HK40092904B - Fault detection for microneedle array based continuous analyte monitoring device - Google Patents

Description

Fault detection of continuous analyte monitoring devices based on microneedle arrays

Cross-references to related applications

This application claims priority to U.S. Provisional Patent 63/186,086, filed May 8, 2021, the entire contents of which are incorporated herein by reference.

Technical Field

This invention generally relates to the field of analyte monitoring, such as continuous glucose monitoring.

Background Technology

Diabetes is a chronic disease in which the body cannot produce or properly use insulin, a hormone that regulates blood sugar. Insulin can be administered to people with diabetes to help regulate their blood sugar levels, but blood sugar levels must be carefully monitored to ensure that the timing and dosage are appropriate. Without proper management, people with diabetes may develop various complications due to either high blood sugar (hyperglycemia) or low blood sugar (hypoglycemia).

Blood glucose monitors help people with diabetes manage their condition by measuring blood glucose levels in a blood sample. For example, a diabetic patient can obtain a blood sample using a finger-stick sampling device, transfer the blood sample onto a test strip using one or more suitable reagents that react with the blood sample, and then use a blood glucose monitor to analyze the test strip to measure the blood glucose level in that blood sample. However, patients using this procedure can typically only measure their blood glucose levels at discrete time points, which may not be able to capture hyperglycemia or hypoglycemia in a timely manner. More recent blood glucose monitors are continuous glucose monitoring (CGM) devices, which include implantable transdermal electrochemical sensors that continuously detect and quantify blood glucose levels via a proxy measurement of blood glucose levels in the subcutaneous interstitial fluid. However, conventional CGM devices also have weaknesses, including tissue damage caused by insertion and signal delay (e.g., due to the time required for the analyte to diffuse from the capillary source to the sensor). These drawbacks also lead to several limitations, such as pain experienced by the patient when the electrochemical sensor is inserted, and limited accuracy of blood glucose measurements, especially when blood glucose levels change rapidly. Therefore, a new and improved analyte monitoring system is needed.

Summary of the Invention

In some variations, an analyte monitoring device based on a microneedle array includes a working electrode, a reference electrode, a counter electrode, a simulation front end, and a controller. The working electrode includes an electrochemical sensing coating configured to generate a sensed current at its surface indicating a redox reaction of the analyte, and the working electrode is located on the surface of a distal portion of a first microneedle in the microneedle array. The reference electrode is located on the surface of a distal portion of a second microneedle in the microneedle array. The counter electrode is located on the surface of a distal portion of a third microneedle in the microneedle array. The simulation 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 maintain a redox reaction at the working electrode. The controller communicates with the analog front end and is configured to: monitor the counter electrode voltage at the counter electrode; identify characteristics of the counter electrode voltage that meet or exceed a threshold; determine the correlation between the counter electrode voltage and the induced current in response to identifying the characteristics of the counter electrode voltage that exceed the threshold; and apply an operating mode to the microneedle array-based analyte monitoring device based on the characteristics of the counter electrode voltage and the correlation.

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 located on the surface of a distal portion of a first microneedle in the microneedle array; identifying a characteristic of the counter electrode voltage that satisfies or exceeds a threshold; determining a correlation between the counter electrode voltage and a sensed current generated on the surface of a working electrode of the microneedle array-based analyte monitoring device in response to identifying the characteristic of the counter electrode voltage exceeding the threshold; and applying an operating mode to the microneedle array-based analyte monitoring device based on the characteristic of the counter electrode voltage and the correlation. The working electrode may include an electrochemical sensing coating configured to generate the sensed current indicative of a redox reaction of an analyte on the surface of the working electrode, the working electrode being located 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 located on the surface of the distal portion of a third microneedle in the microneedle array; and a simulation 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 maintain redox reactions at the working electrode.

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

In some variations, the change in the counter electrode voltage and the change in the induced current indicate the correlation between the counter electrode voltage and the induced current.

In some variations, the operating mode includes ignoring the induced current if the change in the counter electrode voltage corresponds to the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change.

In some variations, the controller is also configured to interrupt the operating mode of ignoring the induced current in response to subsequently determining that the rate of change of the counter electrode voltage does not exceed the threshold rate of change.

In some variations, the operating mode includes stopping the application of a potential between the working electrode and the reference electrode if the lower compliance limit of the counter electrode voltage meets the compliance limit threshold.

In some variations, the operating mode includes stopping the application of a potential between the working electrode and the reference electrode if the change in the counter electrode voltage deviates from the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change.

In some variations, the microneedle array-based analyte monitoring device further includes one or more additional working electrodes, each of which generates a respective sensing current. The controller is also configured to determine the correlation between the counter electrode voltage and the respective sensing current in response to identifying the characteristic of the counter electrode voltage exceeding the threshold.

In some variations, the operating mode is also based on the correlation between the counter electrode voltage and the respective induced current.

In some variations, the induced current at the working electrode and the respective induced current at one or more additional working electrodes are combined to determine the correlation of the combination.

Attached Figure Description

Figure 1 shows an illustrative schematic diagram of an analyte monitoring system with a microneedle array.

Figure 2A shows an illustrative schematic diagram of the analyte monitoring device.

Figure 2B shows an illustrative schematic diagram of the microneedle insertion depth in the analyte monitoring device.

Figure 3A shows an illustrative schematic diagram of the microneedle array. Figure 3B shows an illustrative schematic diagram of the microneedles in the microneedle array shown in Figure 3A.

Figure 4 shows an illustrative schematic diagram of a microneedle array used to sense a variety of analytes.

Figure 5A shows a cross-sectional side view of a columnar microneedle with a tapered distal end. Figures 5B and 5C are perspective and detailed views, respectively, of an embodiment of the microneedle shown in Figure 5A.

Figures 6A-6C show illustrative schematic diagrams of the layered structure of the working electrode, counter electrode, and reference electrode, respectively.

Figures 6D-6F show illustrative schematic diagrams of the layered structure of the working electrode, counter electrode, and reference electrode, respectively.

Figures 6G-6I show illustrative schematic diagrams of the layered structure of the working electrode, counter electrode, and reference electrode, respectively.

Figure 7 shows an illustrative schematic diagram of the microneedle array structure.

Figures 8A-8D show illustrative schematic diagrams of the microneedle array structure.

Figures 9A-9J show illustrative schematic diagrams of different variations of the microneedle array construction.

Figure 10 shows a representation of the potentiostat circuit of the analyte monitoring device.

Figure 11 shows the Randles equivalent circuit of an electrochemical cell representing an analyte monitoring device.

Figure 12 shows the measurement circuit of the analyte monitoring device.

Figure 13A is a representation of an electrochemical cell using Nyquist plot and Bode plot formulas.

Figure 13B is a representation of an electrochemical cell using the Nyquist plot formula.

Figure 14-17 is a graph depicting the current and corresponding voltage at the counter electrode in fault detection.

Figure 18 shows an illustrative schematic diagram of the analyte monitoring device.

Detailed Implementation

This document describes non-limiting examples of various aspects and variations of the invention, which are illustrated in the accompanying drawings.

As generally described herein, an analyte monitoring system may include an analyte monitoring device worn by a user and comprising one or more sensors for monitoring at least one analyte in the user. The sensors may include, for example, one or more electrodes configured to perform electrochemical detection of at least one analyte. The analyte monitoring device may transmit sensor data to an external computing device for storage, display, and/or analysis of the sensor data. For example, as shown in FIG1, an analyte monitoring system 100 may include an analyte monitoring device 110 worn by a user, and the analyte monitoring device 110 may be a continuous analyte monitoring device (e.g., a continuous glucose monitoring device). The analyte monitoring device 110 may, for example, include a microneedle array comprising at least one electrochemical sensor for detecting and/or measuring one or more analytes in the user's bodily fluids. 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 analysis of the sensor data, and/or a communication module (e.g., a wireless communication module) configured to transmit the sensor data to a mobile computing device 102 (e.g., a smartphone) or other suitable computing device. In some variations, mobile computing device 102 may include one or more processors executing mobile applications to process sensor data (e.g., display data, analyze trend data, etc.) and/or provide appropriate alerts or other notifications related to the sensor data and/or its analysis. It should be understood that while in some variations, mobile computing device 102 may perform sensor data analysis locally, one or more other computing devices may alternatively or additionally remotely analyze sensor data and/or communicate information related to such analysis to the mobile computing device (or other suitable user interface) for display to the user. Furthermore, in some variations, mobile computing device 102 may be configured to transmit sensor data and/or the analysis of sensor data via network 104 to one or more storage devices 106 (e.g., a server) to archive data and/or other suitable information relevant to the user of the analyte monitoring device.

The analyte monitoring device described herein possesses several characteristics that improve upon many performance characteristics advantageous for continuous analyte monitoring devices, such as continuous glucose monitoring (CGM) devices. For example, the analyte monitoring device described herein features improved sensitivity (the amount of sensor signal generated per given concentration of the target analyte), improved selectivity (rejection of endogenous and exogenous circulating compounds that may interfere with the detection of the target analyte), and improved stability to help minimize changes in sensor response over time during storage and operation of the analyte monitoring device. Furthermore, compared to conventional continuous analyte monitoring devices, the analyte monitoring device described herein has a shorter warm-up time, enabling one or more sensors to quickly provide a stable sensor signal after implantation, and a short response time, allowing one or more sensors to quickly provide a stable sensor signal after changes in analyte concentration in the user. Moreover, as described in further detail below, the analyte monitoring device described herein can be applied to and function in various abrasion sites, providing a painless sensor insertion for the user. Other performance characteristics, such as biocompatibility, sterility, and mechanical integrity, have also been optimized in the analyte monitoring device described herein.

Although the analyte monitoring systems described herein may be referred to in relation to blood glucose monitoring (e.g., in users with type 2 diabetes or type 1 diabetes), it should be understood that such systems may be additionally or alternatively configured to sense and monitor other suitable analytes. Suitable target analytes for detection, as described further in detail below, may include, for example, blood glucose, ketones, lactate, and cortisol. One target analyte may be monitored, or multiple target analytes may be monitored simultaneously (e.g., in the same analyte monitoring device). For example, monitoring of other target analytes may enable monitoring of other indicators, such as stress (e.g., by detecting elevated cortisol and blood glucose) and ketoacidosis (e.g., by detecting elevated ketones).

As shown in Figure 2A, in some variations, the analyte monitoring device 110 typically includes a housing 112 and a microneedle array 140 extending outwardly from the housing. The housing 112 may, for example, be a wearable housing configured to be worn on a user's skin, such that the microneedle array 140 extends at least partially into the user's skin. For example, the housing 112 may include an adhesive, such that the analyte monitoring device 110 is an adhesive skin patch that can be easily and directly applied to a user. The microneedle array 140 may be configured to pierce the user's skin and includes one or more electrochemical sensors (e.g., electrodes) configured to measure one or more accessible target analytes after the microneedle array 140 has pierced the user's skin. In some variations, the analyte monitoring device 110 may be integrated or self-contained as a single unit, and this unit may be disposable (e.g., used for a period of time and replaced with another instance of the analyte monitoring device 110).

Electronic system 120 may be at least partially arranged within housing 112 and includes various electronic components, such as sensor circuitry 124 configured to perform signal processing (e.g., biasing and readout of electrochemical sensors, converting analog signals from electrochemical sensors into digital signals, etc.). Electronic system 120 may also include at least one microcontroller 122 for controlling analyte monitoring device 110, at least one communication module 126, at least one power supply 130, and/or other various suitable passive circuitry 127. For example, microcontroller 122 may be configured to interpret digital signals output from sensor circuitry 124 (e.g., by executing programming routines in firmware), perform various suitable algorithms or mathematical transformations (e.g., calibration, etc.), and/or route processed data to and/or from communication module 126. In some variations, communication module 126 may include a suitable wireless transceiver (e.g., a Bluetooth transceiver, etc.) for communicating data with external computing device 102 via one or more antennas 128. For example, communication module 126 may be configured to provide one-way and/or two-way data communication with external computing device 102, which is paired with analyte monitoring device 110. Power supply 130 may provide power to analyte monitoring device 110 (e.g., electronic system). Power supply 130 may include a battery or other suitable power source, and in some variations may be rechargeable and/or replaceable. Passive circuitry 127 may include various power-free circuits (e.g., resistors, capacitors, inductors, etc.) that provide 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 electronic system 120 may be arranged on one or more printed circuit boards (PCBs), which may be rigid, semi-rigid, or flexible. Further details of electronic system 120 are described below.

In some variations, the analyte monitoring device 110 may also 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 also 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.

In some variations, the microneedle array 140 in the analyte monitoring device 110 can be configured to puncture the user's skin. As shown in Figure 2B, when the user wears the device 110, the microneedle array 140 can extend into the user's skin such that electrodes on the distal regions of the microneedles remain in the dermis. Specifically, in some variations, the microneedles can be designed to penetrate the skin and enter the upper dermal regions (e.g., dermal papillae and reticular dermis) to allow the electrodes to access the interstitial fluid surrounding the cells in these layers. For example, in some variations, the height of the microneedles is typically in the range of at least 350 μm to about 515 μm. In some variations, one or more microneedles can extend from the housing such that the distal ends of the electrodes on the microneedles are located less than about 5 mm from the skin interface 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.

Compared to conventional continuous analyte monitoring devices (e.g., CGM devices) that include sensors typically implanted percutaneously in the subcutaneous or fat layer of the skin at a depth of approximately 8 to 10 mm, the analyte monitoring device 110 has a shallower microneedle insertion depth of approximately 0.25 mm (allowing the electrode to be implanted in the upper dermal region of the skin), which offers several advantages. These advantages include contact with the dermal interstitial fluid containing one or more target analytes, which is advantageous, at least because measurements of at least some types of analytes from the dermal interstitial fluid have been found to be highly correlated with blood measurements. For example, it has been found that blood glucose measurements using electrochemical sensors that contact the dermal interstitial fluid are advantageously highly linearly correlated with blood glucose measurements. Therefore, blood glucose measurements based on the dermal interstitial fluid are highly representative of blood glucose measurements.

Furthermore, due to the shallow insertion depth of the microneedle in the analyte monitoring device 110, the time delay for analyte detection is reduced compared to conventional continuous analyte monitoring devices. This shallow insertion depth brings the sensor surface very close to the dense and well-perfused capillary bed of the reticular dermis (e.g., within a few hundred micrometers or less), resulting in negligible diffusion hysteresis from the capillaries to the sensor surface. According to t = ^x² /(2D), diffusion time is related to diffusion distance, where t is the diffusion time, x is the diffusion distance, and D is the mass diffusivity of the analyte of interest. Therefore, placing the analyte sensing element at twice the distance from the analyte source in the capillaries will result in a fourfold increase in diffusion delay time. Consequently, conventional analyte sensors located in poorly vascularized adipose tissue under the dermis result in a significantly greater diffusion distance to the vascular system in the dermis, thus exhibiting a significant diffusion delay (e.g., typically 5–20 minutes). In contrast, the shallower microneedle insertion depth of the analyte monitoring device 110 benefits from a low diffusion delay from the capillary 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 delay may be less than 10 minutes, less than 5 minutes, or less than 3 minutes.

Furthermore, when the microneedle array is located in the upper dermis, the lower dermis beneath it exhibits a very high level of vascularization and perfusion to support dermal metabolism, thereby enabling thermoregulation (through vasoconstriction and/or vasodilation) and providing a barrier function to help stabilize the sensing environment around the microneedles. Another advantage of the shallower insertion depth is that the upper dermis lacks pain-sensing organs, resulting in less pain when the microneedle array pierces the user's skin, providing a more comfortable and minimally invasive user experience.

Therefore, the analyte monitoring device and method described herein can improve the continuous monitoring of one or more target analytes for a user. For example, as mentioned above, the analyte monitoring device can be applied simply and directly, which improves ease of use and user compliance. Furthermore, analyte measurement of dermal interstitial fluid provides highly accurate analyte detection. Moreover, compared to conventional continuous analyte monitoring devices, the insertion of microneedle arrays and their sensors may be less invasive and potentially less painful for the user. Additional advantages of other aspects of the analyte monitoring device and method will be further described below.

As illustrated in the schematic diagram of Figure 3A, in some variations, the microneedle array 300 for sensing one or more analytes may include one or more microneedles 310 protruding from a substrate surface 302. For example, the substrate surface 302 may be generally flat, and one or more microneedles 310 may protrude orthogonally from the flat surface. Typically, as shown in Figure 3B, the microneedle 310 may include a body portion 312 (e.g., a rod) and a tapered distal portion 314 configured to pierce the user's skin. In some variations, the tapered distal portion 314 may terminate at an insulated distal apex 316. The microneedle 310 may also include an electrode 320 located on the surface of the tapered distal portion. In some variations, electrode-based measurements may be performed at the interface between the electrode and interstitial fluid within the body (e.g., across the entire outer surface of the microneedle). In some variants, the microneedle 310 may have a solid core (e.g., a solid body portion), although in some variants, the microneedle 310 may include one or more lumens, which may be used for, for example, drug delivery or sampling of dermal interstitial fluid. Other microneedle variants described below may similarly include a solid core or one or more lumens.

The microneedle array 300 may be at least partially formed from a semiconductor (e.g., silicon) substrate and includes various material layers applied and shaped using various suitable microelectromechanical systems (MEMS) fabrication techniques (e.g., deposition and etching techniques), as further described below. The microneedle array can be reflow soldered onto a circuit board, similar to a typical integrated circuit. Furthermore, in some variations, the microneedle array 300 may include a three-electrode arrangement comprising a working (sensing) electrode, a reference electrode, and a counter electrode, having an electrochemical sensing coating (including biorecognition elements such as enzymes) capable of detecting target analytes. In other words, the microneedle array 300 may include at least one microneedle 310 having a working electrode, at least one microneedle 310 having a reference electrode, and at least one microneedle 310 having a counter electrode. Further details of these types of electrodes will be described in further detail below.

In some variations, the microneedle array 300 may include a plurality of microneedles that are insulated, such that the electrode on each of the plurality of microneedles is individually addressable and electrically isolated from each other electrode in the microneedle array. The individual addressability provided by the microneedle array 300 allows for greater control over the function of each electrode, as each electrode can be probed individually. For example, the microneedle array 300 can be used to provide multiple independent measurements of a given target analyte, which improves the sensing reliability and accuracy of the device. Furthermore, in some variations, the electrodes of the plurality of microneedles may be electrically connected to generate enhanced signal levels. As another example, the same microneedle array 500 may be additionally or alternatively polled to simultaneously measure multiple analytes to provide a more comprehensive assessment of physiological status. For example, as illustrated in the schematic diagram of Figure 4, the 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 the microneedle array can be configured to detect any suitable number of analytes (e.g., 1, 2, 3, 4, 5, or more, etc.). Suitable target analytes to be detected may include, for example, blood glucose, ketones, lactate, and cortisol. Therefore, the individual electrical addressability of the microneedle array 300 provides greater control and flexibility in the sensing function of the analyte monitoring device.

In some variations of the microneedle (e.g., microneedles with a working electrode), electrode 320 may be located near the insulated distal vertex 316 of the microneedle. In other words, in some variations, electrode 320 does not cover the vertex of the microneedle. Instead, electrode 320 may be offset from the vertex or tip of the microneedle. The proximity or offset of electrode 320 from the insulated distal vertex 316 of the microneedle advantageously provides more accurate sensor measurements. For example, this arrangement prevents the electric field from concentrating at the tip 316 of the microneedle during manufacturing, thereby avoiding uneven electrodeposition of sensing chemicals on the surface of electrode 320 that could lead to false sensing.

As another example, positioning the electrode 320 off-center from the microneedle apex further improves sensing accuracy by reducing unwanted signal artifacts and/or erroneous sensor readings caused by stress during microneedle insertion. The distal apex of the microneedle is the first area penetrating the skin and therefore experiences the greatest stress due to mechanical shearing phenomena accompanying skin tearing or cutting. If the electrode 320 is placed on the apex or tip of the microneedle, this mechanical stress can cause delamination of the electrochemical sensing coating on the electrode surface when the microneedle is inserted, and/or result in less tissue interference being delivered to the active sensing portion of the electrode. Therefore, positioning the electrode 320 sufficiently off-center 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 from the distal apex or tip of the microneedle (e.g., between about 20 μm and about 30 μm), as measured along the longitudinal axis of the microneedle.

The body portion 312 of the microneedle 310 may also include a conductive path extending between the electrode 320 and a back-side electrode or other electrical contact (e.g., disposed on the back side of the substrate of the microneedle array). The back-side electrode may be soldered to a circuit board, thereby enabling electrical communication with the electrode 320 via the conductive path. For example, during use, a body-induced current (inside the dermis) measured at the working electrode is polled by the back-side electrical contact, and an electrical connection between the back-side electrical contact and the working electrode is facilitated by the conductive path. In some variations, this conductive path may be facilitated by a metal via through the interior of the microneedle body portion (e.g., a rod) between the proximal and distal ends of the microneedle. Alternatively, in some variations, this conductive path may be provided by the entire body portion formed of a conductive material (e.g., doped silicon). In some of these variations, the entire substrate over 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 by an insulating barrier comprising an electrically insulating material (e.g., a dielectric material such as silicon dioxide) surrounding a conductive path extending between the electrode 320 and the back-side electrical contact. For example, the body portion 312 may include an insulating material that forms a sheath around the conductive path, thereby preventing electrical continuity between the conductive path and the substrate. Other example variations of the structure capable of achieving electrical isolation between microneedles are described in more detail below.

This electrical isolation between the microneedles in the microneedle array allows for individual addressing of the sensors. This individual addressability advantageously enables independent and parallel measurements between sensors, as well as dynamic reconfiguration of sensor assignments (e.g., assignment to different analytes). In some variations, the electrodes in the microneedle array can be configured to provide redundant analyte measurements, an advantage over conventional analyte monitoring devices. For example, redundancy can improve performance by increasing accuracy (e.g., averaging multiple analyte measurements for the same analyte, which reduces the impact of extremely high or low sensor signals on analyte level determination) and/or by improving device reliability through a reduced overall failure probability.

In some variations, as described in further detail below for the various variations of microneedles, microneedle arrays can be formed, at least in part, by suitable semiconductor and/or MEMS fabrication techniques and/or mechanical cutting or dicing. For example, such processes may be advantageous for enabling the large-scale, cost-effective fabrication of microneedle arrays.

In some variations, the microneedle may have a generally columnar body portion and a tapered distal portion with electrodes. For example, Figures 5A-5C show example variations of a microneedle 500 extending from a substrate 502. Figure 5A is a schematic cross-sectional side 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 columnar body portion 512, a tapered distal portion 514 terminating at an insulating distal apex 516, and an annular electrode 520 comprising a conductive material (e.g., Pt, Ir, Au, Ti, Cr, Ni, etc.) disposed on the tapered distal portion 514. As shown in Figure 5A, the annular electrode 520 may be close to (or offset from or spaced apart 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, electrode 520 may also be electrically isolated from columnar body portion 512 via a second distal insulating surface 515b. Electrode 520 may be electrically connected to conductive core 540 (e.g., conductive path) that extends along body portion 512 to a back-side electrical contact 530 (e.g., made of Ni/Au alloy) or other electrical pad in or on substrate 502. For example, body portion 512 may include conductive core material (e.g., highly doped silicon). As shown in FIG5A, in some variations, insulating moat 513 comprising insulating material (e.g., _SiO2 ) may be arranged around body portion 512 (e.g., around its periphery) and extends at least partially through substrate 502. Thus, insulating moat 513 may, for example, help prevent electrical contact between conductive core 540 and the surrounding substrate 502. Insulating moat 513 may also extend above the surface of body portion 512. The upper and/or lower surfaces of substrate 502 may also include a substrate insulating layer 504 (e.g., _SiO2 ). Therefore, the insulation provided by the insulating trench 513 and/or the substrate insulation 504 can at least partially contribute to the electrical isolation of the microneedles 500, enabling the microneedles 500 to be individually addressed within the microneedle array. Furthermore, in some variations, the insulating trench 513 extending above the surface of the body portion 512 can be used to increase the mechanical strength of the microneedle 500 structure.

The microneedle 500 can be formed at least in part by a suitable MEMS fabrication technique, such as plasma etching, also known as dry etching. For example, in some variations, the insulating trench 513 surrounding the body portion 512 of the microneedle can be made by first forming a trench in the silicon substrate from the back side of the substrate using depth reactive ion etching (DRIE), and then filling the trench with a _SiO2 /poly-Si/ _SiO2 sandwich structure using low-pressure chemical vapor deposition (LPCVD) or other suitable processes. In other words, the insulating trench 513 can passivate the surface of the body portion 512 of the microneedle and continue to serve as a buried feature in the substrate 502 located near the proximal portion of the microneedle. By primarily comprising silicon compounds, the insulating trench 513 can provide good filling and adhesion to adjacent silicon walls (e.g., the silicon walls of the conductive core 540, substrate 502, etc.). The sandwich structure of the insulating trench 513 can also help provide a perfect match between the coefficient of thermal expansion (CTE) and the adjacent silicon, thereby advantageously reducing faults, fractures and/or other thermally induced weaknesses in the insulating trench 513.

The tapered distal portion can be formed from the front side of the substrate via isotropic dry etching, and the body portion 512 of the microneedle 500 can be formed via DRIE. The front metal electrode 520 can be deposited and patterned on the distal portion via specialized photolithography (e.g., electron beam evaporation), which allows metal to be deposited in the desired annular region of the electrode 520 without coating the distal vertex 516. Furthermore, the back-side electrical contact 530 of Ni/Au can be deposited via appropriate MEMS fabrication techniques (e.g., sputtering).

The microneedle 500 can have any suitable size. As an example, in some variations, the height of the microneedle 500 can be between about 300 μm and about 500 μm. In some variations, the tip angle of the tapered distal portion 514 can be between about 60 degrees and about 80 degrees, and the apex diameter can be between about 1 μm and about 15 μm. In some variations, the surface area of the annular electrode 520 can include between about 9,000 ^μm² and about 11,000 ^μm² , or about 10,000 ^μm² .

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

Typically, the working electrode is the electrode where the oxidation and/or reduction reactions of interest occur when detecting the analyte of interest. The counter electrode's role is to generate (provide) or absorb (accumulate) electrons via current, which are required to sustain the electrochemical reaction at the working electrode. The reference electrode's function is to provide a reference potential for the system; that is, the potential at which the working electrode is biased is called the reference electrode potential. 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 generated or absorbed from the reference electrode. Furthermore, to realize such a three-electrode system, the analyte monitoring device may include a suitable potentiostat or electrochemical simulation front end to maintain a fixed potential relationship (via an electron feedback mechanism) between the working and reference electrode sets within the electrochemical system, while allowing the counter electrode to dynamically swing to the potential required to sustain the redox reaction of interest.

working electrode

As described above, the working electrode is the electrode where the oxidation and/or reduction reactions of interest occur. In some variations, sensing can be performed at the interface between the working electrode and the interstitial fluid in the body (e.g., on the entire outer surface of the microneedle). In some variations, the working electrode may include an electrode material and a biorecognition layer, wherein biorecognition elements (e.g., enzymes) are immobilized on the working electrode to facilitate the quantification of selective analytes. In some variations, the biorecognition layer may also act as an interference barrier layer and may help prevent endogenous and/or exogenous species from being directly oxidized (or reduced) at the electrode.

The redox current detected at the working electrode may be related to the detection concentration of the analyte of interest. This is because, assuming a steady-state, diffusion-limited system, the redox current detected at the working electrode follows the Cottarell relationship:

Where n is the stoichiometric number of electrons that mitigate the redox reaction, F is the Faraday 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 for which the system is biased by the potential. Therefore, the detection current at the working electrode is linearly proportional to the analyte concentration.

Furthermore, since the detected current is a direct function of the electrode surface area A, the electrode surface area can be increased to improve the sensor's sensitivity (e.g., amperes per mole of analyte). For example, multiple individual working electrodes can be grouped into arrays of two or more components to increase the total effective sensing surface area. Additionally or alternatively, for redundancy, multiple working electrodes can be operated as parallel sensors to obtain multiple independent measurements of the concentration of the analyte of interest. The working electrode can be used as an anode (causing oxidation of the analyte surface) or as a cathode (causing reduction of the analyte surface).

Figure 6A illustrates a schematic diagram of a set of exemplary layers for the working electrode 610. For example, as described above, in some variations, the working electrode 610 may include an electrode material 612 and a biometric layer including a biometric element. The electrode material 612 facilitates the electrocatalytic detection of an analyte or a product of the reaction between the analyte and the biometric element. The electrode material 612 also provides an ohmic contact and routes an electrical signal from the electrocatalytic reaction to the processing circuitry. In some variations, the electrode material 612 may include platinum, as shown in Figure 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.

In some variations, the electrode material 612 may be coated with a highly porous electrocatalytic layer, such as a platinum black layer 613, which can increase the electrode surface area to improve sensitivity. Additionally or alternatively, the platinum black layer 613 can enable the electrocatalytic oxidation or reduction of the products 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). Without the platinum black layer 613, the electrode can still achieve the electrocatalytic oxidation or reduction of the products of the biorecognition reaction.

A biorecognition layer 614 may be disposed above electrode material 612 (or platinum black layer 613, if present) and used to immobilize and stabilize the biorecognition element, which facilitates quantification of selective analytes over a longer period. In some variations, the biorecognition element may include an enzyme, such as an oxidase. As an exemplary variation for use in a blood glucose monitoring system, the biorecognition element may include glucose oxidase, which converts glucose into an electroactive product (i.e., hydrogen peroxide) detectable at the electrode surface in the presence of oxygen. Specifically, the redox equations associated with this exemplary variation are glucose + oxygen → hydrogen peroxide + gluconolactone (mediated by glucose oxidase); hydrogen peroxide → water + oxygen (mediated by applying an oxidation potential at the working electrode).

However, in other variants, the biometric element may additionally or alternatively include another suitable oxidase or oxidoreductase, such as lactate oxidase, alcohol oxidase, β-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbic acid oxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, uricase oxidase, urease, and/or xanthine oxidase.

In some variants, the biorecognition element can be crosslinked with an amine condensation carbonyl chemical, which helps stabilize the biorecognition element within the biorecognition layer 614. As further described below, in some variants, crosslinking of the biorecognition element can result in the microneedle array being compatible with ethylene oxide (EO) sterilization, allowing the entire analyte monitoring device (including sensing elements and electronics) to be exposed to the same sterilization cycle, thereby simplifying the sterilization process and reducing manufacturing costs. For example, the biorecognition element can be crosslinked with glutaraldehyde, formaldehyde, glyoxal, malondialdehyde, butyraldehyde, and/or other suitable substances. In some variants, the biorecognition element can be crosslinked with such an amine condensation carbonyl chemical to form crosslinked biorecognition element aggregates. The crosslinked biorecognition element aggregates having at least a threshold molecular weight can then be embedded in a conductive polymer. By embedding only those aggregates having the threshold molecular weight, any uncrosslinked enzymes can be screened out without being incorporated into the biorecognition layer. Therefore, only aggregates with the desired molecular weight can be selected for the conductive polymer to help ensure that the biorecognition layer includes only sufficiently stable cross-linked enzyme entities, thus contributing to a biorecognition layer that is generally more suitable for EO sterilization without sacrificing sensing performance. In some variants, only cross-linked aggregates with a molecular weight at least twice that of glucose oxidase can be embedded in the conductive polymer.

In some variants, conductive polymers may exhibit permeability selectivity, contributing to the robustness of biorecognition layers against circulating amphoteric electroactive substances (such as ascorbic acid, vitamin C, etc.), whose fluctuations can adversely affect sensor sensitivity. Such selectively permeable conductive polymers in biorecognition layers can also be more robust to pharmacological interferences in interstitial fluids (e.g., acetaminophen) that can affect sensor accuracy. For example, conductive polymers can be selectively permeable by removing excess charge carriers through an oxidative electropolymerization process or by neutralizing these charges with counterion dopants, thereby converting the conductive polymer into a non-conductive form. These oxidatively polymerized conductive polymers exhibit permeability selectivity, thus being able to reject ions with similar charge polarity to the dopant ions (net positive or negative), or exclude them due to the dense, compact form of the conductive polymer through pore size.

Furthermore, in some variants, conductive polymers may exhibit self-sealing and/or self-healing properties. For example, conductive polymers can undergo oxidative electropolymerization, during which the conductive polymer may lose its conductivity as the thickness of the conductive polymer deposited on the electrode increases, until a lack of sufficient conductivity leads to a reduction in the deposition of additional conductive polymer. If the conductive polymer is subjected to minor physical damage (e.g., during use), the polymer backbone can reorganize to neutralize free charges, thereby reducing the total surface energy of the molecular structure, which can manifest as self-sealing and/or self-healing properties.

In some variations, the working electrode may also include a diffusion restriction layer 1615 disposed above the biorecognition layer 614. The diffusion restriction layer 615 can be used to limit the flux of the analyte of interest to reduce the sensor's sensitivity to fluctuations in endogenous oxygen. For example, the diffusion restriction layer 615 can attenuate the concentration of the analyte of interest, making it a limiting reactant for aerobic enzymes. However, in some variations (e.g., if the biorecognition element is not aerobic), the diffusion restriction layer 615 may be omitted.

In some variations, the working electrode may also include a hydrophilic layer 616, which provides a biocompatible interface to, for example, reduce foreign body reactions. However, in some variations, the hydrophilic layer 616 may be omitted (e.g., if the diffusion-limiting layer expresses a hydrophilic portion for this purpose), as shown in Figures 6D and 6G. Counter electrode

As described above, a counter electrode is an electrode that generates or absorbs electrons (via current) at the working electrode to sustain the electrochemical reaction. 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 necessary to have an excess counter electrode area relative to the working electrode area to circumvent current carrying capacity limitations. If the working electrode is used as the anode, the counter electrode will act as the cathode, and vice versa. Similarly, if 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 at the working electrode.

As shown in Figure 6B, the counter electrode 620 may include electrode material 622, similar to electrode material 612. For example, like electrode material 612, electrode material 622 in the counter electrode 620 may include noble metals such as gold, platinum, palladium, iridium, carbon, doped diamond, and/or other suitable catalytic and inert materials.

In some variations, the counter electrode 620 may have little or no additional layer above the electrode material 632. However, in some variations, the counter electrode 620 may benefit from 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 to increase the surface area of the electrode material 632, thereby enhancing its current generation or absorption capacity. Additionally or alternatively, the counter electrode 620 may include a platinum black layer 624, which may increase the electrode surface as described above with respect to some variations of the working electrode. However, in some variations of the counter electrode, the platinum black layer may be omitted (e.g., as shown in FIG. 6E). In some variations, the counter electrode may also include a hydrophilic layer that provides a biocompatible interface to, for example, reduce foreign body reactions.

Additionally or alternatively, in some variations shown in FIG. 6H, the counter electrode 620 may include a diffusion confinement layer 625 (e.g., disposed above the electrode). The diffusion confinement layer 625 may, for example, be similar to the diffusion confinement layer 615 described above with respect to FIG. 6A.

Reference electrode

As mentioned above, the function of the reference electrode is to provide a reference potential for the system; that is, the potential that biases the working electrode is called the reference electrode. A fixed or at least controlled potential relationship can be established between the working electrode and the reference electrode, and within practical limits, no current is generated from or absorbed by the reference electrode.

As shown in Figure 6C, the reference electrode 630 may include electrode material 632, similar to electrode material 612. In some variations, like electrode material 612, electrode material 632 in the reference electrode 630 may include a metal salt or metal oxide, which serves as a stable redox coupled to a known electrode potential. For example, the metal salt may include, for instance _, silver/silver chloride (Ag/AgCl), and the metal oxide may include iridium oxide (IrOx/ _Ir₂O₃ / _IrO₂ ). In other variations, noble metal and inert metal surfaces may be used as quasi-reference electrodes, including 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 to enhance adhesion to any subsequent layers. Such a subsequent layer on electrode material 632 may include a platinum black layer 634. However, in some variations, the platinum black layer may be omitted (e.g., as shown in Figures 6F and 6I).

In some variations, the reference electrode 630 may also include a redox coupling layer 636, which primarily comprises a surface-fixed solid-state redox coupling with a stable thermodynamic potential. For example, the reference electrode may operate at a stable standard thermodynamic potential relative to a standard hydrogen electrode (SHE). High stability of the electrode potential can be achieved by employing a redox system in which each participant in the redox reaction has a constant concentration (e.g., buffered or saturated). For example, the reference electrode may include saturated Ag/AgCl (E = +0.197 V with SHE) or IrOx (E = +0.177 V with SHE, pH = 7.00) in the redox coupling layer 636. Other examples of the redox coupling layer 636 may include a suitable conductive polymer with doped molecules, as described in U.S. Patent Publication 2019/0309433, the entire contents of which are incorporated herein by reference. In some variations, the reference electrode may be used as a half-cell to construct a complete electrochemical cell.

Additionally or alternatively, in some variations shown in FIG. 6I, the reference electrode 630 may include a diffusion confinement layer 635 (e.g., disposed over the electrode and/or redox coupling layer). The diffusion confinement layer 635 may, for example, be similar to the diffusion confinement layer 615 described above with respect to FIG. 16A.

Exemplary electrode layer formation

Working electrodes, counter electrodes, and reference electrodes of different layers can be applied to microneedle arrays and/or functionalized using appropriate processes (as described below).

In the pretreatment step of the microneedle array, the microneedle array can undergo plasma cleaning in an inert gas (e.g., an inert gas generated by RF, such as argon) plasma environment to make the material surfaces, including the electrode materials (e.g., the electrode materials 612, 622, and 632 mentioned above), more hydrophilic and more prone to chemical reactions. This pretreatment is not only used for the physical removal of organic debris and contaminants, but also for cleaning and preparing the electrode surfaces to enhance the adhesion of subsequently deposited films on their surfaces.

Multiple microneedles (e.g., any microneedle variant described herein, each of which may have the aforementioned working electrode, counter electrode, or reference electrode) can be arranged in a microneedle array. Considerations for configuring the microneedles include factors such as the desired insertion force for skin penetration with the microneedle array, optimization of electrode signal levels and other performance aspects, manufacturing cost, and complexity.

For example, a microneedle array may include multiple microneedles spaced apart at a predetermined spacing (the distance between the center of a microneedle and the center of its nearest neighbor). In some variations, the microneedles may be spaced sufficiently to distribute the force applied to the user's skin (e.g., to avoid a "bed of nails" effect) to allow the microneedle array to penetrate the skin. As the spacing increases, the force required to insert the microneedle array tends to decrease, and the penetration depth tends to increase. However, it has been found that the spacing only begins to affect the insertion force at low values (e.g., less than about 150 μm). Therefore, in some variations, the spacing of the microneedles in the microneedle array may be 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 spacing may be between about 200 μm and about 800 μm, between about 300 μm and about 700 μm, or between about 400 μm and about 600 μm. In some variations, the microneedles can be arranged in a periodic grid, and the spacing is uniform across all directions and all areas of the microneedle array. Alternatively, the spacing can vary when measured along different axes (e.g., the X and Y directions), and/or some areas of the microneedle array may include smaller spacing while other areas may include larger spacing.

Furthermore, for more consistent penetration, the microneedles can be spaced equidistantly (e.g., with the same spacing in all directions). For this purpose, in some variations, the microneedles in the microneedle array can be arranged in a hexagonal configuration as shown in Figure 7. Alternatively, the microneedles in the microneedle array can be arranged in a rectangular array (e.g., a square array) or in another suitable symmetrical manner.

Another consideration in determining the microneedle array configuration is the total signal level provided by the microneedles. Typically, the signal level at each microneedle is independent of the total number of microneedle elements in the array. However, the signal level can be enhanced by electrically interconnecting multiple microneedles together in the array. For example, an array with a large number of electrically connected microneedles is expected to produce a greater signal strength (and thus improved accuracy) compared to an array with fewer microneedles. However, having more microneedles on the diaphragm increases the diaphragm cost (given a constant spacing) and requires greater force and/or speed for insertion into the skin. Conversely, having fewer microneedles on the diaphragm can reduce diaphragm cost and enable insertion into the skin with reduced applied force and/or speed. Furthermore, in some variations, having fewer microneedles on the diaphragm reduces the overall footprint of the diaphragm, which can result in less unwanted localized edema and/or erythema. Therefore, in some variations, a balance between these factors can be achieved through a microneedle array including 37 microneedles as shown in Figure 7 or a microneedle array including 7 microneedles as shown in Figures 8A and 8C. However, in other variations, the array may contain fewer microneedles (e.g., between about 5 and about 35, between about 5 and about 30, between about 5 and about 25, between about 5 and about 20, between about 5 and about 15, between about 5 and about 100, between about 10 and about 30, between about 15 and about 25, etc.) or more microneedles (e.g., more than 37, more than 40, more than 45, etc.).

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

When considering the characteristics of microneedle array dies, the die size is related to the number of microneedles and the microneedle spacing in the microneedle array. Manufacturing cost is also a consideration, as a smaller die size will help reduce costs because the number of dies that can be formed from a single wafer of a given area will increase. Furthermore, due to the relative brittleness of the substrate, a smaller die size is less prone to brittle fracture.

Furthermore, in some variants, microneedles located on 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 the adhesive layer on the housing, along the outer boundary of the microneedle array, etc.) may exhibit better performance (e.g., sensitivity) compared to microneedles in the center of the microneedle array or die due to their superior penetration. Therefore, in some variants, the working electrode may be arranged mostly or entirely on the microneedles located on the periphery of the microneedle array to achieve more accurate and/or precise analyte measurements.

Figure 7 shows a schematic diagram of 37 microneedles arranged in an example variant of the microneedle array. For example, the 37 microneedles can be arranged in a hexagonal array, wherein the center-to-center spacing between the center of each microneedle and the center of its immediate neighbor in any direction is about 750 μm (or between about 700 μm and about 800 μm, or between about 725 μm and 775 μm).

Figures 8A and 8B show perspective views of illustrative schematic diagrams of seven microneedles 810 arranged in an example variant of microneedle array 800. The seven microneedles 810 are arranged in a hexagonal array on a substrate 802. As shown in Figure 8A, electrodes 820 are arranged on the distal portions of the microneedles 810 extending from a first surface of the substrate 802. As shown in Figure 8B, the proximal portions of the microneedles 810 are electrically connected to corresponding back-side electrical contacts 830 on a second surface of the substrate 802 opposite the first surface. Figures 8C and 8D show plan and side views of illustrative schematic diagrams of a microneedle array similar to microneedle array 800. As shown in Figures 8C and 8D, the seven microneedles are arranged in a hexagonal array, wherein the center-to-center spacing between the center of each microneedle and the center of its immediate neighbor in any direction is approximately 750 μm. In other variants, the center-to-center spacing may, for example, be between approximately 700 μm and approximately 800 μm, or between approximately 725 μm and approximately 775 μm. The approximate outer diameter of the microneedle can be about 170 μm (or between about 150 μm and about 190 μm, or between about 125 μm and about 200 μm) and the height can be about 500 μm (or between about 475 μm and about 525 μm, or between about 450 μm and about 550 μm).

Furthermore, the microneedle array described herein is highly configurable with one or more working electrodes, one or more counter electrodes, and one or more reference electrodes located within the microneedle array. This configurability can be facilitated by electronic systems.

In some variations, the microneedle array may include electrodes distributed in two or more groups in a symmetrical or asymmetrical manner within the microneedle array, each group having the same or different number of electrode components, depending on the requirements for signal sensitivity and/or redundancy. For example, electrodes of the same type (e.g., working electrodes) may be distributed in the microneedle array in a bilaterally or radially symmetrical manner. For example, Figure 9A shows a variation 900A of the microneedle array, which includes two symmetrical groups of seven working electrodes (WE), labeled “1” and “2”. In this variation, the two working electrode groups are distributed in a bilaterally symmetrical manner within the microneedle array. The working electrodes are typically arranged between the central region of three reference electrodes (RE) and the outer peripheral region of twenty counter electrodes (CE). In some variations, each of the two working electrode groups may include seven working electrodes electrically connected to each other (e.g., to enhance the sensor signal). Alternatively, one or only a portion of both of these working electrode groups may include multiple electrodes electrically connected to each other. As yet another alternative, a working electrode group may include independent working electrodes that are not electrically connected to the other working electrodes. Furthermore, in some variants, the working electrode array can be distributed in an asymmetric or random configuration within the microneedle array.

As another example, Figure 9B shows a variant 900B of the microneedle array, which includes four symmetrical groups of three working electrodes (WE), labeled “1”, “2”, “3”, and “4”. In this variant, the four working electrode groups are distributed radially symmetrically within the microneedle array. Each working electrode group is adjacent to one of the two reference electrode (RE) groups in the microneedle array and arranged symmetrically. The microneedle array also includes counter electrodes (CE) arranged around the periphery of the microneedle array, except for two electrodes at the vertices of the hexagons, which are inactive or can be used for other features or operating modes.

In some variants, only a portion of the microneedle array may include active electrodes. For example, Figure 9C shows a variant 900C of the microneedle array with 37 microneedles and a reduced number of active electrodes, including four working electrodes (labeled "1", "2", "3", and "4") arranged symmetrically on both sides, twenty-two 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 set of counter electrodes. Two such sets of working and counter electrode clusters are separated by a row of three reference electrodes.

As another example, Figure 9D shows a variant 900D of the microneedle array, which has 37 microneedles and a reduced number of active electrodes, including four working electrodes (labeled “1”, “2”, “3”, and “4”) arranged symmetrically on both sides, twenty counter electrodes, and three reference electrodes, wherein the remaining ten electrodes in the microneedle array are inactive.

As another example, Figure 9E shows a variant 900E of the microneedle array, which has 37 microneedles and a reduced number of active electrodes, including four working electrodes (labeled "1", "2", "3", and "4"), eighteen counter electrodes, and two reference electrodes. The remaining thirteen electrodes in the microneedle array are inactive. The inactive electrodes are arranged along a portion of the periphery of the entire microneedle array, thereby reducing the effective size and shape of the active microneedle arrangement to a smaller hexagonal array. In the active microneedle arrangement, the four working electrodes are typically arranged radially symmetrically, and each working electrode is surrounded by a set of counter electrodes.

Figure 9F shows another example variant of the microneedle array, 900F, which has 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 thirty 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 arrangement to a smaller hexagonal array centered on the reference electrode. In the active microneedle arrangement, the four working electrodes are arranged symmetrically on both sides, and the counter electrodes are equidistant from the central reference electrode.

Figure 9G shows another example variant 900G of the microneedle array, which has 37 microneedles and a reduced number of active electrodes. The active electrodes in microneedle array 900G are arranged in a similar manner to those 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 active microneedle array is centered on the counter electrode. In the active microneedle arrangement, the four working electrodes are arranged symmetrically on both sides, and the reference electrodes are equidistant from the central counter electrode.

Figure 9H shows another example variant 900H of the microneedle array, which has seven microneedles. This microneedle arrangement includes two microneedles (1 and 2) designated as independent working electrodes, a counter electrode group consisting of four microneedles, and a single reference electrode. The working and counter electrodes are arranged with bilateral symmetry and are equidistant from the central reference electrode. Furthermore, the working electrodes are positioned as far away from the center of the microneedle array as possible (e.g., on the die or at the periphery of the array) to take advantage of locations where the working electrodes are expected to have higher sensitivity and overall performance.

Figure 9I shows another example variant 900I of the microneedle array, which has seven microneedles. This microneedle arrangement comprises four microneedles designated as two separate groups (1 and 2) each containing two working electrodes, a counter electrode group consisting of two microneedles, and a reference electrode. The working and counter electrodes are arranged with bilateral symmetry and are equidistant from the central reference electrode. Furthermore, the working electrodes are positioned as far away from the center of the microneedle array as possible (e.g., on the die or periphery of the array) to take advantage of locations where the working electrodes are expected to have higher sensitivity and overall performance.

Figure 9J shows another example variant 900J of the microneedle array, which has seven microneedles. This microneedle arrangement includes four microneedles (1, 2, 3, and 4) designated as independent working electrodes, a counter electrode group consisting of two microneedles, and a reference electrode. The working and counter electrodes are arranged with bilateral symmetry and are equidistant from the central reference electrode. Furthermore, the working electrodes are positioned as far away from the center of the microneedle array as possible (e.g., on the die or periphery of the array) to take advantage of locations where higher sensitivity and overall performance are expected.

While Figures 9A-9J show example variations of microneedle array constructions, it should be understood that these figures are not limiting, and other microneedle constructions (including different numbers and/or distributions of working electrodes, counter electrodes, and reference electrodes, as well as different numbers and/or distributions of active and inactive electrodes, etc.) can be applied to other variations of microneedle arrays.

Simulated front end

In some variations, the electronic 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 Figure 2A) that converts analog current measurements into digital values that can be processed by a microcontroller. The analog front-end may, for example, include a programmable analog front-end suitable for use with electrochemical sensors. For instance, the analog front-end may include the MAX30131, MAX30132, or MAX30134 components (with 1, 2, and 4 channels, respectively) from Maxim Integrated (San Jose, California), which are ultra-low-power programmable analog front-ends for electrochemical sensors. The analog front-end may also include the AD5940 or AD5941 components from Analog Devices (Norwood, Massachusetts), which are high-precision, impedance, and electrochemical front-ends. Similarly, the analog front-end may include the LMP91000 from Texas Instruments (Dallas, Texas), a configurable analog front-end potentiostat for low-power chemical sensing applications. The analog front end can provide bias and a complete measurement path, including an analog-to-digital converter (ADC). Ultra-low power allows for continuous sensor bias to maintain accuracy and fast response when long-term (e.g., 7 days) measurements are required using wearable battery-operated devices.

In some variants, the analog front-end device can be compatible with two- and three-terminal electrochemical sensors, for example, to enable DC current measurement, AC current measurement, and electrochemical impedance spectroscopy (EIS) measurement capabilities. Furthermore, the analog front-end can include an internal temperature sensor and a programmable voltage reference, supporting external temperature monitoring and external reference sources, and integrating bias voltage and supply voltage monitoring for safety and compliance.

In some variations, the analog front end may include a multichannel potentiostat to multiplex sensor inputs and process multiple signal channels. For example, the analog front end may include a multichannel potentiostat as described in U.S. Patent 9,933,387, the entire contents of which are incorporated herein by reference.

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

microcontroller

In some variations, the electronic system of the analyte monitoring device may include at least one microcontroller (e.g., controller 122 as shown in Figure 2A). This microcontroller may, for example, include a processor with integrated flash memory. In some variations, the microcontroller in the analyte monitoring device may be configured to perform analysis to correlate sensor signals with analyte measurements (e.g., glucose measurements). For example, the microcontroller may execute programming routines in firmware to interpret digital signals (e.g., from an analog front end), perform any relevant algorithms and/or other analyses, and route processed data to and/or from a communication module. By maintaining the analysis on the analyte monitoring device, the device may be able to broadcast one or more analyte measurement results in parallel to multiple devices (e.g., mobile computing devices such as smartphones or smartwatches, therapeutic delivery systems such as insulin pens or pumps, etc.) while ensuring that each connected device has the same information.

In some variations, the microcontroller can be configured to activate and/or deactivate the analyte monitoring device under one or more detected conditions. For example, the device can be configured to activate the analyte monitoring device when the microneedle array is inserted into the skin. This could, for example, enable a power-saving function where the battery is disconnected until the microneedle array is placed in the skin, at which point the device can begin broadcasting sensor data. This feature could, for example, help improve the shelf life of the analyte monitoring device and/or simplify the user's analyte monitoring device-external device pairing process.

Some aspects of the current topic relate to fault detection and diagnostics associated with microneedle array-based analyte monitoring devices (e.g., analyte monitoring device 110). Electrochemical sensors configured to measure one or more target analytes (e.g., electrodes of analyte monitoring device 110) may encounter various faults during use of analyte monitoring device 110. Faults can be deficiencies in one or more aspects of analyte monitoring device 110, where deficiencies affect the operation of analyte monitoring device 110. Examples of malfunctions include degradation of the electrode membrane (e.g., cracking, delamination, and/or other damage to the membrane structure and/or surface affecting sensing), degradation of biometric elements (e.g., disuse and/or denaturation), physiological responses to microneedle array implantation (e.g., foreign body reactions, encapsulation, protein adhesion, or collagen formation in response to the insertion of microneedles with electrodes formed on them), improper placement or insertion of the microneedle array (e.g., microneedles with electrodes formed on them are not placed at a sufficient depth 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). Malfunctions can affect the electrical and/or electrochemical behavior of the analyte monitoring device 110, leading to errors and/or unreliability in the measurement of one or more target analytes. In some cases, malfunctions may be temporary, such as in the case of pressure decay. In other cases, malfunctions may permanently affect the operation of the analyte monitoring device 110.

Some faults can be detected by monitoring current consumption. For example, the induced current value at the working electrode of the analyte monitoring device 110 can indicate and/or be associated with some faults. In these cases, if the induced current exhibits extreme, unstable, and/or unexpected behavior or patterns, the fault can be determined based on the characteristics of the exhibited behavior or patterns of the induced current. Extreme, unstable, and/or unexpected behavior or patterns of the induced current can be characterized by rapid rates of change that are physiologically impossible or improbable. High noise may also contribute to the behavior or patterns of the induced current.

However, other faults do not affect the induced current, but still influence the electrical and/or electrochemical behavior of the analyte monitoring device 110. Therefore, alternative or additional variables are needed to gain insight into and verify changes in 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, faults can be detected by monitoring the voltage at the counter electrode.

While various types of malfunctions, such as those described above, may occur, a malfunction is typically characterized by whether the analyte monitoring device 110 can recover from the malfunction (e.g., the malfunction is temporary) or whether the analyte monitoring device 110 is damaged and should cease operation (e.g., the malfunction is permanent). This characterization can be made by monitoring the counter electrode voltage, and in some variations, how the counter electrode voltage corresponds to or relates to the induced current, and the response to the malfunction can be determined. The response to the malfunction can take the form of operating modes of the analyte monitoring device. For example, if the malfunction is temporary, the operating mode may include blanking and/or ignoring any sensing data during the malfunction. In this case, the sensing data is inaccurate and therefore not reported to the user or used for operational purposes. If the malfunction is permanent, the operating mode may be to stop the operation of the analyte monitoring device. In some variations, this may include stopping the application of a bias potential between the working electrode and the reference electrode.

In some variations, the counter electrode voltage is monitored to identify one or more characteristics that can serve as indicators of a fault. Characteristics indicating a fault may include the rate of change of the counter electrode voltage and/or the lower limit of compliance of the counter electrode voltage. This characteristic can 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. Therefore, the counter electrode voltage can be considered as the voltage required to support the current level (e.g., induced current) at the working electrode. When the induced current fluctuates or changes, the counter electrode voltage fluctuates or changes in a corresponding or opposite manner. If the induced current exhibits a rapid rate of change, the counter electrode voltage responds with a rapid rate of change. The correspondence or correlation between the induced current and the counter electrode voltage can be defined as equal but opposite rates of change (or nearly equal but opposite rates of change (e.g., a difference of up to about 5% between the rates of change)). If the induced current changes at a specified rate, the counter electrode voltage changes at a specified rate in the opposite direction. The rate of change of the counter electrode voltage is then used as an indicator of the rate of change of the induced current. An induced current exhibiting a rapid rate of change is physiologically impossible or unacceptable. Therefore, by monitoring the counter electrode voltage, the physiological feasibility of the induced current can be determined. Since a rapid rate of change is physiologically impossible, this change serves as an indication of a device malfunction. In some variants, a rapid rate of change in the counter electrode voltage can be defined as approximately 0.10 V/min. In other variants, a rapid rate of change in the counter electrode voltage can be defined as between approximately 0.05 V/min and approximately 0.15 V/min. For example, in some variants, a rapid rate of change in the counter electrode voltage can be defined as approximately 0.05 V/min, approximately 0.06 V/min, approximately 0.07 V/min, approximately 0.08 V/min, approximately 0.09 V/min, approximately 0.10 V/min, approximately 0.11 V/min, approximately 0.12 V/min, approximately 0.13 V/min, approximately 0.14 V/min, or approximately 0.15 V/min. The rapid rate of change in the induced current can be correlated with the rate of change of the analyte being measured. In the glucose example, the rapid rate of change could be approximately 4 mg/dL/min. In some variants, the rapid rate of change of glucose can range from about 3.5 mg/dL/min to about 6 mg/dL/min.

The lower limit of compliance of the counter electrode voltage can be defined as the lowest level to which the counter electrode voltage can swing. The counter electrode voltage can also have an upper limit of compliance, i.e., the highest level to which the counter electrode voltage can swing. If the counter electrode voltage swings to the lower limit of compliance, this can serve as an indication that the induced current has reached a physiologically impossible high amplitude, thus indicating the occurrence of a fault.

Therefore, a counter electrode voltage that meets or exceeds a threshold rate of change and/or meets a compliance limit threshold is used as an indication of a fault within the analyte monitoring device 110. In some variations, when a counter electrode voltage rate of change is identified as meeting or exceeding a threshold rate of change and/or when a counter electrode voltage meets a compliance limit threshold, characteristics or parameters of the counter electrode voltage can be compared with characteristics or parameters of the induced 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 induced current.

In some variations, the counter electrode voltage, corresponding to the induced current such that it changes at a rate equal to the induced current, represents pressure-induced signal attenuation. This pressure-induced signal attenuation can be caused by external pressure applied to the analyte monitoring device 110 and can be characterized as a temporary malfunction. When the external pressure is removed, the analyte monitoring device 110 operates as expected.

In some variations, the change in counter electrode voltage, corresponding to the change in induced current to maintain the correspondence, plus the counter electrode voltage satisfying the lower compliance limit, represents a change in the physiological environment surrounding the sensor and/or a change in the sensor surface. In other variations, the counter electrode voltage satisfying the lower compliance limit, regardless of the induced current, represents a change in the physiological environment and/or a change in the sensor surface. In this case, the counter electrode voltage does not need to be correlated with the induced current. Changes in the physiological environment surrounding the sensor and changes in the sensor surface are examples of permanent failures.

In some variations, a change in the counter electrode voltage that deviates from the induced current, causing the counter electrode voltage and the induced current to change in different ways, coupled with a rapid rate of change in the counter electrode voltage, can represent an external influence on the electronics of the analyte monitoring device. An external influence is an example of a permanent malfunction.

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

In some variants, the operating mode includes ignoring the induced current if a change in the counter electrode voltage corresponds to a change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change. As described herein, this represents pressure-induced signal attenuation. When pressure-induced signal attenuation is removed from the counter electrode voltage and induced current (e.g., the rate of change of the counter electrode voltage does not exceed a threshold rate of change), the induced current is no longer ignored because the fault has been repaired.

In some variants, the operating mode includes: if a change in the counter electrode voltage corresponds to a change in the induced current and if the lower compliance limit of the counter electrode voltage meets the compliance limit threshold, then the application of a potential between the working electrode and the reference electrode is stopped. Reaching the compliance limit threshold indicates a permanent fault, at which point the bias potential is eliminated to stop operation.

In some variants, the operating mode includes stopping the application of a potential between the working electrode and the reference electrode if the change in the counter electrode voltage deviates from the change in the induced current and if the rate of change of the counter electrode exceeds a threshold rate of change. This is an indication of a permanent fault, at which point the bias potential is removed to stop operation.

As further described herein, a reference electrode is used to provide a reference potential for a three-electrode electrochemical system realized by analyte monitoring device 110. The potential biased at the working electrode is referred to as 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 generated or absorbed from the reference electrode. To realize such a three-electrode electrochemical system, analyte monitoring device 110 includes a potentiostat or electrochemical simulation front end (e.g., a simulation front end) to maintain a fixed potential relationship between the working electrode and the reference electrode group within the three-electrode electrochemical system, while allowing the counter electrode to dynamically swing to the potential required to sustain the redox reaction of interest. By biasing the electrochemical system with a potentiostat or simulation front end to establish a potential relationship between the working electrode and the reference electrode, a redox reaction is driven at the working electrode, resulting in the counter electrode absorbing current during oxidation or generating current during reduction 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 the impedance or resistance between the working and counter electrodes. Biasing the electrochemical system results in 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 the impedance or resistance between the working and counter electrodes.

The voltage at the counter electrode is adjusted to a potential so that the redox reaction occurring at the working electrode is balanced while the working electrode maintains a potential relationship with the reference electrode. In the event of a fault (where one or more aspects of the analyte monitoring device 110 affect its operation), the voltage at the counter electrode is modulated and reflected in the accumulated impedance 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 that correlate 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 fault types. By correlating or characterizing the impedance with certain conditions including faults in the three-electrode electrochemical system, the voltage value can be associated with one or more faults.

Figure 10 illustrates a potentiostat circuit 1000 of the analyte monitoring device 110. The potentiostat circuit 1000 may be part of the sensor circuit 124, as shown in and described with reference to Figure 2A. The potentiostat circuit 1000 includes an electrochemical cell 1010 connecting the working electrode and the counter electrode of a three-electrode electrochemical system.

Figure 11 shows the Randles equivalent circuit 1100 representing the electrochemical cell 1010 shown in Figure 10A. The Randles equivalent circuit 1100 includes a solution resistance _Rs (also referred to as uncompensated resistance _Ru or _RΩ ), a charge transfer resistance _Rct , and a double-layer capacitance _Cdl between the counter electrode 1120 and the working electrode 1110. The solution resistance _Rs is connected in series with a parallel combination of the charge transfer resistance _Rct and the double-layer capacitance _Cdl . The Randles equivalent circuit 1100 is connected at the terminals between the counter electrode 1120 and the working electrode 1110. The solution resistance _Rs indicates the ohmic contact level between the counter electrode 1120 and the working electrode 1110 and can indicate the electrolytic content/ionic strength of the medium in which the analyte monitoring device 110 is operating (e.g., the liquid in which the electrodes of the microneedle array are located, e.g., interstitial fluid). The charge transfer resistance _Rct indicates the magnitude of the electrochemical reaction occurring at the working electrode 1110. The double-layer capacitor C _dl indicates the surface morphology and selected area at the working electrode 1110 (e.g., the composition and components of the surface of the working electrode 1110).

The Randles equivalent circuit 1100 of the electrochemical cell 1010 of the analyte monitoring device 110 is a simplified representation of the redox reactions occurring within the electrochemical cell 1010. By modeling the electrochemical cell 1010 with the Randles equivalent circuit 1100, contributions from solution resistance R_{_s} , charge transfer resistance R _{_ct} , and double-layer capacitance C _{_dl} can be identified. Frequency response analysis (including amplitude and phase components) can be used to understand the impedance behavior of the electrochemical cell 1010 under DC (ω→0) and AC (ω→∞) frequency perturbations. In the DC case, the voltage at the counter electrode 1120 provides an assessment of the overall resistive components of the system (e.g., R _{_s} + R _{_ct} ) since it is assumed that C _{_dl} has infinite impedance ω→0. At the other extreme, such as ω→∞, C _{_dl} approaches negligible impedance, and R_{_ct} is bypassed. This allows for the individual quantification of R _{_s}, which can be achieved by applying a pulse or unit step function to the counter electrode 1120.

In the DC case (ω→0), when additional current must be generated or absorbed to maintain a fixed potential relationship between the working electrode and the reference electrode, the voltage at the counter electrode 1120 is expected to swing to a more extreme value, reaching the compliance voltage of the potentiostat. This is manifested via the counter electrode voltage migrated 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 provided by the circuit driving the counter electrode 1120. In the Randles equivalent circuit, this operating mode is manifested as the charge transfer resistance _Rct tending towards the value of the solution resistance _Rs . In the DC case, this indicates one or more of the following failures: a short circuit between the working electrode and the counter electrode, a problem with the ability of the reference electrode to maintain a stable thermodynamic potential, damage to the diffusion-limiting film, and a steady increase in the porosity of the sensing layer contained within the analyte-selective sensor.

When the current required to maintain a constant potential relationship between the working electrode and the reference electrode approaches a negligible value (e.g., the current flowing through the system is negligible, i→0), the counter electrode voltage approaches the voltage value that sustains the working electrode 1110. In the Randles equivalent circuit, this operating mode manifests as a charge transfer resistance R _{_ct} approaching infinity. In the DC case, this indicates one or more of the following faults: improper sensor insertion; improper access to a feasible tissue chamber; partial or complete sensor occlusion (e.g., due to bioaccumulation/protein adsorption/collagen formation/encapsulation), resulting in reduced analyte diffusion; and a problem with the reference electrode's ability to maintain a stable thermodynamic potential.

The voltage at the electrode can be measured by a potentiostat, an electrochemical simulation front-end, or a converter (such as a voltage-sensitive or current-sensitive analog-to-digital converter (ADC)).

In some cases, as shown in the measurement circuit 1200 in Figure 12, buffer 1210 and filter 1220 (e.g., low-pass filter) can provide isolation from converter 1230 to isolate components from the counter electrode included in electrochemical sensor 1240. In some embodiments, differential amplifiers, transimpedance amplifiers, or finite-gain amplifiers can be integrated. Filter 1220 can be located before converter 1230 to reduce interference from high-frequency, low-frequency, and/or band-limited signals on the measurement of electrode voltage.

In some cases, the voltage generated at one or more working electrodes is measured and used to supplement and/or supplement fault identification. The working electrode voltage can be compared with the counter electrode voltage to assess and/or determine a fault. An analog-to-digital converter can be in electrical communication with the working electrodes. In some implementations, a constant current device is integrated to establish a desired current relationship between the working and counter electrodes.

According to Ohm's law (v = _Zi , where Z is the cumulative impedance of the analyte sensor), a voltage at the counter electrode approaching the voltage at the working electrode indicates that the analyte sensor impedance or resistance has decayed to a low level. This suggests one or more of the following faults: a short circuit between the working and counter electrodes, a problem with the reference electrode's ability to maintain a stable thermodynamic potential, damage to the diffusion-limiting film, 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 when the counter electrode voltage swings in the positive direction to support the current level at the working electrode (e.g., the induced current).

An increase in the difference between the voltage at the counter electrode and the voltage at the working electrode indicates that the impedance or resistance of the analyte sensor has increased to a very large value. This suggests one or more of the following malfunctions: improper sensor insertion; partial or complete sensor blockage (e.g., due to bioaccumulation/protein adsorption/collagen formation/encapsulation), resulting in reduced analyte diffusion; or a problem with the reference electrode's ability to maintain a stable thermodynamic potential. The difference between the counter electrode voltage and the working electrode voltage increases when the counter electrode voltage swings in the negative direction to support the induced current.

Therefore, in some cases, the voltages at the working electrode and the counter electrode are measured to identify faults. The voltage value at 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 the electrochemical cell using Nyquist plot and Bode plot formulas. The Bode plot shows the amplitude and phase response of the electrochemical cell.

Figure 13B is the Nyquist plot of the electrochemical cell, showing the real part (Re{Z}) and imaginary part (Im{Z}) of the electrochemical impedance as the radian frequency ω changes. According to the Randles equivalent circuit model, the zero imaginary part of the impedance is achieved in two cases: (1) when the radian frequency is close to ∞, allowing the estimation of the solution resistance (R _{_s} /R _{_Ω} ); (2) when the radian frequency is close to 0, allowing the estimation of the charge transfer resistance (R _{_ct} ) combined with the solution resistance R_{_s}. The perturbation of the electrochemical cell at these two extreme frequencies fully characterizes the real (resistive) part of the electrochemical cell. Assuming the electrochemical cell is purely capacitive, the semicircular interpolation between the two Im{Z}→0 intersections allows the calculation of the double-layer capacitance C _{_dl} .

Figure 14-17 is an example diagram illustrating the relationship between current and corresponding counter electrode voltage under different fault conditions, indicating the operational relationship between induced current and counter electrode voltage. This example diagram can be used to provide an indication of the sensor impedance variation between the counter electrode and the working electrode.

Figure 14 shows the relationship between the induced current graph 1410 and the corresponding counter electrode voltage graph 1420 and time. During normal operation (e.g., before points 1411, 1421 and between points 1413, 1423 and 1414, 1424), as the sensor current changes, the counter electrode voltage changes at equal or nearly equal but opposite rates of change, which can be considered as mirror responses in Figures 1410 and 1420. During normal operation without any faults, the rates of change of the counter electrode voltage and the induced current can 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. During normal operation, the difference between the rates of change of the counter electrode voltage and the rates of change of the induced current can vary within a range of nearly equal or substantially equal, up to 5%, or in some cases up to 10%.

Faults are indicated at points 1421, 1422, 1423, 1424, and 1425 in the counter electrode voltage, and correspond to points 1411, 1412, 1413, 1414, and 1415 in the induced current, respectively. 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 induced current. As shown in Figures 1410 and 1420, at the fault location, the counter electrode voltage corresponds to an induced current with an equal or nearly equal rate of change. For example, the difference between the rates of change may be as high as 5%, or in some cases as high as 10%.

Figure 15 (similar to Figure 14) shows the relationship between current graph 1510 and the corresponding counter electrode voltage graph 1520 over time. During normal operation (e.g., before points 1511, 1521 and between points 1511, 1521 and points 1512, 1522), the counter electrode voltage changes at equal but opposite rates of change as the sensor current changes, which can be viewed as a mirror response in Figures 1510 and 1520. During normal operation without any faults, the rates of change of the counter electrode voltage and the rates of change of the induced current can 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. During normal operation, the difference between the rates of change of the counter electrode voltage and the rates of change of the induced current can vary within a range of nearly equal or substantially equal, up to 5%, or in some cases up to 10%.

Faults are indicated at points 1521, 1522, 1523, and 1524 in the counter electrode voltage, and correspond to points 1511, 1512, 1513, and 1514 in the induced current, respectively. 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 induced current. As shown in Figures 1510 and 1520, at the fault location, the counter electrode voltage corresponds to an induced current with an equal or nearly equal rate of change. For example, the difference in the rate of change can be as high as 5%, or in some cases as high as 10%.

Figure 16 shows the relationship between the current graph 1610 and the corresponding counter electrode voltage graph 1620 and time. During normal operation (e.g., before points 1621, 1611), as the sensor current changes, the counter electrode voltage changes at equal or nearly equal but opposite rates of change, which can be considered as mirror responses in Figures 1610 and 1620. During normal operation without any faults, the rates of change of the counter electrode voltage and the rate of change of the induced current can 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. During normal operation, the difference between the rates of change of the counter electrode voltage and the rate of change of the induced current can vary within a range of nearly equal or substantially equal, up to 5%, or in some cases up to 10%.

The counter electrode voltage reaching the lower compliance limit at point 1621 is an indication of a fault. Point 1621 may correspond to a previous current spike at point 1611 in the sensor current, but in some cases, it may not be a clear correlation between the counter electrode voltage and the induced current. A fault at 1621, based on the lower compliance limit reached, represents a change in the physiological environment surrounding the sensor or a change in the sensor surface.

Figure 17 shows the relationship between current graph 1710 and the corresponding counter electrode voltage graph 1720 and time. Points 1721 and 1722, where the exhibited rapid rate of change represents a fault indicated by the counter electrode voltage, are shown in the figure and are independent of the current of the analyte monitoring device. Since there are no substantial fluctuations or unexpected changes in the current, points 1721 and 1722 indicate faults independent of the current of the analyte monitoring device, but related to external environmental influences, such as external effects on the electronics of the analyte monitoring device.

Figure 18 illustrates a schematic diagram of a fault detection and diagnostic system 1800 for monitoring counter electrode voltage and working electrode voltage according to the described embodiment. Aspects of the fault detection and diagnostic system 1800 may be integrated into an analyte monitoring device 110. A simulation front-end 1840, as described herein, maintains a fixed potential relationship between the working electrode 1810 and the reference electrode 1830 within the electrochemical system, while allowing the counter electrode 1820 to dynamically swing to the potential required to sustain the redox reaction of interest at the working electrode. Optionally, a converter 1815 coupled to the working electrode 1810 is 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 the counter electrode 1820 for voltage conversion. Converters 1815, 1825, and/or a single converter may be an analog-to-digital converter.

The digitized voltage signal is transmitted to a controller 1822 coupled to each converter. In some cases, the controller 122 shown in and described with reference to FIG. 2A may include operational aspects of the controller 1822. The controller 1822 may be a separate component. In some cases, the controller 122 is integrated instead of the controller 1822. According to some aspects described herein, the controller 1822 (and/or the controller 122) processes the counter electrode voltage, the induced current, and optionally the operating electrode voltage to identify faults and associated operating modes. The controller 1822 may provide instruction or correction signals to the three-electrode electrochemical system and may provide an output 1824 to alert the user to faults and optionally to fault modes. The output 1824 may be provided on the user interface of the analyte monitoring device and/or may be transmitted (e.g., wirelessly via near-field communication, Bluetooth, or other wireless protocols) to remote devices and/or remote servers.

In some variants, more than one working electrode is integrated and used for analyte detection. For example, in the 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 integrated. In variants that integrate more than one counter electrode, the counter electrodes are shorted together such that when the shorted counter electrodes act as a single counter electrode, a cumulative counter electrode voltage is monitored.

For more than one working electrode, each additional working electrode generates its own induced current. In some variations, the correlation between the counter electrode voltage and the induced current of each working electrode can be determined. Because each working electrode resides on a separate and discrete microneedle within the microneedle array, the faults that occur are inconsistent across the working electrodes. For example, electrode membrane degradation and biometric element degradation can vary across multiple working electrodes. Furthermore, regarding incorrect placement or insertion, in some cases, working electrodes may experience different insertion depths, meaning that while one or more working electrodes may be fully inserted, others may not be. In some cases, pressure decay can also have different effects on the working electrodes. Therefore, based on the differences occurring across the microneedle array, it is useful to monitor and analyze the counter electrode voltage separately for the induced current of each working electrode. Individual monitoring and analysis can be used to provide fault indication at one or more working electrodes. In some variations, when a fault is identified, the corresponding operating mode is applied.

If more than one fault is identified and the faults are different, the operating mode of stopping the application of a potential between the working electrode and the reference electrode takes precedence over the operating mode of blanking and/or ignoring sensor 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 potential applied at the faulty working electrode can be interrupted, while allowing continued operation of the remaining working electrodes. In some variations, a minimum number of operating working electrodes can be defined such that if the number of operating working electrodes meets or exceeds the minimum number, operation of the analyte monitoring device continues.

In some variations, the combined induced current is based on the combined induced currents of the working electrodes. For example, the induced currents from each working electrode can be averaged to form the combined induced current. As described herein, the combined induced current can be used in conjunction with the counter electrode voltage to determine faults and operating modes of the analyte monitoring device.

Further details related to the Randles equivalent model are provided. The impedance Z of the Randles equivalent model is given by the following relationship:

Z = R _{_s} + R _{_ct} || C _{_dl} [1]

Expanding this relationship to express impedance as a function of radian frequency ω:

In the DC case (zero frequency), the impedance is given by the following formula:

In the AC case (high-frequency limit), the impedance is given by the following formula:

Recalculate Equation 2:

The real and imaginary parts of the impedance given in Equation 5 can be easily identified as follows:

Provide a substitution:

The amplitude response of the system is given by the following equation:

The phase response is calculated accordingly:

The current _iCELL supported by the electrochemical reaction can be calculated by applying Kirchoff's voltage law to the Randle cell:

The counter electrode voltage _VCE can be calculated by reformulating the above relationship:

The current can be positive or negative, depending on the configuration of the potentiostat and whether the electrochemical reaction is oxidation or reduction. In the provided model and current working equation, it is assumed that current flows from the counter electrode (held at the highest potential) through the electrochemical cell and into the working electrode, which is held at a lower potential (e.g., the reference ground potential); this model assumes a reduction reaction (e.g., current flows into the working electrode, thus acting as an electron source). Alternatively, the counter electrode can be held at a lower potential than the working electrode (in the case of oxidation), causing current to flow from the working electrode into the counter electrode. In this case, the working electrode acts as an electron trap.

For the DC case:

V _CE ＝V _WE +i _CELL [R _s +R _ct ] [13]

For a given R_{_s} and R _{_ct} , V _{_CE} will track i _{_CELL} . For a finite charge transfer resistance R _{_ct} :

This is the compliant voltage limit of the potentiostat. In this case, there is no ohmic connection between the counter electrode and the working electrode. Similarly:

This represents the ideal operating conditions for an electrochemical system. This is achieved by operating in a medium with sufficient electrolytic/ionic strength (e.g., a buffer solution or the wearer's physiological fluid). Similarly, for a finite solution resistance R_{_s} :

In other words, when the current _iCELL through the electrochemical cell approaches zero due to infinite charge transfer resistance, the counter electrode voltage will approach the working electrode voltage. In practice, this manifests as complete passivation of the working electrode surface, preventing current flow; thus forming an ideal double-layer capacitor. As for the case where the charge transfer resistance approaches zero:

The current flowing through an electrochemical cell becomes independent of the charge transfer process (e.g., in 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 process).

In the AC case, as the frequency approaches its extreme value:

The current through an electrochemical cell becomes independent of the charge transfer process (e.g., in an electrolytic reaction). Similarly, in the DC case, as the frequency approaches zero:

This is the same as Equation 13.

Exemplary embodiments

Example I-1. An analyte monitoring device based on a microneedle array, comprising:

A working electrode includes an electrochemical sensing coating configured to generate a sensing current at the surface of the working electrode that indicates a redox reaction of an analyte, the working electrode being located on the surface of a distal portion of a first microneedle in a microneedle array.

A reference electrode is located on the surface of the distal portion of the second microneedle in the microneedle array;

The electrode is located on the surface of the distal portion of the third microneedle in the microneedle array;

The simulation front end is 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 in order to maintain the redox reaction at the working electrode;

The controller communicates with the analog front end and is configured to:

Monitor the counter electrode voltage at the counter electrode;

Identify the characteristics of the counter electrode voltage that meet or exceed a threshold;

In response to identifying the characteristic of the counter electrode voltage exceeding the threshold, the correlation between the counter electrode voltage and the induced current is determined; and

Based on the characteristics and correlation of the counter electrode voltage, the operating mode is applied to the microneedle array-based analyte monitoring device.

Example 1-2. The analyte monitoring device based on microneedle array according to Example 1-1, wherein the characteristic of the counter electrode voltage includes one or more of the rate of change of the counter electrode voltage or the lower limit of the compliance of the counter electrode voltage.

Example I-3. The analyte monitoring device based on microneedle array according to Example I-2, wherein the change in the counter electrode voltage and the change in the induced current indicate the correlation between the counter electrode voltage and the induced current.

Example I-4. The analyte monitoring device based on microneedle array according to Example I-3, wherein the operating mode includes ignoring the induced current if the change in the counter electrode voltage corresponds to the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change.

Example I-5. The analyte monitoring device based on microneedle array according to Example I-4, wherein the controller is further configured to: interrupt the operating mode of ignoring the induced current in response to subsequently determining that the rate of change of the counter electrode voltage does not exceed the threshold rate of change.

Example I-6. The analyte monitoring device based on microneedle array according to Example I-3, wherein the operating mode includes: if the lower compliance limit of the counter electrode voltage meets the compliance limit threshold, then stop applying a potential between the working electrode and the reference electrode.

Example I-7. The analyte monitoring device based on microneedle array according to Example I-3, wherein the operating mode includes: stopping the application of a potential between the working electrode and the reference electrode if the change in the counter electrode voltage deviates from the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change.

Example I-8. The analyte monitoring device based on microneedle array according to Example I-1 further includes:

One or more additional working electrodes, each of which generates a respective induced current;

The controller is further configured as follows:

In response to identifying the characteristic of the counter electrode voltage exceeding the threshold, the correlation between the counter electrode voltage and the respective induced current is determined.

Examples I-9. The analyte monitoring device based on microneedle array according to Examples I-8, wherein the operating mode is further based on the correlation between the counter electrode voltage and the respective induced current.

Example I-10. The analyte monitoring device based on microneedle array according to Example I-9, wherein the induced current at the working electrode and the respective induced current at one or more additional working electrodes are combined to determine the correlation of the combination.

Example I-11. A method comprising:

Monitoring the counter electrode voltage at the counter electrode of a microneedle array-based analyte monitoring device, the counter electrode being located on the surface of the distal portion of a first microneedle in the microneedle array;

Identify the characteristics of the counter electrode voltage that meet or exceed a threshold;

In response to identifying the characteristic of the counter electrode voltage exceeding the threshold, a correlation between the counter electrode voltage and the induced current generated on the surface of the working electrode of the microneedle array-based analyte monitoring device is determined; and

Based on the characteristics and correlation of the counter electrode voltage, the operating mode is applied to the analyte monitoring device based on the microneedle array;

The working electrode includes an electrochemical sensing coating configured to generate a sensing current on the surface of the working electrode that indicates the redox reaction of the analyte, and the working electrode is located on the surface of the distal portion of a second microneedle in the microneedle array.

The analyte monitoring device based on the microneedle array further includes: a reference electrode located on the surface of the distal portion of the third microneedle in the microneedle array; and a simulation 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 in order to maintain the redox reaction at the working electrode.

Example I-12. The method according to Example I-11, wherein the characteristic of the counter electrode voltage includes one or more of the rate of change of the counter electrode voltage or the lower limit of the compliance of the counter electrode voltage.

Example I-13. The method according to Example I-12, wherein the change in the counter electrode voltage and the change in the induced current indicate the correlation between the counter electrode voltage and the induced current.

Example I-14. The method according to Example I-13, wherein the operating mode includes: ignoring the induced current if the change in the counter electrode voltage corresponds to the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change.

Example I-15. According to the method of Example I-14, wherein, in response to subsequently determining that the rate of change of the counter electrode voltage does not exceed the threshold rate of change, the operating mode of ignoring the induced current is interrupted.

Example I-16. The method according to Example I-13, wherein the operating mode includes: if the lower compliance limit of the counter electrode voltage satisfies the compliance limit threshold, then stopping the application of a potential between the working electrode and the reference electrode.

Example I-17. The method according to Example I-13, wherein the operating mode includes: stopping the application of a potential between the working electrode and the reference electrode if the change in the counter electrode voltage deviates from the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change.

Example I-18. The method according to Example I-11, wherein the analyte monitoring device based on microneedle array further includes one or more additional working electrodes, each of the one or more additional working electrodes generating a respective induced current;

The method further includes: determining the correlation between the counter electrode voltage and the respective induced current in response to identifying the characteristic of the counter electrode voltage exceeding the threshold.

Example I-19. The method according to Example I-18, wherein the operating mode is further based on the correlation between the counter electrode voltage and the respective induced current.

Example I-20. The method according to Example I-19, wherein the induced current at the working electrode and the respective induced current at one or more additional working electrodes are combined to determine the correlation of the combination.

For purposes of explanation, specific terminology has been used in the foregoing description 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 invention. Therefore, the foregoing description presents specific embodiments of the invention for purposes of illustration and description. These are not intended to be exhaustive or to limit the invention to the precise forms disclosed; obviously, many modifications and variations are possible in light of the foregoing teachings. These embodiments were chosen and described to explain the principles of the invention and its practical application, thereby enabling others skilled in the art to utilize the invention and various embodiments with various modifications suitable for the intended particular use. The scope of the invention is contemplated by the following claims and their equivalents.

Claims (20)

1. An analyte monitoring device based on a microneedle array, comprising: A working electrode includes an electrochemical sensing coating configured to generate a sensing current at the surface of the working electrode that indicates a redox reaction of an analyte, the working electrode being located on the surface of a distal portion of a first microneedle in a microneedle array. A reference electrode is located on the surface of the distal portion of the second microneedle in the microneedle array; The electrode is located on the surface of the distal portion of the third microneedle in the microneedle array; The simulation front end is 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 in order to maintain the redox reaction at the working electrode. The controller communicates with the analog front end and is configured to: Monitor the counter electrode voltage at the counter electrode; Identify the characteristics of the counter electrode voltage that meet or exceed a threshold; In response to identifying the characteristic of the counter electrode voltage exceeding the threshold, the correlation between the counter electrode voltage and the induced current is determined; and Based on the characteristics and correlation of the counter electrode voltage, the operating mode is applied to the analyte monitoring device based on the microneedle array. 2. The analyte monitoring device based on a microneedle array according to claim 1, wherein the characteristic of the counter electrode voltage includes one or more of the rate of change of the counter electrode voltage or the lower limit of the compliance of the counter electrode voltage. 3. The analyte monitoring device based on a microneedle array according to claim 2, wherein the change in the counter electrode voltage and the change in the induced current indicate the correlation between the counter electrode voltage and the induced current. 4. The analyte monitoring device based on a microneedle array according to claim 3, wherein the operating mode includes: ignoring the induced current if the change in the counter electrode voltage corresponds to the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change. 5. The analyte monitoring device based on a microneedle array according to claim 4, wherein the controller is further configured to: interrupt the operating mode of ignoring the induced current in response to subsequently determining that the rate of change of the counter electrode voltage does not exceed the threshold rate of change. 6. The analyte monitoring device based on a microneedle array according to claim 3, wherein the operating mode includes: if the lower compliance limit of the counter electrode voltage satisfies the compliance limit threshold, then stopping the application of a potential between the working electrode and the reference electrode. 7. The analyte monitoring device based on a microneedle array according to claim 3, wherein the operating mode includes: stopping the application of a potential between the working electrode and the reference electrode if the change in the counter electrode voltage deviates from the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change. 8. The analyte monitoring device based on a microneedle array according to claim 1 further includes: One or more additional working electrodes, each of which generates a respective induced current; The controller is further configured as follows: In response to identifying the characteristic of the counter electrode voltage exceeding the threshold, the correlation between the counter electrode voltage and the respective induced current is determined. 9. The analyte monitoring device based on a microneedle array according to claim 8, wherein the operating mode is further based on the correlation between the counter electrode voltage and the respective induced current. 10. The analyte monitoring device based on a microneedle array according to claim 9, wherein the induced current at the working electrode and the respective induced current at one or more additional working electrodes are combined to determine the correlation of the combination. 11. A method for monitoring analytes, comprising: Monitoring the counter electrode voltage at the counter electrode of a microneedle array-based analyte monitoring device, the counter electrode being located on the surface of the distal portion of a first microneedle in the microneedle array; Identify the characteristics of the counter electrode voltage that meet or exceed a threshold; In response to identifying the characteristic of the counter electrode voltage exceeding the threshold, a correlation between the counter electrode voltage and an induced current generated on the surface of the working electrode of the microneedle array-based analyte monitoring device is determined; and Based on the characteristics and correlation of the counter electrode voltage, the operating mode is applied to the analyte monitoring device based on the microneedle array; The working electrode includes an electrochemical sensing coating configured to generate a sensing current on the surface of the working electrode that indicates the redox reaction of the analyte, and the working electrode is located on the surface of the distal portion of a second microneedle in the microneedle array. The analyte monitoring device based on the microneedle array further includes: a reference electrode located on the surface of the distal portion of the third microneedle in the microneedle array; and a simulation 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 maintain the redox reaction at the working electrode. 12. The method of claim 11, wherein the characteristic of the counter electrode voltage includes one or more of the rate of change of the counter electrode voltage or the lower limit of the compliance of the counter electrode voltage. 13. The method of claim 12, wherein the change in the counter electrode voltage and the change in the induced current indicate the correlation between the counter electrode voltage and the induced current. 14. The method of claim 13, wherein the operating mode comprises: ignoring the induced current if the change in the counter electrode voltage corresponds to the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change. 15. The method of claim 14, wherein the operating mode of ignoring the induced current is interrupted in response to subsequently determining that the rate of change of the counter electrode voltage does not exceed the threshold rate of change. 16. The method of claim 13, wherein the operating mode includes: stopping the application of a potential between the working electrode and the reference electrode if the lower compliance limit of the counter electrode voltage satisfies a compliance limit threshold. 17. The method of claim 13, wherein the operating mode comprises: stopping the application of a potential between the working electrode and the reference electrode if the change in the counter electrode voltage deviates from the change in the induced current and if the rate of change of the counter electrode voltage exceeds a threshold rate of change. 18. The method of claim 11, wherein the analyte monitoring device based on the microneedle array further comprises one or more additional working electrodes, each of the one or more additional working electrodes generating a respective induced current; The method further includes: determining the correlation between the counter electrode voltage and the respective induced current in response to identifying the characteristic of the counter electrode voltage exceeding the threshold. 19. The method of claim 18, wherein the operating mode is further based on the correlation between the counter electrode voltage and the respective induced current. 20. The method of claim 19, wherein the induced current at the working electrode and the respective induced current at the one or more additional working electrodes are combined to determine the correlation of the combination.