WO2010045247A1 - Sweat glucose sensors and collection devices for glucose measurement - Google Patents

Sweat glucose sensors and collection devices for glucose measurement Download PDF

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Publication number
WO2010045247A1
WO2010045247A1 PCT/US2009/060528 US2009060528W WO2010045247A1 WO 2010045247 A1 WO2010045247 A1 WO 2010045247A1 US 2009060528 W US2009060528 W US 2009060528W WO 2010045247 A1 WO2010045247 A1 WO 2010045247A1
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Prior art keywords
sweat
container
glucose
skin
skin patch
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PCT/US2009/060528
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French (fr)
Inventor
Russell O. Potts
James W. Moyer
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Vivomedical, Inc.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045Devices for taking samples of body liquids
    • A61B10/0064Devices for taking samples of body liquids for taking sweat or sebum samples
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/14517Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for sweat
    • A61B5/14521Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for sweat using means for promoting sweat production, e.g. heating the skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/683Means for maintaining contact with the body
    • A61B5/6832Means for maintaining contact with the body using adhesives
    • A61B5/6833Adhesive patches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0295Strip shaped analyte sensors for apparatus classified in A61B5/145 or A61B5/157
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • A61B2562/125Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes

Abstract

A sweat glucose sensor for determining the glucose concentration in a volume of sweat is disclosed. The sweat glucose sensor may comprise two or more electrodes in contact with sweat in a container defined by two or more layers of a skin patch. The container may additionally contain a glucose enzyme that reacts with glucose in sweat collected by the container. The reaction of the glucose in the sweat with the glucose enzyme may affect an electrical signal passed by the two or more electrodes. The electrical signal may then be used to determine a sweat glucose concentration. The sweat glucose sensor may comprise two or more fill electrodes, also positioned to contact sweat collected by the container. The fill electrodes may be used, for example, to determine whether the skin patch contains a requisite volume of sweat to perform an accurate glucose measurement. Devices, methods, and kits for collecting sweat that has come to a skin surface are also disclosed.

Description

SWEAT GLUCOSE SENSORS AND COLLECTION DEVICES FOR GLUCOSE MEASUREMENT

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 61/105,342 filed on October 14, 2008, the disclosure of which is incorporated by reference herein in its entirety.

FIELD

[0002] The present application relates generally to measuring the concentration of glucose in sweat that has come to a skin surface. More specifically, the present application relates to sweat collection devices that are attachable to a skin surface and capable of collecting a known volume of sweat that is less than one microliter, and/or that are capable of measuring the concentration of glucose in a fixed volume of sweat collected from the skin surface.

BACKGROUND

[0003] The American Diabetes Association reports that approximately 8.0% of the population in the United States, a group of 23.6 million people, has diabetes. Diabetes is a leading cause of death in the United States, and is a life-threatening disease with broad complications, which include blindness, kidney disease, nerve disease, heart disease, amputation, and stroke. Diabetes is believed to be a leading cause of new cases of blindness in individuals between the ages of 20 and 74, and is also a leading cause of end-stage renal disease. Additionally, a high percentage of people with diabetes have mild to severe forms of diabetic nerve damage. In severe forms, such diabetic nerve damage may lead to lower limb amputations. People with diabetes are also more likely to have heart disease and to suffer strokes than people without diabetes.

[0004] Diabetes results from the inability of the body to produce or properly use insulin, a hormone that regulates the level of glucose in the blood and the movement of glucose into cells. Although the cause of diabetes is not completely understood, it is believed that genetics, environmental factors, and viral causes contribute to the incidence of diabetes in the world population. [0005] There are two major types of diabetes: Type 1 and Type 2. Type 1 diabetes (also known as juvenile diabetes) is caused by an autoimmune process destroying the beta cells that secrete insulin in the pancreas. Type 1 diabetes most often occurs in young adults and children. People with Type 1 diabetes must take daily insulin injections to stay alive.

[0006] Type 2 diabetes, which is more common than Type 1 diabetes, is a metabolic disorder resulting from the body's inability to make enough, or to properly use, insulin. In the United States, Type 2 diabetes is nearing epidemic proportions, principally due to an increased number of older Americans and a greater prevalence of obesity and sedentary lifestyles.

[0007] Insulin, in simple terms, is a hormone that regulates the level of glucose in the blood and allows glucose to enter cells. In diabetics, glucose cannot enter the cells, so glucose builds up in the blood to toxic levels.

[0008] Diabetics having Type 1 diabetes are typically required to self- administer insulin using, for example, a syringe or a pen with needle and cartridge. Continuous subcutaneous insulin infusion via external or implanted pumps is also available. Diabetics having Type 2 diabetes are typically treated with changes in diet and exercise, as well as with oral medications. Many Type 2 diabetics become insulin-dependent at later stages of the disease. Diabetics using insulin to help regulate their blood sugar levels are at an increased risk for medically-dangerous episodes of low blood sugar due to errors in insulin administration, or unanticipated changes in insulin absorption.

[0009] It is highly recommended by medical professionals that insulin-using patients practice self-monitoring of blood glucose ("SMBG"). Based upon the level of glucose in the blood, individuals may make insulin dosage adjustments before injection. Adjustments are generally necessary since blood glucose levels vary day to day for a variety of reasons, such as exercise, stress, rates of food absorption, types of food, hormonal changes (pregnancy, puberty, etc.) and the like. Despite the importance of SMBG, several studies have found that the proportion of individuals who self-monitor at least once a day significantly declines with age. This decrease is likely that the result of the typical, most widely used, method of SMBG involving obtaining blood from a capillary finger stick.

[0010] Because SMBG can be painful, it would be desirable to provide non-invasive methods for measuring blood glucose levels. Using sweat is attractive at least because it can be collected non-invasively and because sweat glucose level is correlatable to blood glucose level. However, the glucose concentration in sweat is typically too low to detect using available techniques and devices. In addition, collecting a sample of sweat that can be used to accurately measure the sweat glucose level can be difficult, and sweat glucose is often contaminated with other sources of glucose on the skin's surface which do not correlate with blood glucose.

[0011] Current glucose sensors and measurement devices are used to measure glucose concentrations in blood. Normal blood glucose levels range between about 90 mg/dl and about 140 mg/dl or higher. By contrast, normal sweat glucose levels range between about 0.1 mg/dl and about 5 mg/dl. Because blood has a higher glucose concentration than sweat, blood glucose sensors are configured to measure relatively high concentrations of glucose. Additionally, blood glucose sensors typically require a redox mediator to facilitate electron transfer from the glucose, thereby allowing an electrical charge to be transmitted for the purpose of measuring glucose concentration. The redox mediator may regulate the rate of the glucose electron transfers to make the blood glucose concentration measurement more accurate.

[0012] With respect to sweat collection and evaluation, sweat may be excreted by sweat pores at a variable rate. For example, sweat production can vary significantly in the presence of physical or emotional stimulation such as activity level, stress, and heat. This variation may cause an inaccurate sweat glucose measurement as it can result in a fluctuation in the volume of sweat collected from the skin surface.

[0013] Additionally, collecting a fixed volume of sweat may be difficult as current collection devices may need to curve, bend, or twist to conform to a finger tip or other body surface, and the resulting deformation may change the volume of a container. Further, current collection devices are typically used to collect a large amount of sweat from the skin surface. For example, the MACRODUCT® sweat collection system by Wescor, Inc. (Logan, Utah) is capable of collecting up to sixty microliters of sweat regardless of the rate of sweat production. While using a large volume of sweat may decrease the effects of any variation in the collected volume, the amount of time required to collect the volume may increase.

[0014] In view of the above, it would be desirable to provide devices, methods, and kits for sensing and measuring the concentration of glucose in sweat (e.g., that has been collected from a skin surface). It would also be desirable to provide devices, methods, and kits for collecting a volume of sweat from a skin surface that is suitable for measuring the glucose concentration in the sweat, and for collecting small, fixed volumes of sweat without the collected sweat volumes being affected by a variable sweat rate.

SUMMARY

[0015] Skin patches, methods, and kits for sensing a concentration of glucose in sweat are provided. In some variations, the sweat glucose concentration may be measured based on a signal between two electrodes. In certain variations, a third electrode may be used as a reference electrode. In some variations, a skin patch including a container and the two electrodes placed on opposing sides of the container may be used to measure the sweat glucose concentration. The two electrodes may form a capacitor having electrical properties that change in response to the amount of glucose in the sweat. In certain variations, the skin patch may collect a fixed volume of sweat. In other variations, the volume of sweat collected by the skin patch may vary, and determining the glucose concentration in the volume of sweat may comprise measuring the volume of sweat. In some variations, the volume of the sweat may be relatively small (e.g., less than about 10 microliters, such as about 5 microliters, about 3 microliters, about 1 microliter, about 0.8 microliter, about 0.5 microliter, about 0.3 microliter, about 0.1 microliter, or less). The concentration of glucose in the sweat may be, for example, between about 0.1 mg/dl and about 5 mg/dl.

[0016] Some variations of the skin patches comprising a container may comprise a first layer defining at least a portion of a first surface of the container. The skin patches may also comprise a second layer defining at least a portion of a second surface of the container. The first and second surfaces may each include an electrode. The second surface may be opposite the first surface and may have at least a portion that directly faces the first surface. In some variations, the first surface may define the bottom of the container. In certain variations, the first surface may be substantially parallel to, and/or adjacent to, the surface of the skin when the skin patch is in use. The first layer may include an opening to collect sweat from the surface of the skin into the container. In some variations, the first and/or second layer may be hydrophilic. The skin patch may be single-use or multi-use. In certain variations, the skin patch may be used to measure glucose concentration while the skin patch is in contact with the skin (e.g., affixed to the skin surface). [0017] In some variations, the skin patches may comprise two or more fill electrodes for measuring the filling of the volume of sweat contained in the container. The two or more fill electrodes may pass a second signal indicative of a fill level of the container. If the skin patch is configured to contain a fixed volume, then the two or more fill electrodes may be used to determine whether the container is full. In certain variations, the two or more fill electrodes may be disposed on surfaces defined by third and/or fourth layers of the container. In some variations, the fill electrodes may be disposed along the first and second surfaces. The distance between the two or more fill electrodes may be defined by a length or width of the container.

[0018] In some variations, the skin patch may be interrogated using a glucose measurement device configured to receive one or more signals from the skin patch, such as one or more electrical, optical, mechanical, and/or chemical signals, or any other suitable type of signal. The glucose measurement device may receive first and second signals from the skin patch. The first signal may be the same type of signal as the second signal or may be different. In certain variations, the first and/or second signals may comprise an electrical signal between two or more electrodes, such as voltage, current, resistance, capacitance, impedance, and/or conductance. The first signal may correspond, for example, to the amount of glucose in the sweat, while the second signal may correspond to the volume of the sweat.

[0019] In some variations, the skin patch may include an additional reference electrode to measure the glucose concentration in sweat collected by the skin patch. In certain variations, the glucose measurement device may be biased to ensure that the first signal is measured when the skin patch is within a given voltage level. In some variations, the skin patch may be biased within a linear, or substantially linear, operating range of a glucose measurement device. In certain variations, the skin patch may include a reference electrode that provides a consistent voltage to the working electrode or the counter electrode, relative to ground. The reference electrode may, for example, provide a voltage of about 30OmV.

[0020] In some variations, one or more surfaces of the container may be coated with a reactant such as a glucose enzyme. In certain variations, the surface or surfaces may also be coated with a redox mediator. Examples of glucose enzymes include, but are not limited to, glucose oxidases and glucose dehydrogenases (e.g., pyrroloquinoline quinine glucose dehydrogenase (PQQ)). The reactant(s) may be sprayed, brushed, dipped, coated, or otherwise applied to the one or more surfaces. In some variations, the skin patch may not include a redox mediator.

[0021] In certain variations, the second signal may be used to determine whether the volume of sweat is sufficient to accurately measure a sweat glucose concentration. In some variations, a glucose measurement device may additionally be used to measure the amount of time required to collect the sweat. This amount of time may be useful, for example, in determining whether the measurement of the sweat glucose concentration is likely to be accurate. For example, if the sweat collection takes too long, then the sweat glucose concentration is less likely to be accurate.

[0022] In some variations of sweat collection methods, a fixed volume of sweat may be collected from the surface of the skin each time the sweat glucose level is measured. This may, for example, reduce the likelihood of inaccuracies resulting from estimating an unknown volume of sweat. In certain variations, a fixed- volume device for sweat collection may comprise a channel layer, a container layer, and a vent layer. In some variations, the layers may be combined into a single layer and/or other layers may be added. The channel layer of the fixed volume device may contact the skin surface and direct sweat from the skin surface to an opening. On the skin surface, the sweat may be within or excreted from one or more sweat pores in contact with, or adjacent to, the channel layer. Typically, the container layer may be in fluid communication with an opening in the channel layer and may be in contact with the vent layer. The vent layer may be in contact with the container layer and may allow air to escape during sweat collection.

[0023] The container layer may partially define a container configured to contain less than about one-quarter microliter of sweat, about one-half microliter of sweat, about one microliter of sweat, about two microliters of sweat, about five microliters of sweat, about ten microliters of sweat, or any other suitable volume. In some variations, various properties of the sweat in the container may be measured using two or more electrodes disposed along the walls of the container.

[0024] The channel layer may have any number of channels to contact the skin for sweat collection. Upon contacting the skin surface, the channel layer may deform to contact as much skin as possible so that the channels may efficiently route sweat to the opening. The channel layer may have any suitable geometry or have any suitable dimensions. For example, the channel layer may have a thickness of about two hundred micrometers and the opening may have a diameter of less than about seven hundred micrometers. In some variations, the opening may have a diameter of greater than three hundred micrometers. The top side of the channel layer may define a bottom side of the container for holding the collected sweat. In these instances, the channel layer may or may not include one or more electrodes in contact with the container that is positioned to contact sweat within the container.

[0025] It may be desirable to induce sweat production to reduce the amount of time required to collect the fixed volume of sweat. For example, the channel layer may include a mechanism to deliver pilocarpine, one or more other sweat- stimulating (i.e., diaphoretic) drugs, and/or heat to the skin.

[0026] The container layer may be positioned on top of the channel layer or may extend from the channel layer, and may have the same size and shape as the channel layer or be of a different size and/or shape. The channel layer may include at least one opening opposite the container layer to draw the sweat from the skin surface. The container layer may include a feature that defines at least one side of the container. The feature may be a hole, a well, an indentation, an absorbent portion, or the like. The thickness of the container layer may be selected based on one or more factors such as the shape of the container, the volume of the container, or the rigidity required for the container to maintain its shape when the channel layer is deformed. In some variations, the container layer may have a thickness of approximately 100, 200, 500, 700, or 1,000 micrometers. Like the channel layer, the container layer may also comprise one or more electrodes positioned to contact sweat within the container. The electrodes may be used in conjunction with a measurement device to, for example, determine when the container contains the fixed volume of sweat and/or to measure the sweat glucose level.

[0027] The vent layer may be positioned on top of or extend from the container layer. In some variations, the functions performed by the vent layer may be performed by the container layer. The vent layer may reduce evaporation of sweat and/or provide an escape route for air within the container. In general, larger vents may provide more fluid flow by allowing the air to escape quickly, but may also allow more sweat to evaporate from the container. As such, the dimensions of the vents within the vent layer may be selected to achieve a suitable balance between providing sufficient fluid flow and maintaining a reasonably low rate of evaporation from the container. In some variations, the vent layer may have a thickness of approximately 100, 200, 500, 700, or 1,000 micrometers.

[0028] In some instances, the vent layer may include one or more electrodes in contact with the container. The electrodes may be used, for example, to determine whether the container is filled and/or to measure the sweat glucose level. In certain variations, an external surface of the vent layer may comprise external electrodes that can be contacted by electrodes on a measurement device to measure the volume of sweat in the container and/or a sweat glucose level. Each external electrode may be connected to an internal electrode in contact with the container.

[0029] Methods for measuring a glucose level from sweat are also provided. In general, methods for measuring a glucose level from sweat may comprise collecting a predetermined volume of sweat from skin using a skin patch and measuring the amount of glucose within the volume of sweat. The skin patch may be attached to any location on the body covered by skin. Typically, however, the skin patch may be placed on a fingertip, hand, or forearm, as these areas have a relatively high density of sweat glands, are easily accessible, and are currently used by diabetic patients for blood glucose testing. The skin patch may be a skin patch as described above or may be another skin patch that is configured to collect a predetermined volume of sweat. The predetermined volume of sweat may be less than about one-quarter microliter of sweat, about one -half microliter of sweat, about one microliter of sweat, about two microliters of sweat, about five microliters of sweat, about ten microliters of sweat, or any other suitable volume. Measuring the amount of glucose may comprise contacting the skin patch with a measurement device.

[0030] In some variations, the method may also include stimulating sweat production. In certain variations, sweat production may be simulated chemically (e.g., by delivering pilocarpine to the skin surface). The pilocarpine may, for example, be wiped onto the skin surface prior to attachment of the skin patch. Sweat may also be stimulated by delivering heat or one or more other forms of energy to the surface of the skin. The patch itself may comprise a physical, chemical, or mechanical mechanism of inducing a local sweat response. For example, the patch may comprise pilocarpine, alone or with a permeation enhancer, or may be configured for iontophoretic delivery. Similarly, the patch may comprise one or more chemicals capable of inducing a local temperature increase, thereby initiating a local sweat response. In a like manner, the patch may also comprise one or more heaters for sufficient localized heating of the skin surface to induce an enhanced local sweat response.

[0031] The method for collecting sweat from the skin surface may alternatively or additionally include determining whether the volume of sweat collected is adequate prior to measuring its glucose concentration. In the sweat collection devices described here, the container may be configured to only collect up to the predetermined volume of sweat. Once the container is full, the sweat collection device may stop collecting sweat because there is no longer sufficient force to draw sweat into the container. Alternatively or additionally, by forming the vent layer from a hydrophobic material, the passage of sweat out of the container may be impeded. In some variations, the container may be defined by one or more hydrophilic surfaces while the vents may be defined by one or more hydrophobic surfaces. The determination that the container is full may be performed by an indicator, such as a dye, that changes the appearance of the skin patch, by a volume measuring device, or by an integrated device that also measures the sweat glucose level. In variations not comprising an indicator, the patient may remove the patch from the skin surface after an elapsed period of time with the assumption that the container should be full at that time.

[0032] Also described here are kits for collecting sweat. In some variations, the kits may also be used to measure a sweat glucose level. In general, a kit may comprise one or more skin patches configured to collect a predetermined volume of sweat that is less than one microliter. The kit may also include a measurement device configured to measure an amount of glucose in the sweat, where the measurement is based on the predetermined volume. The skin patches may be configured for single use or for multiple uses (e.g., two to four uses). Each skin patch may have at least two electrodes in contact with the container that are connected to at least two corresponding external electrodes. The measurement device may comprise at least two electrodes configured to contact the skin patch at the external electrodes while the skin patch is attached to the skin surface. In some variations, the measurement device may comprise an inlet configured to receive at least a portion of the skin patch.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure Ia is a perspective view of a variation of a skin patch.

[0034] Figure Ib is a cross- sectional view of the skin patch of Figure Ia. [0035] Figure Ic is an exploded view of the skin patch of Figure Ia.

[0036] Figure 2 depicts a flow diagram of a variation of a method for assembling a skin patch.

[0037] Figure 3a is a perspective view of a variation of a skin patch, Figure 3b is a cross- sectional view of the skin patch of Figure 3a, and Figure 3c is an exploded view of the skin patch of Figure 3a.

[0038] Figures 4a through 4h depict a variation of a method for manufacturing a channel layer of a skin patch.

[0039] Figures 5a through 5f depict a variation of a method for manufacturing a container layer of a skin patch.

[0040] Figures 6a through 6f depict a variation of a method for manufacturing a vent layer of a skin patch.

[0041] Figures 7a and 7b depict a variation of a method for molding the various layers shown in Figures 4a through 6f.

[0042] Figure 8 depicts a flow diagram of a variation of a method for assembling the various layers shown in Figures 4a-6f.

DETAILED DESCRIPTION

Devices, Methods, and Kits for Sensing and Measuring Glucose in Sweat

[0043] Devices, methods, and kits for sensing and measuring glucose in sweat are provided. In general, sweat may be collected from a skin surface of a subject (e.g., a patient) using, for example, a skin patch. Electrodes may be provided within the skin patch, and may be interrogated by another device to measure the amount or concentration of glucose in the collected sweat. For example, the skin patch may define a container having two or more electrodes that sense a reaction between glucose in the sweat and a glucose enzyme. The electrodes may relatively efficiently provide an accurate sweat glucose concentration measurement. [0044] In certain variations, a first pair of electrodes may be used to measure the amount of glucose in sweat collected within the skin patch container. The first pair of electrodes may include a working electrode and a counter electrode. In some variations, the working electrode may be disposed on a bottom surface of the container and the counter electrode may be disposed on a top surface of the container opposite the bottom surface, or vice-versa. The working electrode and/or counter electrode may be at least partially coated with one or more materials that may react with the glucose in the sweat to transmit a signal through the sweat. Non-limiting examples of suitable electrode-coating materials include glucose enzymes and redox mediators. Additionally, the working electrode and/or counter electrode may be connected to one or more contact pads on an external surface of the skin patch via one or more traces.

[0045] The glucose measurement device may be configured to receive one or more signals from the skin patch that are indicative of the amount of glucose in the sweat. For example, the glucose measurement device may comprise at least one electrode positioned to contact one or more contact pads on the skin patch. The glucose measurement device may measure the signal to determine a voltage, current, capacitance, impedance, conductance, or any other suitable characteristic of the signal and/or the sweat in the container. The glucose measurement device may comprise an output to display the glucose concentration.

[0046] The container defined by the skin patch may further comprise one or more fill electrodes that are used to determine the volume of sweat in the container. A minimum volume of sweat may be required in order to accurately measure the glucose concentration of the sweat. If the container has a fixed volume, the fill electrodes may be used to determine whether the container is full. The fill electrodes may be interrogated using the glucose measurement device or a separate device that interfaces with one or more contact pads connected to the fill electrodes.

Devices

b. Skin Patches

[0047] In general, the skin patches described here may comprise two or more electrodes that may be used to determine the concentration of glucose in sweat collected by the skin patches. The skin patches may be configured to collect sweat that has been excreted from sweat pores on a skin surface. Additional information about collecting sweat from sweat pores is provided, for example, in U.S. Patent Application Publication No. US 2006/0004271 Al, entitled "Devices, Methods and Kits for Non-Invasive Glucose Measurement" by Thomas A. Peyser et al., which is hereby incorporated by reference herein in its entirety.

[0048] A skin patch may be applied to a skin surface for a sufficient period of time to allow sweat to be collected into a container in the skin patch. The skin patch may be single- use only, or may be intended for multiple uses. Skin patches for multiple uses may, for example, be manufactured using relatively durable materials, and/or may include multiple containers for collecting sweat. In some variations, the container(s) in a skin patch may be reused. Additional information about skin patches is provided, for example, in U.S. Provisional Application No. 61/095,463, filed on September 9, 2008 and entitled "Sweat Collection Devices for Glucose Measurement" by Russell O. Potts et al., and in U.S. Patent Application Serial No. 12/555,718, filed on September 8, 2009 and entitled "Sweat Collection Devices for Glucose Measurement" by Russell O. Potts et al., both of which are hereby incorporated by reference herein in their entirety.

[0049] Figures Ia-Ic depict a variation of a skin patch (100) comprising one or more layers that form or define a container for collecting sweat. As shown, skin patch (100) may comprise multiple layers such as a channel layer (102), a container layer (104), and/or a vent layer (106). Skin patch (100) is configured to be affixed or held to a skin surface. In certain variations, skin patch (100) may maintain contact with the skin surface via one or more adhesives (not shown) and/or other suitable attachment mechanisms, such as elastic bands, medical tape, or the like. In some variations, skin patch (100) may be configured to remain in contact with a skin surface for at least one minute, two minutes, five minutes, ten minutes, fifteen minutes, twenty minutes, thirty minutes, or longer. The amount of time that a skin patch remains in contact with a skin surface may depend, for example, on the amount of time necessary to collect a volume of sweat sufficient for measuring glucose concentration.

[0050] Skin patch (100) may have any shape (e.g., circular, as shown) and/or may be sized for a specific location on the body. For example, skin patch (100) may be sized for attachment to a fingertip. In some variations, skin patch (100) may be sized and/or shaped for attachment to another area of the hand, or to a forearm or other body location. In certain variations, skin patch (100) may have a diameter of between about 10 mm and about 20 mm, between about 20 mm and about 30 mm, between about 30 mm and about 40 mm, or between about 40 mm and about 50 mm. The skin patch (100) may be larger for patients who have an impaired ability to manipulate smaller objects (e.g., due to impaired vision, joint conditions, or other reasons). A smaller skin patch (100) may be used, for example, by children or by travelers. In some variations, skin patch (100) may be another shape, such as a square, or triangle. In certain variations, skin patch (100) may have a fun or entertaining shape, such as a star, heart, dinosaur, or the like.

[0051] As shown, skin patch (100) may be formed of multiple layers. For example, Figure Ia shows that skin patch (100) is formed of three layers of the same size. However, it should be understood that a skin patch may contain a greater or lesser number of layers, and that the layers need not have a uniform size and/or shape. As an example, a skin patch may comprise two layers defining a container, with one layer being smaller than the other layer (e.g., to reduce the effects of deformation of the skin patch on the volume of the container because the smaller layer may not deform as much as the larger layer). The layers in a skin patch may or may not have a uniform thickness. Moreover, the layers may overlap, interlock, or otherwise interface with one another. Additionally, an individual layer need not be formed of one continuous or contiguous piece of material. For example, a layer may be formed by one or more pieces that are fitted or otherwise coupled together. The layers may be made of the same material or materials, or may be made of different materials, and may be of the same color or different colors. In certain variations, one or more of the layers may be transparent, translucent, or opaque.

[0052] As described above, skin patch (100) comprises channel layer (102). Channel layer (102) may be configured to contact a skin surface when skin patch (100) is affixed to, or otherwise in contact with, the skin surface, and to draw sweat from one or more sweat pores of the skin surface into a container. In certain variations, channel layer (102) may have a thickness of between about 100 and about 500 micrometers. For example, channel layer (102) may have a thickness of between about 100 and about 200 micrometers, between about 200 and about 300 micrometers, between about 300 and about 400 micrometers, or between about 400 and about 500 micrometers. As an example, in some variations, channel layer (102) may have a thickness of about 215 micrometers. The thickness of channel layer (102) may be selected based on, for example, manufacturing cost, durability, ease of use, materials used to manufacture channel layer (102), the presence of microchannels, and/or any other suitable factors. [0053] In some variations, channel layer (102) may also be configured to stimulate sweat production. For example, channel layer (102) may be coated, impregnated, and/or saturated with pilocarpine or another compound that stimulates sweat production. Alternatively or additionally, channel layer (102) may include one or more depots or reservoirs that contain the compound and that are configured to release the compound when in contact with the skin. In some variations in which channel layer (102) includes one or more reservoirs for sweat-inducing compounds, the channel layer may further include one or more micropumps. The micropumps may be used, for example, to deliver the sweat-inducing compounds to skin that is in contact with or adjacent to channel layer (102). In certain variations, channel layer (102) may include one or more channels and/or grooves to direct the sweat to a container in the skin patch, as discussed below in greater detail with reference to Figure Ic.

[0054] While certain compounds that stimulate sweat production have been described, skin patch (100) may alternatively or additionally stimulate sweat production using one or more other pharmacological methods and/or one or more chemical, physical, and/or mechanical methods. For example, in some variations, skin patch (100) may comprise pilocarpine and a penetration or permeation enhancer that induces sweat chemically or pharmacologically. Similarly, heat may be applied to the skin to increase the sweat response. The container layer (102) may include one or more iontophoresis electrodes that may be disposed against the skin during use and configured to deliver pilocarpine or other sweat stimulating substances to the skin.

[0055] While not shown, skin patch (100) may also include at least one release liner that is removable prior to use. For example, a release liner may be employed on a bottom adhesive surface of skin patch (100) to protect the adhesive surface from losing its adhesive properties (e.g., during storage and prior to use). Similarly, a release liner may be placed on top of an upper interface layer of skin patch (100) (e.g., to protect optical and/or electrical components contained therein). In some variations, a skin patch (100) may not include any release liner. In such variations, an interface layer of the skin patch may be topped with, for example, a backing layer that covers skin patch (100) when it is attached to the skin. In certain variations, the backing layer may be 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 may be made from a flexible plastic or rubber. [0056] To prevent the sweat collection device from collecting glucose from other sources (e.g., via desquamation or diffusion), channel layer (102) may comprise one or more sweat permeable membranes configured to collect only sweat excreted by the sweat pores in contact with channel layer (102). A sweat permeable membrane may be formed of, for example, one or more hydrophobic materials, such as petrolatum, paraffin, mineral oils, silicone oils, vegetable oils, waxes, liquid polymer coatings (e.g., a SILGARD® silicon polymer coating), inorganic membranes (e.g., ANOPORE® inorganic membranes), membrane filters (e.g., Whatman NUCLEOPORE® polycarbonate track-etch membrane filters), and the like.

[0057] In some variations, channel layer (102) may be fabricated from one or more hydrophobic materials. The hydrophobic material or materials may be used to repel sweat from the bottom surface of channel layer (102), through an opening, and into a hydrophilic container within skin patch (100). The hydrophobic material or materials may be selected based on flow properties, optical properties, conformability, viscoelasticity, flammability, toxicity, inertness, and/or the like. An example of a hydrophobic material that may be used in the manufacture of channel layer (102) is polydimethylsiloxane (PDMS). Other suitable hydrophobic materials may alternatively or additionally be used.

[0058] In addition to channel layer (102), skin patch (100) comprises container layer (104), which partially defines a container (116) for collecting a fixed volume of sweat. As depicted, container layer (104) defines side walls of container (116), but not the bottom or top surface of container (116). While container layer (104) is depicted as disposed on top of channel layer (102) and in contact with channel layer (102), other suitable layer arrangements may be used in a skin patch, as appropriate. The fixed volume of container (116) may be selected based on, for example, the sensitivity of the glucose detector and/or the amount of time required for collection of the volume of sweat. To preserve a fixed volume of container (116), container layer (104) may be fabricated using, for example, one or more relatively rigid materials (e.g., to prevent deformation and/or change in volume of the container). In some variations, container layer (104) may be fabricated using polymethylmethacrylate (PMMA). Container layer (104) may be hydrophilic, or may be made of any other suitable material or materials.

[0059] As shown in Figures Ia-Ic, skin patch (100) also comprises a vent layer (106) comprising two vents (108) and (109) that cause container (116) to be in fluid communication with an external surface (e.g., a skin surface to which skin patch (100) is affixed). While two vents are shown, a skin patch may include any suitable number of vents, such as just one vent, or more than two vents. Vent layer (106) may be fabricated from any appropriate material or materials including, for example, PDMS and/or PMMA. In some variations, it may be desirable to fabricate vent layer (106) from one or more hydrophobic materials. This may, for example, limit or prevent evaporation from container layer (104) especially, for example, once container (116) has been filled.

[0060] Vents (108) and/or (109) may be in the form of one or more lumens through vent layer (106), or may have any other suitable configuration. In some variations, vents (108) and/or (109) may have a hydrophobic interior surface. A vent in a skin patch may have any suitable cross-sectional geometry. For example, the vent may have a circular, polygonal (e.g., rectangular), or irregular cross-section. In addition, a vent may be vertical, angled, curved, stepped, or any combination thereof. The vent may or may not be configured to change shape if the skin patch is deformed. When a skin patch has multiple vents, the vents may have the same sizes and/or shapes, or may have different sizes and/or shapes.

[0061] Vents (108) and (109) may provide an escape for air trapped in skin patch (100) when the skin patch is applied to a skin surface, and may facilitate the flow of fluid through skin patch (100). As vents (108) and (109) become larger, however, the sweat in the container may be more likely to evaporate. Thus, the size of vents (108) and (109) may be selected to be large enough to provide sufficient fluid flow, while also being small enough to prevent a significant amount of sweat from evaporating. Vents (108) and (109) may be partially offset from container (116). By offsetting vents (108) and (109), some evaporation may be prevented.

[0062] Referring specifically to Figures Ia and Ic, skin patch (100) may additionally comprise one or more electrical contact pads (118). As shown in Figures Ia and Ic, the contact pads may be supported by vent layer (106), or may be in any other appropriate location. Contact pads (118) may be connected via a trace to one or more electrodes that are adjacent to the sweat contained within container (114). Contact pads (118) may be configured to contact one or more electrodes of a glucose measurement device. This may allow contact pads (118) to communicate a signal between the electrodes adjacent to the sweat contained within container (114), and the glucose measurement device. While contact pads (118) are depicted as having the same size and shape, contacts pads may be of any suitable size and shape, and in some variations may have different sizes and/or shapes. Contact pads (118) may be fabricated of one or more conductive materials, such as gold, platinum, carbon, palladium, ruthenium dioxide, and conductive epoxies. Other suitable materials may also be used.

[0063] Contact pads (118) may be disposed on vent layer (108) in any suitable configuration that facilitates proper positioning between skin patch (100) and a glucose measurement device. As an example, contact pads (118) may be disposed in an asymmetrical arrangement to reduce the likelihood of the electrodes on the glucose measurement device improperly aligning with contact pads (118). In some variations, vent layer (106) may include one or more markings (not shown) that indicate the correct positioning of the glucose measurement device with respect to skin patch (100). In other words, the markings may further facilitate the alignment of electrodes on the glucose measurement device with contact pads (118).

[0064] In certain variations, skin patch (100) may comprise one or more layers, other than vent layer (106), that include one or more contact pads. In some such variations, vent layer (106) and/or container layer (104) may comprise one or more cut-outs and/or cutaways (not shown) that expose the contact pads on the other layer or layers. Alternatively or additionally, the layers may comprise one or more tabs or extensions that are in communication with the contact pads (118) and that extend outward to contact the glucose measurement device. Vent layer (106) may further comprise a protective covering over contact pads (118). The protective covering may comprise a release liner that may be removed (e.g., by the user) prior to use.

[0065] Referring specifically now to Figure Ib, which is a cross- sectional view of skin patch (100) taken along line AA-AA of Figure Ia, skin patch (100) may have a total height (H) of between about 500 and about 1500 micrometers (e.g., between about 500 and about 700 micrometers, between about 700 and about 900 micrometers, between about 900 and about 1100 micrometers, between about 1100 and about 1300 micrometers, or between about 1300 and about 1500 micrometers). In some variations, total height (H) may be about 900 micrometers. The total height of skin patch (100) may be selected based on, for example, on manufacturing cost, durability, ease of use, materials used to manufacture skin patch (100), and/or any other suitable factors. [0066] As shown in Figure Ib, channel layer (102) may comprise a plurality of microchannels (110) defined by channel walls (112). Microchannels (110) are positioned to direct sweat that has come to the surface of the skin to an opening (114) in channel layer (102). The dimensions of the microchannels may be selected, for example, based on a desired collection rate and efficiency. In some variations, microchannels (110) may each have a width of about 10 micrometers to about 100 micrometers and/or a depth of about 2 micrometers to about 50 micrometers. As an example, microchannels (110) may each have a width of about 38 micrometers and/or a depth of about 15 micrometers. MicroChannel walls (112) may each have a width of about 20 micrometers to about 250 micrometers. As an example, microchannel walls (112) may each have a width of about 80 micrometers. While microchannels having the same dimensions and microchannel walls having the same dimensions have been shown, in some variations, a skin patch may include microchannels having different dimensions and/or microchannel walls having different dimensions.

[0067] Opening (114) may be located at or near the center of channel layer (102) to provide fluid communication between the skin surface and container (116). While not shown, in some variations, channel layer (102) may include more than one opening. The openings may have the same size and shape, or may have different sizes and/or shapes. In certain variations, the surface of opening (114) may be coated with one or more hydrophilic materials to attract sweat from microchannels (110). Alternatively or additionally, a microfluidic pump may be used to transport sweat from a skin surface in contact with channel layer (102) through opening (114). To direct sweat toward opening (114) and into container (116), the surface of channel layer (102) may be hydrophobic. In some variations, channel layer (102) may be fabricated using one or more hydrophobic materials, such as PDMS. Alternatively or additionally, channel layer (102) may be at least partially coated with one or more hydrophobic materials.

[0068] As shown in Figure Ib, container layer (104) partially defines container (116), which is configured to collect and hold a fixed volume of sweat. While not shown, in some variations a skin patch may include a container that is entirely defined by a container layer of the skin patch (such that the container is not defined by any other layers of the skin patch). In certain variations, container (116) may be configured to hold a relatively small fixed volume of sweat. For example, in some variations, the container may be configured to hold less than one microliter (e.g., less than 0.75 microliter, less than 0.5 microliter, less than 0.25 microliter, or less than 0.1 microliter) of sweat. In certain variations, container layer (104) may have a thickness of approximately 100, 200, 500, 700, or 1000 micrometers. In some variations, container (116) may be formed of one or more relatively rigid materials that allow the container to retain its shape when skin patch (100) is deformed (e.g., thereby allowing the container to maintain its fixed volume). For example, container layer (104) may be fabricated from PMMA.

[0069] Container (116) is cuboid in shape. However, a container in a skin patch may have any suitable shape. As an example, a skin patch may include a cylindrical container. As shown in Figure Ib, the depth (D) of container (116) is approximately equal to the thickness (T) of container layer (104). However, in some variations, a skin patch (100) may include a container layer (104) and a container (116) at least partially defined by the container layer (104), where the container (116) has a depth that is different from the thickness of the container layer (104). This may depend, for example, on the geometry of channel layer (102) and/or vent layer (106), for example, the presence of wells, indents, protrusions, and/or other features that also partially define container (116). Additionally, container (116) may be shallower or deeper based on the shape of container (116), the fixed volume of sweat to be collected, and/or a desirable distance between one or more electrodes. In certain variations, container (116) may be shallower (e.g., to collect a relatively small volume of sweat relatively quickly). In other variations, container (116) may be deeper (e.g., to reduce sweat evaporation).

[0070] In the variation shown, container (116) is defined by channel layer (102), container layer (104), and vent layer (106). More specifically, the bottom of container (116) is defined by a top side of channel layer (102), the sides of container (116) are defined by container layer (104), and the top of container (116) is defined by vent layer (106). However, other variations of skin patches may comprise one or more containers that are defined differently.

[0071] It should be noted that while skin patch (100) comprises vent layer (106), some variations of skin patches may not include any vent layers. In some such variations, sweat may be drawn into one or more containers in the skin patch using, for example, a pressure gradient. As an example, a skin patch container may be evacuated prior to application of the skin patch to a skin surface, or a suction device may be coupled to the container to provide a pressure gradient. In some variations, gentle suction may be applied when the skin patch is on the skin surface.

[0072] In certain variations in which channel layer (102) is hydrophobic, its top surface may be at least partially coated with a hydrophilic coating (not shown) to attract sweat into container (116). Alternatively or additionally, opening (114) may be coated with one or more hydrophilic materials. Hydrophilic materials that may be used include, but are not limited to, glass, 2-hydroxethyl methacrylate (HEMA), poly(oxyethylene) (POE), silicon dioxide, poly(ethylene glycol) (PEG), and polyacrylamide. In some variations in which channel layer (102) is formed of PDMS, the PDMS may be surface-modified using, for example, oxygen plasma treatments and/or UV-mediated grafting.

[0073] In some variations, container (116) may comprise one or more enzymes used to measure glucose, such as glucose oxidase and/or glucose dehydrogenase. Typically, the enzyme may be placed in and/or coated on container (116) during manufacture of skin patch (100). The enzyme or enzymes may be deposited within container (116) so that sweat collected in the container contacts the enzyme or enzymes. In certain variations, container (116) may be adjacent to one or more wells or deposits of the enzyme or enzymes. Alternatively or additionally, one or more surfaces, such as electrode surfaces and/or optical component surfaces, may include, or be coated with, the enzyme or enzymes.

[0074] As depicted in Figure Ib, an enzyme layer (120) may be disposed on the bottom surface of container (116) defined by channel layer (102). Enzyme layer (120) may comprise, for example, any suitable quantity of glucose oxidase and/or glucose dehydrogenase (e.g., PQQ). Enzyme layer (120) may be applied to channel layer (102), to another surface in contact with container (116), and/or to one or more electrodes using, for example, one or more coating methods, spraying methods, brushing methods, dipping methods, and/or printing methods.

[0075] As shown in Figures Ib and Ic, container (116) comprises a working electrode (122) and a counter electrode (124). Working electrode (122) and counter electrode (124) may each be connected to contact pads (118) via separate traces and may be of any suitable size. Generally, working electrode (122) and counter electrode (124) may be disposed on opposite sides of container (116), so that they form a capacitor when container (116) is empty. [0076] In some variations, contact pads (118), working electrode (122), counter electrode (124), and/or any additional electrodes and/or traces may be fabricated from one or more conductive materials such as gold, platinum, carbon, silver, palladium, ruthenium dioxide, and conductive epoxies. The electrodes, contact pads, traces, and other conductive components of skin patch (100) may be applied by printing a carbon or metallic ink, by vapor deposition, or by other suitable methods. Examples of printing techniques that may be used include screen printing, gravure roll printing, transfer printing, and the like. The electrodes, contact pads, and traces described herein may be applied concurrently or at different times. For example, the electrodes may be applied layer-by-layer, or at subsequent times relative to the application of other electrodes, contact pads, and/or traces.

[0077] In certain variations, working electrode (122) may be disposed on the bottom surface of container (116) (as defined by channel layer (102)), and may cover all or a portion of the bottom surface. The surface area of working electrode (122) may be limited by the presence of opening (114). Working electrode (122) may be adjacent to and/or in contact with enzyme layer (120).

[0078] In some variations, counter electrode (124) may be disposed on the top surface of container (116) (as defined by vent layer (106)). The counter electrode may have the same surface area as working electrode (122), or may have a different surface area. In certain variations, the counter electrode may cover the entire top surface of the container, while in other variations, the counter electrode may cover only a portion of the top surface of the container. In some variations, the surface area of counter electrode (124) may be limited by the presence of vents (108) and (109).

[0079] In certain variations, container (116) may comprise a reference electrode (not shown). The reference electrode may provide a consistent voltage between working electrode (122) and counter electrode (124) when all of the electrodes are connected to a glucose measurement device. This consistent voltage may be used to bias a signal passed between working electrode (122) and counter electrode (124) within the operating range of the glucose measuring circuitry in the glucose measurement device. It should be understood that the reference electrode may be parallel to, or in series with, the capacitor formed by working electrode (122) and counter electrode (124). For example, in some variations, the reference electrode may be used to provide a bias voltage of 10OmV, 20OmV, 30OmV, 40OmV, 50OmV, or higher. [0080] Working electrode (122) and counter electrode (124) may pass a first signal (e.g., a voltage, current, capacitance, impedance, conductance, or resistance measure) based on the amount of glucose in the sweat collected in container (116). Generally, when container (116) does not contain any sweat, working electrode (122) and counter electrode (124) may operate as a capacitor having air as its dielectric. The addition of sweat affects the electrical properties of container (116). Moreover, as glucose in the sweat reacts with the enzyme in enzyme layer (120), the electrical properties of container (116) further change. These electrical properties can be measured by a glucose measurement device, which receives the first signal via contact pads (118). In some variations, measurements of the electrical properties of container (116) may be taken over a period of time and/or at multiple points in time as the glucose enzyme reacts with the glucose.

[0081] In certain variations, skin patch (100) may comprise two or more containers having two or more electrodes as described above. At least one of the containers may include a reactant (e.g., a glucose enzyme) while another container may not include the reactant. In some variations, a signal communicated via the container(s) that do not include the reactant may be used as a reference to increase the accuracy and/or specificity of a signal communicated via the container(s) that include the reactant.

[0082] In certain variations, container (116) may comprise a volume indicator configured to indicate when container (116) has collected a predetermined volume of sweat. The volume indicator may be electrical, mechanical, optical, chemical, or the like. For example, the top side of container (116) may be coated with a sweat- sensitive or water- sensitive dye that changes color when container (116) is full.

[0083] Other suitable volume indicators may also be used. As an example, container (116) may comprise fill electrodes (126) (Figures Ib and Ic) that can provide a conductive path through the fixed volume reservoir when the reservoir is full. Changes in resistance or conductance in container (116) may be measured to determine when container (116) has collected the fixed volume of sweat. The modest power required to drive a current through the circuit described here may be provided by an inductive coupling mechanism enclosed within a measurement device, a plastic battery, or the like. Fill electrodes (126) may line two or more portions of the inside surface of container (116) to form a capacitor. As an example, in variations in which container (116) is rectangular, the fill electrodes may be disposed on opposing surfaces of the container. As another example, in variations in which container (116) is cylindrical, the fill electrodes may be curved along opposite sides of a circular wall defining the container. The fill electrodes may not be in contact with one another or with working electrode (122) or counter electrode (124).

[0084] When a glucose measurement device is coupled to contact pads (118), the glucose measurement device may provide power to at least one of fill electrodes (126). Based on a second signal passed between the fill electrodes and back to the glucose measurement device, the volume of sweat collected in container (116) may be confirmed. To illustrate, in some variations, fill electrodes (126) may be separated by distance of about 50 micrometers, about 100 micrometers, about 200 micrometers, or some other suitable distance. When container (116) is empty, fill electrodes (126) can act as a capacitor having air as its dielectric material over the entire overlapping area of the fill electrodes. As container (116) fills with sweat, the dielectric transitions from air to sweat; this, in turn, diminishes the capacitance between the plates. When container (116) contains a sufficient volume of sweat to cover fill electrodes (126), the fill electrodes may act as a resistor, since sweat generally conducts an electric charge.

[0085] Figure Ic is an exploded view of the various layers of skin patch (100). As previously discussed, skin patch (100) comprises channel layer (102), container layer (104), and vent layer (106). However, other variations of skin patches may comprise different layers and layer configurations. The layers of skin patch (100) may be adhered, glued, fastened, interlocked, welded, or otherwise suitably coupled together. As shown in Figure Ic, in some variations, one or more layers of skin patch (100) may be adhered together using adhesives (130) and/or (132). Adhesives (130) and/or (132) may be non-conductive to provide separation between working electrode (122), counter electrode (124), and/or fill electrodes (126). In certain variations, one or more layers of skin patch (100) may include one or more fasteners, slots, tabs, latches, or the like. In some variations, the layers of skin patch (100) may include one or more interlocking features that help to couple the layers to each other.

[0086] Contact pads (118) may be positioned on an outer surface of vent layer (106) (as shown), and/or on a tab and/or other protrusion from skin patch (100). In general, contact pads (118) are connected to working electrode (122), counter electrode (124), and/or fill electrodes (126) via traces (128). The traces (128) may traverse across or through channel layer (102), container layer (104), and/or vent layer (108). The traces (128) may traverse along the inside of container (116) and/or along one or more external surfaces of skin patch (100). In some variations, the positioning of the traces (128) may be based on the shape and/or size of one or more layers, especially if the layers include cutouts and/or cutaways to expose one or more contact pads (118). It is understood that the placement of the traces and electrodes may vary based on cost, method of manufacture, appearance, ease-of-use, configuration of the glucose measurement device, and/or other suitable factors.

[0087] Adhesives (130) and/or (132) may be permanent or temporary, and may be selected based on the materials used to fabricate the layers of skin patch (100). The adhesive between channel layer (102) and container layer (104) may be the same as or different from the adhesive between container layer (104) and vent layer (106). For example, one of the adhesives may be a temporary adhesive, while the other may be a permanent adhesive. Adhesive (130) and/or (132) may be activated by heat, pressure, the presence of a solute, or any other appropriate bonding technique during the manufacture of the skin patch (100). In some variations, adhesive (130) and/or (132) may comprise an acrylic adhesive such as those available from Cemedine Co., Ltd., Japan or a silyl urethane adhesive such as those available from Conishi Co., Ltd., Japan.

[0088] The above described devices are described herein for the purposes of illustration and are not intended to be limiting. Alternative and additional variations may be apparent to those skilled in the art.

[0089] Figure 2 depicts a flow diagram for a variation of a method of assembling skin patch (100). Prior to assembly, one or more of the layers that are used to form the skin patch may be coated, shaped, or otherwise modified. In certain variations, at least a portion of one or more of the layers may be chemically treated to produce a hydrophilic surface, and/or may be coated with one or more hydrophilic materials. In some variations, the surfaces that define container (116) when the skin patch is assembled may be coated with one or more hydrophilic materials and/or electrically conductive materials. For example, channel layer (102) may be coated with a hydrophilic material along its top surface and along the interior of opening (114). Alternatively or additionally, channel layer (102) may be coated with an electrically conductive material to form working electrode (122) and/or a glucose enzyme to form enzyme layer (120). The bottom surface of vent layer (106) may also be coated with a hydrophilic material and/or an electrically conductive material to form counter electrode (126). Alternatively or additionally, portions of container layer (104) may be coated with an electrically conductive material to form fill electrodes (126).

[0090] As shown, the layers of skin patch (100) are sized such that vent layer (106) is smaller than container layer (104), and container layer (104), in turn, is smaller than channel layer (102). However, other variations of skin patches may comprise layers having different relative sizes. In some variations, the sizing of the layers may be selected to expose one or more contact pads printed on one or more of the layers. As an example, because channel layer (102) is larger than the remaining layers of skin patch (100), the contact pad (118) connected to working electrode (122) is exposed at the edge of skin patch (100), as shown in Figure 2. The same is true for the contact pads (118) connected to fill electrodes (126). By exposing the contact pads in this way, the result may be lower manufacturing costs, as there are fewer traces (128) traversing through each of the layers. While Figure 2 depicts the layers as having varying sizes to expose contact pads (118), it should be understood that the same objective may be accomplished in other skin patch variations by employing cutouts and/or cutaways from one or more layers having the same size. In certain variations, layers of the same size may be used, for example, to easily assemble a skin patch (e.g., because the layers may align easily during assembly). For example, the layers may be of the same diameter at least during assembly.

[0091] In some variations, traces (128) may traverse along one or more inner surfaces of skin patch (100). For example, the trace (128) connecting working electrode (122) to its contact pad (118) may traverse along an inner surface of container (116) that is not in electrical contact with fill electrodes (126). Likewise, one or more traces (128) may extend upward along the inner surfaces of vents (108) and (109).

[0092] Channel layer (102), container layer (104), and vent layer (106) may be assembled in any of a number of different ways. As shown in Figure 2, in a step (202), channel layer (102) and container layer (104) may first be aligned and bonded together. The alignment may be performed using, for example, a stereomicroscope, or may be performed automatically. In certain variations, channel layer (102) and container layer (104) may be bonded together using an adhesive (e.g., a urethane or acrylic adhesive) at room temperature. Other adhesives may alternatively or additionally be used. [0093] After channel layer (102) and container layer (104) have been bonded together, vent layer (106) may be bonded to the opposite surface of container layer (104) to form skin patch (100), in a step (204). Prior to bonding, vent layer (106) may be aligned with container (116) such that vents (108) and (109) are offset from, or partially offset from, container (116). In some variations, container (116) and/or vents (108) may be symmetrically positioned and/or shaped. In certain variations, container layer (104) and vent layer (106) may be manufactured as a single layer. A urethane adhesive and/or an acrylic adhesive may be used to bond container layer (104) to vent layer (106) at room temperature. Other bonding techniques and/or adhesives may also be used.

b. Glucose Measurement Device

[0094] As discussed above, a glucose measurement device may be used to measure the amount of glucose in the sweat collected by skin patch (100). In some variations, the glucose measurement device may interrogate skin patch (100). The device may measure the total quantity of glucose present in a fixed volume of sweat, and then convert the glucose measurement into a sweat glucose or blood glucose concentration. Typically, the sweat glucose concentration may be between about 0.1 mg/dl and about 5 mg/dl. In general, the measurement device typically comprises a display to display data. The device may also include one or more warning indicators (e.g., a word prompt, flashing lights, sounds, etc.) to indicate that a subject's glucose levels are dangerously high or dangerously low. In addition, the glucose 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 the glucose measurement device detects the marker, then the measurement proceeds. If the glucose measurement device does not detect the marker, then the measurement does not proceed. In one variation, the glucose measurement device may provide an indication to a user that the skin surface must be cleaned prior to use (e.g., using a word prompt, colored and/or flashing lights, and/or various sounds).

[0095] In some variations, a glucose measurement device may be configured to estimate sweat flux. It may be desirable to use the sweat flux estimate to correct the sweat glucose measurement or to flag sweat collections that are above or below acceptable limits. Sweat flux is generally defined as the flow rate of sweat. Sweat flux may vary in the presence of heat, stress, diaphoretic drugs, or other stimuli. For example, the amount of time between container (116) being about 10% full and container (116) being 100% full may be measured to determine sweat flux. In such variations, skin patch (100) (or a skin patch holder configured to hold skin patch (100) at the surface of the skin) may comprise additional fill sensing and timing circuits.

[0096] The configuration of the glucose measurement device may depend in part on the configuration of the skin patch being interrogated by the glucose measurement device. For example, when the glucose measurement device is to be used with a skin patch having contact pads, the glucose measurement device provides an electrical contact with the contact pads, and is either powered by the electrical contact or by an independent power source (e.g., a battery within the patch itself, etc.). The glucose measurement device also typically comprises a computer processor to analyze data. Conversely, when the glucose measurement device is configured for optical detection, the glucose measurement device may be configured to provide optical contact or interaction with the skin patch. In this variation, the glucose measurement device also typically comprises a light source. In some variations, the glucose measurement device may comprise both the necessary electrical contacts (e.g., electrodes) and the necessary optics so that a single measurement device may be used with a patch having various configurations of patch layers. The skin patch (100) may be interrogated when it is contact with the skin and/or when it is removed from the skin and, for example, inserted into the glucose measurement device.

[0097] The glucose measurement device may further comprise computer executable code containing a calibration algorithm, which relates measured values of detected glucose to blood glucose values. For example, the algorithm may be a multi-point algorithm, which is typically valid for about 30 days or longer. As an example, the algorithm may necessitate multiple capillary blood glucose measurements (e.g., blood sticks) with simultaneous patch measurements over about a one-hour to about a three-day period. This could be accomplished using a separate dedicated blood glucose meter provided with the glucose measurement device described herein, which comprises a wireless (or other suitable) link to the glucose measurement device. In this way, an automated data transfer procedure may be established, and user errors in data input may be minimized.

[0098] 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 100 mg/dl), a calibration curve may be generated, which relates the measured sweat glucose to blood glucose. Patients can perform periodic calibrations checks with single blood glucose measurements, or total recalibrations as desirable or necessary.

[0099] The glucose measurement device may also comprise a memory for saving readings and the like. The glucose measurement device typically comprises a processor configured to access the memory and execute computer executable code stored therein. It should be understood that the glucose measurement device may include other hardware such as an application specific integrated circuit (ASIC). In addition, the glucose measurement device may include a link (wireless, cable, and the like) to a computer. In this way, stored data may be transferred from the glucose measurement device to the computer, for later analysis, etc. The glucose measurement device may further comprise various buttons to control the various functions of the device and to power the device on and off when necessary.

Methods

[0100] Skin patch (100) may be used, for example, by a diabetic patient to collect sweat to measure his or her glucose level. The skin patch may replace a finger stick or other methods of drawing blood. To use, the patient attaches skin patch (100) to a target location on the surface of the skin. When skin patch (100) has collected a sufficient volume of sweat, the patient may use a glucose measurement device to quantitatively measure the sweat glucose level. Based on the sweat glucose level and/or a blood glucose level derived from the sweat glucose level, the patient may self-administer insulin as needed.

[0101] Prior to use, the patient may clean an area of skin to remove residual glucose present at the skin surface. Exemplary wipes that may be used are described, for example, in U.S. Patent Application Publication No. US 2003/0176775 Al, entitled "Cleaning Kit for An Infrared Glucose Measurement System" by Berman, which is hereby incorporated by reference herein in its entirety. For example, the patient may use one or more wipes impregnated with a cleanser that does not interfere with glucose detection and/or a surfactant that modifies one or more properties of the sweat and/or the skin surface (e.g., sodium lauryl sulfate (SLS)). In some variations, the wipes may contain a chemical marker that is identifiable by a measurement device to confirm that the skin was wiped before the sweat was collected in skin patch (100). In certain variations, the wipes may contain a marker used to detect when container (116) is filled. For example, the wipes may comprise a reactant that reacts with another chemical within container (116) to indicate (e.g., via a color change) that the container has been filled.

[0102] Skin patch (100) may be attached to the surface of the skin in any of a number of different ways. In some variations, a patient may remove a release liner from the bottom surface of channel layer (102) to expose a pressure-sensitive adhesive that may adhere to the skin. Alternatively or additionally, other adhesives (e.g., heat-sensitive or soluble adhesives) may be used. In certain variations, skin patch (100) may be positioned using an elastic band configured to hold the skin patch in place. In some variations, the patient may tape skin patch (100) to a skin surface using, for example, medical tape, and/or may hold skin patch (100) to a skin surface. For example, skin patch (100) may be held in place on the skin using a "watch-like" device.

[0103] To determine when a predetermined, known volume of sweat has been collected, the patient may consult a volume indicator. The volume indicator may be integrated into skin patch (100) or may be integrated into another device, such as a glucose measurement device. In some variations, the patient may simply remove skin patch (100) after a certain length of time (e.g., one minute, two minutes, five minutes, or ten minutes).

[0104] After a predetermined volume of sweat has been collected, skin patch (100) may be interrogated using a glucose measurement device. In some variations, the glucose measurement device may be placed in contact with skin patch (100) at one or more contact pads (118). In other variations, skin patch (100) may be removed from the skin and inserted into, or otherwise contacted with, the glucose measurement device. Skin patch (100) may be single-use only, or may be multi-use (e.g., including multiple containers for multiple uses).

Kits

[0105] Also described here are kits. The kits may include one or more packaged skin patches, either alone, or in combination with other skin patches, one or more glucose measurement devices, and/or instructions. In one variation, the kits may comprise at least one skin patch having a volume indicator. Typically the skin patches may be individually packaged in sterile containers or wrappings, and may be configured for a single use. In some variations, multiple skin patches may be individually sealed within one sterile container or wrapping. Devices, Methods, and Kits for Collecting a Fixed Volume of Sweat From a Skin Surface

[0106] Devices, methods, and kits for collecting a fixed volume of sweat that has come to a skin surface are also provided. In some variations, and as appropriate, the devices, methods, and/or kits may have one or more of the same features as one or more of the devices, methods, and/or kits described above. After the fixed volume of sweat has been collected, it may then be interrogated by a measurement device to provide a sweat glucose measurement as the sweat that has come to the skin surface via sweat pores contains an amount of glucose that correlates to the blood glucose level of a patient. For example, the fixed volume may be less than about one-quarter microliter of sweat, about one-half microliter of sweat, about one microliter of sweat, about two microliters of sweat, about five microliters of sweat, about ten microliters of sweat, or any other suitable volume. Additional information about collecting sweat from the sweat pores is provided in U.S. Patent Application Publication No. US 2006/0004271 Al, entitled "Devices, Methods and Kits for Non-Invasive Glucose Measurement" by Thomas A. Peyser et al., which is hereby incorporated by reference herein in its entirety.

[0107] To determine when the fixed volume of sweat is collected, the skin patch may include a volume indicator. The volume indicator may include at least two electrodes which form a short circuit or an open circuit when the volume is collected. In other variations, the volume indicator may be chemical, mechanical, optical, or the like. The volume indicator may also operate concurrently or in conjunction with a measurement device.

[0108] The measurement device may be operated by coming into contact with the skin patch, for example, via optical or conductive measurement. The measurement device may, alternatively, receive the entire skin patch via an inlet. The measurement device may measure the sweat glucose level by any mechanism, including chemical, optical, and/or electro-mechanical mechanisms.

Devices

[0109] In some variations, the sweat collection device may be a skin patch, a chamber, a duct, or another device in fluid communication with one or more sweat pores. A sweat collection device may define a container having a fixed volume of, for example, less than one microliter. The container may be resistant to changes in shape or volume resulting from deformation, heat, or other conditions. In certain variations, the container may comprise an absorbent material configured to absorb only a fixed amount of sweat.

[0110] Figure 3a is a perspective view of a variation of a skin patch (300). The skin patch (300) may comprise one or more layers to form or define a container for collecting sweat. The skin patch (300) may maintain contact with the skin via an adhesive and/or any other suitable attachment mechanism (not shown) such as an elastic band, medical tape, or the like. In some variations, the skin patch (300) may be configured to remain in contact with the skin for one minute, two minutes, five minutes, ten minutes, fifteen minutes, twenty minutes, thirty minutes, or longer, depending on the amount of time required to collect a sufficient volume of sweat.

[0111] The skin patch (300) may have any appropriate shape (e.g., circular, as shown) and/or may be sized for a specific location on the body. For example, the skin patch (300) may be sized to attach to a fingertip. In other variations, the skin patch (300) may be sized and/or shaped to attach to another area of the hand, forearm, or other body location. The skin patch (300) may have a diameter of between about 10 mm and about 20 mm, about 20 mm and about 30 mm, about 30 mm and about 40 mm, and about 40 mm and about 50 mm. In some variations, the skin patch (300) may be another shape, such as a square, or triangle. In certain variations, the skin patch (300) may be a fun shape such as a star, heart, dinosaur, or the like.

[0112] The skin patch (300), as shown, includes three layers of the same size. However, it should be understood that the skin patch (300) may contain a greater or lesser number of layers and that the one or more layers need not have a uniform size and shape. For example, a layer defining a container may be smaller than another layer to reduce the effects of deformation of the skin patch (300) on the volume of the container. The layers may or may not have a uniform thickness. For example, the layers may overlap, interlock, or otherwise interface with one another. The layers need not be continuous or contiguous. For example, a layer may be formed by one or more pieces that fit together. In some variations, the layers may be fabricated using the same or different materials. In certain variations, one or more of the layers may be transparent, translucent, or opaque. The layers may be of different colors or the same color. [0113] The channel layer (302) may be configured to contact the skin and to draw sweat from one or more sweat pores into a container. In some variations, the channel layer (302) may also be configured to stimulate sweat production. For example, the channel layer (302) may be coated, impregnated, or saturated with pilocarpine or another compound known to stimulate sweat production. Alternatively, the channel layer (302) may include depots or reservoirs containing the compound and that release the compound when in contact with the skin. In some variations, the channel layer (302) may include reservoirs for sweat-inducing compounds and/or micropumps for delivering the sweat-inducing compounds to the skin in contact with or adjacent to the channel layer (302). In certain variations, the channel layer (302) may include one or more channels and/or grooves to direct the sweat to the container, as discussed in greater detail in connection with Figure 3c.

[0114] The skin patch (300) may also comprise one or more components to induce sweat by physical, chemical, or mechanical methods. For example, in one variation, the skin patch (300) may comprise pilocarpine and a penetration or permeation enhancer to induce sweat chemically or pharmacologically. Similarly, heat may be applied to the skin to increase the sweat response.

[0115] While not shown in the figures, the skin patch (300) may also include at least one release liner. For example, a release liner on the bottom adhesive surface may protect the adhesive layer from losing its adhesive properties during storage and prior to use. Similarly, a release liner may be placed on top of the upper interface layer to protect the optical and/or electrical components contained therein. In some variations, no release liner is used, and the interface layer is topped with a backing layer. 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.

[0116] To prevent the sweat collection device from collecting glucose from other sources, such as desquamation or diffusion, the channel layer (302) may comprise a sweat permeable membrane configured to collect only sweat being excreted by the sweat pores in contact with the channel layer (302). Examples of sweat permeable membranes include hydrophobic materials such as petrolatum, paraffin, mineral oils, silicone oils, vegetable oils, waxes, a liquid polymer coating such as the SILGARD® silicon polymer, an inorganic membrane such as the ANOPORE® inorganic membranes, a membrane filter such as the Whatman NUCLEOPORE® polycarbonate track-etch membrane filters, and the like. [0117] Alternatively or additionally, the channel layer (302) may be fabricated using one or more hydrophobic materials. Hydrophobic materials may be used to repel sweat from the bottom surface of channel layer (302) through an opening and into a hydrophilic container within the skin patch (300). The hydrophobic material may be selected based on flow properties, optical properties, conformability, viscoelasticity, flammability, toxicity, inertness, and/or the like. An example of a hydrophobic material that can be used in the manufacture of the channel layer (302) is polydimethylsiloxane (PDMS). One process that may be used to fabricate the channel layer (302) is discussed in greater detail in connection with Figures 4a through 4h.

[0118] The container layer (304) is configured to at least partially define a container that collects a fixed volume of sweat. The container layer (304) may be fabricated using a rigid material to prevent deformation and/or change in volume of the container. The fixed volume may be selected based on the sensitivity of the glucose detector and/or the amount of time required for collection of the volume of sweat. In some variations, the container layer (304) may be fabricated using polymethylmethacrylate (PMMA). The container layer (304) may be hydrophilic or may be made of any other suitable material. In certain variations, the channel layer (302) and/or the container layer (304) may comprise one or more micropumps configured to pump the sweat into the container from the skin in contact with the skin patch (300).

[0119] The vent layer (306) may be fabricated using PDMS, PMMA, and/or any other suitable material or materials. It may be desirable to fabricate the vent layer (306) from one or more hydrophobic materials to limit or prevent evaporation from the hydrophilic container layer (304) especially, for example, once the container is filled. The vent layer (306) comprises at least one vent (308) connecting the container to an external surface. The vent or vents (308) may comprise one or more lumens through the vent layer (306). In some variations, the inner surface of the vents (308) may be hydrophobic. The vents (308) may have any suitable cross-sectional geometry. For example, a vent (308) may have a circular, rectangular, regular, irregular, or any other suitable cross-sectional geometry. In addition, the vents (308) may be vertical, angled, curved, stepped, or any combination thereof. The vents (308) may or may not be configured to change shape if the skin patch (300) is deformed.

[0120] The vents (308) may provide an escape for air trapped in the skin patch (300) when it is applied to the skin and may facilitate the fluid flow of the skin patch (300). As the vents (308) become larger, however, the sweat in the container is more likely to evaporate. Thus, the size of the vents (308) may be balanced between being large enough to provide sufficient fluid flow and small enough to prevent a significant amount of sweat from evaporating. The vents (308) may completely or partially overlap a portion of the container. Partially overlapping the vents (308) may prevent some evaporation.

[0121] Figure 3b is a cross- sectional view of the skin patch (300) taken along line AA-AA of Figure 3a. The skin patch (300), as shown, may have a total height of between about 500 and about 1500 micrometers, although other suitable dimensions may also be used. In some variations, the total height may be between about 500 and about 700 micrometers, about 700 and about 900 micrometers, about 900 and about 1100 micrometers, about 1100 and about 1300 micrometers, and about 1300 and about 1500 micrometers. In certain variations, the total height of the skin patch (300) may be about 900 micrometers. The total height of the skin patch (300) may be determined based on, for example, manufacturing cost, durability, ease of use, materials used to manufacture the skin patch (300), or any other suitable factor.

[0122] As shown in the cross- sectional view, the channel layer (302) may comprise a plurality of microchannels (310) defined by channel walls (312). The microchannels (310) are positioned to direct sweat that has come to the surface of the skin to an opening (314). The dimensions of the channels may be adjusted based on, for example, a desired collection rate and efficiency. In some variations, the channel layer (302) may have a thickness of between 100 and 500 micrometers. For example, the thickness of the channel layer (302) may be between 100 and 200 micrometers, between 200 and 300 micrometers, between 300 and 400 micrometers, or between 400 and 500 micrometers. As an example, the thickness of the channel layer (302) may be about 215 micrometers. The microchannels (310) may each have a width of about 10 micrometers to about 100 micrometers and/or a depth of about 2 micrometers to about 50 micrometers. As an example, the microchannels (310) may each have a width of about 38 micrometers and/or a depth of about 15 micrometers. The channel walls (312) may each have a width of about 20 micrometers to about 250 micrometers. As an example, the channel walls (312) may each have a width of about 80 micrometers.

[0123] The opening (314) may be located at or near the center of the channel layer (302) to provide fluid communication between the skin surface and a container (316). In some variations, the channel layer (302) may include more than one opening. In certain variations, a surface of the opening (314) may be coated with one or more hydrophilic materials to attract the sweat from the microchannels (310). Alternatively or additionally, a microfruidic pump may be used to transport the sweat from the skin in contact with the channel layer (302) through the opening (314). To direct the sweat toward the opening (314) and into the container (316), the surface of the channel layer (302) may be hydrophobic. In some variations, the channel layer (302) may be fabricated using a hydrophobic material such as PDMS. Alternatively or additionally, the channel layer (302) may be at least partially coated with a hydrophobic material.

[0124] As shown in Figure 3b, the container layer (304) may at least partially define a container (316) configured to collect and hold a fixed volume of sweat. The fixed volume of sweat may be relatively small. In some variations, the fixed volume of sweat may be less than one microliter, less than 0.75 microliter, less than 0.5 microliter, less than 0.25 microliter, or less than 0.1 microliter. In certain variations, the container layer may have a thickness of approximately 100, 200, 500, 700, or 1,000 micrometers. To maintain the fixed volume, the container (316) may be rigid enough to retain its shape when the skin patch (300) is deformed. For example, the container layer (304) may be fabricated from a rigid material such as PMMA.

[0125] In the variations shown, the container (316) is rectangular in shape. However, the container (316) may be of any suitable shape. For example, the container (316) may be cylindrical. As shown, the depth of the container (316) is approximately equal to the thickness of the container layer (304). In some variations, the depth of the container (316) may be different from the depth of the container layer (304) depending on, for example, the geometry of the channel layer (302) and the vent layer (306). The container (316) may be shallower or deeper based on the shape of the container (316) and/or the fixed volume of sweat to be collected. In some variations, the container (316) may be shallower. In other variations, the container (316) may be deeper (e.g., to reduce sweat evaporation).

[0126] In the variations shown, the container (316) is defined by the channel layer (302), the container layer (304), and the vent layer (306). The bottom of the container (316) is defined by a top side of the channel layer (302). The sides of the container (316) are defined by the container layer (304). The top of the container (316) is defined by the vent layer (306). [0127] In alternative variations, the skin patch (300) may not include a vent layer (306). In these variations, sweat may be drawn into the container (316) using, for example, a pressure gradient. For example, the container (316) may be evacuated prior to application to the skin or a suction device may be coupled to the container (316) to provide a pressure gradient.

[0128] Because the channel layer (302) may be hydrophobic, its top surface may be at least coated with a hydrophilic coating (318) to attract the sweat into the container (316). Further, the opening (314) may also be coated with one or more hydrophilic materials. Hydrophilic materials that may be used include, but are not limited to, glass, 2-hydroxethyl methacrylate (HEMA), poly(oxyethylene) (POE), silicon dioxide, poly(ethylene glycol) (PEG), and polyacrylamide. In some variations in which the channel layer (302) is formed of PDMS, surface modifications of the PDMS may be performed by, for example, oxygen plasma treatments, or UV-mediated grafting.

[0129] The container (316) may include a volume indicator configured to indicate when the container (316) has collected the predetermined volume of sweat. The volume indicator may be electrical, mechanical, optical, chemical, or the like. For example, the top side of the container (316) may be coated with a sweat- sensitive or water-sensitive dye that changes color when the container (316) is full.

[0130] Alternatively, the container (316) may include electrodes that can provide a conductive path through the fixed volume reservoir when the reservoir is full. Changes in resistance or conductance at the top of the reservoir may be measured to determine when the container (316) has collected the fixed volume of sweat. The modest power required to drive a current through the circuit described here may be provided by an inductive coupling mechanism enclosed within a measurement device, a plastic battery, or the like.

[0131] Optical transmission may also be used to determine when the container (316) is filled. When on a skin surface, the skin patch (300) fills with sweat that has passed through the opening (314) and into the container (316). An optical transmission path is established with the container (316). In this way, the volume within the container (316) may be determined by a change in optical transmission (e.g., at the top of the container (316)). An optical fiber path may connect an optical source on one side of the skin patch (300) with an optical detector on the other. Changes in the measured transmission may indicate whether the fluid volume in the container (316) has reached a maximum. Power for the optical source and detector may be included in a measurement device.

[0132] Optical reflection may also be used to determine when the container (316) is filled. A transparent plate (not shown) may be located on the top of the container (316) and may comprise at least a portion of the vent layer (306). This plate may have an optical index of refraction close to that of sweat (about 1.33). Incident light may illuminate the interface between the container (316) and the plate. If the container is not full, the reflected light may have a high intensity because the optical index difference between the plate and air (which has an optical index of refraction of about 1.0) is high. If the container (316) is full, however, the reflected light has a low intensity because the optical index difference between the plate and sweat is low (both have an optical index of refraction of about 1.33). Thus, the drop in reflected light intensity may be used as an indicator that the container (316) is full. An optical source and detector may be included in a measurement device and the skin patch (300) may be interrogated via an optical interface.

[0133] The container (316) may comprise one or more enzymes used to measure glucose, such as glucose oxidase. The enzyme or enzymes may be deposited within the container so that the sweat contacts the enzyme or enzymes. In some variations, the container (316) may be adjacent to one or more wells or deposits of the enzyme or enzymes. One or more surfaces, including electrodes and/or optical components, may include or be coated with the enzyme or enzymes.

[0134] Figure 3c is an exploded view of the various layers of the skin patch of Figure 3a. As previously discussed, the skin patch (300) may comprise a channel layer (302), a container layer (304), and a vent layer (306). The layers may be adhered, glued, fastened, interlocked, welded, or otherwise suitably coupled together. As shown in Figure 3c, in some variations, one or more layers of the skin patch (300) may be adhered together using an adhesive (320). In certain variations, one or more layers of the skin patch (300) may include fasteners, slots, tabs, latches, or the like. In some variations, the layers of the skin patch (300) may include one or more interlocking features.

[0135] The adhesive (320) may comprise a permanent or temporary adhesive and may be selected based on the materials used to fabricate the layers. The adhesive (320) between the channel layer (302) and the container layer (304) may be the same as or different from the adhesive (320) between the container layer (304) and the vent layer (306). For example, one of the adhesives may be a temporary adhesive while the other may be a permanent adhesive. The adhesive (320) may be activated by heat, pressure, the presence of a solute, or any other appropriate bonding technique. In some variations, the adhesive (320) may comprise an acrylic adhesive such as those available from Cemedine Co., Ltd., Japan or a silyl urethane adhesive such as those available from Conishi Co., Ltd., Japan.

[0136] The above described devices are described herein for the purposes of illustration and are not intended to be limiting. Alternative and additional variations may be apparent to those skilled in the art.

Methods of Manufacture

[0137] Various methods may be used to manufacture the skin patch (300). In some variations, the layers may each be manufactured separately and later assembled. In other variations, the layers may be assembled during manufacture, for example, one layer may be fabricated directly on top of or beneath another layer. The layers may be cut, molded, or otherwise fabricated. In some variations, micro-molding techniques and/or photolithography techniques may be used. In other variations, other suitable techniques, such as micro- machining, may be used.

[0138] In some variations, the layers may be treated or modified prior to being assembled. The layers may, for example, be at least partially modified to change the hydrophobic or hydrophilic nature of the materials used. For example, a hydrophilic coating may be applied to at least a portion of a layer fabricated from a hydrophobic material such as PDMS. Hydrophilic materials that may be used include, but are not limited to, glass, 2- hydroxethyl methacrylate (HEMA), poly(oxyethylene) (POE), silicon dioxide, poly(ethylene glycol) (PEG), and polyacrylamide. Surface modifications of PDMS may also be performed by, for example, oxygen plasma treatments and/or UV-mediated grafting.

[0139] Additionally, one or more features may be added to the layers. These features may include electrodes, dyes, a transparent plate, an enzyme coating or deposit (e.g., glucose oxidase), or the like. The electrodes may be positioned so as to be in contact with a portion of the container (316) once the skin patch (300) is assembled. The electrodes may be electrically coupled to one or more leads or external electrodes that can be accessed by a volume indicator or a measurement device. Similarly, a dye, such as a visible dye or a fluorescent dye, may be coated or applied to a portion of at least one of the layers. The dye may be configured to react in response to the presence of sweat. In some instances, a dot of dye may be applied to a top side of the container (316) such that the dye will diffuse along the top of the container, changing the shape of the dot, when the container (316) is full.

[0140] An exemplary method for generating the skin patch (300) is described below for the purposes of illustration only. It should be understood that the methods may be performed in another order, performed in parallel, and/or steps may be added and/or combined. Further, depending on the specific circumstances at the time of fabrication and the materials used, temperatures, times, materials, and techniques may be changed.

Example

[0141] Figures 4a through 4h depict a variation of a method for manufacturing a channel layer (302) of a skin patch (300). As depicted in Figures 4a through 4c, a release layer (402) is generated. As shown in Figure 4a, to form the release layer (402), a negative- tone UV light-sensitive photoresist, such as an SU-8 dry film, of about 50 micrometers thick may be laminated on a four inch silicon wafer (400) under a vacuum using a laminating machine (e.g., VTM- 150M, Takatori Corporation, Japan) and then exposed under UV light (404) (22mw/cm2) for about 20 seconds.

[0142] Next, as shown in Figure 4b, to form a mold (406), an SU-8 dry film of about 15 micrometers may be laminated on the release layer (402). This layer may be exposed to UV light (404) through a mask (408) that defines the plurality of the channels of the channel layer (302) for about 18 seconds. After exposure, the wafer (400) may be baked on a hotplate at about 650C for one minute, and then at about 950C for five minutes. Next, the wafer (400) may be developed in a standard developing solution (available from, e.g., Nippon Kayaku Co., Ltd.) for one minute under stirring and dressed in a fresh developer for 15 seconds, and then rinsed using isopropyl alcohol (IPA) for about thirty seconds and de-ionized (DI) water for about three minutes followed by drying using nitrogen gas. To fabricate a rigid mold, the wafer (400) may be baked on the hotplate at 12O0C for about ten minutes.

[0143] As shown in Figure 4c, to complete the mold (406), an SU-8 layer of about 200 micrometers thick may be formed by laminating the SU-8 film of about 50 micrometers thick four times as described in connection with Figure 4b. The wafer (400) may be exposed under UV light (404) through another mask (410) for about eighty seconds. The mask (410) may define the location of the opening (314). The process of developing, rinsing, and baking may be performed as described above but the time for development for an SU-8 layer of 200 micrometers thick may be about 20 minutes. As a result, a mold (406) of the channel layer (302) may be formed.

[0144] Next, a PDMS prepolymer mixture (412) may be poured onto the mold (406), as depicted in Figure 4d. A PDMS prepolymer mixture may be obtained by mixing a curing agent (e.g., KE- 106, Shin-Etsu Chemical Co. Ltd, Japan) with PDMS prepolymer in a 1:10 volume ratio. After agitating the resulting PDMS prepolymer mixture (412) using a stir stick, the PDMS prepolymer mixture (412) may be degassed in a vacuum container for about one hour. The mold (406) may be heated on a hot plate for curing. After the mold (406) has been cured, it may be peeled off from the release layer (402) along with the PDMS.

[0145] The mold (406) may be peeled or otherwise removed from the channel layer (302), leaving the channel layer (302) behind, as depicted in Figures 4f through 4h. Figure 4f depicts a cross section of the channel layer (302) as discussed herein.

[0146] Figure 4g depicts the bottom side of the channel layer (302). The bottom side of the channel layer (302) may comprise a plurality of microchannels (310) defined by channel walls (312). In the depicted variations, the channel layer (302) comprises two main channels (320). The two main channels (320) may provide fluid communication with the opening (314). The main channels (320) bisect the channel layer (302) but other geometries may be used. The main channels (320) may have a depth and/or thickness larger than the depth and/or thickness of the microchannels (310). For example, the depth and/or thickness of the main channels (320) may be 1.1, 1.2, 1.5, 1.8, 2.0, 3.5, 5.0, or 10.0 times the depth and/or thickness of the microchannels (310).

[0147] Figure 4h depicts the top side of the channel layer (302). The top side includes the opening (314) and may be coated with a hydrophilic material. In some variations, the top side may have embedded therein one or more electrodes, chemical detectors, and/or mechanical indicators that form part, or all, of a volume indicator configured to indicate when the container (316) is full.

[0148] In some variations, the top side of the channel layer (302) and/or the interior surface of the channel layer (302) that defines the opening (314) may be coated with a hydrophilic material. The hydrophilic material may aid the transportation of the sweat from the skin surface to the container (316) by attracting water in the sweat. The hydrophilic material may be sprayed, painted, dropped, impregnated, or otherwise applied to the channel layer (302) by any appropriate means. In some variations where the channel layer (302) is fabricated using PDMS, which is hydrophobic, the hydrophilic material may comprise FOGCLEAR® hydrophilic gel (Unelko Corp., Scottsdale, Arizona).

[0149] In alternative variations, the PDMS may be treated according to methods known to those skilled in the art. These techniques may include coating the PDMS with glass, 2-hydroxethyl methacrylate (HEMA), poly(oxyethylene) (POE), silicon dioxide, poly(ethylene glycol) (PEG), and polyacrylamide. Surface modifications of the PDMS may also be performed by, for example, oxygen plasma treatments, or UV-mediated grafting. Various hydrophilic treatments for PDMS using these techniques are disclosed in, for example, Abate et al., "Glass coating for PDMS microfluidic channels by sol-gel methods," Lab Chip, 2008, 8, 516-518, 20 Feb. 2008; Bodas et al., "Formation of more stable hydrophilic surfaces of PDMS by plasma and chemical treatments," Microelectronic Engineering 83 (2006) 1277-1279, 23 Feb. 2006; Bodas et al., "Fabrication of long-term hydrophilic surfaces of poly(dimethyl siloxane) using 2-hydroxy ethyl methacrylate," Sensors and Actuators B 120 (2007) 719-723, 2 May 2006; Delamarche et al., "Microcontact Printing Using Poly(dimethylsiloxane) Stamps Hydrophilized by Poly(ethylene oxide) Silanes," Langmuir 2003, 19, 8749-8758, 11 Sept. 2003; Eddington et al., "Thermal aging and reduced hydrophobic recovery of polydimethylsiloxane," Sensors and Actuators B 114 (2006) 170-172, 4 June 2005; He et al., "Preparation of Hydrophilic Poly(dimethylsiloxane) Stamps by Plasma-Induced Grafting," Langmuir 2003, 19, 6982-6986, 19 July 2003; Hellmich et al., "Poly(oxyethylene) Based Surface Coatings for Poly(dimethylsiloxane) Microchannels," Langmuir 2005, 21, 7551-7557, 6 July 2005; Hu et al., "Surface-Directed, Graft Polymerization within Microfluidic Channels," Anal. Chem. 2004, 76, 1865-1870, 3 Mar. 2004; Hu et al., "Tailoring the Surface Properties of Poly(dimethylsiloxane) Microfluidic Devices," Langmuir 2004, 20, 5569-5574, 25 May 2004; Kim et al., "Long- Term Stability of Plasma Oxidized PDMS Surfaces," Proceedings of the 26th Annual International Conference of the IEEE EMBS San Francisco, CA, USA, 1-5 Sept. 2004; Makamba et al., "Stable Permanently Hydrophilic Protein-Resistant Thin-Film Coatings on Poly(dimethylsiloxane) Substrates by Electrostatic Self-Assembly and Chemical Cross- Linking" Anal. Chem. 2005, 77, 3971-3978, 20 May 2005; Roman et al. "Surface Engineering of Poly(dimethylsiloxane) Microfluidic Devices Using Transition Metal Sol-Gel Chemistry," Langmuir 2006, 22, 4445-4451, 25 March 2006; Roman et al, "Sol-Gel Modified Poly(dimethylsiloxane) Microfluidic Devices with High Electroosmotic Mobilities and Hydrophilic Channel Wall Characteristics," Anal. Chem. 2005, 77, 1414-1422, 1 Mar. 2005; Sharma et al., "Surface characterization of plasma- treated and PEG-grafted PDMS for micro fluidic applications," Vacuum 81 (2007) 1094-1100, 11 Feb. 2007; Vickers et al., "Generation of Hydrophilic Poly(dimethylsiloxane) for High-Performance Microchip Electrophoresis," Anal. Chem. 2006, 78, 7446-7452, 5 Oct. 2006; Wang et al., "Modification of poly(dimethylsiloxane) microfluidic channels with silica nanoparticles based on layer-by- layer assembly technique," Journal of Chromatography A, 1136 (2006) 111-117, 31 Oct. 2006; and Xiao et al., "Surface Modification of the Channels of Poly(dimethylsiloxane) Microfluidic Chips with Polyacrylamide for Fast Electrophoretic Separations of Proteins," Anal. Chem. 2004, 76, 2055-2061, 25 Feb. 2004.

[0150] Figures 5a through 5f depict an exemplary variation of a method for manufacturing the container layer (304) of the skin patch (300). The container layer (304) may form at least a portion of the side walls of the container (316) and may be fabricated using a hydrophilic material. To maintain a fixed shape, and a fixed volume, the container layer (304) may be rigid or substantially rigid. One material that may be used to fabricate the container layer (304) is PMMA.

[0151] The container layer (304) may be fabricated using similar methods as were used in fabricating the channel layer (302) as discussed in connection with Figures 4a-4h. In the depicted variations using photolithography techniques to create the container layer (304), the release liner (502) is formed on a wafer (500) using UV light (504) in Figure 5a. In Figure 5b, a mask (508) is used during lamination to define the shape of the mold (506) of the container layer (304). In some variations, the lamination may be repeated twice to produce a vent layer having a thickness of approximately 100 micrometers.

[0152] In Figures 5c and 5d, a prepolymer mixture (510) is poured into the mold (506). As discussed, the prepolymer mixture (510) may comprise PMMA. When PMMA is used, a curing agent may be mixed with the PMMA in about a 1:100 weight ratio. To prevent bubbles from forming and to release bubbles that do form, the PMMA may be slowly agitated using a stir stick and/or allowed to stand for about 10 minutes. The PMMA may be cured at room temperature for about two hours. After curing, the mold (506) may be peeled or otherwise removed from the container layer (304), as depicted in Figures 5e and 5f. [0153] Figures 6a through 6f depict a variation of a method for manufacturing a vent layer (306) of a skin patch (300). The vent layer (306) may form at least a portion of the top wall of the container (316) and may be fabricated using one or more hydrophilic or hydrophobic materials. To limit or prevent evaporation of sweat contained within the container (316) while still providing sufficient fluid flow, the vent layer (306) may include one or more vents (308) in fluid communication with the container (316). The vent layer (306) may be fabricated using PDMS, PMMA, or another suitable material.

[0154] The vent layer (306) may be fabricated using similar methods as were used in fabricating the channel layer (302) as discussed in connection with Figures 4a-4h. In the depicted variations using photolithography techniques to create the vent layer (306), the release liner (602) is formed on a wafer (600) using UV light (604) in Figure 6a. In Figure 6b, a mask (608) is used during lamination to define the shape of the mold (606) of the vent layer (306). In some variations, the lamination may be repeated ten times to produce a vent layer having a thickness of approximately 500 micrometers. In Figures 6c and 6d, a prepolymer mixture (610) is poured into the mold (606). After curing, the mold (606) may be peeled or otherwise removed from the vent layer (306), as depicted in Figures 6e and 6f.

[0155] In some variations, the container layer (304) may be fabricated with the channel layer (302) and/or the vent layer (306). For example, a bi-layer mold may be generated that, when filled, results in a single piece that operates as the channel layer (302) and the container layer (304) or that operates as the container layer (304) and the vent layer (306). The bi-layer mold may be filled with a single material (e.g., PMMA) or may be filled with two or more different materials. To illustrate, when the bi-layer mold is used to generate a single piece that operates as the container layer (304) and the vent layer (306), the mold may first be filled using a hydrophilic material to a first level and then filled using a hydrophobic material between the first level and a second level. The first level may be selected so that the surfaces defining the container (316) are hydrophilic while the surfaces of the vents (308) are hydrophobic. The bi-layer mold may be desirable, for example, in variations where an inaccurate alignment of the layers may significantly affect the fluid flow in the skin patch (300).

[0156] Figures 7a and 7b depict a variation of a method for molding the various layers. In some variations where the skin patch (300) comprises PDMS and PMMA, the molding process depicted in Figures 7a and 7b may be used. The molding method for the channel layer (302), the container layer (304), and the vent layer (306) of the skin patch (300) may be substantially the same in these variations.

[0157] For the purposes of illustration, the molding technique used in connection with the vent layer (306) is depicted. The wafer (600), release layer (602), and mold (606) filled with a prepolymer mixture (610) may be placed on a metal plate (702). The prepolymer mixture (610) may comprise PMDS or PMMA. After the prepolymer mixture (610) is poured onto the mold (606), a transparent film (706) may be placed over the prepolymer mixture (610). One end of the transparent film may be fixed by tape (708) at one side of the mold (608), as shown in Figure 7a. The transparent film (706) may be rolled along the top of the mold (606) slowly to prevent bubbles from forming at the interface.

[0158] As shown in Figure 7b, a rigid glass wafer (710) (e.g., a PYREX® glass wafer), a rubber sheet (712), metal plate (714), and weight block (716) may be stacked sequentially to form a compression mold. One technique for doing so is described by B-H et al., "Three- dimensional micro-channel fabrication in polydimethylsiloxane (PDMS) Elastomer," J. Micro electromech. Syst. Vol. 9 pp 76-81, 2000. The compression mold may be heated on the hotplate for curing (e.g., in variations where the prepolymer mixture (610) comprises PDMS). For PDMS, the curing time may be about 30 minutes at about 15O0C. In variations where one or more of the layers formed by a mold (e.g., mold (606)) is thicker than about 500 micrometers, a lower temperature and a longer time for curing may be used to avoid cracking of the mold. In one variation, the curing time may be about three hours at about 1000C. In variations where the prepolymer mixture (610) comprises PMMA, the PMMA may be cured at the room temperature for about two hours.

[0159] Figure 8 depicts a flow diagram of a variation of a method for assembling the various layers. Prior to assembly, one or more of the layers may be coated, shaped, or otherwise modified. In some variations, surfaces that define the container (316) may be coated with a hydrophilic material. For example, the channel layer (302) may be coated with a hydrophilic material along its top surface and along the interior of the opening (314). The bottom surface of the vent layer (306) may also be coated with a hydrophilic material. In some variations, the surfaces that define the container (316) and/or one or more electrodes in contact with the container (316) may be coated with an enzyme that reacts with the glucose in the sweat (e.g., glucose oxidase). [0160] In certain variations, components comprising a volume indicator may be disposed in the container (316) for indicating whether the predetermined volume of sweat has been collected. As discussed herein, the volume indicator may comprise two or more electrodes in contact with the container (316) that are connected to two or more electrodes on a top surface of the vent layer (306). The volume indicator may also be optical, chemical, mechanical, or the like.

[0161] The channel layer (302), the container layer (304), and the vent layer (306) may be assembled in any number of ways. In the variation shown, the channel layer (302) and the container layer (304) are first aligned and bonded together. The alignment may be performed using a stereomicroscope or be performed automatically. In some variations and as shown, the opening (314) and the container (316) are shaped such that the alignment step may be skipped. The channel layer (302) and the container layer (304) may be bonded together using a urethane or an acrylic adhesive at room temperature. Other adhesives may alternatively or additionally be used.

[0162] After the channel layer (302) and the container layer (304) are bonded together, the vent layer (306) may be bonded to the opposite surface of the container layer (304). Prior to bonding, the vent layer (306) may be aligned with the container (316) such that the vents (308) overlap, or partially overlap, the container (316). In some variations, the container (316) and/or the vents (308) may be symmetrically positioned and/or shaped such that the alignment step can be skipped. In other variations, the container layer (304) and the vent layer (306) may be manufactured as a single layer. A urethane adhesive and/or an acrylic adhesive may be used to bond the container layer (304) to the vent layer (306) at room temperature. Other bonding techniques or adhesives may also be used.

[0163] Although examples of methods of making a skin patch (300) have been described, it is understood that alternative or additional variations will be apparent to those skilled in the art. Further, it should be noted that the skin patch (300) may be fabricated using materials other than those specified here. The above disclosure is not intended to limit the scope of the present application. Methods of Use

[0164] The skin patch (300) may be used by a diabetic patient to collect sweat to measure his or her glucose level. The skin patch (300) may replace a finger stick or other methods of drawing blood. To use, the patient attaches the skin patch (300) to a target location on the surface of the skin. When the skin patch (300) has collected a sufficient volume of sweat, the patient may use a measurement device to quantitatively measure the sweat glucose level. The patient, based on the sweat glucose level or a blood glucose level that corresponds to the sweat glucose level, may self-administer insulin as needed. Prior to use, the patient may clean an area of skin to remove residual glucose present at the skin surface. Exemplary wipes that may be used are described in U.S. Patent Publication No. US 2003/0176775 Al, filed February 4, 2003 and entitled "Cleaning Kit for An Infrared Glucose Measurement System." For example, the patient may use a wipe impregnated with a cleanser that does not interfere with glucose detection and/or a surfactant that modifies one or more properties of the sweat and/or the skin surface (e.g., sodium lauryl sulfate (SLS)). In some variations, the wipe may contain a chemical marker that is identifiable by a measurement device to confirm that the skin was wiped before the sweat was collected in the skin patch (300). In certain variations, the wipes may contain a marker used to detect when the container (316) is filled. For example, the wipe may comprise a reactant that reacts with another chemical within the container (316) to indicate (e.g., via a color change) that the container (316) is filled.

[0165] The skin patch (300) may be attached to the surface of the skin in a number of ways. In some variations, the patient may remove a release liner from the bottom surface of the channel layer (302) to expose a pressure- sensitive adhesive that may adhere to the skin. In other variations, other adhesives may be used such as heat- sensitive or soluble adhesives. Alternatively, the skin patch (300) may be positioned using an elastic band configured to hold the skin patch (300) in place. In other variations, the patient may tape the skin patch (300) to the surface of the skin using, for example, medical tape, or may hold the skin patch (300) to the surface of the skin.

[0166] To determine when the predetermined volume is collected, the patient may consult a volume indicator. The volume indicator may be integrated into the skin patch (300) or may be interrogated by another device, such as a measurement device. In some variations, the patient may simply remove the skin patch (300) after a certain length of time, for example, one minute, two minutes, five minutes, or ten minutes.

[0167] After the predetermined volume is collected, the skin patch (300) may be interrogated using a measurement device. In some variations, the measurement device may be placed in contact with the skin patch (300) at one or more electrodes. In other variations, the skin patch (300) may be removed from the skin and inserted into, or otherwise contacted with, the measurement device. The skin patch (300) may be single-use only.

Measurement Device

[0168] As discussed above, a measurement device may be used to measure the amount of glucose in the sweat collected by the skin patch (300). In some variations, the measurement device may interrogate the skin patch (300). The device measures the total quantity of glucose present in a fixed volume, and then converts the glucose measurement into a sweat glucose or blood glucose concentration. In general, the measurement device typically comprises a display, to display data. The device may also include warning indicators (e.g., a word prompt, flashing lights, sounds, etc.) to indicate that a patient's glucose levels are dangerously high or dangerously low. In addition, 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 the measurement device detects the marker, then the measurement proceeds. If the measurement device does not detect the marker, the measurement does not proceed. In one variation, the measurement device provides an indication to the user, that the skin surface must be cleaned prior to use (e.g., using a word prompt, colored and/or flashing lights, and/or various sounds).

[0169] In some variations, the measurement device may be configured to estimate sweat flux. It may be desirable to use the sweat flux estimate to correct the sweat glucose measurement or to flag sweat collections that are above or below acceptable limits. Sweat flux is generally defined as the flow rate of the sweat. Sweat flux may vary in the presence of heat, stress, diaphoretic drugs, or other stimulus. For example, the amount of time from when the container (316) is about 10% full to when it is full may be measured to determine sweat flux. In these variations, the skin patch (300) (or a skin patch holder configured to hold a skin patch (300) at the surface of the skin) may comprise additional fill sensing and timing circuits.

[0170] The configuration of the measurement device is dependent on the configuration of the skin patch. For example, when the measurement device is to be used with a skin patch (300) having electrodes, the measurement device provides an electrical contact with the interface layer, and is either powered by the electrical contact, or is powered by an independent power source (e.g., a battery within the patch itself, etc.). The measurement device also typically comprises a computer processor to analyze data. Conversely, when the measurement device is configured for optical detection, the measurement device is configured to provide optical contact or interaction with the skin patch (300). In this variation, the measurement device also typically comprises a light source. In some variations, the measurement device comprises both the necessary electrical contacts and the necessary optics so that a single measurement device may be used with a patch having various configurations of patch layers.

[0171] The measurement device may further comprise computer executable code containing a calibration algorithm, which relates measured values of detected glucose to blood glucose values. For example, 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 one day to about a three 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 may be minimized.

[0172] 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 may be generated, which relates the measured sweat glucose to blood glucose. Patients can perform periodic calibrations checks with single blood glucose measurements, or total recalibrations as desirable or necessary.

[0173] The measurement device may also comprise a memory for saving readings and the like. The measurement device typically may comprise a processor configured to access the memory and execute computer executable code stored therein. It should be understood that the measurement device may include other hardware such as an application specific integrated circuit (ASIC). In addition, the measurement device may include a link (wireless, cable, and the like) to a computer. In this way, stored data may be transferred from the measurement device to the computer, for later analysis, etc. The measurement device may further comprise various buttons, to control the various functions of the device and to power the device on and off when necessary.

Kits

[0174] Also described here are kits. The kits may include one or more packaged skin patches, either alone, or in combination with other skin patches, a measurement device, and/or instructions. In one variation, the kits comprise at least one patch having a volume indicator. Typically the skin patches are individually packaged in sterile containers or wrappings and are configured for a single use.

Claims

CLAIMSWhat is claimed is:
1. A skin patch comprising: a first layer defining at least a portion of a first surface of a container and having an opening configured to collect sweat from skin; a second layer defining at least a portion of a second surface of the container opposite the first surface; a working electrode in contact with one surface of the container; and a counter electrode in contact with another surface of the container, wherein the container comprises a glucose enzyme and the skin patch is configured to interact with a glucose measurement device that measures a glucose concentration in sweat collected in the container based on a first signal between the working electrode and the counter electrode.
2. The skin patch of claim 1, further comprising: a first fill electrode in contact with a third surface of the container; and a second fill electrode in contact with a fourth surface of the container opposite the third surface, wherein the skin patch is further configured to interact with a glucose measurement device that, based on a second signal between the first fill electrode and the second fill electrode, evaluates whether the container contains a sufficient volume of sweat for measurement of a concentration of glucose in the volume of sweat.
3. The skin patch of claim 2, further comprising a third layer disposed between the first and second layers and defining the third and fourth surfaces.
4. The skin patch of claim 2, wherein the container has a dimension defining a distance between the first and second fill electrodes.
5. The skin patch of claim 2, wherein the skin patch is further configured to interact with a glucose measurement device that determines an amount of time required to fill the container with a volume of sweat sufficient for measurement of a concentration of glucose in the volume of sweat.
6. The skin patch of claim 1, further comprising a reference electrode configured to provide a consistent voltage between a ground and the working electrode.
7. The skin patch of claim 1, wherein the container has a dimension defining a distance between the working and counter electrodes.
8. The skin patch of claim 1, wherein the glucose enzyme comprises glucose oxidase or glucose dehydrogenase.
9. The skin patch of claim 1, wherein the container is configured to contain a volume of less than about 0.3 microliter.
10. The skin patch of claim 1, wherein the first surface is at least a portion of a bottom surface of the container and the second surface is at least a portion of a top surface of the container.
11. The skin patch of claim 1, wherein the opening is in a bottom surface of the container.
12. The skin patch of claim 1, wherein at least a portion of at least one surface of the container is hydrophilic.
13. A method comprising: collecting a volume of sweat from a skin surface into a container of a skin patch, wherein the container includes a glucose enzyme; detecting a first signal indicative of a reaction between glucose in the sweat and the glucose enzyme; and determining a glucose concentration in the volume of sweat based on the first signal.
14. The method of claim 13, wherein the first signal is selected from the group consisting of voltage, current, resistance, capacitance, impedance, and conductance.
15. The method of claim 13, further comprising: detecting a second signal indicative of the volume of sweat in the container; and determining whether the volume of sweat in the container is sufficient to provide an accurate measurement of glucose concentration in the volume of sweat.
16. The method of claim 15, wherein the volume of the sweat is less than about 1 microliter.
17. The method of claim 15, wherein the volume of the sweat is about 0.3 microliter.
18. The method of claim 13, wherein the glucose concentration in the volume of sweat is determined when the skin patch is in contact with the skin.
19. The method of claim 13, wherein the glucose concentration in the volume of sweat is determined when the skin patch is not in contact with the skin.
20. The method of claim 13, wherein the glucose concentration is between about 0.1 mg/dl and about 5 mg/dl.
21. A kit comprising: one or more skin patches each comprising a sweat collection container defined in part by a first layer of the skin patch and in part by a second layer of the skin patch, wherein the first and second layers comprise first and second electrodes, respectively, and wherein the second electrode is opposite the first electrode; and a glucose measurement device configured to measure a sweat glucose concentration based on a signal between the first and second electrodes.
22. The kit of claim 21, wherein at least one of the one or more skin patches is configured to measure a sweat glucose concentration of between about 0.1 mg/dl and about 5 mg/dl.
23. The kit of claim 21, wherein the glucose measurement device is configured to measure the sweat glucose concentration when at least one of the skin patches is affixed to a skin surface of a subject.
24. The kit of claim 21, wherein the glucose measurement device is configured to measure the sweat glucose concentration after at least one of the skin patches is removed from a skin surface of a subject.
25. The kit of claim 21, wherein the one or more skin patches are single-use.
26. The kit of claim 21, wherein the glucose measurement device is further configured to determine whether a sufficient volume of sweat has been collected in the sweat collection container prior to measuring the sweat glucose concentration.
27. The kit of claim 21, wherein the signal is selected from the group consisting of voltage, current, resistance, capacitance, impedance, and conductance.
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