Fault detection for microneedle array-based continuous analyte monitoring devices

Abstract

To provide fault detection for a microneedle array based continuous analyte monitoring device.SOLUTION: Fault detection and diagnostics for a microneedle array based continuous analyte monitoring device are provided. Electrochemical sensors, including electrodes of the analyte monitoring device configured for measuring one or more target analytes, may experience various faults during use of the analyte monitoring device. By modeling the sensors as an electrical network, measurements of the electrical network may be correlated with operational parameters of the sensor. The voltage at a counter electrode provides an indication of resistance or impedance between a working electrode and a counter electrode and is used to identify an occurrence of faults occurring at the continuous analyte monitoring device.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent No. 63 / 186,086, filed May 8, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates generally to the field of analyte monitoring, such as continuous glucose monitoring. [Background technology]

[0003] Diabetes is a chronic disease in which the body does not produce or properly utilize insulin, a hormone that regulates blood sugar. Insulin can be administered to diabetic patients to help regulate blood sugar levels, but blood sugar levels must nevertheless be carefully monitored to help ensure that timing and dosage are appropriate. Without proper management of their condition, diabetic patients can suffer from a variety of complications resulting from hyperglycemia (high blood sugar levels) or hypoglycemia (low blood sugar levels).

[0004] Blood glucose monitors help diabetic patients manage their condition by measuring blood glucose levels from a sample of blood. For example, a diabetic patient may obtain a blood sample through a finger-prick sampling mechanism, transfer the blood sample to a test strip with a suitable reagent that reacts with the blood sample, and use the blood glucose monitor to analyze the test strip and measure the glucose level in the blood sample. However, patients using this process are typically only able to measure their glucose levels at discrete time points, which may not capture hyperglycemic or hypoglycemic conditions in a timely manner. Another more recent variety of glucose monitor is the continuous glucose monitor (CGM) device, which includes an implantable transcutaneous electrochemical sensor used to continuously detect and quantify blood glucose levels by surrogate measurement of glucose levels in subcutaneous interstitial fluid. However, conventional CGM devices also have weaknesses, including tissue trauma from insertion and signal latency (e.g., due to the time required for the glucose analyte to diffuse from the capillary source to the sensor). These weaknesses also lead to several drawbacks, such as pain experienced by the patient when the electrochemical sensor is inserted and limited accuracy in measuring glucose, especially when blood glucose levels are changing rapidly. Therefore, a need exists for new and improved analyte monitoring systems. Summary of the Invention [Means for solving the problem]

[0005] In some variations, the microneedle array-based analyte monitoring device includes a working electrode, a reference electrode, a counter electrode, an analog front end, and a controller. The working electrode includes an electrochemical sensing coating configured to generate a sensing current indicative of an analyte redox reaction at the working electrode, and the working electrode is positioned on a surface of a distal portion of a first microneedle in the microneedle array. The reference electrode is positioned on a surface of a distal portion of a second microneedle in the microneedle array. The counter electrode is positioned on a surface of a distal portion of a third microneedle in the microneedle array. The analog front end is configured to maintain a fixed potential relationship between the working electrode and the reference electrode and allow the potential of the counter electrode to swing to sustain the redox reaction at the working electrode. The controller is configured to communicate with the analog front end, monitor the counter electrode voltage at the counter electrode, identify a characteristic of the counter electrode voltage that meets or exceeds a threshold, determine a correlation between the counter electrode voltage and the sensed current in response to identifying the characteristic of the counter electrode voltage that exceeds the threshold, and apply an operational mode to the microneedle array-based analyte monitoring device based on the characteristic and correlation of the counter electrode voltage.

[0006] In some variations, a method includes monitoring a counter electrode voltage at a counter electrode of a microneedle array-based analyte monitoring device, the counter electrode being positioned on a surface of a distal portion of a first microneedle in the microneedle array, identifying a characteristic of the counter electrode voltage that meets or exceeds a threshold, determining a correlation between the counter electrode voltage and a sense current in response to identifying the characteristic of the counter electrode voltage that exceeds the threshold, the sense current being generated on the surface of a working electrode of the microneedle array-based analyte monitoring device, and applying an operating mode to the microneedle array-based analyte monitoring device based on the characteristic and correlation of the counter electrode voltage. The working electrode may include an electrochemical sensing coating configured to generate a sense current indicative of an analyte redox reaction at the surface of the working electrode and may be positioned on the surface of a distal portion of a second microneedle in the microneedle array. The microneedle array-based analyte monitoring device may further include a reference electrode positioned on the surface of a distal portion of a third microneedle in the microneedle array, and an analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and allow the potential of the counter electrode to swing to sustain the redox reaction at the working electrode.

[0007] In some variations, the characteristic of the counter electrode voltage includes one or more of a rate of change of the counter electrode voltage or a lower compliance limit of the counter electrode voltage.

[0008] In some variations, the change in counter electrode voltage and the change in sensed current indicate a correlation between the counter electrode voltage and the sensed current.

[0009] In some variations, the operating mode includes ignoring the sensed current if the change in counter electrode voltage matches the change in the sensed current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0010] In some variations, the controller is further configured to discontinue the mode of operation of ignoring the sensed current in response to a subsequent determination that the rate of change of the counter electrode voltage does not exceed the threshold rate of change.

[0011] In some variations, the mode of operation includes discontinuing application of a potential between the working electrode and the reference electrode when the lower compliance limit of the counter electrode voltage meets a threshold compliance limit.

[0012] In some variations, the operating mode includes discontinuing application of the potential between the working electrode and the reference electrode when the change in counter electrode voltage deviates from the change in sensed current and when the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0013] In some variations, the microneedle array-based analyte monitoring device further includes one or more additional working electrodes, each generating a respective sense current, and the controller is further configured to determine a correlation between the counter electrode voltage and the respective sense current in response to identifying a characteristic of the counter electrode voltage that exceeds a threshold.

[0014] In some variations, the mode of operation is further based on a correlation between the counter electrode voltage and the individual sensed current.

[0015] In some variations, the sensed current at the working electrode and the individual sensed currents at one or more additional working electrodes are combined to determine a composite correlation. The present invention provides, for example, the following items. (Item 1) 1. A microneedle array-based analyte monitoring device comprising: a working electrode comprising an electrochemical sensing coating configured to generate a sensing current indicative of an analyte redox reaction at a surface of the working electrode, the working electrode being positioned on a surface of a distal portion of a first microneedle in the microneedle array; a reference electrode positioned on a surface of a distal portion of a second microneedle in the microneedle array; a counter electrode positioned on a surface of a distal portion of a third microneedle in the microneedle array; an analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and to allow the potential of the counter electrode to swing to sustain the redox reaction at the working electrode; a controller in communication with the analog front end; monitoring a counter electrode voltage at the counter electrode; identifying a characteristic of the counter electrode voltage that meets or exceeds a threshold; determining a correlation between the counter electrode voltage and the sensed current in response to identifying a characteristic of the counter electrode voltage that exceeds the threshold; applying an operating mode to the microneedle array-based analyte monitoring device based on the characteristic of the counter electrode voltage and the correlation; a controller configured to: A microneedle array-based analyte monitoring device comprising: (Item 2) Item 10. The microneedle array-based analyte monitoring device of item 1, wherein the characteristic of the counter electrode voltage comprises one or more of the rate of change of the counter electrode voltage or a lower compliance limit of the counter electrode voltage. (Item 3) 3. The microneedle array-based analyte monitoring device of item 2, wherein the change in the counter electrode voltage and the change in the sensed current indicate the correlation between the counter electrode voltage and the sensed current. (Item 4) 4. The microneedle array-based analyte monitoring device of claim 3, wherein the operating mode includes ignoring the sensed current if the change in the counter electrode voltage matches the change in the sensed current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change. (Item 5) 5. The microneedle array-based analyte monitoring device of item 4, wherein the controller is further configured to discontinue the operational mode of ignoring the sensed current in response to a subsequent determination that the rate of change of the counter electrode voltage does not exceed the threshold rate of change. (Item 6) 4. The microneedle array-based analyte monitoring device of claim 3, wherein the operating mode includes discontinuing application of a potential between the working electrode and the reference electrode when the lower compliance limit of the counter electrode voltage meets a threshold compliance limit. (Item 7) 4. The microneedle array-based analyte monitoring device of claim 3, wherein the operating mode includes discontinuing application of a potential between the working electrode and the reference electrode when the change in the counter electrode voltage deviates from the change in the sense current and when the rate of change of the counter electrode voltage exceeds a threshold rate of change. (Item 8) further comprising one or more additional working electrodes, each of the one or more additional working electrodes generating a respective sensing current; The controller further configured, in response to identifying the characteristic of the counter electrode voltage exceeding a threshold, to determine a correlation between the counter electrode voltage and the individual sensed current. Item 1. The microneedle array-based analyte monitoring device of item 1. (Item 9) 9. The microneedle array-based analyte monitoring device of claim 8, wherein the mode of operation is further based on the correlation between the counter electrode voltage and the individual sensed current. (Item 10) 10. The microneedle array-based analyte monitoring device of claim 9, wherein the sensed current at the working electrode and the individual sensed currents at the one or more additional working electrodes are combined to determine a composite correlation. (Item 11) 1. A method comprising: monitoring a counter electrode voltage at a counter electrode of a microneedle array-based analyte monitoring device, the counter electrode being positioned on a surface of a distal portion of a first microneedle in the microneedle array; identifying a characteristic of the counter electrode voltage that meets or exceeds a threshold; determining a correlation between the counter electrode voltage and a sensed current in response to identifying a characteristic of the counter electrode voltage that exceeds the threshold, the sensed current being generated at a working electrode of the microneedle array-based analyte monitoring device; applying an operating mode to the microneedle array-based analyte monitoring device based on the characteristic of the counter electrode voltage and the correlation; Including, the working electrode comprises an electrochemical sensing coating configured to generate the sensing current indicative of an analyte redox reaction at a surface of the working electrode, the working electrode being positioned on a surface of a distal portion of a second microneedle in the microneedle array; The method, wherein the microneedle array-based analyte monitoring device further comprises a reference electrode positioned on a surface of a distal portion of a third microneedle in the microneedle array, and an analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and allow the potential of the counter electrode to swing to sustain the redox reaction at the working electrode. (Item 12) 12. The method of claim 11, wherein the characteristic of the counter electrode voltage comprises at least one of a rate of change of the counter electrode voltage or a lower compliance limit of the counter electrode voltage. (Item 13) 13. The method of claim 12, wherein the change in the counter electrode voltage and the change in the sensed current indicate the correlation between the counter electrode voltage and the sensed current. (Item 14) 14. The method of claim 13, wherein the operating mode includes ignoring the sensed current if the change in the counter electrode voltage matches the change in the sensed current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change. (Item 15) 15. The method of claim 14, wherein the operational mode of ignoring the sensed current is discontinued in response to a subsequent determination that the rate of change of the counter electrode voltage does not exceed the threshold rate of change. (Item 16) 14. The method of claim 13, wherein the operating mode includes discontinuing application of a potential between the working electrode and the reference electrode when the lower compliance limit of the counter electrode voltage meets a threshold compliance limit. (Item 17) 14. The method of claim 13, wherein the operating mode includes discontinuing application of a potential between the working electrode and the reference electrode when the change in the counter electrode voltage deviates from the change in the sense current and when the rate of change of the counter electrode voltage exceeds a threshold rate of change. (Item 18) the microneedle array-based analyte monitoring device further comprising one or more additional working electrodes, each of the one or more additional working electrodes generating a respective sensing current; The method further includes determining a correlation between the counter electrode voltage and the individual sensed current in response to identifying the characteristic of the counter electrode voltage exceeding the threshold. Item 12. The method according to item 11. (Item 19) 20. The method of claim 18, wherein the mode of operation is further based on the correlation between the counter electrode voltage and the individual sensed current. (Item 20) 20. The method of claim 19, wherein the sensed current at the working electrode and the individual sensed currents at the one or more additional working electrodes are combined to determine a composite correlation. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 depicts an illustrative schematic of an analyte monitoring system involving a microneedle array.

[0017] [Figure 2A] FIG. 2A depicts an illustrative schematic diagram of an analyte monitoring device.

[0018] [Figure 2B] FIG. 2B depicts an illustrative schematic of microneedle insertion depth in an analyte monitoring device.

[0019] [Figure 3A] Figure 3A depicts an illustrative schematic diagram of a microneedle array. Figure 3B depicts an illustrative schematic diagram of a microneedle in the microneedle array depicted in Figure 3A. [Figure 3B] Figure 3A depicts an illustrative schematic diagram of a microneedle array. Figure 3B depicts an illustrative schematic diagram of a microneedle in the microneedle array depicted in Figure 3A.

[0020] [Figure 4] FIG. 4 depicts an illustrative schematic of a microneedle array used to sense multiple analytes.

[0021] [Figure 5] Figure 5A depicts a cross-sectional side view of a pillar-shaped microneedle having a tapered distal end. Figures 5B and 5C are images depicting a perspective view and a detailed view, respectively, of the microneedle embodiment shown in Figure 5A.

[0022] [Figure 6-1] 6A-6C depict illustrative schematic diagrams of the layered structures of the working, counter, and reference electrodes, respectively.

[0023] [Figure 6-2] 6D-6F depict illustrative schematic diagrams of the layered structures of the working, counter, and reference electrodes, respectively.

[0024] [Figure 6-3] 6G-6I depict illustrative schematic diagrams of the layered structures of the working, counter, and reference electrodes, respectively.

[0025] [Figure 7] FIG. 7 depicts an illustrative schematic of a microneedle array configuration.

[0026] [Figure 8-1] 8A-8D depict illustrative schematics of microneedle array configurations. [Figure 8-2] 8A-8D depict illustrative schematics of microneedle array configurations.

[0027] [Figure 9-1] 9A-9J depict illustrative schematics of different variations of microneedle array configurations. [Figure 9-2] 9A-9J depict illustrative schematics of different variations of microneedle array configurations. [Figure 9-3]9A-9J depict illustrative schematics of different variations of microneedle array configurations. [Figure 9-4] 9A-9J depict illustrative schematics of different variations of microneedle array configurations.

[0028] [Figure 10] FIG. 10 depicts a representation of the potentiostat circuitry of the analyte monitoring device.

[0029] [Figure 11] FIG. 11 depicts the Randles equivalent circuit, which represents the electrochemical cell of the analyte monitoring device.

[0030] [Figure 12] FIG. 12 depicts the measurement circuitry of the analyte monitoring device.

[0031] [Figure 13A] FIG. 13A is a representation of an electrochemical cell using both Nyquist and Bode plot formation.

[0032] [Figure 13B] FIG. 13B is a representation of the electrochemical cell using Nyquist plot formation.

[0033] [Figure 14] 14-17 are plots of the current and corresponding voltage at the counter electrode, illustrating the fault detection aspects. [Figure 15] 14-17 are plots of the current and corresponding voltage at the counter electrode, illustrating the fault detection aspects. [Figure 16] 14-17 are plots of the current and corresponding voltage at the counter electrode, illustrating the fault detection aspects. [Figure 17] 14-17 are plots of the current and corresponding voltage at the counter electrode, illustrating the fault detection aspects.

[0034] [Figure 18]FIG. 18 depicts an illustrative schematic of an analyte monitoring device. DETAILED DESCRIPTION OF THE INVENTION

[0035] Detailed Description Non-limiting examples of various aspects and variations of the present invention are described herein and illustrated in the accompanying drawings.

[0036] Generally, as described herein, an analyte monitoring system may include an analyte monitoring device worn by a user and including one or more sensors for monitoring at least one analyte of the user. The sensor may include, for example, one or more electrodes configured to perform electrochemical detection of at least one analyte. The analyte monitoring device may communicate sensor data to an external computing device for storage, display, and / or analysis of the sensor data. For example, as shown in FIG. 1 , analyte monitoring system 100 may include analyte monitoring device 110 worn by a user, which may be a continuous analyte monitoring device (e.g., a continuous glucose monitoring device). Analyte monitoring device 110 may include, for example, a microneedle array with at least one electrochemical sensor for detecting and / or measuring one or more analytes in the user's bodily fluid. In some variations, the analyte monitoring device may be applied to the user using a suitable applicator 160 or may be applied manually. The analyte monitoring device 110 may include one or more processors for performing analyses on the sensor data and / or a communications module (e.g., a wireless communications module) configured to communicate the sensor data to the mobile computing device 102 (e.g., a smartphone) or other suitable computing device. In some variations, the mobile computing device 102 may include one or more processors that execute mobile applications to handle the sensor data (e.g., display the data, analyze the data for trends, etc.) and / or provide suitable alerts or other notifications related to the sensor data and / or its analyses.In some variations, the mobile computing device 102 may perform sensor data analysis locally, although it should be understood that other computing devices may alternatively or additionally analyze the sensor data remotely and / or communicate information related to such analysis with the mobile computing device 102 (or other suitable user interface) for display to a user. Further, in some variations, the mobile computing device 102 may be configured to communicate the sensor data and / or analysis of the sensor data to one or more storage devices 106 (e.g., servers) via the network 104 for archiving data and / or other suitable information related to a user of the analyte monitoring device.

[0037] The analyte monitoring devices described herein have characteristics that improve several properties that are advantageous relative to continuous analyte monitoring devices, such as continuous glucose monitoring (CGM) devices. For example, the analyte monitoring devices described herein have improved sensitivity (the amount of sensor signal generated per given concentration of target analyte), improved selectivity (rejection of endogenous and exogenous circulating compounds that may interfere with detection of the target analyte), and improved stability, which helps minimize changes in sensor response over time throughout storage and operation of the analyte monitoring device. In addition, compared to conventional continuous analyte monitoring devices, the analyte monitoring devices described herein have a shorter warm-up time, which enables the sensor to quickly provide a stable sensor signal following implantation, and a shorter response time, which enables the sensor to quickly provide a stable sensor signal following changes in analyte concentration in the user. Furthermore, as described in more detail below, the analyte monitoring devices described herein can be applied to and function at a variety of application sites, providing painless sensor insertion for the user. Other properties such as biocompatibility, sterility, and mechanical integrity are also optimized in the analyte monitoring devices described herein.

[0038] While the analyte monitoring systems described herein may be described with reference to monitoring glucose (e.g., in patients with type 2 diabetes, type 1 diabetes), it should be understood that such systems may be configured to sense and monitor other suitable analytes in addition to, or instead of, detecting other suitable analytes. As described in further detail below, target analytes suitable for detection may include, for example, glucose, ketones, lactate, and cortisol. A single target analyte may be monitored, or multiple target analytes may be monitored simultaneously (e.g., in the same analyte monitoring device). For example, monitoring other target analytes may enable monitoring of other indications such as stress (e.g., through detection of elevated cortisol and glucose) and ketoacidosis (e.g., through detection of elevated ketones).

[0039] As shown in FIG. 2A , in some variations, analyte monitoring device 110 may generally include a housing 112 and a microneedle array 140 extending outward from the housing. Housing 112 may be a wearable housing configured to be worn on a user's skin, such that microneedle array 140 extends at least partially into the user's skin. For example, housing 112 may include an adhesive such that analyte monitoring device 110 is a skin-adhesive patch that is simple and easy to apply to a user. Microneedle array 140 may be configured to include one or more electrochemical sensors (e.g., electrodes) configured to pierce the user's skin and measure one or more target analytes accessible after microneedle array 140 pierces the user's skin. In some variations, analyte monitoring device 110 may be integrated or self-contained as a single unit, which may be disposable (e.g., used for a period of time and replaced with another instance of analyte monitoring device 110).

[0040] Electronics system 120 may include various electronic components, such as sensor circuitry 124, arranged at least in part within housing 112 and configured to perform signal processing (e.g., biasing and readout of electrochemical sensors, converting analog signals from the electrochemical sensors to digital signals, etc.). Electronics system 120 may also include at least one microcontroller 122 for controlling analyte monitoring device 110, at least one communications module 126, at least one power source 130, and / or various other suitable passive circuitry 127. Microcontroller 122 may be configured, for example, to interpret digital signals output from sensor circuitry 124 (e.g., by executing programmed routines in firmware), perform various suitable algorithms or mathematical transformations (e.g., calibration, etc.), and / or route processed data to and / or from communications module 126. In some variations, communications module 126 may include a suitable wireless transceiver (e.g., a Bluetooth transceiver or equivalent) for communicating data with external computing device 102 via one or more antennas 128. For example, communications module 126 may be configured to provide unidirectional and / or bidirectional communication of data with an external computing device 102 paired with analyte monitoring device 110. Power supply 130 may provide power for analyte monitoring device 110, such as for the electronics system. Power supply 130 may include a battery or other suitable source and, in some variations, may be rechargeable and / or replaceable. Passive circuitry 127 may include various parasitic electrical circuitry (e.g., resistors, capacitors, inductors, etc.) that provides interconnections between other electronic components, etc. Passive circuitry 127 may be configured, for example, to perform noise reduction, biasing, and / or other purposes. In some variations, electronic components in electronics system 120 may be arranged on one or more printed circuit boards (PCBs), which may, for example, be rigid, semi-rigid, or flexible.Additional details of electronics system 120 are described further below.

[0041] In some variations, the analyte monitoring device 110 may further include one or more additional sensors 150 to provide additional information that may be relevant to user monitoring. For example, the analyte monitoring device 110 may further include at least one temperature sensor (e.g., a thermistor) configured to measure skin temperature, thereby enabling temperature compensation for sensor measurements obtained by the microneedle array electrochemical sensor.

[0042] In some variations, the microneedle array 140 in the analyte monitoring device 110 may be configured to pierce a user's skin. As shown in FIG. 2B, when the device 110 is worn by a user, the microneedle array 140 may extend into the user's skin such that electrodes on distal regions of the microneedles rest within the dermis. Specifically, in some variations, the microneedles may be designed to penetrate the skin and access the upper dermal regions of the skin (e.g., the papillary dermis and upper reticular dermis) to allow the electrodes to access the interstitial fluid surrounding cells in these layers. For example, in some variations, the microneedles may generally have a height ranging from at least 350 μm to about 515 μm. In some variations, one or more microneedles may extend from the housing such that the distal end of the electrode on the microneedle is located less than about 5 mm from the skin interface contact surface of the housing, less than about 4 mm from the housing, less than about 3 mm from the housing, less than about 2 mm from the housing, or less than about 1 mm from the housing.

[0043] In contrast to conventional continuous analyte monitoring devices (e.g., CGM devices), which typically include sensors implanted about 8 mm to about 10 mm below the skin surface in the subcutaneous or adipose layer of the skin, the analyte monitoring device 110 has a shallower microneedle insertion depth of about 0.25 mm (such that the electrodes are implanted within the upper dermal region of the skin), providing numerous benefits. These benefits include access to dermal interstitial fluid, which contains one or more target analytes for detection, which is advantageous because at least some types of analyte measurements in dermal interstitial fluid have been found to correlate closely with those in blood. For example, glucose measurements performed using electrochemical sensors that access dermal interstitial fluid have been found to advantageously correlate highly linearly with blood glucose measurements. Thus, glucose measurements based on dermal interstitial fluid accurately represent blood glucose measurements.

[0044] Additionally, due to the shallower microneedle insertion depth of the analyte monitoring device 110, a reduced time delay in analyte detection is obtained compared to conventional continuous analyte monitoring devices. Such a shallower insertion depth positions the sensor surface in close proximity (e.g., within a few hundred micrometers or less) to the dense and well-perfused capillary bed of the reticular dermis, resulting in negligible diffusion delay from the capillaries to the sensor surface. The diffusion time is t=x 2The diffusion distance is related to the diffusion time according to ∂t / (2D), where t is the diffusion time, x is the diffusion distance, and D is the mass diffusion coefficient of the analyte of interest. Thus, positioning the analyte sensing element twice as far away from the source of the analyte in the capillaries would result in a diffusion delay time that is four times longer. Thus, conventional analyte sensors residing in the poorly vascularized adipose tissue below the dermis experience significantly longer diffusion distances from the vessels within the dermis, and thus substantial diffusion latencies (e.g., typically 5-20 minutes). In contrast, the shallower microneedle insertion depth of the analyte monitoring device 110 benefits from less diffusion latency from the capillaries to the sensor, thereby reducing the time delay in analyte detection and providing more accurate results in real time or near real time. For example, in some embodiments, the diffusion latency may be less than 10 minutes, less than 5 minutes, or less than 3 minutes.

[0045] Furthermore, when the microneedle array rests within the upper dermal region, the lower dermis beneath the microneedle array contains very high levels of vascularization and perfusion to support dermal metabolism, which allows for thermoregulation (via vasoconstriction and / or vasodilation) and provides a barrier function that helps stabilize the sensing environment around the microneedles. Another advantage of a shallower insertion depth is the lack of pain receptors in the upper dermal layer, thus resulting in reduced pain sensation when the microneedle array pierces the user's skin, providing a more comfortable, minimally invasive user experience.

[0046] Thus, the analyte monitoring devices and methods described herein enable improved continuous monitoring of one or more target analytes in a user. For example, as described above, the analyte monitoring devices can be simple and easy to apply, which improves ease of use and user compliance. In addition, analyte measurement in dermal interstitial fluid can provide highly accurate analyte detection. Furthermore, compared to conventional continuous analyte monitoring devices, insertion of the microneedle array and its sensors can be less invasive and less painful for the patient. Additional benefits of other aspects of the analyte monitoring devices and methods are further described below.

[0047] As shown in the schematic diagram of FIG. 3A, in some variations, a microneedle array 300 for use in sensing one or more analytes may include one or more microneedles 310 extending from a substrate surface 302. The substrate surface 302 may be, for example, generally planar, and the one or more microneedles 310 may extend orthogonally from the planar surface. Generally, as shown in FIG. 3B, the microneedle 310 may include a body portion 312 (e.g., a shaft) and a tapered distal portion 314 configured to pierce a user's skin. In some variations, the tapered distal portion 314 may terminate at an insulated distal apex 316. The microneedle 310 may further include an electrode 320 on the surface of the tapered distal portion. In some variations, electrode-based measurements may be performed at the interface of an electrode located within the body (e.g., on the outer surface of the entire microneedle) and interstitial fluid. In some variations, the microneedles 310 may have a solid core (e.g., a solid body portion), while in some variations, the microneedles 310 may include one or more lumens, which may be used, for example, for drug delivery or sampling of dermal interstitial fluid. Other microneedle variations, such as those described below, may similarly include either a solid core or one or more lumens.

[0048] The microneedle array 300 may be formed, at least in part, from a semiconductor (e.g., silicon) substrate and include various material layers applied and shaped using various suitable microelectromechanical systems (MEMS) fabrication techniques (e.g., deposition and etching techniques), as described further below. The microneedle array may be reflow soldered to a circuit board, similar to a typical integrated circuit. Furthermore, in some variations, the microneedle array 300 may include a three-electrode setup including a working (sensing) electrode having an electrochemical sensing coating (including a biorecognition element such as an enzyme) that enables detection of a target analyte, a reference electrode, and a counter electrode. In other words, the microneedle array 300 may include at least one microneedle 310 including a working electrode, at least one microneedle 310 including a reference electrode, and at least one microneedle 310 including a counter electrode. Additional details of these types of electrodes are described in more detail below.

[0049] In some variations, the microneedle array 300 may include multiple insulated microneedles such that the electrode on each microneedle in the multiple microneedles is individually addressable and electrically isolated from all other electrodes on the microneedle array. The resulting individual addressability of the microneedle array 300 may allow for greater control over the function of each electrode, since each electrode can be probed separately. For example, the microneedle array 300 may be used to provide multiple independent measurements of a given target analyte, improving the sensing reliability and accuracy of the device. Furthermore, in some variations, the electrodes of multiple microneedles may be electrically connected to generate enhanced signal levels. As another example, the same microneedle array 500 may additionally or alternatively be interrogated to simultaneously measure multiple analytes and provide a more comprehensive assessment of physiological status. For example, as shown in the schematic diagram of FIG. 4, a microneedle array may include a portion of microneedles for detecting a first analyte A, a second portion of microneedles for detecting a second analyte B, and a third portion of microneedles for detecting a third analyte C. It should be understood that a microneedle array may be configured to detect any suitable number of analytes (e.g., one, two, three, four, five, or more, etc.). Suitable target analytes for detection may include, for example, glucose, ketones, lactate, and cortisol. Thus, the individual electrical addressability of the microneedle array 300 provides additional control and flexibility over the sensing function of the analyte monitoring device.

[0050] In some variations of microneedles (e.g., microneedles with a working electrode), the electrode 320 may be located proximal to the insulated distal apex 316 of the microneedle. In other words, in some variations, the electrode 320 does not cover the apex of the microneedle. Rather, the electrode 320 may be offset from the apex or tip of the microneedle. An electrode 320 that is proximal to or offset from the insulated distal apex 316 of the microneedle advantageously provides more accurate sensor measurements. For example, this arrangement prevents concentration of the electric field at the microneedle apex 316 during fabrication, thereby avoiding uneven deposition of sensing chemistry on the surface of the electrode 320, which would result in erroneous sensing.

[0051] As another example, placing the electrode 320 offset from the microneedle apex further improves sensing accuracy by reducing undesirable signal artifacts and / or erroneous sensor readings caused by stresses upon microneedle insertion. The distal apex of the microneedle is the first area to penetrate into the skin and therefore experiences most of the stresses caused by the mechanical shearing phenomena associated with tearing or cutting the skin. If the electrode 320 is placed on the apex or tip of the microneedle, this mechanical stress may peel off the electrochemical sensing coating on the electrode surface as the microneedle is inserted and / or transport a small but interfering amount of tissue onto the active sensing portion of the electrode. Therefore, placing the electrode 320 sufficiently offset from the microneedle apex can improve sensing accuracy. For example, in some variations, the distal edge of the electrode 320 may be located at least about 10 μm (e.g., about 20 μm to about 30 μm) from the distal apex or tip of the microneedle, as measured along the longitudinal axis of the microneedle.

[0052] The body portion 312 of the microneedle 310 may further include a conductive pathway extending between the electrode 320 and a back electrode or other electrical contact (e.g., arranged on the back side of the microneedle array substrate). The back electrode may be soldered to a circuit board, allowing electrical communication with the electrode 320 via a conductive pathway. For example, during use, the in vivo sensing current (inside the dermis) measured at the working electrode is interrogated by the back electrical contact, and the electrical connection between the back electrical contact and the working electrode is facilitated by the conductive pathway. In some variations, this conductive pathway may be facilitated by a metal via extending through the interior of the microneedle body portion (e.g., shaft) between the proximal and distal ends of the microneedle. Alternatively, in some variations, the conductive pathway may be provided by forming the entire body portion from a conductive material (e.g., doped silicon). In some of these variations, the entire substrate on which the microneedle array 300 is constructed may be conductive, and each microneedle 310 in the microneedle array 300 may be electrically isolated from adjacent microneedles 310, as described below. For example, in some variations, each microneedle 310 in the microneedle array 300 may be electrically isolated from adjacent microneedles 310 using an insulating barrier comprising an electrically insulating material (e.g., a dielectric material such as silicon dioxide) surrounding the conductive pathway extending between the electrode 320 and the backside electrical contact. For example, the body portion 312 may include an insulating material that forms a sheath around the conductive pathway, thereby preventing electrical communication between the conductive pathway and the substrate. Other exemplary variations of structures that enable electrical isolation between microneedles are described in further detail below.

[0053] Such electrical isolation between microneedles in a microneedle array allows the sensors to be individually addressable. This individual addressability advantageously allows for independent, parallelized measurements between sensors and dynamic reconfiguration of sensor assignments (e.g., to different analytes). In some variations, the electrodes in a microneedle array can be configured to provide redundant analyte measurements, which is an advantage over conventional analyte monitoring devices. For example, redundancy can improve performance by improving accuracy (e.g., averaging multiple analyte measurements for the same analyte, reducing the effect of extremely high or low sensor signals on analyte level determinations) and / or improving the reliability of the device by reducing the likelihood of complete failure.

[0054] In some variations, as described in further detail below with individual different variations of microneedles, the microneedle arrays may be formed, at least in part, using suitable semiconductor and / or MEMS processing techniques and / or mechanical cutting or dicing. Such processes may be advantageous, for example, to enable large-scale, cost-effective manufacture of microneedle arrays.

[0055] In some variations, the microneedle may have a generally cylindrical body portion and a tapered distal portion with an electrode. For example, Figures 5A-5C illustrate an exemplary variation of a microneedle 500 extending from a substrate 502. Figure 5A is a side cross-sectional schematic view of the microneedle 500, while Figure 5B is a perspective view of the microneedle 500, and Figure 5C is a detailed perspective view of the distal portion of the microneedle 500. As shown in Figures 5B and 5C, the microneedle 500 may include a cylindrical body portion 512, a tapered distal portion 514 terminating in an insulated distal apex 516, and a ring electrode 520 comprising a conductive material (e.g., Pt, Ir, Au, Ti, Cr, Ni, etc.) and arranged on the tapered distal portion 514. As shown in Figure 5A, the ring electrode 520 may be proximal to (or offset or spaced from) the distal apex 516. For example, the electrode 520 may be electrically isolated from the distal apex 516 by a distal insulating surface 515a comprising an insulating material (e.g., SiO2). In some variations, the electrode 520 may also be electrically isolated from the columnar body portion 512 by a second distal insulating surface 515b. The electrode 520 may be in electrical communication with a conductive core 540 (e.g., a conductive pathway) that passes along the body portion 512 to a backside electrical contact 530 (e.g., made from a Ni / Au alloy) or other electrical pad in or on the substrate 502. For example, the body portion 512 may include a conductive core material (e.g., highly doped silicon). As shown in FIG. 5A, in some variations, an insulating moat 513 comprising an insulating material (e.g., SiO2) may be arranged around (e.g., around the periphery of) the body portion 512 and extend at least partially through the substrate 502. Thus, insulating moat 513 may help to prevent electrical contact between, for example, conductive core 540 and surrounding substrate 502. Insulating moat 513 may also extend across the surface of body portion 512. The upper and / or lower surfaces of substrate 502 may also include a layer of substrate insulator 504 (e.g., SiO2). Thus, the insulation provided by insulating moat 513 and / or substrate insulator 504 may contribute, at least in part, to electrical isolation of microneedles 500, enabling individual addressability of microneedles 500 within a microneedle array.Additionally, in some variations, insulating moats 513 extending across the surface of body portion 512 may function to increase the mechanical strength of the microneedle 500 structure.

[0056] The microneedle 500 may be formed, at least in part, by suitable MEMS processing techniques such as plasma etching, also known as dry etching. For example, in some variations, the insulating moat 513 around the microneedle body portion 512 may be fabricated by first forming a trench in a silicon substrate by deep reactive ion etching (DRIE) from the backside of the substrate and then filling the trench with a SiO2 / polycrystalline silicon (poly-Si) / SiO2 sandwich by low-pressure chemical vapor deposition (LPCVD) or other suitable process. In other words, the insulating moat 513 passivates the surface of the microneedle body portion 512 and may continue as a buried feature in the substrate 502 near the proximal portion of the microneedle. By comprising a primarily silicon compound, the insulating moat 513 may provide good filling and adhesion to adjacent silicon walls (e.g., of the conductive core 540, substrate 502, etc.). The sandwich structure of insulating moat 513 further helps to provide an excellent coefficient of thermal expansion (CTE) match with the adjacent silicon, which may advantageously reduce defects, cracks, and / or other thermally induced weaknesses in insulating moat 513.

[0057] The tapered distal portion may be shaped by isotropic dry etching from the front side of the substrate, and the body portion 512 of the microneedle 500 may be formed by DRIE. The front metal electrode 520 may be deposited and patterned on the distal portion by specialized lithography (e.g., electron beam evaporation) that allows metal deposition in the desired annular region about the electrode 520 without coating the distal apex 516. Additionally, the Ni / Au backside electrical contact 530 may be deposited by a suitable MEMS fabrication technique (e.g., sputtering).

[0058] The microneedles 500 may have any suitable dimensions. By way of example, in some variations, the microneedles 500 may have a height of about 300 μm to about 500 μm. In some variations, the tapered distal section 514 may have a tip angle of about 60 degrees to about 80 degrees and an apex diameter of about 1 μm to about 15 μm. In some variations, the surface area of ​​the ring electrode 520 may be about 9,000 μm. 2 ~approx. 11,000μm 2 or approximately 10,000 μm 2 may include:

[0059] As described above, each microneedle in the microneedle array may include an electrode. In some variations, multiple distinct types of electrodes may be included between the microneedles in the microneedle array. For example, in some variations, the microneedle array may function as an electrochemical cell capable of operating in an electrolytic mode with three types of electrodes. In other words, the microneedle array may include at least one working electrode, at least one counter electrode, and at least one reference electrode. Thus, the microneedle array may include three distinct electrode types, although one or more of each electrode type may form a complete system (e.g., the system may include multiple distinct working electrodes). Furthermore, multiple distinct microneedles may be electrically joined to form an effective electrode type (e.g., a single working electrode may be formed from two or more connected microneedles with working electrode sites). Each of these electrode types may include a metallization layer and one or more coatings or layers over the metallization layer that help facilitate the function of that electrode.

[0060] Generally, the working electrode is the electrode where the oxidation and / or reduction reaction of interest occurs for the detection of the analyte of interest. The counter electrode functions to source or sink (store) the electrons required to sustain the electrochemical reaction at the working electrode via current. The reference electrode functions to provide a reference potential for the system; i.e., the potential to which the working electrode is biased is referenced to the reference electrode. A fixed, time-varying, or at least controlled potential relationship is established between the working and reference electrodes, and, within practical limits, no current is sourced from or sunk to the reference electrode. In addition, to implement such a three-electrode system, the analyte monitoring device may include a suitable potentiostat or electrochemical analog front end to maintain a fixed potential relationship between the working and reference electrode components in the electrochemical system (via an electronic feedback mechanism) while allowing the counter electrode to dynamically swing to the potential required to sustain the redox reaction of interest.

[0061] working electrode As explained above, the working electrode is the electrode at which the oxidation and / or reduction reaction of interest occurs. In some variations, sensing may be performed at the interface of a working electrode located within the body (e.g., on the outer surface of the entire microneedle) and interstitial fluid. In some variations, the working electrode may include an electrode material and a biorecognition layer in which a biorecognition element (e.g., an enzyme) is immobilized on the working electrode to facilitate selective analyte quantification. In some variations, the biorecognition layer may also function as an interference blocking layer, helping to prevent endogenous and / or exogenous species from directly oxidizing (or reducing) at the electrode.

[0062] The redox current detected at the working electrode can be correlated to the detected concentration of the analyte of interest because, assuming a steady-state diffusion-limited system, the redox current detected at the working electrode obeys the Cottrell relationship: [ka] where n is the stoichiometric number of electrons mitigating the redox reaction, F is Faraday's constant, A is the electrode surface area, D is the diffusion coefficient of the analyte of interest, C is the concentration of the analyte of interest, and t is the duration the system is biased with a potential. Thus, the current detected at the working electrode is linearly proportional to the analyte concentration.

[0063] Furthermore, because the detected current is a direct function of the electrode surface area A, the surface area of ​​the electrode may be increased to enhance the sensitivity of the sensor (e.g., amperes per mole of analyte). For example, multiple single working electrodes may be grouped into arrays of two or more components to increase the total effective sensing surface area. Additionally or alternatively, to obtain redundancy, multiple working electrodes may be operated as paralleled sensors to obtain multiple independent measurements of the concentration of an analyte of interest. The working electrode can be operated either as an anode (so that the analyte is oxidized at its surface) or as a cathode (so that the analyte is reduced at its surface).

[0064] FIG. 6A depicts a schematic diagram of an exemplary set of layers for a working electrode 610. For example, as described above, in some variations, the working electrode 610 may include an electrode material 612 and a biorecognition layer including a biorecognition element. The electrode material 612 functions to facilitate electrocatalytic detection of an analyte or a product of a reaction between the analyte and the biorecognition element. The electrode material 612 also provides ohmic contact and routes an electrical signal from the electrocatalytic reaction to processing circuitry. In some variations, the electrode material 612 may include platinum, as shown in FIG. 6A. However, the electrode material 612 may alternatively include, for example, palladium, iridium, rhodium, gold, ruthenium, titanium, nickel, carbon, doped diamond, or other suitable catalytic and inert materials.

[0065] In some variations, the electrode material 612 may be coated with a highly porous electrocatalytic layer, such as a platinum black layer 613, which may increase the electrode surface area for enhanced sensitivity. Additionally or alternatively, the platinum black layer 613 may enable electrocatalytic oxidation or reduction of the product of the biorecognition reaction facilitated by the biorecognition layer 614. However, in some variations, the platinum black layer 613 may be omitted (e.g., as shown in Figures 6D and 6G). The electrode may enable electrocatalytic oxidation or reduction of the product of the biorecognition reaction in the absence of the platinum black layer 613.

[0066] A biorecognition layer 614 may be disposed over the electrode material 612 (or platinum-black layer 613, if present) and serves to immobilize and stabilize the biorecognition element, which facilitates selective analyte quantification over extended periods of time. In some variations, the biorecognition element may include an enzyme such as an oxidase. As an exemplary variation for use in a glucose monitoring system, the biorecognition element may include glucose oxidase, which, in the presence of oxygen, converts glucose to an electroactive product (i.e., hydrogen peroxide) that can be detected at the electrode surface. Specifically, the redox equation associated with this exemplary variation is glucose + oxygen → hydrogen peroxide + gluconolactone (mediated by glucose oxidase), hydrogen peroxide → water + oxygen (mediated by applying an oxidizing potential at the working electrode).

[0067] However, in other variations, the biorecognition element may additionally or alternatively comprise another suitable oxidase or oxidoreductase, such as lactate oxidase, alcohol oxidase, β-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbate oxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, urate oxidase, urease, and / or xanthine oxidase.

[0068] In some variations, the biorecognition elements may be crosslinked with amine-condensed carbonyl species, which may help stabilize the biorecognition elements in the biorecognition layer 614. As described further below, in some variations, crosslinking the biorecognition elements may render the microneedle array compatible with ethylene oxide (EO) sterilization, allowing the entire analyte monitoring device (including the sensing elements and electronics) to be subjected to the same sterilization cycle, thereby simplifying the sterilization process and reducing manufacturing costs. For example, the biorecognition elements may be crosslinked with glutaraldehyde, formaldehyde, glyoxal, malonaldehyde, succinaldehyde, and / or other suitable species. In some variations, the biorecognition elements may be crosslinked with such amine-condensed carbonyl species to form crosslinked biorecognition element assemblies. Crosslinked biorecognition element assemblies having at least a threshold molecular weight may then be embedded in a conducting polymer. By embedding only those assemblies having a threshold molecular weight, any uncrosslinked enzymes are screened out and cannot be incorporated into the biorecognition layer. Thus, only assemblies having the desired molecular weight can be selected for use in the conducting polymer, helping to ensure that only sufficiently stabilized cross-linked enzyme entities are included within the biorecognition layer, thereby contributing to a biorecognition layer that is overall more suitable for EO sterilization without loss of sensing performance. In some variations, only cross-linked assemblies having a molecular weight that is at least twice that of glucose oxidase may be embedded in the conducting polymer.

[0069] In some variations, the conducting polymer may be permselective to contribute to the robustness of the biorecognition layer against circulating androgynous electroactive species (e.g., ascorbic acid, vitamin C, etc.), fluctuations of which can adversely affect sensor sensitivity. Such permselective conducting polymers in the biorecognition layer may also be more robust against pharmacological interferences in interstitial fluid (e.g., acetaminophen), which can affect sensor accuracy. Conducting polymers can be made permselective, for example, by removing excess charge carriers through an oxidative electropolymerization process or by neutralizing these charge carriers using a counterion dopant, thereby converting the conducting polymer to a non-conducting form. These oxidatively polymerized conducting polymers exhibit permselectivity and are therefore capable of rejecting ions of a charge polarity (net positive or negative) similar to that of the dopant ion or rejecting ions via size exclusion due to the conducting polymer's dense and compact morphology.

[0070] Furthermore, in some variations, the conducting polymer may exhibit self-sealing and / or self-healing properties. For example, the conducting polymer may undergo oxidative electropolymerization, during which the conducting polymer may lose its conductivity as the thickness of the deposited conducting polymer on the electrode increases until the lack of sufficient conductivity reduces the deposition of additional conducting polymer. In the event that the conducting polymer suffers minor physical damage (e.g., during use), the polymer backbone may reassemble and neutralize free charges, thereby lowering the overall surface energy of the molecular structure, which may manifest as self-sealing and / or self-healing properties.

[0071] In some variations, the working electrode may further include a diffusion-limiting layer 1615 disposed over the biorecognition layer 614. The diffusion-limiting layer 615 may function to limit the flux of the analyte of interest to reduce the sensor's sensitivity to endogenous oxygen fluctuations. For example, the diffusion-limiting layer 615 may attenuate the concentration of the analyte of interest so that it becomes the limiting reactant for an aerobic enzyme. However, in some variations (e.g., if the biorecognition element is not aerobic), the diffusion-limiting layer 615 may be omitted.

[0072] The working electrode may further include a hydrophilic layer 616 in some variations to provide a biocompatible interface, e.g., to reduce foreign body response. However, in some variations, the hydrophilic layer 616 may be omitted (e.g., when the diffusion-limiting layer represents the hydrophilic portion for this purpose), as shown, for example, in Figures 6D and 6G.

[0073] Counter electrode As explained above, the counter electrode is the electrode that sources or sinks the electrons (via current) required to sustain the electrochemical reaction at the working electrode. The number of counter electrode components can be increased in the form of a counter electrode array to increase the surface area so that the current-carrying capacity of the counter electrode does not limit the redox reaction at the working electrode. Therefore, it may be desirable to have excess counter electrode area relative to the working electrode area to avoid current-carrying capacity limitations. When the working electrode is operated as an anode, the counter electrode will serve as a cathode, and vice versa. Similarly, when an oxidation reaction occurs at the working electrode, a reduction reaction occurs at the counter electrode, and vice versa. Unlike the working electrode or reference electrode, the counter electrode is allowed to dynamically swing to the potential required to sustain the redox reaction of interest on the working electrode.

[0074] 6B, counter electrode 620 may include an electrode material 622 similar to electrode material 612. For example, like electrode material 612, electrode material 622 in counter electrode 620 may include a precious metal such as gold, platinum, palladium, iridium, carbon, doped diamond, and / or other suitable catalytic and inert materials.

[0075] In some variations, the counter electrode 620 may have little or no additional layer over the electrode material 632. However, in some variations, the counter electrode 620 may benefit from an increased surface area to increase the amount of current it can support. For example, the counter electrode material 632 may be textured or otherwise roughened in a manner that increases the surface area of ​​the electrode material 632 for enhanced current sourcing or sinking capabilities. Additionally or alternatively, the counter electrode 620 may include a layer of platinum black 624, which may increase the electrode area, as described above with respect to some variations of the working electrode. However, in some variations of the counter electrode, the layer of platinum black may be omitted (e.g., as shown in FIG. 6E). In some variations, the counter electrode may further include a hydrophilic layer that provides a biocompatible interface, e.g., to reduce foreign body response.

[0076] Additionally or alternatively, in some variations, such as that shown in Figure 6H, the counter electrode 620 may include a diffusion-limiting layer 625 (arranged across the electrode). The diffusion-limiting layer 625 may be similar to the diffusion-limiting layer 615 described above with respect to Figure 6A, for example.

[0077] reference electrode As explained above, the reference electrode functions to provide a reference potential for the system, i.e., the potential to which the working electrode is biased is referenced to the reference electrode. A fixed, or at least controlled, potential relationship may be established between the working and reference electrodes, and, within practical limits, no current is sourced from or sunk to the reference electrode.

[0078] As shown in FIG. 6C , the reference electrode 630 may include an electrode material 632 similar to the electrode material 612. In some variations, like the electrode material 612, the electrode material 632 in the reference electrode 630 may include a metal salt or metal oxide, which serves as a stable redox couple with a known electrode potential. For example, the metal salt may include silver-silver chloride (Ag / AgCl), and the metal oxide may include iridium oxide (IrOx / Ir2O3 / IrO2). In other variations, noble and inert metal surfaces may function as quasi-reference electrodes and include gold, platinum, palladium, iridium, carbon, doped diamond, and / or other suitable catalytic and inert materials. Furthermore, in some variations, the reference electrode 630 may be textured or otherwise roughened in a manner to enhance adhesion with any subsequent layers. Such subsequent layers on the electrode material 632 may include a platinum-black layer 634. However, in some variations, the platinum black layer may be omitted (eg, as shown in Figures 6F and 6I).

[0079] The reference electrode 630 may further include, in some variations, a redox couple layer 636, which primarily contains a surface-immobilized solid-state redox couple with a stable thermodynamic potential. For example, the reference electrode may operate at a stable standard thermodynamic potential relative to the standard hydrogen electrode (SHE). High stability of the electrode potential may be achieved by employing a redox system with a constant (e.g., buffered or saturated) concentration of each participant in the redox reaction. For example, the reference electrode may include saturated Ag / AgCl (E = +0.197 V vs. SHE) or IrOx (E = +0.177 V vs. SHE, pH = 7.00) in the redox couple layer 636. Other examples of the redox couple layer 636 may include a suitable conducting polymer with dopant molecules, such as those described in U.S. Patent Publication No. 2019 / 0309433 (herein incorporated by reference in its entirety). In some variations, the reference electrode may be used as a half-cell to construct a complete electrochemical cell.

[0080] Additionally or alternatively, in some variations, such as that shown in Figure 6I, the reference electrode 630 may include a diffusion-limiting layer 635 (e.g., arranged across the electrode and / or redox pair layer). The diffusion-limiting layer 635 may be similar to the diffusion-limiting layer 615 described above with respect to Figure 16A, for example.

[0081] Exemplary Electrode Layer Formation The various layers of working, counter, and reference electrodes may be applied and / or functionalized, etc. to the microneedle array using suitable processes such as those described below.

[0082] In a pretreatment step for the microneedle array, the microneedle array may be plasma cleaned in an inert gas (e.g., an RF-generated inert gas such as argon) plasma environment to render the surfaces of materials, including the electrode materials (e.g., electrode materials 612, 622, and 632 as described above), more hydrophilic and chemically reactive. This pretreatment not only physically removes organic debris and contaminants, but also serves to clean and prepare the electrode surfaces to enhance adhesion of films subsequently deposited thereon.

[0083] Multiple microneedles (e.g., any of the microneedle variations described herein, each of which may have a working electrode, a counter electrode, or a reference electrode as described above) may be arranged in a microneedle array. Considerations for how to configure the microneedles include factors such as the desired insertion force for penetrating the skin with the microneedle array, optimization of electrode signal levels and other performance aspects, and manufacturing cost and complexity.

[0084] For example, a microneedle array may include multiple microneedles spaced apart at a predetermined pitch (the distance between the center of one microneedle and the center of its nearest neighboring microneedle). In some variations, the microneedles may be spaced apart with sufficient pitch to distribute the force applied to a user's skin to cause the microneedle array to penetrate the skin (e.g., avoid a "bed of needles" effect). As the pitch increases, the force required to insert the microneedle array tends to decrease and the depth of penetration tends to increase. However, it has been found that the pitch begins to affect the insertion force only at low values ​​(e.g., less than about 150 μm). Thus, in some variations, the microneedles in the microneedle array may have a pitch of at least 200 μm, at least 300 μm, at least 400 μm, at least 500 μm, at least 600 μm, at least 700 μm, or at least 750 μm. For example, the pitch may be about 200 μm to about 800 μm, about 300 μm to about 700 μm, or about 400 μm to about 600 μm. In some variations, the microneedles may be arranged in a periodic grid, and the pitch may be uniform in all directions and across all regions of the microneedle array. Alternatively, the pitch may vary as measured along different axes (e.g., X, Y directions), and / or some regions of the microneedle array may include a smaller pitch while others include a larger pitch.

[0085] Additionally, for more consistent penetration, the microneedles may be spaced equal distances from one another (e.g., the same pitch in all directions). To that end, in some variations, the microneedles in the microneedle array may be arranged in a hexagonal configuration as shown in Figure 7. Alternatively, the microneedles in the microneedle array may be arranged in a rectangular array (e.g., a square array) or in another suitable symmetrical manner.

[0086] Another consideration for determining the configuration of a microneedle array is the overall signal level provided by the microneedles. Generally, the signal level at each microneedle is invariant to the total number of microneedle elements in the array. However, the signal level can be enhanced by electrically interconnecting multiple microneedles together in an array. For example, an array with a large number of electrically connected microneedles is expected to generate a signal strength (and therefore increased accuracy) greater than one with fewer microneedles. However, a larger number of microneedles on a die will increase the die cost (assuming a constant pitch) and require more force and / or speed to insert into the skin. In contrast, a smaller number of microneedles on a die may reduce die cost and enable insertion into the skin with reduced applied force and / or speed. Furthermore, in some variations, a smaller number of microneedles on a die may reduce the overall footprint of the die, which may lead to less unwanted localized edema and / or erythema. Thus, in some variations, a balance between these factors may be achieved using a microneedle array containing 37 microneedles as shown in Figure 7 or a microneedle array containing 7 microneedles as shown in Figures 8A and 8C. However, in other variations, there may be fewer microneedles in the array (e.g., about 5 to about 35, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 100, about 10 to about 30, about 15 to about 25, etc.) or more microneedles in the array (e.g., more than 37, more than 40, more than 45, etc.).

[0087] Additionally, as described in more detail below, in some variations, only a subset of the microneedles in the microneedle array may be active during operation of the analyte monitoring device. For example, some of the microneedles in the microneedle array may be inactive (e.g., no signal is read from the electrodes of the inactive microneedles). In some variations, some of the microneedles in the microneedle array may be activated at some point during operation and remain active for the remainder of the operational life of the device. Furthermore, in some variations, some of the microneedles in the microneedle array may additionally or alternatively be deactivated at some point during operation and remain inactive for the remainder of the operational life of the device.

[0088] When considering die characteristics for a microneedle array, die size is a function of the number of microneedles in the microneedle array and the pitch of the microneedles. Manufacturing cost is also a consideration, as a smaller die size will increase the number of dies that can be formed from a single wafer of a given area, contributing to lower costs. Furthermore, a smaller die size will also be less susceptible to brittle fracture due to the relative fragility of the substrate.

[0089] Furthermore, in some variations, microneedles at the periphery of the microneedle array (e.g., near the edge or boundary of the die, near the edge or boundary of the housing, near the edge or boundary of an adhesive layer on the housing, along the outer edge of the microneedle array, etc.) may be found to have better performance (e.g., sensitivity) due to better penetration compared to microneedles at the center of the microneedle array or die. Thus, in some variations, the working electrode may be arranged mostly or entirely on microneedles located at the periphery of the microneedle array to obtain more accurate and / or precise analyte measurements.

[0090] 7 depicts an illustrative schematic of 37 microneedles arranged in an exemplary variation of a microneedle array. The 37 microneedles may be arranged in a hexagonal array, for example, with a center-to-center pitch between the needles of about 750 μm (or about 700 μm to about 800 μm, or about 725 μm to about 775 μm) between the center of each microneedle and the center of its immediate neighbor in any direction.

[0091] 8A and 8B depict perspective views of an illustrative schematic of seven microneedles 810 arranged in an exemplary variation of microneedle array 800. The seven microneedles 810 are arranged in a hexagonal array on a substrate 802. As shown in FIG. 8A, electrodes 820 are arranged on distal portions of the microneedles 810 extending from a first surface of the substrate 802. As shown in FIG. 8B, proximal portions of the microneedles 810 are conductively connected to individual backside electrical contacts 830 on a second surface of the substrate 802 opposite the first surface of the substrate 802. FIGS. 8C and 8D depict top and side views of an illustrative schematic of a microneedle array similar to microneedle array 800. As shown in FIGS. 8C and 8D, the seven microneedles are arranged in a hexagonal array with a center-to-center pitch between each microneedle and the center of its immediate neighbor in any direction of approximately 750 μm. In other variations, the center-to-center pitch between needles may be, for example, about 700 μm to about 800 μm or about 725 μm to about 775 μm. The microneedles may have an approximate outer shaft diameter of about 170 μm (or about 150 μm to about 190 μm or about 125 μm to about 200 μm) and a height of about 500 μm (or about 475 μm to about 525 μm or about 450 μm to about 550 μm).

[0092] Additionally, the microneedle arrays described herein may have a high degree of configurability regarding where the working, counter, and reference electrodes are located within the microneedle array, and this configurability may be facilitated by the electronics system.

[0093] In some variations, the microneedle array includes electrodes distributed symmetrically or asymmetrically into two or more groups in the microneedle array, with each group featuring the same or different numbers of electrode components, depending on requirements for signal sensitivity and / or redundancy. For example, the same type of electrodes (e.g., working electrodes) may be distributed bilaterally or in a radially symmetric manner in the microneedle array. For example, FIG. 9A depicts a variation of a microneedle array 900A including two symmetric groups of seven working electrodes (WE), the two working electrode groups being labeled "1" and "2." In this variation, the two working electrode groups are distributed bilaterally and symmetrically within the microneedle array. The working electrodes are generally arranged between a central region of three reference electrodes (RE) and an outer peripheral region of 20 counter electrodes (CE). In some variations, each of the two working electrode groups may include seven working electrodes electrically connected among themselves (e.g., to enhance the sensor signal). Alternatively, only a portion of one or both of the working electrode populations may include multiple electrodes that are electrically connected among themselves. As yet another alternative, the working electrode populations may include working electrodes that are stand-alone and not electrically connected to other working electrodes. Furthermore, in some variations, the working electrodes may be distributed in the microneedle array in an asymmetric or random configuration.

[0094] As another example, Figure 9B depicts a variation of a microneedle array 900B that includes four symmetric groups of three working electrodes (WE), labeled "1," "2," "3," and "4." In this variation, the four working electrode groups are distributed in a radially symmetric manner in the microneedle array. Each working electrode group is adjacent to one of two reference electrodes (RE) in the microneedle array, arranged in a symmetric manner. The microneedle array also includes counter electrodes (CE) arranged around the periphery of the microneedle array, except for the two electrodes at the vertices of the hexagon, which may be inactive or used for other features or modes of operation.

[0095] In some variations, only a portion of the microneedle array may include active electrodes. For example, Figure 9C depicts a variation of a microneedle array 900C with 37 microneedles and a reduced number of active electrodes, including four working electrodes (labeled "1," "2," "3," and "4") in a bilaterally symmetrical arrangement, 22 counter electrodes, and three reference electrodes. The remaining eight electrodes in the microneedle array are inactive. In the microneedle array shown in Figure 9C, each working electrode is surrounded by a group of counter electrodes. The two groups of such clusters of working and counter electrodes are separated by a row of three reference electrodes.

[0096] As another example, Figure 9D depicts a variation of microneedle array 900D with 37 microneedles and a reduced number of active electrodes, including four working electrodes (labeled "1," "2," "3," and "4") in a bilaterally symmetrical arrangement, 20 counter electrodes, and three reference electrodes; the remaining 10 electrodes in the microneedle array are inactive.

[0097] As another example, Figure 9E depicts a variation of a microneedle array 900E with 37 microneedles and a reduced number of active electrodes, including four working electrodes (labeled "1," "2," "3," and "4"), 18 counter electrodes, and two reference electrodes. The remaining 13 electrodes in the microneedle array are inactive. The inactive electrodes are along a partial perimeter of the entire microneedle array, thereby reducing the effective size and shape of the active microneedle array to a smaller hexagonal array. Within the active microneedle array, the four working electrodes are generally arranged in a radially symmetrical fashion, with each working electrode surrounded by a group of counter electrodes.

[0098] Figure 9F depicts another exemplary variation of a microneedle array 900F with 37 microneedles and a reduced number of active electrodes, including four working electrodes (labeled "1," "2," "3," and "4"), two counter electrodes, and one reference electrode. The remaining 30 electrodes in the microneedle array are inactive. The inactive electrodes are arranged in two layers around the periphery of the entire microneedle array, thereby reducing the effective size and shape of the active microneedle array to a smaller hexagonal array centered around the reference electrode. Within the active microneedle array, the four working electrodes are arranged bilaterally symmetrically, and the counter electrodes are equidistant from the central reference electrode.

[0099] Figure 9G depicts another exemplary variation of a microneedle array 900G with 37 microneedles and a reduced number of active electrodes. The active electrodes in microneedle array 900G are arranged in a manner similar to that in microneedle array 900F shown in Figure 9F, except that microneedle array 900G includes one counter electrode and two reference electrodes, and the smaller hexagonal array of active microneedles is centered around the counter electrode. Within the active microneedle array, the four working electrodes are arranged bilaterally symmetrically, and the reference electrode is equidistant from the central counter electrode.

[0100] Figure 9H depicts another exemplary variation of a microneedle array 900H with seven microneedles. The microneedle array contains two microneedles (1 and 2) assigned as independent working electrodes, a counter electrode configuration consisting of four microneedles, and a single reference electrode. There is bilateral symmetry in the arrangement of working and counter electrodes, which are equidistant from the central reference electrode. In addition, the working electrodes are arranged as far away from the center of the microneedle array as possible (e.g., on the periphery of the die or array) to take advantage of locations where the working electrodes are expected to have greater sensitivity and overall performance.

[0101] Figure 9I depicts another exemplary variation of a microneedle array 900I with seven microneedles. The microneedle array contains four microneedles (1 and 2), each assigned as two independent groups of two working electrodes, a counter electrode configuration consisting of two microneedles, and a single reference electrode. There is bilateral symmetry in the arrangement of the working and counter electrodes, which are equidistant from the central reference electrode. In addition, the working electrodes are arranged as far away from the center of the microneedle array as possible (e.g., on the periphery of the die or array) to take advantage of locations where the working electrodes are expected to have greater sensitivity and overall performance.

[0102] Figure 9J depicts another exemplary variation of a microneedle array 900J with seven microneedles. The microneedle array contains four microneedles (1, 2, 3, and 4) assigned as independent working electrodes, a counter electrode configuration consisting of two microneedles, and a single reference electrode. There is bilateral symmetry in the arrangement of working and counter electrodes, which are equidistant from the central reference electrode. In addition, the working electrodes are arranged as far away from the center of the microneedle array as possible (e.g., on the periphery of the die or array) to take advantage of locations where the working electrodes are expected to have greater sensitivity and overall performance.

[0103] While Figures 9A-9J illustrate exemplary variations of microneedle array configurations, it should be understood that these figures are not limiting and that other microneedle configurations (including different numbers and / or distributions of working, counter, and reference electrodes, and different numbers and / or distributions of active and inert electrodes, etc.) may be suitable in other variations of microneedle arrays.

[0104] Analog Front End In some variations, the electronics system of the analyte monitoring device may include an analog front end. The analog front end may include sensor circuitry (e.g., sensor circuitry 124 as shown in FIG. 2A) that converts analog current measurements into digital values ​​that can be processed by a microcontroller. The analog front end may include a programmable analog front end, suitable for use with, for example, electrochemical sensors. For example, the analog front end may include MAX30131, MAX30132, or MAX30134 components (having one, two, and four channels, respectively) available from Maxim Integrated (San Jose, CA), which are ultra-low power programmable analog front ends for use with electrochemical sensors. The analog front end may also include MAX30131, MAX30132, or MAX30134 components (having one, two, and four channels, respectively) available from Analog Devices (Norwood, MA), which are high-precision, impedance, and electrochemical front ends. The analog front end may include AD5940 or AD5941 components available from Texas Instruments (Dallas, TX). Similarly, the analog front end may also include the LMP91000, available from Texas Instruments (Dallas, TX), a configurable analog front-end potentiostat for low-power chemical sensing applications. The analog front end may provide a complete measurement path, including bias and an analog-to-digital converter (ADC). Ultra-low power may enable continuous biasing of the sensor to maintain accuracy and fast response when measurements are required over long durations (e.g., 7 days) using a body-worn, battery-operated device.

[0105] In some variations, the analog front-end device may be compatible with both two- and three-terminal electrochemical sensors, such as to enable both DC and AC current measurements and electrochemical impedance spectroscopy (EIS) measurement capabilities. Additionally, the analog front-end may include an internal temperature sensor and programmable voltage reference, support external temperature monitoring and external reference sources, and integrate voltage monitoring of bias and supply voltages for safety and compliance.

[0106] In some variations, the analog front end may include a multi-channel potentiostat to multiplex sensor inputs and handle multiple signal channels. For example, the analog front end may include a multi-channel potentiostat such as that described in U.S. Pat. No. 9,933,387, which is incorporated herein by reference in its entirety.

[0107] In some variations, the analog front end and peripheral electronics may be integrated into an application specific integrated circuit (ASIC), which may help to reduce costs, for example. This integrated solution may, in some variations, include a microcontroller, as described below.

[0108] Microcontroller In some variations, the electronics system of the analyte monitoring device may include at least one microcontroller (e.g., controller 122 as shown in FIG. 2A). The microcontroller may include, for example, a processor with integrated flash memory. In some variations, the microcontroller in the analyte monitoring device may be configured to perform analyses and correlate sensor signals to analyte measurements (e.g., glucose measurements). For example, the microcontroller may execute programmed routines in firmware, interpret digital signals (e.g., from the analog front end), perform any associated algorithms and / or other analyses, and route processed data to and / or from a communications module. Keeping the analyses onboard the analyte monitoring device may, for example, enable the analyte monitoring device to broadcast analyte measurements to multiple devices in parallel (e.g., mobile computing devices such as smartphones or smartwatches, therapy delivery systems such as insulin pens or pumps, etc.), while ensuring that each connected device has identical information.

[0109] In some variations, the microcontroller may be configured to activate and / or deactivate the analyte monitoring device in response to one or more detected conditions. For example, the device may be configured to power on the analyte monitoring device in response to insertion of the microneedle array into the skin. This may enable a power-saving feature, for example, where the battery is disconnected until the microneedle array is placed within the skin, at which point the device may begin broadcasting sensor data. Such a feature may help, for example, to improve the shelf life of the analyte monitoring device and / or simplify the analyte monitoring device-external device pairing process for the user.

[0110] Aspects of the current subject matter are directed to fault detection, and diagnostics related to fault detection, in microneedle array-based analyte monitoring devices, such as analyte monitoring device 110. Electrochemical sensors (e.g., electrodes of analyte monitoring device 110) configured to measure one or more target analytes can experience various faults during use of analyte monitoring device 110. A fault can be a failure of one or more aspects of analyte monitoring device 110, where the fault affects the operation of analyte monitoring device 110. Examples of faults include electrode membrane degradation (e.g., cracking, delamination, and / or other damage to the membrane structure and / or surface that affects sensing), biorecognition element degradation (e.g., inactivation and / or denaturation), physiological response to microneedle array implantation (e.g., foreign body response, insolubilization, protein adhesion, or collagen formation in response to insertion of the microneedles on which electrodes are formed), improper placement or insertion of the microneedle array (e.g., the microneedles on which electrodes are formed are not placed deep enough for analyte sensing), pressure decay (e.g., pressure applied to the analyte monitoring device 110), and external environmental influences (e.g., external influences on the electronics of the analyte monitoring device 110). Faults can affect the electrical and / or electrochemical behavior of the analyte monitoring device 110, resulting in errors and / or unreliability in the measurement of a target analyte or analytes. In some cases, the fault may be temporary, such as in the case of pressure decay. In other cases, the fault may permanently affect the operation of the analyte monitoring device 110.

[0111] Some disturbances may be detectable by monitoring the current draw. For example, the value of the sensed current at the working electrode of the analyte monitoring device 110 may indicate and / or correlate to some disturbances. In these cases, if the sensed current exhibits extreme, erratic, and / or unexpected behavior or patterns, the disturbance may be determinable based on the characteristics of the sensed current behavior or pattern exhibited. The extreme, erratic, and / or unexpected behavior or patterns of the sensed current may be characterized by a rapid rate of change that is or may be unphysiological. High noise may also contribute to the sensed current behavior or pattern.

[0112] However, other faults, while not affecting the sensed current, may still affect the electrical and / or electrochemical behavior of the analyte monitoring device 110. Therefore, alternative or additional variables are needed for insight into and verification of changes to the electrical and / or electrochemical behavior of the analyte monitoring device 110. The voltage at the counter electrode is an example of a variable that provides such insight and verification. Thus, by monitoring the voltage at the counter electrode, faults can be detected.

[0113] While various types of faults, such as those described above, can occur, a fault can generally be characterized by whether the analyte monitoring device 110 is able to recover from the fault (e.g., the fault is temporary) or whether the analyte monitoring device 110 is damaged (e.g., the fault is permanent) and should be taken out of operation. By monitoring the counter electrode voltage, and in some variations, by monitoring how the counter electrode voltage matches or correlates with the sensed current, such characterization can be performed and a response to the fault can be determined. The response to the fault can be in the form of an operational mode for operating the analyte monitoring device. For example, if the fault is temporary, the operational mode may include blanking and / or ignoring any sensed data during the fault. In this situation, the sensed data will be inaccurate and therefore not reported to the user or used for operational purposes. If the fault is permanent, the operational mode may be to pause operation of the analyte monitoring device. In some variations, this may include ceasing application of a bias potential between the working and reference electrodes.

[0114] In some variations, the counter electrode voltage is monitored to identify one or more characteristics that may serve as an indication of a fault. Characteristics indicative of a fault may include the rate of change of the counter electrode voltage and / or a lower compliance limit for the counter electrode voltage. This characteristic may be interpreted by considering the relationship between the counter electrode potential and the current at the working electrode. That is, as further described herein, the counter electrode voltage dynamically swings or adjusts to the potential required to sustain the redox reaction at the working electrode. The counter electrode voltage may therefore be viewed as the voltage required to support the level of current (e.g., the sense current) at the working electrode. As the sense current fluctuates or changes, the counter electrode voltage fluctuates or changes in a corresponding or reciprocal manner. If the sense current undergoes a rapid rate of change, the counter electrode voltage responds with a rapid rate of change. The correspondence or correlation between the sense current and the counter electrode voltage may be defined as equal but opposite in rate of change (or approximately equal but opposite (e.g., up to about a 5% difference between the rates of change)). When the sense current changes at a predetermined rate, the counter electrode voltage changes at a predetermined rate in the opposite direction. The rate of change of the counter electrode voltage then serves as an indicator of the rate of change of the sense current. A sense current exhibiting a rapid rate of change is non-physiologically possible or probable. Thus, by monitoring the counter electrode voltage, a determination can be made regarding the physiological feasibility of the sense current. If the rapid rate of change is not physiologically probable, such a change serves as an indication that something is wrong with the device. In some variations, a rapid rate of change of the counter electrode voltage may be defined as about 0.10 volts / minute. In some variations, a rapid rate of change of the counter electrode voltage may be defined as about 0.05 volts / minute to about 0.15 volts / minute. For example, in some variations, the rapid rate of change of the counter electrode voltage may be defined as about 0.05 volts / minute, about 0.06 volts / minute, about 0.07 volts / minute, about 0.08 volts / minute, about 0.09 volts / minute, about 0.10 volts / minute, about 0.11 volts / minute, about 0.12 volts / minute, about 0.13 volts / minute, about 0.14 volts / minute, or about 0.15 volts / minute.The rate of change of the sense current can be related to the rate of change of the analyte being measured. In the example of glucose, the rate of change can be about 4 mg / dL / min. In some variations, the rate of change of glucose can be about 3.5 mg / dL / min to about 6 mg / dL / min.

[0115] The counter electrode voltage's lower compliance limit can be defined as the lowest level the counter electrode voltage can swing. The counter electrode voltage may also have an upper compliance limit, i.e., the highest level the counter electrode can swing. If the counter electrode voltage swings to the lower compliance limit, this can serve as an indication that the sensed current has reached a high magnitude that is not physiologically possible, and may indicate the occurrence of a fault.

[0116] Thus, a counter electrode voltage that meets or exceeds a threshold rate of change and / or experiences a rate of change that meets a threshold compliance limit serves as an indication that there is a fault within the analyte monitoring device 110. In some variations, in response to identifying that the rate of change of the counter electrode voltage meets or exceeds a threshold rate of change and / or that the counter electrode voltage meets a threshold compliance limit, a characteristic or parameter of the counter electrode voltage may be compared to a characteristic or parameter of the sensed current to determine whether the fault is temporary or permanent. This comparison may include determining a correspondence or correlation between the counter electrode voltage and the sensed current.

[0117] In some variations, a counter electrode voltage that coincides with the sense current, whereby the counter electrode voltage is changing at a rate equal to the sense current, represents pressure-induced signal decay. Such pressure-induced signal decay may be caused by external pressure being applied to the analyte monitoring device 110 and may be characterized as a temporary fault. When the external pressure is removed, the analyte monitoring device 110 operates as intended.

[0118] In some variations, a change in counter electrode voltage that coincides with a change in the sensed current, coupled with a counter electrode voltage that meets the compliance floor, thereby maintaining that correspondence, represents a change in the physiological environment surrounding the sensor and / or a change in the sensor surface. In other variations, a counter electrode voltage that meets the compliance floor represents a change in the physiological environment and / or a change in the sensor surface, regardless of the sensed current. In this scenario, the counter electrode voltage need not correlate with the sensed current. A change in the physiological environment surrounding the sensor and a change in the sensor surface can be an example of a permanent impairment.

[0119] In some variations, a change in the counter electrode voltage that deviates from a change in the sense current, whereby the counter electrode voltage and the sense current are changing in different ways, coupled with a rapid rate of change of the counter electrode voltage, may represent an external influence on the electronics of the analyte monitoring device, which may be an example of a permanent fault.

[0120] When a correlation between the counter electrode voltage and the sensed current is determined, the analyte monitoring device 110 (e.g., a controller) responds by applying an operational mode consistent with the fault. For example, based on the identified characteristic of the counter electrode voltage and the correspondence of the counter electrode voltage and the sensed current, an operational mode is applied to the microneedle array-based analyte monitoring device.

[0121] In some variations, the operating mode includes ignoring the sensed current when the change in the counter electrode voltage matches the change in the sensed current and when the rate of change of the counter electrode voltage exceeds a threshold rate of change. As described herein, this may represent pressure-induced signal decay. When the pressure-induced signal decay is removed from the counter electrode voltage and the sensed current (e.g., the rate of change of the counter electrode voltage does not exceed the threshold rate of change), the sensed current is no longer ignored because the fault has been remedied.

[0122] In some variations, the operating mode includes discontinuing application of the potential between the working and reference electrodes when a change in the counter electrode voltage matches a change in the sensed current and when the lower compliance limit of the counter electrode voltage meets a threshold compliance limit, the threshold compliance limit being reached is an indication of a permanent fault and the bias potential is removed to halt operation.

[0123] In some variations, the operating mode includes discontinuing application of the potential between the working and reference electrodes when the change in counter electrode voltage deviates from the change in sensed current and when the rate of change of the counter electrode voltage exceeds a threshold rate of change, which is an indication of a permanent fault and the bias potential is removed to halt operation.

[0124] As further described herein, the reference electrode functions to provide a reference potential for the three-electrode electrochemical system implemented by the analyte monitoring device 110. The potential to which the working electrode is biased is referenced to the reference electrode. A fixed, time-varying, or at least controlled potential relationship is established between the working electrode and the reference electrode, and, within practical limits, no current is sourced from or sunk to the reference electrode. To implement such a three-electrode electrochemical system, the analyte monitoring device 110 includes a potentiostat or electrochemical analog front end (e.g., analog front end) to maintain a fixed potential relationship between the working and reference electrodes in the three-electrode electrochemical system while allowing the counter electrode to dynamically swing to the potential required to sustain the redox reaction of interest. Biasing the electrochemical system with the potentiostat or analog front end to establish a potential relationship between the working electrode and the reference electrode drives the redox reaction at the working electrode and causes the counter electrode to sink current in an oxidation process or source current in a reduction process to sustain the redox reaction at the working electrode. The magnitude of the current is proportional to the magnitude of the redox reaction occurring at the working electrode and to the impedance or resistance between the working and counter electrodes. Biasing the electrochemical system results in the formation of a voltage at the counter electrode, the value of which is also proportional to the magnitude of the redox reaction at the working electrode and to the impedance or resistance between the working and counter electrodes.

[0125] The voltage at the counter electrode, when maintained at a potential relative to the reference electrode, is adjusted relative to the potential to balance the redox reaction occurring at the working electrode. In response to the occurrence of a fault in one or more aspects of the analyte monitoring device 110 that affects its operation, the voltage at the counter electrode is modulated to reflect the impedance built up between the working and counter electrodes. By monitoring the voltage at the counter electrode, an indication of the impedance between the working and counter electrodes can be determined. The three-electrode electrochemical system of the analyte monitoring device 110 can be modeled as an electrical network or system including electrical components for correlating the voltage at the counter electrode with the impedance or resistance between the working and counter electrodes, which can be correlated with one or more conditions, including types of faults. By relating or characterizing the impedance with certain conditions, including faults in the three-electrode electrochemical system, voltage values ​​can be correlated with one or more faults.

[0126] 10 depicts a representation of a potentiostat circuit of analyte monitoring device 110. Potentiostat circuit 1000 is part of sensor circuitry 124 and is depicted in and may be described with reference to FIG. 2A. Potentiostat circuit 1000 includes an electrochemical cell 1010 that connects the working and counter electrodes of a three-electrode electrochemical system.

[0127] 11 depicts a Randles equivalent circuit 1100 representing the electrochemical cell 1010 shown in FIG. 10A. The Randles equivalent circuit 1100 includes a solution resistance R s (Uncompensated resistance R u or R Ω (also called the charge transfer resistance) and the charge transfer resistance R ct and the double layer capacitance C between the counter electrode 1120 and the working electrode 1110 dl Liquid resistance R s is the charge transfer resistance R ct and double layer capacitance C dlThe Randles equivalent circuit 1100 connects the terminals between the counter electrode 1120 and the working electrode 1110. The solution resistance R s indicates the level of ohmic contact between the counter electrode 1120 and the working electrode 1110, and may indicate the electrolytic content / ionic strength of the medium in which the analyte monitoring device 110 is operating (e.g., the fluid in which the microneedle array electrodes are located, such as interstitial fluid). ct indicates the magnitude of the electrochemical reaction occurring at the working electrode 1110. The double layer capacitance C dl indicates the surface morphology and constituents of the working electrode 1110 (eg, the surface composition and constituents of the working electrode 1110).

[0128] The Randles equivalent circuit 1100 of the electrochemical cell 1010 of the analyte monitoring device 110 is a simplification of the redox reactions occurring within the electrochemical cell 1010. By modeling the electrochemical cell 1010 with the Randles equivalent circuit 1100, the solution resistance R s contribution from the charge transfer resistance R ct , and double layer capacitance C dl can be identified. Frequency response analysis, including amplitude and phase components, may be used to understand the impedance behavior of the electrochemical cell 1010 under DC (ω→0) and AC (ω→∞) frequency perturbations. The voltage at the counter electrode 1120 is given by C dl is assumed to have infinite impedance as ω → 0, so the total resistive component of the system (e.g., R s +R ct ) is provided. At other extremes as ω→∞, C dl approximates negligible impedance, and R ct is bypassed. This means that R s This allows for a single quantification, which can be achieved using an impulse or unit step function applied to the counter electrode 1120.

[0129] In the DC case (ω→0), the voltage at the counter electrode 1120 is expected to swing to larger extremes relative to the potentiostat's compliance voltage when additional current must be sourced or sunk to maintain a fixed potential relationship between the working and reference electrodes. This is manifested via the counter electrode voltage moving away from the voltage established at the working electrode 1110. In extreme cases, the voltage at the counter electrode 1120 approaches the compliance voltage, or the maximum voltage imposed by the circuit driving the counter electrode 1120. A manifestation of this mode of operation in a Randles equivalent circuit is the solution resistance R s The charge transfer resistance R tends towards a value of ct In the case of DC, this is an indication that one or more of the following failures have occurred: a short circuit is developed between the working and counter electrodes, a failure of the reference electrode's ability to maintain a stable thermodynamic potential, a violation of the diffusion-limiting membrane, and a steady increase in the porosity of the sensing layer contained within the analyte-selective sensor.

[0130] The counter electrode voltage approximates the voltage value at which the working electrode 1110 is maintained in a scenario where the current requirement to maintain a fixed potential relationship between the working and reference electrodes tends toward negligible values ​​(e.g., negligible values ​​of current flow through the system, i→0). Manifestation in this mode of operation in a Randles equivalent circuit is the charge transfer resistance R, which tends toward infinity. ct In the case of DC, this is an indication that one or more of the following has occurred: improper sensor insertion, inadequate access to a viable anatomical compartment, partial or complete blockage of the sensor such that analyte diffusion is attenuated (e.g., due to biofouling / protein adsorption / collagen formation / insolubilization), and impaired ability of the reference electrode to maintain a stable thermodynamic potential.

[0131] Measurement of the voltage at the counter electrode can be accomplished by a converter such as a potentiostat, an electrochemical analog front end, or a voltage- or current-sensitive analog-to-digital converter (ADC).

[0132] 12, a buffer 1210 and a filter 1220 (e.g., a low-pass filter) may provide isolation from the converter 1230 to isolate components from a counter electrode included within the electrochemical sensor 1240. In some implementations, a differential amplifier, a transimpedance amplifier, or a finite-gain amplifier may be incorporated. The filter 1220 may be positioned before the converter 1230 to reduce high-frequency, low-frequency, both high-frequency and low-frequency, and / or band-limited signals from interfering with the measurement of the counter electrode voltage.

[0133] In some cases, the voltage generated at one or more working electrodes is measured and used to supplement and / or complement fault identification. The working electrode voltage can be compared to the counter electrode voltage to access and / or determine the fault. An analog-to-digital converter may be in electrical communication with the working electrode. In some implementations, a galvanostat is incorporated to establish the desired current relationship between the working and counter electrodes.

[0134] A scenario in which the voltage at the counter electrode approaches the value of the voltage at the working electrode indicates that the impedance or resistance of the analyte sensor has decayed to a low level by virtue of Ohm's law (v = Zi, where Z is the accumulated impedance of the analyte sensor). This is an indication that any one or more of the following failures have occurred: a short circuit developed between the working and counter electrodes; failure of the reference electrode's ability to maintain a stable thermodynamic potential; violation of the diffusion-limiting membrane; or a steady increase in the porosity of the sensing layer contained within the analyte-selective sensor. The counter electrode voltage approaches the working electrode voltage in situations in which the counter electrode voltage is swinging in a positive direction to support the level of current (e.g., sensing current) at the working electrode.

[0135] If the difference between the voltages at the counter electrode and the working electrode increases, this indicates that the impedance or resistance of the analyte sensor has increased to a very large value. This is an indication that any one or more of the following failures have occurred: improper sensor insertion, partial or complete blockage of the sensor such that analyte diffusion is attenuated (e.g., due to biofouling / protein absorption / collagen formation / insolubilization), or failure of the reference electrode's ability to maintain a stable thermodynamic potential. The increase in the difference between the counter electrode voltage and the working electrode voltage occurs when the counter electrode voltage swings negatively to support the sensing current.

[0136] Therefore, in some cases, voltages are measured at the working and counter electrodes to identify faults. The voltage value of the counter electrode is dynamically adjusted to support the specified current requirements of the analyte sensor, as shown in Figure 13A. Figure 13A is a representation of an electrochemical cell using both Nyquist and Bode plot generation. The Bode plot illustrates the amplitude and phase response of the electrochemical cell.

[0137] FIG. 13B is a Nyquist plot of the electrochemical cell, illustrating the real (Re{Z}) and imaginary (Im{Z}) components of the electrochemical impedance as the angular frequency ω is varied. The zero imaginary component of the impedance occurs in two cases according to the Randles equivalent circuit model: (1) when the angular frequency approaches ∞ and the solution resistance (R s / R Ω ) and (2) when the angular frequency is close to 0 and the liquid resistance R s Charge transfer resistance (R ct ) is achieved when perturbing the electrochemical cell at both frequency extremes allows for a complete characterization of the real (resistive) component of the electrochemical cell. Assuming the electrochemical cell is purely capacitive, interpolating the semicircle between both Im{Z} → 0 crossings yields the double layer capacitance C dl This allows the calculation of

[0138] 14-17 are exemplary plots illustrating the relationship between current and corresponding counter electrode voltage under different fault conditions, showing the operational relationship between sensed current and counter electrode voltage. The exemplary plots may be used to provide an indication of changes in sensor impedance between the counter electrode and working electrode.

[0139] FIG. 14 includes a sensed current plot 1410 and a corresponding counter electrode voltage plot 1420 versus time. During normal operation (e.g., before points 1411, 1421, and between points 1413, 1423 and points 1414, 1424), as the sensor current changes, the counter electrode voltage changes equally or nearly equally, but at opposite rates, which is visually depicted in plots 1410 and 1420 as a mirror image response. During normal operation without any faults being exhibited, the rate of change of the counter electrode voltage and the rate of change of the sensed current may be nearly equal or substantially equal. For example, there may be a difference of up to about 5% between the rates of change. In some variations, there may be a difference of up to 10% between the rates of change. The difference between the rate of change of the counter electrode voltage and the rate of change of the sensed current may vary within a range nearly equal to or substantially equal to up to 5%, or in some cases, up to 10%, during normal operation.

[0140] Faults are shown at points 1421, 1422, 1423, 1424, and 1425 in the counter electrode voltage, which correspond to points 1411, 1412, 1413, 1414, and 1415 in the sense current, respectively. The faults at points 1421, 1422, 1423, 1424, and 1425 represent pressure-induced signal attenuation and are identified by deviations in the correspondence between the counter electrode voltage and the sense current. As shown in plots 1410 and 1420, at the faults, the counter electrode voltage corresponds to the sense current with equal or nearly equal rates of change. For example, the rates of change may differ from each other by up to 5%, or in some cases up to 10%.

[0141] FIG. 15 (similar to FIG. 14) includes a current plot 1510 and a corresponding counter electrode voltage plot 1520 versus time. During normal operation (e.g., before points 1511, 1521 and between points 1511, 1521 and points 1512, 1522), as the sensor current changes, the counter electrode voltage changes equally but at opposite rates, which is visually depicted in plots 1510 and 1520 as a mirror image response. During normal operation when no faults are present, the rate of change of the counter electrode voltage and the rate of change of the sensed current may be approximately equal or substantially equal. For example, there may be a difference of up to about 5% between the rates. In some variations, there may be a difference of up to 10% between the rates. The difference between the rate of change of the counter electrode voltage and the rate of change of the sensed current may vary within a range approximately equal to or substantially equal to up to 5%, or in some cases, up to 10%, during normal operation.

[0142] Faults are shown at points 1521, 1522, 1523, and 1524 in the counter electrode voltage, which correspond to points 1511, 1512, 1513, and 1514 in the sense current, respectively. The faults at points 1521, 1522, 1523, and 1524 represent pressure-induced signal attenuation and are identified by deviations in the correspondence between the counter electrode voltage and the sense current. As shown in plots 1510 and 1520, at the faults, the counter electrode voltage corresponds to the sense current with equal or nearly equal rates of change. For example, the rates of change may differ from one another by up to 5%, or in some cases up to 10%.

[0143] FIG. 16 includes a current plot 1610 and a corresponding counter electrode voltage plot 1620 versus time. During normal operation (e.g., before points 1621, 1611), as the sensor current changes, the counter electrode voltage changes equally or nearly equally, but at opposite rates of change, which is visually depicted in plots 1610 and 1620 as a mirror image response. During normal operation without any faults being exhibited, the rate of change of the counter electrode voltage and the rate of change of the sensed current may be nearly equal or substantially equal. For example, there may be a difference of up to about 5% between the rates of change. In some variations, there may be a difference of up to 10% between the rates of change. The difference between the rate of change of the counter electrode voltage and the rate of change of the sensed current may vary within a range nearly equal to or substantially equal to up to 5%, or in some cases, up to 10%, during normal operation.

[0144] The counter electrode voltage reaching the compliance lower limit at point 1621 is an indication of a fault. Point 1621 may correspond to the preceding current spike at point 1611 in the sensor current, although in some cases this may not be a clear correlation between the counter electrode voltage and the sensed current. The fault at 1621 represents a change in the physiological environment surrounding the sensor or a change in the sensor surface based on which the compliance lower limit is being reached.

[0145] 17 includes a current plot 1710 and a corresponding counter electrode voltage plot 1720 versus time. Points 1721 and 1722, representing faults due to the rapid rate of change exhibited, are shown in the counter electrode voltage and, as shown, are unrelated to the current of the analyte monitoring device. Because the current is not undergoing substantial or unexpected fluctuations, points 1721 and 1722 are indications of faults that are unrelated to the current of the analyte monitoring device and are instead correlated to external environmental influences, such as external influences on the electronics of the analyte monitoring device.

[0146] FIG. 18 is an illustrative schematic diagram of a fault detection and diagnostic system 1800 for monitoring counter electrode voltages and working electrode voltages according to a described implementation. Aspects of the fault detection and diagnostic system 1800 may be incorporated into the analyte monitoring device 110. An analog front-end 1840 as described herein is included to allow the counter electrode 1820 to dynamically swing to the potential required to sustain the redox reaction of interest at the working electrode while maintaining a fixed potential relationship between the working electrode 1810 and the reference electrode 1830 in the electrochemical system. A converter 1815 coupled to the working electrode 1810 is optionally provided to convert the working electrode voltage. A converter 1825 coupled to the counter electrode 1820 is provided to convert the counter electrode voltage. In some cases, a single converter may be provided and coupled to each of the working electrode 1810 and counter electrode 1820 to convert the voltages. The converter 1815, the converter 1825, and / or the single converter may be an analog-to-digital converter.

[0147] The digitized voltage signals are transmitted to a controller 1822 coupled to each transducer. In some cases, the controller 122 shown in and described with reference to FIG. 2A may incorporate operational aspects of the controller 1822. The controller 1822 may be a separate component. In some cases, the controller 122 is incorporated in place of the controller 1822. The controller 1822 (and / or the controller 122) processes the counter electrode voltage, the sensed current, and optionally the working electrode voltage to identify faults and associated operating modes according to aspects described herein. The controller 1822 may provide command or corrective signals to the three-electrode electrochemical system and may provide an output 1824 to alert a user of the faults and optionally operating modes. The output 1824 may be provided on a user interface of the analyte monitoring device and / or may be communicated to a remote device and / or server (e.g., wirelessly via near-field communications, Bluetooth, or other wireless protocols).

[0148] In some variations, more than one working electrode is incorporated and used to detect the analyte. For example, in microneedle array configurations 900H, 900I, and / or 900J shown in Figures 9H, 9I, and 9J, more than one working electrode and more than one counter electrode are incorporated. In variations in which more than one counter electrode is incorporated, the counter electrodes are shorted together, whereby one cumulative counter electrode voltage is monitored as the shorted counter electrodes act together as one counter electrode.

[0149] With more than one working electrode, each additional working electrode generates a separate sense current. In some variations, a correlation between the counter electrode voltage and the sense current of each working electrode may be determined. When each working electrode is positioned on a separate and distinct microneedle in a microneedle array, the resulting faults may not be consistent between working electrodes. For example, electrode membrane degradation and biorecognition element degradation may vary across multiple working electrodes. Additionally, due to improper placement or insertion, in some cases, working electrodes may experience different insertion depths, such that one or more working electrodes may be fully inserted while others are not. Pressure decay may also affect working electrodes differently in some cases. Therefore, it may be useful to separately monitor and analyze the counter electrode voltage relative to the sense current of each working electrode based on possible differences across the microneedle array. Separate monitoring and analysis may serve to provide an indication of a fault at one or more working electrodes. In some variations, when a fault is identified, a corresponding operating mode is applied.

[0150] If more than one fault is identified and the faults are different, an operational mode for ceasing application of a potential between the working electrode and the reference electrode takes precedence over an operational mode for blanking and / or ignoring sensed data. In some variations, if a fault is detected at one working electrode but one or more additional working electrodes are operating according to normal operation (e.g., no fault is detected), the applied potential at the working electrode exhibiting the fault may be discontinued while operation may be allowed to continue using the remaining working electrodes. In some variations, a minimum number of operable working electrodes may be defined, whereby operation of the analyte monitoring device continues if the number of operable working electrodes meets or exceeds that minimum number.

[0151] In some variations, the composite sense current is based on the sense currents of the associated working electrodes. For example, the sense currents from each working electrode may be averaged to form a composite sense current. The composite sense current may be used in conjunction with the counter electrode voltage to determine faults and operating modes of the analyte monitoring device, as described herein.

[0152] Additional details relating to the Randles equivalent model are provided. The impedance Z of the Randles equivalent model is given by the following relationship: [ka]

[0153] Expanding this relationship to express the impedance as a function of angular frequency ω gives: [ka]

[0154] In the DC (zero frequency) case, the impedance is given by: [ka]

[0155] In the AC (high frequency extreme) case, the impedance is given by: [ka]

[0156] Recalculating equation 2 gives: [ka]

[0157] The real and imaginary components of the impedance given in Equation 5 can be easily identified as follows: [ka]

[0158] Substituting, we get the following: [ka]

[0159] The magnitude response of the system is given by: [ka]

[0160] The phase response is calculated accordingly. [ka]

[0161] Electrochemical Reaction i CELL The current supported by can be calculated by applying Kirchhoff's voltage law to the Randles cell. [ka]

[0162] Counter electrode voltage V CE , can be calculated by reformulating the above relationship. [ka]

[0163] The current can be a positive or negative quantity, depending on the configuration of the potentiostat and whether the electrochemical reaction is undergoing oxidation or reduction. In the provided model and equations by which current works, it is assumed that current flows through the electrochemical cell and from the counter electrode (held at the highest potential) into the working electrode, which is held at a lower potential (e.g., ground reference); the model assumes a reduction reaction (e.g., current flows into the working electrode, thus acting as an electron source). It is also possible for the counter electrode to be held at a lower potential than the working electrode (during oxidation), causing current to flow from the working electrode into the counter electrode. In this case, the working electrode acts as an electron sink.

[0164] For the DC case: [ka]

[0165] Given R s and R ct Regarding V CE is i CELL The finite charge transfer resistance R ct Regarding this, it is as follows: [ka]

[0166] This is the compliance voltage limit of the potentiostat. In this scenario, there is no ohmic connection between the counter electrode and the working electrode. Similarly, [ka]

[0167] This represents the ideal operating condition for an electrochemical system. This is achieved by operating in a medium of sufficient electrolytic / ionic strength (e.g., a buffer solution or the wearer's physiological fluid). Similarly, the finite liquid resistance R s Regarding this, it is as follows: [ka]

[0168] In other words, the current i through the electrochemical cell CELL , approaches zero due to infinite charge transfer resistance, the counter electrode voltage will approach the working electrode voltage. A practical manifestation of this is complete passivation of the working electrode surface, whereby no current can flow, and thus an ideal double-layer capacitor is formed. For the case when the charge transfer resistance approaches zero, [ka]

[0169] The current flowing through the electrochemical cell will be invariant to the charge transfer process (e.g., in the case of an electrolysis reaction). Instead, the counter electrode will track the current flowing through the electrochemical cell (assuming the solution resistance / electrolyte content remains constant throughout the electrolysis).

[0170] In the AC case, if the frequency tends towards the extreme values, then: [ka]

[0171] The current through an electrochemical cell is invariant to charge transfer processes (e.g., electrolysis reactions). Similarly, in the DC case, as the frequency tends towards zero, [ka]

[0172] This is the same as equation 13.

[0173] Exemplary Embodiments Embodiment I-1. A microneedle array-based analyte monitoring device comprising: a working electrode comprising an electrochemical sensing coating configured to generate a sensing current indicative of an analyte redox reaction at a surface of the working electrode, the working electrode being positioned on a surface of a distal portion of a first microneedle in the microneedle array; a reference electrode positioned on a surface of a distal portion of a second microneedle in the microneedle array; a counter electrode positioned on a surface of a distal portion of a third microneedle in the microneedle array; an analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and to allow the potential of the counter electrode to swing to sustain the redox reaction at the working electrode; a controller in communication with the analog front end; monitoring a counter electrode voltage at the counter electrode; identifying a characteristic of the counter electrode voltage that meets or exceeds a threshold; determining a correlation between the counter electrode voltage and the sensed current in response to identifying a characteristic of the counter electrode voltage that exceeds a threshold; Applying modes of operation to microneedle array-based analyte monitoring devices based on characteristics and correlations of counter electrode voltages; a controller configured to: A microneedle array-based analyte monitoring device comprising:

[0174] Embodiment I-2. The microneedle array-based analyte monitoring device of embodiment I-1, wherein the characteristic of the counter electrode voltage comprises at or above one of the rate of change of the counter electrode voltage or a lower compliance limit of the counter electrode voltage.

[0175] Embodiment I-3. The microneedle array-based analyte monitoring device of embodiment I-2, wherein the change in counter electrode voltage and the change in sensed current indicate a correlation between the counter electrode voltage and the sensed current.

[0176] Embodiment I-4. A microneedle array-based analyte monitoring device as described in embodiment I-3, wherein the mode of operation includes ignoring the sensed current when the change in counter electrode voltage coincides with the change in sensed current and when the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0177] Embodiment I-5. A microneedle array-based analyte monitoring device as described in embodiment I-4, wherein the controller is further configured to discontinue the operational mode of ignoring the sensed current in response to a subsequent determination that the rate of change of the counter electrode voltage does not exceed a threshold rate of change.

[0178] Embodiment I-6. A microneedle array-based analyte monitoring device as described in embodiment I-3, wherein the mode of operation includes ceasing application of a potential between the working electrode and the reference electrode when the lower compliance limit of the counter electrode voltage meets a threshold compliance limit.

[0179] Embodiment I-7. A microneedle array-based analyte monitoring device as described in embodiment I-3, wherein the mode of operation includes discontinuing application of a potential between the working electrode and the reference electrode when the change in counter electrode voltage deviates from the change in sensed current and when the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0180] Embodiment I-8. The method further comprises one or more additional working electrodes, each of which generates a separate sensing current; The controller further configured, in response to identifying a characteristic of the counter electrode voltage that exceeds a threshold, to determine a correlation between the counter electrode voltage and the respective sensed current; The microneedle array-based analyte monitoring device of embodiment I-1.

[0181] Embodiment I-9. The microneedle array-based analyte monitoring device of embodiment I-8, wherein the mode of operation is further based on a correlation between the counter electrode voltage and the individual sensed current.

[0182] Embodiment I-10. The microneedle array-based analyte monitoring device of embodiment I-9, wherein the sensed current at the working electrode and the individual sensed currents at one or more additional working electrodes are combined to determine a composite correlation.

[0183] Embodiment I-11. A method comprising: monitoring a counter electrode voltage at a counter electrode of the microneedle array-based analyte monitoring device, the counter electrode being positioned on a surface of a distal portion of a first microneedle in the microneedle array; identifying a characteristic of the counter electrode voltage that meets or exceeds a threshold; determining a correlation between the counter electrode voltage and a sensed current in response to identifying a characteristic of the counter electrode voltage that exceeds a threshold, the sensed current being generated at a surface of a working electrode of the microneedle array-based analyte monitoring device; Applying modes of operation to microneedle array-based analyte monitoring devices based on characteristics and correlations of counter electrode voltages; Including, the working electrode comprises an electrochemical sensing coating configured to generate a sensing current indicative of an analyte redox reaction at a surface of the working electrode, the working electrode being positioned on a surface of a distal portion of a second microneedle in the microneedle array; The method, wherein the microneedle array-based analyte monitoring device further comprises a reference electrode positioned on the surface of a distal portion of a third microneedle in the microneedle array, and an analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and allow the potential of the counter electrode to swing to sustain the redox reaction at the working electrode.

[0184] Embodiment I-12. The method of embodiment I-11, wherein the characteristic of the counter electrode voltage comprises at or above one of a rate of change of the counter electrode voltage or a counter electrode voltage lower compliance limit.

[0185] Embodiment I-13. The method of embodiment I-12, wherein the change in counter electrode voltage and the change in sensed current indicate a correlation between the counter electrode voltage and the sensed current.

[0186] Embodiment I-14. The method of embodiment I-13, wherein the operating mode includes ignoring the sensed current if the change in counter electrode voltage matches the change in the sensed current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0187] Embodiment I-15. The method of embodiment I-14, wherein the operational mode of ignoring the sensed current is discontinued in response to a subsequent determination that the rate of change of the counter electrode voltage does not exceed a threshold rate of change.

[0188] Embodiment I-16. The method of embodiment I-13, wherein the mode of operation includes discontinuing application of the potential between the working electrode and the reference electrode if the lower compliance limit of the counter electrode voltage meets the threshold compliance limit.

[0189] Embodiment I-17. The method of embodiment I-13, wherein the mode of operation includes discontinuing application of a potential between the working electrode and the reference electrode when the change in counter electrode voltage deviates from the change in sensed current and when the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0190] Embodiment I-18. The microneedle array-based analyte monitoring device further comprises one or more additional working electrodes, each generating a separate sensing current; The method further includes determining a correlation between the counter electrode voltage and the individual sensed current in response to identifying a characteristic of the counter electrode voltage that exceeds a threshold. The method of embodiment I-11.

[0191] Embodiment I-19. The method of embodiment I-18, wherein the mode of operation is further based on a correlation between the counter electrode voltage and the individual sensed current.

[0192] Embodiment I-20. The method of embodiment I-19, wherein the sensed current at the working electrode and the individual sensed currents at one or more additional working electrodes are combined to determine a composite correlation.

[0193] The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that specific details are not required to practice the present invention. Thus, the foregoing descriptions of specific embodiments of the present invention are presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously, many modifications and variations are possible in light of the above teachings. The embodiments were chosen and described in order to explain the principles of the invention and its practical application, so as to enable those skilled in the art to utilize the invention and its various embodiments with various modifications as appropriate for the identified uses envisioned. It is intended that the following claims and their equivalents define the scope of the invention.

Claims

1. 1. A microneedle array-based analyte monitoring device, comprising: a first microneedle comprising a working electrode; a second microneedle comprising a reference electrode; a third microneedle comprising a counter electrode; a controller configured to determine whether a fault in the microneedle array-based analyte monitoring device is temporary or permanent based on a comparison of a characteristic or parameter of a counter electrode voltage at the counter electrode and a characteristic or parameter of a sensed current indicative of an analyte redox reaction at the surface of the working electrode, and to apply a mode for operating the microneedle array-based analyte monitoring device consistent with the fault; a potentiostat or analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and to allow the counter electrode voltage to swing to sustain the redox reaction at the working electrode; A microneedle array-based analyte monitoring device comprising:

2. The microneedle array-based analyte monitoring device of claim 1 , wherein the controller is configured to apply the mode for operating the microneedle array-based analyte monitoring device in response to the counter electrode voltage meeting or exceeding one of a threshold rate of change and a threshold compliance limit.

3. The microneedle array-based analyte monitoring device of claim 2 , wherein the mode for operating the microneedle array-based analyte monitoring device corresponds to a correlation between the counter electrode voltage and the sensed current.

4. A microneedle array-based analyte monitoring device as described in claim 2, wherein when the fault is determined to be temporary, the mode for operating the microneedle array-based analyte monitoring device includes ignoring the sensed current.

5. The microneedle array-based analyte monitoring device of claim 4, wherein the mode for operating the microneedle array-based analyte monitoring device includes determining the analyte concentration by taking into account the sensed current when the rate of change of the counter electrode voltage is less than the threshold rate of change.

6. The counter electrode voltage exhibits pressure-induced signal decay; the mode for operating the microneedle array-based analyte monitoring device includes determining an analyte concentration in consideration of the sense current when the source of the pressure-induced signal attenuation is removed. The microneedle array-based analyte monitoring device of claim 4 .

7. 3. The microneedle array-based analyte monitoring device of claim 2, wherein the mode for operating the microneedle array-based analyte monitoring device includes discontinuing application of a potential between the working electrode and the reference electrode when the counter electrode voltage meets the threshold compliance limit.

8. The microneedle array-based analyte monitoring device of claim 2, wherein when the failure is determined to be permanent, the mode for operating the microneedle array-based analyte monitoring device includes ceasing application of a potential between the working electrode and the reference electrode.

9. the working electrode is a first working electrode, the sensing current is a first sensing current, and the microneedle array-based analyte monitoring device comprises: a fourth microneedle with a second working electrode; Furthermore, The controller is further configured to determine whether a second fault in the microneedle array-based analyte monitoring device is temporary or permanent based on a comparison of the characteristic or parameter of the counter electrode voltage with a characteristic or parameter of a second sensed current indicative of an oxidation-reduction reaction at the surface of the second working electrode, and to apply a mode for operating the microneedle array-based analyte monitoring device consistent with the second fault. The microneedle array-based analyte monitoring device of claim 1 .

10. 1. A method for monitoring an analyte, the method comprising: monitoring a counter electrode voltage at a counter electrode of a microneedle array-based analyte monitoring device, wherein the microneedle array-based analyte monitoring device comprises: a first microneedle comprising a working electrode; a second microneedle comprising a reference electrode; a third microneedle comprising the counter electrode; a potentiostat or analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and to allow the counter electrode voltage to swing to sustain an analyte redox reaction at the working electrode; and determining whether a fault in the microneedle array-based analyte monitoring device is temporary or permanent based on a comparison of a characteristic or parameter of the counter electrode voltage with a characteristic or parameter of the sensed current indicative of the redox reaction; applying a mode for operating the microneedle array-based analyte monitoring device consistent with the impairment; and A method comprising:

11. 11. The method of claim 10, wherein applying the mode for operating the microneedle array-based analyte monitoring device occurs in response to the counter electrode voltage meeting or exceeding one of a threshold rate of change and a threshold compliance limit.

12. The method of claim 11 , wherein the mode for operating the microneedle array-based analyte monitoring device corresponds to a correlation between the counter electrode voltage and the sensed current.

13. The method of claim 11, wherein when the fault is determined to be temporary, the mode for operating the microneedle array-based analyte monitoring device includes ignoring the sensed current.

14. 14. The method of claim 13, wherein the mode for operating the microneedle array-based analyte monitoring device includes determining the analyte concentration by taking into account the sense current when the rate of change of the counter electrode voltage is less than the threshold rate of change.

15. The method of claim 13, wherein the counter electrode voltage exhibits pressure-induced signal attenuation, and the mode for operating the microneedle array-based analyte monitoring device includes determining the analyte concentration by taking into account the sensed current when a source of the pressure-induced signal attenuation is removed.

16. 12. The method of claim 11, wherein the mode for operating the microneedle array-based analyte monitoring device comprises discontinuing application of a potential between the working electrode and the reference electrode when the counter electrode voltage meets the threshold compliance limit.

17. The method of claim 11, wherein when the failure is determined to be permanent, the mode for operating the microneedle array-based analyte monitoring device includes discontinuing application of a potential between the working electrode and the reference electrode.

18. 1. A microneedle array-based analyte monitoring device, comprising: a first microneedle comprising a working electrode; a second microneedle comprising a reference electrode; a third microneedle comprising a counter electrode; a controller configured to determine whether a fault in the microneedle array-based analyte monitoring device is temporary or permanent based on a comparison of a characteristic or parameter of a counter electrode voltage at the counter electrode and a characteristic or parameter of a sensed current indicative of an analyte redox reaction at the surface of the working electrode, and to apply a mode for operating the microneedle array-based analyte monitoring device consistent with the fault; a potentiostat or analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and to allow the counter electrode voltage to swing to sustain the redox reaction at the working electrode; Equipped with When the fault is determined to be temporary, the mode for operating the microneedle array-based analyte monitoring device includes ignoring the sensed current; the mode for operating the microneedle array-based analyte monitoring device includes discontinuing application of a potential between the working electrode and the reference electrode when the counter electrode voltage meets a threshold compliance limit; When the fault is determined to be permanent, the mode for operating the microneedle array-based analyte monitoring device includes discontinuing application of the potential between the working electrode and the reference electrode. Microneedle array-based analyte monitoring device.

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