Improved analyte sensors and methods of making and using the same

Abstract

To provide methods and systems for providing continuous analyte monitoring including in vivo sensors that do not require user's calibration during in vivo use.SOLUTION: Also provided are methods and devices including continuous analyte monitoring systems that include in vivo sensors which do not require system-executed calibration or which do not require factory-based calibration, and which exhibit stable sensor sensitivity characteristics. Methods of manufacturing which require no calibration sensors and post-manufacturing packaging and storage techniques are also provided.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] This application is based on U.S. Provisional Patent Application No. 61 / 155,889, filed February 26, 2009, entitled "Analyte Measurement Sensors and Methods for Fabricating the Same," No. 61 / 155,891, filed February 26, 2009, entitled "Analyte Measurement Sensors and Methods for Fabricating the Same," No. 61 / 155,893, filed February 26, 2009, entitled "Analyte Measurement Sensors and Methods for Fabricating the Same," No. 61 / 165,499, filed March 31, 2009, entitled "Analyte Measurement Sensors and Methods for Fabricating the Same," This application claims priority to Ser. No. 61 / 238,461, filed Aug. 31, 2009, entitled "Implantable Analyte Sensors for Use with Continuous Analyte Measurement Systems and Methods for Packaging the Sensors," and Ser. No. 61 / 290,847, filed Dec. 29, 2009, entitled "Implantable Analyte Sensors for Use with Continuous Analyte Measurement Systems and Methods for Packaging the Sensors," the disclosures of each of which are incorporated by reference in their entirety for all purposes.

[0002] The present invention relates to continuous analyte monitoring. More specifically, the present invention relates to methods and systems for providing continuous analyte monitoring with in vivo sensors that do not require user calibration during in vivo use. [Background technology]

[0003] Continuous glucose monitoring (CGM) systems typically provide a comprehensive concept of blood glucose monitoring for a subject. For patients diagnosed with type 1 or type 2 diabetes, the benefits of such systems are obvious. Commercially available CGM systems typically use transcutaneous or percutaneously inserted glucose sensors for periods ranging from several days to about one week, during which real-time blood glucose information is monitored to regulate potential blood glucose excursions and allow the patient to take any necessary corrective action. Typical glucose sensors are manufactured in batches or lots and are discarded and replaced with new sensors after each use (intended 3, 5, 7 days or some other predefined period).

[0004] Furthermore, existing CGM systems require periodic calibration of the glucose sensor, which involves performing a finger prick test to determine blood glucose concentration and periodically revising the sensor calibration using the determined concentration information to account for, among other things, sensitivity variations between manufactured sensors and drift in sensor stability over time. Frequent in vitro blood glucose testing for sensor calibration is an inconvenience for patients in addition to the actual perceived pain associated therewith. Summary of the Invention [Problem to be solved by the invention]

[0005] It would therefore be desirable to provide an in vivo sensor for use in a continuous analyte monitoring system that does not require sensor calibration by the user or the system during in vivo use. [Means for solving the problem]

[0006] Improved in vivo analyte sensors, methods of manufacturing the improved sensors, and methods of using the improved sensors are provided. Embodiments include in vivo analyte monitoring devices, e.g., blood glucose monitoring devices, methods, systems, manufacturing processes, and post-manufacturing processes, such as post-manufacturing storage processes, that provide analyte monitoring without the need for user calibration after in vivo placement of the device by a user.

[0007] Embodiments of devices and methods are provided that exhibit stability and / or sensitivity profiles that do not change by more than a clinically significant amount over the lifetime of the device and / or have predictable stability profiles and / or sensitivity.

[0008] The embodiments include manufacturing processes. For example, the embodiments include calibration factors or parameters, such as device sensitivity, determined (e.g., empirically, statistically, or theoretically) during the manufacture of one or more analyte sensor lots and stored in memory or suitable storage for one or more manufactured sensor lots (and / or coded into the sensors in the lots themselves). The calibration factors may be used by the device when the sensor is placed in the user's body for active analyte monitoring to match the sensor to a standard, including matching analyte data obtained therefrom (e.g., a current signal obtained from the sensor, measured in amperes) to blood glucose data (e.g., in mg / dL) derived from interstitial fluid. For example, the embodiments include sensors from the same and / or different lots given and the same calibration factor is used, the calibration factor being determined prior to the manufacture of a given sensor lot, for example, using historical data from a previous lot.

[0009] Embodiments include sensor lots and sensors derived therefrom, where the sensors are assigned the same and / or different manufacturing lots and use the same calibration factor, which is determined substantially contemporaneously, e.g., instantly with respect to manufacturing, for one or more manufactures, including all of a given lot.

[0010] Embodiments include sensor manufacturing lots that have extremely low coefficients of variation (CV) of sensor sensitivity within and / or between sensor lots. For example, the CV is about 5% or less, such as about 3% or less, such as about 2% or less, such as about 1% or less. In certain embodiments, the extremely low CV is achieved by at least one or more robust manufacturing processes.

[0011] The user-calibration-free analyte monitoring devices and methods also include embodiments that have extremely high sensor stability in a given user over the entire life of the sensor. For example, the sensor stability profile in a user does not vary by more than a clinically and / or statistically significant amount over the life of the sensor. For example, the stability may not vary by more than about 5%, such as about 3% or less, such as about 2% or less, such as about 1% or less.

[0012] As discussed above, embodiments include in vivo analyte monitoring devices having extremely low variability / high accuracy in flux limiting membrane thickness within and / or between manufacturing lots. The manufacturing techniques and methods provide reproducible active sensing areas of the sensor working electrodes with controlled, substantially uniform membrane thickness such that the coefficient of variation (CV) of sensitivity between sensors within a manufacturing lot or batch of sensors is about 5% or less, such as 3% or less, such as about 2% or less, such as about 1% or less.

[0013] Embodiments include in vivo manufacturing techniques and methods that provide, for example, control of the area and / or film thickness of the sensor working electrode, for example, to control sensor sensitivity across manufacturing lots or batches. Because glucose concentration at the working electrode surface (e.g., active sensing area) is proportional to the thickness of the membrane and sensitivity is proportional to the area of ​​the working electrode, selective and precise control of the film thickness and area (e.g., active area) of the sensor's working electrode can produce sensors that do not require calibration by the user or the CGM system.

[0014] Additionally, in further aspects of the present disclosure, the glucose limiting membrane of the analyte sensor provides biocompatibility when positioned or deployed in vivo such that potential or suspected biofouling is minimized and does not adversely affect the in vivo stability of the sensor such that in vivo calibration is required. For example, the analyte sensor, in one embodiment, may exhibit a variation of about 2% to about 3% or less, such as a variation of about 1% to about 2% or less, or in a further aspect, may exhibit less than about 1% variation in in vivo sensor sensitivity stability over the sensing period of the sensor (e.g., 3 days, 5 days, 7 days, 14 days or more) during in vivo use and may not require user or system based calibration.

[0015] The embodiment includes a reproducible active region of the analyte sensor where the sensing chemistry is applied to the working electrode of the sensor. The active region is approximately 0.01 mm 2 ~about 1.5mm 2 The following size range, for example, about 0.0025 mm 2 ~ approx. 1.0 mm 2 Less than or equal to, for example, about 0.05 mm 2 ~about 0.1mm 2 The embodiment may have the following dimensional range: The active area of ​​the sensor may have a reproducible active area with a void or well. The active area void / well may have a dimensional range of about 0.01 mm. 2 ~ approx. 1.0 mm 2 or, for example, about 0.04 mm 2 ~about 0.36mm 2The dimensions of the voids / wells at least partially define the shape (and therefore size) of the active area of ​​the sensor. The shape of the voids / wells may be varied to achieve the same desired volume and / or surface area. For example, the height of the voids / wells may be gradually increased or decreased. In addition, the surface area of ​​the voids / wells may be shaped to taper or have other variations, including, for example, a triangular shape, an elliptical shape, etc.

[0016] The embodiment further includes a reproducible sensor configuration with precise dimensions of the sensor distal portion. The width of the conductive layer of the sensor can be influenced by the width of the substrate of the sensor distal portion. The active area of ​​the sensor is approximately 0.0025 mm. 2 ~about 3mm 2 For example, about 0.01 mm 2 ~ approx. 0.9mm 2 The range may be:

[0017] Embodiments further include an analyte sensor having a substantially constant width and comprising sensing and conductive layers in the form of, e.g., a strip, that are perpendicular to one another (e.g., an orthogonal relationship between the sensing and conductive layers) to form a substantially constant active area along the length and width of the sensor distal portion.

[0018] Additionally, embodiments also include a precision laser process, such as, for example, laser ablation, to remove, trim, modify, or ablate excess or unwanted material from the sensor body to precisely define and recreate the desired active area of ​​the sensor, having a clinically insignificant CV and reporting accurate instantaneous glucose monitoring over the life of the in vivo sensor without the need for user-initiated or CGM system based calibration.

[0019] Embodiments further include post-manufacture and pre-in vivo use storage techniques, including sensor packaging that has a controlled and / or minimal adverse environmental impact on the packaged sensor prior to in vivo use, e.g., to minimize degradation of sensor stability during storage. For example, embodiments include sensor packaging techniques that maintain a water vapor transmission rate (MVTR) of about 0.5 mg / day or less, e.g., about 0.46 mg / day or less, e.g., about 0.4 mg / day or less. Desiccant material can be provided on, in, within, or with the sensor packaging to maintain a substantially stable environment for the shelf life of the sensor (e.g., about 0 to about 24 months, e.g., 0 to about 18 months).

[0020] Embodiments include in vivo glucose sensors that provide predictable and stable in vivo sensor sensitivity, eliminate the need or requirement for sensor calibration during in vivo use, i.e., no calibration by the user and / or the CGM system during this time, and provide methods to compensate for intra- and inter-subject variations in in vivo responses.

[0021] The embodiments further include in vivo sensors that do not require factory calibration and further do not require user or system-made or implemented sensor calibration. That is, in certain aspects, the manufactured in vivo sensors exhibit characteristics including a substantially stable sensitivity profile after manufacturing and during in vivo use. For example, interferents such as oxygen, acetaminophen or ascorbic acid that may be present during the use of the in vivo sensor can be minimized by careful selection of the sensor membrane material (e.g., membranes with low oxygen permeability), sensing chemistry (e.g., designed or selected to have minimal effect from interferents such as oxygen), in addition to a well-defined and reproducible active area of ​​the sensor, the sensor geometry, and a tightly controlled post-manufacturing environment during the sensor shelf life.

[0022] For example, a feedback algorithm may be programmed or programmable in the CGM system such that sensor sensitivity is compensated or modified during in vivo use based on a stability profile determined a priori for each subject and applied to signals received from the in vivo sensor during use, thereby providing for or compensating for variations in interstitial to blood glucose concentrations between each in vivo environment (e.g., between each subject using the in vivo sensor). Such algorithms or routines may be generated or determined based on prior in vivo sensor feedback signals and may be programmed or programmable (and subsequently modifiable) in the CGM system and applied to signals received from the sensor during in vivo use.

[0023] In the manner described above, embodiments of the present disclosure provide in vivo sensors, and CGM systems that employ and manufacture and package in vivo sensors, for example, but not limited to, no user-initiated or user-based calibration, no system-based calibration, no factory-based calibration, only system calibration (e.g., one or more calibration routines are automatically performed or executed), or only a single user-initiated calibration or sensitivity check over the life of the sensor during in vivo use of the sensor.

[0024] A detailed description of various aspects, features and embodiments of the present disclosure is provided herein with reference to the accompanying drawings, which are briefly described below. The drawings are illustrative and are not necessarily to scale, and some components and features are exaggerated for clarity. The drawings illustrate various aspects or features of the present disclosure and may 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 component or feature may be used to refer to a similar component or feature in another drawing. [Brief description of the drawings]

[0025] [Figure 1] FIG. 1 is a plan view of an analyte sensor according to one embodiment of the present disclosure. [Diagram 2] FIG. 2 is a plan view of an analyte sensor according to another aspect of the present disclosure. [Diagram 3] 3A is a plan view of the tail or distal end of the analyte sensor of FIG. 1 in fluid contact with interstitial fluid during in vivo use in one embodiment; FIG. 3B is a side cross-sectional view of the analyte sensor at line B at the distal end shown in FIG. 3A in one embodiment. [Figure 4] 11 illustrates an analyte sensor configuration according to another embodiment of the present disclosure. [Diagram 5] 1A and 1B show plan and cross-sectional views of an analyte sensor according to one embodiment. [Figure 6] 1A and 1B show plan and cross-sectional views of an analyte sensor according to another embodiment. [Figure 7] 1A and 1B show plan and cross-sectional views of an analyte sensor according to yet another embodiment. [Figure 8] 1A and 1B show plan and cross-sectional views of an analyte sensor according to yet another embodiment. [Figure 9] 1A-C show top (A), bottom (B) and cross-sectional side (C) views of a double-sided analyte sensor according to one embodiment. [Figure 10] 1A-C show top (A), bottom (B) and cross-sectional side (C) views of a double-sided analyte sensor according to one embodiment. [Figure 11] 1A-C show top view (A), cross-sectional side view (B), and end view (C) of an analyte sensor prior to laser trimming of the sensing layer of the sensor according to one embodiment. [Figure 12] 11A-11C after laser trimming of the sensing layer of the sensor according to one embodiment. [Figure 13] 1A-C show top view (A), cross-sectional side view (B), and end view (C) of an analyte sensor prior to laser trimming of the sensing layer and working electrode layer of the sensor according to another embodiment. [Figure 14]13A-13C after laser trimming of the sensing layer and working electrode layer of the sensor according to another embodiment. [Figure 15] 1A-C show top view (A), cross-sectional side view (B), and end view (C) of an analyte sensor prior to laser trimming of the sensing and working electrode layers of the sensor in yet another embodiment. [Figure 16] 15A-15C after laser trimming of the sensing layer and working electrode layer of the sensor according to yet another embodiment. [Figure 17] FIG. 2 is an exploded perspective view of one embodiment of a packaged sensor assembly according to one aspect of the present disclosure. [Figure 18] FIG. 18 is an assembled perspective view of one embodiment of the packaged sensor assembly of FIG. 17. [Figure 19] 18A, B and C are side (A), bottom (B) and end (C) views of the tray element of the package of FIG. 17. [Figure 20] 20A shows a top view of a working electrode of an analyte sensor according to one embodiment of the present disclosure; FIG. 20B shows a cross-sectional view taken along line B in FIG. 20A; FIG. 20C shows a cross-sectional view taken along line C in FIG. 20A. [Figure 21] FIG. 20B illustrates the application of a sensing layer to the working electrode shown in FIG. 20A in accordance with an embodiment of the present disclosure. [Figure 22] 1 is a typical time-varying sensitivity drift profile associated with an analyte sensor according to one embodiment of the present disclosure. [Figure 23] Sensitivity variation of 16 analyte sensors from a sensor lot manufactured according to one or more methods of the present disclosure in response to beaker solutions having known glucose concentrations. [Figure 24] In one embodiment, the response of sensors from the same lot as described in conjunction with FIG. 23. [Diagram 25] 11 is a Clarke Error Grid based on an analyte sensor manufactured in accordance with one or more embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Before the present disclosure is described, it is to be understood that this disclosure is not limited to particular embodiments described, which may, of course, vary. It is also to 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 present disclosure will be limited only by the appended claims.

[0027] Where a range of values ​​is provided, each intervening value is understood to be encompassed in the disclosure to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, as are any other stated or intervening values ​​between the upper and lower limits of the range and within that stated range. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, which are also encompassed in the disclosure, subject to any specifically excluded limits in the stated range. Where a stated range includes one or both limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0028] As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual elements and characteristics that may be readily separated from or combined with the characteristics of any of the other several embodiments without departing from the scope or spirit of the disclosure.

[0029] Embodiments of the present disclosure relate to methods and devices for detecting at least one analyte, e.g., glucose, in a bodily fluid. Embodiments relate to continuous and / or automated in vivo monitoring of one or more analyte concentrations using an analyte monitoring system including an analyte sensor for in vivo detection of an analyte in a bodily fluid, e.g., glucose, ketones, lactate, etc. Embodiments include fully implantable analyte sensors and transcutaneous analyte sensors where only a portion of the sensor is placed subcutaneously and a portion of the sensor remains on the skin for connection to, e.g., a controller, transmitter, receiver, transceiver, processor, etc. At least a portion of the sensor may be configured to be placed subcutaneously on a patient for monitoring the concentration of an analyte in the interstitial fluid of the patient for a period of time, e.g., about 3 days or more, about 5 days or more, about 7 days or more, about 10 days or more, about 14 days or more, etc., or based on a sensor lifetime determined by sensor characteristics, e.g., the sensor's sensing chemistry formulation, to provide accurate sensing results, and / or sensor packaging and / or storage conditions, or combinations thereof. For the purposes of this description, semi-continuous monitoring and continuous monitoring are used interchangeably unless otherwise stated.

[0030] Embodiments include an analyte sensor. A sensor response may be obtained and correlated to and / or converted to an analyte concentration in blood or other fluid. In certain embodiments, the analyte sensor may be placed in contact with interstitial fluid to detect glucose concentration, which may be used to infer glucose concentration in the patient's bloodstream. The analyte sensor may be insertable into a vein, artery, or other site that contains bodily fluids. Analyte sensor embodiments of the present disclosure are configured to substantially continuously monitor the analyte concentration over a sensing or monitoring period that may range from minutes, hours, days, weeks, months, or longer, and generate a signal related to the analyte (e.g., a pre- or post-processing signal that is converted to a glucose measurement corresponding to the period of sensing).

[0031] Analytes that may be monitored include, but are not limited to, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase (e.g., CK-MB), creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth hormone, hormones, ketone bodies, lactate, oxygen, peroxide, prostate specific antigen, prothrombin, RNA, thyroid stimulating hormone, and troponin. Concentrations of drugs, such as antibiotics (e.g., gentamicin, vancomycin, etc.), digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may also be monitored. In embodiments where more than one analyte is monitored, the analytes may be monitored simultaneously or at different times.

[0032] An embodiment of the sensor or sensor system includes an in vivo analyte sensor for use in an analyte monitoring system, such as a continuous glucose monitoring system, that does not require calibration during in vivo use. More specifically, a factory calibration system in certain embodiments includes an in vivo analyte monitoring system with an analyte sensor that does not require calibration related to the in vivo sensor data using any reference analyte tests, such as in vitro finger stick glucose tests or YSI tests, and the results of the reference tests by a user during in vivo use. Advantages of the present system, including a factory calibration system and / or not including a user calibration system, are apparent, including reducing inconvenience to the user by eliminating the need for periodic in vitro finger test glucose testing and reducing potential sources of error in reading the in vivo sensor during use.

[0033] The embodiments further include in vivo sensors that provide characteristics including sensor-to-sensor reproducibility within and / or between each manufactured sensor lot. A typical sensor lot as described herein includes a batch of in vivo sensors manufactured using the same manufacturing equipment during a manufacturing process using the same materials and methods. The embodiments include manufactured sensor lots that have very similar or identical sensor characteristics, including sensor stability profiles (e.g., similar or identical sensor sensitivity, shelf life characteristics, etc.). For example, a sensor lot may include two or more sensors, e.g., about 1,000 or more, about 5,000 or more, or about 10,000 or more (or other suitable number of sensors that can be manufactured in a lot or batch), in vivo sensors that are streamlined to be manufactured using the same manufacturing equipment and methods in addition to being manufactured from the same materials, including substrate or non-conductive materials, conductive materials for electrodes, sensing chemical composition, and sensor film properties such as thickness, size, and other physical and / or chemical properties. A sensor lot as defined herein is merely for exemplary purposes, and the number of sensors manufactured in a lot is primarily constrained by the production volume supported by the equipment that manufactures the sensors. To this end, in accordance with embodiments of the present disclosure, a sensor lot may be greater than approximately 1,000 of the in vivo sensors of the exemplary embodiments herein.

[0034] Embodiments of the in vivo sensors have shelf-life stability after manufacture, thereby minimizing, including eliminating, degradation of sensor sensitivity prior to in vivo use, and minimizing or making insignificant or eliminating variation in shelf-life stability. Embodiments include, for example, packaging of the sensors and / or sensor systems using desiccants and / or other materials to provide a stable shelf-life environment to maintain the effectiveness of the sensors and / or sensor systems during storage and prior to in vivo use.

[0035] Embodiments of the sensor may be used in analyte monitoring systems that implement data processing techniques and / or signal compensation to adjust for or compensate for variations in sensor response during in vivo use to minimize inter- and intra-subject variability in sensor sensitivity. These embodiments may include ensuring early signal decay of the sensor signal during the initial implantation period where spurious or transient signals from the sensor are detected.

[0036] Embodiments further include a calibration code or parameter, which may be generated or determined during one or more sensor manufacturing processes, encoded or programmed into the data processing device of the analyte monitoring system as part of the manufacturing process, or into the sensor itself, e.g., as a bar code, laser tag, RFID tag, or other machine readable information provided on the sensor, or the physical configuration of the sensor from which the calibration code or parameter information may be derived (e.g., configuration based on dimensions including, e.g., height, width, circumference, radius, surface area, volume, or one or more combinations thereof, of the formations or indentations in the surface of the sensor body, arrangement of the formations or indentations in the surface of the sensor body, etc.), thereby eliminating user-initiated sensor calibration during in vivo use of the sensor or reducing the frequency of in vivo calibration during use of the sensor. In embodiments in which the calibration code or parameter is provided on the sensor itself, the calibration code or parameter may be automatically transmitted or provided to the data processing device of the analyte monitoring system prior to or upon initiation of use of the sensor.

[0037] Multiple analyte systems from the same and / or different lots, including all analyte systems manufactured by a given manufacturer for a period ranging from about one day to about one year or more, e.g., more than one year, may contain the same calibration code.

[0038] Embodiments include sensors and sensor systems in which the calibration code or parameters determined during sensor manufacture may be sensor or lot specific and, upon determination, may be automatically or manually provided to a data processor of an analyte monitoring system. For example, a calibration code or parameters determined for a particular manufactured sensor may be provided on the sensor packaging requiring a user to manually enter the code or parameters into a data processor of an analyte monitoring system prior to in vivo use.

[0039] As discussed above and in further detail below, embodiments of the analyte sensors of the present disclosure include sensors manufactured with techniques and procedures that control the active area of ​​the sensor, including the glucose sensing layer of the working electrode and / or the glucose limiting membrane. For example, analyte sensors according to embodiments of the present disclosure provide (1) reproducible active area of ​​the sensor, (2) uniform sensor membrane thickness and composition, (3) stable active enzyme, and (4) predictable biocompatibility. For example, because the flux of glucose to the working electrode is proportional to the thickness of the sensor membrane, sensors manufactured with a substantially uniform membrane thickness provide sensors that do not require in vivo calibration by the user, i.e., that can be factory calibrated or that do not require calibration after manufacture and during in vivo use.

[0040] General sensor structure FIG. 1 illustrates a plan view of an analyte sensor according to one aspect of the present disclosure. With reference to FIG. 1, in one embodiment, the analyte sensor 100 comprises a sensor body having a proximal portion 110 and a distal portion 120. The distal end 126 of the distal portion 120 of the sensor 100 may have a width suitable or appropriate for transcutaneous placement through a skin surface of a user. For example, in one aspect, the distal portion 120 may be dimensioned to have a width of about 2 mm or less, or about 1 mm or less, or about 0.5 mm or less, or about 0.3 mm or less, or about 0.25 mm or less to define the distal end 126 for insertion beneath the skin layer of a user.

[0041] In one particular aspect, as shown in FIG. 1, a conductive material is disposed in the sensor 100. The conductive material may comprise one or more of electrodes 121a, 121b, 121c, conductive pathways 122a, 122b, 122c, and contacts 123a, 123b, 123c. In one embodiment, the one or more electrodes 121a, 121b, 121c are disposed near a distal end 126 of the distal portion 120 of the sensor 100. As such, the one or more electrodes 121a, 121b, 121c are implanted in the tissue of a user in fluid contact with interstitial fluid, for example, to detect and measure the bodily fluid of an analyte of interest. A signal generated by the analyte sensor is transmitted through the conductive pathways 122a, 122b, 122c and ultimately to a transmitter circuit, as described below. The one or more electrodes 121a, 121b, 121c may include one or more working electrodes, one or more counter electrodes, one or more reference electrodes, or one or more combinations thereof. In one embodiment, the sensor 100 may include three electrodes, e.g., a working electrode, a counter electrode, and a reference electrode. However, other embodiments may include more or less electrodes, as described in U.S. Patent Application Nos. 61 / 247,519 and 12 / 393,921, the disclosures of which are incorporated herein by reference. In further embodiments, multiple working electrodes may be provided in the sensor. Although the electrodes 121a, 121b, 121c in FIG. 1 are shown in a side-by-side configuration, however, other electrode configurations may be used, including, but not limited to, a stacked configuration. Additionally, embodiments of sensors according to the present disclosure include, but are not limited to, planar sensors, wire sensors, sensors having stacked or laminated electrodes (e.g., where the electrodes are separated by insulating or substrate material), as well as sensors having electrodes disposed side-by-side in the same plane on a substrate.

[0042] Suitable conductive materials include, but are not limited to, lamp black carbon, glassy carbon, graphite, silver, silver chloride, platinum, palladium, iridium, platinum iridium, titanium, gold, and the like in a polymer thick film binder. The conductive material can be applied to the sensor by a variety of techniques, including sputtering, evaporation, printing, or extrusion, or the substrate can be patterned using laser ablation or photolithography. In certain aspects, for example, when using gold as the conductive material applied to the sensor, the thickness of the gold material can be in the range of approximately 40 nm to 120 nm, such as approximately 50 nm to 80 nm, for example, approximately 60 nm. Although exemplary ranges of dimensions of the materials are set forth above, embodiments of the present disclosure contemplate other dimensions greater than or less than the stated ranges, and the scope of the present disclosure should not be construed as being limited to the exemplary dimensions set forth above.

[0043] Figure 2 shows a plan view of an analyte sensor according to another aspect of the disclosure. Figure 2 illustrates another sensor configuration of the sensor 100 of Figure 1. In one embodiment, the analyte sensor 200 shown in Figure 2 comprises a proximal portion 210 and a distal portion 220 with a distal end 226. The dimensions of the distal portion 220 and distal end 226 of the sensor 200 are configured in one aspect to facilitate transcutaneous placement through a user's skin surface, as described in more detail above in conjunction with Figure 1.

[0044] In certain aspects, the sensor 200 of FIG. 2 also includes conductive material disposed on the sensor 200 that forms one or more of the electrodes 221, conductive pathways 222a, 222b, 222c, and contacts 223a, 223b, 223c (as described in more detail above in conjunction with FIG. 1). The electrodes 221 of FIG. 2 are shown in a stacked configuration, with the conductive material of each electrode stacked on top of one another and separated by non-conductive dielectric layers, however, as noted above, other configurations are possible, including, but not limited to, side-by-side configurations. In other embodiments, electrodes, conductive pathways, and / or contacts are provided on both sides of the sensor body. Other sensor designs and electrode configurations are also provided within the scope of the present disclosure, including, but not limited to, planar and wire sensors and stacked, side-by-side, and twisted electrode configurations. Other exemplary sensor and electrode configurations can be found in, inter alia, U.S. Pat. Nos. 6,175,752, 6,134,461 and 6,284,478, and U.S. Patent Application Publication No. 2007 / 0135697, which are incorporated herein by reference for all purposes.

[0045] Figure 3A illustrates the distal end 126 of the distal portion 120 of the analyte sensor 100 of Figure 1 in one embodiment. In one aspect, the distal end 126 of the sensor 100 is adapted to be placed at least in part in subcutaneous and / or transcutaneous tissue of a user and to contact bodily fluids, such as interstitial fluid. The sensor 100, in one aspect, may include a substrate 102 fabricated from a polymeric material, such as, for example, a polyester-based material or a polyimide.

[0046] Referring again to FIG. 3A, in one embodiment, the analyte sensor 100 comprises a working electrode 121a, a counter electrode 121b, and a reference electrode 121c. Conductive pathways 122a, 122b, 122c provide electrical connection between the electrodes 121a, 121b, 121c with their respective corresponding contacts 123a, 123b, 123c (FIG. 1). A sensing layer 112 used to detect the analyte, such as an enzyme and an optional electron transfer agent, described in more detail below, is applied to at least the working electrode 121a. Sensing material (e.g., without one or more of the components applied to the working electrode, e.g., without the enzyme and / or optional electron transfer agent) may be applied to one or more of the other electrodes. At least the distal end 126 of the sensor 100 may be covered with a biocompatible membrane 114.

[0047] 3B illustrates a cross-sectional view of the distal end 126 of the sensor 100 in one embodiment. As shown, in one embodiment, the sensor 100 comprises a dielectric or substrate 102 and an optional first layer 116, which may be a conductive layer such as glassy carbon, graphite, silver, silver chloride, platinum, palladium, platinum iridium, titanium, gold, or iridium, applied to the substrate 102. The layer 116 may be an adhesion layer using a sputtering or evaporation method. A working electrode 121a, which may comprise a conductive material such as glassy carbon, graphite, silver, silver chloride, platinum, palladium, platinum iridium, titanium, gold, or iridium, may be applied to the adhesion layer 116 of the substrate 102 in some embodiments. In other embodiments, the conductive material may be applied only to an area on the adhesive layer 116 to form the working electrode 121a, or may be applied to an area on the adhesive layer 116 that is greater than the area of ​​the working electrode 121a, or may be applied across the entire adhesive layer 116. The edges of the working electrode 121a may be precisely defined by techniques such as laser ablation to modify the edges, for example by removing excess material or another molding material. Similar techniques of applying conductive material and laser ablation may also be used in connection with forming or providing the traces 122a, 122b, 122c, the counter electrode 121b, the reference electrode 121c, or any other areas where conductive material is applied to the sensor.

[0048] In certain embodiments, the reference electrode 121c may be coated with silver / silver chloride, for example, using screen printing, extrusion, or electrolytic deposition or electroplating. In certain aspects, the thickness of the conductive material, such as gold, applied to the sensor may range from about 40 nm to 120 nm, such as about 50 nm to 80 nm, for example, about 60 nm. Furthermore, in one aspect, the first layer 116 may range from about 10 nm to 30 nm, for example, about 20 nm.

[0049] Referring again to FIG. 3B, in one aspect, a coverlay material 118 may be applied to the distal end 126 of the sensor 100. In one embodiment, the coverlay material 118 is applied only to the electrodes 121a, 121b, 121c. In yet another embodiment, the coverlay material is applied to the working electrode 121a, or to substantially the entire substrate 102. The coverlay material 118 may be used to encapsulate some or all of the electrodes and provide environmental and electrical insulation. In certain aspects, the coverlay material 118 may include a photoimageable material, such as, but not limited to, a polyimide or polyester-based material. That is, in certain embodiments, the polymer or coverlay material 118 may be photoimageable, rendering portions of the polymer removable, such as, for example, exposure of the contacts and / or sensor electrodes to applications such as sensor chemistry. In certain embodiments of the present disclosure, portions of the coating polymer or coverlay material 118 may be masked to form a pattern, then exposed and developed to remove portions of the polymer coating for further processing of the sensor. In certain embodiments, the coating polymer may be removed by other methods, such as laser ablation, chemical polishing, etc. A secondary photoresist may also be used to target specific areas of the polymer or coverlay material 118 for removal during the sensor fabrication process.

[0050] In certain embodiments, openings 120, such as voids or wells, can be created or defined in the coverlay material 118 using photolithography techniques, such as, for example, photoetching, to a depth sufficient to expose one or more of the electrodes, such as, for example, working electrode 121a. Photolithography techniques, in certain embodiments, use positive or negative photoresists, where the exposed portions become soluble or insoluble, respectively, after exposure. The solubilized portions are removed after exposure through a wash or develop, etch and strip process. The exposure process, in certain embodiments, uses a precision mask aligner that aligns a photomask (e.g., on the coverlay material 118) through (X,Y) or (X,Y,θ) steps, using the metal layer reference features specific to the vision mechanism of the mask aligner, relative to the existing metal layer before the mask exposure process occurs. The mask exposure process exposes the desired portions of the photomask to, for example, ultraviolet light, which changes the solubility of the exposed portions of the photomask. The photomask, in one specific embodiment, is made of a material that is transparent at ultraviolet wavelengths, such as quartz, glass, or polyester.

[0051] The sensing layer 112 is then placed in the formed void or well, shown as an opening 120, on the working electrode 121a for use in reacting with the analyte. In certain embodiments, one or more sensing layer components may be deposited on one or more other electrodes. As further shown in FIG. 3B, the biocompatible membrane 114 surrounds the distal end 126 of the sensor 100. In other embodiments, the biocompatible membrane 114 may surround the entire sensor 100 configured for transcutaneous placement.

[0052] In certain aspects of the present disclosure, the coverlay material 118 disposed over the one or more electrodes, partially or completely covering the one or more electrodes, may include, for example, a non-conductive polymer. Suitable insulating materials include, but are not limited to, polyethylene terephthalate, parylene, fluorinated polymers, polyurethane, polyimide, other non-conductive polymers, glass, or ceramic. The insulating material may be coated onto the electrodes by a variety of coating methods, including, but not limited to, chemical or physical vapor deposition, hot roller lamination, spray coating, dip coating, slot die extrusion, direct coating, or other coating techniques. In some embodiments, the insulating coating is partially or selectively stripped from the electrodes to expose the electroactive surfaces. In some embodiments, the insulating substrate (e.g., dielectric material) and the electrodes may be arranged in a stacked geometry (i.e., the insulating substrate is disposed between the electrodes). In other embodiments, the electrodes may be arranged in a side-by-side geometry, as described in U.S. Pat. No. 6,175,752, the disclosure of which is incorporated herein by reference.

[0053] Figures 4A and 4B show an analyte sensor configuration according to another embodiment of the present disclosure. More specifically, Figure 4A shows a top view of a sensor substrate body, and Figure 4B illustrates a sensor body configured with a bent or angled portion for transcutaneous placement in fluid contact with interstitial fluid through a skin layer. As further shown in Figure 4A, the arrangement / configuration of the various electrodes, conductive paths and contacts may be different as compared to the embodiment shown in Figures 1 and 2. However, the distal end of the sensor shown in Figure 4A configured for subcutaneous and / or transcutaneous placement may be similar or identical to the calibration and / or configuration shown in Figures 3A and 3B.

[0054] 4A and 4B, in one embodiment, the sensor 400 comprises a proximal portion 410, a distal portion 420, and an intermediate portion 425. The intermediate portion 425 may be provided at an angle relative to a position and / or orientation from the distal portion 420. For example, the intermediate portion 425 may be laterally offset or skewed from the distal portion 420. To this end, a gap may be defined between the intermediate portion 425 and the distal portion 420. The gap may have a constant spacing along its length or a variable spacing along its length such that the major axes of the intermediate portion 425 and the distal portion 420 remain parallel to one another.

[0055] 4B, the proximal portion 410 of the sensor 400 may be provided at a predetermined location and / or orientation relative to the intermediate portion 425 and / or the distal portion 420. In this manner, a second gap may be defined between the proximal portion 410 and the intermediate portion 425 of the sensor body 400, where at least a portion of the proximal portion 410 is laterally offset from the intermediate portion 425. The intermediate portion 425 and corresponding gaps between the intermediate portion 425 and the proximal and distal portions 410 and 420 may be configured such that the intermediate portion 425 may be used to aid in the removal of a sharp penetrator (e.g., an introducer needle) used during sensor insertion, and subsequent removal or withdrawal of the introducer needle or sharp penetrator from the user or patient after sensor insertion or placement beneath the skin layer.

[0056] 4A and 4B, in one particular aspect, the sensor 400 of FIG. 4A and 4B also includes conductive material (described in further detail above in conjunction with FIG. 1) disposed on the sensor 400 forming one or more electrodes 421 at a distal end 426 configured to facilitate transcutaneous placement through a skin surface of a user, conductive pathways 422a, 422b, 422c and contacts 423a, 423b, 423c. In one embodiment, no conductive material is disposed on an intermediate portion 425 of the sensor 400. Various other configurations and / or arrangements of the electrodes 421, conductive paths 422a, 422b, 422c and contacts 423a, 423b, 423c are also included within the scope of the present disclosure, such as, but not limited to, the arrangements and configurations with respect to Figures 1 and 2, including coplanar or coaxial arrangements or orientations of the conductive paths 422a, 422b, 422c and contacts 423a, 423b, 423c of the sensor and corresponding electrodes of twisted, stacked or laminated electrodes of the sensor, or double-sided sensor configurations including electrodes provided on both sides or surfaces of a substrate.

[0057] Sensor Active Area In certain embodiments, in vivo sensors according to the present disclosure have a reproducible active area of ​​the working electrode, i.e., for each manufactured sensor, the parameters or characteristics of the active area (defined as the area of ​​the sensing chemistry at the working electrode) are reproducible such that the coefficient of variation (CV) of the active area is less than about 5%, e.g., less than about 3%, e.g., less than about 1%, from sensor to sensor within a sensor lot. This can be achieved by controlled manufacturing processes and defined procedures during in vivo sensor manufacturing, where the active area is precisely defined.

[0058] Reproducibility of the active area of ​​the sensor is, in one embodiment, achieved by maintaining substantially constant dimensions (width, length, radius and thickness) of the active area, i.e., the area of ​​the working electrode that contacts the sensing element, in manufactured sensors, thereby minimizing sensitivity to sensor-to-sensor variations.

[0059] In certain embodiments, the active area of ​​the working electrode may be indefinite during the manufacturing process until the magnitude or range of values ​​(e.g., related to the viscosity or permeability of the membrane polymer lot used, or the activity of the enzyme used in the lot), or the variation of such values, e.g., related to parameters that affect manufacturing precision (and thus reproducibility) from one sensor lot to another, are determined, understood, analyzed, or otherwise learned. For example, the area of ​​the working electrode and enzyme / sensing layer pot may be larger than the final desired active area of ​​the working electrode until values ​​related to the above-mentioned parameters are determined, understood, analyzed, or otherwise learned, at which point the active area of ​​the working electrode may be trimmed to the desired size or geometry. The trimming method may be one of the laser-based methods described below, e.g., ultraviolet (UV), infrared (IR) laser, or short pulses delivered or provided via a scanner, fixed beam, or ablation mask.

[0060] 5A and 5B respectively illustrate a plan view and a cross-sectional view of an analyte sensor in one aspect of the disclosure. More specifically, FIGS. 5A and 5B show an analyte sensor configuration including at least a sensing layer dimensioned to be as large as or larger than at least a portion of a conductive layer 504 of a working electrode. More specifically, with reference to FIGS. 5A and 5B, a sensor 500 comprises a substrate 502 having a conductive layer 504 that, in one embodiment, extends along at least a portion of the length 502 of the substrate and forms the working electrode of the sensor. The conductive layer 504 can include proximal and distal portions that can be of the same or different sizes and / or shapes, e.g., a sensing layer 504 extending along the length of the substrate 502 and having a width or radial dimension W C 504a terminating in a wider or larger distal portion 504b having a narrow proximal portion 504a.

[0061] In certain embodiments, the conductive layer 504 may be fabricated to have a substantially constant width over its entire length, and may have a wide proximal portion and a narrow distal portion, etc. The distal portion 504b may have any suitable shape, including but not limited to circular (as shown), oval, rectilinear, or other equivalent shapes. Distal portion 504b of the conductive layer 504 has a sensing layer 506 disposed thereon. Again, the sensing layer 506 may have any suitable shape and area dimensions, and may cover a portion or the entire distal portion 504b of conductive material. As shown, the sensing layer 506, in one embodiment, has a substantially identical circular shape as the distal portion 504b, and a width / radius dimension W that is greater than (or at least as large as) the distal portion 504b, such that the periphery extends beyond the outer edge of the distal portion 504b. S The region has the following structure:

[0062] Regardless of the area of ​​the sensing material 506, the active area 510 of the sensor may be determined by the area of ​​the distal conductive portion 504b. Thus, the size of the active area 510 may be varied by varying the area of ​​the distal portion 504b of the conductive layer 504. Depending on the dimensions of the conductive layer 504 of the working electrode, the area of ​​the corresponding sensing layer may vary, but as shown, the sensing layer has an active area at least as large as the area of ​​the corresponding conductive layer 504 that forms the working electrode as described above.

[0063] In a particular embodiment, the sensing layer W S The width / radius of the conductive layer W may range from about 0.05 mm to about 1.0 mm, for example, from about 0.1 mm to about 0.6 mm. C The width / radius of the active region is in the range of about 0.1 mm to about 1.0 mm, for example, about 0.2 mm to about 0.6 mm, and the resulting active region is about 0.0025 mm. 2 ~ approx. 1.0 mm 2 For example, the range is about 0.01 mm. 2 ~about 0.36mm 2 It is.

[0064] 5A and 5B, in one particular embodiment, an insulating / dielectric layer 508 is disposed or laminated onto at least a portion of the proximal portion 504a of the conductive layer 504. Additional conductive and dielectric layers may also be provided.

[0065] 6A and 7A illustrate a top view of the piercing tip or tail of each sensor with a precisely defined active area, and FIGS. 6B and 7B are cross-sectional side views of each sensor taken along line BB of FIGS. 6A and 7A, respectively. With reference to FIGS. 6A and 6B, sensor 600 comprises a substrate 602 having a conductive layer 604 extending along at least a portion of the length of the substrate to form the working electrode of the sensor. Conductive layer 604 may terminate near a distal end 610 of substrate 602, thus providing a "finger" configuration. Alternatively, conductive layer 604a may extend to the distal end 610 of sensor 600 as shown. In one embodiment, working electrode 604 has a width W that is less than the width of substrate 602. C , and extends a selected distance from each of the side edges 612 of the substrate, which may be equal or different distances from each of the side edges 612. Disposed on a portion of the length of the conductive layer 604 is a sensing layer 606 which, as shown in this embodiment, is substantially perpendicular to the length of the conductive layer and provides a continuous strip / band that extends from side edge 612 to side edge 612 of the substrate 602. The sensing layer 606 has a width W S As shown, the active area 614 is defined by the overlapping portion of the working electrode 604 and the sensing layer 606.

[0066] 6A and 6B, in certain embodiments of the present disclosure, the width W of the sensing layer S may be in the range of about 0.05 mm to about 5 mm, for example, about 0.1 mm to about 3 mm, and the width W C may range from about 0.05 mm to about 0.6 mm, for example, from about 0.1 mm to about 0.3 mm, and the resulting active area is about 0.0025 mm 2~about 3mm 2 For example, about 0.01 mm 2 ~ approx. 0.9mm 2 The range is.

[0067] The orthogonal relationship of the sensing layer 606 and the conductive layer 604 results in an intersection or overlap, resulting in an active area 614 having a rectilinear polygonal configuration. However, any suitable shape of active area may be formed or provided within the scope of the present disclosure. The dimensions of the active area 614 may be varied by varying one or both of the respective width dimensions of the sensing and conductive layers. Referring again to the figure, the insulating / dielectric layer 608 is disposed or laminated at least proximate to the conductive layer 604.

[0068] 7A and 7B, in another embodiment, a sensor 700 comprises a substrate 702 having a conductive layer 704 (which in certain embodiments may be the first of several conductive layers, each corresponding to a respective one of the working, counter, and reference electrodes) extending along the length of the substrate and forming the working electrode of the sensor 700. In embodiments of the present disclosure, the conductive layer 704 for each electrode may be provided on the same side of the substrate 702 such that the conductive layers for the working, counter, and reference electrodes are disposed or provided side-by-side on the substrate 702. In one aspect, the conductive layer 704 forming the working electrode extends at least a portion of the length of the substrate 702 and is formed over a width dimension W, which in this embodiment is shown to span the width of the substrate 702. C The distal portion has at least one of:

[0069] A sensing layer 706 is disposed on a portion of the length of the conductive layer 704 at a substantially right angle and providing a continuous strip / band extending from edge 712 to edge 712 of the substrate 702. In one embodiment, the sensing layer 706 is disposed on the conductive layer 704 at a substantially right angle and provides a continuous strip / band extending from edge 712 to edge 712 of the substrate 702. In one embodiment, the sensing layer 706 is disposed on the conductive layer 704 at a substantially right angle and extending from edge 712 to edge 712 of the substrate 702 at a substantially right angle. C (as well as the width of the substrate 702) S, but may be substantially the same as or wider than the working electrode and / or substrate. In certain embodiments, the sensing layer may have a width W S may be in the range of about 0.05 mm to about 5 mm, for example, about 0.1 mm to about 3 mm, and the conductive layer W C The width of the substrate is in the range of about 0.1 mm to about 1 mm, for example, about 0.2 mm to about 0.5 mm, and the resulting active region is about 0.005 mm. 2 ~about 5mm 2 For example, the range is about 0.02 mm. 2 ~about 1.5mm 2 It is.

[0070] Again, as shown, the orthogonal relationship of the sensing layer 706 and the conductive layer 704 results in an intersection or overlap that defines an active area 714 having a rectilinear polygonal configuration, although any suitable shape may be provided within the scope of this disclosure. The dimensions of the active area 714 are, in this case, a measure of the width W of the conductive layer. C The width of the sensing layer W is equal to S and / or by varying the dimensions of the width of the substrate. As further shown, an insulating / dielectric layer 708 may be disposed or laminated at least proximate to the conductive layer 704.

[0071] According to certain embodiments, analyte sensors having precisely defined active areas as described above are reproducibly manufactured. More specifically, one approach involves providing, depositing, printing, or coating a strip / band of sensing elements perpendicular to the length of a conductive layer, where the conductive layer typically functions as the working electrode. This approach may be performed prior to singulating / cutting the sensors from a sheet or web. In particular, if the manufacturing process is web-based, volumes of sensing layer material are provided in a continuous manner (stripping) on ​​adjacent sensors. A "sensing strip" may be provided in such a way that the width dimension of the sensing strip is at least constant across the width of the conductive layer of a single sensor, perpendicular to the width dimension of the conductive material.

[0072] The length of the sensing material may extend beyond one or both ends of the width of the conductive layer. In certain embodiments, the portion of the conductive layer on which the sensing strip is provided may also have a constant width, either extending across the entire width of the sensor's substrate (FIG. 7A) or terminating or receding near one or both side edges of the substrate (FIG. 6A). The length of the conductive layer may extend the entire length of the sensor to the distal end of the sensor's substrate (FIG. 7A) or may terminate at a defined distance proximal to the distal end of the substrate (FIG. 6A), the latter configuration being referred to as a "finger" configuration.

[0073] The intersection pattern of the active area, with both the sensing and conductive layers / strips having a substantially constant width and provided at substantially right angles to one another, is substantially constant along both the length and width of the sensor. In such embodiments, the active area has a rectilinear polygonal shape that may be easier to provide in a reproducible manner from sensor to sensor.

[0074] 8A and 8B show plan and cross-sectional views, respectively, of an analyte sensor in yet another aspect of the disclosure, in which the active area of ​​the sensor is defined by a void or well in a dielectric layer (e.g., coverlay) over a sensor electrode (e.g., working electrode) and filled with a sensing element. Referring to the drawings, in one embodiment, the sensor 800 comprises a substrate 802 having a conductive layer 804 that extends along a portion of the length of the substrate and forms the working electrode of the sensor. The conductive layer 804 extends the majority of the length of the substrate 802 and has a width or radial dimension W C 8B 。 In certain aspects, the conductive layer 804 may have a narrow proximal portion 804a terminating in a wider or larger distal portion 804b having a width of 10 mm. In certain aspects, the conductive layer 804 may have a substantially constant width over its entire length, and may have a wide proximal portion and a narrow distal portion, etc. The distal portion 804b may have any suitable shape, including but not limited to, rectilinear, oval, circular, or other equivalent shape. The conductive layer 804 has a dielectric layer 808 disposed thereon, as shown in FIG. 8B , having a void or well 810 disposed on the distal portion 804b of the conductive layer 804. The dielectric layer 808 is shown overlaying the substrate 802a to a peripheral edge 812, although the outer edge of the dielectric layer 808 may have any suitable boundary. A sensing material 806 is disposed within the void 810 and defines an active area of ​​the sensor. Embodiments may further include a glucose flow limiting layer, an interference layer, a biocompatible layer, etc., that may be disposed at or over the tip of the void 810. For example, an embodiment may include a dielectric layer 808 that is sized to approximate the dimensions of the void / well and is not laminated to other portions of the sensor 800 .

[0075] 8A and 8B, the sidewalls of the sensor cavity / well 810 and the shape of the active area 806 may have any suitable shape, including but not limited to circular (as shown), oval, rectilinear, etc. The area dimensions of the cavity 810 are defined by a radial dimension D VThe dimensions of the active area 806 are determined based on the area of ​​the gap 810 (for a circular gap) and the width and length dimensions (for a linear gap) are selected based on the desired area of ​​the active area 806 of the sensor. Thus, the dimensions of the active area 806 may be varied by varying the area of ​​the gap 810 during the manufacturing process. In addition, the defined and reproducible gap / well 810 in one embodiment shown in Figures 8A and 8B may define the thickness of the glucose limiting membrane of the in vivo sensor. For example, referring again to Figure 3B, in one embodiment, the portion of the coverlay material 118 that is removed to define or expose a predetermined active sensing area on the working electrode 121a may also define the thickness of the glucose limiting membrane that is disposed over the active sensing area 112.

[0076] Although the area of ​​the void 810 is illustrated as being smaller than the area of ​​the distal conductive portion 804b, in certain embodiments it can be as large as the area of ​​the latter. However, in certain embodiments it is not larger than the area of ​​the distal conductive portion. Additionally, although the void 810 / active area 806 is illustrated as being centrally located within the interior area of ​​the distal conductive portion 804b, it is within the scope of the present disclosure that a portion of the void 810 / active area 806 may be offset within the area of ​​the distal conductive portion 804b rather than being centrally located. In certain embodiments, the area of ​​the active area is approximately 0.01 mm 2 ~ approx. 1.0 mm 2 For example, the range is about 0.04 mm. 2 ~about 0.36mm 2 It is.

[0077] 8A and 8B is dependent on the area of ​​the voids 810 in the dielectric material 808, fabrication techniques using dielectric materials support very precise application and precise techniques for applying the dielectric material and providing for the formation of voids therein. For example, photoimageable polymeric materials may be used for dielectric applications that are deposited onto the substrate / conductive material from solution or by roll pressing using a photoimageable film and voids formed therein by photolithography techniques.

[0078] Exact Sensor Dimensions Figures 9A-9C respectively illustrate top, bottom and cross-sectional side views of a double-sided analyte sensor according to one embodiment, where both sides of the dielectric comprise conductive material. With reference to Figures 9A-9C, an embodiment of a double-sided implantable portion of a sensor 900, such as the distal portion of the tail of the sensor, is illustrated. In particular, Figures 9A and 9B provide top and bottom views, respectively, of the tail 900, and Figure 9C provides a cross-sectional side view of the same along line CC of Figure 9A.

[0079] Referring to the drawings, in one embodiment, the sensor tail 900 includes a substrate 902 (FIG. 9C) having a top conductive layer 904a that covers substantially the entire surface area of ​​the top surface of the substrate 902. That is, the conductive layer 904a extends to a distal end 912 and substantially the entire length of the substrate, spanning the entire width of the substrate from side end 914a to side end 914b. Similarly, a bottom conductive layer 904b covers substantially the entire bottom side of the substrate tail 900. As further shown, one or both of the conductive layers may terminate near the distal end 912 and / or have a width that is less than the width of the substrate 902, where said width terminates a selected distance from the substrate side ends 914a, 914b, which may be equidistant or may vary from each of the side ends.

[0080] In one aspect, one of the top or bottom conductive layers, here top conductive layer 904a, may be configured to act as the working electrode of the sensor, while the opposing conductive layer, i.e. bottom conductive layer 904b, may be configured as a reference electrode and / or counter electrode. In certain embodiments, the working electrodes may be disposed on both sides of the sensor to provide a single sensor with two working electrodes. In embodiments having conductive layer 904b configured as a reference electrode or counter electrode, but not both, a third electrode may optionally be provided on a surface region (not shown) of the proximal portion of the sensor. For example, conductive layer 904b may be configured as a reference electrode and a third conductive layer (not shown) present on a non-implantable proximal portion of the sensor may function as a counter electrode of the sensor.

[0081] Referring again to the figure, a sensing element 906 is located at the distal portion of the length of the conductive layer / working electrode 904a. Locating the sensing layer 906 at or near the distal end of the sensor tail reduces the amount of material required since only a small amount of sensing material is required to facilitate oxidation or reduction of the analyte. The sensing layer 906 may be provided in a continuous strip / band between and substantially perpendicular to the side edges 914a, 914b of the substrate with the overlap or intersection of the working electrode 904a and the sensing layer 906 defining the active area of ​​the sensor. Due to the orthogonal relationship of the sensing layer 906 and the conductive layer 904, the active area has a rectilinear polygonal configuration. However, any suitable shape may be provided. The dimensions of the active area 914 may be varied by varying either or both of the dimensions of the width of the sensing and conductive layers, respectively. The width W of the sensing layer 906 may be provided in a range of 100 nm to 150 nm. S The width W of the conductive layer may cover the entire length of the working electrode or only a portion of it. C is affected by the substrate width of the tail in this embodiment, eliminating registration or resolution mismatches between the conductive layer and the substrate. In one particular embodiment, the width W of the sensing layer S is in the range of about 0.05 mm to about 5 mm, for example, in the range of about 0.1 mm to about 3 mm;C is in the range of about 0.05 mm to about 0.6 mm, for example, in the range of about 0.1 mm to about 0.3 mm, and is about 0.0025 mm 2 ~about 3mm 2 For example, about 0.01 mm 2 ~ approx. 0.9mm 2 With a resulting active area in the range of

[0082] Referring again to the electrodes, in certain embodiments, the same materials and methods may be used to fabricate the top and bottom electrodes, although different materials and methods may also be used. In certain embodiments having working and reference electrodes disposed on opposite sides of a substrate, such as the embodiment illustrated in Figures 9A-9C, two or more different types of conductive materials may be used to form each electrode.

[0083] The selection of conductive materials for each electrode is based in part on the desired reaction rate of the mediator of the sensing layer in the sensor electrode. In certain embodiments, the reaction rate of the redox mediator in the counter / reference electrode is controlled by the selection of the material of the counter / reference electrode, which may require, for example, an overpotential or potential higher than the applied potential to increase the reaction rate in the counter / reference electrode. For example, some redox mediators may react faster at a carbon electrode than at a silver / silver chloride (Ag / AgCl) or gold electrode.

[0084] Thus, in certain aspects, the sensor embodiment shown in Figures 9A-9C provides a sensor configuration with substantially full length conductive layers 904a, 904b comprising a material such as titanium, gold carbon or other suitable material, with a secondary layer of conductive layer 910 of a material such as Ag / AgCl disposed on a distal portion of bottom conductive layer 904b to collectively form the sensor's reference electrode. Similar to sensing layer 906, conductive material 910 may be provided in a continuous strip / band between and substantially perpendicular to side edges 914a, 914b of the substrate. Although layer 910 is shown disposed on substrate 902 near sensing layer 906 (but on the opposite side of the substrate), layer 910 may be disposed in any suitable location on tail 900 of reference electrode 904a. For example, as shown in FIGS. 10A-10C, the secondary conductive material 1010 of the reference electrode 1008b may be coincident with and / or distal to the sensing layer 1006.

[0085] Referring again to the figures, insulating / dielectric layers 908a, 908b may be disposed on each side of the sensor 900 over at least the sensor body portion (not shown) to insulate the proximal portion of the electrode, i.e., the portion of the electrode that will remain partially external to the skin during transcutaneous placement. The top dielectric layer 908a disposed over the working electrode 904a may extend distally but not over the sensing layer 906 portion, or in certain embodiments may cover some, but not all, of the sensing layer 906. Alternatively, as shown in Figures 10A-10C, the dielectric layer 1008a on the working electrode side of the sensor may be provided prior to the sensing layer 1006, such that the dielectric layer 1008a has at least two portions spaced apart on the conductive layer 1004a, as best shown in Figure 10C. The sensing material 1006 is then provided in the space between the two portions.

[0086] With respect to the dielectric layer on the bottom / reference electrode of the sensor, it may extend any suitable length into the tail of the sensor, i.e., it may extend the entire length of both the primary and secondary conductive layers or a portion thereof. For example, as shown in FIGS. 10A-10C, the bottom dielectric layer 1008b extends across the entire bottom surface area of ​​the secondary conductive material 1010, but terminates near the distal end 1012 of the length of the primary conductive layer 1004b. It should be noted that at least the ends of the secondary conductive material 1010 extending along the side edge substrate 1002 are initially covered by the dielectric layer 1008b, but after singulation of the sensor, the secondary conductive layer 1010 is exposed along the side edge of the substrate 1002, and thus is exposed to the in vivo environment during operational use. As further shown in FIGS. 10A-10C, the bottom dielectric layer 1008b may have a length that terminates near the secondary conductive layer 1010 in certain embodiments.

[0087] Additionally, one or more membranes may be provided around the sensor as one or more outermost layers, which may function as one or more analyte flux modulating layers and / or interferent-eliminating layers and / or biocompatible layers. In certain embodiments, a first membrane layer 916 may be provided solely on the sensing element 906 of the working electrode 904a, as shown in FIG. 9C, to modulate the diffusion or flux rate of the analyte into the sensing layer. In embodiments where a membrane layer is provided on a single element / material, it may be appropriate to do so using the same strip configuration and method as used for the other materials / elements. Here, the strip / band of membrane material 916 may have a width greater than the width of the sensing strip / band 906.

[0088] Control of the thickness of the membrane 916 is important since it acts to limit the flux of analyte to the active area of ​​the sensor and therefore contributes to sensor sensitivity. That is, the production of reproducible analyte sensors involves a substantially constant membrane thickness. Providing the membrane 916 in the form of a strip / band facilitates thickness control. A second membrane layer 918 covering the remaining surface area of ​​the sensor tail may also be provided to act as a biocompatible conformal coating and provide smooth edges across the sensor. In other embodiments, a single homogenous membrane 1018 may be coated over the entire sensor surface area or at least on both sides of the distal tail, as shown in FIG. 10C. Note that to coat the distal and side ends of the sensor, the membrane material must be subjected to subsequent singulation of the sensor precursor.

[0089] In certain embodiments, highly accurate film coating onto the sensor lots can be achieved in several ways. If the film is applied after the sensor singulation step, the film can be applied, for example, by spray coating or dipping. In the case of dipping, adjustment of the viscosity of the film formulation across the sensor lot is controlled, for example, by lowering the temperature of the dip bath. Alternatively, the sensors can be taken up in a dip bath, where the viscosity can be determined directly, and dipping parameters such as the exit rate can be controlled to account for viscosity changes across the sensor lot, thereby maintaining substantially the same dip thickness despite potential manufacturing process variations of the raw components (e.g., sensor composite).

[0090] In certain embodiments, other detectors or measuring devices or systems may be used to monitor the thickness of the applied film and adjust process parameters to ensure low thickness variability across sensor lots. For example, the detector or measuring device or system may be selected from, for example, laser displacement detectors, confocal laser displacement detectors, including those operating at short wavelengths, capacitance detectors, and other detectors or measuring devices that can measure, detect, or determine the thickness of one or more of the film and / or underlying electrodes, such that adjustments can be made to the sensor lots based on the measured or detected information to maintain low thickness variability and produce minimal or insignificant sensor-to-sensor variation within each sensor lot during manufacturing. In aspects of the present disclosure, the aforementioned measurements or detections of film thickness may be performed for each sensor, and sensors with film thicknesses measured or detected to be outside the thickness tolerance range (as defined or determined based on tolerance criteria for sensor-to-sensor variation) may be discarded during the manufacturing process or tagged or notified as unsuitable for in vivo use.

[0091] Sensor Manufacturing Process - Double-Sided Sensor Improving the precision of the provision of the sensing element on the sensor, and therefore the resulting active area, can significantly reduce sensitivity variability between sensors and largely eliminate the need for sensor calibration during in vivo use. Additionally, the method provides a finished sensor that is smaller than currently available sensors, with micro-sized tails that are highly immune to in situ environmental conditions that can cause erroneous low readings.

[0092] In variations of the subject method, web-based manufacturing techniques are used to perform one or more steps in the fabrication of the subject sensors, many of which are described in U.S. Patent No. 6,103,033, which is incorporated by reference in its entirety for all purposes. To begin the manufacturing process, a continuous film or web of substrate material is provided and optionally heat treated. The web may have pre-slits or perforations that define the individual sensor precursors. Various conductive layers are then formed on the substrate web by one or more of the various techniques described above, with working and reference (or counter / reference) electrode traces provided on both sides of the web.

[0093] Also, as discussed above, a third optional electrode trace (e.g., which may function as a counter electrode) may be provided in the proximal body portion of the sensor precursor. The "first" conductive pathway provided in the tail region of the precursor sensor has a width dimension that is greater than the desired or predetermined width of the tail of the final sensor configuration. The width of the precursor conductive pathway may range from about 0.3 mm to about 10 mm, including widths in the range of about 0.5 mm to about 3 mm, or may be narrower, for example, about 2 mm to about 3 mm. In certain embodiments, the primary conductive layer may be formed extending distally along the tail of the sensor precursor to any suitable length, but preferably extends at least to the intended distal end of the finished sensor to minimize the required sensor tail length.

[0094] Next, the sensing layer and secondary conductive layer, if used, are formed on the primary conductive layer on each side of the substrate or substrate web. As described above, each of these layers may be formed into strips or bands of respective material arranged perpendicular to the length of the primary conductive layer / sensor tail. With a single continuous deposition step, the average width of the sensing strip is substantially constant along the substrate web and ultimately from sensor to sensor. The secondary conductive layer (e.g., Ag / AgCl in the reference electrode), if provided, may be formed into continuous orthogonal strips / bands using similar techniques. One method of providing the various strips / bands of material on the sensor is by deposition, printing or coating of the sensing element / material using inkjet printing techniques (e.g., piezoelectric inkjet manufactured by Scienion Inc. and distributed by BioDot Inc.). Another method of applying these materials is by a precision pump (e.g., piston driven or peristaltic actuation) and / or footed needle, as described in more detail in U.S. patent application Ser. No. 61 / 165,488, entitled "Precise Fluid Dispending Method and Device," the entire disclosure of which is incorporated by reference for all purposes. Each strip / band may be provided on a web of sensor precursors that are aligned in series prior to singulating the sensors, or on a plurality of sensors / electrodes that have been singulated from one another prior to providing one or more strips / bands.

[0095] The active area formed by the intersection of both the sensing and conductive layers / strips having a substantially constant width and provided at substantially right angles to one another is also substantially constant along both the length and width of the sensor. In such embodiments, the active area (as well as the intersection area of ​​the primary and secondary conductive layers forming the reference electrode) has a rectilinear polygonal shape that may be easy to provide in a reproducible manner from sensor to sensor, however, any relative arrangement of layers that results in any suitable active area geometry may be used.

[0096] The sensor precursors, i.e., templates of substrate material (and conductive and sensing materials on the substrate, if provided, when singulated), can be singulated from one another using any convenient cutting or separation procedure, including slitting, shearing, punching, laser singulation, and the like. These cutting methods are also very accurate, further ensuring that the active area of ​​the sensor, which depends to some extent on the width of the sensor (i.e., the substrate tail), has very accurate dimensions between the sensors. Furthermore, with each material (i.e., primary and secondary conductive materials, sensing elements, dielectric materials, films, etc.) provided with width and / or length dimensions that extend beyond the intended dimensions or boundaries of the final sensor unit, problems with resolution and registration of materials are minimized, if not eliminated altogether.

[0097] The final singulated double-sided sensor structure has dimensions in the following ranges: width of about 600 μm to about 100 μm, including widths in the range of about 400 μm to about 150 μm; tail length of about 10 mm to about 3 mm, including lengths in the range of about 6 mm to about 4 mm; and thickness of about 500 μm to about 100 μm, including thicknesses in the range of about 300 μm to about 150 μm. Thus, the implantable portion of the sensor is reduced in width as well as cross-section by about 20% to about 80% over conventional sensors. The reduction in size minimizes bleeding and embolization upon implantation and impaction of the sensor in adjacent tissues and blood vessels, thereby minimizing obstruction to lateral diffusion of analytes to the sensing elements of the sensor.

[0098] Sensor Manufacturing Process As discussed above, at least one factor in minimizing variation in sensor sensitivity within the same batch or lot of sensors (or with all sensors made to the same specifications) can include maintaining the dimensions (such as area, width, length, and / or radius) of the active area from sensor to sensor. Accordingly, aspects of the present disclosure include analyte sensors having precisely defined active areas. This precision is achieved by maintaining substantially identical geometry / shape and dimensions of the sensing layer. In current practice, methods of applying the sensing layer (e.g., by inkjet printing or by high precision pumps and / or footed needles) result in significant variations in the geometry / shape and dimensions of the sensing layer.

[0099] In certain embodiments, methods and processes are provided for fabricating analyte sensors having substantially identical active areas from sensor to sensor. Certain aspects include removing portions of the sensing layer and / or conductive layer to achieve the desired dimensions and surface area of ​​the intended active area. Any suitable subtractive method may be used to remove the desired material. One such method includes using a laser to ablate or trim the desired material.

[0100] Generally, a laser ablation system includes a power supply (e.g., with a pulse generator), a laser medium, and a beam delivery subsystem. The power supply pulse generator, if used, generates a pulsed laser output at a selected pulse repetition rate. The beam delivery subsystem positions the laser pulse relative to the material to be trimmed, and the optical subsystem includes at least one beam deflector for focusing the laser pulse to a spot within the area of ​​the optical subsystem.

[0101] In certain embodiments, a beam delivery system for the fabrication of highly accurate analyte sensors comprises a scanner system (scan head system) with one or more movable mirrors that direct a laser beam delivered to the scanner through a fixed working area. Such a scanner system may comprise a flat field objective lens (fθ lens) that serves to focus the beam on a plane. Alternatively, a fast focusing lens such as VarioScan (ScanLab, Germany) may be used to focus the beam in three-dimensional space. Further configurations may use a scanner that moves in one or more axes connected to a motion platform that moves the part in one or more axes, for example perpendicular to at least one scanner axis. The second axis may operate independently or in a coordinated manner, possible computer numerical control (CNC), where the scanner moves in concert with the motion system to fabricate the part.

[0102] Alternative beam delivery systems include fixed beam delivery systems, where the part typically moves in X, Y and / or theta, while the optical elements remain fixed. In alternative embodiments, the fixed beam system may be configured to move in one or more axes relative to a stage holding the part to be machined, which moves in one or more axes, for example perpendicular to the first axis. Combinations of the above-mentioned fixed beam delivery systems and scanner systems may also be used.

[0103] In yet another embodiment, a mask projection system can be used to remove material through the open areas of the mask. Each laser pulse has a pulse energy, laser wavelength, pulse width, frequency (or repetition rate) and spot radius. These parameters are selected based on the type, density and thickness of the material desired, and the size of the element, area or layer of material to be removed / trimmed. In the sensor manufacturing application of the present invention, the wavelength selected is short enough to produce the desired short wavelength benefits of small spot size, tight tolerance, high absorption, and reduced or eliminated heat affected zone (HAZ) along the course of the trimming.

[0104] In one embodiment, an ultraviolet (UV) laser is used to trim or ablate the excess material. UV lasers used in the manufacturing process include lasers with ultraviolet wavelengths less than 400 nm, such as excimer lasers and diode-pumped solid-state lasers with third and fourth harmonics. In certain embodiments, UV wavelengths in the range of about 10 nm to about 380 nm are used. In certain embodiments, the wavelength of the UV laser used is less than about 355 nm, and more specifically, in the range of about 266 nm to about 355 nm. Due to the use of relatively short wavelengths, the ablation of the target material occurs by a photochemical reaction rather than a thermal reaction. Ablation does not involve substantial heat conduction or thermal shock, and therefore does not cause serious damage, such as cracks, to the ablated material or any underlying layer or substrate material. Thus, this type of ablation is often referred to as "low temperature ablation." Additionally, using low temperature ablation, the ablated surface is substantially free of material redeposition or resolidification.

[0105] In certain embodiments, the concentration is about 100 nanometers (10 -9Lasers having pulse widths shorter than about 10 pico (10 ns) seconds (ns) and repetition rates of about 20 to about 80 kilohertz (KHz) can be used to fabricate these sensors. In one particular embodiment of the invention, laser ablation may be performed using an ultrafast laser. An "ultrafast laser" refers to a laser with a pulse width of about 10 pico (10 ns) seconds (ns) or less. -12 ) seconds (ps), femtoseconds (10 -15 Ultrafast lasers refer to lasers that consist of pulses with durations approaching the fs range. These lasers ablate using a multiphoton mechanism that differs from the single-photon ablation mechanism used by UV lasers. Thus, the requirement of linear optical absorption does not apply to ultrafast lasers, which can use wavelengths ranging from the UV to the near-infrared (IR) spectrum. One example of an industrial ultrafast laser suitable for this purpose is the 1552 nm laser manufactured by Raydiance, Petaluma, California, USA, with a pulse width of 800 fs and a repetition rate of approximately 200 KHz.

[0106] Examples of UV lasers for use in conjunction with the manufacturing process of analyte sensors according to embodiments of the present disclosure include neodymium YAG (Nd:YAG) (1064 nm) lasers such as diode-pumped solid-state lasers, YAG lasers with third or fourth harmonic generation packages, XeF excimer lasers, argon fluoride (ArF) lasers having a wavelength of 193 nm, and fluorine (F2) lasers having a wavelength of 152 nm. Excimer lasers available from Coherent, Inc., Santa Clara, Calif., USA, machined by suppliers such as Photomachining, Inc., Pelham, NH, USA, Tamarack Scientific, Inc., Los Angeles, Calif., USA, Resonetics Corporation, Nashua, NH, USA, and Exitech Limited, Oxford, UK, among others, may be used.

[0107] In a further embodiment, a fiber laser or a diode-pumped solid-state laser having a wavelength of 1064 nm may be used to trim or ablate excess material during the sensor fabrication process.

[0108] The intensity (fluence) of the laser radiation required to trim the material depends on the material to be ablated. By adjusting the laser intensity, it is possible to ablate the entire thickness of the sensing material without ablating the electrode material, or in some cases, it is possible to ablate both the sensing and conductive materials without ablating the substrate. Alternatively, the thickness of the coating may be estimated before ablation, and the laser intensity and / or pulse number can be adjusted to adequately ablate the estimated thickness. In particular, each material has its own laser-induced optical breakdown (LIOB) threshold that characterizes the fluence required to ablate the material at a particular pulse width. The fluence of the laser suitable for the present invention can also be selected according to the layer or layer thickness that is intended for ablation. Furthermore, the number of pulses required to ablate completely through the material can be calculated for a given energy or fluence. In other words, a laser with an appropriate intensity can be used to trim one or more targeted or selected layers without ablating one or more of the underlying layers. For example, a UV laser may be tuned to trim the sensing layer of a sensor without ablating the underlying conductive layer or any intervening layers, if present. Alternatively, by way of further example, the laser may be tuned to trim to a depth or thickness of both the sensing and conductive layers, but below the conductive layer.

[0109] In one embodiment, material is removed from the sensing layer such that the surface area size and / or geometry / shape of the sensing layer matches that of the underlying conductive material of the working electrode. In another embodiment where the dimensions of both the conductive and sensing materials extend beyond the periphery of the intended surface area of ​​the sensor active area, portions of both layers can be ablated / trimmed down to the desired dimensions. Yet another embodiment involves removing only a small portion or wedge of the sensing layer and the lower conductive layer to affect the desired active area. Each of the three exemplary sensors described below is shown first in a pre-ablation or pre-trimming configuration (see FIGS. 11A-11C, 13A-13C, and 15A-15C, respectively) and then in a post-ablation or pre-trimming configuration (see FIGS. 12A-12C, 14A-14C, and 16A-16C, respectively).

[0110] 11A-11C and 12A-12C, the illustrated sensor 1100 comprises a substrate 1102 having a conductive layer 1104 that extends along at least a portion of the length of the substrate and forms the working electrode of the sensor. The conductive layer 1104 extends along most of the length of the substrate 1102 and has a width or radial dimension W A The conductive layer 1104 comprises a narrow proximal portion 1104a that terminates in a wider or larger distal portion 1104b having a width of 0.01 mm. In certain embodiments, the conductive layer 1104 may have a constant width along its entire length, or may have a wider proximal portion and a narrower distal portion. The distal portion 1104b may have any suitable shape, including, but not limited to, circular (as shown), oval, rectilinear, or other suitable shape.

[0111] In this embodiment, only the distal portion 1104b is intended to define the surface area dimension (width / length or radius) of the active area of ​​the sensor, i.e., W Adefines the desired width or radius of the intended active area 1110 (FIGS. 12A-12C). Disposed over the distal portion 1104b of the conductive layer 1104 is the sensing layer 1106. Preferably, the sensing layer 1106 has a shape or has a geometry and surface area that closely or substantially closely equals or matches the geometry and dimensions of the lower conductive layer 1104. This can be verified automatically using a computer-controlled digital camera or by visual inspection with a microscope.

[0112] However, should an excess amount of sensing material 1106 be provided such that its boundary or perimeter extends completely or to some extent beyond the boundary or perimeter of the lower conductive layer 1104, as shown in Figures 11A-11C, the excess material margin 1105 may be trimmed by the laser methods described above to provide the desired shape and dimensions of the active area 1110, as shown in Figures 12A-12C. The sensor 1100 further comprises an insulating or dielectric layer 1108 disposed or laminated on at least a portion of the proximal portion 1104a of the conductive layer 1104. The insulating / dielectric layer 1108, as well as any additional conductive and dielectric layers, are typically provided prior to the laser trimming described above.

[0113] Another sensor fabricated according to the above methods and techniques is illustrated in FIGS. 13A-13C in a pre-ablation configuration, and in FIGS. 14A-14C in a post-ablation configuration. The sensor 1300 comprises a substrate 1302 having a conductive layer 1304 (which may be the first of several conductive layers, one for each sensor electrode) that extends along at least a portion of the length of the substrate to form the working electrode of the sensor. The conductive layer 1304 has a configuration similar to the conductive layer 1104 (FIGS. 11A-11C) described above (and any previously described variations thereof), having a narrow proximal portion 1304a that extends the majority of the length of the substrate 1302 and terminates in a wider or larger distal portion 1304b. However, as shown in FIGS. 13A and 14A, for example, the distal portion 1304b is less than the surface area (W) of the intended active area 1310 of the sensor. A ×LA ) (FIGS. 14A-14C) and, in this embodiment, has a square or rectangular shape.

[0114] A sensing layer 1306 is disposed over the distal portion 1304b of the conductive layer 1304. Unlike the larger, pre-trimmed sensing layer 1106 of FIGS. 11A-11C, the sensing layer 1306 is smaller than the lower conductive layer 1304, but still larger than the desired amount of the intended active area 1310. As such, the dimensions of the sensing layer 1306, as well as the dimensions of the conductive layer 1304b, extend beyond the intended active area 1310. Using the laser techniques of the embodiments of the present disclosure described above, the excess material margin 1305 can be trimmed or ablated to provide the shape and dimensions of the desired active area 1310, as shown in FIGS. 14A-14C. Also shown is an insulating / dielectric layer 1308 disposed or laminated over at least a portion of the proximal portion 1304a of the conductive layer 1304.

[0115] Another sensor fabricated according to the methods and techniques described above is illustrated in Figures 15A-15C in a pre-ablation configuration and in Figures 16A-16C in a post-ablation configuration. As shown, the sensor 1500 comprises a substrate 1502 having a conductive layer 1504 (which may be the first of several conductive layers, one for each sensor electrode) that extends along at least a portion of the length of the substrate and forms the working electrode of the sensor. The conductive layer 1504 has a similar configuration to the conductive layers described above and variations discussed, having a narrow proximal portion 1504a that extends the majority of the length of the substrate 1502 and terminates in a wider or larger distal portion 1504b. Disposed on the distal portion 1504b of the conductive layer 1504 is a sensing layer 1506 that has a similar geometry to the lower conductive layer 1504, but has a smaller surface area than the lower conductive layer 1504. Since the size of the intended active area 1510 (FIGS. 16A-16C) depends on the overlapping surface area of ​​the conductive material 1504 and the sensing material 1506, it may not be important whether the conductive layer extends beyond the perimeter of the sensing layer, or vice versa. Thus, as long as each of the two layers has a surface area at least as large as the intended active area 1510, excess material 1505 of one or both layers may be trimmed or removed to provide a net overlapping surface area and thus the desired active area. In this embodiment, the surface areas of both the conductive layer 1504 and the sensing layer 1506 are larger than the intended surface area of ​​the active area 1510, as shown in FIGS. 16A-16C.

[0116] Using the laser techniques described above, any excess material 1505 of one or both layers may be trimmed or ablated to provide the desired active area 1510 surface area, where the shape of the excess material 1505 to be removed may be any suitable shape to facilitate the trimming method. For example, as shown in FIGS. 15A and 16A, approximately one-quarter of each layer has been trimmed by removing an element or wedge 1505 of the layer. In some embodiments, the excess material to be removed may be exclusively within the perimeter of both layers. If the shape of a particular laser cut is unsuitable, it may be preferable to then laser trim along the shortest necessary path. As with the sensor embodiments described above, an insulating / dielectric layer 1508 has been disposed or laminated over at least a portion of the proximal conductive portion 1504a. Additional conductive and dielectric layers may be provided as described herein.

[0117] In certain embodiments described, the radius or width / length dimension (W A , L A ) ranges from about 0.1 mm to about 1.0 mm, preferably from about 0.2 mm to about 0.6 mm, and the resulting surface area ranges from about 0.05 mm 2 ~about 0.5mm 2 and preferably about 0.08 mm 2 ~about 0.15mm 2 It is.

[0118] As discussed above, in accordance with various embodiments of the present disclosure, the manufacturing processes and procedures described herein provide well-defined active areas and substantially constant membrane dimensions (e.g., thickness) that result in reproducible analyte sensors with minimal sensor-to-sensor sensitivity variation within a sensor lot or batch. Thus, in addition to a substantially stable shelf-life profile, the minimal sensitivity variation results in the elimination of the need for sensor calibration during in vivo use. In certain embodiments, manufactured intra-lot and / or inter-lot sensors may be provided with a coefficient of variation (CV) of about 5% or less, such as about 4.5% or less, such as about 4% or less, such as about 3% or less, with certain embodiments achieving a CV of 1-3%.

[0119] Sensor Packaging An embodiment of the present disclosure comprises packaging the in vivo analyte sensor such that the sensor is substantially immune to environmental influences of the ambient air, particularly humidity, to which the sensor may be exposed prior to in vivo use, i.e., minimizing drift in sensor characteristics and degradation of sensor stability during the sensor's shelf life and eliminating the need for user-based calibration.

[0120] In aspects of the present disclosure, the subject sensors are individually packaged (but may also be packaged in pairs or in bulk at the factory in removable packaging that should not be removed until the enclosed sensor is to be used, i.e., implanted within the user's body). The removable packaging may include one or more elements, parts or materials.

[0121] The packaging comprises a two-element housing structure having a tray and a lid or cover. The tray may have a relatively rigid configuration to protect the sensor during shipping, handling, and storage over the shelf life of the sensor. In one embodiment, the tray has an opening through which the sensor is received and retrieved, and a closed or receptive portion that provides a space or compartment to hold the sensor. In one aspect, the tray has a shape and size that minimizes the unoccupied volume of the package to minimize the amount of air in the package while minimizing the movement of the sensor within the packaging. Furthermore, the tray may be contoured on an inner surface to conform to the shape of the sensor and any other packaged contents and eliminate excess volume within the enclosed package. The tray may also be contoured on an outer surface to conform to other packaging, etc., and may have outwardly extending edges or lips that mate with a corresponding cover or lid.

[0122] In one aspect, the cover or lid for the packaging extends over at least the opening of the tray and provides a substantially airtight seal while the package is unopened. In one variation, the cover is a relatively flexible sheet or the like having an adhesive surface at least around its periphery, which is easily applied to and peeled off an edge or lip extending around the opening of the tray. In another embodiment, the cover is a relatively rigid lid having a substantially planar structure with a periphery configured to provide a tight-fit with the opening of the tray. In particular, the lid can have a contoured periphery with a shape that matches the shape of the opening of the tray to provide a snap-fit ​​closure with the tray. In this embodiment, the same material as used for the tray, such as an injection molded polymer, can be used to form the lid.

[0123] In another embodiment, the package may have a clamshell structure made from either two mating halves or a single element with a hinge, e.g., a living hinge, between the two mating parts. The two halves or parts may be of similar structure, e.g., mirror images of each other, or may have variable shapes, sizes, and / or volumes. The two halves or parts may be relatively rigid and may be held closed by adhesive around their meeting edges or by a snap-fit ​​mating structure.

[0124] In any embodiment, the packaging may be made of a material that prevents or inhibits air and moisture from entering the interior of the housing containing the analyte sensor. Additionally, the packaging, e.g., a tray or one or more package housing portions, may include spaces or compartments for containing desiccant material that helps maintain an appropriate or desired humidity level within the packaging to protect the reagents within the analyte sensor and thereby maintain or extend the shelf life and / or desired use life of the sensor, i.e., the period after the sensor is removed from the packaging material when in use. The desiccant may be in a form that minimizes the overall profile of the sensor packaging and minimizes the risk of contamination of the sensor reagents by the desiccant material.

[0125] Embodiments of the present disclosure also include methods of packaging analyte sensors, either individually or collectively in an array format or set arrangement, comprising providing the sensors within the packaging, Certain methods further include sealing the sensors under dry conditions.

[0126] Even nominal variations in sensitivity between sensors or between sensor lots during the manufacture of a sensor lot, factory calibrated sensors or sensors that do not require factory correction may suffer drift in sensitivity after manufacture due to environmental exposure during the shelf life of the sensor. To minimize the environmental effects, particularly humidity effects, such as ambient air effects, to which the sensors may be exposed prior to use, i.e., during their shelf life, which may be about 6 to about 18 months or more, the subject sensors are individually packaged (but may also be packaged in pairs or in bulk) at the factory in removable sterile packaging that is not removed until the enclosed sensor is to be used, i.e., implanted in the user's body.

[0127] The removable packaging may include one or more housing elements and / or materials. In one embodiment, as shown in Figures 17 and 18, a sensor packaging housing 1700 includes a tray 1702 and a lid or cover 1704 and a desiccant 1706 contained therein. An analyte sensor assembly 1705, including an analyte sensor manufactured according to one or more embodiments described above, is hermetically sealed within the packaging 1700, where the analyte sensor is typically operably attached to a sensor inserter having an optional safety element (e.g., a safety pin) that maintains the sensor within the inserter until removed (e.g., upon initiation of sensor insertion). The present disclosure provides variations of the packaging 1700 and its various elements in addition to those illustrated and discussed herein. Additional information can be found in U.S. patent application Ser. No. 12 / 981,129, filed Feb. 1, 2010, entitled "Analyte Sensor and Apparatus for Insertion of the Sensor," the disclosure of which is incorporated by reference for all purposes.

[0128] In one variation, as shown in Figures 19A-19C, the tray 1702 has a relatively rigid structure to protect the enclosed sensor assembly 1705 (only shown in Figures 17 and 18) during shipping, handling, and storage over the shelf life of the sensor. The tray 1702 has an opening or side 1708 through which the sensor 1705 is received and retrieved, and a closure or housing 1710 that provides receptacles or compartments 1710a, 1710b within which the sensor assembly 1705 and desiccant 1706 are held, respectively. The tray housing 1710 may have a shape and size that minimizes the unoccupied volume of the package (i.e., the space not occupied by the sensor assembly 1705 or the desiccant 1706) to minimize the amount of air within the package 1700. In particular, the housing 1710 may be contoured on an inner surface to conform to the shape of the enclosed sensor assembly 1705 and any other packaged contents, such as the desiccant 1706, to further eliminate excess volume within the enclosed packaging and to minimize movement of the sensor assembly 1705 and desiccant 1706 after being sealed within the packaging. The tray housing 1710 may be contoured on an outer surface for mating engagement or nesting, such as within an outer packaging (not shown). The housing 1710 may be transparent or opaque. The tray 1702 may have an edge or lip 1712 extending radially outward from the closure portion 1710 for engaging with a corresponding cover or lid 1704. A suitable material for achieving these features and purposes of the tray 1702 is an injection molded polymer, such as polypropylene.

[0129] The packaging cover or lid 1704 may cover the opening 1708 of the tray 1702 and provide a substantially airtight seal while the package 1700 is in an unopened sealed condition. In one variation, the cover 1704 may be a relatively flexible sheet or the like having an adhesive surface at least around its periphery, which is easily applied to and peeled off from the edge or lip 1712 around the tray opening 1708. Suitable materials for this cover variation include aluminum foil, polyethylene film, and the like, or a laminated composite of two or more of these materials. In another variation, the cover may be a relatively rigid lid having a substantially planar structure with a periphery configured to provide a tight fit with the tray opening 1708. In particular, the lid may have a contoured periphery with a shape that matches the inner periphery of the tray opening to provide a snap-fit ​​closure with the tray. In this variation, the material used to manufacture the tray may be used to form the lid, such as an injection molded polymer, for example polypropylene.

[0130] In another embodiment (not shown), the package may have at least two relatively rigid elements that fit together in a mating manner. For example, the package may have moveable clamshell structures that are interconnected to each other (opening and closing) via a hinge, e.g., a living hinge. The two halves or portions may be of similar structure, e.g., mirror images of each other, or may have variable shapes, sizes, and / or volumes. The two halves or portions are preferably relatively rigid and may be held closed by adhesive around their contacting edges or by a snap-fitting structure.

[0131] In any embodiment, the analyte sensor packaging may be made of a material that prevents or inhibits moisture and vapor from entering the interior of the enclosure containing the analyte sensor. For example, the moisture vapor transmission rate (MVTR) of the packaging 1700 of Figures 17 and 18 may be about 0.5 mg / day or less, e.g., less than about 0.46 mg / day, given the required dimensions of the tray and lid for a typical size sensor / inserter.

[0132] In addition to maintaining a relatively minimal MVTR, the packaging, e.g., tray 1702 or one or more package housing portions, includes a space or compartment 1710b for containing a desiccant material 1706 that helps maintain an appropriate humidity level within the packaging to protect the reagents within the analyte sensor and thereby maintain or extend the shelf life and / or desired use life of the sensor, i.e., the period after the sensor 1705 is removed from the packaging material. The desiccant 1706 can be in a form and has a volume that minimizes the overall profile of the sensor packaging 1700 and minimizes the risk of contamination of the sensor reagents with the desiccant material. In certain embodiments, as shown in FIGS. 17 and 18, the desiccant material 1706 is present in a single solid form, such as a tablet, block or sheet, e.g., thick paper, etc. In other embodiments (not shown), the desiccant can be in a granular form packaged in a sachet or in the form of a gel-like packet. The single element of desiccant 1706 may be coated with a pharmaceutical grade coating material to prevent the desiccant material from scattering on the sensor assembly 1705. The mass of the desiccant depends on various factors, including but not limited to the MVTR of the package, the moisture of the packaged elements, and the storage temperature and humidity. Desiccants of interest may have an absorptivity of about 17.5% or greater at typical ambient storage conditions, i.e., about 25° C. and about 30% RH, and a safety factor of about 90.0% or greater. Suitable desiccant materials for use with the present invention include, for example, silica gel, calcium sulfate, calcium chloride, and molecular sieves. Examples of such desiccants suitable for packaging with a sensor / inserter assembly include, for example, 2.6 g silica gel tablets and 10 g silica gel packs manufactured by Multisorb Technologies, Inc. (325 Harlem Road, Buffalo, NY 14224, USA).

[0133] The subject dry packaging allows for the provision of implantable analyte sensors that may extend the sensor's shelf life (e.g., about 18 months) and use life (e.g., from about 3 to about 30 days or more, e.g., from 3 days to about 14 days, e.g., from 3 days to about 10 days, e.g., from 3 days to about 7 days) over a period of time that is substantially unaffected by negative environmental effects from the ambient air (substantially typical storage temperature, humidity and atmospheric pressure conditions, i.e., about 25° C., 60% relative humidity and 19.0 mbar). In certain embodiments, the sensor shelf life may be extended up to about 24 months or more, and the sensor use life may be extended from about 3 days to about 14 days or more.

[0134] Due to the protection afforded to the sensor, and particularly to the analyte reagent material of the sensor, by the present packaging structure, the sensitivity of the sensor is subject to only nominal changes and therefore user-based calibration may not be required, i.e., the sensor requires only factory calibration. Furthermore, if sensor lots are reproducible from the outset with sufficiently minimal variation in sensitivity between sensors, sensors packaged with the present packaging may not require calibration or adjustment of sensor characteristics during or after manufacture or during in vivo use.

[0135] The disclosure also includes methods of packaging an implantable analyte sensor for a continuous analyte monitoring system. In one method, the sensor or sensor / inserter assembly is placed in a first packaging element and a second packaging element is sealed to the first packaging element. Sealing may be accomplished by adhesive or heat fusing the two elements. In the tray cover embodiment 1700 of Figures 17 and 18, for example, the sensor assembly (sensor and inserter) 1705 is placed in the tray 1702 along with the desiccant 1706, and then the cover or lid 1704 is hermetically sealed to the tray 1702, for example, by applying heat and pressure around the perimeter 1712 of the tray.

[0136] Sensitivity adjustment using preset channel length FIG. 20A illustrates a top view of a working electrode of an analyte sensor in one embodiment of the present disclosure, and FIGS. 20B and 20C illustrate cross-sectional views of the working electrode of FIG. 20A at lines B and C, respectively. With reference to FIGS. 20A-20C, the working electrode 2000 can include one or more channels 2040. In certain aspects, the channels 2040 are used to define the location and amount of sensing material applied to the working electrode 2000. The length L and number of channels 2040 in the working electrode 2000 can determine the sensitivity of the sensor. In certain embodiments, the channels 2040 are inscribed into a coverlay material 2030 (see FIG. 20B) and applied over the conductive layer 2020 of the working electrode 2000. As discussed, in some embodiments, the conductive layer 2020 may include gold, and the conductive layer 2020 of the working electrode 2000 is formed over at least a portion of the length 2010 of the substrate of the sensor.

[0137] 20A-20C, in certain embodiments, a well 2050 is cut into the coverlay material 2030 (see FIG. 20C) and connected to the channel 2040. The well 2050 can be used for application of a sensing layer such that the sensing layer is placed into the well 2050, and in certain embodiments, the sensing layer fills the channel 2040 by capillary action. After the sensing layer fills the channel 2040 and is then dried, the electrode is cut along line B and the well 2050 is removed, leaving only the channel 2040 filled with the sensing layer. In other embodiments, instead of using the well 2050, the sensing layer may be placed directly on the channel 2040.

[0138] 21A-21D illustrate various stages of application of a sensing layer to the working electrode of FIG. 20A in one embodiment. With reference to FIGS. 21A-21D, one or more channels 2040 (FIG. 20A) and wells 2050 are cut into the coverlay material 2030 of the working electrode 2000 (FIG. 21A). The sensing layer is deposited into the wells 2050, and the channels 2040 are filled with the sensing layer by capillary action, as shown in FIG. 21B. After deposition, in one embodiment, the sensing layer migrates into the channel 2040 and to the edges of the well 2050 and dries annularly around the periphery of the well 2050, as shown in FIG. 21C. As the sensing layer migrates to the edges of the channel 2040, the channel 2040 is configured to narrow in width such that the channel 2040 is narrow enough to cover substantially all of the conductive area of ​​the channel 2040 as the sensing layer dries. As shown in FIG. 21D, the working electrode is then cut and the well 2050 is removed, leaving only the channel 2040 filled with the sensing layer on the working electrode.

[0139] Thus, in certain aspects of the present disclosure, an in vivo analyte sensor may include a channel defining conductive substrate (e.g., using gold) with a sensing layer provided thereon, and techniques for filling the channel and trimming the channel to desired dimensions (e.g., length) to control sensor sensitivity (e.g., by precisely defining the area of ​​the conductive gold substrate that is covered by the sensing layer).

[0140] General Systems and Algorithms In a further aspect, the programming or executable instructions may be provided to or stored in a data processor of the analyte monitoring system, e.g., comprising an electronics assembly and / or a receiver / controller unit, e.g., comprising a data processor, memory elements, communication elements, etc., to provide a time-varying adjustment algorithm to the in vivo sensor during use. That is, in one embodiment, based on retrospective statistical analysis of the analyte sensors used in vivo and feedback of corresponding glucose concentrations, a predefined or analyzed curve or database is generated that is time-based and configured to provide additional adjustments to one or more in vivo sensor parameters to compensate for potential sensor drift, or other factors in the stability profile.

[0141] For example, if in vivo sensor sensitivity declines for a certain period of time measured from initial sensor insertion or transcutaneous placement, sensor sensitivity may approach a steady-state level over a predetermined period of time (e.g., but not limited to, one or two days from initial sensor insertion). Thus, for example, a database such as a look-up table having varying time-based adjustment criteria or factors may be provided or programmed into the data processor of the electronics assembly and / or receiver / controller unit such that for a predetermined post-manufacturing period, such as, for example, about 24 hours to about 36 hours starting from initial in vivo sensor insertion, stored adjustment parameters from the look-up table may be applied to correct for or otherwise compensate for expected sensitivity variations over the initial 24 or 36 hour period (or some other suitable period that may be statistically determined). Thus, in certain embodiments, sensor behavior may be statistically estimated during manufacturing testing and / or characterization of the sensor to generate or determine a sensitivity adjustment schedule for automatic execution by the analyte sensor by the CGM system during in vivo use.

[0142] Figure 22 illustrates an exemplary time-varying sensitivity drift profile for an analyte sensor for use in an analyte monitoring system according to one embodiment of the present disclosure. As shown in Figure 22, a time-varying parameter β(t) is defined or determined based on an analysis of sensor behavior during in vivo use, and a time-varying drift profile is determined as shown in Figure 22, where the defined time-varying parameter β(t) may be coded or programmed with each manufactured sensor and automatically provided to a data processing device of the analyte monitoring system, e.g., a receiving device, for applying the time-varying parameter β(t) to signals obtained from the sensor.

[0143] That is, in one aspect, using a sensor drift profile such as that shown in FIG. 22, for example, an analyte monitoring system may be configured to compensate or adjust the sensor sensitivity based on the sensor drift profile. In certain aspects, the compensation or adjustment to the sensor sensitivity may be programmed into a receiving device or a control device or a data processing device of the analyte monitoring system such that the compensation or adjustment or both is performed automatically and / or recurringly as sensor data is received from the analyte sensor. In alternative embodiments, the adjustment or compensation algorithm may be user initiated or executed (as opposed to self-initiated or self-performing) such that an adjustment or compensation to the analyte sensor sensitivity profile is made or performed upon user initiation or activation of a corresponding function or routine.

[0144] FIG. 23 illustrates the sensitivity variation in response to in vitro testing of 16 analyte sensors from a sensor lot manufactured according to the method described above. More specifically, the 16 analyte sensors were tested under in vitro test conditions (e.g., in a beaker) with solutions of known glucose concentrations to determine the sensor response. With reference to FIG. 23, it is observed that over a period of approximately four hours, each of the 16 sensors exhibited a substantially consistent response or sensitivity to increasing glucose concentrations. That is, each of the 16 sensors from the same manufactured sensor lot responded in a very similar manner to the same known glucose concentration. For example, with reference again to FIG. 23, each step shown in the plot for each of the 16 sensors relates to an increase in glucose concentration (over a period of time shown on the X-axis) and the sensor response to the increase in glucose concentration shown on the Y-axis.

[0145] In other words, with further reference to FIG. 23, it can be seen that each of the 16 sensors tested in a beaker having a known glucose concentration exhibited a nearly identical or very similar response (i.e., current signal generated by each sensor) to the glucose concentration in the beaker solution compared to each other. The results or responses of the 16 sensors tested in a beaker solution based on known glucose concentration levels are shown in FIG. 24. That is, with reference to FIG. 24, it can be seen that the 16 sensors manufactured according to the above method, when tested in vitro as described above, exhibited the response or characteristics shown in FIG. 24, in which the signal response of all 16 sensors to increasing glucose concentration in the beaker solution is substantially consistent. That is, it can be observed from the experimental results that the coefficient of variation of the 16 sensors tested in vitro is less than approximately 5%, and more specifically, approximately 3%. Sensors from the same manufacturing lot as the 16 sensors tested in vitro were further tested or used in vivo in subjects with diabetic conditions, the results of which are described and illustrated below in conjunction with FIG. 25.

[0146] 25 is a Clarke Error Grid based on analyte sensors manufactured according to one or more embodiments of the present disclosure described above. More specifically, data from 24 sensors manufactured according to one or more embodiments described above was obtained based on 12 diabetic subjects who wore each sensor for two 5-day cycles (e.g., a total of about 10 days). It should be noted that the experimental results described herein include a simulated factory calibration by applying one calibration factor or parameter to each of the 24 sensors, and that the calibration factors were determined retrospectively.

[0147] The data obtained from the 24 sensors further shows in the table below that 87.4% of the obtained data points are in Zone A of the Clark Error Grid (clinically accurate) and 11.9% of the obtained data points are in Zone B of the Clark Error Grid (clinically acceptable).

[0148] [Table 1]

[0149] Using a single calibration factor for all sensors in a sensor lot provides approximately 99.3% accuracy, summing zones A and B of the Clark Error Grid. Based on the foregoing and the above results of sensors from a manufacturing lot of sensors, the results from the beaker tests to determine sensor response and in vivo sensor response in diabetic subjects exhibit very similar characteristics, resulting in predictable sensor sensitivity such that the factory correction results in clinically acceptable sensor accuracy. Thus, it can be seen that sensors manufactured according to the above-described embodiments provide minimal or negligible sensitivity variation, eliminating the need for the user to initiate calibration of the sensor during in vivo use in certain embodiments.

[0150] This embodiment also includes determining a normalization curve or slope (or definable functional relationship) based on a selected number of sample sensors in a sensor lot to be manufactured, e.g., 10 sample sensors from a sensor lot of 1,000 or more sensors, or 16 sample sensors from a sensor lot of 1,000 or more sensors, or 25 sample sensors from a sensor lot of 1,000 or more sensors, etc. Using the defined sample size of the sensor lot, characteristics or parameters of each sample sensor from the sensor lot are determined, including, for example, membrane thickness at one or many points, or dimensions of the active sensing area, such as, for example, the surface area, volume, height, length, and / or shape (e.g., concave, convex, flat, sloped, etc., measured at one or many points) of the active area defined on the sensor. Then, in certain embodiments, average values ​​of these properties may be determined, for example, by averaging measurements to determine, for example, the average film thickness of the sample sensors of the sensor lot, the average film thickness at one or more points on the membrane surface, the average surface area of ​​the sensing region, or the average dimensions of the sensing region and / or the average surface area thickness at one or more points on the active region surface. Additionally, in certain embodiments, the coefficient of variation (CV) of these measured or determined parameters or properties from the sample sensors of the sensor lot is also determined. Additionally, the sensitivity of the sample sensors of each sensor lot may also be determined.

[0151] Based on the above-described determination of the sample sensor characteristics, embodiments include comparing the determined characteristics against an accepted value or level of each determined value or characteristic of the sample sensor to determine whether the sample sensor exhibits a characteristic that is within an acceptable standard or range. For example, the average sensitivity of the sample sensors may be compared to a predetermined sensitivity associated with a sensor sensitivity having a coefficient of variation of less than 5%, or less than 3%, etc. If the comparison indicates an acceptable average sensitivity value, the entire sensor lot is accepted and each sensor in the sensor lot is given the average sensitivity value determined based on the sample sensors.

[0152] In certain embodiments, each sensor in the sensor lot (other than the sample sensor) may be non-destructively tested to measure or determine characteristics such as film thickness at one or more points on the sensor, and other characteristics may be measured or determined, including physical characteristics such as surface area / volume of the active area. Such measurements or determinations may be performed automatically, for example, using an optical scanner or other suitable measurement device or system, and the determined sensor characteristics of each sensor in the sensor lot are compared to corresponding average values ​​based on the sample sensors for possible modification of the calibration parameters or codes assigned to each sensor. For example, with a calibration parameter defined as sensor sensitivity, the sensitivity is approximately inversely proportional to the film thickness, so that for a sensor having a measured film thickness approximately 4% greater than the average film thickness of sample sensors from the same sensor lot as the sensor, the sensitivity assigned to that sensor in one embodiment is the average sensitivity determined from the sampled sensors divided by 1.04. Similarly, sensitivity is approximately proportional to the active area of ​​a sensor, so that for a sensor with a measured active area that is approximately 3% lower than the average active area of ​​sampled sensors from the same sensor lot, the assigned sensitivity for that sensor is the average sensitivity multiplied by 0.97. The assigned sensitivity may be determined from the average sensitivity from the sampled sensors by multiple successive adjustments for each test or measurement of the sensor. In certain embodiments, the testing or measurement of each sensor may further include a measurement of the consistency or texture of the film in addition to the film thickness and / or surface area or volume of the active sensing area.

[0153] In certain embodiments, each sensor in a sensor lot may be independently analyzed or tested, measured optically or otherwise, using, for example, an optical or other suitable measurement device or system, to determine characteristics such as, for example, but not limited to, film thickness at one or more locations on the sensor, film consistency and / or texture, size, surface area, volume, and / or dimensions of the active area, including, for example, the geometry of the active area, and each of the measured parameters of each sensor is compared to a predetermined value or range of values ​​stored in a database or storage medium, where the predetermined value or range of values ​​corresponds to a value or range of values ​​considered acceptable such that if the measured value of the sensor corresponds to the predetermined value or range of values, the sensor characteristic is considered to be within an acceptable coefficient of variation (CV), such as, for example, within about 5%, within about 3%, or within about 1%. The sensitivity given to a particular sensor is thus determined without determining the sensitivity using sampling of the lot (i.e., sampling of each sensor in a sensor lot, for example, to determine the sensitivity). Alternatively, the sensitivity determined from these measurements may be confirmed, for example, during manufacturing, as part of a validation procedure, along with the average sensitivity of the sensor lot samples.

[0154] An embodiment further includes a time-varying drift profile configured with a database or look-up table stored in a memory element or storage device or alternatively programmed or programmable into the receiving or transmitting device of the CGM system, with appropriate adjustment or correction values ​​for each time measured from initial sensor insertion, and thereafter, starting from the first in vivo use of the sensor, and corresponding values ​​in the look-up table are retrieved and applied or otherwise included in the sensor sensitivity such that the sensor output data is representative of the glucose concentration being monitored.

[0155] In certain embodiments, the calibration parameters or codes are loaded or programmed into a memory or data processing device of the electronics assembly that is physically connected to the analyte sensor. Programming or loading of the calibration parameters or codes may be accomplished, for example, by serial commands using a wired or wireless connection to one or more COM ports of the electronics assembly. During in vivo use, in one embodiment, the receiver / controller unit is configured to interrogate the electronics assembly and retrieve the calibration parameters or codes that were loaded or programmed into the memory or storage device of the electronics assembly for use in converting the measured raw sensor signal from the analyte sensor to a corresponding glucose value. Alternatively, the sensor electronics may include programming to perform this conversion.

[0156] In certain embodiments where a sensor exhibits drift (e.g., the sensor sensitivity drifts an expected percentage over a certain period of time), a drift profile may be defined by an algorithm of the monitoring system to determine a drift correction factor that may be applied to the sensor signal to obtain a glucose measurement (mg / dL). Due at least in part to the high reproducibility of the manufacturing process resulting in a low manufacturing coefficient of variation (CV), a single drift correction factor may be used for all sensors of a given sensor manufacturing lot or batch.

[0157] Thus, because the sensitivity of each sensor in a given manufacturing lot according to embodiments herein is substantially identical, a factory determined sensitivity or calibration parameter may be provided to all sensors in such lot, i.e., a single calibration algorithm may be used for all sensors in a given lot. In one embodiment, the calibration code or parameter is programmed or programmable into the software of the monitoring system, e.g., into one or more processing devices. For example, the factory determined calibration parameter or code may be provided to the user with the sensor and uploaded into the calibration algorithm manually or automatically (e.g., via a bar code and reader, etc.), or may be pre-stored in a memory or storage device of the analyte monitoring system. Calibration of the sensor signal may be performed using appropriate hardware / software of the system.

[0158] In accordance with various embodiments of the present disclosure, a continuous analyte monitoring system is provided that includes an analyte sensor manufactured in the manner described above that does not require sensor calibration by the user during in vivo use. In certain aspects, the analyte sensor has at least negligible sensor-to-sensor variability and exhibits a highly reproducible and substantially stable sensor profile after manufacture and prior to placement in a user.

[0159] Additionally, embodiments of the analyte sensor of the present disclosure include a predictable sensitivity drift determined during in vivo use to minimize potential in vivo variation, whereby one or more defined algorithms (programmed during manufacture or during use) programmed or programmable in the data processor or receiver of the CGM system of a predetermined sensor drift profile are applied to correct or adjust the CGM system to eliminate the need for user calibration. Such correction or adjustment to the CGM system may include adjustments to the sensor stability profile and one or more feedback algorithms programmed or programmable in the analyte monitoring system to apply correction or adjustment profiles or templates determined a priori or in real time by the CGM system such that the accuracy of the glucose values ​​reported from the sensor during in vivo use is maintained within a clinically acceptable range. Thus, in certain embodiments of the present disclosure, clinically significant inter-person variability in the ratio of interstitial glucose concentration to blood glucose concentration ascertained during in vivo sensor use may be compensated for by one or more feedback algorithms or routines programmed in the CGM system. In one embodiment, one or more feedback algorithms or routines may involve the in vivo sensor responses collected, analyzed and profiled for a particular subject or user, respectively, such that the analyzed and profiled information related to a particular user of the analyte monitoring system is stored in a memory or storage device of the analyte monitoring system, or elsewhere, and used or applied to signals from the in vivo sensor during use.

[0160] Thus, in certain embodiments, an in vivo sensor that does not require user or system based calibration may be provided by minimizing variation in sensor characteristics during or after manufacture, which can be accomplished, for example, by providing a defined and reproducible active area of ​​the sensor, controlling sensor membrane thickness and enzyme stability, and providing a substantially stable post-manufacture environment by adjusting relative humidity to maintain a stable sensor profile during shelf-life, and packaging the construct, for example, to provide storage conditions after manufacture and prior to in vivo use that are substantially unaffected by negative environmental influences.

[0161] In one embodiment, the analyte sensor comprises: substrate, a conductive layer disposed on at least a portion of the substrate; and a sensing layer disposed substantially perpendicularly over at least a distal portion of the conductive layer; where The area of ​​the sensing layer is at least as large as the area of ​​the distal portion of the conductive layer.

[0162] The distal portion of the conductive layer may have a width that is greater than a width of the proximal portion of the conductive layer.

[0163] The distal portion of the conductive layer may terminate near the distal end of the substrate.

[0164] In another embodiment, a method of manufacturing an analyte sensor can include disposing a sensing layer over the entire distal portion of the conductive layer.

[0165] In yet another embodiment, the analyte sensor comprises: substrate, a conductive layer disposed on at least a portion of the substrate; and a sensing layer disposed substantially perpendicularly over at least a portion of said conductive layer; wherein the width of the sensing layer is substantially continuous.

[0166] The sensing layer may include strips or bands of sensing material.

[0167] The conductive layer may extend to a distal end of the substrate.

[0168] The conductive layer may terminate near a distal end of the substrate.

[0169] In one embodiment, there may be substantially no sensitivity variation between sensors.

[0170] In another embodiment, a method of manufacturing an analyte sensor may include disposing the sensing layer in a strip having a substantially constant width.

[0171] In yet another embodiment, a method of manufacturing a plurality of analyte sensors includes: Providing a substrate; disposing a conductive layer on the substrate, the conductive layer forming a plurality of electrodes; disposing the sensing layer in a strip having a substantially constant width over the plurality of electrodes, the strip being substantially perpendicular to each of the plurality of electrodes; Singulating the substrate into a plurality of sensors; Each step may be included.

[0172] In yet another embodiment, the analyte sensor comprises: substrate, a conductive layer disposed on at least a portion of the substrate; a dielectric layer disposed over the conductive layer, the dielectric layer having a void or well therein; and A sensing layer disposed within the gap. It may be equipped with.

[0173] The void may be located in a distal portion of the conductive layer.

[0174] Embodiments include voids or wells having variable dimensions within the defined active area and / or along the distal portion of the sensor. As a non-limiting exemplary example, the voids or wells may be substantially circular shaped with a depth that varies gradually toward the center of the circular shape such that the center of the circular shape is deeper compared to the perimeter of the void, and the depth may be substantially constant or may vary gradually away from the center of the circular shape such that the perimeter of the void or well is relatively deeper compared to the center of the circular shape.

[0175] Embodiments may also include voids or wells having circular, rectangular, triangular, or other geometric shapes as may be suitable. Each such geometric shape may further include variations in one or more dimensions, including the volume, surface area, height of the void or well, depending on the geometry, size, or length of the void.

[0176] In another embodiment, a method of manufacturing an analyte sensor comprises: Providing a substrate; disposing a conductive layer on the substrate; disposing a dielectric layer on the conductive layer, the dielectric layer having an air gap therein; disposing a sensing material within the gap; Each step may be included.

[0177] In yet another embodiment, the analyte sensor comprises: a substrate having an embeddable portion having a length and a width; a first conductive pathway disposed over an entire length and width of a first side of the substrate; a second conductive pathway disposed over the entire length and width of the second side of the substrate; and a sensing material forming a strip disposed over at least a portion of the first conductive pathway defining an active area; where The strips of sensing material are substantially perpendicular to the length of the substrate.

[0178] The substrate may further comprise a non-implantable portion, and the sensor further comprises a third conductive pathway disposed over at least a portion of the non-implantable portion.

[0179] The first conductive pathway may function as a working electrode and the second conductive pathway functions as at least a reference electrode.

[0180] The third conductive pathway may function as a counter electrode.

[0181] Additionally, at least one membrane may be disposed over the sensing material.

[0182] The first membrane may regulate the flux of the analyte to the sensing material.

[0183] The first membrane may be disposed on the sensing material in the form of a strip arranged substantially perpendicular to the length of the embeddable portion of the substrate.

[0184] The second film may provide a conformal coating over at least the implantable portion of the substrate.

[0185] The second conductive pathway may include a primary layer covering an entire surface area of ​​a second side of the embeddable portion of the substrate, and a secondary layer in the form of a strip disposed on at least a portion of the primary layer, where the secondary layer is substantially perpendicular to the length of the substrate.

[0186] The substrate width may range from about 0.05 mm to about 0.6 mm, where the sensing material width ranges from about 0.05 mm to about 5 mm.

[0187] The active area is approximately 0.0025 mm 2 ~about 3mm 2 The range may be:

[0188] Additionally, a dielectric layer may be disposed over at least a portion of the first conductive pathway, but not over at least a top surface of the sensing material.

[0189] A dielectric layer may be provided on the two spaced apart portions, with the sensing material disposed between the spaced apart portions.

[0190] In another embodiment, a method of fabricating an analyte sensor having an active area with a desired surface area defined by an overlapping area of ​​a conductive layer and a sensing layer includes the steps of: disposing a conductive material on a surface of the substrate to form a conductive layer; disposing a sensing material over at least a portion of the conductive layer to form a sensing layer; removing at least a portion of the sensing layer to provide a desired surface area of ​​an active region; Each step may include: The overlap area of ​​the conductive layer and the sensing layer is at least as large as the desired surface area of ​​the active region.

[0191] The sensing layer may overlap the conductive layer at a distal portion of the conductive layer.

[0192] The surface area of ​​the sensing layer can be greater than the surface area of ​​the distal portion of the conductive layer prior to removing at least a portion of the sensing layer.

[0193] The surface area of ​​the distal portion of the conductive layer can be greater than the surface area of ​​the sensing layer prior to removing at least a portion of the sensing layer.

[0194] The surface area of ​​the sensing layer and the surface area of ​​the distal portion of the conductive layer may be substantially equal prior to removing at least a portion of the sensing layer.

[0195] The surface area of ​​the sensing layer and the surface area of ​​the distal portion of the conductive layer may differ from one another after removing at least a portion of the sensing layer.

[0196] The surface area of ​​the sensing layer and the surface area of ​​the distal portion of the conductive layer may be substantially the same after removing at least a portion of the sensing layer.

[0197] The shape of the end of the sensing layer and the shape of the distal portion of the conductive layer may be substantially the same after removing at least a portion of the sensing layer.

[0198] Only portions of the sensing layer may be removed.

[0199] The removed end of the sensing layer may surround the end of the distal portion of the conductive layer.

[0200] Additionally, the method may include removing portions of the conductive layer to provide a desired surface area of ​​the active region.

[0201] The portions of the conductive layer that are removed may surround the edges of the sensing layer.

[0202] The portion of the sensing layer that is removed and the portion of the conductive layer that is removed may overlap.

[0203] The sensing layer portion and the conductive layer portion may be removed simultaneously.

[0204] No calibration of the analyte sensor may be performed during manufacture of the sensor.

[0205] The removal step may include laser trimming.

[0206] The pulsed output of the laser used may include wavelengths in the ultraviolet range.

[0207] The wavelengths can range from about 266 nm to about 355 nm.

[0208] The laser used can be an ultrafast laser.

[0209] The laser used may be a diode-pumped solid-state laser.

[0210] The laser used can be a fiber laser.

[0211] In one embodiment, the manufactured plurality of analyte sensors may not contain substantial sensor-to-sensor sensitivity variation.

[0212] In another embodiment, a method of providing an implantable analyte sensor for use with a continuous analyte monitoring system includes: Perform a batch calibration for the sensor; packaging the batch calibrated sensor in a hermetically sealed enclosure containing a desiccant; Each process can include a process where the enclosure has a relatively low water vapor transmission rate.

[0213] Additionally, the method may further include drying the packaged sensor, wherein the coefficient of variation of sensor sensitivity within a sensor batch is 10% or less.

[0214] The coefficient of variation of sensor sensitivity within a sensor batch can be 5% or less in vitro.

[0215] The coefficient of variation of sensor sensitivity within a sensor batch can be less than 10% in vivo.

[0216] Additionally, the method may include storing the packaged sensor, where conditions inside the package in which the sensor is stored include a RH of about 30% and the desiccant has an absorptive capacity of at least about 17%.

[0217] Ambient conditions for storing the packaged sensor may include about 25° C. and about 30% RH, where the desiccant has a safety factor of at least about 90.0%.

[0218] Embodiments include sensors that have predictable shelf-life sensitivity drift.

[0219] Embodiments include sensors that have substantially no shelf-life sensitivity drift.

[0220] Embodiments include sensors that have predictable in vivo sensitivity drift.

[0221] Embodiments include sensors that have substantially no in vivo drift.

[0222] The embodiment includes a sensor packaging process that includes compartmentalizing the desiccant from the sensor. In another embodiment, a method for providing implantable analyte sensors from the same manufacturing lot for use with a continuous analyte monitoring system includes: The sensor batch is calibrated, where the coefficient of variation in sensitivity between sensors is approximately 5%; each of the batch-calibrated sensors is individually packaged in a hermetically sealed housing containing a desiccant, wherein the housing has a relatively low water vapor transmission rate; Each step may be included.

[0223] An embodiment includes storing the packaged sensor, where the ambient conditions for storing the packaged sensor can include about 25° C. and about 30% RH, and the desiccant can have an absorptive capacity of at least about 17.5%.

[0224] Ambient conditions for storing the packaged sensor may include about 25° C. and about 30% RH, where the desiccant has a safety factor of at least about 90.0%.

[0225] The embodiment includes: substrate, a conductive layer disposed on at least a portion of the substrate; a dielectric layer having an air gap therein disposed on the conductive layer; and an analyte sensor comprising a sensing layer disposed within the gap; wherein: The area of ​​the sensing layer in contact with the conductive layer has a sensor-to-sensor coefficient of variation within a sensor lot of less than approximately 5%.

[0226] Embodiments include a coefficient of variation within a sensor lot of less than approximately 3%.

[0227] An embodiment further includes a membrane disposed on a region of the sensing layer in contact with the conductive layer, wherein the membrane has a specified thickness having an inter-sensor coefficient of variation of less than approximately 5% within a sensor lot.

[0228] An embodiment includes a membrane having a substantially uniform thickness disposed over a region of the sensing layer in contact with the conductive layer.

[0229] An embodiment includes a membrane disposed on an area of ​​the sensing layer in contact with the conductive layer, the membrane having a substantially uniform distribution.

[0230] An embodiment includes a membrane that has low oxygen permeability.

[0231] The embodiment includes a region of the sensing layer in contact with the conductive layer that substantially defines the active area of ​​the sensor.

[0232] The embodiment includes a void located in the distal portion of the conductive layer.

[0233] The embodiment includes a conductive layer in contact with a sensing layer that defines at least a portion of a working electrode of the analyte sensor.

[0234] Embodiments include conductive layers comprising one or more of glassy carbon, graphite, silver, silver chloride, platinum, palladium, platinum iridium, titanium, gold, or iridium.

[0235] An embodiment includes a dielectric layer that includes a photoimageable polymeric material.

[0236] An embodiment includes a conductive layer and a dielectric layer including a photoimageable film disposed on at least a portion of the substrate.

[0237] An embodiment includes an air gap formed by photolithographic techniques.

[0238] The embodiment further includes one or more of a glucose flow limiting layer, an interference layer, or a biocompatible layer disposed in the void.

[0239] In the embodiment, the thickness is about 0.01 mm. 2 ~ approx. 1.0 mm 2 The sensing layer includes an area in contact with the conductive layer, where

[0240] In the embodiment, the thickness is about 0.04 mm. 2 ~about 0.36mm 2 The sensing layer includes an area in contact with the conductive layer, where

[0241] The embodiment includes a surface area of ​​the sensing layer in contact with the conductive layer on the substrate that is substantially constant.

[0242] The embodiment includes dimensions of the voids formed in the dielectric layer that are substantially constant.

[0243] In another embodiment, the analyte sensor comprises: a substrate having a distal portion; a conductive layer disposed on at least a portion of the distal portion of the substrate; a dielectric layer having a void therein disposed on the conductive layer such that the location of the void coincides with a distal portion of the substrate and a sensing layer disposed within the void; wherein: the area of ​​the sensing layer in contact with the conductive layer has a sensor-to-sensor coefficient of variation within a sensor lot of less than approximately 5%; The distal portion of the substrate maintains fluid contact with the interstitial fluid for a predetermined period of time.

[0244] Embodiments include a predetermined period of time of about 3 days or greater.

[0245] The embodiment includes an area of ​​the sensing layer in contact with the conductive layer that defines at least a portion of the working electrode of the analyte sensor that is in fluid contact with the interstitial fluid for a predetermined period of time.

[0246] Embodiments include an analyte sensor further comprising a membrane disposed on a region of the sensing layer in contact with the conductive layer, where the membrane has a specified thickness having an inter-sensor coefficient of variation of less than approximately 5% within a sensor lot.

[0247] An embodiment includes a membrane having a substantially uniform thickness disposed over a region of the sensing layer in contact with the conductive layer.

[0248] An embodiment includes a membrane having a substantially uniform distribution disposed on an area of ​​the sensing layer in contact with the conductive layer.

[0249] An embodiment includes a surface area of ​​the sensing layer in contact with a conductive layer on a substrate that is substantially constant from sensor to sensor in a sensor lot.

[0250] An embodiment includes dimensions of the gaps formed in the dielectric layer that are substantially constant from sensor to sensor in a sensor lot.

[0251] The embodiment further includes one or more of a glucose flow limiting layer, an interference layer, or a biocompatible layer disposed in the void.

[0252] Various other modifications and alterations in the structure and method of operation of the embodiments of the present disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the present disclosure. Although the present disclosure has been described in connection with certain specific embodiments, it should be understood that the present disclosure as set forth in the claims should not be unduly limited to such embodiments, and that the following claims define the scope of the present disclosure, and are therefore intended to cover structures and methods within the scope of the claims and their equivalents.

[0253] The following patents, patent applications, and / or publications are incorporated herein by reference for all purposes: U.S. Patent Nos. 4,545,382; 4,711,245; 5,262,035; 5,262,305; 5,264,104; 5,320,715; 5,509,410; 5,543,326; 5,593,852; 5 , 601,435; 5,628,890; 5,820,551; 5,822,715; 5,899,855; 5,918,603; 6,071,391; No. 6,103,033; No. 6,120,676; No. 6,121,009; No. 6,134,461; No. 6,143,164; No. 6,144,837; No. 6,161,095 ; Same No. 6,175,752; Same No. 6,270,455; Same No. 6,284,478; Same No. 6,299,757; Same No. 6,338,790; Same No. 6,377,894; Same No. 6,461,4 No. 96; No. 6,503,381; No. 6,514,460; No. 6,514,718; No. 6,540,891; No. 6,560,471; No. 6,579,690; No. 6,591 , No. 6,592,745; No. 6,600,997; No. 6,605,200; No. 6,605,201; No. 6,616,819; No. 6,618,934; No. 6,6 50,471; 6,654,625; 6,676,816; 6,676,819; 6,730,200; 6,736,957; 6,746,582;Nos. 6,749,740; 6,764,581; 6,773,671; 6,881,551; 6,893,545; 6,932,892; 6,932,894; 6,942,518; 7,167,818; and 7,299,082; U.S. Patent Application Publication Nos. 2004 / 0186365; 2005 / 0182306; 2007 / 0056858; 2007 / 0068807; 2007 / 0227911; 2007 / 0233013; 2008 Nos. 2008 / 0081977; 2008 / 0161666; and 2009 / 0054748; U.S. patent application nos. 12 / 131,012; 12 / 242,823; 12 / 363,712; 12,698,124; and 12 / 981,129; and U.S. provisional patent application nos. 61 / 149,639; 61 / 155,889; 61 / 155,891; 61 / 155,893; 61 / 165,499; 61 / 230,686; 61 / 227,967 and 61 / 238,461.

Claims

1. substrate; a conductive layer disposed over at least a portion of the substrate; a dielectric layer having an air gap therein disposed on the conductive layer; and A sensing layer disposed within the gap. Equipped with the area of ​​the sensing layer in contact with the conductive layer has a sensor-to-sensor coefficient of variation within a sensor lot of less than approximately 5%. Analyte Sensors.

2. 10. The analyte sensor of claim 1, wherein the coefficient of variation is less than about 3% within a sensor lot.

3. a membrane disposed on a region of the sensing layer in contact with the conductive layer; 10. The analyte sensor of claim 1, wherein the membrane has a specified thickness with an inter-sensor coefficient of variation within a sensor lot of less than about 5%.

4. 4. The analyte sensor of claim 3, wherein the coefficient of variation is less than about 3% within a sensor lot.

5. 4. The analyte sensor of claim 3, wherein the membrane disposed over the area of ​​the sensing layer in contact with the conductive layer has a substantially uniform thickness.

6. 4. The analyte sensor of claim 3, wherein the membrane disposed on the area of ​​the sensing layer in contact with the conductive layer has a substantially uniform distribution.

7. 4. The analyte sensor of claim 3, wherein the membrane has low oxygen permeability.

8. 10. The analyte sensor of claim 1, wherein the area of ​​the sensing layer in contact with the conductive layer substantially defines an active area of ​​the sensor.

9. The analyte sensor of claim 1 , wherein the void is located on a distal portion of the conductive layer.

10. 10. The analyte sensor of claim 1, wherein the conductive layer in contact with the sensing layer defines at least a portion of a working electrode of the analyte sensor.

11. 10. The analyte sensor of claim 1, wherein the conductive layer comprises one or more of glassy carbon, graphite, silver, silver chloride, platinum, palladium, platinum iridium, titanium, gold, or iridium.

12. 10. The analyte sensor of claim 1, wherein the dielectric layer comprises a photoimageable polymeric material.

13. 10. The analyte sensor of claim 1, wherein the dielectric layer comprises a photoimageable film disposed on the conductive layer and on at least a portion of the substrate.

14. 10. The analyte sensor of claim 1, wherein the gap is formed by optical lithography.

15. 10. The analyte sensor of claim 1, further comprising one or more of a glucose flux limiting layer, an interference layer, or a biocompatible layer disposed over the gap.

16. The area of ​​the sensing layer in contact with the conductive layer is about 0.01 mm 2 ~ approx. 1.0 mm 2 2. The analyte sensor of claim 1,

17. The area of ​​the sensing layer in contact with the conductive layer is about 0.04 mm 2 ~Approx. 0.36mm 2 2. The analyte sensor of claim 1,

18. 10. The analyte sensor of claim 1, wherein a surface area of ​​the sensing layer in contact with the conductive layer on the substrate is substantially constant.

19. 2. The analyte sensor of claim 1, wherein the size of the gap formed in the dielectric layer is substantially constant.

20. 1. An analyte sensor comprising: a substrate having a distal portion; a conductive layer disposed over at least a portion of the distal portion of the substrate; a dielectric layer disposed on the conductive layer, the dielectric layer having a void therein, the void being located coincident with a distal portion of the substrate; and a sensing layer disposed within the gap, a region of the sensing layer in contact with the conductive layer comprising a sensing having a sensor-to-sensor coefficient of variation of less than approximately 5% within a sensor lot; the distal portion of the substrate maintains fluid contact with the interstitial fluid for a predetermined period of time; Analyte Sensors.

21. 21. The analyte sensor of claim 20, wherein the predetermined period of time is greater than or equal to about three days.

22. 21. The analyte sensor of claim 20, wherein the area of ​​the sensing layer in contact with the conductive layer defines at least a portion of a working electrode of the analyte sensor that is in fluid contact with the interstitial fluid for a predetermined period of time.

23. the analyte sensor further comprising a membrane disposed on an area of ​​the sensing layer in contact with the conductive layer; 21. The analyte sensor of claim 20, wherein the membrane has a specified thickness having an inter-sensor coefficient of variation within the sensor lot of less than about 5%.

24. 24. The analyte sensor of claim 23, wherein the membrane disposed over the area of ​​the sensing layer in contact with the conductive layer has a substantially uniform thickness.

25. 24. The analyte sensor of claim 23, wherein the membrane disposed on the area of ​​the sensing layer in contact with the conductive layer has a substantially uniform distribution.

26. 21. The analyte sensor of claim 20, wherein a surface area of ​​the sensing layer in contact with the conductive layer on the substrate is substantially constant from sensor to sensor in the sensor lot.

27. 21. The analyte sensor of claim 20, wherein a size of the gap formed in the dielectric layer is substantially constant from sensor to sensor in the sensor lot.

28. 21. The analyte sensor of claim 20, further comprising one or more of a glucose flux limiting layer, an interference layer, or a biocompatible layer disposed over the gap.

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