WO2009025698A1

WO2009025698A1 - Devices, systems, and methods for the measurement of analytes

Info

Publication number: WO2009025698A1
Application number: PCT/US2008/007932
Authority: WO
Inventors: Russell O. Potts; James W. Moyer
Original assignee: Vivomedical, Inc.
Priority date: 2007-08-17
Filing date: 2008-06-25
Publication date: 2009-02-26

Abstract

Devices, systems, and methods for measuring analytes such as glucose are described herein. Some variations of the systems described herein are configured to collect sweat, and comprise a sweat collection device comprising a gradient and defining a collection location, where the gradient is configured to direct sweat toward the collection location when the sweat collection device is applied to a skin surface. Certain variations of the methods described herein comprise applying a system comprising a sweat collection device to a skin surface, where the sweat collection device comprises a gradient configured to direct sweat toward a collection location.

Description

DEVICES, SYSTEMS, AND METHODS FOR THE MEASUREMENT OF

ANALYTES

TECHNICAL FIELD

[0001] The devices, systems, and methods described here relate to the measurement of analytes brought to the skin surface via sweat, and more specifically to the non-invasive measurement of glucose brought to the skin surface via sweat.

BACKGROUND

[0002] Diabetes is a life-threatening disease that poses a threat to a relatively high percentage of the United States population. A leading cause of death in the United States, diabetes is associated with broad complications, including blindness, kidney disease, nerve disease, heart disease, amputation and stroke. Diabetes results from a body's inability to produce or properly use insulin, a hormone needed to convert sugar, starches, and the like into energy. The cause of diabetes is not currently completely understood, but genetics, environmental factors, and viral factors have been identified as partial causes.

[0003] There are two major types of diabetes: Type 1 and Type 2. Also known as juvenile diabetes, Type 1 diabetes is caused by an autoimmune process that destroys beta cells, which are located in the pancreas and secrete insulin. Type 1 diabetes occurs most often in young adults and children, and these diabetics must take regular injections of insulin in order to stay alive. Type 2 diabetes, on the other hand, is a metabolic disorder resulting from a body's inability to produce sufficient amounts of, or properly use, insulin. Likely a result of an increasing number of older Americans and a greater prevalence of obesity and sedentary lifestyles, Type 2 diabetes is nearing epidemic proportions.

[0004] Insulin plays a role in controlling the uptake of glucose by cells in the body. In diabetics, glucose cannot enter body cells, which results in a potentially toxic buildup of glucose in the blood. As a result, Type 1 and many Type 2 diabetics are typically required to self-administer insulin. It is highly recommended that these insulin-using patients practice self-monitoring of blood glucose ("SMBG"), so that they may adjust their insulin dosages based on the current amount of glucose in the bloodstream. These adjustments are necessary, since blood glucose levels vary from day to day as a result of factors such as exercise, stress, rates of food absorption, types of food, hormonal changes (pregnancy, puberty, etc.) and the like. Despite the importance of SMBG, studies have found that the proportion of individuals who self-monitor at least once a day decreases with age. This decrease is likely due to the fact that the typical method of SMBG involves obtaining blood from a capillary finger stick, which many patients find to be much more painful than the self-administration of insulin.

[0005] Non- or minimally- invasive techniques are being investigated, some of which have begun to focus on the measurement of glucose on the skin surface or in interstitial fluid. Some techniques have been directed to measuring analytes that come to the skin surface via diffusion, but the amount of time required for this passive diffusion (e.g., a few hours to several days) would not allow for a practical non-invasive glucose monitoring solution. Other techniques have focused on using patches containing wet and dry chemistry components to extract analytes from interstitial fluid. In these techniques, the liquid phase contact with the skin surface would make it nearly impossible to distinguish between glucose on the skin surface originating from many day old epidermal debris, glucose on the skin surface originating from many hours old transdermal diffusion, and finally, glucose on the skin surface from the more timely output of eccrine sweat glands.

[0006] Still other techniques have investigated glucose measurement in sweat. Early techniques either failed to demonstrate a correlation between blood glucose levels and sweat glucose levels, or were unable to establish or demonstrate that only glucose from sweat was being measured. More recently, however, devices have been created that are capable of isolating glucose in sweat from other sources on the skin surface.

[0007] It would be desirable to provide additional non- or minimally-invasive devices and techniques for measuring glucose in sweat. It would further be desirable for such devices to be relatively easily manufactured, and/or to be operable without requiring an energy input or dilution of a collected sweat sample.

BRIEF SUMMARY

[0008] Sweat collection devices and related systems and methods are described herein. Generally, the sweat collection devices may be used to collect an amount of sweat from a skin surface of a subject, so that the sweat can be evaluated for its concentration of one or more analytes. A non-limiting example of an analyte that may be collected and evaluated this way is glucose. The concentration of the glucose in the sweat may then be used to determine blood glucose levels. [0009] Some variations of the sweat collection devices described herein comprise a gradient and define a collection location (e.g., which is centrally located in or on the sweat collection device). The gradient is configured to direct sweat toward the collection location when the sweat collection device is applied to a skin surface. Certain variations of the systems described herein are configured for collecting sweat and comprise the above- described sweat collection device. The sweat collection device may comprise a patch having any of a number of different shapes, such as circular, rectangular, or oval. The sweat collection device may be configured to passively collect sweat, such as by allowing the sweat to travel along the gradient. As a result, the sweat collection device may not require an extra energy input (e.g., from a pump) to collect sweat.

[0010] Different types of gradients may be used in the systems and devices described herein. For example, the sweat collection device may comprise a gradient comprising a surface energy gradient or a radial gradient. Generally, the gradient is located in a region of the sweat collection device that is configured to contact a skin surface; for example, the gradient may be located on an exterior surface of the sweat collection device. In certain variations, the gradient comprises at least one hydrophilic portion and/or at least one hydrophobic portion. The presence of such hydrophilic and/or hydrophobic portions may assist in the collection of sweat, as sweat typically will be more attracted to the hydrophilic portions than to the hydrophobic portions. The gradient may include a specific pattern of hydrophilic portions and/or hydrophobic portions that enhances or maximizes the sweat collection device's ability to collect sweat from a skin surface. For example, the gradient may comprise a hydrophobic portion at least partially surrounding a hydrophilic portion, or may comprise a plurality of hydrophilic portions in the form of spokes radially projecting from the collection location. In certain variations, the gradient comprises hydrophobic portions and hydrophilic portions in the form of concentric rings. In some variations, the hydrophilicity of the sweat collection device increases from an outer region of the sweat collection device to an inner region, while the hydrophobicity of the sweat collection device decreases from the outer region to the inner region.

[0011] The sweat collection device may comprise a collection chamber for collecting the sweat. In some variations, the collection chamber is configured to collect a fixed volume of sweat from a skin surface. The collection chamber may disposed, for example, in the collection location and/or at the center of the gradient. Certain variations of sweat collection devices may comprise multiple collection chambers, such as 2, 3, 4, 5, or 10 collection chambers. In some variations, the system comprises an overflow chamber. The overflow chamber may be in fluid communication with the collection chamber and may be configured to collect excess sweat (e.g., that has exceeded the volume of the collection chamber).

[0012] The sweat collection devices described herein may include other features such as, for example, a sweat-permeable membrane and/or a detector (e.g., an electrochemical detector or an optical detector). Moreover, the systems described herein may also include additional features, including but not limited to a measurement device configured to interrogate the sweat collection device to measure a concentration of an analyte in the sweat.

[0013] Certain variations of methods described herein comprise applying a system comprising a sweat collection device to a skin surface, where the sweat collection device comprises a gradient configured to direct sweat toward a collection location. Some variations of methods described herein are methods of making a system for collecting sweat. The methods may comprise forming a sweat collection device comprising a gradient and defining a collection location, where the gradient is configured to direct sweat toward the collection location when the sweat collection device is applied to a skin surface. One or more of the methods described herein further comprise forming the gradient. The gradient may be formed, for example, by chemically derivatizing a surface of a material to form the gradient on the surface, and/or by applying a first material to a surface of a second material (e.g., using vapor deposition or a printer).

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 is a schematic illustration of glucose transport from the blood of a subject to the skin of the subject.

[0015] FIG. 2A is an illustration of a variation of a glucose-monitoring patch affixed to a skin surface of a subject.

[0016] FIG. 2B is a side cross-sectional view of the glucose-monitoring patch of FIG. 2A.

[0017] FIGS. 3A-3H are illustrations of different variations of glucose-monitoring patches.

[0018] FIGS. 4A-4E are illustrations of gradients on surfaces of glucose-monitoring patches. [0019] FIGS. 5 A and 5B are side cross-sectional views of variations of glucose-monitoring patches.

[0020] FIGS. 6A-6C are enlarged views of regions of glucose-monitoring devices in which glucose concentration is measured.

[0021] FIG. 7 is an illustration of a detector detecting glucose concentration in a glucose- monitoring patch.

DETAILED DESCRIPTION

[0022] Described here are devices, methods and systems for non-invasively measuring analytes, such as glucose, from a sample of sweat collected from a skin surface. These devices, methods, and systems use one or more gradients to direct sweat to a target location. In some variations, the sweat is passively directed to the target location. After the sweat has been collected at the target location, the sweat is evaluated for its concentration of the selected analyte or analytes. Also described here are methods of manufacturing devices having one or more gradients that are configured to direct sweat to a target location.

[0023] FIG. 1 illustrates different routes by which glucose in blood migrates to the skin (114). As shown in FIG. 1, glucose in blood (102) passes either to the interstitial fluid (104) or to sweat glands (108). The glucose then reaches the skin surface either through passive diffusion from the interstitial fluid (104) through the stratum corneum (as epidermal contaminants (110) resulting from desquamation of the stratum corneum), or via sweat glands (108).

[0024] When glucose in blood (102) passes to the interstitial fluid (104), the glucose levels in the blood and the interstitial fluid reach an equilibrium over time. The period of time over which this equilibrium is established is relatively short (on the order of five to ten minutes in healthy subject). However, the glucose derived from the interstitial fluid also is transported through the stratum corneum to the skin surface via diffusion (106). The relative impermeability of the stratum corneum and/or the high quality barrier function of intact stratum corneum tissue result in significant time delay for the passage of glucose across the stratum corneum by transdermal diffusion. As a result, the level of glucose that reaches the skin surface via transdermal diffusion (106) at a given time corresponds to a blood glucose level from several hours prior. This time delay renders measuring transdermally diffused glucose for medical diagnostic purposes unsuitable.

[0025] Glucose may also arrive on the skin surface via the process of stratum corneum desquamation, which results in epidermal contaminants (110) and the like. For example, epidermal glucose can be generated from the specific enzymatic cleavage of certain lipids. This produces free glucose, a source of energy for the upper layers of the epidermis, which are avascular and therefore not perfused with blood. This free glucose is not representative of the corresponding glucose levels in the blood, or of the interstitial glucose values. As such, the amount of such glucose that is found on the skin surface is unsuitable for evaluating glucose concentration in blood.

[0026] However, the sweat glands (108) function as shunts that traverse the stratum corneum, thereby allowing mass transport of material through an otherwise relatively impermeable barrier. Glucose from the interstitial fluid is the primary source of energy for the work-or-pump function of the eccrine sweat glands (108). The sweat secreted by the eccrine sweat glands leaves the body through tiny pores or orifices on the skin surface and contains a fraction of glucose from the blood (102). A fraction of the secreted sweat may be re-absorbed by the stratum corneum — the amount of glucose back-absorbed into the stratum corneum varies throughout the day. In addition, the water in sweat may extract glucose from the stratum corneum. Thus, without blocking the back transfer of glucose between sweat and the stratum corneum, it may be difficult to develop an instrument that could correlate the glucose on the skin with that in the blood.

[0027] Cunningham and Young measured the glucose content in the stratum corneum using a variety of methods including serial tape stripping and aqueous extraction, and found approximately ten nanograms per square centimeter per micron of depth of stratum corneum. See Cunningham, D. D. and Young, D. F., "Measurements of Glucose on the Skin Surface, in Stratum Corneum and in Transcutaneous Extracts: Implications for Physiological Sampling", CHn. Chem. Lab Med, 41, 1224-1228, 2003, which is hereby incorporated by reference. In their experiments in collecting and harvesting glucose from the skin surface, Cunningham and Young found that the stratum corneum was the source of epidermal contaminants on the skin surface, and that these contaminants were not correlatable to blood glucose. [0028] The glucose from epidermal contaminants typically reflects glucose abundance in the tissue anywhere from days to weeks prior to its appearance during desquamation, since epidermal turnover occurs approximately every 28 days. See, e.g., Rao, G. et al., Reverse iontophoresis: noninvasive glucose monitoring in vivo in humans," Pharm. Res., 12, 1869- 1873 (1995), which is hereby incorporated by reference. In a like manner, it is unlikely that glucose brought to the skin surface via diffusion (106) can be correlated to blood glucose. In addition, because the glucose has to traverse the tortuous path of the skin layers to reach the surface, the glucose brought to the skin surface via diffusion often results in a lag time (e.g., in the range of a few hours to a few days), which is undesirable for purposes of monitoring blood glucose levels.

[0029] In view of the foregoing, in order for a device to be effective in measuring the level of glucose in the blood (102) using sweat (112), it is desirable to isolate the glucose in sweat from epidermal contaminants (110) and glucose brought to the skin surface via diffusion (106). The devices, systems, and methods described herein provide for such isolation and measurement of glucose in sweat. Moreover, the devices, systems, and methods described herein operate in a relatively simple and efficient manner, and can provide for the relatively cost-effective evaluation of blood glucose levels. For example, certain of the devices, systems, and/or methods described herein may allow for the passive collection of sweat from a skin surface, and the relatively simple evaluation of that sweat for glucose concentration.

[0030] In general, the devices described here have any suitable configuration that includes one or more gradients. The gradients in turn are configured to direct sweat to target location, where the collected sweat will then be evaluated to determine the corresponding blood glucose concentration.

[0031] FIGS. 2A & 2B depict one variation of such a sweat collection device which, as shown there, is in the form of a patch (200). In FIG. 2A, patch (200) is illustrated as being affixed to a fingertip (202). However, patch (200) may be placed in any location that is suitable for collecting sweat, including without limitation a wrist or other area of the arm, stomach, or leg. Patch (200) may also be any shape and/or size that is suitable for collecting a sufficient amount of sweat to evaluate blood glucose levels. In some variations, a patch such as patch (200) may have an area of less than about 20 cm², such as about 3 cm². While the devices described here generally are in the form of patches, they need not be limited as such. Moreover, other possible forms of sweat-collection devices may include devices that are perfusion-based. Certain variations of perfusion-based sweat collection devices allow sweat to accumulate for a period of time (e.g., about 10 minutes or less), after which point a liquid (e.g., water or a buffer) is perfused across the surface and collected.

[0032] FIG. 2B shows a cross-sectional view of patch (200), as deposited on a skin surface (204) of fingertip (202). As shown in FIG. 2B, patch (200) includes a collection layer (206), a sweat-permeable membrane (208), an adhesive layer (210), and an interface layer (211). Patch (200) further includes a collection chamber (212), which in turn includes a constant volume chamber (214) and an overflow chamber (218). Collection chambers may, for example, be in the form of a tube, but need not be. Constant volume chamber (214) is defined by a detector (215) comprising electrodes (216) and (217). The dimensions of electrodes (216) and (217) define a space therebetween (illustrated with dashed lines in FIG. 2B) in which a constant volume of sweat can be evaluated at any time when patch (200) is in use. Detector (215), which is configured to measure the amount of glucose in collected sweat samples, is connected to interface layer (211).

[0033] Referring back to FIG. 2A, patch (200), when viewed as affixed to fingertip (202), has a generally oval shape. However, and as described briefly above, a patch may have any suitable shape. For example, FIG. 3 A shows a circular patch (302), FIG. 3B shows another variation of an oval patch (304), and FIG. 3C shows a patch (306) having an oblong shape. In some variations, a patch may have an angular shape, such as a polygonal shape. For example, FIG. 3D shows a square patch (308), and FIG. 3E shows a rectangular patch (310). In certain variations, patches may have irregular shapes. Furthermore, patches may include fun designs thereon, or may have fun geometries (e.g., to entertain children). Examples of such patches include dinosaur-shaped patch (312), shown in FIG. 3F; spider-shaped patch (314), shown in FIG. 3G; and train-shaped patch (316), shown in FIG. 3H.

[0034] The patches described herein also have one or more gradients located on at least one surface of the patch. For example, and referring back to FIG. 2B, patch (200) may include a gradient located on a patch surface (220) that is configured to contact skin surface (204) when patch (200) is affixed to finger (202). The proximity of the gradient to the skin surface can allow sweat that is excreted from the skin surface to contact patch surface (220) and travel along the gradient on the patch surface in a specific direction, as determined by the gradient. [0035] The gradients used with the patches described herein may include any type of gradient that is capable of directing sweat toward a collection location, including but not limited to chemical, pressure, and electrical gradients. A chemical gradient may be configured, for example, such that surface energy changes occur where water is attracted toward a hydrophilic domain. A pressure gradient may employ high pressure to induce fluid flow. An electrical gradient, in turn, may induce flow of molecules in response to an electrical field, such as iontophoresis or electro-osmosis. In some variations, the gradients are configured to passively direct sweat toward a collection location (e.g., without requiring energy input, such as the use of a pump). In such variations, the gradients may be in the form of, for example, surface energy gradients.

[0036] The gradients may take on any of a number of different configurations, certain variations of which are shown in FIGS. 4A-4E. FIGS. 4A-4E illustrate gradients on skin- contacting surfaces of various patches. In FIG. 4A, a patch (400) includes a gradient (402) formed on a skin-contacting surface (404) of the patch. As shown, gradient (402) is formed of pie-shaped hydrophobic regions (406) separated by hydrophilic radial spokes (408). At the center of skin-contacting surface (404) is a collection location (410), from which hydrophilic radial spokes (408) radially project. Gradient (402) is formed as a result of an increase in the overall hydrophilicity of skin-contacting surface (404), moving from the outer boundary of skin-contacting surface (404) toward collection location (410). Hydrophilicity and hydrophobicity may be evaluated, for example, by measuring the water advancing contact angle on a surface. See, e.g., Zhao et al., "Surface-Directed Liquid Flow Inside Microchannels," Science, 291, 1023-1026 (2001), which is hereby incorporated by reference. A hydrophobic material will have a relatively high contact angle (e.g., about 90°) in comparison to a hydrophilic material, since water tends to bead up when it contacts a hydrophobic surface. The presence of gradient (402) causes sweat that is collected from the skin surface to which patch (400) is applied to be directed toward collection location (410), since the sweat is drawn toward the more hydrophilic regions of skin-contacting surface (404), and away from its more hydrophobic regions. As a result, patch (400) may provide for the passive collection of sweat from a skin surface.

[0037] While the spokes shown in FIG. 4A project from the center of patch (400) in straight lines, other forms of spokes may be used. As an example, spokes may project in spiral patterns, or in any other suitable patterns. Moreover, any appropriate number of spokes may be used, such as 1, 2, 3, 4, 5, or 10 spokes. Furthermore, although spokes (408) are described as being uniformly hydrophilic, spokes may, for example, become more hydrophilic as they near a collection location.

[0038] Although the gradients described here include both hydrophobic and hydrophilic surfaces, they need not include both. As an example, in some variations, a gradient may include only hydrophilic surfaces, with some of the hydrophilic surfaces being more hydrophilic than others. Similarly, a gradient may include only hydrophobic surfaces, with some of the hydrophobic surfaces being more hydrophobic than others. As such, any gradient that is described here as including hydrophilic and hydrophobic surfaces may also be created using only hydrophilic surfaces or only hydrophobic surfaces.

[0039] Any of a number of appropriate methods may be used to create a gradient. For example, some methods of forming a gradient such as gradient (402) above may include covering a hydrophobic material (e.g., a medical-grade polymer such as medical-grade silicone) with a protective resist layer (e.g., a photoresist), and then selectively removing portions of the resist layer. The portions that are selectively removed may be removed using, for example, an ablation method (e.g., photoablation) and/or by exposing the portions to light followed by a washing process. The resulting exposed areas are then chemically derivatized to make them hydrophilic. Other methods for forming patches having gradients include depositing a hydrophilic or chemically derivatizing material onto a hydrophobic surface (e.g., to form hydrophilic spokes). For example, medical-grade silicone adhesives, which are highly hydrophobic, may be made more hydrophilic by oxidization using oxygen and/or other appropriate oxidizing agents. In some variations, one or more methods that are used to form printed circuits may be applied to forming a gradient. While silicone has been described as an appropriate hydrophobic material, other appropriate hydrophobic materials, such as other medical-grade hydrophobic polymers, may be used.

[0040] FIG. 4B illustrates another variation of a gradient (420) on a skin-contacting surface (422) of a patch (424) having a central collection location (426). Gradient (420) includes concentric rings (428) that increase in hydrophobicity from the outer boundary of patch (424) toward collection location (426). In other words, the ring that is farthest from collection location (426) is the least hydrophilic or most hydrophobic, and the ring that is closest to collection location (426) is the most hydrophilic or least hydrophobic. [0041] Gradients including concentric rings may be manufactured by a number of different methods. One such method includes forming a skin-contacting surface of a patch from a hydrophobic material, and then masking the hydrophobic material with a protective resist layer (e.g., a photoresist). A circle of the resist layer surrounding a collection location on the skin-contacting surface is then removed, and the resulting exposed hydrophobic material is derivatized. A larger circle of the resist layer is then removed, and once again, the resulting exposed material is derivatized. The process is repeated according to the desired number of concentric rings. As a result, during the process, the areas nearest the collection location may be derivatized multiple times (depending on the desired number of concentric rings). The repeated derivatization of these rings causes them to become more hydrophilic than the surrounding rings, which are not exposed to as much derivatization. Other methods of forming gradients may include layering or depositing rings of materials of different hydrophilicity onto a surface. Still other methods include selectively derivatizing rings of a hydrophobic material with different derivatizing agents.

[0042] FIG. 4C depicts a variation of a gradient similar to the gradient shown in FIG. 4B. However, rather than including distinct gradient steps, gradient (440) of FIG. 4C is continuous. As shown in FIG. 4C, a patch (442) has a skin-contacting surface (444) including gradient (440). Gradient (440) is generally hydrophobic in its outer region (446). However, gradient (440) gradually transitions to being hydrophilic as the collection location (448) at the center of skin-contacting surface (444) is neared. This transition may be linear, but need not be. Indeed, the gradient may make any suitable transition, for example becoming exponentially more hydrophilic approaching the collection location (448).

[0043] There are a number of methods by which a continuous gradient may be formed. In some methods, a continuous gradient may be formed using a deposition method (e.g., vapor deposition) to deposit a hydrophilic substance onto a hydrophobic surface. Other methods may include positioning a volatile derivatizing agent in proximity to a hydrophobic surface (e.g. a silicone surface) for a period of time. During this period of time, the volatile derivatizing agent may derivatize regions of the hydrophobic surface that are closest to it to a greater extent than regions of the hydrophobic surface that are farther away. As a result, the closer regions may become more hydrophilic than the farther away regions.

[0044] Additional methods of forming gradients include printing methods. As an example, in some variations, a printer, such as an ink jet printer, may be used to form a gradient. See, e.g., Lam et al., "Surface-Tension Controlled Microfluidics," Langmuir 2002, 18, 948-951, which discloses forming surface-tension-confined microfluidics devices by patterning surfaces with a Hewlett-Packard plotter and a modified pen, and which is hereby incorporated by reference. Methods of forming gradients are also described, for example, in Chuang et al., "A Spontaneous and Passive Waste-Management Device (PWMD) for a Micro Direct Methanol Fuel Cell," J. Micromech. Microeng. 17 (2007) 915-922, which is hereby incorporated by reference. Additionally, methods of forming hydrophobic and hydrophilic regions are described, for example, in Zhao et al., "Surface-Directed Liquid Flow Inside Microchannels," Science, 291, 1023-1026 (2001), which was previously incorporated by reference, and in Yao et al., "Micro-Electro-Mechanical Systems (MEMS)-Based Micro- Scale Direct Methanol Fuel Cell Development," Energy 31 (2006), 636-639, which is hereby incorporated by reference.

[0045] As discussed above, although the gradients shown in FIGS. 4A-4C are located on circular patches, gradients may be created on patches of any shape. For example, FIG. 4D shows a rectangular patch (460) having a skin-contacting surface (462) with a continuous gradient, and FIG. 4E similarly shows a rectangular patch (480) having a skin-contacting surface (482) with a continuous gradient. Gradients created from concentric rings, as well as radial spokes, or gradients having any other suitable configuration, may also be created on non-circular or circular patches. Moreover, while the collection locations shown in FIGS. 4A-4D are centrally located, collection locations may be located in any appropriate on a patch. For example, patch (480) of FIG. 4E has a collection location (484) that is not centrally located. Additionally, some variations of patches may have multiple collection locations, and/or multiple gradients.

[0046] FIGS. 5 A and 5B each illustrate cross-sectional views of a patch (500) and a patch (502), respectively. Patch (500) comprises a collection layer (504), a sweat-permeable membrane (506), an adhesive layer (508), an interface layer (510), and a collection chamber (512). Collection chamber (512) further includes a constant volume chamber (514). An overflow chamber (516) is configured to collect additional sweat when the capacity of the rest of the collection chamber has been exceeded. Patch (500) also includes a detector (517) that comprises electrodes (518) and (520), and that is connected to interface layer (510).

[0047] Similarly, patch (502) comprises a collection layer (554), a sweat-permeable membrane (556), an adhesive layer (558), an interface layer (560), and a collection chamber (562). Collection chamber (562) further includes a constant volume chamber (564). An overflow chamber (566) is configured to collect additional sweat when the capacity of the rest of the collection chamber has been exceeded. Patch (502) also includes a detector (567) that comprises electrodes (568) and (570), and that is connected to interface layer (560).

[0048] The sweat-permeable membranes of patches (500) and (502) are permeable to sweat, but act as barriers to epidermal contaminants, such as those contaminants brought to the skin surface via desquamation. The sweat-permeable membranes also act as barriers to non-correlatable glucose brought to the skin surface via diffusion. In this way, non- correlatable glucose, and otherwise interfering glucose, does not pass into the collection chamber, and does not get measured. The sweat-permeable membranes may also aid in preventing or minimizing the reabsorption of glucose that has been brought to the skin surface via sweat, in the outer layer of the stratum corneum.

[0049] In general, sweat-permeable membranes that are included in the devices described herein may comprise any material that allows sweat to pass therethrough, is non-toxic, and prevents reabsorption of the sweat into the skin. For example, some variations of sweat- permeable membranes may be in the form of a hydrophobic coating or a porous hydrophobic film. In variations that are in the form of a film, the film should be thick enough to coat the skin, but thin enough to allow sweat to pass therethrough. Examples of hydrophobic materials that may be used to form sweat-permeable membranes include petrolatum, paraffin, mineral oils, silicone oils, vegetable oils, waxes, and the like.

[0050] While the sweat-permeable membranes shown in FIGS. 5A and 5B are shown as being located above the patches' adhesive layers, certain variations of sweat collection devices may include sweat-permeable membranes that are located elsewhere. In some variations, a sweat-permeable membrane may be in the form of an oil and/or petrolatum coating applied to the skin surface. In this way, only that glucose that comes to the skin surface via the eccrine sweat gland will be detected. Similarly, a liquid polymer coating, or a liquid bandage may be used as a sweat-permeable membrane. Typically, these materials are liquid membranes with low surface tension, which leave openings over the sweat gland pores when they cure (e.g., silicon polymers such as SIGARD®). Liquid polymer coatings have significant advantages in that they are impermeable to water everywhere except the sweat gland pores. However, in some variations, a polymer layer with micropores may be used. An example of such a polymer layer is a Whatman NUCLEOPORE® polycarbonate track- etch membrane filter. Other suitable sweat-permeable membranes include ANOPORE® inorganic membranes consisting of a high-purity alumina matrix with a precise non- deformable honeycomb pore structure.

[0051] While the sweat-permeable membranes shown in FIGS. 5A and 5B are separate from the patches' adhesive layers, this need not be the case. As an example, in some variations, an adhesive polymer may be combined with the liquid polymers described above. In such variations, the liquid polymer would begin to cure (or set up as a solid) when exposed to oxygen (e.g., when a release liner covering the combined liquid polymer and adhesive polymer is removed). The layer would cover the epidermis, but would leave holes only over the sweat gland orifices. In this way, only glucose brought to the skin surface via the sweat glands would be passed through to the collection layer. As noted above, in addition to allowing glucose in sweat to be transported to the skin surface, a sweat-permeable membrane may also be useful in blocking diffusion and in blocking the generation of epidermal debris resulting from desquamation. Accordingly, only the glucose from the sweat, which can be correlated with blood glucose, will be measured. While patches including sweat-permeable membranes have been described, some variations of sweat collection devices may not include any sweat-permeable membranes.

[0052] Adhesive layers, such as adhesive layers (508) and (558), may comprise an annular overlay layer, or may comprise a layer of adhesive contemporaneous and coextensive with at least one other patch layer. Any suitable adhesive may be used. For example common pressure-sensitive adhesives known in the transdermal patch arts, such as silicone, polyacrylates, and the like, may be used. In some circumstances, it may be desirable to provide an adhesive layer, or an adhesive and sweat-permeable barrier combination layer, that is relatively dry. This is because it is thought that excessive wetting of the stratum corneum may inhibit sweat gland function. See, e.g., Nadel, E. R. and Stolwijk, J.A.J., "Effect of skin wettedness on sweat gland response," J. Appl. Physiol, 35, 689-694, 1973, which is hereby incorporated by reference. In addition, the excessive wetting of the skin may help aid the liberation of glucose on the skin, resulting from desquamation. Accordingly, it may be desirable to limit the aqueous or otherwise wet nature of the interface between the skin and the patch.

[0053] While not shown in the figures, a sweat collection device such as a patch may also include at least one release liner, as briefly described above. For example, an adhesive layer on a patch may be temporarily covered by a release liner that protects the adhesive layer from losing its adhesive properties during storage and prior to use. When the patch is ready for use, the release liner may be removed (e.g., peeled off) to expose the adhesive layer, thereby allowing the patch to be adhered to a skin surface. Similarly, a release liner may be placed on top of an interface layer of a patch to protect optical or electrical components contained therein. In some variations, no release liner is used, and the interface layer may be topped with a backing layer (a topmost layer that is integral to the patch). In certain variations, the backing layer is made from a woven or non-woven flexible sheet, such as those known in the art of transdermal patches. In other variations, the backing layer is made from a flexible plastic or rubber.

[0054] In certain variations, a patch may comprise a component to induce sweat by physical, chemical, or mechanical methods. For example, in one variation, a patch comprises pilocarpine and a penetration or permeation enhancer to induce sweat chemically or pharmacologically. The use of a penetration enhancer can help increase the rate at which the pilocarpine enters the body and thereby, increase the onset of the enhanced sweat response. Examples of suitable permeation enhancers include, but are not limited to, ethanol and other higher alcohols, N-decylmethylsulfoxide (nDMS), polyethylene glycol monolaurate, propylene glycol monolaurate, dilaurate and related esters, glycerol mono-oleate and related mono-, di-, and trifunctional glycerides, diethyl toluamide, alkyl or aryl carboxylic acid esters of polyethyleneglycol monoalkyl ether, and polyethyleneglycol alkyl carboxymethyl ethers. Pilocarpine may also be driven into the skin using iontophoresis. It has been shown that the infusion of pilocarpine into the skin using iontophoresis increases the amount of sweat by about 20-fold per unit area. Similarly, other chemicals may be introduced into the skin to increase the sweat response.

[0055] In some variations, a patch may comprise a component that increases the sweat response by initiating a local temperature increase. For example, a heater (e.g., an electrical resistance heater) may be used to increase the skin surface temperature and thus increase sweating. Thermal induction of a sweat response may also be achieved by the application of energy (e.g., in the visible or near infrared regions). For example, a lamp may be used to generate heat and induce sweating.

[0056] Direct electrical stimulation (i.e., Faradic stimulation) may alternatively or additionally be used to induce a sweat response. Similarly, a chemical compound, or a combination of compounds, may be used to initiate a local temperature increase and therefore induce or increase the sweat response. As an example, a patch may include two chemical compounds, separated by a thin membrane. The membrane may be removed by a pull-tab when the patch is adhered to the skin, thereby bringing the compounds into contact with each other, and causing an exothermic reaction. In this way, a source of heat is provided.

[0057] Physical mechanisms of inducing or increasing sweat may also be used. For example, in one variation, a measurement device (described in further detail below) is brought into contact with a patch, and force is applied to the patch in a manner sufficient to cause an increase in the transport of sweat to the skin. The applied pressure over the patch results in fluid from the sweat gland lumen being expressed and delivered to the skin surface. In addition, the measurement device could include a suction or vacuum mechanism, which in combination with the applied pressure would result in a larger amount of sweat being delivered to the collection layer of the patch. Vibration may also be used to induce sweat.

[0058] Sweat may also be induced by the use of an occlusive layer within the patch, which inhibits evaporative loss from the skin surface and thereby permits a more efficient sweat accumulation into the patch collection layer. This occlusive layer may comprise an element within the patch, or may be a removable overlay which is separated from the patch prior to use of the measurement device. This occlusive layer may be, e.g., a thin polyvinyl film or some other suitable water vapor-impermeable material.

[0059] As illustrated in FIGS. 6A-6C, sweat collection devices, such as patches, may employ different types of detectors and/or constant volume chambers. Several types of suitably sensitive detectors may be used. For example, FIGS. 6 A and 6B show electrochemical detectors, while FIG. 6C shows an optical detector. These figures are all discussed in further detail below. In some variations, a sweat collection device may include a combination of different types of detectors, such as both electrochemical detectors and optical detectors. Suitable electrochemical detectors may be those comprising an immobilized glucose oxidase or other enzyme(s) in or on a polymer or other support, and those comprising glucose oxidase or other enzyme(s) in a microfluidic configuration. Optical detectors may include, for example, detectors that are fluorescent-based (e.g., based on enhanced or suppressed fluorescence of a glucose-sensitive fluorescent molecule), or other appropriate optical detectors. [0060] Referring again to FIG. 6A, a collection chamber (600) includes a constant volume chamber (602) defined by an electrochemical detector (604) comprising two electrodes (606) and (608). Collection chamber (600) further includes additional portions (610) and (612). As shown in FIG. 6A, constant volume chamber (602) has an enlarged width relative to additional portions (610) and (612), but this need not be the case. For example, FIG. 6B shows a collection chamber (620) including a constant volume chamber (622) defined by an electrochemical detector (624) comprising two electrodes (626) and (628). Collection chamber (620) further includes an additional portions (630) and (632) having the same width as constant volume chamber (622).

[0061] The electrochemical detectors described herein may be polymer-based, based on microfluidics, and the like. Electrochemical detectors that are polymer-based include polymer layers that are deposited on at least a portion of the constant volume chambers. The polymer(s) in such polymer layers are typically permeable to glucose. Additionally, one or more glucose-reactive enzymes are immobilized on or within the polymer layers. The interface layers (not shown in FIGS. 6 A and 6B) and electrochemical detectors include at least two electrodes. One or more of the electrodes may, for example, have an area of about 1 square millimeter, and/or may be formed of materials such as platinum, paladium, or iridium. Generally, the electrodes are aligned with each other to define a measurement volume therebetween. The electrodes may be added to the devices using, for example, screen-printing and/or vapor deposition methods. These electrodes are typically activated by a measurement device when the measurement device is brought into electrical contact with the patch.

[0062] In certain variations, the devices use glucose oxidase, an enzyme that produces hydrogen peroxide. This hydrogen peroxide reacts at one or more of the electrodes to produce a measurable electrical current proportional to the glucose concentration. That is, using an enzymatic process known in the art, the glucose oxidase catalyzes the reaction of glucose and oxygen to produce gluconic acid and hydrogen peroxide. The hydrogen peroxide is then electrochemically reduced at the electrode, producing two electrons for detection. The electrical contact between the measurement device and the patch may also serve to provide power to the patch, although the patch may include a battery therein. The measurement device interrogates the patch (i.e., the detector) and provides a single discrete reading. [0063] Sensitivity to electrochemical detectors may be increased by increasing one or more of the temperature during the detection cycles, the length of the detection cycles, or the area of the detectors, by appropriately selecting the operating potential, and/or by the use of selective membranes to screen interfering substances such as ascorbic acid, uric acid, acetaminophen, etc. In addition, differential methods may be used where a glucose sample is measured in the presence and absence of a glucose-specific enzyme and the glucose concentration is determined from the difference between these two signals.

[0064] As discussed above, in some variations, a sweat collection device may include one or more optical detectors. For example, FIG. 6C shows a fluorescent detector (680) including a light source (682) and an optical detector (684). Light source (682) and optical detector (684) may be any suitable devices, for example, an LED and a spectrometer. In these variations, a beam of light is passed through the constant volume chamber (692), and the fluorescence is measured by optical detector (684).

[0065] The non-invasive glucose measuring system may also include a measurement device, such as measurement device (700) shown in FIG. 7, which interrogates a patch to measure glucose. Measurement device (700) measures the total quantity of glucose present in a fixed volume, and then converts the glucose measurement into a concentration. In general, the measurement device typically includes a display (704), to display data. The device may also include warning indicators (e.g., a word prompt, flashing lights, sounds, etc.) to indicate that a user's glucose levels are dangerously high or dangerously low. In addition, and as described briefly above, the measurement device may also be configured to verify that a skin-cleaning procedure has been performed. For example, when wipes with a marker have been used, the marker remains on the skin surface. If measurement device (700) detects the marker, then the measurement proceeds. If measurement device (700) does not detect the marker, then the measurement does not proceed. In one variation, measurement device (700) provides an indication to the user that the skin surface must be cleaned prior to use (e.g., using a word prompt, colored or flashing lights, or various sounds). Measurement device (700) may also comprise an iontopheric source, for example, to be used to help drive pilocarpine, or other molecules of interest, into the skin.

[0066] The configuration of measurement device (700) may depend on the configuration of the detector that is used in the patch. For example, when measurement device (700) is to be used with an electrochemical detector, measurement device (700) may provide an electrical contact with the interface layer, and may either be powered by the electrical contact or by an independent power source (e.g., a battery within the patch itself, etc.). Measurement device (700) also typically comprises a computer processor to analyze data. Conversely, when measurement device (700) is configured for optical detection, measurement device (700) is configured to provide optical contact or interaction with the interface layer. In this variation, measurement device (700) also typically comprises a light source to stimulate fluorescence or absorbance. In other variations, measurement device (700) may include contacts to detect a signal from an optical detector contained within patch (702), or contacts to provide power to a light source and optical detector contained within patch (702). In some variations, measurement device (700) comprises both the necessary electrical contacts and the necessary optics so that a single measurement device (700) may be used with a patch having various configurations of patch layers (e.g., one layer comprising a fluorescent-based molecule, and another layer comprising an electrochemical detector).

[0067] Measurement device (700) further comprises computer-executable code containing a calibration algorithm, which relates measured values of detected glucose to blood glucose values. In some variations, the algorithm may be a multi-point algorithm, which is typically valid for about 30 days or longer. For example, the algorithm may necessitate the performance of multiple capillary blood glucose measurements (e.g., blood sticks) with simultaneous patch measurements over about a 1-day to about a 3 -day period. This could be accomplished using a separate dedicated blood glucose meter provided with the measurement device described herein, which comprises a wireless (or other suitable) link to the measurement device. In this way, an automated data transfer procedure is established, and user errors in data input are minimized.

[0068] Once a statistically significant number of paired data points have been acquired having a sufficient range of values (e.g., covering changes in blood glucose of about 200 mg/dl), a calibration curve will be generated, which relates the measured sweat glucose to blood glucose. Patients can perform periodic calibration checks with single blood glucose measurements, or total recalibrations as desirable or necessary.

[0069] Measurement device (700) may also comprise memory, for saving readings and the like. In addition, measurement device (700) may include a link (wireless, cable, and the like) to a computer. In this way, stored data may be transferred from measurement device (700) to the computer, for later analysis, etc. Measurement device (700) may further comprise various buttons, to control the various functions of the device and to power the device on and off when necessary.

[0070] As noted above, methods for measuring glucose from sweat collected from the skin surface are also provided here. Some methods generally comprise cleaning the skin surface with a glucose solvent, collecting sweat from the skin surface using a gradient, and measuring the collected glucose.

[0071] Cleaning the skin surface (e.g., by wiping it clean) is typically performed to remove any "old" or residual glucose remaining on the skin, hi variations in which a wipe is used, the wipe is typically made of a material suitable for wiping the skin and comprises a solvent for removing glucose. For ease of description only, the term "wipe" will be used herein to include any type of fabric, woven, non- woven, cloth, pad, polymeric or fibrous mixture, and similar such supports capable of absorbing a solvent or having a solvent impregnated therein.

[0072] In certain variations, the skin is cleaned by rinsing or otherwise treating it with a glucose solvent to remove potentially contaminating residual glucose. After cleaning the skin, it may be dried (or allowed to dry), removing excess cleaning solution. A separate drying step is unnecessary in some variations.

[0073] In some variations, the sweat collection devices described herein may be used to collect a quantity of sweat that is in the microliter range, or that is even smaller. For example, in certain variations, a sweat collection device, such as a patch, may be used to collect less than 20 microliters of sweat (e.g., less than 1 microliter of sweat). In some variations, a sweat collection device may be designed to collect a relatively large volume of sweat, such as from about 50 to about 100 microliters of sweat.

[0074] While patches are generally described herein, the methods, devices, and systems described herein may also be applicable to other types of sweat collection devices, and are not limited to sweat collection devices that are in the form of a patch.

[0075] Moreover, while the measurement of glucose has generally been described here, other analytes may be measured using the devices, systems, and/or methods described herein. Non-limiting examples of such analytes include lactic acid, cholesterol, and substances of abuse. [0076] While certain variations of sweat collection devices (e.g., patches) and related systems and methods are disclosed herein, further variations of sweat collection devices and related systems and methods are disclosed, for example, in U.S. Patent Application Serial Nos. 11/159,587 and 11/451,738, both of which are hereby incorporated by reference in their entireties.

[0077] While devices, systems, and methods have been described in some detail here by way of illustration and example, such illustration and example is for purposes of clarity of understanding only. It will be readily apparent to those of ordinary skill in the art in light of the teachings herein that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A system for collecting sweat, comprising: a sweat collection device comprising a gradient and defining a collection location, wherein the gradient is configured to direct sweat toward the collection location when the sweat collection device is applied to a skin surface.

2. The system of claim 1, wherein the sweat collection device comprises a patch.

3. The system of claim 2, wherein the patch is circular.

4. The system of claim 2, wherein the patch is rectangular.

5. The system of claim 2, wherein the patch is oval.

6. The system of claim 1, wherein the sweat collection device is configured to passively collect sweat.

7. The system of claim 1, wherein the gradient comprises a surface energy gradient.

8. The system of claim 1, wherein the gradient comprises a radial gradient.

9. The system of claim 1, wherein the gradient comprises at least one hydrophilic portion.

10. The system of claim 9, wherein the gradient further comprises at least one hydrophobic portion.

11. The system of claim 1 , wherein the gradient comprises a hydrophilic portion, and a hydrophobic portion at least partially surrounding the hydrophilic portion.

12. The system of claim 1, wherein the gradient comprises a plurality of hydrophilic portions in the form of spokes radially projecting from the collection location.

13. The system of claim 12, wherein the sweat collection device further comprises at least one collection chamber that is disposed in the collection location.

14. The system of claim 1 , wherein the gradient comprises hydrophobic portions and hydrophilic portions in the form of concentric rings.

15. The system of claim 14, wherein the sweat collection device further comprises at least one collection chamber that is disposed in the center of the concentric rings.

16. The system of claim 14, wherein the hydrophilicity of the sweat collection device increases from an outer region of the sweat collection device to an inner region of the sweat collection device, and the hydrophobicity of the sweat collection device decreases from an outer region of the sweat collection device to an inner region of the sweat collection device.

17. The system of claim 1 , wherein the gradient is located on an exterior surface of the sweat collection device, and is configured to be placed in contact with the skin surface.

18. The system of claim 1, further comprising a collection chamber.

19. The system of claim 18, wherein the collection chamber is positioned at the collection location.

20. The system of claim 18, wherein the collection chamber is configured to collect a fixed volume of sweat from the skin surface.

21. The system of claim 18, wherein the system further comprises an overflow chamber.

22. The system of claim 21, wherein the overflow chamber is in fluid communication with the collection chamber.

23. The system of claim 22, wherein the collection chamber is positioned at the collection location.

24. The system of claim 1, wherein the collection location is centrally located in or on the sweat collection device.

25. The system of claim 1, wherein the sweat collection device further comprises a sweat- permeable membrane configured to act as a barrier to epidermal contaminants and glucose brought to the skin surface via diffusion.

26. The system of claim 25, wherein the gradient is located adjacent to the sweat-permeable membrane.

27. The system of claim 25, wherein the sweat-permeable membrane comprises a material that is generally occlusive, but allows sweat to pass therethrough.

28. The system of claim I₅ wherein the sweat collection device is configured to collect an amount of sweat from the skin surface, and the sweat collection device further comprises a detector.

29. The system of claim 28, wherein the detector comprises an electrochemical detector.

30. The system of claim 28, wherein the detector comprises an optical detector.

31. The system of claim 28, wherein the detector is configured to detect and measure quantities of one or more substances from the amount of sweat collected from the skin surface.

32. The system of claim 28, wherein the detector is configured to detect and measure glucose collected from the skin surface.

33. The system of claim I₅ wherein the sweat collection device is configured to collect less than 20 microliters of sweat.

34. The system of claim I₅ wherein the sweat collection device is configured to collect less than 1 microliter of sweat.

35. The system of claim I₅ wherein the sweat collection device further comprises an adhesive configured to adhere the sweat collection device to the skin surface.

36. The system of claim 1, further comprising a measurement device configured to interrogate the sweat collection device to measure a concentration of an analyte in the sweat.

37. A sweat collection device, comprising: a gradient, wherein the sweat collection device defines a collection location, and the gradient is configured to direct sweat toward the collection location when the sweat collection device is applied to a skin surface.

38. The sweat collection device of claim 37, wherein the sweat collection device comprises a patch.

39. The sweat collection device of claim 38, wherein the gradient comprises a surface energy gradient.

40. The sweat collection device of claim 37, further comprising a collection chamber.

41. The sweat collection device of claim 37, further comprising a sweat-permeable membrane configured to act as a barrier to epidermal contaminants and glucose brought to the skin surface via diffusion when the sweat collection device is applied to the skin surface.

42. A method, comprising: applying a system comprising a sweat collection device to a skin surface, wherein the sweat collection device comprises a gradient configured to direct sweat toward a collection location.

43. The method of claim 42, wherein the sweat collection device comprises a patch.

44. The method of claim 42, wherein the sweat collection device collects a sweat sample from the skin surface.

45. The method of claim 42, wherein the sweat collection device further comprises a detector.

46. The method of claim 45, wherein the detector comprises an electrochemical detector.

47. The method of claim 45, wherein the detector comprises an optical detector.

48. The method of claim 42, wherein the sweat collection device further comprises a collection chamber configured to collect sweat.

49. The method of claim 42, wherein the sweat collection device is configured to passively collect sweat.

50. The method of claim 42, further comprising cleaning the skin surface prior to applying the sweat collection device to the skin surface.

51. The method of claim 42, further comprising inducing sweat from the skin surface.

52. A method of making a system for collecting sweat, the method comprising: forming a sweat collection device comprising a gradient and defining a collection location, wherein the gradient is configured to direct sweat toward the collection location when the sweat collection device is applied to a skin surface.

53. The method of claim 52, wherein the sweat collection device comprises a patch.

54. The method of claim 52, wherein the method further comprises forming the gradient.

55. The method of claim 54, wherein forming the gradient comprises chemically derivatizing a surface of a material to form the gradient on the surface of the material.

56. The method of claim 55, wherein chemically derivatizing the surface of the material comprises masking a first region of the surface, leaving a second region of the surface exposed, and applying a derivatizing agent to the second region.

57. The method of claim 55, wherein chemically derivatizing the surface of the material comprises masking the entire surface, removing a region of the mask using photoablation, and applying a derivatizing agent to the photoablated region.

58. The method of claim 54, wherein forming the gradient comprises applying a first material to a surface of a second material.

59. The method of claim 58, wherein the first material is applied to the surface of the second material using vapor deposition.

60. The method of claim 58, wherein the first material is applied to the surface of the second material using a printer.