transducers: potentiometric, amperometric, optical, and physiochemical. An amperometric sensor monitors currents generated when electrons are exchanged between a biological system and an electrode. Blood glucose sensors frequently are of this type.
Sensing information or signals can be transferred optically (e.g., refractive index) or electrically (e.g., measuring changes in electrical impedance, resistance, current, voltage, or combination thereof). For example, it may be useful to measure a change in the resistance of tissue to an electrical current, wherein different resistances are calibrated to signal that withdrawal has been completed.
In a preferred embodiment, the microneedle device may include an integrated sensor, such as a chemical sensor, biosensor, or other measurement system to form a complete extraction/measurement system. The unit can be constructed to function as a closed loop drug delivery unit, including drug delivery means, analyte recovery means, sensing means to measure the analyte, and control means to provide a signal to the drug delivery means. In a preferred embodiment, the unit would include subunits to withdraw fluid and calculate the concentration of glucose, for example, to determine the amount of insulin needed and deliver that amount of insulin.
The device can include means for assaying the amount of analyte extracted. For example, an assay method that results in a color change could be used. The change in color could be detected using a light beam that enters into a disposable collection chamber through a window on top. The analyte may also be detected in the chamber through the use of an enzyme electrode or biosensor. The analyte sensing system can include enzymes that react with the analyte of interest and either electrochemical or optical transducers that measure the content of reaction. Examples of such enzymes are glucose oxidase and glucose dehydrogenase.
An example of an enzyme electrode for glucose is a screen-printed electrode on the surface of which is immobilized glucose oxidase and an electron mediator such as ferrocene or its derivatives. Electrons generated by the oxidation of glucose are transferred from glucose oxidase to the electrode via the mediator. Thus, the concentration of glucose in the analyte solution is proportional to the current generated. Yet another detection mechanism may be used based on near-infrared spectroscopy. In this method, concentration of extracted glucose in a gel is detected by the absorption of the near-infrared light that passes through the chamber through two windows.
(ii). Microneedle as Sensing Element
In one embodiment, the microneedle is adapted to be the sensing element. For example, an assay material, such as glucose oxidase, can be (i) coated onto the external surface of hollow or solid microneedles, (ii) distributed within the pores of porous microneedles, or (iii) line or fill the bore(s) of hollow microneedles. See
In this embodiment, the assay material contacts the analyte for which it is selective and undergoes a change, such as an oxidation reaction. This change is communicated, either directly or indirectly, to the user. For example, change may be indicated optically (change in color or refractive index) or electrically. Alternatively, the change may induce a shift in pH that can be measured and communicated using conventional techniques. In more complex embodiments, the analyte may be adsorbed to the microneedle or a coating thereon, such that mechanical sensing can be used, for example, by measuring vibration changes caused by the adsorption.
(iii). Sensor Electronics
In a preferred embodiment, the sensors are selectively in communication with an electronics package. The electronics package typically includes a power source (e.g., a battery), as well as electronic hardware and software for the transduction, storage, transmission, and display of measured values. The electronics package can be selectively fixed to the microneedle device, for example, so that the electronics package can be reused with a new, disposable microneedle device. The electronics package can include a mechanism for wireless or wire-based transmission of measured values to a remote device for analysis and/or display. The electronics also may include mathematical manipulation of the sensed data, for example, to average measured values or eliminate outlying datapoints so as to provide more useful measurements.
The electronics package also can include software and hardware to initiate or automate the sensing and analysis processes. It may be desirable to design a microneedle device capable of taking multiple measurements to withdraw/sense samples on a preprogrammed schedule (e.g., periodic or random), for example, to monitor the blood plasma levels of an illegal drug. Such a device could be adapted for use with a transmitter designed to lock onto the wrist or ankle of a drug offender or other probationer. The device would then be able to randomly test the wearer without his knowledge in order to assess his compliance with orders to abstain from drug or alcohol use.
In an alternative embodiment, the electronics package includes a device for controlling the withdrawal or sensing process. For example, sensing could be activated based on elapsed time, body temperature, or in response to an external trigger (e.g., motion sensor or push-button). The electronics package, for example, could provide substantially instantaneous readings of glucose levels by depressing a button, or in a microneedle device (e.g., adapted to be worn for an extended period of time), the electronics could it could display a summary of intermittent glucose measurements taken automatically throughout the day. Such a microneedle device would be highly useful to diabetic patients to routinely monitor their blood glucose levels following insulin dosing, between or following meals, and at other times throughout the day.
(iv). Single Unit Multiple Sensing
A single microneedle device can be designed to provide multiple, preferably sequential, measurements. In a preferred embodiment, the device includes a plurality of discrete fluid collection chambers, each of which is in communication with a defined subset of microneedles in an array of microneedles. The sensing unit of the device can sense each of the collection chambers independently. The sensing can be triggered manually or device electronics can be preprogrammed to automatically trigger, for example at specific time intervals. The device can include a means for storing, displaying, or transmitting the multiple measured values as needed.
(v). Sensor Calibration
Calibration of the sensor can be accomplished using the concentration of a second analyte or the same analyte measured by another means. The primary analyte can be normalized, lowering extraction to extraction and site to site variability, by the concentration of the second analyte or same analyte from a separate measurement. Normalization may be a linear or non-linear relationship.
In a preferred embodiment for glucose sensing, a reusable sensor, which assays glucose concentration in interstitial fluid, can be calibrated daily by correlating interstitial fluid glucose values with values obtained from glucose measurements obtained from blood, similar to the approach used by Cygnus Inc.'s "Gluco-Watch."
e. Attachment Feature
In a preferred embodiment, the microneedle device includes an adhesive material to secure the microneedle device to the skin, temporarily immobilizing the microneedles while inserted into the skin to sense or withdraw fluid. The adhesive agent typically is applied to the substrate (in between the microneedles at their base) or to an attachment collar or tabs adjacent the microneedles.
Care must be taken so that any adhesive agent does not plug the bores of hollow microneedles. For example, the adhesive agent can be applied in a liquid solution by flooding the top of the substrate below the tips of the microneedles, such as from the side of an array of microneedles, or by using a three-dimensional printing process or spin coating. The solvent can then be evaporated from the adhesive agent solution, thereby precipitating or gelling the adhesive agent to yield a tacky surface. An alternate method of keeping the tips free of an applied adhesive agent is to choose materials of construction having a hydrophobicity or hydrophilicity to control the wetting of the surface to the microneedle tips.
Where a vacuum is used to induce fluid flow into the device, it may be necessary to provide means for creating a gas-tight seal around the edge of the device so that air is not drawn in through the microneedles at the biological barrier hole/microneedle shaft periphery. The attachment collar or adhesive material can be adapted to provide this function using techniques common to the those skilled in the art. One example is to design the attachment collar to function as a "suction-cup" and wet the interface of the skin and attachment collar with water or another physiologically acceptable sealant.
For sustained use, such as for taking sequential measurements, the device preferably is adapted to be worn by the user, by including a securing means for securing the whole device to the user's body. For example, the device can be integrated into an adhesive patch or an elastic band, which may be worn, for example, around the user's arm or ankle.
Feedback about Withdrawal
In a preferred embodiment, the microneedle device includes a feedback means so that the user can determine whether withdrawal and/or sensing has been completed. Representative feedback means include a sound, a color (change) indicator, or a change in the position or shape of a reservoir.
2. Manufacture of Microneedles
The microneedle devices are made by microfabrication processes, by creating small mechanical structures in silicon, metal, polymer, and other materials. These microfabrication processes are based on well-established methods used to make integrated circuits, electronic packages and other microelectronic devices, augmented by additional methods used in the field of micromachining. The microneedle devices can have dimensions as small as a few nanometers and can be mass-produced at low per-unit costs.
a. Microfabrication Processes
Microfabrication processes that may be used in making the microneedles disclosed herein include lithography; etching techniques, such as wet chemical, dry, and photoresist removal; thermal oxidation of silicon; electroplating and electroless plating; diffusion processes, such as boron, phosphorus, arsenic, and antimony diffusion; ion implantation; film deposition, such as evaporation (filament, electron beam, flash, and shadowing and step coverage), sputtering, chemical vapor deposition (CVD), epitaxy (vapor phase, liquid phase, and molecular beam), electroplating, screen printing, lamination, stereolithography, laser machining, and laser ablation (including projection ablation). See generally Jaeger, Introduction to Microelectronic Fabrication (Addison-Wesley Publishing Co., Reading Mass. 1988); Runyan, et al., Semiconductor Integrated Circuit Processing Technology (Addison-Wesley Publishing Co., Reading Mass. 1990); Proceedings of the IEEE Micro Electro Mechanical Systems Conference 1987-1998; Rai-Choudhury, ed., Handbook of Microlithography, Micromachining & Microfabrication (SPIE Optical Engineering Press, Bellingham, Wash. 1997); and Madou, Fundamentals of Microfabrication (CRC Press 1997).
The following methods are preferred for making microneedles.
(i). Electrochemical Etching of Silicon
In this method, electrochemical etching of solid silicon to porous silicon is used to create extremely fine (on the order of 0.01 μm) silicon networks which can be used as piercing structures. This method uses electrolytic anodization of silicon in aqueous hydrofluoric acid, potentially in combination with light, to etch channels into the silicon. By varying the doping concentration of the silicon wafer to be etched, the electrolytic potential during etching, the incident light intensity, and the electrolyte concentration, control over the ultimate pore structure can be achieved. The material not etched (i.e. the silicon remaining) forms the microneedles. This method has been used to produce irregular needle-type structures measuring tens of nanometers in width.
(ii). Plasma Etching
This process uses deep plasma etching of silicon to create microneedles with diameters on the order of 0.1 μm or larger. Needles are patterned directly using photolithography, rather than indirectly by controlling the voltage (as in electrochemical etching), thus providing greater control over the final microneedle geometry.
In this process, an appropriate masking material (e.g., metal) is deposited onto a silicon wafer substrate and patterned into dots having the diameter of the desired microneedles. The wafer is then subjected to a carefully controlled plasma based on fluorine/oxygen chemistries to etch very deep, high aspect ratio trenches into the silicon. See, e.g., Jansen, et al., "The Black Silicon Method IV: The Fabrication of Three-Dimensional Structures in Silicon with High Aspect Ratios for Scanning Probe Microscopy and Other Applications," IEEE Proceedings of Micro Electro Mechanical Systems Conference, pp. 88-93 (1995). Those regions protected by the metal mask remain and form the needles. This method is further described in Example 3 below.
(iii). Electroplating
In this process, a metal layer is first evaporated onto a planar substrate. A layer of photoresist is then deposited onto the metal to form a patterned mold which leaves an exposed-metal region in the shape of needles. By electroplating onto the exposed regions of the metal seed layer, the mold bounded by photoresist can be filled with electroplated material. Finally, the substrate and photoresist mold are removed, leaving the finished microneedle array. The microneedles produced by this process generally have diameters on the order of 1 μm or larger. See, e.g., Frazier, et al., "Two dimensional metallic microelectrode arrays for extracellular stimulation and recording of neurons", IEEE Proceedings of the Micro Electro Mechanical Systems Conference, pp. 195-200 (1993).
(iv). Other Processes
Another method for forming microneedles made of silicon or other materials is to use microfabrication techniques such as photolithography, plasma etching, or laser ablation to make a mold form (A), transferring that mold form to other materials using standard mold transfer techniques, such as embossing or injection molding (B), and reproducing the shape of the original mold form (A) using the newly-created mold (B) to yield the final microneedles (C). Alternatively, the creation of the mold form (A) could be skipped and the mold (B) could be microfabricated directly, which could then be used to create the final microneedles (C).
Another method of forming solid silicon microneedles is by using epitaxial growth on silicon substrates, as is utilized by Containerless Research, Inc. (Evanston, Ill., USA) for its products.
b. Hollow or Porous Microneedles
In a preferred embodiment, microneedles are made with pores or other pathways through which material may be transported. The following descriptions outline representative methods for fabricating either porous or hollow microneedles.
(i). Porous Microneedles
Rather than having a single, well-defined hole down the length of the needle, porous needles are filled with a network of channels or pores which allow conduction of fluid or energy through the needle shaft. It has been shown that by appropriate electrochemical oxidation of silicon, pore arrays with high aspect ratios and a range of different pore size regimes can be formed; these pore regimes are defined as (1) microporous regime with average pore dimensions less than 2 nm, (2) mesoporous regime with average pore sizes of between 2 nm and 50 nm, and (3) macroporous regime with pores greater than 50 mm. The mesoporous and macroporous regimes are expected to be most useful for drug delivery. Two approaches to porous needles are generally available, either (a) the silicon wafer is first made porous and then etched as described above to form needles or (b) solid microneedles are etched and then rendered porous, for example, by means of electrochemical oxidation, such as by anodization of a silicon substrate in a hydrofluoric acid electrolyte. The size distribution of the etched porous structure is highly dependent on several variables, including doping kind and illumination conditions, as detailed in Lehmann, "Porous Silicon—A New Material for MEMS", IEEE Proceedings of the Micro Electro Mechanical Systems Conference, pp. 1-6 (1996). Porous polymer or metallic microneedles can be formed, for example, by micromolding a polymer containing a volatilizable or leachable material, such as a volatile salt, dispersed in the polymer or metal, and then volatilizing or leaching the dispersed material, leaving a porous polymer matrix in the shape of the microneedle.
(ii). Hollow Needles
Three-dimensional arrays of hollow microneedles can be fabricated, for example, using combinations of dry etching processes (Laermer, et al., "Bosch Deep Silicon Etching: Improving Uniformity and Etch Rate for Advanced MEMS Applications," Micro Electro Mechanical Systems, Orlando, Fla., USA, (Jan. 17-21, 1999); Despont et al., "High-Aspect-Ratio, Ultrathick, Negative-Tone Near-UV Photoresist for MEMS", Proc. of IEEE 10th Annual International Workshop on MEMS, Nagoya, Japan, pp. 518-522 (Jan. 26-30, 1997)); micromold creation in lithographically-defined and/or laser ablated polymers and selective sidewall electroplating; or direct micromolding techniques using epoxy mold transfers.
One or more distinct and continuous pathways are created through the interior of microneedles. In a preferred embodiment, the microneedle has a single annular pathway along the center axis of the microneedle. This pathway can be achieved by initially chemically or physically etching the holes in the material and then etching away microneedles around the hole. Alternatively, the microneedles and their holes can be made simultaneously or holes can be etched into existing microneedles. As another option, a microneedle form or mold can be made, then coated, and then etched away, leaving only the outer coating to form a hollow microneedle. Coatings can be formed either by deposition of a film or by oxidation of the silicon microneedles to a specific thickness, followed by removal of the interior silicon. Also, holes from the backside of the wafer to the underside of the hollow needles can be created using a front-to-backside infrared alignment followed by etching from the backside of the wafer.
a. Silicon Microneedles
One method for hollow needle fabrication is to replace the solid mask used in the formation of solid needles by a mask that includes a solid shape with one or more interior regions of the solid shape removed. One example is a "donut-shaped" mask. Using this type of mask, interior regions of the needle are etched simultaneously with their side walls. Due to lateral etching of the inner side walls of the needle, this may not produce sufficiently sharp walls. In that case, two plasma etches may be used, one to form the outer walls of the microneedle (i.e., the 'standard' etch), and one to form the inner hollow core (which is an extremely anisotropic etch, such as in inductively-coupled-plasma "ICP" etch). For example, the ICP etch can be used to form the interior region of the needle followed by a second photolithography step and a standard etch to form the outer walls of the microneedle.
Alternatively, this structure can be achieved by substituting the chromium mask used for the solid microneedles described in Example 3 by a silicon nitride layer 94 on the silicon substrate 95 covered with chromium 96, deposited as shown in
Another method uses the solid silicon needles described previously as 'forms' around which the actual needle structures are deposited. After deposition, the forms are etched away, yielding the hollow structures. Silica needles or metal needles can be formed using different methods. Silica needles can be formed by creating needle structures similar to the ICP needles described above prior to the oxidation described above. The wafers are then oxidized to a controlled thickness, forming a layer on the shaft of the needle form which will eventually become the hollow microneedle. The silicon nitride is then stripped and the silicon core selectively etched away (e.g., in a wet alkaline solution) to form a hollow silica microneedle.
In a preferred embodiment, an array of hollow silicon microtubes is made using deep reactive ion etching combined with a modified black silicon process in a conventional reactive ion etcher, as described in Example 4 below. First, arrays of circular holes are patterned through photoresist into SiO2, such as on a silicon wafer. Then the silicon can be etched using deep reactive ion etching (DRIE) in an inductively coupled plasma (ICP) reactor to etch deep vertical holes. The photoresist is then removed. Next, a second photolithography step patterns the remaining SiO2 layer into circles concentric to the holes, leaving ring shaped oxide masks surrounding the holes. The photoresist is then removed and the silicon wafer again deep silicon etched, such that the holes are etched completely through the wafer (inside the SiO2 ring) and simultaneously the silicon is etched around the SiO2 ring leaving a cylinder.
This latter process can be varied to produce hollow, tapered microneedles. After an array of holes is fabricated as described above, the photoresist and SiO2 layers are replaced with conformal DC sputtered chromium rings. The second ICP etch is replaced with a SF6/O2 plasma etch in a reactive ion etcher (RIE), which results in positively sloping outer sidewalls. Henry, et al., "Micromachined Needles for the Transdermal Delivery of Drugs," Micro Electro Mechanical Systems, Heidelberg, Germany, pp. 494-98 (Jan. 26-29, 1998).
b. Metal Microneedles
Metal needles can be formed by physical vapor deposition of appropriate metal layers on solid needle forms, which can be made of silicon using the techniques described above, or which can be formed using other standard mold techniques such as embossing or injection molding. The metals are selectively removed from the tips of the needles using electropolishing techniques, in which an applied anodic potential in an electrolytic solution will cause dissolution of metals more rapidly at sharp points, due to concentration of electric field lines at the sharp points. Once the underlying silicon needle forms have been exposed at the tips, the silicon is selectively etched away to form hollow metallic needle structures. This process could also be used to make hollow needles made from other materials by depositing a material other than metal on the needle forms and following the procedure described above.
A preferred method of fabricating hollow metal microneedles utilizes micromold plating techniques, which are described as follows and in Examples 5 and 6. In a method for making metal microtubes, which does not require dry silicon etching, a photo-defined mold first is first produced, for example, by spin casting a thick layer, typically 150 μm, of an epoxy (e.g., SU-8) onto a substrate that has been coated with a thin sacrificial layer, typically about 10 to 50 nm. Arrays of cylindrical holes are then photolithographically defined through the epoxy layer, which typically is about 150 μm thick. (Despont, et al., "High-Aspect-Ratio, Ultrathick, Negative-Tone Near-UV Photoresist for MEMS," Proc. of IEEE 10th Annual International Workshop on MEMS, Nagoya, Japan, pp. 518-22 (Jan. 26-30, 1997)). The diameter of these cylindrical holes defines the outer diameter of the tubes. The upper surface of the substrate, the sacrificial layer, is then partially removed at the bottom of the cylindrical holes in the photoresist. The exact method chosen depends on the choice of substrate. For example, the process has been successfully performed on silicon and glass substrates (in which the upper surface is etched using isotropic wet or dry etching techniques) and copper-clad printed wiring board substrates. In the latter case, the copper laminate is selectively removed using wet etching. Then a seed layer, such as Ti/Cu/Ti (e.g., 30 nm/200 nm/30 nm), is conformally DC sputter-deposited onto the upper surface of the epoxy mold and onto the sidewalls of the cylindrical holes. The seed layer should be electrically isolated from the substrate. Subsequently, one or more electroplatable metals or alloys, such as Pd, Pt, Ni, NiFe, Au, Cu, or Ti, are electroplated onto the seed layer. The surrounding epoxy is then removed, leaving microtubes which each have an interior annular hole that extends through the base metal supporting the tubes. The rate and duration of electroplating is controlled in order to define the wall thickness and inner diameter of the microtubes. In one embodiment, this method was used to produce microtubes having a height of between about 150 and 250 μm, an outer diameter of between about 40 and 120 μm, and an inner diameter of between about 30 and 110 μm (i.e., having a wall thickness of 10 μm). In a typical array, the microtubes have a tube center-to-center spacing of about 150 μm, but can vary depending on the desired needle density.
A variation of this method is preferred for forming tapered microneedles. As described above, photolithography yields holes in the epoxy which have vertical sidewalls, such that the resulting shafts of the microneedles are straight, not tapered. This vertical sidewall limitation can be overcome by molding a preexisting 3D structure, i.e., a mold-insert. The subsequent removal of the mold-insert leaves a mold which can be surface plated similarly to the holes produced by photolithography described above.
Alternatively, non-vertical sidewalls can be produced directly in the polymeric mold into which electroplating will take place. For example, conventional photoresists known in the art can be exposed and developed in such as way as to have the surface immediately adjacent to the mask be wider than the other surface. Specialized greyscale photoresists in combination with greyscale masks can accomplish the same effect. Laser-ablated molds can also be made with tapered sidewalls, e.g., by optical adjustment of the beam (in the case of serial hole fabrication) or of the reticle or mold during ablation (in the case of projection ablation).
To form hollow tapered microneedles, the mold-insert is an array of solid silicon microneedles, formed as described in Henry, et al., "Micromachined Needles for the Transdermal Delivery of Drugs," Micro Electro Mechanical Systems, Heidelberg, Germany, Jan. 26-29, pp. 494-98 (1998). First, a layer of a material, such as an epoxy (e.g., SU-8) or a polydimethylsiloxane ("PDMS"), is spin cast onto the array of silicon microneedles to completely blanket the entire array. The epoxy settles during pre-bake to create a planar surface above the silicon needle tips; the material is then fully pre-baked, photolithographically cross-linked, and post-baked.
The upper surface of the epoxy is then etched away, for example with an O2/CHF3 plasma, until the needle tips are exposed, preferably leaving between about 1 and 5 μm of tip protruding from the epoxy. The silicon is then selectively removed, for example by using a SF6 plasma or a HNO3/HF solution. The remaining epoxy micromold is the negative of the microneedles and has a small diameter hole where the tip of the microneedle formerly protruded.
After the removal of the silicon, a seed layer, such as Ti—Cu—Ti, is conformally sputter-deposited onto the epoxy micromold. Following the same process sequence described for hollow metal microtubes, one or more electroplatable metals or alloys (such as Ni, NiFe, Au, Pd, Pt, or Cu) are electroplated onto the seed layer. Finally, the epoxy is removed, for example by using an O2/CHF3 plasma, leaving an array of hollow metal microneedles. An advantage of using PDMS in this application is that the micromold can be physically removed from the silicon mold insert by mechanical means, such as peeling, without damaging the silicon mold insert, thus allowing the silicon mold insert to be reused. Furthermore, the electroplated microneedles can be removed from the PDMS mold by mechanical means, for example by peeling, thereby allowing the PDMS to also be reused.
In a preferred embodiment, this method is used to produce microneedles having a height of between about 150 and 350 μm, an outer diameter of between about 40 and 120 μm, and an inner diameter of between about 20 and 100 μm. In a typical array, the microneedles have a center-to-center spacing of between about 150 and 300 μm, but can vary depending on the desired needle density. Tapered microneedles preferably are 200 to 300 μm in height with a base diameter of 80 μm, a tip diameter of 30 μm, and a needle-to-needle spacing of 150 μm.
c. Silicon Dioxide Microneedles
Hollow microneedles formed of silicon dioxide can be made by oxidizing the surface of the silicon microneedle forms (as described above), rather than depositing a metal and then etching away the solid needle forms to leave the hollow silicon dioxide structures. This method is illustrated in
In one embodiment, hollow, porous, or solid microneedles are provided with longitudinal grooves or other modifications to the exterior surface of the microneedles. Grooves, for example, should be useful in directing the flow of molecules along the outside of microneedles.
d. Polymer Microneedles
In a preferred method, polymeric microneedles are made using microfabricated molds. For example, the molds can be made as described herein and injection molding techniques can be applied to form the microneedles in the molds (Weber, et al., "Micromolding—a powerful tool for the large scale production of precise microstructures", Proc. SPIE—International Soc. Optical Engineer. 2879: 156-67 (1996); Schift, et al., "Fabrication of replicated high precision insert elements for micro-optical bench arrangements" Proc. SPIE—International Soc. Optical Engineer. 3513: 122-34 (1998)). Suitable molds can be formed, for example, from epoxy, silicon, or metal, using or adapting known microfabrication techniques. These micromolding techniques are preferred, as they can provide relatively less expensive replication, i.e. lower cost of mass production. In a preferred embodiment, the polymer is biodegradable.
3. Biological Fluids for Withdrawal or Sensing
The devices disclosed herein are useful in the transport of biological fluids from within or across a variety of biological barriers including the skin (or parts thereof); the blood-brain barrier; mucosal tissue; blood vessels; lymphatic vessels; cell membranes; epithelial tissue; and endothelial tissue. The biological barriers can be in humans or other types of animals, as well as in plants, insects, or other organisms, including bacteria, yeast, fungi, and embryos. In preferred embodiments, biological fluids are withdrawn from skin, more preferably human skin, for minimally invasive diagnostic sensing.
Biological fluids useful with the devices described herein include blood, lymph, interstitial fluid, and intracellular fluid. In a preferred embodiment, the biological fluid to be withdrawn or sensed is interstitial fluid.
A variety of analytes are routinely measured in the blood, lymph or other body fluids. Examples of typical analytes that can be measured include blood sugar (glucose), cholesterol, bilirubin, creatine, various metabolic enzymes, hemoglobin, heparin, hematocrit, vitamin K or other clotting factors, uric acid, carcinoembryonic antigen or other tumor antigens, and various reproductive hormones such as those associated with ovulation or pregnancy. Other substances or properties that would be desirable to detect include lactate (important for athletes), oxygen, pH, alcohol, tobacco metabolites, and illegal drugs (important for both medical diagnosis and law enforcement).
In a preferred embodiment, interstitial fluids are removed from the dermis or epidermis across the stratum corneum to assay for glucose concentration, which is useful in aiding diabetics in determining their required insulin dose.
4. Using the Microneedle Device
The device is applied to the skin or other biological barrier at the site where the sample is to be collected or measured. Then, biological fluid, or a component thereof, is drawn into or through the pores or bores of the microneedles, and optionally collected in the collection chamber. Alternatively, where the microneedles function as the sensor, sensing occurs without transfer of biological fluid into a collection chamber.
a. Feedback about Penetration of the Microneedles into the Tissue
The user of the microneedle device typically can determine if the microneedles have been properly inserted into the skin or other tissue through visual or tactile means, that is assessing whether the substrate has been pressed essentially flush to the tissue surface. A coloring agent can be used to enhance the visual feedback by indicating a color change triggered by biological fluid filing the collection chamber.
In a more complex embodiment, an electrical or chemical measurement is adapted to provide the feedback. For example, penetration can be determined by measuring a change in electrical resistance at the skin or other tissue, or a pH change. Alternately, needle-to-needle electrical resistance can be measured. In a preferred embodiment, the microneedle device includes a disposable cartridge containing the microneedles. In these devices, an LED (e.g., green light/red light) or liquid crystal display can be provided with the reusable portion or the device.
b. Initiating and Controlling Fluid Withdrawal
In a preferred embodiment, the microneedle device is capable of transporting molecules across or from the tissue at a useful rate. That rate will, of course, depend on the particular application. For assaying blood glucose, for example, the device preferably withdraws at least between about 5 and 10 μl of interstitial fluid, preferably in about a minute or less time. For other applications, it may be desirable to apply the device to the barrier for several hours or more in order to monitor the changing blood plasma level of a particular analyte, such as an exogenous drug or hormone level, for example on a real-time basis or to obtain a time-averaged value.
The rate of withdrawal can be controlled by altering one or more of several design variables. For example, the amount of material flowing through the needles can be controlled by manipulating the volumetric through-capacity of a single device array, for example, by using more or fewer microneedles, by increasing or decreasing the number or diameter of the bores in the microneedles, by filling at least some of the microneedle bores with a diffusion-limiting material, or by varying the driving force applied to the biological fluid. It is preferred, however, to simplify the manufacturing process by limiting the needle design to two or three "sizes" of microneedle arrays to accommodate, for example small, medium, and large volumetric flows, for which the withdrawal rate is controlled by other means.
The flow of biological fluid from the tissue through the microneedle and into the collection chamber or into contact with the sensors occurs due to capillary action, diffusion, or is induced using conventional mechanical pumps or nonmechanical driving forces, such as electroosmosis or electrophoresis, thermal gradients, or convection. For example, in electroosmosis, electrodes are positioned on the biological barrier surface, on one or more microneedles, and/or on the substrate adjacent the needles, to create a convective flow which carries charged ionic species and/or neutral molecules toward and/or through at least one of the microneedles.
Transportation of molecules through the microneedles can be controlled or monitored using, for example, various combinations of semi-permeable membranes, valves, pumps, sensors, actuators, and microprocessors. These components can be produced using standard manufacturing or microfabrication techniques. Actuators that may be useful with the microneedle devices disclosed herein include micropumps, microvalves, and positioners.
In a preferred embodiment, the microneedle device is used in combination with another mechanism that enhances the permeability of the biological barrier, for example by increasing cell membrane disruption, using electric fields, ultrasound, chemical enhancers, vacuum, viruses, pH, heat, and/or light. Chemical and/or physical enhancers can be applied to the biological barrier at the site of insertion of the device before or during the withdrawal of the device, for example, to draw analyte closer to the skin surface.
(i). Bulk Flow Extraction
A preferred microneedle device is shown in
Other spring means can be adapted to cause a change in the volume, and thus internal pressure, of the collection chamber. For example, the fluid collection chamber can be adapted to have a movable, rigid top with fixed, rigid side walls, wherein the interface between the walls and top form a gas-tight seal (such as by using a gasket). The volume of the piston-like apparatus can be expanding by activating one or more compressed springs to move the top of the chamber as desired, thereby reducing the pressure in the collection chamber.
In an alternative embodiment, withdrawal can be initiated by activating an osmotic pump, as described, for example, in U.S. Pat. No. 4,320,758 to Eckenhoff, which has been engineered to create a volume expansion/pressure reduction in the collection chamber to draw biological fluid to be drawn into the collection chamber.
In a preferred embodiment, withdrawal is conducted using a microneedle device fitted to a Luer-Lock syringe or similar conventionally-used devices that currently uses hypodermic needles in the barrier penetration method.
(ii). Diffusion-Based Extraction
One preferred embodiment uses diffusion to move the analyte fluid into the fluid collection chamber. A microneedle device using this method generally includes microneedle bores or pores, and/or a fluid collection chamber, that are filled with a diffusion medium, such as water, a saline solution, or a gel, which is physiologically compatible with the biological barrier tissue. Once the needle is inserted into the biological barrier (e.g., the skin), the diffusion medium contacts the biological fluid. Typically, the diffusion medium in the microneedles initially contains none of the analyte to be measured; therefore, analyte at a higher concentration in the biological fluid diffuses into the diffusion medium in the microneedle until a detectable level of analyte in collected or measured. This should be achieved rapidly due to the very small size/length of the microneedles, thereby providing an analyte concentration for sensing that is rapidly response to that in the tissue.
(iii). Hybrid Bulk Flow/Diffusion
In another embodiment, the microneedle device is designed to employ a combination of forces to drive the analyte into the collection chamber. A preferred hybrid design includes the preferred bulk flow microneedle device described above, but with two primary differences. First, the fluid collection chamber has no one-way valve and contains a fluid diffusion medium, preferably physiological saline. Second, a temporary barrier is interposed between the fluid collection chamber and the base of the microneedles. The temporary barrier can be a fracturable membrane, mechanical gate, or other means for containing the diffusion medium within the device until the barrier is broken or removed at a selected time to permit flow of molecules between the microneedles and fluid collection chamber.
In a preferred embodiment, the temporary barrier is an easily fracturable membrane. The device can function as follows: The microneedles first are inserted into the skin of the user. Then the user depresses the elastic cap, causing the fluid diffusion medium to fracture the membrane and fill the bores or pores of the microneedles and contact the biological fluid. After the user releases the elastic cap, it partially or fully returns to its undeformed shape, reducing the pressure in the interior and causing a mixture of the biological fluid and diffusion medium to be drawn through the microneedles and into fluid collection chamber. Once bulk fluid flow ceases, diffusion may continue until the concentration of biological fluid or analyte equilibrates. The mixture can be assayed as described herein, considering the dilution effect induced by the presence of the diffusion medium.
Any of these embodiments of the microneedle device can be adapted to function a series of micro-assays (e.g., as can be provided with an electronics package) or single assays (e.g., standard glucose strips).
e. Multi-Cartridge Microneedle Device
A modification of the disposable, single use microneedle device utilizes a reusable portion providing the withdrawal force (e.g., suction) or electronics package in combination with a cartridge containing one or more, preferably a plurality, of single-use, disposable microneedle devices for collection and/or sensing. For example, the cartridge can be a circular disk having 10 or 12 microneedle arrays connected to a single-assay element, wherein the cartridge can be loaded into and unloaded from the reusable portion. The triggering device can, for example, be designed to move a new microneedle array into position, withdraw or sense the sample of biological fluid, and then eject or immobilize the used microneedle array. This type of reusable triggering device also can include a power source, such as a battery, used to operate a built-in measurement device, for example, for analyte measurement of interstitial fluids.
In one embodiment, the devices are provided in a multipack (e.g., six or twelve pack) form of complete devices, that is, each device is fully sufficient for use. Individual devices can be separated as needed for each sensing measurement.
The present invention will be further understood with reference to the following non-limiting examples.
Studies were performed to demonstrate transport of molecules using either solid silicon microneedles or using hollow silicon microneedles. Transport was measured across human cadaver epidermis in vitro using Franz diffusion chambers at 37� C. using methods described in Henry, et al., "Microfabricated microneedles: A novel method to increase transdermal drug delivery" J. Pharm. Sci. 87:922-25 (1998).
Removal of calcein was measured. Removal refers to the ability to transport calcein from the viable epidermis side of the epidermis to the stratum corneum side. This is the direction of transport associated with removing from the body compounds found in the body, such as glucose. Other compounds were tested for delivery only.
In all cases shown in Table 1, transport of these compounds across skin occurred at levels below our detection limit when no needles were inserted into the skin. When solid microneedles were inserted into the skin and left in place, large skin permeabilities were measured, indicating that the microneedles had created pathways for transport across the skin. Furthermore, in all cases, when solid microneedles were inserted into the skin and then removed, even greater skin permeabilities resulted. Finally, when hollow microneedles were inserted into the skin and left in place, still greater skin permeabilities resulted for those compounds tested. These studies show that microneedles can dramatically increase skin permeability and can thereby increase transport of a number of different compounds across the skin. It also shows that when solid microneedles are used, a preferred embodiment involves inserting and then removing microneedles, rather than leaving them in place. It also shows that using hollow microneedles are a preferred embodiment over the use of solid microneedles.
To demonstrate that fluid can be forced through hollow microneedles at meaningful rates, the flow rate of water through a microneedle array was measures as a function of pressure. The array used contained 100 hollow silicon microneedles having an inner diameter of 50 μm and an outer diameter of 80 μm. The results, which are shown in Table 2, demonstrate that significant flow rates of water through microneedles can be achieved at modest pressures. The measured flow rates are comparable to flow rates through hypodermic needles attached to syringes.
A chromium masking material was deposited onto silicon wafers and patterned into dots having a diameter approximately equal to the base of the desired microneedles. The wafers were then loaded into a reactive ion etcher and subjected to a carefully controlled plasma based on fluorine/oxygen chemistries to etch very deep, high aspect ratio valleys into the silicon. Those regions protected by the metal mask remain and form the microneedles.
<100>-oriented, prime grade, 450-550 μm thick, 10-15 Ω-cm silicon wafers (Nova Electronic Materials Inc., Richardson, Tex.) were used as the starting material. The wafers were cleaned in a solution of 5 parts by volume deionized water, 1 part 30% hydrogen peroxide, and 1 part 30% ammonium hydroxide (J. T. Baker, Phillipsburg, N.J.) at approximately 80� C. for 15 minutes, and then dried in an oven (Blue M Electric, Watertown, Wis.) at 150� C. for 10 minutes. Approximately 1000 Å of chromium (Mat-Vac Technology, Flagler Beach, Fla.) was deposited onto the wafers using a DC-sputterer (601 Sputtering System, CVC Products, Rochester, N.Y.). The chromium layer was patterned into 20 by 20 arrays of 80 μm diameter dots with 150 μm center-to-center spacing using the lithographic process described below.
A layer of photosensitive material (1827 photoresist, Shipley, Marlborough, Mass.) was deposited onto the chromium layer covering the silicon wafers. A standard lithographic mask (Telic, Santa Monica, Calif.) bearing the appropriate dot array pattern was positioned on top of the photoresist layer. The wafer and photoresist were then exposed to ultraviolet (UV) light through the mask by means of an optical mask aligner (Hybralign Series 500, Optical Associates, Inc., Milpitas, Calif.). The exposed photoresist was removed by soaking the wafers in a liquid developer (354 developer, Shipley, Marlborough, Mass.) leaving the desired dot array of photoresist on the chromium layer. Subsequently, the wafers were dipped into a chromium etchant (CR-75; Cyanteck Fremont, Calif.), which etched the chromium that had been exposed during the photolithography step, leaving dot arrays of chromium (covered with photoresist) on the surface of the silicon wafer. The photoresist still present on the chromium dots formed the masks needed for fabrication of the microneedles, described below.
The microneedles were fabricated using a reactive ion etching techniques based on the Black Silicon Method developed at the University of Twente. The patterned wafers were etched in a reactive ion etcher (700 series wafer/batch Plasma Processing System, Plasma Therm, St. Petersburg, Fla.) with means for ensuring good thermal contact between the wafers and the underlying platen (Apiezon N, K. J. Lesker, Clairton, Pa.). The wafers were etched using the following gases and conditions: SF6 (20 standard cubic centimeters per minute) and O2 (15 standard cubic centimeters per minute) at a pressure of 150 mTorr and a power of 150 W for a run time of approximately 250 minutes. These conditions caused both deep vertical etching and slight lateral underetching. By controlling the ratio of flow rates of the SF6 and O2 gases used to form the plasma, the aspect ratio of the microneedles could be adjusted. The regions protected by the chromium masks remained and formed the microneedles. Etching was allowed to proceed until the masks fell off due to underetching, resulting in an array of sharp silicon spikes.
Three-dimensional arrays of microtubes were fabricated from silicon, using deep reactive ion etching combined with a modified black silicon process in a conventional reactive ion etcher. The fabrication process is illustrated in
Hollow metal microtubes were prepared without dry silicon etching, using a thick, photo-defined mold of epoxy. The sequences are illustrated in
A micromold having tapered walls was fabricated by molding a preexisting 3-D array of microneedles, i.e. the mold-insert, and subsequently removing the mold insert. The micromold was then surface plated in a manner similar to that for the microtubes described in Example 5. The fabrication sequence is illustrated in
First, an array of solid silicon microneedles 50 were prepared as described in Henry, et al., "Micromachined Needles for the Transdermal Delivery of Drugs," Micro Electro Mechanical Systems, Heidelberg, Germany, pp. 494-98 (Jan. 26-29, 1998). Then, a layer of epoxy 52 (SU-8) was spin cast onto the microneedle array to completely blanket the array (
Then, the upper surface of the epoxy 52 was etched away using an O2/CHF3 plasma until approximately 1 to 2 μm of the needle tips 51 were exposed, protruding from the epoxy 52 (
Micromold-based microneedles also have been successfully manufactured using a process in which the epoxy mold material was replaced with PDMS. In this case, it was possible to remove the mold from the mold insert, as well as the microneedles from the mold, using only physical techniques such as peeling. This approach advantageously requires no dry etching and allows one to reuse both the mold and the mold insert.
A micromold having tapered walls was fabricated by use of laser ablation techniques, as shown in
Alternate polymer removal methods, such as thermal, solvent, aqueous, or photo-degradation followed by solvent or aqueous removal, are also possible if the polymer material is chosen appropriately (e.g., a photoresist resin).
Formation of a microneedle by embossing is shown in
Publications cited herein and the material for which they are cited are specifically incorporated by reference. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended claims.
Patent Citations
Non-Patent Citations
Referenced by
Legal Events
Original Image


text:
Now we know one sure-fire way to make headlines across the globe: Pick a fight with Ted Koppel.
Sinclair Broadcast Group did just that two weeks ago, and the Baltimore County-based company is still basking in national - and even international - coverage. Newspapers throughout the country wrote about the flap. Papers and news services in Australia, Canada, France, Ireland, Italy and the United Kingdom did, too. A lot of the coverage was negative, but at least it was coverage.

subset: commoncrawl


text:
Marketing Information
Wii Sports Resort is an immersive, expansive active-play game that includes a dozen fun resort-themed activities. It maintains the wide-ranging appeal that attracted millions to the original Wii Sports. Wii Sports Resort is easy to pick up and play, but comes coupled with deeper levels of play that are sure to challenge even the most experienced gamers. Wii Sports Resort whisks players away to a resort that's full of action, while introducing an unprecedented experience in physical reality. From the moment players skydive onto Wuhu Island,they're presented with a huge selection of fun activities that everyone can play.
General Information
Product Information
Physical Characteristics
License Information
Service Information


text:
Register now for free, or sign in with any of these services:
Want to set your local edition?
Select an edition for more focused local news coverage when you visit mlive.
Don't worry. You can change this setting at any time to another local edition.
David, I think your wrong there are huge differences between the GOP candidates. All you have to do is go to their web sites and review their policies. I personally believe Newt is the candidate that will help create jobs here in MI and in turn help my small blue collar business survive. If your white collar or a soft conservative you will probably side with Romney. If you are more liberal/conservative Santorum is most likely your choice. But saying there is no difference between the choices you need to get out and research the facts. Unless you an Obama supporter in that case it just dosen't matter either way.
Registration on or use of this site constitutes acceptance of our User Agreement and Privacy Policy
© 2015 MLive Media Group All rights reserved (About Us).
The material on this site may not be reproduced, distributed, transmitted, cached or otherwise used, except with the prior written permission of MLive Media Group
Community Rules apply to all content you upload or otherwise submit to this site. Contact interactivity management.


text:
|Posted by 9dotstrategies on March 6, 2014 at 12:30 AM
As a business owner, it is your job to know where to best place your money to make the most out of it. For any type of business that needs a web store front, the Philippines is an excellent option for you. Why? Read the top four reasons stated below.
Current Hotspot for Start-ups
Evidenced by lots of start-ups, even Silicon Valley-basedones, the Philippines is currently a very attractive option for start-ups today. Why? Because the tech teams are rapidly gaining knowledge, they are better managed and there are lots of business opportunities in Asia itself. The positioning of the country as a business hub for the whole region means a merging of networks, leads and customers.
Affordable Operations costs means affordable Service Packages
A practical thing to consider especially if you want tomaintain a lean start-up mentality is to consider the relatively low cost of getting a team from the Philippines. For the same (or even better quality)services offered in developed countries, this nation offers services for almost half the cost.
This is brought by a cheaper cost of living in the city, more affordable office spaces and operational expenses which translates to bigger savings for the team and eventually, for the customers like you.
Excellent English Communication Skills
No doubt about it, the Philippines is one of the best English speaking nations in the world. Most people can easily converse both in written and oral English, making meetings and contract negotiations very easy.This also means an easier time understanding requirements for written works like blog articles.
Other useful considerations for their excellent English skills are:
· Writing and Editing Web Content
· Providing Instructional Materials for Several Products
· Customer Support
· Technical Support
· Chat Support
· Product and Project Management
· Software Design and Development
Experienced Workforce with Multi-region Exposure
The Philippines has long been a good venue for outsourced work and they've been steadily building their portfolio for at least ten years. This means you already have industry experts within the city who know how to scale products at the fastest possible time.You have marketing and operational experts who know when to spend and on what.
Categories: Digital Marketing
Oops, you forgot something.
The words you entered did not match the given text. Please try again.


text:
A "working draft" of the genetic blueprint of rice has been completed, making it the first crop plant to be sequenced. Leroy Hood and his colleagues at the University of Washington in Seattle finished the job in three years on behalf of Monsanto. The company has made the draft openly available to researchers who register, but it expects first refusal on licenses for patented inventions. Tony Combes of Monsanto says this is the company's first major gesture since its chairman, Bob Shapiro, apologised for "arrogance" (
To continue reading this article, subscribe to receive access to all of newscientist.com, including 20 years of archive content.


text:
Dry winter brings burning restrictions
January 6, 2012 at 8:16 am in The Farmington Independent
Weird as it may be, the city of Farmington isn't issuing any permits for open burning these days.
It's a little unusual, Farmington fire marshal John Powers said, but a lack of snow is causing drought conditions in most of the state. The Minnesota Department of Natural Resources is urging caution. Continue Reading


text:
Pro Career: Originally selected by the New England Patriots in the sixth round (205th overall) of the 2010 NFL Draft. Released by the Patriots on 9/4/10 and was claimed off waivers by the Buccaneers on 9/5/10. Signed a two-year contract with the Cardinals on 3/12/14 as an unrestricted free agent.
Pro Career: Originally selected by the New England Patriots in the sixth round (205th overall) of the 2010 NFL Draft. Released by the Patriots on 9/4/10 and was claimed off waivers by the Buccaneers on 9/5/10. Signed a two-year contract with the Cardinals on 3/12/14 as an unrestricted free agent.
2013: Appeared in all 16 games for the third consecutive season, earning four starts (two at center, two at left guard) … made his first start of the season vs. Phi (10/13) … started the following week vs. Atl (10/20), helping the Bucs pile up 111 rushing yards on 28 attempts (4.0 avg.) … made his third start of the season four days later vs. Car (10/24), as the Bucs faced the Panthers on Thursday Night … with the Bucs trailing the Lions 14-10 in the second quarter @ Det (11/24), recovered a crucial TB fumble on a kickoff return on their own 39-yard line, allowing the Buccaneers to hold possession.
2012: Appeared in all 16 games with nine starts at center and his first four career starts at right guard … started the first four games of the season at RG before making nine starts at center in games 8-16 … started the season opener at RG vs. Car (9/9) and helped lead the way as the Buccaneers rushed for 130 yards on 36 carries in a 16-10 win over the Panthers … started at RG the following week @ NYG (9/16) … started at RG @ Dal (9/23) and recovered a fumble by QB Josh Freeman at the TB 42-yard line … saw action vs. KC (10/14) and helped the offense amass 463 yards in a 38-10 victory; Bucs rushed for 145 yards and a TD on 24 carries (6.0 avg.) while Freeman threw for 328 yards and three TDs with just one sack in 26 pass attempts … saw action the following week vs. NO (10/21) and helped the offense collect 513 total yards, the third-best single-game total in team history and the most ever in a home game; TB had 102 rushing yards and Freeman threw for 420 yards in the game … helped the offense to 416 yards @ Min (10/25), which marked the first time in franchise history that the Buccaneers recorded three consecutive games with 400+ yards offensively … made his first career start at center @ Oak (11/4) following injuries to fellow linemen, and helped the offense to 515 yards from scrimmage, the second-highest single-game total in team history … started at center and helped the Bucs post 403 yards of offense in a 27-21 OT victory @ Car (11/18); Tampa Bay rushed for 167 yards on 30 attempts (5.6 avg.) while Freeman threw for three TDs and was sacked just once in 46 pass attempts.
2011: Appeared in all 16 games for the first time in his career, including three starts at left guard … started at LG in the season opener vs. Det (9/11) … saw action in a 24-17 win on Monday Night Football vs. Ind (10/3); helped the offense finish with 466 yards and 192 rushing yards and two TDs on 36 attempts (5.3 avg.) while Freeman threw for 287 yards and a TD on 39 attempts … saw action on offense and helped the Bucs gain 420 total yards in a 26-20 win vs. NO (10/16); yardage total included 117 rushing yards and 303 passing yards from Freeman on 41 attempts without a sack … received his second start of the season vs. Chi (10/23) … started his second consecutive game and third of the season @ NO (11/6) … saw action @ GB (11/20) and helped the offense to a 455-yard performance, including 121 rushing yards on 20 attempts (6.1 avg.) and 342 passing yards.
2010: Started 11 of the 12 games he appeared in during his rookie season, with all 11 starts coming at left guard … team finished with a 7-4 record in the games he started … inactive for the first four games of the season after being acquired off waivers on 9/5 … made his NFL debut vs. NO (10/17), appearing on special teams … started his first career game the following week vs. StL (10/24), starting at LG in place of the injured Keydrick Vincent; helped the offense collect 124 rushing yards on 21 attempts (5.9 avg.) in the 18-17 victory … earned his second career start the following week @ Ari (10/31), helping the offense tie a season-high with 38 points as RB LeGarrette Blount rushed for 120 yards and two TDs on 22 attempts … helped the offense to a season-high 439 yards vs. Sea (12/26), including 208 yards rushing on just 26 attempts (8.0 avg.).
College: Started 30 of the 43 games he appeared in at North Carolina State, including five starts in 23 games at defensive tackle and 25 starts at center after switching positions prior to his junior season … played DT during his first three seasons (2005-07), including a redshirt year in 2005 where he appeared on the scout team, before switching to center for his final two seasons of eligibility … recorded 23 tackles, four sacks, 5.5 tackles for loss, a pass defensed and a forced fumble during his time on defense and 185 knockdowns, 19 TD-resulting blocks and eight downfield blocks during his two seasons on the offensive line … as a senior in 2009, named to the watch list for the Rimington Trophy as the nation's top center and earned All-ACC second-team honors by the NFL Draft Report … switched from DT to center prior to his junior season in 2008, and despite never having played the position was named to the watch list for the Rimington Award and earned N.C. State's Jim Ritcher Award for the most outstanding offensive lineman.
Personal: Attended University (Palm Harbor, FL) High School where he was named as the district Player of the Year by The Florida Athletic Coaches Association and earned All-Pinellas County first-team and All-Sun Coast Florida second-team honors as a senior, when he recorded 65 tackles, including eight sacks and one blocked kick … as a junior, was named all-county second-team after tallying 85 tackles and 15.0 sacks … also competed in the shot put and the discus during track season … member of the National Honor Society … holds a degree in History.
USAA and the Arizona Cardinals team up during a special base tour at Papago Park Military Reservation with members of the Arizona National Guard.
Bruce Arians says that Ted Larsen will start over Jonathan Cooper at left guard.
Darren Urban and Kyle Odegard talk guard Ted Larsen and the need to improve the pass rush.


text:
What did you do with your Trials Bike today?
View Single Post
Career Rookie/Novice
Joined: Jul 2012
Location: near Danville IL
Oddometer: 203
... burrs in my britches....
So...got to go work on the setup for the Tilton Trials all day Saturday. Had a BLAST!!
Of course, being a mile or so out into the woods, there isn't exactly easy access to a porta-potty. So, I rode off a bit from our work crew, found a secluded space, made SURE there was no poison ivy or other nasty monsters in the area, and, well, "dropped drawer".
Unfortunately, the section I'd been last working in was covered in stickers and burrs, and i hadn't noticed the burrs that had gotten stuck all up the side of my riding pants and my sweatshirt, even the inside of my open coat. Not noticed, that is, until I attempted to pull up my Football Pads Shorts I wear for protection ... and found them scraping all up the outside of both legs... it seems the stickers from the inside of the coat and other areas had rolled quite nicely onto the inside of the shorts and were well secured there.
I spent the rest of the afternoon periodically pulling burrs and other stickers out of the inside of my shorts!! (Thanks heavens it was at least down the outside of the thigh and not somewhere, er... more sensitive!!)
AnnMarie Cross, permanent Noob! & proud wife of "macattack"
Join us in 2014 at the 2nd annual Tilton Trials, Illinois!
Novice owner of "GheeGhee", '01 GG 80big & also '01 GG280 "TriXTer"
View Public Profile
Visit amcross's homepage!
Find More Posts by amcross


text:
Personalized Wearables
Personalized Lanyards Make Functional Gifts
Personalized lanyards help you display your ID cards in style! Add your school mascot, company name, or an inspirational message and use them for giveaways at trade shows, incentives for fundraisers, or even a gift to a graduating class!
Sporting Events, Trade Shows, Fundraisers...So Many Great Ways to Use Custom Lanyards
Show your team spirit by proudly wearing your season tickets around your neck with our custom lanyards! Just add your school or team name and mascot on a coordinating color and you're set. Check out our full line of stadium gear, too.
Personalized lanyards are also a perfect answer to the employee ID challenge. Your employees can keep their ID in full view with a lanyard that coordinates with the colors in your company logo.
Hosting a conference? Keep your guests' credentials in clear view while also providing them with a favor from your event! Check out our banners that are great to display in your conference venue, too.


text:
Editorial: "Augmented reality offers a new layer of intrigue"
IT'S Sunday afternoon in London's Trafalgar Square. Not far from the fountains, someone has left an enigmatic message on the steps: "Fine mist washes over my face," it reads. "Gray skies seem bluer here." Tourists wander by, but none of them can see the words.
In fact, there are hidden messages painted all over the square. On the side of the National Gallery, somebody has scribbled a declaration in large letters: "Maria, I love you". That graffiti has been there for more than a month without anybody cleaning it off. And inside a nearby restaurant, waiters are serving pizza, blissfully unaware of the message on the wall saying the food looks like pigeon droppings. The square is home to invisible images too - and even strange creatures. A yellow pufferfish, for example, is floating in the air above a metal ...
To continue reading this article, subscribe to receive access to all of newscientist.com, including 20 years of archive content.


text:
The WindPaddle Cruiser Sail shares all the lightweight, easy-to-use features of the WindPaddle Adventure Sail but cranks the power up a few notches to accommodate heavier boats.
WindPaddle Cruiser Kayak Sail
Why work harder than you have to? Harness the power of the wind instead! The lightweight, compact WindPaddle Adventure Sail makes kayak touring faster, easier and more fun.
WindPaddle Adventure Kayak Sail
The WindPaddle Scout Sail will pull your kayak or canoe quickly downwind, yet is easy enough for kids 8-80 to handle. Great for solo boaters looking for a simple and forgiving sail to help the trip go...
WindPaddle Scout Kayak Sail
Not finding what you're looking for? Search the site above, or feel free to contact us directly.


text:
Unsure of What to Do after Graduation?
Date: 11/14/2012
Time: 2:30 PM – 3:30 PM (CST)
Location: Oxford Campus, Shoemaker Hall
|Invitation: Come to Shoemaker 219, Wednesday, Nov. 14th between 2:30-3:30 for info about graduate studies at VA Tech. Refreshments provided.
Full Details: PDF Link
For assistance related to a disability, contact: Biology Department - 915-7203
Event posted by: email@example.com


text:
SpecialtyFamily Medicine
GroupAustin Regional Clinic, P.A.
Contact InfoARC Far West - Family Medicine
6835 Austin Ctr Blvd
Austin, TX 78731
Phone: (512) 346-6611
Fax: (512) 406-7315
Year Joined ARC: 2000
Medical School: University of Texas Medical Branch at Galveston, 1997
Residency Internship: University of Texas Medical Branch at Galveston, 2000
Certification: Board Certified in Family Medicine
Professional Positions and Honors:
- Associate Chief, ARC Family Medicine Department
- USA Today's new most influential Doctors
- Austin Monthly's annual "Top Doctors" formerly (Best Doctors): 2011, 2013, 2014
- Texas Monthly Super Doctors 2011, 2012, 2013, 2014
Personal Summary:
Both Dr. Markley and her husband are native Austinites. She received all of her schooling in Texas schools, Texas A&M for undergrad and UTMB for medical school and residency. She has three wonderful children and they all enjoy traveling and doing anything outdoors together.
Provider Bio: Currently, Dr. Markley has long wait times for new patients. If you would like to establish care at Austin Regional Clinic, Dr. Markley highly recommends her ARC Far West Family Medicine colleagues,
Views on political or religious issues expressed by medical staff may not necessarily represent the views of the Seton Healthcare Family.


text:
THE size of a woman's brain changes throughout her menstrual cycle, with some areas growing by as much as 2 per cent in the run-up to ovulation, when women are at their most fertile.
So say Belinda Pletzer and colleagues at the University of Salzburg, Austria, who took MRI scans of the brains of women during their monthly cycles.
In women not taking the pill, the team found an increase in the volume of grey matter in the right parahippocampal and fusiform gyri, areas of the brain involved in spatial location and facial recognition (Brain Research, DOI: 10.1016/j.brainres.2010.06.019).
This boosts women's abilities to recognise faces, bodies and landscapes, says Pletzer, adding that this may help them to locate a high-quality mating partner.
The team found that the effect is short-lived, however. After ovulation, rising levels of progesterone cause the gyri to shrink back.
The team also found that ...
To continue reading this article, subscribe to receive access to all of newscientist.com, including 20 years of archive content.


text:
Soup-loving runs in my family. Sort of. I'm pretty sure my basic genetics education would confirm that I cannot inherit traits from my father-in-law. But what I didn't get from his genes, I certainly have absorbed through environment.
Paw-in-Law is a soup-lover. His restaurant mantra, if he had one, would be "Give Soup a Chance." The SOUPer Bowl put on this past Saturday by the Starkville Young Professionals would have been right up his alley. But since he is in Florida, I brought along someone who actually did inherit some of his genes: Firstborn.
Right in the door we met Zorba's Sun-Dried Tomato Focaccia Cheese Bread over Saffron Tomato Soup with Herbed Crème Fraiche, a creation of Chef Ty Thames. The crème fraiche melted into the soup, making it even richer, and we saved the flavor-soaked focaccia bread for a beautiful last bite.
Our next stop was the Harvey's table, where they served us a cup of Roasted Turkey and Kielbasa Chowder, garnished with Craisins, little chunks of kielbasa and a round of cranberry crostini. Firstborn, after his first bite, said "this tastes like Thanksgiving dinner." I don't know if that's what they were going for, but it was a good thing.
A few steps further in we got Loaded Potato Soup from Old Venice — thick and rich and popping with flavor — serious comfort food for a dismal-weather day. It had a kick that we know came from a Cajun spice blend, and I am convinced that there was a mystery herb that gave it an extra boost of flavor — this was no bland potato soup.
Next up was Bin 612's Butter Bean Soup garnished with Tobacco Onions and Fennel. Rest easy, no actual tobacco was harmed in the production of this garnish. These were just slivers of fried onion that resembled shredded tobacco, thus the name. I love a good, hearty bean soup, and this is one I'd like to have again, tobacco onions and all.
Beside Bin 612 was its cousin, Restaurant Tyler, whose chefs had developed Surf and Turf Chowder. The chef told us they started with lobster stock and beef broth, then built a chowder around it with bacon, onion, corn and potato. All those flavors were there, in sweet contrast with bits of house-smoked bacon cured in sherry.
The Veranda's entry was a Braised Short Rib with Root Vegetables Soup. I queried Chef Jay Yates on which veggies he used — there were so many I lost track. He was also kind enough to educate me on the origins and cooking techniques of short ribs that created a perfectly tender bite of meat. The result was a soup that brought back fond memories of beef stew, yet was bumped up a notch or three in flavor and texture.
Central Station Grill made a Chicken Corn Chowder with a kick. I didn't get a chance to ask about the source of said kick, but I could see with my own two eyes a generous amount of black pepper. My taste buds told me a hot pepper of another sort might have been mixed in, too. Whatever it was, it gave a heap of life to the chowder.
Bulldog Deli and Sweet Pepper's shared the next table, but offered two very different soups. Pepper's featured their Chicken and Sausage Gumbo, which was super chunky and had just the right degree of heat. Bulldog Deli dished out their creamy Crawfish Bisque. I usually prefer my crawfish tails in deep-fried form, but I think I've found another way to enjoy them.
Around the bend was the Dudy Gras Surprise from the Great American Grill at the Hilton Garden Inn. They told me this prize-winning soup was anchored on collard greens and northern beans and supported with ham, bacon, and andouille sausage. Before the Food Pyramid and My Plate came along, weren't those the five basic food groups?
Café Ritz from West Point had Shrimp Bisque garnished with Herbed Mascarpone Cheese and Tasso Bits. Tasso is a highly seasoned and smoked Cajun pork creation, and I had never had it before. The mascarpone cheese melted into the bisque, multiplying the richness, and the Tasso bits added a great savory, chewy contrast.
I heard some great comments about the Chicken and Gnocchi Dumplings from Chef Dave's Smoked Meats and Fine Catering — Firstborn and I agreed. Chef Dave told us that everything in the soup, even the cream of chicken base, was made from scratch — and it showed. The gnocchi dumplings were amazingly tender, not in a mushy way but in a melt-in-your-mouth kind of way. Chef Dave also works on campus providing meals for a sorority house, so I am looking into becoming an honorary Zeta.
Last but not least on the circle of soup was Three Little Pigs. It was hard to miss the stuffed boar head and the sign advertising "Angel Pig Stew." I am a big fan of Brunswick stew, and had been looking forward to trying theirs. It was hearty and chunky and tasted like Brunswick stew ought to, but had another level of flavor from smokiness of the meat. I don't know who decided BBQ places ought to serve Brunswick stew, but God bless 'em.
This SOUPer Bowl was held at the old State Theater, and there were several of us at the event who could conjure up interesting memories from its days as the main movie theater in town. It was great to be back and make some new memories — and at least soup is something we can share with our kids.
Jay Reed is a local foodie and pharmacist. The culinary tastes expressed here are his and do not necessarily reflect the appetites of the Starkville Daily News or individual members of its staff. He welcomes your comments at firstname.lastname@example.com [2].
[1] http://www.starkvilledailynews.com/sites/default/files/JayForWeb_1.jpg
[2] mailto:email@example.com