ES2980736T3 - Analyte sensors with a sensing surface having small sensing spots - Google Patents

Abstract

Embodiments of the present disclosure relate to analyte determination methods and devices (e.g., electrochemical analyte monitoring systems) having a sensing surface including two or more sensing elements disposed laterally relative to one another, where the sensing surface is over a working electrode of in vivo and/or in vitro analyte sensors, e.g., continuous and/or automatic in vivo monitoring using analyte sensors and/or test strips. Systems and methods of using the analyte sensors, e.g., electrochemical, in analyte monitoring are also provided.

Description

DESCRIPTION

Analyte sensors with a sensing surface having small sensing spotsINTRODUCTION

[0001]In many cases, it is desirable or necessary to regularly monitor the concentration of particular constituents in a fluid.

[0002]There are several systems available that analyze the constituents of bodily fluids, such as blood, urine, and saliva. Examples of such systems conveniently monitor the level of particular medically significant fluid constituents, such as, for example, cholesterol, ketones, vitamins, proteins, and various metabolites or blood sugars, such as glucose. Diagnosis and treatment of patients suffering from diabetes mellitus, a disorder of the pancreas where insufficient insulin production prevents normal regulation of blood sugar levels, requires careful monitoring of blood glucose levels on a daily basis. Several systems are currently available that allow individuals to easily monitor their blood glucose. Such systems include electrochemical biosensors, including those comprising a glucose sensor that is adapted for insertion into a subcutaneous site within the body for continuous monitoring of glucose levels in the body fluid at the subcutaneous site (see, e.g., U.S. Patent No. 6,175,752 to Say et al.).

[0003] The person may obtain the blood sample by drawing blood from a blood source in his or her body, such as a vein, using a needle or syringe, for example, or by puncturing a portion of his or her skin, using a lancing device, for example, to make the blood available outside the skin, in order to obtain the sample volume necessary for the in vitro test. The person may then apply the fresh blood sample to a test strip, after which suitable detection procedures, such as calorimetric, electrochemical, or photometric detection procedures, for example, may be used to determine the person's actual blood glucose level. The above procedure provides a blood glucose concentration for a particular or isolated time point and should therefore be repeated periodically, in order to monitor blood glucose over a longer period.

[0004] In addition to the in vitro, discrete or periodic blood glucose monitoring systems described above, at least partially implantable, or in vivo, blood glucose monitoring systems that are constructed to provide a continuous in vivo measurement of an individual's blood glucose concentration have been described and developed.

[0005]Such analyte monitoring devices are constructed to provide continuous or automatic monitoring of analytes, such as glucose, in the bloodstream or interstitial fluid. Such devices include electrochemical sensors, at least a portion of which are operatively positioned in a blood vessel or subcutaneous tissue of a user.

[0006] While continuous glucose monitoring is desirable, there are several challenges associated with optimizing manufacturing protocols to improve the performance and uniformity of sensing elements of biosensors constructed for use in vivo. Accordingly, further development of manufacturing techniques and methods, as well as analyte monitoring devices, systems or kits employing them, is desirable. WO 2010/028708 describes an electrode system for measuring the concentration of an analyte under in vivo conditions, where the enzyme layer of the working electrode is provided in the form of multiple fields that are arranged at a distance from each other on the conductor of the working electrode. US 2009/198117 and US 2009/308742 describe analyte sensors having nanostructured electrodes. US 2008/214916 describes delivery of a fluid through a device or mechanism that is also capable of detecting one or more analytes in vivo. US 2005/230270 describes carbon nanotube nanoelectrode arrays for sensing. US 2005/051427 describes an electrode array for use in an electrochemical device.

SUMMARY

[0007]The present invention relates to an analyte sensor as defined in claim 1 and to a method as defined in claim 11. Preferred embodiments of the invention are defined in the dependent claims.

[0008]The following aspects and embodiments of the disclosure are also described, but not claimed.

[0009] Embodiments of the present disclosure relate to analyte determination methods and devices (e.g., electrochemical analyte monitoring systems) having a sensing surface including two or more sensing elements laterally disposed relative to one another, wherein the sensing surface is a working electrode of in vivo and/or in vitro analyte sensors, e.g., continuous and/or automatic in vivo monitoring using analyte sensors and/or test strips. Systems and methods of using, for example, electrochemical analyte sensors in analyte monitoring are also provided.

[0010] Aspects of the present disclosure include an analyte sensor including: a working electrode; and a counter electrode, wherein the working electrode includes a sensing surface having two or more sensing elements disposed laterally relative to one another, wherein each sensing element includes an enzyme sensitive to the analyte.

[0011] In certain embodiments, the sensing elements are discontinuous. In some cases, the sensing elements are arranged as individual sensing elements on the working electrode. For example, the sensing surface may include an array of two or more individual sensing elements. In some cases, the sensing surface includes an array of 100 or more individual sensing elements. In certain cases, the sensing surface has a sensing element density ranging from 2-1000 sensing elements/mm2.

[0012] In certain embodiments, the sensing surface further includes inter-feature areas. The inter-feature areas may surround the sensing elements. In some cases, the sensing elements have an inter-feature distance ranging from 1 µm to 500 µm. In certain cases, the inter-feature areas are free of the analyte-sensitive enzyme. In some cases, the inter-feature areas are free of a redox mediator.

[0013] In certain embodiments, the working electrode further includes a second layer of two or more sensing elements disposed on the sensing surface. In some cases, the sensing elements have an average diameter of 200 µm or less.

[0014]In certain embodiments, at least a portion of the analyte sensor is adapted to be placed subcutaneously in a subject.

[0015]In some cases, the analyte sensor further includes a membrane disposed over the sensing elements that restricts the flow of analyte to the sensing elements.

[0016]In some cases, the analyte-sensitive enzyme includes a glucose-sensitive enzyme. In certain cases, the sensing elements include a redox mediator. For example, the redox mediator may include a ruthenium-containing complex or an osmium-containing complex.

[0017] In certain embodiments, the analyte sensor is a glucose sensor. In some cases, the analyte sensor is an in vivo sensor. In other cases, the analyte sensor is an in vitro sensor.

[0018] Aspects of the present disclosure also include a method of monitoring a level of an analyte in a subject. The method includes placing at least a portion of an analyte sensor on the skin of a subject, and determining a level of an analyte over a period of time from signals generated by the analyte sensor, wherein the determination over a period of time provides monitoring of the level of the analyte in the subject. As described above, the analyte sensor includes: a working electrode; and a counter electrode, wherein the working electrode includes a sensing surface having two or more sensing elements disposed laterally relative to one another, wherein each sensing element includes an enzyme sensitive to the analyte.

[0019] In certain embodiments, the sensing elements are discontinuous. In some cases, the sensing elements are arranged as individual sensing elements on the working electrode. For example, the sensing surface may include an array of two or more individual sensing elements. In some cases, the sensing surface includes an array of 100 or more individual sensing elements. In certain cases, the sensing surface has a sensing element density ranging from 2-1000 sensing elements/mm2.

[0020] In certain embodiments, the sensing surface further includes inter-feature areas. The inter-feature areas may surround the sensing elements. In some cases, the sensing elements have an inter-feature distance ranging from 1 µm to 500 µm. In certain cases, the inter-feature areas are free of the analyte-sensitive enzyme. In some cases, the inter-feature areas are free of a redox mediator.

[0021] In certain embodiments, the working electrode further includes a second layer of two or more sensing elements disposed on the sensing surface. In some cases, the sensing elements have an average diameter of 200 µm or less.

[0022] In certain embodiments, at least a portion of the analyte sensor is adapted to be placed subcutaneously in a subject.

[0023] In some cases, the analyte sensor further includes a membrane disposed over the sensing elements that restricts the flow of analyte to the sensing elements.

[0024] In some cases, the analyte-sensitive enzyme includes a glucose-sensitive enzyme. In certain cases, the sensing elements include a redox mediator. For example, the redox mediator may include a ruthenium-containing complex or an osmium-containing complex.

[0025] In certain embodiments, the analyte sensor is a glucose sensor. In some cases, the analyte sensor is an in vivo sensor. In other cases, the analyte sensor is an in vitro sensor.

[0026] Aspects of the present disclosure further include a method of monitoring a level of an analyte using an analyte monitoring system. The method includes: inserting at least a portion of an analyte sensor into the skin of a patient; attaching a control unit of the analyte sensor to the skin of the patient; coupling a plurality of conductive contacts of the analyte sensor control unit to a plurality of contact pads of the analyte sensor; collecting data, using the analyte sensor control unit, regarding a level of an analyte from signals generated by the analyte sensor; and transmitting the collected data from the analyte sensor control unit to a receiving unit. As described above, the analyte sensor includes a working electrode and a counter electrode, wherein the working electrode includes a sensing surface having two or more sensing elements laterally disposed relative to one another, wherein each sensing element includes an analyte-sensitive enzyme.

[0027] In certain embodiments, the sensing elements are discontinuous. In some cases, the sensing elements are arranged as individual sensing elements on the working electrode. For example, the sensing surface may include an array of two or more individual sensing elements. In some cases, the sensing surface includes an array of 100 or more individual sensing elements. In certain cases, the sensing surface has a sensing element density ranging from 2-1000 sensing elements/mm2.

[0028] In certain embodiments, the sensing surface further includes inter-feature areas. The inter-feature areas may surround the sensing elements. In some cases, the sensing elements have an inter-feature distance ranging from 1 µm to 500 µm. In certain cases, the inter-feature areas are free of the analyte-sensitive enzyme. In some cases, the inter-feature areas are free of a redox mediator.

[0029] In certain embodiments, the working electrode further includes a second layer of two or more sensing elements disposed on the sensing surface. In some cases, the sensing elements have an average diameter of 200 µm or less.

[0030] In certain embodiments, the analyte is glucose.

[0031] In some cases, data collection includes generating analyte sensor signals and processing the signals into data. In certain cases, the data comprises the analyte sensor signals.

[0032] In certain embodiments, the method further includes triggering an alarm if the data indicates an alarm condition. In some cases, the method further includes administering a drug in response to the data. For example, the drug may be insulin.

[0033] In certain cases, the procedure does not include a calibration step.

[0034] Aspects of the present disclosure also include a method of manufacturing an electrode for use in an analyte sensor. The method includes contacting a sensing surface of a working electrode with two or more sensing elements disposed laterally relative to one another, wherein each sensing element comprises an analyte-sensitive enzyme.

[0035] In certain embodiments, the sensing elements are discontinuous. In some cases, the sensing elements are arranged as individual sensing elements on the working electrode. For example, the sensing surface may include an array of two or more individual sensing elements. In some cases, the sensing surface includes an array of 100 or more individual sensing elements. In certain cases, the sensing surface has a sensing element density ranging from 2-1000 sensing elements/mm2.

[0036] In certain embodiments, the sensing surface further includes inter-feature areas. The inter-feature areas may surround the sensing elements. In some cases, the sensing elements have an inter-feature distance ranging from 1 µm to 500 µm. In certain cases, the inter-feature areas are free of the analyte-sensitive enzyme. In some cases, the inter-feature areas are free of a redox mediator.

[0037] In certain embodiments, the working electrode further includes a second layer of two or more sensing elements disposed on the sensing surface. In some cases, the sensing elements have an average diameter of 200 µm or less.

[0038] In certain embodiments, the method is a method of manufacturing two or more electrodes for use in a plurality of analyte sensors. In these embodiments, the method includes contacting a sensing surface on each of the two or more electrodes with two or more sensing elements disposed laterally relative to one another, where each sensing element comprises an enzyme sensitive to the analyte. In some cases, the electrodes have a coefficient of variation in sensitivity of 8% or less.

[0039] In certain cases, at least a portion of the analyte sensor is adapted to be placed subcutaneously in a subject. In some cases, the analyte sensor further includes a membrane disposed over the sensing elements.

[0040] In certain embodiments, the analyte-responsive enzyme includes a glucose-responsive enzyme. In some cases, the sensing elements include a redox mediator. For example, the redox mediator may include a ruthenium-containing complex or an osmium-containing complex.

[0041] In certain cases, the analyte sensor is a glucose sensor. In some cases, the analyte sensor is an in vivo sensor. In other cases, the analyte sensor is an in vitro sensor.

[0042] In certain embodiments of the method, contacting includes depositing one or more droplets comprising the sensing elements onto the sensing surface of the working electrode. In some cases, the method further includes contacting the sensing elements with a membrane that restricts the flow of analyte to the sensing elements.

[0043] Aspects of the present disclosure also include an analyte test strip including: a first substrate having a first surface; a second substrate having a second surface opposite the first surface, the first and second substrates arranged such that the first surface is in facing relationship with the second surface; a working electrode disposed on the first surface; and a counter electrode disposed on one of the first surface and the second surface, wherein the working electrode includes a sensing surface having two or more sensing elements disposed laterally relative to one another, wherein each sensing element includes an enzyme sensitive to the analyte.

[0044] In certain embodiments, the sensing elements are discontinuous. In some cases, the sensing elements are arranged as individual sensing elements on the working electrode. For example, the sensing surface may include an array of two or more individual sensing elements. In some cases, the sensing surface includes an array of 100 or more individual sensing elements. In certain cases, the sensing surface has a sensing element density ranging from 2-1000 sensing elements/mm2.

[0045] In certain embodiments, the sensing surface further includes inter-feature areas. The inter-feature areas may surround the sensing elements. In some cases, the sensing elements have an inter-feature distance ranging from 1 µm to 500 µm. In certain cases, the inter-feature areas are free of the analyte-sensitive enzyme. In some cases, the inter-feature areas are free of a redox mediator.

[0046] In certain embodiments, the working electrode further includes a second layer of two or more sensing elements disposed on the sensing surface. In some cases, the sensing elements have an average diameter of 200 µm or less.

[0047] In certain embodiments, the analyte test strip further includes a spacer between the first substrate and the second substrate.

[0048] In some cases, the analyte-sensitive enzyme includes a glucose-sensitive enzyme. In certain cases, the sensing elements include a redox mediator. For example, the redox mediator may include a ruthenium-containing complex or an osmium-containing complex.

[0049]In certain embodiments, the analyte test strip is a glucose test strip.

[0050] Aspects of the present disclosure further include a method for monitoring a level of an analyte in a subject. The method includes contacting a sample from a subject with an analyte test strip and determining a level of an analyte from a signal generated by the analyte test strip, wherein the determination provides for monitoring the level of the analyte in the subject. As described above, the analyte test strip includes: a first substrate having a first surface; a second substrate having a second surface opposite the first surface, the first and second substrates being arranged such that the first surface is in facing relationship with the second surface; a working electrode disposed on the first surface; and a counter electrode disposed on one of the first surface and the second surface, wherein the working electrode includes a sensing surface having two or more sensing elements disposed laterally relative to one another, wherein each sensing element includes an enzyme sensitive to the analyte.

[0051] In certain embodiments, the sensing elements are discontinuous. In some cases, the sensing elements are arranged as individual sensing elements on the working electrode. For example, the sensing surface may include an array of two or more individual sensing elements. In some cases, the sensing surface includes an array of 100 or more individual sensing elements. In certain cases, the sensing surface has a sensing element density ranging from 2-1000 sensing elements/mm2.

[0052] In certain embodiments, the sensing surface further includes inter-feature areas. The inter-feature areas may surround the sensing elements. In some cases, the sensing elements have an inter-feature distance ranging from 1 µm to 500 µm. In certain cases, the inter-feature areas are free of the analyte-sensitive enzyme. In some cases, the inter-feature areas are free of a redox mediator.

[0053] In certain embodiments, the working electrode further includes a second layer of two or more sensing elements disposed on the sensing surface. In some cases, the sensing elements have an average diameter of 200 µm or less.

[0054]In certain embodiments, the method further includes a spacer between the first substrate and the second substrate.

[0055]In some cases, the analyte-sensitive enzyme includes a glucose-sensitive enzyme. In certain cases, the sensing elements include a redox mediator. For example, the redox mediator may include a ruthenium-containing complex or an osmium-containing complex.

[0056]In certain embodiments, the analyte test strip is a glucose test strip.

[0057] Aspects of the present disclosure also include a method of monitoring a level of an analyte using an analyte monitoring system. The method includes: coupling a conductive contact of an analyte test strip to an analyte monitoring system; contacting a sample from a subject with the analyte test strip; collecting data, using the analyte monitoring system, regarding a level of an analyte from a signal generated by the analyte test strip; and determining a level of an analyte from the collected data, wherein the determination enables monitoring of the level of the analyte in the subject. As discussed above, the analyte test strip includes: a first substrate having a first surface; a second substrate having a second surface opposite the first surface, the first and second substrates being disposed such that the first surface is in facing relationship with the second surface; a working electrode disposed on the first surface; and a counter electrode disposed on one of the first surface and the second surface, wherein the working electrode includes a sensing surface having two or more sensing elements disposed laterally relative to each other, wherein each sensing element includes an analyte-sensitive enzyme.

[0058] In certain embodiments, the sensing elements are discontinuous. In some cases, the sensing elements are arranged as individual sensing elements on the working electrode. For example, the sensing surface may include an array of two or more individual sensing elements. In some cases, the sensing surface includes an array of 100 or more individual sensing elements. In certain cases, the sensing surface has a sensing element density ranging from 2-1000 sensing elements/mm2.

[0059] In certain embodiments, the sensing surface further includes inter-feature areas. The inter-feature areas may surround the sensing elements. In some cases, the sensing elements have an inter-feature distance ranging from 1 µm to 500 µm. In certain cases, the inter-feature areas are free of the analyte-sensitive enzyme. In some cases, the inter-feature areas are free of a redox mediator.

[0060] In certain embodiments, the working electrode further includes a second layer of two or more sensing elements disposed on the sensing surface. In some cases, the sensing elements have an average diameter of 200 µm or less.

[0061] In certain embodiments, the analyte is glucose.

[0062] In some embodiments of the method, collecting data includes generating the signal from the analyte test strip and processing the signal into data. In certain embodiments, the data includes the signals from the analyte test strip.

[0063] In certain cases, the method further includes triggering an alarm if the data indicates an alarm condition. In some cases, the method further includes administering a drug in response to the data. For example, the drug may be insulin.

[0064] In certain embodiments, the method does not include a calibration step.

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] A detailed description of various embodiments of the present disclosure is provided herein with reference to the accompanying drawings, which are briefly described below. The drawings are illustrative and have not necessarily been drawn to scale. The drawings illustrate various embodiments of the present disclosure and may illustrate one or more embodiments or examples of the present disclosure in whole or in part. A reference number, letter and/or symbol used in one drawing to refer to a particular element may be used in another drawing to refer to a similar element.

Figure 1 shows a block diagram of one embodiment of an analyte monitoring system according to embodiments of the present disclosure.

Figure 2 shows a block diagram of one embodiment of a data processing unit of the analyte monitoring system shown in Figure 1.

Figure 3 shows a block diagram of one embodiment of the primary receiving unit of the analyte monitoring system of Figure 1;

Figure 4 shows a schematic diagram of one embodiment of an analyte sensor according to embodiments of the present disclosure.

Figures 5A-5B illustrate a perspective view and a cross-sectional view, respectively, of one embodiment of an analyte sensor.

Figure 5C shows a schematic view of a working electrode according to embodiments of the present disclosure.

Figure 6 shows a photograph of a working electrode coated with six sensing elements with a radius of approximately 150 pm each at a distance of approximately 150 pm from each other. The resulting sensors have a coefficient of variation in sensitivity of 5% or less.

Figure 7A shows a perspective view of one embodiment of an analyte sensor having an array of sensor elements in substantially aligned rows according to embodiments of the present disclosure. Figure 7B shows a perspective view of another embodiment of an analyte sensor having an array of sensor elements in offset rows according to embodiments of the present disclosure.

Figure 8 shows a perspective view of one embodiment of an analyte sensor having an array of sensing elements in offset rows with minimal areas between features according to embodiments of the present disclosure.

Figure 9 shows a perspective view of one embodiment of an analyte sensor having layered arrays of sensor elements according to embodiments of the present disclosure.

Figure 10 shows a cross-sectional view of a working electrode having a plurality of sensing elements on the surface of a working electrode according to embodiments of the present disclosure. Figure 11 shows an exploded perspective view of an analyte sensor test strip, the layers are illustrated individually with the electrodes in a first configuration according to embodiments of the present disclosure.

Figure 12 shows an exploded perspective view of an analyte sensor test strip, the layers are illustrated individually with the electrodes in a second configuration according to embodiments of the present disclosure.

Figure 13 shows a graph of current (gA) versus time (seconds) for a sensing layer formulation deposited as an array of small sensing elements vs. a strip coating in accordance with embodiments of the present disclosure.

DETAILED DESCRIPTION

[0066] Before describing the embodiments of the present disclosure, it is to be understood that this invention is not limited to the particular embodiments described, as they may, of course, vary. It is also to be understood that the terminology used in this invention is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the embodiments of the invention will be incorporated by the appended claims. The following description will also relate to analyte sensors comprising contiguous sensing elements disposed on a working electrode. Such analyte sensors do not form part of the claimed invention.

[0067] Where a range of values is given, it is understood that each intermediate value, up to one-tenth of a unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically described. Each smaller range between any stated value or intermediate value in a stated range and any other stated or intermediate value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may be independently included or excluded in the range, and each range where neither or both limits are included in the smaller ranges is also included within the present disclosure, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of those limits, ranges that exclude both or one of those included limits are also encompassed by the invention.

[0068] In describing the invention herein, it will be understood that a word appearing in the singular encompasses its plural counterpart, and a word appearing in the plural encompasses its singular counterpart, unless otherwise implied or explicitly understood. Merely by way of example, reference to "an" or "the" "analyte" encompasses a single analyte as well as a combination and/or mixture of two or more different analytes, reference to "a" or "the" "concentration value" encompasses a single concentration value as well as two or more concentration values, and the like, unless otherwise implied or explicitly understood. Furthermore, it will be understood that for any given component described herein, any of the possible candidates or alternatives listed for that component, generally may be used singly or in combination with each other, unless otherwise implied or explicitly understood. Furthermore, it will be understood that any listing of such candidates or alternatives is merely illustrative, not limiting, unless otherwise implied or explicitly understood.

[0069] Various terms are described below to facilitate understanding of the invention. It will be understood that a corresponding description of these various terms applies to corresponding linguistic or grammatical variations or forms of these various terms. It will also be understood that the invention is not limited to the terminology used in this invention, or the descriptions thereof, for the description of particular embodiments. Merely by way of example, the invention is not limited to particular analytes, body or tissue fluids, blood or capillary blood, or sensor constructions or uses, unless otherwise implied or explicitly understood or indicated, as these may vary.

[0070] The publications discussed herein are provided solely for description prior to the filing date of the application. Nothing contained herein should be construed as an admission that embodiments of the invention are not entitled to antedate such publication by virtue of prior invention. Furthermore, the publication dates provided may be different from the actual publication dates which may need to be independently confirmed.

Systems and procedures that have two or more detection elements

[0071] Embodiments of the present disclosure relate to methods and devices for reducing variation in sensor sensitivity by including a sensing surface that includes two or more sensing elements laterally disposed relative to one another, where the sensing surface is at a working electrode of the sensor, such as in vivo and/or in vitro analyte sensors, including continuous and/or automated in vivo analyte sensors. For example, embodiments of the present disclosure provide a sensing surface of a working electrode that includes an array of two or more individual sensing elements, resulting in a decrease in variation in sensor sensitivity between individual sensors. Systems and methods of using the analyte sensors in analyte monitoring are also provided.

[0072] Embodiments of the present disclosure are based on the discovery that deposition of two or more sensing elements laterally disposed relative to one another on a sensing surface of a working electrode in the fabrication of in vivo and/or in vitro biosensors reduces variation in sensor sensitivity between sensors. In certain embodiments, a sensor that includes two or more sensing elements laterally disposed relative to one another on a sensing surface of a working electrode has a variation in sensor sensitivity that is less than a sensor with a single, larger sensing element. Stated another way, sensors may have a smaller variation in sensor sensitivity for a sensor that includes two or more sensing elements laterally disposed relative to one another on a sensing surface of a working electrode such that the total sensing element area per sensor is less than a sensor that has a single, larger sensing element with a larger total sensing element area per sensor. In certain embodiments, sensors including two or more sensing elements laterally disposed relative to each other on a sensing surface of a working electrode have a coefficient of variation in sensitivity of 20% or less, such as 15% or less, including 10% or less, such as 8% or less, or 5% or less, or 3% or less, or 2% or less, or 1% or less.

[0073] During the process of manufacturing the subject analyte sensors, an aqueous solution (e.g., a sensing element formulation) is contacted with a surface of a substrate (e.g., a surface of a working electrode), forming a deposition of the solution (e.g., a sensing element) on the surface of the substrate. The sensing elements may include an enzyme sensitive to the analyte. In certain cases, the sensing elements include a redox mediator. In some cases not covered by the claimed invention, the sensing element formulation is deposited such that the sensing elements are non-continuous. By "non-contiguous" it is meant that a sensing element does not share an edge (e.g., is not touching) an adjacent sensing element. For example, the sensing elements may be arranged as individual (e.g., discrete) sensing elements on the surface of the working electrode. In accordance with the claimed invention, the sensing elements are deposited on the surface of the working electrode in such a manner that the edges of the sensing elements come into contact with the edges of one or more adjacent sensing elements. In these embodiments, the sensing elements may be referred to as "adjacent".

[0074] In certain embodiments, the sensing surface includes an array of two or more individual sensing elements on the working electrode. As used herein, the term "array" refers to any one-dimensional, two-dimensional, or substantially two-dimensional (as well as three-dimensional) arrangement of regions having a particular composition associated with that region. In some cases, the arrays are arrays of a formulation, such as a sensing element formulation. As such, in some embodiments, the arrays are arrays of individual sensing elements, where each sensing element includes a sensing element formulation.

[0075] Any given substrate may carry one, two, four or more arrays of sensing elements disposed on a surface of the substrate. Depending on the use, any or all of the arrays may be the same or different from each other and each may contain multiple points or features (e.g., sensing elements). For example, an array may include two or more, 5 or more, ten or more, 25 or more, 50 or more, 100 or more features, or even 1000 or more features, in an area of 100 mm2 or less, such as 75 mm2 or less, or 50 mm2 or less, for example 25 mm2 or less, or 10 mm2 or less, or 5 mm2 or less, such as 2 mm2 or less, or 1 mm2 or less, 0.5 mm2 or less, or 0.1 mm2 or less. For example, the features may have widths (i.e., diameter, for a round spot) in the range of 0.1 µm to 1 mm, or 1 µm to 1 mm, such as ranging from 1 µm to 500 µm, including 10 µm to 250 µm, for example 50 µm to 200 µm. In certain embodiments, the sensing elements have an average diameter of 500 µm or less, such as 250 µm or less, including 200 µm or less, or 150 µm or less, or 100 µm or less, such as 50 µm or less, or 10 µm or less, or 1 µm or less, or 0.1 µm or less. Non-round features may have area ranges equivalent to those of circular features with the above width (diameter) ranges.

[0076] In certain embodiments, the sensing surface includes inter-feature areas. The inter-feature areas do not carry any sensing element formulation. As such, in some cases, the inter-feature areas do not include (e.g., are substantially free of) an analyte-sensitive enzyme. Further, in some cases, the inter-feature areas do not include (e.g., are substantially free of) a redox mediator or covalently or non-covalently bound polymeric redox mediator. The inter-feature areas may substantially surround the sensing elements, such that, as described herein, the sensing elements are discontinuous. In some cases, the sensing elements have inter-feature areas, where the distance between adjacent sensing elements (e.g., the inter-feature distance) is such that analyte flow to one sensing element does not significantly interfere with analyte flow to adjacent sensing elements. For example, the inter-feature spacing may be 0.1 µm or more, 0.5 µm or more, 1 µm or more, such as 10 µm or more, including 50 µm or more, or 100 µm or more, or 150 µm or more, or 200 µm or more, or 250 µm or more, for example 500 µm or more. The inter-feature spacing may range from 0.1 µm to 500 µm, or from 0.5 µm to 500 µm, or from 1 µm to 500 µm, such as from 1 µm to 250 µm, including from 5 µm to 200 µm, for example from 10 µm to 200 µm. Such inter-feature areas may be present when the arrays are formed by methods involving the deposition of droplets of the sensing element formulation onto a sensing surface of a working electrode, as described in more detail below. It will be appreciated that the areas between features, where present, could be of various sizes and configurations.

[0077] Each array may cover an area of 100 mm2 or less, or 50 mm2, or 25 mm2 or less, such as 10 mm2, 5 mm2 or less, 1 mm2 or less, or 0.1 mm2 or less, or 0.01 mm2 or less, for example 0.001 mm2 or less. In some embodiments, the sensing surface has a sensing element density of 2 sensing elements/mm2 or more, such as 5 sensing elements/mm2 or more, including 10 sensing elements/mm2 or more, or 50 sensing elements/mm2 or more, or 100 sensing elements/mm2 or more, such as 250 sensing elements/mm2 or more, including 500 sensing elements/mm2 or more, or 1000 sensing elements/mm2 or more. For example, the sensing surface may have a sensing element density ranging from 2-1000 sensing elements/mm2, such as 2-500 sensing elements/mm2, including 2-250 sensing elements/mm2, or 2-100 sensing elements/mm2, or 2-50 sensing elements/mm2, such as 2-10 sensing elements/mm2.

[0078] Arrays may be fabricated using drop deposition of the sensing element formulation onto a sensing surface of a working electrode. For example, the sensing element formulation may be deposited by any non-impact or impact printing method, such as, for example, from a pulse jet device. A "pulse jet" is a device that can dispense droplets into the formation of an array. Pulse jet devices operate by delivering a pressure pulse to the liquid adjacent an outlet or orifice such that a droplet will be dispensed therefrom (e.g., by a piezoelectric or thermoelectric element positioned in the same chamber as the orifice). In certain embodiments, the droplets may be dispensed using a dispensing device configured to operate in a manner similar to an inkjet printing device, as described above. In certain embodiments, the pulse jet device includes a dispensing head configured to dispense droplets, such as, but not limited to, sensing layer formulation, into the formation of an array. The dispensing head may be of a type commonly used in an inkjet type printer and may, for example, include one or more deposition chambers for holding the formulation(s) to be deposited. The amount of fluid that is deposited in a single pulse jet activation event may be controlled by changing one or more of a number of parameters, including the size of the orifice in the dispensing head (e.g., orifice diameter), the size of the deposition chamber, the size of the piezoelectric or thermoelectric element, etc. The amount of fluid deposited during a single activation event may range from 0.01 to 1000 picoliters (pL), such as 0.1 to 750 pL, even 1 to 500 pL, or 1 to 250 pL, or 1 to 100 pL, for example 1 to 75 pL, or 1 to 50 pL, such as 1 to 25 pL, or 1 to 10 pL, for example 1 to 5 pL. In certain cases, the amount of fluid deposited during a single activation event may range from 1 to 50 pL.

[0079] In certain embodiments, during the process of manufacturing the subject analyte sensors, an aqueous solution (e.g., a sensing layer formulation) is contacted with a surface of a substrate (e.g., a surface of a working electrode), forming a deposition of the solution on the surface of the substrate. In some cases, the solution is allowed to dry and cure. Without being limited to any particular theory, in certain cases, during drying, constituents of the solution may tend to migrate toward the outer edges of the deposition due to a faster evaporation rate at the thinner peripheral edges of the deposition. This results in a higher concentration of the solution constituents at the peripheral edges of the deposition, resulting in the so-called "coffee ring" effect. Analyte sensors are typically fabricated by depositing a relatively large strip or drop of a sensing layer formulation onto the surface of an electrode, which, in some cases, may result in a "coffee ring" effect as described above. For example, as described above, when an elongated stripe of sensing layer formulation is dried on the electrode surface, constituents in the sensing layer formulation may migrate toward the outer edges of the stripe, resulting in uneven coating of the sensing layer formulation on the electrode surface with a higher concentration of the sensing layer formulation near the edges of the sensing layer stripe.

[0080] In certain embodiments of the present disclosure, deposition of an array of small sensing elements may result in a reduction, and in some cases, complete elimination of the "coffee ring" effect. For example, the coffee ring effect may be minimized by depositing an array of two or more individual sensing elements on the working electrode. In some cases, due to their small size, the small sensing elements in the array have an evaporation rate that is greater than the evaporation rate of a sensing layer formulation deposited as a relatively large strip or droplet on the electrode surface. In certain embodiments, the faster evaporation rate results in a more uniform distribution of the constituents of the deposited solution on the substrate upon drying and curing compared to a solution deposited as a relatively larger strip or droplet of the sensing layer formulation. This, in turn, may improve the coefficient of variation and the overall manufacturing process of the sensor and overall system. In certain embodiments, small sensing elements may facilitate faster sensor fabrication due to faster drying of the very small sensing element spots, even at room temperature. Drying time may be further decreased by drying the sensing elements above room temperature, such as at a temperature of 25-100 °C, such as 30-80 °C, including 40-60 °C.

[0081] In some cases, each sensing element (e.g., array feature) has a volume ranging from 0.01 to 1000 picoliters (pL), such as 0.1 to 750 pL, even 1 to 500 pL, or 1 to 250 pL, or 1 to 100 pL, for example 1 to 75 pL, or 1 to 50 pL, such as 1 to 25 pL, or 1 to 10 pL, for example 1 to 5 pL. In certain cases, each sensing element has a volume ranging from 1 to 50 pL. As described above, the array of sensing elements may be deposited on the electrode surface such that there is an inter-feature area between each individual sensing element in the array, such that the sensing elements are discontinuous.

[0082] In certain embodiments, a single layer of sensing elements is deposited on the surface of the working electrode. In other cases, two or more layers of sensing elements are deposited on the surface of the working electrode. For example, the working electrode may include a sensing surface that includes a first layer of sensing elements as described above, and may further include a second layer of sensing elements disposed on the sensing surface. In these cases, the first layer may be deposited as a first array of sensing elements on the surface of the working electrode. A second layer of sensing elements may be deposited as a second array of sensing elements disposed on the first array of sensing elements. In some cases, the second array of sensing elements is deposited such that each sensing element in the second array is substantially aligned on top of a corresponding sensing element of the first array of sensing elements. In other cases, the second array of sensing elements is deposited such that each sensing element in the second array is deposited substantially on top of an area between features of the first array of sensing elements. In these cases, the second array of sensing elements may be offset from the positions of the array sensing elements in the first array of sensing elements. In some cases, the second layer of sensing elements may overlie at least a portion of one or more sensing elements in the underlying first layer of sensing elements. Deposition of a first array and a second array of sensing elements in an offset configuration as described above may facilitate formation of a contiguous coating of the sensing layer formulation on the surface of the working electrode. Additional layers of sensing elements may be deposited on the working electrode either substantially aligned with the underlying layer or offset from the underlying layer, as desired. Deposition of multiple layers of sensing elements on the surface of the working electrode can facilitate cumulative deposition of a desired total amount of the sensing layer formulation on the surface of the working electrode.

[0083] Without being limited to any particular theory, in certain instances, the sensitivity of an analyte sensor depends on the area of the sensing layer, for example, a layer disposed on a surface of a working electrode that includes a sensing formulation having an analyte-sensitive enzyme and, in some instances, a redox mediator or a redox mediator bound, covalently or non-covalently, to a polymer. For sensing layers that are a contiguous layer of the sensing layer formulation, the sensitivity of the sensor depends on the area of the sensing layer and does not significantly depend on edge effects of the sensing layer. For example, the sensitivity of the sensor may depend on the flow of analyte through a flow-limiting membrane disposed on the sensing layer in a two-dimensional manner toward a surface of the working electrode (e.g., toward a planar surface). In certain embodiments, the inclusion of two or more sensing elements arranged laterally to each other allows the area of the sensing elements to be minimized, such that edge effects of the sensing layer are maximized. This may result in the sensitivity of the sensor being dependent on the edge effects of the sensing elements, rather than the total area of the sensing elements. As such, the sensitivity of the sensor may be dependent on the flow of analyte through a flow-limiting membrane disposed over the sensing elements in a three-dimensional radial manner toward the working electrode (e.g., toward a point). In certain cases, the sensing elements have an arcuate profile to promote radial diffusion of the analyte through the flow-limiting membrane disposed over the sensing elements toward the working electrode. For example, Figure 10 shows a cross-sectional view of a working electrode 1000 having a plurality of sensing elements 1020 on the surface of a working electrode 1010. The sensing elements 1020 have an arcuate cross-sectional profile configured to promote radial diffusion of analyte through the flow-limiting membrane 1030 disposed over the sensing elements 1020 toward the working electrode 1010.

[0084] In some cases, the sensing elements have an arcuate profile. By "arcuate" is meant that the cross-sectional profile of the sensing elements has an arcuate or rounded shape. In certain cases, the sensing elements have a shape approximating that of a half sphere, where the rounded hemispherical portion of the sensing element is convex and extends a distance above the surface of the substrate (e.g., the surface of the working electrode). In some cases, the hemispherical sensing elements may have a surface area that is larger than the surface area of a typical substantially flat or non-hemispherical shaped sensing element. For example, hemispherical sensing elements may have a surface area that is 1.1 or more times greater than the surface area of a typical substantially flat (e.g., non-hemispherical in shape) sensing element, such as 1.2 or more, including 1.3 or more, or 1.4 or more, or 1.5 or more, or 1.6 or more, or 1.7 or more, or 1.8 or more, or 1.9 or more, or 2 or more times greater than the surface area of a typical substantially flat (e.g., non-hemispherical in shape) sensing element. In certain embodiments, sensing elements having a greater surface area may facilitate an increase in the surface area of the sensing layer formulation that is capable of coming into contact with the analyte as the analyte diffuses through the flux-limiting membrane into the sensing elements.

[0085] In some cases, because sensor sensitivity is dependent on edge effects, rather than the overall area of the sensing elements, small relative changes in the area of the sensing elements will not significantly affect sensor sensitivity. In certain embodiments, this results in a decrease in the variation in sensor sensitivity. A decrease in the variation in sensor sensitivity may facilitate calibration of the sensor during the manufacturing process. For example, embodiments of sensors of the present disclosure may be calibrated during the manufacturing process such that calibration of the sensors by a user is not required. As such, in some cases, systems utilizing sensors of the present disclosure do not need to perform a calibration step prior to use of the sensors by the user for analyte detection.

[0086] One embodiment of a sensor element can be described as the area schematically shown in Figure 5B as 508. The sensor element can be described as the active chemical area of the biosensor. The sensor element formulation, which can include a glucose transducing agent, can include, for example, among other constituents, a redox mediator, such as, for example, a hydrogen peroxide or a transition metal complex, such as a ruthenium-containing complex or an osmium-containing complex, and an analyte-responsive enzyme, such as, for example, a glucose-responsive enzyme (e.g., glucose oxidase, glucose dehydrogenase, etc.) or a lactate-responsive enzyme (e.g., lactate oxidase). The sensing region can also include other optional components, such as, for example, a polymer and a bifunctional, short-chain epoxide crosslinker, such as polyethylene glycol (PEG). As described in this application, two or more sensing elements may be provided on a sensing surface of the working electrode, where the two or more sensing elements are arranged laterally relative to each other. For example, Figure 5C shows a schematic view of a portion of the working electrode 501. The working electrode 501 includes a plurality of individual sensing elements 508. The sensing elements 508 are discontinuous, such that the sensing elements 508 are arranged in an array of individual sensing elements 508 on the working electrode 501.

[0087] Figure 7A shows a schematic view of a portion of an analyte sensor 700 that includes an array of sensing elements 710 deposited on a portion of a working electrode 720. The array of sensing elements 710 is arranged such that each row of sensing elements in the array is substantially aligned with sensing elements in an adjacent row. As shown in Figure 7A, the sensing elements 710 are arranged in an array of individual discontinuous sensing elements on the working electrode 720. Figure 7B shows a schematic view of another embodiment of an analyte sensor 750. The portion of the analyte sensor 750 shown includes an array of sensing elements 760 deposited on a portion of a working electrode 770. The array of sensing elements 760 is arranged such that each row of sensing elements in the array is offset from sensing elements in an adjacent row. As shown in Figure 7B, the sensing elements 760 are arranged in an array of individual discontinuous sensing elements on the working electrode 770. In some cases, arranging the rows of sensing elements in an offset configuration may facilitate fabrication of an array with a higher density of sensing elements per unit area compared to an array with substantially aligned rows of sensing elements, while maintaining an array of individual discontinuous sensing elements.

[0088] As described above, in other embodiments, the array of sensing elements may be configured such that the areas between features are minimized. For example, Figure 8 shows one embodiment of an analyte sensor 800 that includes an array of sensing elements 81C) disposed on a portion of a working electrode 820. The array of sensing elements 810 is arranged such that each row of sensing elements in the array is offset from the sensing elements in an adjacent row. As shown in Figure 8, the sensing elements 810 are arranged such that the edges of the sensing elements are in contact with one or more adjacent sensing elements. In some cases, arranging the rows of sensing elements in an offset configuration with the sensing elements in contact with one or more adjacent sensing elements may facilitate fabrication of an array with a higher density of sensing elements per unit area compared to an array with non-contiguous sensing elements.

[0089] As described above, in certain embodiments, two or more layers of sensing elements may be deposited on the surface of a working electrode. For example, Figure 9 shows a schematic of an analyte sensor 900 that includes sensing elements 910 and 930. The sensing elements 910 of a first layer are deposited as a first array on the surface of a working electrode 920. The sensing elements 930 of a second layer are deposited as a second array disposed on the sensing elements 910 of the first array. As shown in Figure 9, the sensing elements 930 of the second array are deposited such that each sensing element 930 in the second array is deposited substantially on top of an area between features of the sensing elements 910 of the first array. The sensing elements 930 of the second array are offset from the positions of the sensing elements 910 in the first array. The sensing elements 930 of the second array overlie at least a portion of one or more sensing elements 910 in the underlying first array (see expanded inset in Figure 9). Deposition of the sensing elements 910 in a first array and the sensing elements 930 in a second array in an offset configuration as described above may facilitate formation of a contiguous coating of the sensing layer formulation on the surface of the working electrode 920. Additional layers of sensing elements may be deposited on the working electrode either substantially aligned with the underlying layer or offset from the underlying layer, as desired.

[0090] In one electrochemical embodiment, the sensor is placed, for example transcutaneously, at a subcutaneous site such that subcutaneous fluid at the site comes into contact with the sensor. In other in vivo embodiments, placement of at least a portion of the sensor may be in a blood vessel. The sensor functions to electrolyze an analyte of interest in the subcutaneous fluid or blood such that a current is generated between the working electrode and the counter electrode. A value for the current associated with the working electrode is determined. If multiple working electrodes are used, current values from each of the working electrodes may be determined. A microprocessor may be used to collect these periodically determined current values or to further process these values.

[0091]If an analyte concentration is successfully determined, it may be displayed, stored, transmitted, and/or otherwise processed to provide useful information. For example, the raw signal or analyte concentrations may be used as a basis for determining a rate of change in the analyte concentration, which should not change at a rate greater than a predetermined threshold amount. If the rate of change in the analyte concentration exceeds the predefined threshold, an indication may be displayed or transmitted to indicate this fact.

[0092] As demonstrated herein, the methods of the present disclosure are useful in connection with a device that is used to measure or monitor a glucose analyte, such as any device described herein. These methods may also be used in connection with a device that is used to measure or monitor another analyte (e.g., ketones, ketone bodies, HbA1c, and the like), including oxygen, carbon dioxide, proteins, drugs, or other moiety of interest, for example, or any combination thereof, that is found in the body fluid, including subcutaneous fluid, dermal fluid, interstitial fluid, or other body fluid of interest, for example, or any combination thereof. In general, the device is in good contact, such as complete and substantially continuous contact, with the body fluid.

[0093] According to embodiments of the present disclosure, the measurement sensor is one suitable for electrochemical measurement of analyte concentration, e.g. glucose concentration, in a body fluid. In these embodiments, the measurement sensor includes at least one working electrode and a counter electrode. Other embodiments may further include a reference electrode. The working electrode may be associated with a glucose-sensitive enzyme. A mediator may also be included. In certain embodiments, hydrogen peroxide, which may be characterized as a mediator, is produced by a reaction of the sensor and may be used to infer glucose concentration. In some embodiments, a mediator is added to the sensor by a manufacturer, e.g., included with the sensor prior to use. The redox mediator may be disposed relative to the working electrode and is capable of transferring electrons between a compound and a working electrode, either directly or indirectly. The redox mediator may be, for example, immobilized on the working electrode, e.g., entrapped on a surface or chemically bonded to a surface.

[0094] Additional embodiments of a sensor that may include a working electrode with a sensing surface including two or more sensing elements laterally disposed relative to one another are described in U.S. Patent Nos. 5,262,035, 5,262,305, 6,134,461, 6,143,164, 6,175,752, 6,338,790, 6,579,690, 6,605,200, 6,605,201, 6,654,625, 6,736,957, 6,746,582, 6,932,894, 7,090,756, as well as those described in U.S. Patent Application Nos. 11/701,138, ... 11/948,915, 12/625,185, 12/625,208, and 12/624,767. Additionally, embodiments described herein may be incorporated into battery-powered or self-powered analyte sensors, such as self-powered analyte sensors, as described in U.S. Patent Application No. 12/393,921 (U.S. Patent Application Publication No. 2010/0213057). Furthermore, the embodiments described in this application may be incorporated into analyte monitoring systems and devices that utilize one or more rivets to attach an analyte sensor having one or more conductive traces to a sensor control unit, as described in U.S. Provisional Patent Application No. 61/498,142, filed June 17, 2011.

[0095] Aspects of the present disclosure also include embodiments that include a sensing surface having two or more sensing elements disposed laterally relative to one another, where the sensing surface is at a working electrode of an analyte sensor test strip. For example, Figure 11 shows an exploded perspective view of an analyte sensor test strip, the layers are illustrated individually with the electrodes in a first configuration. As shown in Figure 11, the test strip 1100 has a first substrate 1110, a second substrate 1120, and a spacer 1130 positioned therebetween. The test strip 1100 includes at least one working electrode 1140 and at least one counter electrode 1160. The working electrode 1140 is present on a surface of the first substrate 1110 and the counter electrode 1160 is present on a surface of the second substrate 1120 opposite the surface of the first substrate 1110 in an facing relationship with the surface of the first substrate. The working electrode 1140 has an array of sensing elements 1150 disposed on the sensing surface of the working electrode 1140. The test strip 1100 is a layered construction, in certain embodiments having a generally rectangular shape, e.g., its length is longer than its width, although other shapes are also possible. Another embodiment of a test strip is illustrated in Figure 12, which shows an exploded perspective view of an analyte sensor test strip, the layers are individually illustrated with the electrodes in a second configuration1°. As shown in Figure 12, the test strip 1200 has a first substrate 1210, a second substrate 1220, and a spacer 1230 positioned therebetween. The test strip 1200 includes at least one working electrode 1240 and at least one counter electrode 1260. The counter electrode 1260 is present on a surface of the first substrate 1210 adjacent the working electrode 1240, such that both the working electrode 1240 and the counter electrode 1260 are present on the surface of the first substrate 1210. The working electrode 1240 has an array of sensing elements 1250 disposed on the sensing surface of the working electrode 1240. Similar to the embodiment shown in Figure 11, the test strip 1200 shown in Figure 12 has a layered construction, in certain embodiments it has a generally rectangular shape, for example, its length is greater than its width, although other shapes are also possible. Additional embodiments of test strips and analyte sensors for use therein are described in more detail in U.S. Application Ser. No. 11/281,883.

[0096] Analyte test strips for use with the present devices may be of any type, size, or shape known to those skilled in the art; for example, FREESTYLE® and FREESTYLE LITE™ test strips, as well as PRECISION™ test strips sold by ABBOTT DIABETES CARE Inc. In addition to the embodiments specifically described herein, the devices of the present disclosure may be configured to operate with a wide variety of analyte test strips, for example, those described in U.S. Patent Application No. 11/461,725, filed August 1, 2006; U.S. Patent Application Publication No. 2007/0095661; U.S. Patent Application Publication No. 2006/0091006; U.S. Patent Application Publication No. 2006/0025662; U.S. Patent Application Publication No. 2008/0267823; U.S. Patent Application Publication No. 2007/0108048; U.S. Patent Application Publication No. 2008/0102441; U.S. Patent Application Publication No. 2008/0066305; U.S. Patent Application Publication No. 2007/0199818; U.S. Patent Application Publication No. 2008/0148873; U.S. Patent Application Publication No. 2007/0068807; U.S. Patent Application No. 12/102,374, filed Apr. 14, 2008, and U.S. Patent Application Publication No. 2009/0095625; U.S. Patent No. 6,616,819; U.S. Patent No. 6,143,164; U.S. Patent No. 6,592,745; U.S. Patent No. 6,071,391; and U.S. Patent No. 6,893,545.

Electrochemical sensors

[0097] Embodiments of the present disclosure relate to methods and devices for detecting at least one analyte such as glucose in bodily fluid. Embodiments relate to continuous and/or automatic in vivo monitoring of the level of one or more analytes using a continuous analyte monitoring system that includes an analyte sensor, at least a portion of which will be placed beneath the surface of a user's skin for a period of time and/or discrete monitoring of one or more analytes using an in vitro blood glucose ("BG") meter and an analyte test strip. Embodiments include combined or combinable devices, systems, and methods and/or data transfer between a continuous in vivo system and an in vivo system. In some embodiments, the systems, or at least a portion of the systems, are integrated into a single unit.

[0098] A sensor as described in this application may be an in vivo sensor or an in vitro sensor (i.e., a discrete monitoring test strip). This sensor may be formed on a substrate, for example, a substantially planar substrate. In certain embodiments, the sensor is a wire, for example, an inner portion of a working electrode wire with one or more electrodes associated (e.g., on, including wrapped around) thereto. The in vitro sensor may also include at least one counter electrode (or counter/reference electrode) and/or at least one reference electrode or at least one counter/reference electrode.

[0099] Accordingly, embodiments include analyte monitoring devices and systems that include an analyte sensor, at least a portion of which is positionable beneath the surface of a user's skin for in vivo detection of an analyte, such as glucose, lactate, and the like, in a body fluid. Embodiments include fully implantable analyte sensors and analyte sensors where only a portion of the sensor is positioned beneath the skin and a portion of the sensor resides above the skin, e.g., for contact with a sensor control unit (which may include a transmitter), receiver/display unit, transceiver, processor, etc. The sensor may, for example, be subcutaneously positionable in a user for continuous or periodic monitoring of a level of an analyte in the user's interstitial fluid. For purposes of this disclosure, continuous monitoring and periodic monitoring will be used interchangeably unless otherwise indicated. The sensor response may be correlated and/or converted to analyte levels in the blood or other fluids. In certain embodiments, an analyte sensor may be placed in contact with an interstitial fluid to detect the level of glucose; such detected glucose may be used to infer the level of glucose in the patient's bloodstream. Analyte sensors may be inserted into a vein, artery, or other fluid-containing portion of the body. Embodiments of analyte sensors may be configured to monitor the level of analytes over a period of time that may range from minutes, hours, days, weeks, or longer.

[0100]Of interest are analyte sensors, such as glucose sensors, that are capable of detecting an analyte in vivo for an hour or more, e.g., a few hours or more, e.g., a few days or more, e.g., three or more days, e.g., five days or more, e.g., seven days or more, e.g., several weeks or more, or a month or more. Future analyte levels can be predicted based on the information obtained, e.g., the current analyte level at time t0, the rate of change of the analyte, etc. Predictive alarms can notify the user of predicted analyte levels that may be of concern before the analyte level reaches the predicted future level. This provides the user with the opportunity to take corrective action.

[0101] Figure 1 shows a data monitoring and management system such as, for example, an analyte monitoring system 100 (e.g., glucose) according to certain embodiments. Aspects of the subject disclosure are further described primarily with respect to glucose monitoring devices and systems, and glucose detection methods, for convenience only and such description is not intended in any way to limit the scope of the embodiments. It should be understood that the analyte monitoring system may be configured to monitor a variety of analytes at the same time or at different times.

[0102] Analytes that may be monitored include, but are not limited to, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, glycosylated hemoglobin (HbA1c), creatine kinase (e.g., CK-MB), creatine, creatinine, DNA, fructosamine, glucose, glucose derivatives, glutamine, growth hormones, hormones, ketones, ketone bodies, lactate, peroxide, prostate specific antigen, prothrombin, RNA, thyroid stimulating hormone, and troponin. The concentration of drugs such as, for example, antibiotics (e.g., gentamicin, vancomycin, and the like), digitoxin, digoxin, addictive drugs, theophylline, and warfarin, may also be monitored. In those embodiments that monitor more than one analyte, the analytes may be monitored at the same time or at different times.

[0103]The analyte monitoring system 100 includes an analyte sensor 101, a data processing unit 102 connectable to the sensor 101, and a primary receiver unit 104. In some cases, the primary receiver unit 104 is configured to communicate with the data processing unit 102 via a communication link 103. In certain embodiments, the primary receiver unit 104 may be further configured to transmit data to a data processing terminal 105 that evaluates or otherwise processes or formats the data received by the primary receiver unit 104. The data processing terminal 105 may be configured to receive data directly from the data processing unit 102 via a communication link 107 that may optionally be configured in two-way communication. Furthermore, the data processing unit 102 may include a transmitter or transceiver for transmitting and/or receiving data to and/or from the primary receiving unit 104, and/or the data processing terminal 105 and/or, optionally, the secondary receiving unit 106.

[0104] As also shown in Figure 1, there is an optional secondary receiver unit 106 that is operatively coupled to the communication link 103 and is configured to receive data transmitted from the data processing unit 102. The secondary receiver unit 106 may be configured to communicate with the primary receiver unit 104 as well as the data processing terminal 105. In certain embodiments, the secondary receiver unit 106 may be configured for two-way wireless communication with each of the primary receiver unit 104 and the data processing terminal 105. As discussed in more detail below, in some instances, the secondary receiver unit 106 may be a feature-free receiver compared to the primary receiver unit 104, for example, the secondary receiver unit 106 may include a limited or minimal number of functions and features compared to the primary receiver unit 104. As such, the secondary receiver unit 106 may be configured to communicate with the primary receiver unit 104, as well as the data processing terminal 105. include a smaller (in one or more, including all dimensions), compact housing or incorporated into a device including a wristwatch, bracelet, PDA, mp3 player, mobile phone, etc., for example. Alternatively, the secondary receiver unit 106 may be configured with the same or substantially similar functions and features as the primary receiver unit 104. The secondary receiver unit 106 may include a coupling portion configured to couple with a docking cradle unit for placement, for example, at the bedside for overnight monitoring and/or a two-way communication device. A docking cradle may recharge a power supply.

[0105] Only one analyte sensor 101, data processing unit 102, and data processing terminal 105 are shown in the embodiment of the analyte monitoring system 100 illustrated in Figure 1. However, one skilled in the art will appreciate that the analyte monitoring system 100 may include more than one sensor 101 and/or more than one data processing unit 102, and/or more than one data processing terminal 105. Multiple sensors may be placed on a patient for analyte monitoring at the same time or at different times. In certain embodiments, analyte information obtained by a first sensor placed on a user may be used as a comparison to analyte information obtained by a second sensor. This may be useful to confirm or validate analyte information obtained from one or both sensors. This redundancy may be useful if analyte information is considered in critical decisions related to therapy. In certain embodiments, a first sensor may be used to calibrate a second sensor.

[0106]The analyte monitoring system 100 may be a continuous monitoring system, or a semi-continuous or discrete monitoring system. In a multi-component environment, each component may be configured to be uniquely identified by one or more of the other components in the system, such that communication conflict may be readily resolved between the various components within the analyte monitoring system 100. For example, unique identifiers, communication channels, and the like may be used.

[0107] In certain embodiments, the sensor 101 is physically positioned in or on the body of a user whose analyte level is being monitored. The sensor 101 may be configured to at least periodically sample the user's analyte level and convert the sampled analyte level into a corresponding signal for transmission by the data processing unit 102. The data processing unit 102 may be coupled to the sensor 101 such that both devices are positioned in or on the user's body, with at least a portion of the analyte sensor 101 positioned transcutaneously. The data processing unit 102 may include an attachment element, such as an adhesive or the like, to secure it to the user's body. A support point (not shown) may be used, which may be attached to the user and coupled with the data processing unit 102. For example, a support point may include an adhesive surface. The data processing unit 102 performs data processing functions, where such functions may include, but are not limited to, filtering and encoding data signals each corresponding to a sampled analyte level from the user for transmission to the main receiving unit 104 via communication link 103. In one embodiment, the sensor 101 or the data processing unit 102 or a combined data processing/sensor unit may be implantable entirely beneath the surface of the user's skin.

[0108] In certain embodiments, the primary receiver unit 104 may include an analog interface section including an RF receiver and an antenna that is configured to communicate with the data processing unit 102 via the communication link 103, and a data processing section for processing data received from the data processing unit 102 including data decoding, error detection and correction, data clock generation, data bit recovery, etc., or any combination thereof.

[0109] In operation, the main receiving unit 104 in certain embodiments is configured to synchronize with the data processing unit 102 and uniquely identify the data processing unit 102, based on, for example, identification information of the data processing unit 102, and subsequently periodically receive signals transmitted from the data processing unit 102 associated with analyte levels monitored and detected by the sensor 101.

[0110]Referring again to Figure 1, the data processing terminal 105 may include a personal computer, a laptop computer including a laptop or portable device (e.g., a personal digital assistant (PDA), a telephone including a cellular telephone (e.g., a multimedia and Internet-enabled mobile telephone, including an iPhone™, a Blackberry®, or similar telephone), an mp3 player (e.g., an iPOD™, etc.), a pager, and the like), and/or a medication delivery device (e.g., an infusion device), each of which may be configured to communicate data with the recipient via a wired or wireless connection. Additionally, the data processing terminal 105 may be further connected to a data network (not shown) to store, retrieve, update, and/or analyze data corresponding to the level of analytes detected in the user.

[0111] The data processing terminal 105 may include a drug delivery device (e.g., an infusion pump), such as an insulin infusion pump or the like, that may be configured to deliver a drug (e.g., insulin) to the user, and that may be configured to communicate with the primary display device 104 and receive, among others, the level of analytes that has been measured. Alternatively, the primary display device 104 may be configured to integrate an infusion device therein such that the primary display device 104 is configured to deliver a suitable drug (e.g., insulin) to users, for example, to deliver and modify basal profiles, as well as to determine suitable boluses for delivery based on, among others, the levels of analytes sensed and received from the data processing unit 102. An infusion device may be an external device or an internal device, such as, for example, a device that is completely implantable in a user.

[0112] In certain embodiments, the data processing terminal 105, which may include an infusion device, for example, an insulin pump, may be configured to receive the analyte signals from the data processing unit 102, and thus, incorporate the functions of the main display device 104, including data processing to deliver insulin therapy to the patient and analyte monitoring. In certain embodiments, the communication link 103, as well as one or more of the other communication interfaces shown in Figure 1, may utilize one or more RF communication protocols, an infrared communication protocol, a Bluetooth communication protocol, an 802.11x wireless communication protocol, or an equivalent wireless communication protocol that allows for secure, wireless communication of multiple units (e.g., as required by the Health Insurance Portability and Accountability Act (HIPPA)), while avoiding potential data collisions and interference.

[0113] Figure 2 shows a block diagram of one embodiment of a data processing unit 102 of the analyte monitoring system shown in Figure 1. Input and/or user interface components may be included or a data processing unit may be free of input and/or user interface components. In certain embodiments, one or more application-specific integrated circuits (ASICs) may be used to implement one or more functions or routines associated with operations of the data processing unit (and/or the receiving unit), using, for example, one or more buffers or state machines.

[0114] As can be seen in the embodiment of Figure 2, the analyte sensor 101 (Figure 1) includes four contacts, three of which are electrodes; the working electrode (W) 210, the reference electrode (R) 212, and the counter electrode (C) 213, each operatively coupled to the analog interface 201 of the data processing unit 102. This embodiment also shows an optional guard contact (G) 211. Fewer or more electrodes may be employed. For example, the counter electrode and reference electrode functions may be served by a single counter/reference electrode. In some cases, there may be more than one working electrode and/or reference electrode and/or counter electrode, etc.

[0115] Figure 3 is a block diagram of one embodiment of a receiver/monitoring unit, such as the primary display device 104 of the analyte monitoring system of Figure 1. The primary receiver unit 104 includes one or more of: a test strip interface 301, an RF receiver 302, a user input 303, an optional temperature sensing section 304, and a clock 305, each of which is operatively coupled to a processor and storage. article 307. The primary receiver unit 104 also includes a power supply 306 operatively coupled to a power monitoring and conversion section 308. In addition, the power monitoring and conversion section 308 is also coupled to the processing and storage section 307. In addition, a receiver serial communication section 309, and an output 310, each operatively coupled to the processing and storage section 307, are also shown. The primary receiver unit 104 may include user interface and/or input components or may be free of user interface and/or input components.

[0116] In certain embodiments, the test strip interface 301 includes an analyte testing portion (e.g., a glucose level testing portion) that receives an analyte test in the blood (or other bodily fluid sample) or information related thereto. For example, the test strip interface 301 may include a test strip port that receives a test strip (e.g., a glucose test strip). The device may determine the analyte level of the test strip and optionally display (or otherwise note) the analyte level at the output 310 of the primary receiving unit 104. Any suitable test strip may be employed, e.g., test strips that only require a very small amount (e.g., 3 microliters or less, e.g., 1 microliter or less, e.g., 0.5 microliters or less, e.g., 0.1 microliter or less) of sample applied to the strip to obtain accurate glucose information. Test strip embodiments include, for example, FreeStyle® blood glucose test strips from Abbott Diabetes Care, Inc. (Alameda, CA). Glucose information obtained by an in vitro glucose testing device may be used for a variety of purposes, calculations, etc. For example, the information may be used to calibrate sensor 101, confirm results from sensor 101 to increase sensor confidence (e.g., in cases where information obtained by sensor 101 is used in therapy-related decisions), etc.

[0117] In further embodiments, the data processing unit 102 and/or the primary receiving unit 104 and/or the secondary receiving unit 106, and/or the data processing terminal/infusion device 105 may be configured to receive the analyte value wirelessly via a communication link from, for example, a blood glucose meter. In further embodiments, a user manipulating or using the analyte monitoring system 100 (Figure 1) may manually enter the blood glucose value using, for example, a user interface (e.g., a keypad, touch pad, voice commands, and the like) incorporated into the data processing unit 102, the primary receiving unit 104, the secondary receiving unit 106, or the data processing terminal/infusion device 105.

[0118]Additional detailed descriptions are provided in U.S. Patent Numbers

5,262,035; 5,264,104; 5,262,305; 5,320,715; 5,593,852; 6,175,752; 6,650,471; 6,746,582 and 7,811,231.

[0119] Figure 4 schematically shows one embodiment of an analyte sensor 400 according to embodiments of the present disclosure. This embodiment of the sensor includes electrodes 401, 402, and 403 on a base 404. The electrodes (and/or other features) may be applied or otherwise processed using any suitable technology, for example, chemical vapor deposition (CVD), physical vapor deposition, spraying, reactive spraying, printing, coating, ablation (e.g., laser ablation), painting, dip coating, etching, and the like. Conductive materials include, but are not limited to, aluminum, carbon (including graphite), cobalt, copper, gallium, gold, indium, iridium, iron, lead, magnesium, mercury (as an amalgam), nickel, niobium, osmium, palladium, platinum, rhenium, rhodium, selenium, silicon (e.g., doped polycrystalline silicon), silver, tantalum, tin, titanium, tungsten, uranium, vanadium, zinc, zirconium, mixtures thereof, and alloys, oxides, or metallic compounds of these elements.

[0120]The analyte sensor 400 may be implanted entirely in a user or may be configured such that only one (internal) portion is positioned within a user and another (external) portion is positioned outside of a user. For example, the sensor 400 may include a first portion that is positionable above a surface of the skin 410 and a portion that is positioned below the surface of the skin. In such embodiments, the external portion may include contacts (connected to the respective electrodes of the second portion via traces) for connecting to another device, also external to the user, such as a transmission unit. While the embodiment of Figure 4 shows three electrodes side by side on the same surface of the base 404, other configurations are contemplated, for example, fewer or more electrodes, some or all of the electrodes on different surfaces of the base or present on another base, some or all of the electrodes stacked together, electrodes of different materials and dimensions, etc.

[0121] Figure 5A shows a perspective view of one embodiment of an analyte sensor 500 having a first portion (which, in this embodiment, may be characterized as a major portion) positionable above a skin surface 510, and a second portion (which, in this embodiment, may be characterized as a minor portion) including an insertion tip 530, positionable beneath the skin surface, e.g., penetrating through the skin and into, for example, a subcutaneous space 520, in contact with the user's biofluid, such as interstitial fluid. Contact portions of a working electrode 511, a reference electrode 512, and a counter electrode 513 are positioned in the first portion of the sensor 500 located above the skin surface 510. The working electrode 501, a reference electrode 502, and a counter electrode 503 are shown in the second portion 500 and, particularly, in the insertion tip 530. Traces may be provided from the electrode at the contact tip, as shown in Figure 5A. It should be understood that more or fewer electrodes may be provided in a sensor. For example, a sensor may include more than one working electrode and/or the counter and reference electrodes may be a single counter/reference electrode, etc.

[0122] Figure 5B shows a cross-sectional view of a portion of the sensor 500 of Figure 5A. The electrodes 501, 502, and 503 of the sensor 500, as well as the substrate and dielectric layers are provided in a layered configuration or construction. For example, as shown in Figure 5B, in one embodiment, the sensor 500 (like the analyte sensor 101 of Figure 1), includes a substrate layer 504 and a first conductive layer 501, such as carbon, gold, etc., disposed on at least a portion of the substrate layer 504 and which may provide the working electrode. Also shown disposed on at least a portion of the first conductive layer 501 is a sensor element 508. As described in this application, two or more sensor elements may be provided on a sensing surface of the working electrode, where the two or more sensor elements are disposed laterally relative to one another. For example, Figure 5C shows a schematic view of a portion of the working electrode 501. The working electrode 501 includes a plurality of individual sensing elements 508. The sensing elements 508 are discontinuous, such that the sensing elements 508 are arranged in an array of individual sensing elements 508 on the working electrode 501.

[0123] A first insulating layer 505, such as a first dielectric layer in certain embodiments, is disposed or laminated on at least a portion of the first conductive layer 501, and in addition, a second conductive layer 509 may be disposed or stacked above at least a portion of the first insulating layer (or dielectric layer) 505. As shown in Figure 5B, the second conductive layer 509 may provide the reference electrode 502, as described in this application, that has an extended useful life, which includes a redox polymer layer as described in this application.

[0124] A second insulation layer 506, such as a second dielectric layer in certain embodiments, may be disposed or laminated to at least a portion of the second conductive layer 509. In addition, a third conductive layer 503 may be disposed to at least a portion of the second insulation layer 506 and may provide the counter electrode 503. Finally, a third insulation layer 507 may be disposed or laminated to at least a portion of the third conductive layer 503. In this manner, the sensor 500 may be laminated such that at least a portion of each of the conductive layers is separated by a respective insulation layer (e.g., a dielectric layer). The embodiments of Figures 5A and 5B show that the layers have different lengths. In certain cases, some or all of the layers may have the same or different lengths and/or widths.

[0125] In certain embodiments, some or all of the electrodes 501, 502, 503 may be provided on the same face of the substrate 504 in the layered construction, as described above, or, alternatively, may be provided in a coplanar manner, such that two or more electrodes may be positioned in the same plane (e.g., side-by-side (e.g., in parallel) or at an angle relative to each other) on the substrate 504. For example, the coplanar electrodes may include an appropriate space between them and/or include a dielectric material or an insulating material disposed between the conductive layers/electrodes. Furthermore, in certain embodiments, one or more of the electrodes 501, 502, 503 may be disposed on opposite faces of the substrate 504. In such dual-sided sensor embodiments, the contact pads may be on the same side or on different sides of the substrate. For example, an electrode may be on a first side and its respective contact may be on a second side, e.g., a trace connecting the electrode and contact may pass through the substrate.

[0126] As noted above, analyte sensors may include an analyte-sensitive enzyme to provide a sensing element. Some analytes, such as oxygen, can be electrooxidized or electroreduced directly in a sensor, and more specifically at at least one working electrode of a sensor. Other analytes, such as glucose and lactate, require the presence of at least one electron transfer agent and/or at least one catalyst to facilitate electrooxidation or electroreduction of the analyte. Catalysts may also be used for those analytes, such as oxygen, that can be electrooxidized or electroreduced directly on the working electrode. For these analytes, each working electrode includes a sensing region (see, e.g., sensing region 508 of FIG. 5B) proximate or on a surface of a working electrode. In many embodiments, a sensing element is formed near or on only a small portion of at least one working electrode.

[0127]Each sensor element includes one or more components constructed to facilitate electrochemical oxidation or reduction of the analyte. The sensor element may include, for example, a catalyst to catalyze a reaction of the analyte and produce a response at the working electrode, an electron transfer agent to transfer electrons between the analyte and the working electrode (or other component), or both.

[0128] A variety of different configurations of sensing elements may be used. In certain embodiments, the sensing elements are deposited on the conductive material of a working electrode. The sensing elements may extend beyond the conductive material of the working electrode. In some cases, the sensing elements may also extend onto other electrodes, for example, onto the counter electrode and/or the reference electrode (or counter/reference is provided). In other embodiments, the sensing elements are contained in the working electrode such that the sensing elements do not extend beyond the conductive material of the working electrode.

[0129]Sensing elements that are in direct contact with the working electrode may contain an electron transfer agent for transferring electrons directly or indirectly between the analyte and the working electrode, and/or a catalyst for facilitating a reaction of the analyte. For example, a glucose, lactate, or oxygen electrode may be formed having a sensing region containing a catalyst, such as glucose oxidase, glucose dehydrogenase, lactate oxidase, or lactase, respectively, and an electron transfer agent that facilitates the electro-oxidation of the glucose, lactate, or oxygen, respectively.

[0130] In other embodiments the sensing elements are not deposited directly on the working electrode. Instead, the sensing elements 508 may be spaced from the working electrode, and separated from the working electrode, for example, by a separation layer. A separation layer may include one or more membranes or films or a physical distance. In addition to separating the working electrode from the sensing elements, the separation layer may also act as a mass transport limiting layer and/or an interference scavenging layer and/or a biocompatible layer.

[0131] In certain embodiments that include more than one working electrode, one or more of the working electrodes may not have corresponding sensing elements, or may have sensing elements that do not contain one or more components (e.g., an electron transfer agent and/or catalyst) necessary to electrolyze the analyte. Accordingly, the signal at this working electrode may correspond to background signal that can be removed from the analyte signal obtained from one or more other working electrodes associated with the fully functional sensing regions by, for example, signal subtraction.

[0132] In certain embodiments, the sensing elements include one or more electron transfer agents. Electron transfer agents that may be employed are electroreducible and electrooxidizable ions or molecules that have redox potentials that are a few hundred millivolts above or below the standard calomel electrode (SCE) redox potential. The electron transfer agent may be organic, organometallic, or inorganic. Examples of organic redox species are quinones and species that, in their oxidized state, have quinoid structures, such as Nile blue and indophenol.

Examples of organometallic redox species are metallocenes such as ferrocene. Examples of inorganic redox species are hexacyanoferrate(III), ruthenium hexamine, etc. Additional examples include those described in U.S. Patent Nos. 6,736,957, 7,501,053, and 7,754,093.

[0133] In certain embodiments, the electron transfer agents have structures or charges that prevent or substantially reduce diffusion loss of the electron transfer agent during the time period where the sample is analyzed. For example, electron transfer agents include, but are not limited to, redox species, e.g., bound to a polymer which may, in turn, be disposed at or near the working electrode. The bonding between the redox species and the polymer may be covalent, coordinate, or ionic. While any organic, organometallic, or inorganic redox species may be bound to a polymer and used as an electron transfer agent, in certain embodiments, the redox species is a transition metal compound or complex, e.g., osmium, ruthenium, steel, and cobalt compounds or complexes. It will be recognized that many redox species described for use with a polymeric component may also be used, without a polymeric component.

[0134] Embodiments of polymeric electron transfer agents contain a covalently bonded redox species in a polymer composition. An example of this type of mediator is poly(vinylferrocene). Another type of electron transfer agent contains an ionically bonded redox species. This type of mediator can include a charged polymer coupled to an oppositely charged redox species. Examples of this type of mediator include a negatively charged polymer coupled to a positively charged redox species, such as an osmium or ruthenium polypyridyl cation. Another example of an ionically bonded mediator is a positively charged polymer including quaternized poly(4-vinylpyridine) or poly(l-vinylimidazole) coupled to a negatively charged redox species such as ferricyanide or ferrocyanide. In other embodiments, the electron transfer agents include redox species coordinatively bonded to a polymer. For example, the mediator can be formed by coordination of a 2,2'-bipyridyl complex of osmium or cobalt to poly(1-vinylimidazole) or poly(4-vinylpyridine).

[0135] Suitable electron transfer agents are osmium transition metal complexes with one or more ligands, with each ligand having a nitrogen-containing heterocycle, such as 2,2'-bipyridine, 1,10-phenanthroline, 1-methyl, 2-pyridyl biimidazole, or derivatives thereof. Electron transfer agents may also have one or more ligands covalently attached in a polymer, with each ligand having at least one nitrogen-containing heterocycle, such as pyridine, imidazole, or derivatives thereof. An example of an electron transfer agent includes (a) a polymer or copolymer having imidazole or pyridine functional groups, and (b) osmium cations in complexes with two ligands, with each ligand containing 2,2'-bipyridine, 1,10-phenanthroline, or derivatives thereof, without the two ligands necessarily being the same. Some 2,2'-bipyridine derivatives for complexation with the osmium cation include, but are not limited to, 4,4'-dimethyl-2,2'-bipyridine and mono-, di- and polyalkoxy-2,2'-bipyridines, including 4,4'-dimethoxy-2,2'-bipyridine. 1,10-Phenanthroline derivatives for complexation with the osmium cation include, but are not limited to, 4,7-dimethyl-1,10-phenanthroline and mono-, di- and polyalkoxy-1,10-phenanthrolines, such as 4,7-dimethyloxy-1,10-phenanthroline. Polymers for complexation with the osmium cation include, but are not limited to, poly(1-vinyl imidazole) (referred to as "PVI") and poly(4-vinyl pyridine) (referred to as "PVP") polymers and copolymers. Suitable poly(1-vinyl imidazole) copolymer substituents include acrylonitrile, acrylamide, and substituted or quaternized N-vinyl imidazole, e.g., electron transfer agents with osmium in a complex to a poly(1-vinylimidazole) polymer or copolymer.

[0136] Embodiments may employ electron transfer agents that have a redox potential ranging from about -200 mV to about 200 mV, versus the standard calomel electrode (SCE). The sensing elements may also include a catalyst that is capable of catalyzing a reaction of the analyte. In some embodiments, the catalyst may also act as an electron transfer agent. An example of a suitable catalyst is an enzyme that catalyzes a reaction of the analyte. When the analyte of interest is glucose, for example, a catalyst such as a glucose oxidase, a glucose dehydrogenase (e.g., pyrroloquinoline quinone (PQQ), a glucose-dependent dehydrogenase, a flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenase, or a nicotinamide adenine dinucleotide (NAD)-dependent glucose dehydrogenase) may be used. When the analyte of interest is lactate, a lactate oxidase or a lactate dehydrogenase may be used. Laccase may be used when the analyte of interest is oxygen or when oxygen is generated or consumed in response to the analyte reaction.

[0137] In certain embodiments, a catalyst may be attached to a polymer, by cross-linking the catalyst with another electron transfer agent which, as described above, may be polymeric. In certain embodiments, a second catalyst may also be used. This second catalyst may be used to catalyze a reaction of a product compound resulting from the catalyzed reaction of the analyte. The second catalyst may operate with an electron transfer agent to electrolyze the product compound to generate a signal at the working electrode. Alternatively, a second catalyst may be provided in an interferent scavenging layer to catalyze reactions that scavenge interferents.

[0138] In certain embodiments, the sensor operates at a low oxidation potential, for example, a potential of about 40 mV versus Ag/AgCl. These sensor elements utilize, for example, an osmium (Os)-based mediator constructed for low potential operation. Accordingly, in certain embodiments the sensor elements are redox active components including: (1) osmium-based mediator molecules including ligands (bidents) and (2) glucose oxidase enzyme molecules. These two constituents are combined together in the sensing elements of the sensor.

[0139] A mass transport limiting layer (not shown), for example an analyte flux modulating layer, may be included with the sensor to act as a diffusion limiting barrier to reduce the mass transport rate of the analyte, for example glucose or lactate, within the region around the working electrodes. Mass transport limiting layers are useful for limiting the flux of an analyte to a working electrode in an electrochemical sensor such that the sensor responds linearly over a wide range of analyte concentrations and is easily calibrated. Mass transport limiting layers may include polymers and may be biocompatible. A mass transport limiting layer may provide many functions, for example biocompatibility and/or interference suppression functions, etc.

[0140]In certain embodiments, a mass transport limiting layer is a membrane composed of cross-linked polymers containing heterocyclic nitrogen groups, such as polyvinylpyridine and polyvinylimidazole polymers. Embodiments also include membranes that are made of a polyurethane or polyetherurethane, or a related chemical material, or membranes that are made of silicone and the like.

[0141] A membrane can be formed by cross-linking in situ a polymer, modified with a zwitterionic moiety, a non-pyridine copolymer component, and optionally another moiety that is hydrophilic or hydrophobic and/or has other desirable properties, in an alcohol buffer solution. The modified polymer can be made from a precursor polymer containing heterocyclic nitrogen groups. For example, a precursor polymer can be polyvinylpyridine or polyvinyl imidazole. Optionally, hydrophilic or hydrophobic modifiers can be used to "tune" the permeability of the resulting membrane to an analyte of interest. Optional hydrophilic modifiers, such as poly(ethylene glycol), hydroxyl, and polyhydroxyl modifiers, can be used to improve the biocompatibility of the resulting polymer or membrane.

[0142] A membrane may be formed in situ by applying an alcohol buffer solution of a crosslinker and a modified polymer onto the enzyme-containing sensor elements and allowing the solution to cure for about one to two days or other appropriate period of time. The crosslinking polymer solution may be applied onto the sensor elements by placing one or more drops of the membrane solution onto the sensor, dipping the sensor into the membrane solution, spraying the membrane solution onto the sensor, and the like. In general, the thickness of the membrane is controlled by the concentration of the membrane solution, by the number of drops of the solution applied, by the number of times the sensor is dipped into the solution, by the volume of solution sprayed onto the sensor, or by any combination of these factors. A membrane applied in this manner may have any combination of the following functions: (1) mass transport limitation, i.e., reduction of the flux of analyte that can reach the sensor elements, (2) enhancement of biocompatibility, or (3) reduction of interference.

[0143] In some embodiments, the membrane may form one or more bonds with the sensor elements. By bonds is meant any type of interaction between atoms or molecules that allows chemical compounds to form associations with one another, such as, but not limited to, covalent bonds, ionic bonds, dipole-dipole interactions, hydrogen bonds, London dispersion forces, and the like. For example, in situ polymerization of the membrane may form cross-links between the polymers of the membrane and the polymers of the sensor elements. In certain embodiments, cross-linking of the membrane to the sensor element facilitates a reduction in the occurrence of delamination of the membrane from the sensor.

[0144] In certain embodiments, the sensing system detects that hydrogen peroxide infers glucose levels. For example, a hydrogen peroxide sensing sensor can be constructed where the sensing elements include an enzyme such as glucose oxidase, glucose dehydrogenase, or the like, and is placed on the working electrode. The sensing elements can be covered by one or more layers, for example, a membrane that is selectively permeable to glucose. Once glucose passes through the membrane, it is oxidized by the enzyme and the reduced glucose oxidase, then can be oxidized by reaction with molecular oxygen, so as to produce hydrogen peroxide.

[0145] Certain embodiments include a hydrogen peroxide detection sensor constructed from sensor elements prepared by combining with each other, for example: (1) a redox mediator having a transition metal complex including a polypyridyl Os complex with oxidation potentials of about 200 mV versus SCE, and (2) periodate oxidized horseradish peroxidase (HRP). Such a sensor operates in a reductive mode; the working electrode is controlled at a negative potential relative to that of the Os complex, resulting in mediated reduction of hydrogen peroxide through the HRP catalyst.

[0146] In another example, a potentiometric sensor can be constructed as follows. Glucose sensing elements can be constructed by combining (1) a redox mediator having a transition metal complex including polypyridyl Os complexes with oxidation potentials of about -200 mV to 200 mV vs. SCE, and (2) glucose oxidase. This sensor can then be used in a potentiometric mode by exposing the sensor to a glucose-containing solution under zero current flow conditions and allowing the reduced/oxidized Os ratio to reach an equilibrium value. The reduced/oxidized Os ratio varies in a reproducible manner with glucose concentration and will cause the electrode potential to vary in a similar manner.

[0147]The substrate may be formed using a range of non-conductive materials, including, for example, polymeric or plastic materials and ceramic materials. Suitable materials for a particular sensor may be determined, at least in part, based on the desired use of the sensor and the properties of the materials.

[0148] In some embodiments, the substrate is flexible. For example, if the sensor is configured for implantation into a patient, then the sensor can be made flexible (although rigid sensors can also be used for implantable sensors) to reduce pain to the patient and tissue damage caused by implantation and/or use of the sensor. A flexible substrate often increases patient comfort and allows for a wider range of activities. Suitable materials for a flexible substrate include, for example, non-conductive plastic or polymeric materials and other non-conductive, flexible, deformable materials. Examples of useful plastic or polymeric materials include thermoplastics such as polycarbonates, polyesters (e.g., Mylar™ and polyethylene terephthalate (PET)), polyvinyl chloride (PVC), polyurethanes, polyethers, polyamides, polyimides, or copolymers of these thermoplastics, such as PETG (polyethylene terephthalate modified with glycol).

[0149] In other embodiments, the sensors are fabricated using a relatively rigid substrate, for example, to provide structural support against bending or breaking. Examples of rigid materials that can be used as the substrate include poorly conductive ceramics, such as aluminum oxide and silicon dioxide. The implantable sensor having a rigid substrate may have a sharp tip and/or a sharp edge to aid in implantation of a sensor without an additional insertion device.

[0150]It will be appreciated that for many sensors and sensor applications, both rigid and flexible sensors function adequately. Sensor flexibility can also be controlled and varied over a continuous spectrum by changing, for example, the composition and/or thickness of the substrate.

[0151]In addition to considerations regarding flexibility, it is often desirable for implantable sensors to have a substrate that is physiologically harmless, for example, a substrate approved by a regulatory agency or private institution for use in vivo.

[0152] The sensor may include optional features to facilitate insertion of an implantable sensor. For example, the sensor may be pointed at tip 123 to facilitate insertion. In addition, the sensor may include a tab that helps anchor the sensor within the patient's tissue during operation of the sensor. However, the tab is typically small enough to cause little damage to subcutaneous tissue when the sensor is removed for replacement.

[0153] Optionally, an implantable sensor may also have an anticoagulant agent disposed on a portion of the substrate that is implanted in a patient. This anticoagulant agent may reduce or eliminate clotting of blood or other bodily fluid around the sensor, particularly after insertion of the sensor. Blood clots may foul the sensor or irreproducibly reduce the amount of analyte diffusing to the sensor. Examples of useful anticoagulant agents include heparin and tissue plasminogen activator (TPA), as well as other known anticoagulant agents.

[0154] The anticoagulant agent may be applied to at least a portion of that portion of the sensor to be implanted. The anticoagulant agent may be applied, for example, by bathing, spraying, brushing, or dipping, etc. The anticoagulant agent is allowed to dry on the sensor. The anticoagulant agent may be immobilized on the sensor surface or allowed to diffuse away from the sensor surface. The amounts of anticoagulant agent dispensed on the sensor may be far less than amounts typically used for the treatment of medical conditions involving blood clots and thus have only a limited and localized effect.

Insertion device

[0155] An insertion device may be used to insert the sensor subcutaneously into the user. The insertion device is typically formed using structurally rigid materials, such as metal or rigid plastic. Materials may include stainless steel and ABS (acrylonitrile-butadiene-styrene) plastic. In some embodiments, the insertion device is pointed and/or tapered at the tip to facilitate penetration of the user's skin. A thin, tapered insertion device may reduce the pain felt by the user when inserting the sensor. In other embodiments, the tip of the insertion device has other shapes, including a blunt or flat shape. These embodiments may be useful when the insertion device does not penetrate the skin but instead serves as a structural support for the sensor when the sensor is pushed into the skin.

Sensor control unit

[0156] The sensor control unit may be integrated into the sensor, part or all of which is implanted subcutaneously, or may be configured to be placed on the skin of a user. The sensor control unit optionally has a shape that is comfortable for the user and may allow for concealment, for example, under the user's clothing. The thigh, leg, upper arm, shoulder, or abdomen are convenient parts of the user's body to place the sensor control unit to maintain concealment. However, the skin-positioned sensor control unit 44 may be placed on other portions of the patient's body. One embodiment of the skin-positioned sensor control unit 44 has a thin, oval shape to enhance concealment, as illustrated in Figures 14-16. However, other shapes and sizes may be used.

[0157]The particular profile, as well as the height, width, length, weight and volume of the sensor control unit may vary and depends, at least in part, on the components and associated functions included in the sensor control unit. In general, the sensor control unit includes a housing typically formed as a single integral unit that rests on the skin of the user. The housing typically contains most or all of the electronic components of the sensor control unit.

[0158] The sensor control unit housing may be formed using a variety of materials, including, for example, plastic and polymeric materials, such as rigid thermoplastics and engineering thermoplastics. Suitable materials include, for example, polyvinyl chloride, polyethylene, polypropylene, polystyrene, ABS polymers, and copolymers thereof. The sensor control unit housing may be formed using a variety of techniques, including, for example, injection molding, compression molding, casting, and other molding methods. Recessed or hollow areas may be formed in the sensor control unit housing. Electronic components of the sensor control unit and/or other elements, including a battery or speaker for an audible alarm, may be placed in the recessed or hollow areas.

[0159] The sensor control unit is typically attached to the user's skin, for example, by adhering the sensor control unit directly to the user's skin with an adhesive provided on at least a portion of the sensor control unit housing that contacts the user's skin, or by suturing the sensor control unit to the skin via suture openings in the sensor control unit.

[0160]When placed on the skin of a user, the sensor and electronic components within the sensor control unit are coupled via conductive contacts. The one or more working electrodes, the counter (or counter/reference) electrode, the optional reference electrode, and the optional temperature probe are attached to individual conductive contacts. For example, the conductive contacts are provided on the interior of the sensor control unit. Other embodiments of the sensor control unit have the conductive contacts disposed on the exterior of the housing. The placement of the conductive contacts is such that they are in contact with the contact pads of the sensor when the sensor is properly positioned within the sensor control unit.

Sensor control unit electronics

[0161] The sensor control unit also typically includes at least a portion of the electronic components that operate the sensor and the analyte monitoring device system. The electronic components of the sensor control unit typically include a power supply for operating the sensor control unit and the sensor, a sensor circuit for obtaining signals from the sensor and operating it, a measurement circuit that converts the sensor signals to a desired format, and a processing circuit that, at a minimum, obtains signals from the sensor circuit and/or measurement circuit and provides the signals to an optional transmitter. In some embodiments, the processing circuit may also partially or completely evaluate the sensor signals and transmit the resulting data to the optional transmitter and/or activate an optional alarm system if the analyte level exceeds a threshold. The processing circuit often includes digital logic circuits.

[0162] The sensor control unit may optionally contain a transmitter for transmitting sensor signals or processed data from the processing circuit to a receiver/display unit; a data storage unit for temporarily or permanently storing data from the processing circuit; a temperature probe circuit for receiving signals from, and operating, a temperature probe; a reference voltage generator for providing a reference voltage for comparison with signals generated by the sensor; and/or a watchdog circuit that monitors the operation of electronic components in the sensor control unit.

[0163] In addition, the sensor control unit may also include digital and/or analog components utilizing semiconductor devices, including transistors. To operate these semiconductor devices, the sensor control unit may include other components including, for example, a bias control generator to properly bias the analog and digital semiconductor devices, an oscillator to provide a clock signal, and a timing and digital logic component to provide timing signals and logic operations for the digital components of the circuit.

[0164]As an example of the operation of these components, the sensor circuit and optional temperature probe circuit provide raw signals from the sensor to the measurement circuit. The measurement circuit converts the raw signals to a desired format, using, for example, a current to voltage converter, a current to frequency converter, and/or a binary counter or other indicator that produces a signal proportional to the absolute value of the raw signal. This can be used, for example, to convert the raw signal to a format that can be used by digital logic circuits. Optionally, the processing circuit may then evaluate the data and provide commands to operate the electronics.

Calibration

[0165]Sensors may be configured to not require system or user calibration. For example, a sensor may be factory calibrated and need no additional calibration. In certain embodiments, calibration may be required, but may be performed without user intervention, i.e., may be automatic. In those embodiments where user calibration is required, calibration may be according to a predetermined schedule or may be dynamic, i.e., the time over which may be determined by the system in real time according to various factors, including, but not limited to, glucose concentration and/or temperature and/or rate of change of glucose, etc.

[0166]In addition to a transmitter, an optional receiver may be included in the sensor control unit. In some cases, the transmitter is a transceiver that functions as both a transmitter and a receiver. The receiver may be used to receive calibration data for the sensor. The calibration data may be used by the processing circuit to correct signals from the sensor. This calibration data may be transmitted by the receiver/display unit or from some other source such as a control unit in a physician's office. In addition, the optional receiver may be used to receive a signal from the receiver/display units to direct the transmitter, for example, to change frequencies or frequency bands, to activate or deactivate the optional alarm system, and/or to direct the transmitter to transmit at a higher rate.

[0167]Calibration data may be obtained in a range of ways. For example, calibration data may be factory-determined calibration measurements which may be entered into the sensor control unit using the receiver or alternatively may be stored in a calibration data storage unit within the sensor control unit itself (in which case a receiver may not be necessary). The calibration data storage unit may be, for example, a readable or readable/writable memory circuit. In some cases, a system may only need to be calibrated once during the manufacturing procedure, where recalibration of the system is not required.

[0168] If necessary, calibration may be accomplished using an in vitro test strip (or other reference), for example, a small sample test strip, such as a test strip that requires less than about 1 microliter of sample (e.g., FreeStyle® blood glucose monitoring test strips from Abbott Diabetes Care, Alameda, CA). For example, test strips that require less than about 1 nanoliter of sample may be used. In certain embodiments, a sensor may be calibrated using only one body fluid sample per calibration event. For example, a user only needs to prick a body part once to obtain a sample for a calibration event (e.g., for one test strip), or may prick more than once in a short period of time if an insufficient volume of sample is obtained first. Embodiments include obtaining and using multiple body fluid samples for a given calibration event, where the glucose values of each sample are substantially similar. Data obtained from a given calibration event may be used independently to calibrate or combined with data obtained from previous calibration events, e.g., averaged, including weighted averages, etc., to calibrate. In certain embodiments, a system only needs to be calibrated once by a user, where recalibration of the system is not required.

[0169]Alternative or additional calibration data may be provided based on testing performed by a healthcare professional or the user. For example, it is common for diabetic individuals to determine their own blood glucose using commercially available test kits. The results of this test are entered into the sensor control unit either directly, if an appropriate input device (e.g., a keyboard, optical signal receiver, or port for connection to a keyboard or computer) is incorporated into the sensor control unit, or indirectly by inputting calibration data into the receiver/display unit and transmitting the calibration data to the sensor control unit.

[0170]Other methods of independently determining analyte levels may also be used to obtain calibration data. This type of calibration data may replace or supplement factory-determined calibration values.

[0171] In some embodiments of the invention, calibration data may be required at periodic intervals, for example, every eight hours, once a day, or once a week, to confirm that accurate analyte levels are being reported. Calibration may also be required each time a new sensor is implanted or if the sensor exceeds a threshold minimum or maximum value or if the rate of change in the sensor signal exceeds a threshold value. In some cases, it may be necessary to wait a period of time after implantation of the sensor before calibrating it to allow the sensor to reach equilibrium. In some embodiments, the sensor is calibrated only after it has been inserted. In other embodiments, no calibration of the sensor is required.

Analyte monitoring device

[0172] In some embodiments of the invention, the analyte monitoring device includes a sensor control unit and a sensor. In these embodiments, the processing circuit of the sensor control unit is capable of determining a level of the analyte and activating an alarm system if the level of the analyte exceeds a threshold value. The sensor control unit, in these embodiments, has an alarm system and may also include a display, such as an LCD or LED display.

[0173] A threshold value is exceeded if the data point has a value that is greater than the threshold value in a direction that indicates a particular condition. For example, a data point that correlates to a glucose level of 200 mg/dL exceeds a threshold value for hyperglycemia of 180 mg/dL, because the data point indicates that the patient has entered a hyperglycemic state. As another example, a data point that correlates to a glucose level of 65 mg/dL exceeds a threshold value for hypoglycemia of 70 mg/dL because the data point indicates that the patient is hypoglycemic, as defined by the threshold value. However, a data point that correlates to a glucose level of 75 mg/dL would not exceed the same threshold value of 70 mg/dL for hypoglycemia because the data point does not indicate that particular condition defined by the chosen threshold value.

[0174]An alarm may also be triggered if sensor readings indicate a value that is outside (e.g., above or below) a sensor measurement range. For glucose, the physiologically relevant measurement range is typically 30 to 400 mg/dL, including 40 to 300 mg/dL and 50 to 250 mg/dL of glucose in the interstitial fluid.

[0175] The alarm system may also, or alternatively, be activated when the rate of change or the acceleration of the rate of change in the analyte level increases or decreases, reaches or exceeds a threshold rate or acceleration. For example, in the case of a subcutaneous glucose monitor, the alarm system may be activated if the rate of change in glucose concentration exceeds a threshold value that may indicate that a hyperglycemic or hypoglycemic condition is likely to occur. In some cases, the alarm system is activated if the acceleration of the rate of change in glucose concentration exceeds a threshold value that may indicate that a hyperglycemic or hypoglycemic condition is likely to occur.

[0176] A system may also include system alarms that notify a user of the system of information such as battery condition, calibration, sensor detachment, sensor malfunction, etc. The alarms may be, for example, auditory and/or visual. Other sensory stimulation alarm systems may be used, including alarm systems that heat, cool, vibrate, or produce a mild electrical shock when activated.

Drug delivery systems

[0177] The present invention also includes sensors used in sensor-based drug delivery systems. The system may provide a drug to counteract the high or low level of the analyte in response to signals from one or more sensors. Alternatively, the system may monitor the concentration of drug to ensure that the drug remains within a desired therapeutic range. The drug delivery system may include one or more (e.g., two or more) sensors, a processing unit, such as a transmitter, a receiver/display unit, and a drug delivery system. In some cases, some or all of the components may be integrated into a single unit. A sensor-based drug delivery system may use data from the one or more sensors to provide input necessary for a control algorithm/mechanism to adjust drug delivery, e.g., automatically or semi-automatically. For example, a glucose sensor may be used to monitor and adjust insulin delivery from an external or implanted insulin pump.

[0178]Other embodiments and modifications within the scope of the present disclosure will be apparent to those skilled in the relevant art. Various modifications, methods, as well as numerous structures to which embodiments of the invention may be applicable will be readily apparent to those skilled in the art to which the invention is directed upon review of the specification. Various aspects and features of the invention may have been explained or described in connection with understandings, beliefs, theories, underlying assumptions, and/or working or prophetic examples, although it will be understood that the invention is not bound to any particular understanding, belief, theory, underlying assumption, and/or working or prophetic example. Although various aspects and features of the invention may have been described largely with respect to applications, or more specifically, medical applications, involving diabetic humans, it will be understood that such aspects and features also relate to any of a variety of applications involving non-diabetic humans and any and all other animals. Furthermore, although various aspects and features of the invention may have been described largely with respect to applications involving partially implanted sensors, such as transcutaneous or subcutaneous sensors, it will be understood that such aspects and features also relate to any of a variety of sensors that are suitable for use in connection with the body of an animal or a human, such as those suitable for use as fully implanted in the body of an animal or a human. Finally, although the various aspects and features of the invention have been described with respect to various specific embodiments and examples herein, all of which may be performed or carried out in a conventional manner, it will be understood that the invention is entitled to protection within the full scope of the appended claims.

[0179]The following examples are presented to provide those skilled in the art with a complete description of how to make and use embodiments of the invention, and are not intended to limit the scope of what the inventors consider to be their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts were made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is the weight average molecular weight, temperature is in degrees Celsius, and pressure is, or approximates, atmospheric pressure.

EXAMPLES

Example 1

[0180] Figure 6 shows a photograph of a working electrode coated with six sensing elements (labeled 1 through 6) with a radius of approximately 150 pm each at a distance of approximately 150 pm from each other. The resulting sensors have a coefficient of variation in sensitivity of 5% or less. The diameters of each sensing element in Figure 6 are shown in Table 1 below.

T l 1

Example 2

[0181] Figure 10 shows a plot of current (pA) versus time (seconds) for a sensing layer formulation deposited as an array of small sensing elements (9 pL/drop), and a sensing layer formulation deposited as a stripe coating on the surface of a gold working electrode. The sensor with the sensing layer formulation deposited as an array of small sensing elements recovered 26% more charge than the stripe-coated sensor under the same test conditions.

Claims (15)

1. An analyte sensor (100, 500, 800, 900) comprising: a first working electrode (820, 920) comprising a first sensing surface having an array of two or more laterally disposed adjacent sensing elements (810, 910), each separately deposited thereon, where each detection element comprises an analyte-sensitive enzyme; and a counter electrode (503). 2. The analyte sensor according to claim 1, wherein the sensing elements have an average diameter ranging from 0.1 µm to 500 µm. 3. The analyte sensor according to any of the preceding claims, wherein the sensing elements have a volume ranging from 0.01 pL to 1000 pL. 4. The analyte sensor according to any of the preceding claims, wherein at least a portion of the analyte sensor is configured to come into contact with a bodily fluid and the sensing elements are configured to detect one or more analytes in vivo therein. 5. The analyte sensor according to claim 4, wherein the one or more in vivo analytes comprise glucose. 6. The analyte sensor according to claim 4, wherein one or more in vivo analytes comprise lactate. 7. The analyte sensor according to any of the preceding claims, wherein the analyte sensor is factory calibrated and does not require calibration or recalibration by the user. 8. The analyte sensor according to any of the preceding claims further comprising a second working electrode comprising a second sensing surface disposed thereon, the second sensing surface including two or more laterally disposed sensing elements, each separately deposited thereon. 9. The analyte sensor according to claim 8, wherein the sensing elements of the second sensing surface are discontinuous or contiguous. 10. The analyte sensor according to claim 9, wherein the first working electrode is disposed on a surface of a substrate, a dielectric is disposed on the first working electrode and the second working electrode is disposed on the dielectric. 11. A procedure comprising: monitoring a level of one or more analytes from signals generated by an analyte sensor, the analyte sensor being configured to come into contact with a bodily fluid comprising the one or more analytes and comprising: a first working electrode (820, 920) comprising a first sensing surface having an array of two or more laterally disposed adjacent sensing elements (810, 910), each separately deposited thereon, where each detection element comprises an analyte-sensitive enzyme; and a counter electrode (503). 12. The method according to claim 11, wherein the monitoring of the level of the one or more analytes is over a period of time. 13. The method according to claim 11 or 12, wherein said monitoring comprises coupling a plurality of conductive contacts of an analyte sensor control unit to a plurality of contact pads of the analyte sensor. 14. The method according to claim 13, further comprising collecting data, using the analyte sensor control unit, regarding a level of the one or more analytes from the signals generated by the analyte sensor. 15. The method according to claim 14, further comprising transmitting the collected data from the analyte sensor control unit to a receiving unit.