CN103261433A - Analyte sensors with a sensing surface having small sensing spots - Google Patents

Abstract

Embodiments of the present disclosure relate to analyte determining methods and devices (e.g., electrochemical analyte monitoring systems) that have a sensing surface that includes two or more sensing elements disposed laterally to each other, where the sensing surface is on 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. Also provided are systems and methods of using the, for example electrochemical, analyte sensors in analyte monitoring.

Description

Analyte sensor with sensing surface comprising small sensing spots

Cross References to Related Applications

This application claims priority under 35 USC. §119(e) to US Provisional Patent Application No. 61/421,371, filed December 9, 2010, which is hereby incorporated by reference in its entirety.

Background of the invention

In many situations it is desirable or necessary to periodically monitor the concentration of a particular component in a fluid. Many systems are used to analyze the composition of body fluids such as blood, urine and saliva. Examples of such systems conveniently monitor the levels of fluid constituents of particular medical importance, such as cholesterol, ketones, vitamins, proteins and various metabolites or blood sugar, such as glucose. The diagnosis and management of people with diabetes, which is a disorder of the pancreas that does not produce enough insulin, requires careful daily monitoring of blood sugar levels, which prevents the normal regulation of blood sugar levels. Many systems now allow individuals to easily monitor their blood glucose. Such systems include electrochemical biosensors, including electrochemical biosensors having a glucose sensor adapted for insertion into the subcutaneous site of the body for continuous monitoring of glucose levels in body fluids at the subcutaneous site (see US Patent 6,175,752 to Say et al.).

An individual can use a needle and syringe to draw blood from a blood source in his or her body, such as a vein, to obtain a blood sample, or use a piercing device to puncture a part of his or her skin so that blood can be obtained outside the skin, necessary for in vitro testing sample size. The individual then applies a fresh blood sample to a test strip so that an appropriate detection method, such as calorimetric, electrochemical, or photometric, can be used to determine the individual's actual blood glucose level. The foregoing procedures provide blood glucose concentrations at specific or discrete time points and therefore must be repeated periodically in order to monitor blood glucose over a longer period of time.

In addition to the discrete or periodic in vitro blood glucose monitoring systems described above, at least partially implantable or in vivo blood glucose monitoring systems configured to provide continuous in vivo testing of an individual's blood glucose concentration have also been disclosed and developed.

Such analyte monitoring devices are configured to provide continuous or automated monitoring of analytes, such as glucose, in blood or interstitial fluid. Such devices include electrochemical sensors that are at least partially operatively disposed in a blood vessel or subcutaneous tissue of a user.

When continuous monitoring of glucose is required, there are several challenges associated with optimizing manufacturing protocols to improve the yield and consistency of biosensor sensing elements used in vitro. There is therefore a need for further development of manufacturing techniques and methods and analyte monitoring devices, systems or kits using these techniques and methods.

Summary of the invention

Embodiments of the present disclosure relate to analyte determination methods and devices (e.g., electrochemical analyte monitoring systems) having a sensing surface comprising two or more sensing elements disposed laterally to one another, wherein the sensing surface Continuous and/or automated in vivo monitoring such as using analyte sensors and/or test strips on working electrodes of in vivo and/or in vitro analyte sensors. Systems and methods for using electrochemical analyte sensors in analyte monitoring are also provided.

An analyte sensor encompassed by aspects of the present disclosure includes: a working electrode; and a counter electrode, wherein the working electrode comprises a sensing surface, wherein the sensing surface has two or more sensing elements disposed laterally to each other, and each sensing The detection element includes an analyte-responsive enzyme.

In some embodiments, the sensing elements are not in contact. In some cases, the sensing element is provided as a single sensing element on the working electrode. For example, a sensing surface may comprise an array of two or more individual sensing elements. In some cases, a sensing surface may include an array of 100 or more individual sensing elements. In some cases, the sensing element density of the sensing surface is in the range of 2-1000 sensing elements/mm ² .

In certain embodiments, the sensing surface further includes inter-feature regions. The inter-feature region may surround the sensing element. In some cases, the sensing element has an inter-feature distance in the range of 1 μm to 500 μm. In some cases, the interfeature region is devoid of analyte-responsive enzymes. In some cases, the interfeature region is devoid of redox mediators.

In certain embodiments, the working electrode further includes a second layer having two or more sensing elements disposed on the sensing surface. In some cases, the average diameter of the sensing elements is less than or equal to 200 μm.

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

In some cases, the analyte sensor further includes a membrane disposed on the sensing element that restricts the flow of the analyte to the sensing element.

In certain instances, the analyte-responsive enzyme includes glucose-responsive enzyme. In some cases, the sensing element includes a redox mediator. For example, the redox mediator can include a ruthenium-containing complex or an osmium-containing complex.

In certain embodiments, the analyte sensor is a glucose sensor. In certain instances, the analyte sensor is an in vivo sensor. In other cases, the analyte sensor is an in vitro sensor.

Aspects of the present disclosure also include methods for monitoring analyte levels in a subject. The method includes positioning at least a portion of the analyte sensor in the skin of the subject, and determining the level of the analyte over a period of time based on a signal generated by the analyte sensor, wherein the determination over the period of time is used to monitor the level of the analyte in the subject. As described above, the analyte sensor comprises: a working electrode; and a counter electrode, wherein the working electrode comprises a sensing surface having two or more sensing elements disposed laterally to one another, wherein each sensing element comprises an analyte-responsive enzyme .

In some embodiments, the sensing elements are not in contact. In some cases, the sensing element is provided as a single sensing element on the working electrode. For example, a sensing surface may comprise an array of two or more individual sensing elements. In some cases, a sensing surface may include an array of 100 or more individual sensing elements. In some cases, the sensing element density of the sensing surface is in the range of 2-1000 sensing elements/mm ² .

In certain embodiments, the sensing surface further includes inter-feature regions. The inter-feature region may surround the sensing element. In some cases, the sensing element has an inter-feature distance in the range of 1 μm to 500 μm. In some cases, the interfeature region is devoid of analyte-responsive enzymes. In some cases, the interfeature region is devoid of redox mediators.

In certain embodiments, the working electrode further includes a second layer having two or more sensing elements disposed on the sensing surface. In some cases, the average diameter of the sensing elements is less than or equal to 200 μm.

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

In some cases, the analyte sensor further includes a membrane disposed on the sensing element that restricts the flow of the analyte to the sensing element.

In certain instances, the analyte-responsive enzyme includes glucose-responsive enzyme. In some cases, the sensing element includes a redox mediator. For example, the redox mediator can include a ruthenium-containing complex or an osmium-containing complex.

In certain embodiments, the analyte sensor is a glucose sensor. In certain instances, the analyte sensor is an in vivo sensor. In other cases, the analyte sensor is an in vitro sensor.

Aspects of the present disclosure further include methods of monitoring analyte levels using an analyte monitoring system. The method includes: inserting at least a portion of an analyte sensor into the patient's skin; attaching an analyte sensor control unit to the patient's skin; coupling a plurality of conductive contacts of the analyte sensor control unit to a plurality of conductive contacts of the analyte sensor on the contact pad; collecting data, using the analyte sensor control unit, collecting data about analyte levels from signals generated by the analyte sensor; and transmitting the collected data by the analyte sensor control unit to a receiver 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 disposed laterally to each other, wherein each sensing element includes Analyte-reactive enzymes.

In some embodiments, the sensing elements are not in contact. In some cases, the sensing element is provided as a single sensing element on the working electrode. For example, a sensing surface may comprise an array of two or more individual sensing elements. In some cases, a sensing surface may include an array of 100 or more individual sensing elements. In some cases, the sensing element density of the sensing surface is in the range of 2-1000 sensing elements/mm ² .

In certain embodiments, the sensing surface further includes inter-feature regions. The inter-feature region may surround the sensing element. In some cases, the sensing element has an inter-feature distance in the range of 1 μm to 500 μm. In some cases, the interfeature region is devoid of analyte-responsive enzymes. In some cases, the interfeature region is devoid of redox mediators.

In certain embodiments, the working electrode further includes a second layer having two or more sensing elements disposed on the sensing surface. In some cases, the sensing element has an average diameter less than or equal to 200 μm.

In certain embodiments, the analyte is glucose.

In some cases, collecting data includes generating a signal from an analyte sensor and processing the signal into data. In some cases, the data includes signals from analyte sensors.

In certain embodiments, the method further includes activating 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 can be insulin.

In some cases, the method does not include a calibration step.

Aspects of the present disclosure also include methods of making electrodes for analyte sensors. The method includes contacting a sensing surface of each of two or more electrodes and two or more sensing elements disposed laterally to one another, wherein each sensing element includes an analyte-reactive enzyme.

In some embodiments, the sensing elements are not in contact. In some cases, the sensing element is provided as a single sensing element on the working electrode. For example, the sensing surface may comprise an array of two or more individual sensing elements. In some cases, the sensing surface may include an array of 100 or more individual sensing elements. In some cases, the sensing surface has a sensing element density in the range of 2-1000 sensing elements/mm ² .

In certain embodiments, the sensing surface further includes inter-feature regions. The inter-feature region may surround the sensing element. In some cases, the sensing element has an inter-feature distance in the range of 1 μm to 500 μm. In some cases, the interfeature region is devoid of analyte-responsive enzymes. In some cases, the interfeature region is free of redox mediators.

In certain embodiments, the working electrode further includes a second layer having two or more sensing elements disposed on the sensing surface. In some cases, the sensing element has an average diameter less than or equal to 200 μm.

In certain embodiments, the method is a method of fabricating two or more electrodes for use in a multiple analyte sensor. In these embodiments, the method includes contacting a sensing surface of each of two or more electrodes and two or more sensing elements disposed laterally to one another, wherein each sensing element includes an analyte-reactive enzyme. In some cases, the sensitivity coefficient of variation of the electrodes is less than or equal to 8%.

In some cases, at least a portion of the analyte sensor is adapted to be positioned subcutaneously of the subject. In some cases, the analyte sensor further includes a membrane disposed on the sensing element.

In certain embodiments, the analyte-responsive enzyme comprises glucose-responsive enzyme. In some cases, the sensing element includes a redox mediator. For example, the redox mediator can include a ruthenium-containing complex or an osmium-containing complex.

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

In certain embodiments of the method, contacting comprises depositing one or more droplets comprising the sensing element on the sensing surface of the working electrode. In some cases, the method further includes contacting the sensing element and the membrane that restricts flow of the analyte to the sensing element.

Aspects of the present disclosure also include an analyte test strip comprising: a first substrate having a first surface; a second substrate having a second surface opposite the first surface, the first and second substrates disposed so that the first surface and the second surface are in facing relationship; 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 A sensing surface is included having two or more sensing elements disposed laterally to each other, and each sensing element includes an analyte-reactive enzyme.

In some embodiments, the sensing elements are not in contact. In some cases, the sensing element is provided as a single sensing element on the working electrode. For example, the sensing surface may comprise an array of two or more individual sensing elements. In some cases, the sensing surface may include an array of 100 or more individual sensing elements. In some cases, the sensing surface has a sensing element density in the range of 2-1000 sensing elements/mm ² .

In certain embodiments, the sensing surface further includes inter-feature regions. The inter-feature region may surround the sensing element. In some cases, the sensing element has an inter-feature distance in the range of 1 μm to 500 μm. In some cases, the interfeature region is devoid of analyte-responsive enzymes. In some cases, the interfeature region is free of redox mediators.

In certain embodiments, the working electrode further includes a second layer having two or more sensing elements disposed on the sensing surface. In some cases, the sensing element has an average diameter less than or equal to 200 μm.

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

In certain instances, the analyte-responsive enzyme includes glucose-responsive enzyme. In some cases, the sensing element includes a redox mediator. For example, the redox mediator may comprise a ruthenium-containing complex or an osmium-containing complex.

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

Aspects of the present disclosure further include methods for monitoring analyte levels in a subject. The method includes contacting a sample of a subject with an analyte test strip and determining an analyte level from a signal generated by the analyte test strip, wherein the determination provides monitoring of the analyte level 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 configured so that the A first surface and the second surface are in facing relationship; 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 comprises a sensing surface , the sensing surface has two or more sensing elements arranged laterally to each other, and each sensing element includes an analyte-reactive enzyme.

In some embodiments, the sensing elements are not in contact. In some cases, the sensing element is provided as a single sensing element on the working electrode. For example, the sensing surface may comprise an array of two or more individual sensing elements. In some cases, the sensing surface may include an array of 100 or more individual sensing elements. In some cases, the sensing surface has a sensing element density in the range of 2-1000 sensing elements/mm ² .

In certain embodiments, the sensing surface further includes inter-feature regions. The inter-feature region may surround the sensing element. In some cases, the sensing element has an inter-feature distance in the range of 1 μm to 500 μm. In some cases, the interfeature region is devoid of analyte-responsive enzymes. In some cases, the interfeature region is free of redox mediators.

In certain embodiments, the working electrode further includes a second layer having two or more sensing elements disposed on the sensing surface. In some cases, the sensing element has an average diameter less than or equal to 200 μm.

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

In certain instances, the analyte-responsive enzyme includes glucose-responsive enzyme. In some cases, the sensing element includes a redox mediator. For example, the redox mediator may comprise a ruthenium-containing complex or an osmium-containing complex.

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

Aspects of the present disclosure also include methods of monitoring analyte levels using an analyte monitoring system. The method includes: coupling the conductive contacts of the analyte test strip to the analyte monitoring system; contacting a sample of the subject to the analyte test strip; collecting data from the analyte test strip using the analyte monitoring system. collecting data on the level of the analyte from the signal generated by the strip; and determining the level of the analyte from the collected data, wherein the determination provides monitoring of 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 configured to The first surface and the second surface are in facing relationship; 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 comprises a sensing A sensing surface having two or more sensing elements disposed laterally to each other, and each sensing element includes an analyte-reactive enzyme.

In some embodiments, the sensing elements are not in contact. In some cases, the sensing element is provided as a single sensing element on the working electrode. For example, the sensing surface may comprise an array of two or more individual sensing elements. In some cases, the sensing surface may include an array of 100 or more individual sensing elements. In some cases, the sensing surface has a sensing element density in the range of 2-1000 sensing elements/mm ² .

In certain embodiments, the sensing surface further includes inter-feature regions. The inter-feature region may surround the sensing element. In some cases, the sensing element has an inter-feature distance in the range of 1 μm to 500 μm. In some cases, the interfeature region is devoid of analyte-responsive enzymes. In some cases, the interfeature region is free of redox mediators.

In certain embodiments, the working electrode further includes a second layer having two or more sensing elements disposed on the sensing surface. In some cases, the sensing element has an average diameter less than or equal to 200 μm.

In certain embodiments, the analyte is glucose.

In some examples of the method, collecting data includes generating a signal from the analyte test strip and processing the signal into data. In some cases, the data includes signals from analyte strips.

In some cases, the method further includes activating 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 can be insulin.

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

Brief description of the drawings

Various embodiments of the present disclosure will be described in detail below with reference to the accompanying drawings, and a brief description of the accompanying drawings is as follows. The drawings are illustrative and not necessarily to scale. The figures illustrate various embodiments of the present disclosure and illustrate one or more embodiments or examples of the present disclosure in whole or in part. Reference numbers, letters and/or symbols 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 an embodiment of an analyte monitoring system according to an embodiment of the disclosure.

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

FIG. 3 shows a block diagram of an embodiment of the main receiver unit of the analyte monitoring system shown in FIG. 1 .

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

5A-5B show perspective and cross-sectional views, respectively, of an analyte sensor embodiment. Figure 5C shows a schematic diagram of a working electrode according to an embodiment of the disclosure.

Figure 6 shows a photograph of a working electrode coated with six sensing elements with a radius of approximately 150 μm and a distance of approximately 150 μm from each other. The sensitivity variation coefficient of the obtained sensor is less than or equal to 5%.

7A shows a perspective view of an analyte sensor embodiment having an array of substantially row-aligned sensing elements according to an embodiment of the disclosure. 7B illustrates another embodiment perspective view of an analyte sensor with a row-shifted array of sensing elements according to an embodiment of the disclosure.

8 illustrates an embodiment perspective view of an analyte sensor having an array of sensing elements with row offset and minimal inter-feature area according to an embodiment of the disclosure.

Figure 9 shows a perspective view of an analyte sensor embodiment having a layered array of sensing elements according to an embodiment of the disclosure.

10 shows a cross-sectional view of a working electrode with multiple sensing elements on its surface according to an embodiment of the disclosure.

11 shows an exploded perspective view of an analyte sensor test strip according to an embodiment of the disclosure, with layers showing electrodes in a first configuration.

12 shows an exploded perspective view of an analyte sensor test strip according to an embodiment of the present disclosure, with layers showing electrodes in a second configuration.

13 shows a graph of current (μA) versus time (seconds) for a sensing layer formulation and a test paper coating deposited as an array of small sensing elements according to an embodiment of the disclosure.

Detailed ways

Before the embodiments of the present disclosure are described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the embodiments of the present invention is defined by the claims.

Where a range of values is provided, it is understood that each interpolation between the upper and lower limits of that range is also specifically disclosed to the tenth of the unit of the lower limit, unless expressly stated otherwise. The invention includes each smaller range between any stated value or interpolation in a stated range and any other stated value or interpolation in that stated range. The upper and lower limits of these smaller ranges may independently be included in or excluded from the stated ranges, and each range inclusive of either limit, exclusive limit, or both limits is also encompassed within the invention as indicated. Any limited effects expressly excluded. Where the stated range includes one or both of the limits, ranges excluding either or both of the included limits are also included.

In the description of the present invention, it should be understood that words appearing in the singular include their plural, and words appearing in the plural include the singular unless otherwise implicitly or explicitly understood or indicated. By way of example only, reference to "a" or "the" "analyte" includes a single analyte, as well as combinations and/or mixtures of two or more different analytes, and reference to "a" or "the" "concentration value" includes A single concentration value, and two or more concentration values, etc., unless otherwise implicitly or explicitly understood or indicated. Furthermore, it should be understood that for any given component described herein, any possible alternatives or substitutions listed for that component can generally be used alone or in combination with each other, unless otherwise implicitly or explicitly understood or indicated. Also, it should be understood that any list of such alternatives or substitutions is illustrative only and not limiting unless otherwise understood or indicated, either implicitly or explicitly.

Various terms are explained below to facilitate understanding of the present invention. It should be understood that the corresponding descriptions of these various terms apply to linguistic or grammatical variants or forms of these various terms. It is also to be understood that the invention is not to be limited by the terminology used herein to describe the specific embodiments, or the description therein. By way of example only, the present invention is not limited to a particular analyte, bodily or interstitial fluid, blood or capillary blood, or sensor configuration or usage unless otherwise implicitly or explicitly understood or indicated.

The application publications discussed herein refer only to publications prior to the filing date of the present application. Nothing herein is to be construed as an admission that embodiments of the invention are not entitled to antedate such application by virtue of prior invention. Furthermore, the publication date of the application provided may be different from the actual publication date of the application which requires independent confirmation.

Systems and methods with two or more sensing elements

Embodiments of the present disclosure relate to methods and apparatus for reducing variations in sensor sensitivity by including a sensing surface comprising two or more sensing elements disposed laterally to one another, wherein the sensing surface is on 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 sensing surfaces that include working electrodes of two or more arrays of individual sensing elements, resulting in reduced variation in sensor sensitivity between sensors. Systems and methods for using analyte sensors in analyte monitoring are also provided.

Embodiments of the present disclosure are based on the discovery that in fabrication of in vivo/in vitro biosensors, deposition of two or more sensing elements positioned lateral to each other on the sensing surface of a working electrode can reduce sensor-to-sensor variation in sensor sensitivity. In a certain embodiment, a sensor comprising two or more sensing elements disposed laterally to each other on the working electrode sensing surface has a lower sensor sensitivity variation than a sensor having a single larger sensing element. In other words, a sensor comprising two or more sensing elements positioned laterally to each other on the working electrode sensing surface has a lower variation in sensor sensitivity so that the total sensing element area of each sensor is smaller than having a single larger total sensing element area. sensing elements, wherein each sensor of a single larger total sensing element sensor has a larger total sensing element area. In certain embodiments, a sensor comprising two or more sensing elements disposed laterally to each other on the sensing surface of the working electrode has a coefficient of variation of sensitivity of less than or equal to 20%, such as less than or equal to 15%, including less than or equal to 10%, such as less than or equal to 8%, or less than or equal to 5%, or less than or equal to 3%, or less than or equal to 2%, or less than or equal to 1%.

During fabrication of the subject analyte sensor, an aqueous solution (eg, sensing element formulation) contacts a substrate surface (eg, the surface of a working electrode), forming a deposit of the solution (eg, sensing element) on the substrate surface. The sensing element may include an analyte-responsive enzyme. In some cases, the sensing element includes a redox mediator. In some cases, the sensing element formulation is deposited in such a way that the sensing element is not connected. "Not in contact" means that the sense elements do not share edges or boundaries (eg, do not touch) with adjacent sense elements. For example, the sensing elements may be provided as individual (discrete) sensing elements on the surface of the working electrode. In other embodiments, the sensing element is deposited on the surface of the working electrode such that an edge of the sensing element contacts an edge of one or more adjacent sensing elements. In these embodiments, the sensing element may be referred to as "contacted."

In certain embodiments, the sensing surface includes an array of two or more individual sensing elements on a 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 that carries a particular composition associated with that region. In some cases, the array is an array of formulations, such as sensing element formulations. Likewise, in certain embodiments, the array is an array of individual sensing elements, wherein each sensing element comprises a sensing element formulation.

Any given substrate may carry one, two, four or more arrays of sensing elements disposed on the surface of the substrate. Depending on the application, any or all of the arrays may be the same or different from each other, and each may contain multiple spots or features (eg, sensing elements). For example, the array may be over an area less than or equal to 100 mm ² , such as less than or equal to 75 mm ² , or less than or equal to 50 mm ² , such as less than or equal to 25 mm ² , or less than or equal to 10 mm ² , or less than or equal to 5 mm ² , such as 2 mm ² or less, or 1 mm ² or less, 0.5 mm ² or less, or 0.1 mm ² or less including two or more, 5 or more, 10 or more, 25 or More, 50 or more, 100 or more features, or even 1000 or more features. For example, the width of the feature (ie the diameter of the circular spot) is in the range of 0.1 μm to 1 mm, or in the range of 1 μm to 1 mm, such as in the range of from 1 μm to 500 μm, including in the range of from 10 μm to 250 μm, For example in the range from 50 μm to 200 μm. In certain embodiments, the average diameter of the sensing element is less than or equal to 500 μm, such as less than or equal to 250 μm, including less than or equal to 200 μm, or less than or equal to 150 μm, or less than or equal to 100 μm, such as less than or equal to 50 μm, or less than Or equal to 10 μm, or less than or equal to 1 μm, or less than or equal to 0.1 μm. The area extent of a non-circular feature is equal to the area extent of a circular feature with the aforementioned width (diameter) range.

In certain embodiments, the sensing surface includes inter-feature regions. The inter-feature region does not carry any sensing element formulation. Likewise, in some cases, the interfeature region does not include (eg, is substantially free of) analyte-responsive enzymes. Additionally, in some cases, the interfeature region does not include (eg, is substantially free of) redox mediators or polymer bound, covalent or non-covalent redox mediators. The inter-feature region can substantially surround the sensing element such that, as described herein, the sensing element is not in contact. In some cases, the sensing element has an inter-feature region, wherein the distance between adjacent sensing elements (e.g., the inter-feature distance) is such that analyte flow to the sensing element does not significantly interfere with flow to adjacent sensing elements. Analyte flow rate of the element. For example, the inter-feature distance may be greater than or equal to 0.1 μm, greater than or equal to 0.5 μm, greater than or equal to 1 μm, such as greater than or equal to 10 μm, including greater than or equal to 50 μm, or greater than or equal to 100 μm, or greater than or equal to 150 μm, or greater than Or equal to 200 μm, or greater than or equal to 250 μm, for example greater than or equal to 500 μm. The inter-feature distance may be in the range of 0.1 μm to 500 μm, or in the range of 0.5 μm to 500 μm, or in the range of 1 μm to 500 μm, for example in the range of 1 μm to 250 μm, including from 5 μm to 200 μm, for example, 10 μm to 200 μm. Such inter-feature regions occur when the array is formed by droplet deposition of the sensing element formulation on the working electrode sensing surface, as described in more detail below. It should be understood that the inter-feature region, when present, can be of various sizes and configurations.

Each array may cover an area less than or equal to 100mm ² , or 50mm ² , or less than or equal to 25mm ² , such as 10mm ² , less than or equal to 5mm ² , less than or equal to 1mm ² , or less than or equal to 0.1mm ² , or less than Or equal to 0.01mm ² , for example, less than or equal to 0.001mm ² . In certain embodiments, the sensing surface has a sensing element density greater than or equal to 2 sensing elements/mm ² , for example, greater than or equal to 5 sensing elements/mm ² , including greater than or equal to 10 sensing elements /mm ² , or greater than or equal to 50 sensing elements/mm ² , or greater than or equal to 100 sensing elements/mm ^{2 , such as greater than or equal to 250 sensing elements/mm 2 ,} including greater than or equal to 500 sensing elements/mm 2 sensing elements/mm ² , or greater than or equal to 1000 sensing elements/mm ² . For example, the sensing element density on the sensing surface is in the range of 2-1000 sensing elements/mm ² , for example in the range of 2-500 sensing elements/mm ² , including 2-250 sensing elements/mm 2 . sensing elements/ ^mm2 , in the range of 2-100 sensing elements/ ^mm2 , or in the range of 2-50 sensing elements/ ^mm2 , for example in the range of 2-10 sensing elements/mm2 within the range of ^mm2 .

Arrays can be fabricated using droplet deposition of sensing element formulations on the working electrode sensing surface. For example, the sensing element formulation can be deposited by any non-impact printing or impact printing method, such as from a pulse jet device. A "pulse injector" is a device that dispenses droplets in an array. Pulse ejector devices operate by delivering a pressure pulse to a liquid adjacent an outlet or orifice so that droplets are dispensed from the outlet or orifice (eg, by a piezoelectric or thermoelectric element disposed in the same chamber as the orifice). In certain embodiments, the droplets may be dispensed using a dispenser device configured to operate in a manner similar to an inkjet printing device, as above. In certain embodiments, the pulse-ejector device includes a dispensing head configured to dispense liquid droplets, such as, but not limited to, a sensing layer formulation, in an array. The dispense head may be of the type commonly used in inkjet printers, and may include one or more deposition chambers for containing the formulation. The amount of fluid deposited in a single activation event of a pulse injector can be controlled by varying one or more of a number of parameters, including the size of the orifice in the dispense head (e.g., orifice diameter), the size of the deposition chamber, piezoelectric or The size of the thermoelectric element, etc. The amount of fluid deposited in a single activation event is between 0.01 and 1000 picoliters (pL), such as between 0.1 and 750 picoliters (pL), including from 1 to 500 picoliters (pL), or from 1 to Between 250 picoliters (pL), or from 1 to 100 picoliters (pL), such as from 1 to 75 picoliters (pL), or from 1 to 50 picoliters (pL), such as from Between 1 and 25 picoliters (pL), or from 1 to 10 picoliters (pL), such as from 1 to 5 picoliters (pL). In some cases, the amount of fluid deposited in a single activation event was between 1 and 50 pL.

In certain embodiments, during fabrication of the subject analyte sensor, an aqueous solution (eg, sensing layer formulation) contacts a substrate surface (eg, the surface of a working electrode), forming a deposit of the solution on the substrate surface. In some cases, the solution was allowed to dry and cure. Without being bound by any particular theory, in some cases, during drying, components of the solution tend to migrate towards the outer edges of the deposit due to faster evaporation rates where the outer edges of the deposit are thinner. This results in a higher concentration of constituents in the solution at the periphery of the deposit, creating the so-called "coffee ring" effect. Analyte sensors are typically fabricated by depositing strips or relatively large droplets of sensing layer formulations on the surface of electrodes, which in some cases can produce the aforementioned "coffee ring" effect. For example, as described above, when the elongated strip of sensing layer formulation dries on the electrode surface, components of the sensing layer formulation may migrate toward the outer edges of the strip, resulting in an uneven coating of the sensing layer formulation on the electrode surface, wherein Sensing layer formulation concentrations were higher near the edges of the sensing layer strips.

In certain embodiments of the present disclosure, depositing an array of small sensing elements results in a reduction, and in some cases, complete disappearance of this "coffee ring" effect. For example, the coffee ring effect can 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 evaporation rate of the small sensing elements in the array is greater than that of the sensing layer formulation deposited as stripes or relatively large droplets on the electrode surface. In certain embodiments, upon drying and curing, a faster rate of evaporation results in a more uniform distribution of solution components deposited on the substrate as compared to solutions deposited as relatively larger stripes or droplets of the sensing layer formulation. This in turn can improve the coefficient of variation and overall manufacturing process of the sensor and the overall system. In certain embodiments, small sensing elements can facilitate faster sensor fabrication due to faster drying rates for very small sensing element spots, even at room temperature. The drying time may be further reduced by drying the sensing element at a temperature above room temperature, for example at a temperature of 25-100°C, such as 30-80°C, including 40-60°C.

In some cases, each sensing element (eg, a feature on an array) has a volume between 0.01 and 1000 picoliters (pL), such as between 0.1 and 750 picoliters (pL), including from 1 to 500 Between picoliters (pL), or from 1 to 250 picoliters (pL), or from 1 to 100 picoliters (pL), such as from 1 to 75 picoliters (pL), or from 1 Between 50 picoliters (pL), such as from 1 to 25 picoliters (pL), or from 1 to 10 picoliters (pL), such as from 1 to 5 picoliters (pL). In some cases, each sensing element has a volume between 1 and 50 pL. As described above, an array of sensing elements may be deposited on the surface of the electrodes such that inter-feature regions are formed between each individual sensing element on the array so that the sensing elements do not touch.

In certain embodiments, a single layer sensing element 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 can include a sensing surface that includes a first layer of sensing elements as described above, and can further include a second layer of sensing elements disposed on the sensing surface. In these cases, the first layer can be deposited as a first array of sensing elements on the surface of the working electrode. The 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 of 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 of the second array is deposited substantially on top of the inter-feature regions of the first array of sensing elements. In these cases, the sensing elements of the second array may be offset from the sensing elements of the first array of sensing elements. In some cases, the second layer of sensing elements may overlap at least a portion of one or more of the underlying first layer of sensing elements. Depositing the first array and the second array of sensing elements in the offset configuration described above can facilitate the formation of a contact coating of the sensing layer formulation on the surface of the working electrode. Additional layers of sensing elements can be deposited on the working electrode, either substantially aligned with or offset from the underlying layer, as desired. Depositing multiple layers of sensing elements on the working electrode surface facilitates cumulative deposition of the desired total amount of sensing layer formulation on the working electrode surface.

Without being bound by any particular theory, in some cases the sensitivity of an analyte sensor depends on the area of the sensing layer, such as a layer disposed on the surface of a working electrode comprising a sensing formulation with an analyte-reactive enzyme, and at Some instances include redox mediators or redox mediators that are covalently or non-covalently linked to the polymer. For the sensing layer as the contact layer of the sensing layer formulation, the sensor sensitivity depends on the area of the sensing layer and not significantly on the edge effect of the sensing layer. For example, the sensitivity of the sensor may depend on the analyte flux to the surface of the working electrode (eg, to a flat surface) through a flux-limiting membrane disposed on the sensing layer in a 2-dimensional manner. In some embodiments, including two or more sensing elements positioned laterally to each other allows the sensing element area to be minimized so that edge effects of the sensing layer can be maximized. This results in sensor sensitivity being dependent on the edge effects of the sensing element rather than the overall area of the sensing element. Likewise, the sensitivity of the sensor may depend on the analyte flux to the working electrode surface (eg, to a point) through a flow restricting membrane disposed on the sensing element in a radial 3-dimensional manner. In some cases, the sensing element has an arcuate profile to facilitate radial diffusion of analyte to the working electrode through a flow restricting membrane disposed on the sensing element. 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 the working electrode 1010. The sensing element 1020 has an arcuate profile configured to facilitate radial diffusion of analytes through a flow restricting membrane 1030 disposed on the sensing element 1020 towards the working electrode 1010 .

In some cases, the sensing element has an arcuate profile. "Arcuate" means that the cross-sectional profile of the sensing element is arcuate or circular. In some cases, the sensing element is desired to be approximately hemispherical in shape, when the circular hemispherical portion of the sensing element is convex and extends a distance over the substrate surface (eg, the working electrode surface). In some cases, the surface area of the hemispherical sensing element is greater than the surface area of a typical substantially flat or non-hemispherical sensing element. For example, a hemispherical sensing element may have a surface area equal to or greater than 1.1 times, such as equal to or greater than 1.2 times, including equal to or greater than 1.3 times, or equal to or greater than the surface area of a typical substantially planar (e.g., non-hemispherical) sensing element. Greater than 1.4 times, or equal to or greater than 1.5 times, or equal to or greater than 1.6 times, or equal to or greater than 1.7 times, or equal to or greater than 1.8 times, or equal to or greater than 1.9 times, or equal to or greater than typical substantially flat (for example, non-hemispherical) twice the surface area of the sensing element. In certain embodiments, a sensing element with a greater surface area can facilitate an increased surface area of the sensing layer formulation that is capable of contacting the analyte as it diffuses through the flux-limiting membrane to the sensing element.

In some cases, relatively small changes in the area of the sensing element will not significantly affect the sensitivity of the sensor because the sensor sensitivity depends on edge effects rather than the overall area of the sensing element. In certain embodiments, this results in reduced sensor sensitivity variation. Reduced sensor sensitivity variation can facilitate calibration of sensors during manufacturing. For example, sensor embodiments of the present disclosure may be calibrated during manufacture, such that the user is not required to calibrate the sensor. Likewise, in some cases, systems using the sensors of the present disclosure need not perform a calibration step before a user uses the sensor for analyte detection.

An embodiment of a sensing element is schematically shown as region 508 in FIG. 5B. The sensing element can be described as the active chemical region of the biosensor. Sensing element formulations that may include a glucose-transducing agent may include, among other ingredients, for example redox mediators such as hydrogen peroxide or transition metal complexes such as ruthenium-containing complexes or An osmium-containing complex, and an analyte-reactive enzyme, for example, a glucose-reactive enzyme (eg, glucose oxidase, glucose dehydrogenase, etc.) or a lactate-reactive enzyme (eg, lactate oxidase). The sensing element may also include other optional components such as polymers and bifunctional short-chain epoxy crosslinkers such as polyethylene glycol (PEG). As described herein, two or more sensing elements may be provided on the sensing surface of the working electrode, wherein the two or more sensing elements are positioned lateral to each other. For example, FIG. 5C shows a schematic diagram of a portion of working electrode 501 . Working electrode 501 includes a plurality of individual sensing elements 508 . The sensing elements 508 are not in contact so that the sensing elements 508 can be arranged as an array of individual sensing elements 508 on the working electrode 501 .

FIG. 7A shows a schematic diagram of a portion of an analyte sensor 700 comprising an array of sensing elements 710 deposited on a portion of a working electrode 720 . The array of sensing elements 710 is arranged in such a way that each row of sensing elements in the array is substantially aligned with the sensing elements of an adjacent row. As shown in FIG. 7A , the sensing elements 710 are arranged as a single non-contact sensing element array on the working electrode 720 . FIG. 7B shows a schematic diagram of another embodiment of an analyte sensor 750 . The portion of analyte sensor 750 shown includes sensing element array 760 deposited on a portion of working electrode 770 . The array of sensing elements 760 is arranged in such a way that each row of sensing elements in the array is offset from an adjacent row of sensing elements. As shown in FIG. 7B , the sensing elements 760 are arranged as a single non-contact sensing element array on the working electrode 770 . In some cases, arranging the rows of sense elements in an offset configuration facilitates the fabrication of arrays with a greater density of sense elements per unit area than arrays in which the rows of sense elements are substantially aligned, while maintaining a single contactless sensing element. Measuring element array.

As noted above, in other embodiments, the array of sensing elements can be configured so that the area between features is minimized. For example, FIG. 8 shows an analyte sensor 800 embodiment that includes an array of sensing elements 810 disposed on a portion of a working electrode 820 . The array of sensing elements 810 is arranged in such a way that each row of sensing elements in the array is offset from an adjacent row of sensing elements. As shown in FIG. 8, the sensing element 810 is arranged in such a way that the edge of the sensing element is in contact with one or more adjacent sensing elements. In some cases, arranging rows of sense elements in an offset configuration such that a sense element contacts one or more adjacent sense elements may facilitate fabrication of the sensor elements per unit area compared to arrays that do not contact the sense elements. A denser array of sensing elements.

As noted above, in certain embodiments, two or more sensing element layers may be deposited on the surface of the working electrode. For example, FIG. 9 shows a schematic diagram of an analyte sensor 900 including sensing elements 910 and 930 . The first layer of sensing elements 910 is deposited as a first array on the surface of the working electrode 920 . The sensing elements 930 of the second layer are deposited as a second array disposed on the sensing elements 910 of the first array. As shown in FIG. 9 , the second array of sensing elements 930 is deposited such that each sensing element 930 in the second array is deposited substantially on top of the inter-feature regions of the first array of sensing elements 910 . The second array sensing element 930 is offset from the first array sensing element 910 . The second array of sensing elements 930 overlaps at least a portion of one or more sensing elements 910 of the underlying first array (see enlarged inset of FIG. 9 ). Depositing the first array sensing elements 910 and the second array sensing elements 930 in the offset configuration described above can facilitate the formation of a sensing layer formulation contact coating on the working electrode 920 surface. Additional layers of sensing elements can be deposited on the working electrode, either substantially aligned with or offset from the underlying layer, as desired.

In an electrochemical embodiment, the sensor is implanted at a subcutaneous site such that subcutaneous fluid at the site can contact the sensor. In other in vivo embodiments, at least a portion of the sensor is placed in a blood vessel. The sensor operates to electrolyze the analyte of interest in the subcutaneous fluid so that a current flow occurs between the working electrode and the counter electrode. A current value associated with the working electrode is determined. If multiple working electrodes are used, determine the value of the current generated by each working electrode. These periodically judged current values can be collected or further processed using a microprocessor.

If the analyte concentration is successfully determined, the analyte concentration may be displayed, stored, transmitted and/or processed to provide useful information. As an example, the raw signal or analyte concentration can be used as the basis for determining the rate of change of the analyte concentration, which does not change at a rate greater than a predetermined threshold. If the rate of change of the analyte concentration exceeds a predetermined threshold, an indication is displayed or sent to indicate this fact.

As shown herein, the methods of the present disclosure are useful when combined with a device for measuring or monitoring a glucose analyte, such as any such device described herein. These methods can also be used in conjunction with equipment used to measure or monitor another analyte (e.g., ketones, ketone bodies, HbA1c, etc.), including oxygen, carbon dioxide, proteins, drugs, or another moiety of interest (mioety) , such as any combination of those found in bodily fluids, including subcutaneous fluid, dermal fluid (sweat, tears, etc.), interstitial fluid, or other bodily fluids of interest such as any combination thereof. Typically, the device is in good contact with bodily fluids, eg, substantially or substantially continuously.

According to an embodiment of the invention, the measurement sensor is suitable for the electrochemical measurement of the concentration of an analyte, for example the concentration of glucose in a body fluid. In these embodiments, the measurement sensor includes at least a working electrode and a counter electrode. Other embodiments may further include a reference electrode. The working electrode can be associated with a glucose responsive enzyme. A mediator may also be included. In certain embodiments, hydrogen peroxide, which can be characterized as a mediator, is produced by the sensor's reaction and can be used to infer glucose concentration. In certain embodiments, the mediator is added to the sensor by the manufacturer, eg, included in the sensor prior to use. The redox mediator can be positioned relative to the working electrode and can transfer electrons directly or indirectly between the working electrode and the compound. The redox mediator can be, for example, immobilized on the working electrode, eg entrapped on the surface or chemically bonded to the surface.

美国专利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以及美国专利申请11/701,138、11/948,915、12/625,185、12/625,208和12 Additional embodiments comprising a sensor comprising a working electrode having a sensing surface comprising two or more sensing elements disposed laterally to one another are described in /624,767, the full text of which is incorporated herein by reference in References are included here. Furthermore, embodiments disclosed herein may be incorporated into battery-powered or self-powered analyte sensors, such as self-powered analyte sensors as disclosed in U.S. Patent Application 12/393,921 (U.S. Patent Application Publication 2010/0213057), the entirety of which incorporated herein by reference. Additionally, embodiments disclosed herein may be incorporated into analyte monitoring systems and devices that use one or more rivets to attach an analyte sensor having one or more conductive traces to a sensor control unit, such as filed on June 17, 2011 as disclosed in U.S. Provisional Patent Application No. 61/498,142, which is hereby incorporated by reference in its entirety.

Aspects of the present disclosure also include embodiments comprising a sensing surface having two or more sensing elements disposed laterally to one another, wherein the sensing surface is on a working electrode of an analyte strip sensor. For example, Figure 11 shows an exploded perspective view of an analyte sensor test strip with layers showing electrodes in a first configuration. As shown in FIG. 11 , the test strip 1100 has a first substrate 1110 , a second substrate 1120 and a spacer layer 1130 disposed 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 the surface of the first substrate 1110, and the counter electrode 1160 is present on the surface of the second substrate 1120 opposite to and facing the first substrate surface. 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 structured in layers and, in some embodiments, is generally rectangular, eg, its length is longer than its width, although other shapes are possible. Another embodiment of a test strip is shown in Figure 12, which shows an exploded perspective view of an analyte sensor test strip, with layers showing electrodes of a second configuration. As shown in FIG. 12 , the test strip 1200 has a first substrate 1210 , a second substrate 1220 and a spacer layer 1230 disposed 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 the surface of the first substrate 1210 adjacent to 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 FIG. 11 , the test strip 1200 shown in FIG. 12 has a layered configuration and, in some embodiments, is generally rectangular, eg, longer than it is wide, although other shapes are possible. Additional embodiments of test strips and analyte sensors for use therein are described in more detail in US patent application Ser. No. 11/281,883, which is hereby incorporated by reference in its entirety.

和FREESTYLELITE^TM试纸条，以及ABBOTT DIABETES CARE公司所售的PRECISION^TM试纸条。除了本文具体公开的实施方案，本公开的设备经配置可以与很多种分析物试纸条一起使用，例如于2006年8月1日提交的美国专利申请No.11/461,725；美国专利申请公开No.2007/0095661；美国专利申请公开No.2006/0091006；美国专利申请公开No.2006/0025662；美国专利申请公开No.2008/0267823；美国专利申请公开No.2007/0108048；美国专利申请公开No.2008/0102441；美国专利申请公开No.2008/0066305；美国专利申请公开No.2007/0199818；美国专利申请公开No.2008/0148873；美国专利申请公开No.2007/0068807；2008年4月14日提交的美国专利申请No.12/102,374和美国专利申请公开No.2009/0095625；美国专利No.6,616,819；美国专利No.6,143,164；美国专利No.6,592,745；美国专利No.6,071,391和美国专利No.6,893,545所公开的试纸条，这些文献全文以参考的方式包括在此。The analyte test strips used with the device can be of any kind, size, or shape known to those skilled in the art, such as

and FREESTYLELITE ^™ test strips, and PRECISION ^™ test strips sold by the company ABBOTT DIABETES CARE. In addition to the embodiments specifically disclosed herein, devices of the present disclosure can be configured for use with a wide variety of analyte test strips, such as 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; .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 No. 12/102,374 and U.S. Patent Application Publication No. 2009/0095625 filed on . 6,893,545, which are hereby incorporated by reference in their entirety.

Electrochemical sensors

Embodiments of the present disclosure relate to methods and devices for detecting at least one analyte, including glucose, in bodily fluids. Embodiments relate to continuous and/or automated in vivo monitoring of one or more analyte levels using a continuous analyte monitoring system comprising an analyte sensor, wherein at least a portion of the analyte sensor is disposed on a user's Under the skin, and/or embodiments of the present disclosure also involve discrete monitoring of one or more analytes using an in vivo blood glucose ("BG") meter and analyte test strips. Embodiments include combined or combinable devices, systems and methods and/or transfer of data between in vivo continuum systems and in vivo systems. In certain embodiments, a system or at least a portion of a system is integrated into a single unit.

The sensors described herein can be in vivo sensors or in vitro sensors (eg, discrete monitoring test strips). Such sensors may be formed on a substrate, such as a substantially planar substrate. In certain embodiments, the sensor is a lead, eg, an inner portion of a working electrode lead in which one or more other electrodes are associated (eg, over, including wrapped). The sensor may also comprise at least one counter electrode (or counter/reference electrode) and/or at least one reference electrode or at least one reference/counter electrode.

Accordingly, embodiments include analyte monitoring devices and systems that include at least a portion of an analyte sensor, including glucose, lactate, and the like, that can be placed under the surface of a user's skin for in vivo detection of analytes in bodily fluids. Embodiments include fully implantable analyte sensors, and wherein only a portion is placed subcutaneously and a portion resides on the skin, such as for contacting a sensor control unit (which may include a transmitter), a receiver/display unit, a transceiver, Analyte sensors for processors and the like. The sensor may, for example, be placed under the skin of the user to continuously or periodically monitor the level of the analyte in the user's interstitial fluid. For purposes of illustration, continuous monitoring and periodic detection are used interchangeably unless otherwise stated. The sensor response can be correlated to and/or converted to analyte levels in blood or other fluid. In certain embodiments, the analyte sensor can be configured to contact interstitial fluid to detect glucose levels, which can be used to infer glucose levels in the user's bloodstream. Analyte sensors may be inserted into veins, arteries, or other parts of the body that contain fluid. Embodiments of the analyte sensor are configured to monitor the level of the analyte over a period of time, which can range from seconds, minutes, hours, days, weeks to months or longer.

In certain embodiments, the analyte sensor, such as a glucose sensor, is capable of detecting the analyte in vivo within one hour or longer, such as several hours or longer, such as several days or longer, such as three days or longer. A longer period of time, such as five days or longer, such as seven days or longer, such as several weeks or longer, such as one month or longer. From the information obtained, eg, the current analyte level at time _t0 , the rate of change of the analyte level, etc., future analyte levels can be predicted. Predictive alerts may inform the user of predicted analyte levels of concern before the user's analyte levels reach future predicted analyte levels. This provides the user with an opportunity to take corrective action.

Figure 1 illustrates a data monitoring and management system, such as an analyte (eg, glucose) monitoring system 100, according to certain embodiments. For convenience only, further, the disclosed aspects of the present invention mainly describe various aspects about the glucose monitoring device and system and the glucose detection method, and such description is by no means intended to limit the protection scope of the embodiment. It should be understood that the analyte monitoring system is configured to monitor multiple analytes simultaneously or at different times.

Analytes monitored include, but are not limited to, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, glycated hemoglobin (HbAlc), creatine kinase (eg, CK-MB), creatine, creatinine, DNA , fructosamine, glucose, glucose derivatives, glutamine, growth hormone, hormones, ketones, ketone bodies, lactate, peroxides, prostate specific antigen, prothrombin, RNA, thyrotropin, and troponin. Drugs such as antibiotics (such as gentamicin, vancomycin, etc.), digitoxin, digoxin levels, drugs of abuse, theophylline, warfarin ( warfarin). In embodiments where more than one analyte is monitored, the analytes may be monitored simultaneously or at different times.

The analyte monitoring system 100 includes an analyte sensor 101 , a data processing unit 102 connectable to the sensor 101 , and a main receiver unit 104 . In some cases, the main receiver unit 104 is configured to communicate with the data processing unit 102 via a communication link 103 . In some embodiments, the main receiver unit 104 is further configured to send data to a data processing terminal 105 to evaluate or process or format the data received by the main receiver unit 104 . The data processing terminal 105 is configured to receive data directly from the data processing unit 102 via a communication link 107, which may optionally be configured for two-way communication. Furthermore, the data processing unit 102 may comprise a transmitter or transceiver to send and/or receive data to and/or from the primary receiver unit 104 and/or the data processing terminal 105 and/or the optional secondary receiver unit 106 .

FIG. 1 also shows an optional secondary receiver unit 106 operatively coupled to communication link 103 and configured to receive data from data processing unit 102 . The secondary receiver unit 106 may be configured to communicate with the primary receiver unit 104 and the data processing terminal 105 . In certain embodiments, the secondary receiver unit 106 is configured for two-way wireless communication with each of the primary receiver unit 104 and the data processing terminal 105 . As discussed in further detail below, in some cases the secondary receiver unit 106 is a de-featured receiver compared to the primary receiver unit 104, e.g., the secondary receiver unit 106 is de-featured compared to the primary receiver Unit 104 may include a limited or minimum number of functions or features. Likewise, the secondary receiver unit 106 may comprise a smaller (in one or more, including all dimensions) compact housing or be implemented in a device, including a wrist watch, armband, PDA, mp3 player, cell phone, etc. wait. 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 docking portion configured to mate with a docking cradle unit for placement next to a bed for nighttime monitoring, and/or a two-way communication device. The base can charge the power source.

The analyte monitoring system 100 shown in FIG. 1 only shows an analyte sensor 101 , a data processing unit 102 and a data processing terminal 105 . However, those skilled in the art should 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 can be placed in the user's body to monitor analytes simultaneously or at different times. In certain embodiments, analyte information obtained by a first sensor placed in the user's body can be used as a comparison to analyte information obtained by a second sensor. This is useful to confirm or validate the analyte information obtained from the one or both sensors. This redundancy is useful if analyte information is considered in key treatment-related decisions. In certain embodiments, a first sensor can be used to calibrate a second sensor.

The analyte monitoring system 100 can be a continuous detection system, or a semi-continuous monitoring system, or a discrete monitoring system. In a multi-component environment, each component is configured to be uniquely identified by one or more other components in the system so that communication conflicts between different components in the analyte monitoring system 100 are easily resolved. For example, unique IDs, communication channels, etc. may be used.

In certain embodiments, the sensor 101 is physically placed in or on the body of the user whose analyte level is being monitored. The sensor 101 may be configured to at least periodically sample an analyte level of a user and convert the sampled analyte level into a corresponding signal sent by the data processing unit 102 . The data processing unit 102 may be coupled to the sensor 101 so that both devices are placed in or on the user's body such that at least a part of the analyte sensor 101 is placed subcutaneously. The data processing unit may comprise fixation elements to ensure its attachment to the user's body, such as adhesives. A mount (not shown) attachable to the user and cooperable with the data processing unit 102 may be used. For example, the base 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 of data signals for transmission to the main receiver unit 104 via the communication link 103, wherein each signal corresponds to a user sampled analyte levels. In certain embodiments, the sensor 101 or the data processing unit 102 or a combined sensor/data processing unit may be fully implanted under the skin of a user.

In some embodiments, the main receiver unit 104 may include analog interface components including an RF receiver and an antenna configured to communicate with the data processing unit 102 via the communication link 103, and also includes a A data processing component of the data received by the processing unit 102, wherein the data processing includes data decoding, error detection and calibration, data clock generation, data bit recovery, etc., or any combination thereof.

In operation, the master receiver unit 104 is configured in some embodiments to be synchronized with the data processing unit 102 so as to uniquely identify the data processing unit 102 based on, for example, identity information of the data processing unit 102, and thus periodically receive A signal from the data processing unit 102 that correlates to the level of the monitored analyte detected by the sensor 101 .

或类似电话）、mp3播放器（例如，iPOD^TM等等）、寻呼机等等，和/或药物递送设备（例如，输液设备），其中每一个都经配置用于经由有线或无线连接与该接收器通信数据。此外该数据处理终端105可以进一步连接至数据网络（未示出），以便用于存储、检索、更新、和/或分析相应于所检测的用户分析物水平的数据。Referring again to FIG. 1, data processing terminals 105 may include personal computers, portable computers, including laptops or handheld devices (e.g., personal digital assistants (PDAs)), telephones, including cell phones (e.g., multimedia and networked mobile Phones, including iPhone ^TM , a

or similar telephone), mp3 player (e.g., iPOD ^TM, etc.), pager, etc., and/or drug delivery device (e.g., infusion device), each of which is configured to communicate with the receiving device via a wired or wireless connection device communication data. In addition, the data processing terminal 105 may be further connected to a data network (not shown) for storing, retrieving, updating, and/or analyzing data corresponding to detected user analyte levels.

The data processing terminal 105 may comprise a drug delivery device (eg, an infusion device), such as an insulin infusion pump, etc., configured to administer a drug (eg, insulin) to a user, and configured to communicate with the main receiver unit 104, to receive the measured analyte levels and other data. Alternatively, the main receiver unit 104 may be configured to integrate an infusion device, such that the main receiver unit 104 is configured to administer an appropriate drug (eg, insulin) to the user, for example, based on the detected Analyte levels and other data, management and correction of basal profile, and determination of appropriate pills to take. The infusion device may be an external device or an internal device, such as a device that is fully implantable in the user.

In certain embodiments, the data processing terminal 105 comprising an infusion device, such as an insulin pump, is configured to receive the analyte signal from the data processing unit 102, and thus includes the functionality of the main receiver unit 104, including for administering the user's insulin Data processing for therapeutic and analyte monitoring. In some embodiments, communication link 103, as well as one or more other communication interfaces shown in FIG. 1, may use one or more wireless communication protocols, such as but not limited to: Bluetooth communication protocols, 802.11x wireless communication protocols, or allow several units to communicate wirelessly securely (for example, as required by the Health Insurance Portability and Accountability Act (HIPPA)), while avoiding potential data collisions and interference, etc. active wireless protocol.

FIG. 2 shows a block diagram of an embodiment of the data processing unit 102 of the analyte monitoring system shown in FIG. 1 . User input and/or interface components may be included, or the data processing unit may be free of user input and/or interface components. In certain embodiments, one or more application-specific integrated circuits (ASICs) may be used to implement one or more functions or subroutines associated with the operation of the data processing unit (and/or receiver unit) using One or more state machines or buffers.

As can be seen from the embodiment in Figure 2, analyte sensor 101 (Figure 1) includes four contacts, three of which are electrodes: working electrode (W) 210, reference electrode (R) 212, and 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 can be used. For example, the counter electrode and reference electrode functions can be provided 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.

FIG. 3 shows a block diagram of an embodiment of a receiver/monitor unit, such as the main receiver unit 104 of the analyte monitoring system shown in FIG. 1 . The main receiver unit 104 includes one or more of the following: a test strip interface 301, an RF receiver 302, a user input 303, an optional temperature detection component 304, and a clock 305, each operatively coupled to a processing and storage unit 307. The main receiver unit 104 also includes a power supply 306 operatively coupled to a power conversion and monitoring component 308 . Furthermore, the power conversion and monitoring component 308 is also coupled to the processing and storage component 307 . Also shown is a receiver serial communication component 309 , and an output 310 , each operatively coupled to the processing and storage component 307 . The main receiver unit 104 may include user input and/or interface components, or no user input and/or interface components.

血糖试纸条。体内葡萄糖测试设备所获得的葡萄糖信息可用于各种目的、计算等等。例如，该信息可用于校准传感器101、确认传感器101的结果从而增加其置信度（例如，传感器101所获得的信息用于治疗相关的决策情形中）等等。In certain embodiments, the test strip interface 301 includes an analyte testing portion (eg, a glucose level testing portion) to receive blood (or other bodily fluid sample) analyte testing or related information. For example, the test strip interface 301 may include a test strip port to receive a test strip (eg, a glucose test strip). The device can determine the analyte level of the test strip and optionally display (or notify) the analyte level on the output 310 of the main receiver unit 104 . Any suitable test strip can be used, e.g., only requiring a very small amount (e.g., 3 microliters or less, such as 1 microliter or less, such as 0.5 microliters or less, such as 0.1 microliters or less, to be applied to the test strip. Microliter) samples can obtain accurate glucose information test strips. Embodiments of test strips include, for example, those manufactured by Abbott DiabetesCare, Inc. (Alameda, Calif.)

Blood sugar test strips. Glucose information obtained by the in vivo glucose testing device can be used for various purposes, calculations, and the like. For example, this information may be used to calibrate the sensor 101 , confirm the results of the sensor 101 to increase its confidence (eg, information obtained by the sensor 101 is used in a treatment-related decision situation), etc.

In a further embodiment, the data processing unit 102 and/or the primary receiver unit 104 and/or the secondary receiver unit 106, and/or the data processing terminal/infusion set 105 are configured to receive from For example, a blood glucose meter wirelessly receives analyte values. In a further embodiment, a user operating or using the analyte monitoring system 100 (FIG. 1) may, by using, for example, incorporate data processing unit 102, primary receiver unit 104, secondary receiver unit 106, or a data processing terminal/ One or more user interfaces (eg, keyboard, keypad, voice command, etc.) in infusion set 105 manually enter the analyte value.

Additional detailed descriptions are provided in US Patent Nos. 5,262,035; 5,264,104; 5,262,305; 5,320,715; 5,593,852;

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

The analyte sensor 400 may be fully placed within the user's body, or configured so that only a portion is placed within the user (in vivo) and another portion is placed within the user (outside the body). For example, the sensor 400 includes a first portion that can be placed on the skin surface 410, and a second portion that can be placed below the skin surface. In such embodiments, the outer part may include contacts (connected by wires to the respective electrodes of the second part) for connection to another device, such as a transmitter unit, also located outside the user's body. While the embodiment of FIG. 4 shows three electrodes side-by-side on the same surface of the base 404, other configurations are also contemplated, such as fewer or more electrodes, some or all of the electrodes on different surfaces of the base, or presenting On another base, some or all of the electrodes are stacked together, electrodes of different materials and sizes, and so on.

5A shows a perspective view of an embodiment of an analyte sensor 500 having a first portion (depicted in this embodiment as the main portion) that can be placed on the surface of the skin 510 and including an insertion tip 530 that can be placed under the surface of the skin. , eg, penetrates the skin into the subcutaneous space 520 to contact the second portion of the user's biological fluid, such as interstitial fluid (depicted in this embodiment as the secondary portion). Contact portions of working electrode 511 , reference electrode 512 and counter electrode 513 are placed on a first portion of sensor 500 on skin surface 510 . Working electrode 501 , reference electrode 502 and counter electrode 503 are shown at the second portion of sensor 500 , and specifically at insertion tip 530 . As shown in Figure 5A, traces are provided between the electrodes inserted into the tip to the contacts. It should be understood that more or fewer electrodes may be provided on the sensor. For example, a sensor may include more than one working electrode and/or the counter electrode, and the reference electrode may be a single counter/reference electrode, and so on.

FIG. 5B shows a cross-sectional view of a portion of the sensor 500 of FIG. 5A. The electrodes 501, 502 and 503 of the sensor 500 and the substrate and dielectric layers are provided in a layered configuration or construction. For example, as shown in FIG. 5B, in one embodiment, the sensor 500 (e.g., analyte sensor unit 101 of FIG. 1) includes a substrate layer 504, and is disposed on at least a portion of the substrate layer 504 and provides the The first conductive layer 501 of the working electrode, such as carbon, gold and so on. Also shown is a sensing element 508 disposed on at least a portion of the first conductive layer 501 . As described herein, two or more sensing elements are provided on the sensing surface of the working electrode, wherein the two or more sensing elements are positioned lateral to each other. For example, FIG. 5C shows a schematic diagram of a portion of working electrode 501 . Working electrode 501 includes a plurality of individual sensing elements 508 . The sensing elements 508 are not in contact so that the sensing elements 508 can be arranged in an array of individual sensing elements 508 on the working electrode 501 .

A first insulating layer 505, such as a first dielectric layer in some embodiments, is disposed or stacked on at least a portion of the first conductive layer 501, and further, a second conductive layer 509 may be disposed or stacked on at least a portion of the first insulating layer (or dielectric layer) 505 on top. As shown in FIG. 5B , the second conductive layer 509 can provide the reference electrode 502 with an extended lifetime as described herein, comprising a layer of redox polymer as described herein.

A second insulating layer 506 , such as a second dielectric layer in some embodiments, may be disposed or laminated on at least a portion of the second conductive layer 509 . Also, a third conductive layer 503 may be disposed on at least a portion of the second insulating layer 506, and a counter electrode 503 may be provided. Finally, the third insulating layer 507 may be disposed or stacked on at least a part of the third conductive layer 503 . In this manner, sensor 500 may be layered such that at least a portion of each conductive layer is separated by a respective insulating layer (eg, a dielectric layer). The embodiments of Figures 5A and 5B show layers having different lengths. In some cases, some or all of the layers may have the same or different lengths and/or widths.

In certain embodiments, some or all of the electrodes 501, 502, and 503 may be provided on the same side of the substrate 504 in a layered configuration as described above, or alternatively, provided in a coplanar manner so that two or more The electrodes are disposed on the same face of the substrate 504 (eg, side-by-side (eg, parallel) or at an angle to each other). For example, coplanar electrodes may include suitable spacing therebetween, and/or include a dielectric or insulating material disposed between the conductive layers/electrodes. Also, in certain embodiments, one or more of the electrodes 501 , 502 , 503 may be disposed on opposite sides of the substrate 504 . In such embodiments, the contact pads may be on the same side of the substrate or on different sides. For example, electrodes may be on a first side and their contacts may be on a second side, eg, traces connecting the electrodes and contacts may traverse the substrate.

As noted above, an analyte sensor may include an analyte-responsive enzyme to provide a sensing element. Certain analytes, such as oxygen, can be electrooxidized or electroreduced directly on the sensor, and more specifically at least on the working electrode of the 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 can also be used for analytes such as oxygen that can be electrooxidized or electroreduced directly at the working electrode. For these analytes, each working electrode includes a sensing element near or on the working electrode surface (see eg sensing element 508 in FIG. 5B ). In many embodiments, a sensing element is formed near or on a small portion of at least one working electrode.

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

A variety of different sensing element configurations can be used. In certain embodiments, the sensing element is deposited on the conductive material of the working electrode. The sensing element may extend beyond the conductive material of the working electrode. In some cases, the sensing element may also extend on other electrodes, such as on the counter electrode and/or the reference electrode (or provide a counter/reference). In other embodiments, the sensing element is included on the working electrode such that the sensing element does not extend beyond the conductive material of the working electrode.

The sensing element in direct contact with the working electrode may contain an electron transfer agent to transfer electrons directly or indirectly between the analyte and the working electrode, and/or a catalyst to facilitate the reaction of the analyte. For example, glucose, lactic acid, or oxygen electrodes can be formed with a sensing element that includes a catalyst including glucose oxidase, glucose dehydrogenase, lactate oxidase, or laccase, and an electron transfer agent that promotes glucose, glucose, or laccase, respectively. Electrooxidation of lactic acid or oxygen.

In other embodiments, the sensing element is not deposited directly on the working electrode. Rather, the sensing element 508 is separated from the working electrode and separated from the working electrode by a separation layer. The separation layer may comprise one or more membranes or thin films or physical distances. In addition to separating the working electrode from the sensing element, the separation layer can also serve as a mass transport limiting layer and/or an interferent eliminating layer and/or a biocompatible layer.

In certain embodiments that include more than one working electrode, one or more working electrodes may not have a corresponding sensing element, or may not include one or more components required to electrolyze the analyte (e.g., electron transfer agent and/or catalyst) sensing element. Thus, the signal of the working electrode corresponds to a background signal which can be removed by subtraction from the analyte signal obtained from one or more other working electrodes associated with the fully functional sensing element.

In certain embodiments, the sensing element includes one or more electron transfer agents. Electron transfer agents that can be used are electroreducible and electrooxidizable ions or molecules with a redox potential several hundred millivolts higher or lower than that of the standard calomel electrode (SCE). The electron transfer agent can be organic, organometallic, or inorganic. Examples of organic redox substances are quinones and substances having a quinoid structure in the oxidized state, such as nile blue and indophenol. Examples of organometallic redox species are metallocene complexes, including ferrocene. Examples of inorganic redox species are hexacyanoferrate (III), ruthenium hexamine and the like. Other examples include those described in US Patent Nos. 6,736,957, 7,501,053, and 7,754,093, the disclosures of which are hereby incorporated by reference in their entirety.

In certain embodiments, the electron transfer agent has a structure or charge that prevents or significantly reduces electron transfer agent diffusion loss during sample analysis. For example, electron transfer agents include, but are not limited to, redox species such as bonded polymers that can in turn be disposed on or near a working electrode. The bonding between the redox species and the polymer can be covalent, coordinative or ionic. While any organic, organometallic, or inorganic redox species can be bonded to the polymer and act as an electron transfer agent, in certain embodiments, the redox species is a transition metal compound or complex, such as osmium, ruthenium, Iron and cobalt compounds or complexes. It should be recognized that many of the redox species described for use with the polymer component can also be used without the polymer component.

Embodiments of polymeric electron transfer agents may comprise redox species covalently linked in the polymer composition. An example of such a mediator is poly(vinylferrocene). Another type of electron transfer agent comprises ionically linked redox species. Such mediators may include charged polymers coupled to oppositely charged redox species. Examples of such mediators include charge-loaded polymers, such as osmium or ruthenium polypyridinium cations, coupled to positively charged redox species. Another example of an ionically linked mediator is a positively charged polymer, including quaternized poly(4-vinylpyridine) or poly(( 1-vinylimidazole). In other embodiments, the electron transfer agent comprises a redox species coordinately bonded to the polymer. For example, mediators can be formed by coordination of osmium or cobalt 2,2′-bipyridine complexes to poly(1-vinylimidazole) or poly(4-vinylpyridine).

Suitable electron transfer agents are osmium transition metal complexes with one or more ligands, each of which has a nitrogen-containing heterocycle, such as 2,2'-bipyridine, 1,10-phenanthroline, 1 - methyl, 2-pyridine biimidazole, or derivatives thereof. The electron transfer agent may also have one or more ligands covalently bonded in the polymer, wherein each ligand has 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 with pyridine or imidazole functional groups, and (b) an osmium ion complexed with two ligands, each of which contains a 2,2'-linked pyridine, 1,10-phenanthroline or derivatives thereof, and the two ligands do not have to be the same. Certain 2,2'-bipyridine derivatives that complex with osmium ions include, but are not limited to, 4,4'-dimethyl-2,2'-bipyridine and mono-, bis-, and polyalkoxy- 2,2'-bipyridine, including 4,4'-dimethoxy-2,2'-bipyridine. Phenanthroline derivatives complexed with osmium ions include, but are not limited to, 4,7-dimethyl-1,10-phenanthroline and mono-, bis-, and polyalkoxy-1,10-phenanthroline , such as 4,7-dimethoxy-1,10-phenanthroline. Polymers that complex with osmium ions include, but are not limited to, polymers and copolymers of poly(1-vinylimidazole) (referred to as "PVI") and poly(4-vinylpyridine) (referred to as "PVP"). Suitable copolymer substituents for poly(1-vinylimidazole) include acrylonitrile, acrylamide, and substituted or quaternized N-vinylimidazoles such as polymers of osmium and poly(1-vinylimidazole) or copolymer complexed electron transfer agents.

Embodiments may use electron transfer agents with redox potentials between about -200 mV and about +200 mV versus a standard calomel electrode (SCE). The sensing element may also include a catalyst capable of catalyzing a reaction of the analyte. In certain embodiments, the catalyst can also function as an electron transfer agent. An example of a suitable catalyst is an enzyme that catalyzes a reaction of an analyte. For example, when the analyte of interest is glucose, catalysts that can be used include glucose oxidase, glucose dehydrogenase (e.g., pyrroloquinoline quinone (PQQ)-dependent glucose dehydrogenase, flavin adenine dinucleotide ( FAD)-dependent glucose dehydrogenase, nicotinamide adenine dinucleotide (NAD)-dependent glucose dehydrogenase). When the analyte of interest is lactate, lactate oxidase or lactate dehydrogenase can be used. Laccases can be used when the analyte of interest is oxygen or when the reaction of the analyte produces or consumes oxygen.

In certain embodiments, a catalyst can be attached to a polymer such that the catalyst is crosslinked with another electron transfer agent, where the other electron transfer agent can be a polymer, as described above. A second catalyst may also be used in certain embodiments. The second catalyst can be used to catalyze the reaction of a product compound resulting from the catalyzed reaction of the analyte. The second catalyst can act in conjunction 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 on the interferent-removing layer to catalyze the interferer-removing reaction.

In certain embodiments, the sensor operates at a low oxidation potential, such as a potential of about +40 mV versus silver/silver chloride. The sensing element uses, for example, an osmium (Os) based mediator configured for low potential operation. Accordingly, in certain embodiments, the sensing element is a redox-active component comprising: (1) an osmium-based mediator molecule comprising a (bidentate) ligand, and (2) a glucose oxidase molecule . These two components are combined in the sensing element of the sensor.

A mass transport limiting layer (not shown), such as an analyte flux modifying layer, may be included in the sensor to act as a diffusion limiting barrier in order to reduce the rate of mass transport of analytes, such as glucose or lactate, to the working electrode region. The mass transport limiting layer can be used to limit the flow of analyte to the working electrode in an electrochemical sensor so that the sensor responds linearly and is easily calibrated over a wide range of analyte concentrations. The mass transport layer may comprise a polymer and may be biocompatible. Mass transport limiting layers can serve many functions, such as biocompatibility and/or interfering species removal functions, among others.

In certain embodiments, the mass transport limiting layer is a film composed of a cross-linked polymer comprising nitrogen-containing heterocyclic groups, such as polymers of polyvinylpyridine and polyethyleneimidazole. Embodiments also include films made of polyurethane or polyether urethane, or chemically related materials, or films made of silicone or the like.

Membranes can be formed by in situ polymer crosslinking in alcohol buffered solutions and modified with zwitterionic moieties, one of which is a non-pyrimidine copolymer component, and optionally the other moiety is hydrophilic Or hydrophobic, and/or have other desirable properties. The modified polymer can be made from a precursor polymer containing nitrogen heterocyclic groups. For example, the precursor polymers may be polyvinylpyridine and polyethyleneimidazole. Optionally, hydrophilic or hydrophobic modifiers can be used to "fine-tune" the permeability of the synthetic membrane to the analyte of interest. Optional hydrophilic modifiers, such as poly(ethylene glycol), hydroxyl or polyhydroxy modifiers, can be used to enhance the biocompatibility of the polymer or synthetic membrane.

The membrane can be formed in situ by applying an alcohol buffer solution of the crosslinker and modified polymer to the enzyme-containing sensing element and allowing the solution to solidify within about one to two days or other suitable period of time. The crosslinker-polymer solution can be applied to the sensing element by applying one or several drops of the membrane solution to the sensor, by dipping the sensor in the membrane solution, by spraying the membrane solution on the sensor, etc. Typically, the thickness of the membrane is controlled by the concentration of the membrane solution, the number of droplets of the membrane solution applied, the number of times the sensor is immersed in the membrane solution, the volume of the membrane solution sprayed on the sensor, or any combination of these factors. Membranes applied in this manner have any combination of the following functions: (1) mass transport limitation, that is, reducing the flux of analyte that can reach the sensing element, (2) improving biocompatibility, or (3) reducing interfering substances.

In certain embodiments, the membrane can form one or more bonds with the sensing element. A bond refers to any type of interaction between atoms or molecules that allows chemical compounds to relate to each other, such as, but not limited to, covalent bonds, ionic bonds, orientation forces, hydrogen bonds, dispersion forces, and the like. For example, in situ polymerization of the membrane can form crosslinks between the membrane polymer and the polymer in the sensing element. In certain embodiments, crosslinking of the membrane and sensing element facilitates reducing the occurrence of delamination of the membrane from the sensor.

In certain embodiments, the sensing system detects hydrogen peroxide to infer glucose levels. For example, a hydrogen peroxide detection sensor can be constructed in which the sensing element includes an enzyme, such as glucose oxidase, glucose dehydrogenase, etc., and is disposed on a working electrode. The sensing element may be covered by one or more layers, such as a selectively glucose permeable membrane. Once the glucose passes through the membrane, it is oxidized by the enzyme, and the reduced glucose oxidase is oxidized by reacting with molecular oxygen, thereby producing hydrogen peroxide.

Certain embodiments include hydrogen peroxide detection sensors constructed from sensing elements prepared by combining, for example: (1) redox mediators with transition metal complexes, including oxidation potentials relative to SCE About +200mV osmium polypyridine complex, and (2) periodate oxidized horseradish peroxidase (HRP, horseradishperoxidase). This sensor operates in a reduction mode; the working electrode is controlled at a potential negative to that of the osmium complex, resulting in a hydrogen peroxide-mediated reduction by the HRP catalyst.

In another example, a potentiometer sensor may be constructed as follows. Glucose sensing elements can be constructed by combining: (1) redox mediators with transition metal complexes, including osmium polypyridine complexes with an oxidation potential of about -200 mV to +200 mV vs. SCE, and (2 ) Glucose oxidase. The sensor can also be used in potentiometer mode by exposing the sensor to a glucose-containing solution under zero current conditions and allowing the reduced/osmium oxide ratio to reach an equilibrium value. The reduced/osmium oxide ratio varied in a reproducible manner with glucose concentration and caused the electrode potential to vary in a similar manner.

The substrate can be formed using a variety of non-conductive materials including, for example, polymeric or plastic materials and ceramic materials. Suitable materials for a particular sensor can be determined, at least in part, based on the sensor's desired use and material properties.

In certain embodiments, the substrate is flexible. For example, if the sensor is configured for implantation in the user, the sensor can be made flexible (although rigid sensors can also be used as implantable sensors), thereby reducing the user's pain and the impact of implanting and/or wearing the sensor on tissue damage caused. Flexible substrates often increase user comfort and allow for a wider range of motion. Suitable materials for flexible substrates 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 , polyamide, polyimide or copolymers of these thermoplastics, such as PETG (ethylene glycol-modified polyethylene terephthalate).

In other embodiments, the sensor is fabricated using a relatively rigid substrate, providing structural support that resists bending or breaking. Examples of rigid materials that can be used as substrates include poorly conductive ceramics such as alumina and silica. Implantable sensors with rigid substrates may have sharp points and/or sharp edges to facilitate sensor implantation without resorting to additional insertion equipment.

It should be understood that many sensors and sensor applications, including rigid and flexible sensors, are suitable for operation. By changing, for example, the composition and/or thickness of the substrates, the flexibility of the sensor can be continuously controlled and varied.

In addition to flexibility considerations, implantable sensors are often required to have a physiologically innocuous substrate, such as one approved by regulatory agencies or private institutions for use in vivo.

The sensor may include optional features that facilitate insertion of the implantable sensor. For example, the sensor may have a sharp point on the end to facilitate insertion. Additionally, the sensor may include barbs that assist in securing the sensor within the user's tissue during operation of the sensor. However, the barb is usually small enough that the sensor can be removed for replacement with little damage to the subcutaneous tissue.

The implantable sensor may also optionally have an anticoagulant disposed on a portion of the substrate that is implanted in the user. Anticoagulants reduce or eliminate clotting of blood or other bodily fluids around the sensor, especially after the sensor is inserted. Blood clots can foul the sensor or irreproducibly reduce the amount of analyte that diffuses to the sensor. Examples of useful anticoagulants include heparin and tissue plasminogen activator (TPA), among other known anticoagulants.

An anticoagulant may also be applied to at least a portion of the sensor-implanted portion. Anticoagulants can be applied by, for example, plating, spraying, brushing or dipping. Allow the anticoagulant to dry on the sensor. The anticoagulant can be immobilized on the sensor surface or allowed to diffuse outward from the sensor surface. The amount of anticoagulant placed on the sensor surface may be lower than the amount normally used to treat medical conditions involving blood clots and thus have only limited local effect.

plug in device

An insertion device may be used to insert the sensor under the user's skin. Insertion devices are typically formed from a structurally rigid material, such as metal or rigid plastic. Materials may include stainless steel and ABS (acrylonitrile-butadiene-styrene copolymer) plastic. In certain embodiments, the insertion device may be pointed and/or sharpened at the tip to facilitate penetration through the user's skin. A sharp, thin insertion device can reduce the pain felt by the user when the sensor is inserted. In other embodiments, the tip of the insertion device may have other shapes, including blunt or flattened. These embodiments are useful when the insertion device does not penetrate the skin, but serves as a structural support when pushing the sensor into the skin.

Sensor Control Unit

The sensor control unit may be integrated in the sensor, wherein the sensor control unit may be partially or fully implanted subcutaneously, or configured to be placed on the user's skin. The sensor control unit is optionally shaped to be comfortable to the user and allow concealment, eg within the user's clothing. Parts of the user's body where it is convenient to place the sensor control unit to remain concealed include the thigh, calf, upper arm, shoulder or abdomen. However, the sensor control unit may be provided on other parts of the user's body. One embodiment of the sensor control unit has a thin oval shape for enhanced concealment. However, other shapes and sizes can also be used.

The specific profile, as well as the height, width, length, weight and volume of the sensor control unit may vary and depend at least in part on the components and associated functions included in the sensor control unit. Typically, the sensor control unit includes a housing that is generally formed as a single integral unit that is placed on the user's skin. The housing typically contains most or all of the sensor control unit electronics.

The housing of the sensor control unit can be formed using a variety of materials including plastics and polymeric materials such as thermoplastic rigid plastics and thermoplastic engineering plastics. Suitable materials include, for example, polyvinyl chloride, polyethylene, polypropylene, polystyrene, ABS polymers and copolymers thereof. The housing of the sensor control unit may be formed using a variety of techniques including, for example, injection molding, compression molding, casting, and other molding methods. Hollow or recessed areas may be formed in the sensor control unit. Electronic components of the sensor control unit and/or other items, including batteries or speakers for audible alarms, may be placed in this hollow or recessed area.

The sensor control unit is typically attached to the user's skin, for example by means of an adhesive provided on at least a portion of the sensor control unit housing that contacts the skin, directly by bonding the sensor control unit to the user's skin, or by bonding the sensor control unit to the user's skin. The suture opening sutures the sensor control unit to the skin.

When positioned on the user's skin, the sensor and electronics within the sensor control unit are coupled via conductive contacts. One or more working electrodes, counter electrodes (or counter/reference electrodes), optional reference electrodes, and optional temperature probes are attached to each conductive contact. For example, the conductive contacts are provided inside the sensor control unit. Other embodiments of the sensor control unit have conductive contacts arranged outside the housing. When the sensor is positioned within the sensor control unit, the conductive contacts are positioned so as to contact the contact pads on the sensor.

sensor control unit electronics

The sensor control unit typically also includes at least a portion of the electronics that operate the sensor and analyte monitoring device system. The electronic components of a sensor control unit typically include a power supply for operating the sensor control unit and the sensor, sensor circuitry for obtaining a signal from the sensor and operating the sensor, measurement circuitry for converting the sensor signal into the required format, and at least and/or measurement circuitry to obtain a signal and provide processing circuitry for that signal to an optional transmitter. In certain embodiments, the processing circuitry can also partially or fully evaluate signals from the sensors and deliver the resulting data to optional transmitters and/or activate optional alarms if analyte levels exceed thresholds system. The processing circuitry often includes digital logic circuitry.

The sensor control unit optionally includes a transmitter for transmitting sensor signals or processed data from the processing circuit to the receiver/display unit; a data storage unit for temporarily or permanently storing data from the processing circuit; for A temperature probe circuit that receives a signal from a temperature probe and operates the temperature probe; a reference voltage generator for providing a reference voltage for comparison with the signal generated by the sensor; and/or monitoring the operation of the electronic components in the sensor control unit watchdog circuit.

Furthermore, the sensor control unit may also comprise digital and/or analog components using semiconductor devices, including transistors. In order to operate these semiconductor devices, the sensor control unit may include other elements including, for example, a bias control generator to properly bias the analog and digital semiconductor devices, an oscillator to provide a clock signal, and to provide timing signals and Digital logic and sequential elements for logic operations.

As an example of the operation of these elements, the sensor circuit and optional temperature probe circuit provide the raw signal from the sensor to the measurement circuit. The measurement circuit converts the raw signal to the 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 into a format usable by digital logic circuits. The processing circuitry then optionally evaluates the data and provides commands to operate the electronic device.

calibration

The sensor is configured to require no system calibration or user calibration. For example, a sensor may be factory calibrated and require no further calibration. In some embodiments, calibration is required, but without user intervention, eg, automatically. In those embodiments where user calibration is required, calibration may be on a predetermined schedule or may be dynamic, i.e. the system determines the timing of calibration in real time based on various factors including, but not limited to, glucose concentration and/or temperature and/or glucose variation rate etc.

In addition to the transmitter, an optional receiver can be included in the sensor control unit. In some cases, the transmitter is a transceiver that operates as both a transmitter and a receiver. The receiver can be used to receive calibration data for the sensor. The processing circuitry may use the calibration data to calibrate signals from the sensors. Calibration data may be sent by the receiver/display unit or some other source, such as a control unit in a doctor's office. Additionally, an optional receiver may be used to receive a signal from the receiver/display unit to instruct the transmitter, for example, to change frequency or band, activate or deactivate an optional alarm system, and/or instruct the transmitter to transmit at a higher rate.

Calibration data can be obtained in a number of ways. For example, the calibration data may be factory predetermined calibration measurements which may be input to the sensor control unit using a receiver or alternatively stored in the sensor control unit's own calibration data storage unit (in which case no receiver is required). The calibration data storage unit may be, for example, a readable or readable/writable storage circuit. In some cases, the system only needs to be calibrated once during the manufacturing process, where there is no need to recalibrate the system.

血糖监视试纸条）。例如，可以使用需要少于1纳升样本的试纸条。在某些实施方案中，每次校准事件只需使用一份体液样本校准传感器。例如，用户只需穿刺身体部位一次从而获得用于校准事件的样本（例如，用于试纸条），或如果首次获得的样本量不足，则可在短时间内穿刺身体部位一次以上。实施方案包括获得和使用多个用于给定校准事件的血液样本，其中每个样本的葡萄糖值基本上相似。从给定校准事件获得的数据可以独立地用于校准，或结合之前校准事件所获得的数据，例如包括加权平均的平均等等，从而进行校准。在某些实施方案中，系统只需用户校准一次，其中系统无需重新校准。If desired, calibration can be achieved using in vitro test strips (or other references), such as small sample strips, such as those requiring less than about 1 mL of sample (e.g., manufactured by Abbott Diabetes Care, Alameda, CA)

blood glucose monitoring test strips). For example, test strips that require less than 1 nanoliter of sample can be used. In certain embodiments, only one bodily fluid sample is used to calibrate the sensor per calibration event. For example, the user only needs to puncture the body part once to obtain a sample for a calibration event (eg, for a test strip), or more than one time in a short period of time if the first sample obtained is insufficient. Embodiments include obtaining and using multiple blood samples for a given calibration event, wherein the glucose values of each sample are substantially similar. Data obtained from a given calibration event may be used independently for calibration, or combined with data obtained from previous calibration events, for example averaging including weighted averages, etc., for calibration. In some embodiments, the system only needs to be calibrated once by the user, where the system does not need to be recalibrated.

Alternative or additional calibration data may be provided based on tests performed by the care professional or user. For example, it is common for individuals with diabetes to determine their own blood sugar levels using commercially available test kits. If an appropriate input device (e.g., keypad, optical signal receiver, or port for connection to a keypad or computer) is incorporated into the sensor control unit, the test results can be entered directly into the sensor control unit, or via a calibration Data is input to the receiver/display unit and the calibration data is sent to the sensor control unit, indirectly inputting test results.

Other methods of independently judging analyte levels can also be used to obtain calibration data. Such calibration data may replace or supplement factory predetermined calibration values.

In certain embodiments of the invention, it is desirable to calibrate the data periodically, eg, every eight hours, once a day, or once a week, to confirm that accurate analyte levels are being reported. Calibration is also required each time a new sensor is implanted, or if the sensor exceeds a minimum or maximum threshold, or if the rate of change in the sensor signal exceeds a threshold. In some cases, it is necessary to wait a period of time after the sensor is implanted before calibration, allowing the sensor to equilibrate. In some embodiments, the sensor is only calibrated after insertion. In other embodiments, the sensors need not be calibrated.

Analyte Monitoring Equipment

In certain embodiments of the invention, an analyte monitoring device includes a sensor control unit and a sensor. In these embodiments, the processing circuitry of the sensor control unit is able to determine the analyte level and activate the alarm system if the analyte level exceeds a threshold. In these embodiments, the sensor control unit, has an alarm system and may also include a display, such as an LCD or LED display.

A threshold is exceeded if a data point has a value that exceeds the threshold in a direction indicative of a particular condition. For example, a data point associated with a glucose level of 200 mg/dL has a threshold of 180 mg/dL for hyperglycemia because this data point indicates that the user has entered a hyperglycemic state. As another example, a data point associated with a glucose level of 65 mg/dL has a threshold of 70 mg/dL for hyperglycemia because this data point indicates that the user is hyperglycemic, as defined by the threshold. However, a data point associated with a glucose level of 75 mg/dL would not exceed the threshold of 70 mg/dL which defines the same hyperglycemia as the selected threshold, since this data point is not indicative of a particular condition.

If the sensor reading indicates a value outside (eg, above or below) the sensor's measurement range, an alarm may be initiated. For glucose, the physiologically relevant measurement range for glucose in interstitial fluid is typically 30-400 mg/dL, inclusive of 40-300 mg/dL and 50-250 mg/dL.

The alarm system may also or alternatively be activated when the rate of change of the analyte level or the acceleration of the rate of change increases or decreases by reaching or exceeding a threshold rate or acceleration. For example, in the case of subcutaneous glucose monitoring, an alarm system may be activated if the rate of change in glucose concentration exceeds a threshold indicating a possible hyperglycemic or hypoglycemic condition. In some cases, the alarm system may be activated if the acceleration of the rate of change of the glucose concentration exceeds a threshold indicating a possible hyperglycemic or hypoglycemic condition.

The system can also include system alerts that notify the user of system information such as battery status, calibration, sensor displacement, sensor failure, etc. Alerts can be, for example, audible and/or visual. Other sensory-stimulating alarm systems are also available, including those that heat, cool, vibrate, or deliver a mild electric shock when activated.

drug delivery system

The subject invention also includes sensors for use in sensor-based drug delivery systems. The system can deliver drugs to counteract high or low levels of an analyte in response to signals from one or more sensors. Alternatively, the system can monitor drug concentrations to ensure that the drug remains within the desired therapeutic range. The drug delivery system may include one or more (eg, two or more) sensors, a processing unit such as a transmitter, a receiver/display unit, and a drug administration system. In some cases, some or all of the elements may be integrated into a single unit. A sensor-based drug delivery system may use data from one or more sensors to provide the necessary input to a control algorithm/mechanism to automatically or semi-automatically administer the drug. As an example, a glucose sensor can be used to control and regulate insulin delivery from an external or implanted insulin pump.

The various references, presentations, publications, provisional and/or non-provisional US patent applications, US patents, non-US patent applications, and/or non-US patents identified herein are each incorporated by reference in their entirety.

Other embodiments and modifications within the scope of the present disclosure will be apparent to those skilled in the art. Various modifications, processes and many structures applicable to the embodiments of the present invention can be easily understood by those skilled in the art after reading this specification. While various aspects and features of the present invention have been explained in terms of an understanding, acceptance of thought, theory, underlying assumptions, and/or fabricated or prophetic examples, it should be understood that the invention is not subject to a particular understanding, acceptance of thought, theory, underlying assumptions, or , and/or production instance or preview instance limitations. While various aspects and features of the present invention have been described with respect to use, or more specifically medical applications involving diabetic patients, it should be understood that these aspects and features are also relevant to any of a variety of applications, including non-diabetic patients and any and all other animals. Further, although the various aspects and features of the present invention have been described generally with respect to applications involving partially implanted sensors, such as transdermal or subcutaneous sensors, it should be understood that these aspects and features also relate to various applications suitable for use in conjunction with the animal or human body. Any type of sensor, such as a sensor suitable for use fully implanted in an animal or human body. Finally, while various aspects and features of the invention have been described herein with respect to various embodiments and specific examples, all of which can be conventionally practiced or performed, it is to be understood that the full scope of the invention is defined by the claims.

The following examples are given in order to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the embodiments of the present invention, not to limit the scope of protection of the inventor's invention, nor to represent that the following experiments are all The experiment performed or the only experiment performed. Efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, temperature, etc.), but some experimental errors or deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or about atmospheric.

implementation plan

Implementation 1

Figure 6 shows photographs of a working electrode coated with six sensing elements (labeled 1 to 6) with a radius of approximately 150 μm and a distance of approximately 150 μm from each other. The sensitivity variation coefficient of the obtained sensor is less than or equal to 5%. The diameter of each sensing element in Figure 6 is shown in Table 1 below.

Table 1

sensing element Diameter (μm) 1 146.85 2 156.50 3 153.91 4 165.58 5 145.04 6 166.89

Example 2

Figure 10 shows the current (μA) and time (seconds) for a sensing layer formulation deposited as an array of small sensing elements (9 pL/droplet), and a sensing layer formulation deposited as a test paper coating on the gold working electrode surface Graph. Under the same test conditions, the sensor with the sensing layer formulation deposited as an array of small sensing elements recovered 26% more charge than the dipstick-coated sensor.

Claims (62)

1. analyte sensor comprises:

Working electrode; With

Counter electrode,

Wherein said working electrode comprises sensitive surface, and described sensitive surface comprises two or more sensing elements of arranged transversely each other, and wherein each sensing element comprises the analyte response enzyme.

2. according to the described analyte sensor of claim 1, wherein said sensing element is discontiguous.

3. according to the described analyte sensor of any aforementioned claim, wherein said sensing element is set to the single sense element on the described working electrode.

4. according to the described analyte sensor of any aforementioned claim, wherein said sensitive surface comprises the array of two or more single sense elements.

5. according to the described analyte sensor of any aforementioned claim, wherein said sensitive surface comprises the array of 100 or more single sense elements.

6. according to the described analyte sensor of any aforementioned claim, the sensing element density of wherein said sensitive surface is at 2-1000 sensing element/mm ²Scope in.

7. according to the described analyte sensor of any aforementioned claim, wherein said sensitive surface further comprises zone between feature.

8. analyte sensor according to claim 7, the zone surrounds described sensing element between wherein said feature.

9. according to the described analyte sensor of any aforementioned claim, the feature pitch of wherein said sensing element from 1 μ m in the scope of 500 μ m.

10. according to claim 7 or 8 described analyte sensors, the zone does not have the analyte response enzyme between wherein said feature.

11. according to each described analyte sensor in the claim 7,8 or 10, the zone does not have redox mediators between wherein said feature.

12. according to the described analyte sensor of any aforementioned claim, wherein said working electrode further comprises the second layer that is arranged on two or more sensing elements on the described sensitive surface.

13. according to the described analyte sensor of any aforementioned claim, the mean diameter of wherein said sensing element is less than or equal to 200 μ m.

14. according to the described analyte sensor of any aforementioned claim, wherein to be suitable for being arranged on object subcutaneous at least a portion analyte sensor.

15. according to the described analyte sensor of any aforementioned claim, further comprise being arranged on the film that limits the analyte flow that flows to described sensing element on the described sensing element.

16. according to the described analyte sensor of any aforementioned claim, wherein said analyte response enzyme comprises the glucose response enzyme.

17. according to the described analyte sensor of any aforementioned claim, wherein said sensing element comprises redox mediators.

18. according to the described analyte sensor of claim 17, wherein said redox mediators comprises and contains ruthenium complex or contain osmium complex.

19. according to the described analyte sensor of any aforementioned claim, wherein said analyte sensor is glucose sensor.

20. according to the described analyte sensor of any aforementioned claim, wherein said analyte sensor is the body inner sensor.

21. according to the described analyte sensor of any aforementioned claim, wherein said analyte sensor is external sensor.

22. the method for a monitored object bodily analytes level, described method comprises:

At least a portion of the described analyte sensor of any aforementioned claim is arranged in the subject's skin; With

From the analyte level of signal in judgement for some time that is taken place by described analyte sensor, wherein the judgement in for some time provides the supervision of object bodily analytes level.

23. a method of using analyte monitoring system to monitor analyte level, described method comprises:

At least a portion of any described analyte sensor of claim among the claim 1-21 is inserted in the patient skin;

The analyte sensor control unit is attached on the described patient skin;

A plurality of conductive contacts of described analyte sensor control unit are coupled on a plurality of contact mats of described analyte sensor;

Use signal collection that described analyte sensor control unit takes place from described analyte sensor about the data of analyte level; And

The data of described collection are emitted to acceptor unit from described analyte sensor control unit.

24. according to the described method of claim 23, wherein said analyte is glucose.

25. according to claim 23 or 24 described methods, wherein said collection data comprise from described analyte sensor generation signal and with described signal processing and become data.

26. according to any described method of claim among the claim 23-25, wherein said data comprise the signal from described analyte sensor.

27. according to any described method of claim among the claim 23-26, further comprise if described data indication alert consitions just starts alarm.

28. according to any described method of claim among the claim 23-27, further comprise the described data drug administration of response.

29. according to the described method of claim 28, wherein said medicine is Regular Insulin.

30. according to any described method of claim among the claim 23-29, wherein said method does not comprise calibration steps.

31. a manufacturing is used for the method for the electrode of the described analyte sensor of claim arbitrarily according to claim 1-21, described method comprises:

The sensitive surface of contact working electrode and two or more are the sensing element of arranged transversely each other, and wherein each sensing element comprises the analyte response enzyme.

32. method according to claim 31, wherein said method are to make the method that two or more are used for the electrode of a plurality of analyte sensors, described method comprises:

Contact in described two or more electrodes sensitive surface on each and two or more sensing element of arranged transversely each other, wherein each sensing element comprises the analyte response enzyme.

33. method according to claim 32, the sensitivity drift coefficient of wherein said electrode is less than or equal to 8%.

34. according to any described method of claim among the claim 31-33, wherein said contact comprises:

At one or many drop that comprises described sensing element of described working electrode sensitive surface deposition.

35. according to any described method of claim among the claim 31-34, comprise that further contact has the described sensing element of the film that limits the analyte flow that flows to described sensing element.

36. an analyte test strip comprises:

First substrate, it has first surface;

Second substrate, it has the second surface with respect to described first surface, and described first and second substrates are through arranging so that described first surface faces described second surface;

Working electrode, it is arranged on the described first surface; And

Counter electrode, it is arranged on one of described first surface and described second surface,

Wherein said working electrode comprises sensitive surface, and described sensitive surface comprises two or more sensing elements of arranged transversely each other, and wherein each sensing element comprises the analyte response enzyme.

37. analyte test strip according to claim 36, wherein said sensing element is discontiguous.

38. according to claim 36 or 37 described analyte test strip, wherein said sensing element is set to the single sense element on the described working electrode.

39. according to any described analyte test strip of claim among the claim 36-38, wherein said sensitive surface comprises the array of two or more single sense elements.

40. according to any described analyte test strip of claim among the claim 36-39, wherein said sensitive surface comprises the array of 100 or more single sense elements.

41. according to any described analyte test strip of claim among the claim 36-40, the sensing element density of wherein said sensitive surface is at 2-1000 sensing element/mm ²Scope in.

42. according to any described analyte test strip of claim among the claim 36-41, wherein said sensitive surface further comprises zone between feature.

43. according to the described analyte test strip of claim 42, the zone surrounds described sensing element between wherein said feature.

44. according to any described analyte test strip of claim among the claim 36-43, the feature pitch of wherein said sensing element from 1 μ m in the scope of 500 μ m.

45. according to claim 42 or 43 described analyte test strip, the zone does not have the analyte response enzyme between wherein said feature.

46. according to any described analyte test strip of claim in the claim 42,43 or 45, the zone does not have redox mediators between wherein said feature.

47. according to any described analyte test strip of claim among the claim 36-46, wherein said working electrode further comprises the second layer that is arranged on two or more sensing elements on the described sensitive surface.

48. according to any described analyte test strip of claim among the claim 36-47, the mean diameter of wherein said sensing element is less than or equal to 200 μ m.

49. according to any described analyte test strip of claim among the claim 36-48, further be included in the wall between described first substrate and described second substrate.

50. according to any described analyte test strip of claim among the claim 36-49, wherein said analyte response enzyme comprises the glucose response enzyme.

51. according to any described analyte test strip of claim among the claim 36-50, wherein said sensing element comprises redox mediators.

52. according to the described analyte test strip of claim 51, wherein said redox mediators comprises and contains ruthenium complex or contain osmium complex.

53. according to any described analyte test strip of claim among the claim 36-52, wherein said analyte test strip is the glucose test strip.

54. the method for a monitored object bodily analytes level, described method comprises:

Will be from any described analyte test strip of claim among the sample contact claim 36-53 of object; With

From the signal discriminatory analysis thing level that described analyte test strip takes place, wherein said judgement provides the supervision of described object bodily analytes level.

55. a method of using analyte monitoring system to monitor analyte level, described method comprises:

The conductive contact of any described analyte test strip of claim among the claim 36-53 is coupled to analyte monitoring system;

To contact described analyte test strip from the sample of object;

Use described analyte monitoring system from the signal collection that taken place by the described analyte test strip data about analyte level; And

From the data discriminatory analysis thing level of described collection, wherein said judgement provides the supervision of described analyte level in the described subject.

56. according to the described method of claim 55, wherein said analyte is glucose.

57. according to claim 55 or 56 described methods, wherein said collection data comprise from described analyte test strip generation signal with described signal processing is become data.

58. according to any described method of claim among the claim 55-57, wherein said data comprise the described signal from described analyte test strip.

59. according to any described method of claim among the claim 55-58, further comprise if described data indication alert consitions then starts alarm.

60. according to any described method of claim among the claim 55-59, further comprise the described data drug administration of response.

61. according to the described method of claim 60, wherein said medicine is Regular Insulin.

62. according to any described method of claim among the claim 55-61, wherein said method does not comprise calibration steps.

Images