Fault detection for microneedle array based continuous analyte monitoring device

Abstract

It provides fault detection and diagnosis for a continuous analyte monitoring device based on a microneedle array. An electrochemical sensor comprising electrodes of an analyte monitoring device configured to measure one or more target analytes may experience various failures during operation of the analyte monitoring device. By modeling the sensor as an electrical network, measurements of the electrical network can be correlated with the sensor's operating parameters. The voltage of the counter electrode represents the resistance or impedance between the working electrode and the counter electrode and is used to identify the occurrence of failures in the continuous analyte monitoring device.

Description

Technology Field

[0001] (Cross-reference to related applications)

[0002] This application claims priority to U.S. provisional patent application No. 63 / 186,086, filed on May 8, 2021, the entire contents of which are incorporated herein by reference.

[0003] (Technology field)

[0004] The present invention generally relates to the field of analyte monitoring, such as continuous blood glucose monitoring. Background Technology

[0005] Diabetes is a chronic disease in which the body fails to produce or properly utilize insulin, a hormone that regulates blood sugar. While insulin can be administered to diabetic patients to help control blood sugar levels, blood sugar levels must nevertheless be carefully monitored to ensure that the timing and dosage are appropriate. If diabetic patients do not manage their condition properly, they may experience various complications resulting from hyperglycemia (high blood sugar levels) or hypoglycemia (low blood sugar levels).

[0006] Blood glucose monitors help diabetic patients manage their condition by measuring blood glucose levels from blood samples. For example, a diabetic patient can collect a blood sample via a fingerstick sampling mechanism, transfer the sample to a test strip containing appropriate reagent(s) that react with the blood sample, and measure the blood glucose level of the sample by analyzing the test strip using a blood glucose monitor. However, patients using this process can generally only measure their blood glucose levels at individual time instances, which may fail to detect hyperglycemia or hypoglycemia in a timely manner. However, various more recent blood glucose monitors are continuous glucose monitor (CGM) devices that include implantable transdermal electrochemical sensors used to continuously detect and quantify blood glucose levels by proxy measurements of blood glucose levels in the subcutaneous interstitial fluid. However, conventional CGM devices also have vulnerabilities, including tissue trauma caused by insertion and signal latency (e.g., due to the time required for blood glucose analytes to diffuse from the capillary source to the sensor). Furthermore, these vulnerabilities cause many disadvantages, such as patient pain when electrochemical sensors are inserted and limitations in the accuracy of blood glucose measurements, particularly when blood glucose levels fluctuate rapidly. Therefore, a new and improved analyte monitoring system is required. means of solving the problem

[0007] In some variations, a microneedle array-based analyte monitoring device comprises a working electrode, a reference electrode, a counter electrode, an analog front end, and a controller. The working electrode comprises an electrochemical sensing coating configured to generate a sensing current indicating a redox reaction of the analyte on the surface of the working electrode, and the working electrode is located on the surface of the distal portion of a first microneedle of the microneedle array. The reference electrode is located on the surface of the distal portion of a second microneedle of the microneedle array. The counter electrode is located on the surface of the distal portion of a third microneedle of the microneedle array. The analog 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 to maintain the redox reaction at the working electrode. The controller communicates with the analog front end and: monitors the counter electrode voltage at the counter electrode; identifies characteristics of the counter electrode voltage that meet or exceed a threshold; and, in response to identifying the characteristics of the counter electrode voltage that exceed the threshold, determines a correlation between the counter electrode voltage and the sensing current; and is configured to apply an operating mode to the microneedle array-based analyte monitoring device based on the characteristics of the counter electrode voltage and the correlation.

[0008] In some variations, the method comprises the step of monitoring a counter electrode voltage at a counter electrode of a microneedle array-based analyte monitoring device, wherein the counter electrode is located on the surface of the distal portion of a first microneedle of the microneedle array; the step of identifying a characteristic of the counter electrode voltage that satisfies or exceeds a threshold value; the step of determining a correlation between a sensing current occurring on the surface of a working electrode of the microneedle array-based analyte monitoring device and the counter electrode voltage in response to identifying the characteristic of the counter electrode voltage that exceeds the threshold value; and the step of 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 a sensing current indicating a redox reaction of an analyte on the surface of the working electrode, and the working electrode is located on the surface of the distal portion of a second microneedle of the microneedle array. The microneedle array-based analyte monitoring device may further include a reference electrode located on the surface of a distal portion of a third microneedle of the microneedle array, and an analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and to allow the potential of the counter electrode to swing, thereby maintaining the redox reaction at the working electrode.

[0009] 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 compliance limit of the counter electrode voltage.

[0010] In some variations, the change in the counter electrode voltage and the change in the sensing current represent the correlation between the counter electrode voltage and the sensing current.

[0011] In some variations, the operating mode includes a step of ignoring the sensing current when the change in the counter electrode voltage corresponds to the change in the sensing current and the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0012] In some variations, the controller is further configured to discontinue the operating mode of the step of ignoring the sensing current in response to a subsequent determination that the rate of change of the counter electrode voltage does not exceed the threshold rate of change.

[0013] In some variations, the operating mode includes the step of stopping the application of potential between the working electrode and the reference electrode when the compliance lower limit of the counter electrode voltage meets the threshold compliance limit.

[0014] In some variations, the operating mode includes the step of stopping the application of potential between the working electrode and the reference electrode when the change in the counter electrode voltage deviates from the change in the sensing current and the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0015] In some variations, the microneedle array-based analyte monitoring device further comprises one or more additional working electrodes, each of which generates a respective sensing current. The controller is further 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 value.

[0016] In some variations, the above operating mode is also based further on the correlation between the counter electrode voltage and the respective sensing current.

[0017] In some variations, the sensing current at the working electrode and the respective sensing currents at one or more additional working electrodes are combined to determine a combined correlation. Brief explanation of the drawing

[0018] Figure 1 illustrates an exemplary schematic diagram of an analyte monitoring system having a microneedle array. FIG. 2a illustrates an exemplary schematic diagram of an analyte monitoring device. FIG. 2b illustrates an exemplary schematic diagram of the microneedle insertion depth within an analyte monitoring device. FIG. 3a illustrates an exemplary schematic diagram of a microneedle array. FIG. 3b illustrates an exemplary schematic diagram of a microneedle within the microneedle array illustrated in FIG. 3a. Figure 4 illustrates an exemplary schematic diagram of a microneedle array used to detect multiple analytes. FIG. 5a shows a side cross-sectional view of a cylindrical micro-needle having a tapered distal end. FIG. 5b and FIG. 5c are drawings showing a perspective view and a detail view, respectively, of an embodiment of the micro-needle shown in FIG. 5a. FIGS. 6a to 6c each illustrate exemplary schematic diagrams of the layer structures of the working electrode, the counter electrode, and the reference electrode. FIGS. 6d to 6f each illustrate exemplary schematic diagrams of the layer structures of the working electrode, the counter electrode, and the reference electrode. FIGS. 6g to 6i each illustrate exemplary schematic diagrams of the layer structures of the working electrode, the counter electrode, and the reference electrode. Figure 7 illustrates an exemplary schematic diagram of a microneedle array configuration. FIGS. 8a through 8d illustrate exemplary schematic diagrams of a microneedle array configuration. FIGS. 9a through 9j illustrate exemplary schematic diagrams of different variations of a microneedle array configuration. Figure 10 illustrates a representative diagram of the potentiometer circuit of an analyte monitoring device. Figure 11 illustrates a Randall's equivalent circuit representing an electrochemical cell of an analyte monitoring device. Figure 12 illustrates the measurement circuit of an analyte monitoring device. Figure 13a shows an electrochemical cell using both the Nyquist plot and Bode plot formulas. Figure 13b shows an electrochemical cell using the Nyquist plot formula. Figures 14-17 are plots of current and corresponding voltage at a counter electrode illustrating a fault detection mode. FIG. 18 illustrates an exemplary schematic diagram of an analyte monitoring device. Specific details for implementing the invention

[0019] Now, various non-limiting embodiments and variations of the present invention are described and illustrated in the accompanying drawings.

[0020] As generally described in this specification, an analyte monitoring system may include an analyte monitoring device that includes one or more sensors for monitoring at least one analyte of the user, which is worn by the user. The sensors may include, for example, one or more electrodes configured to perform electrochemical detection of one or more analytes. The analyte monitoring device may transmit sensor data to an external computing device for storage, display, and / or analysis of sensor data. For example, as illustrated in FIG. 1, the analyte monitoring system (100) may include an analyte monitoring device (110) worn by the user, and the analyte monitoring device (110) may be a continuous analyte monitoring device (e.g., a continuous blood glucose monitoring device). The analyte monitoring device (110) may include, for example, an array of microneedles including at least one electrochemical sensor for detecting and / or measuring one or more analytes in the user's body 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 analysis monitoring device (110) may include one or more processors for performing analysis on sensor data and / or a communication module (e.g., a wireless communication module) configured to transmit sensor data to a mobile computing device (102) (e.g., a smartphone) or other suitable computing device. In some variations, the mobile computing device (102) may include one or more processors running a mobile application to process sensor data (e.g., data display, data analysis of trends, etc.) and / or provide appropriate alarms or other notifications related to the sensor data and / or its analysis.It should be understood that in some variations, the mobile computing device (102) may perform sensor data analysis locally, but other computing device(s) may, as an alternative or additional measure, transmit information related to such analysis to the mobile computing device (102) (or other suitable user interface) to analyze sensor data remotely and / or display it to a user. Additionally, in some variations, the mobile computing device (102) may be configured to transmit sensor data and / or analysis of sensor data via a network (104) to one or more storage devices (106) (e.g., a server) to archive data and / or other suitable information related to the user of the analysis monitoring device.

[0021] The analyte monitoring device described herein has features that improve a number of characteristics advantageous to continuous analyte monitoring devices, such as continuous glucose monitoring (CGM) devices. For example, the analyte monitoring device described herein has 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 that helps minimize changes in sensor response over time through the storage and operation of the analyte monitoring device. Furthermore, compared to conventional continuous analyte monitoring devices, the analyte monitoring device described herein has a short warm-up time that allows the sensor(s) to rapidly provide a stable sensor signal after implantation, as well as a short response time that allows the sensor to rapidly provide a stable sensor signal in response to changes in the user's analyte concentration. Additionally, as described in more detail below, the analyte monitoring device described herein can be applied to and function at various wearing sites and can provide pain-free sensor insertion for the user. Other characteristics, such as biocompatibility, sterility, and mechanical integrity, are also optimized in the analyte monitoring device described herein.

[0022] While the analyte monitoring system described herein may be described in relation to blood glucose monitoring (e.g., for users with type 2 or type 1 diabetes), it should be understood that such a system may be configured to detect and monitor other suitable analytes as an additional or alternative. As described in more detail below, suitable target analytes for detection may include, for example, blood glucose, ketones, lactate, and cortisol. A single target analyte may be monitored, or multiple target analytes may be monitored simultaneously (e.g., in the same analyte monitoring device). For example, monitoring other target analytes may enable the monitoring of other signs such as stress (e.g., through the detection of elevated cortisol and blood glucose) and ketoacidosis (e.g., through the detection of elevated ketones).

[0023] As illustrated in FIG. 2a, in some variations, the analyte monitoring device (110) may generally comprise a housing (112) and a microneedle array (140) extending outward from the housing. The housing (112) may be a wearable housing configured to be worn on the user's skin, for example, so that the microneedle array (140) extends at least partially into the user's skin. For example, the housing (112) may include an adhesive so that the analyte monitoring device (110) becomes a skin-attachable patch that is simple and intuitive to apply to the user. The microneedle array (140) may be configured to puncture the user's skin and may include one or more electrochemical sensors (e.g., electrodes) configured to measure one or more target analytes accessible after the microneedle array (140) has punctured the user's skin. In some variations, the analyte monitoring device (110) may be integrated as a single unit or self-contained, and the unit may be disposable (e.g., used for a certain period and replaced with another instance of the analyte monitoring device (110)).

[0024] The electronic system (120) may include various electronic components, such as a sensor circuit (124), which may be at least partially arranged within the housing (112) and configured to perform signal processing (e.g., biasing and reading of an electrochemical sensor, converting an analog signal of an electrochemical sensor into a digital signal, etc.). Additionally, the electronic system (120) may include at least one microcontroller (122) for controlling an analyte monitoring device (110), at least one communication module (126), at least one power supply (130), and / or various other suitable passive circuits (127). The microcontroller (122) may be configured to interpret a digital signal output from the sensor circuit (124) (e.g., by executing a routine programmed in the firmware), perform various suitable algorithms or mathematical transformations (e.g., calibration, etc.), and / or route the processed data to and / or from the communication module (126). In some variations, the communication module (126) may include a suitable wireless transceiver (e.g., a Bluetooth transceiver, etc.) for communicating data with an external computing device (102) via one or more antennas (128). For example, the communication module (126) may be configured to provide unidirectional and / or bidirectional communication of data with an external computing device (102) paired with an analyte monitoring device (110). The power supply (130) may provide power to the analyte monitoring device (110), such as an electronic system. The power supply (130) may include a battery or other suitable source and, in some variations, may be rechargeable and / or replaceable. The passive circuit (127) may include various power-free electrical circuits (e.g., resistors, capacitors, inductors, etc.) that provide interconnection between other electronic components. The passive circuit (127) may be configured to perform, for example, noise reduction, biasing, and / or other purposes.In some variations, electronic components within the electronic system (120) may be arranged on one or more printed circuit boards (PCBs) that may be, for example, rigid, semi-rigid, or flexible. Further details of the electronic system (120) are described below.

[0025] In some variations, the analyte monitoring device (110) may further include one or more additional sensors (150) to provide additional information that may be relevant to user monitoring. For example, the analyte monitoring device (110) may further include at least one temperature sensor (e.g., a thermistor) configured to measure skin temperature, thereby enabling temperature compensation for sensor measurements obtained by the microneedle array electrochemical sensor.

[0026] In some variations, the microneedle array (140) within the analyte monitoring device (110) may be configured to puncture the user's skin. As illustrated in FIG. 2b, when the device (110) is worn by the user, the microneedle array (140) may extend into the user's skin so that electrodes on the distal regions of the microneedle are placed within the dermis. Specifically, in some variations, the microneedle is designed to penetrate the skin and access the upper dermal regions of the skin (e.g., papillary dermis and upper reticular dermis), making it possible for the electrodes to access the interstitial fluid surrounding the cells within these layers. For example, in some variations, the microneedle may generally have a height ranging from at least 350 µm to about 515 µm. In some variations, one or more microneedles may extend from the housing such that the distal end of the electrode on the microneedle is located at a distance of less than about 5 mm from the skin-interface 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.

[0027] Unlike traditional continuous analyte monitoring devices (e.g., CGM devices) that include a sensor implanted between about 8 mm and about 10 mm below the skin surface of the subcutaneous tissue or the fat layer of the skin, the analyte monitoring device (110) has a shallower microneedle insertion depth of about 0.25 mm, which offers many advantages (so that the electrode is implanted in the epithelial area of ​​the skin). These advantages include access to dermal interstitial fluid containing one or more target analytes for detection, which is advantageous because analyte measurements in at least some types of dermal interstitial fluid have been found to be closely related to analyte measurements in blood. For example, blood glucose measurements performed using an electrochemical sensor accessing dermal interstitial fluid have been found to have a very linear correlation with blood glucose measurements. Therefore, blood glucose measurements based on dermal interstitial fluid are a representative method of blood glucose measurement.

[0028] In addition, because the micro-needle insertion depth of the analyte monitoring device (110) is shallower, the time delay of analyte detection is reduced compared to conventional continuous analyte monitoring devices. This shallow insertion depth allows the sensor surface to be positioned very close (e.g., within several hundred micrometers) to the dense and well-perfused capillary layer of the reticular dermis, which makes the diffusion delay from the capillaries to the sensor surface negligible. The diffusion time is t = x 2It relates to the diffusion distance according to / (2D), where t is the diffusion time, x is the diffusion distance, and D is the mass diffusivity of the analyte of interest. Thus, if the analyte detection element is placed two times farther from the analyte source in the capillary, the diffusion delay time increases fourfold. Therefore, conventional analyte sensors located in adipose tissue where the blood vessels beneath the dermis are very poor result in a significantly greater diffusion distance from the vascular system of the dermis, resulting in a significant diffusion delay time (e.g., generally 5 to 20 minutes). In contrast, a shallower microneedle insertion depth of the analyte monitoring device (110) has the advantage of a low diffusion delay from the capillary to the sensor, reducing the time delay of 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.

[0029] Furthermore, when the microneedle array is positioned in the upper dermis, the lower dermis beneath the array supports dermal metabolism, including very high levels of vascularization and perfusion. This provides a barrier function that enables thermoregulation (through vasoconstriction and / or vasodilation) and helps stabilize the sensory environment around the microneedle. Another advantage of the shallower insertion depth is that, due to the absence of pain receptors in the epithelial layer, pain sensation is reduced when the microneedle array punctures the user's skin, providing a more comfortable and minimally invasive user experience.

[0030] Accordingly, the analyte monitoring device and method described herein enable improved continuous monitoring of one or more target analytes by a user. For example, as described above, the analyte monitoring device can be easy to apply and intuitive, which improves ease of use and user compliance. Furthermore, the measurement of analytes in dermal interstitial fluid can provide highly accurate analyte detection. Additionally, compared to conventional continuous analyte monitoring devices, the insertion of the microneedle array and sensor may be less invasive and may entail less pain for the user. Other advantages of other embodiments of the analyte monitoring device and method are further described below.

[0031] As illustrated in the schematic diagram of FIG. 3a, in some variations, a microneedle array (300) for use in detecting one or more analytes may include one or more microneedles (310) protruding from a substrate surface (302). The substrate surface (302) may be, for example, generally flat, and one or more microneedles (310) may protrude perpendicularly from the flat surface. Generally, as illustrated in FIG. 3b, the microneedle (310) may include a body portion (312) (e.g., a shaft) and a tapered distal portion (314) configured to puncture the user's skin. In some variations, the tapered distal portion (314) may terminate at an insulated distal apex (316). The microneedle (310) may further include an electrode (320) on the surface of the tapered distal portion. In some variations, electrode-based measurements may be performed at the interface between the electrode and the interstitial fluid located within the body (e.g., on the outer surface of the entire microneedle). In some variations, the microneedle (310) may have a solid core (e.g., a solid body portion), but in some variations, the microneedle (310) may include one or more lumens that can be used, for example, for drug delivery or sampling of dermal interstitial fluid. Other microneedle variations, such as those described below, may similarly include a solid core or one or more lumens.

[0032] The microneedle array (300) may be formed at least partially from a semiconductor (e.g., silicon) substrate and may include various material layers applied and formed using various suitable MEMS (Microelectromechanical Systems) manufacturing techniques (e.g., deposition and etching techniques) as further described below. The microneedle array may be reflow-soldered onto a circuit board similar to a typical integrated circuit. Additionally, in some variations, the microneedle array (300) may include a three-electrode setup comprising a working (sensing) electrode having an electrochemical sensing coating (including a biorecognition element such as an enzyme) that enables detection of a target analyte, a reference electrode, and a counter electrode. That is, the microneedle array (300) may include at least one microneedle (310) comprising a working electrode, at least one microneedle (310) comprising a reference electrode, and at least one microneedle (310) comprising a counter electrode. Further details regarding this type of electrode are described in more detail below.

[0033] In some variations, the microneedle array (300) may comprise a plurality of insulated microneedles, so that the electrodes on each microneedle within the plurality of microneedles can be individually addressed and electrically isolated from all other electrodes on the microneedle array. Due to the resulting individually addressable nature of the microneedle array (300), greater control over the function of each electrode is possible because 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 detection reliability and accuracy of the device. Additionally, in some variations, the electrodes of the plurality of microneedles can be electrically connected to generate an enhanced signal level. As another example, the same microneedle array (500) may be investigated additionally or alternatively to measure multiple analytes simultaneously to provide a more comprehensive assessment of physiological conditions. For example, as illustrated in the schematic diagram of FIG. 4, the microneedle array may include a first microneedle portion for detecting a first analyte (A), a second microneedle portion for detecting a second analyte (B), and a third microneedle portion for detecting a third analyte (C). It should be understood that the microneedle array may be configured to detect any suitable number of analytes (e.g., 1, 2, 3, 4, 5, or more). Suitable target analytes for detection may include, for example, glucose, ketones, lactate, and cortisol. Thus, the individual electrical addressability of the microneedle array (300) provides greater control and flexibility regarding the sensing function of the analyte monitoring device.

[0034] In some variations of the microneedle (e.g., a microneedle with a working electrode), the electrode (320) may be positioned close to the insulated distal apex (316) of the microneedle. That is, in some variations, the electrode (320) does not cover the apex of the microneedle. Rather, the electrode (320) may be offset from the apex or tip of the microneedle. An electrode (320) positioned close to or offset from the insulated distal apex (316) of the microneedle advantageously provides more accurate sensor measurements. For example, this arrangement prevents the concentration of the electric field at the microneedle apex (316) during manufacturing, thereby preventing uneven electro-deposition of the sensing chemical on the surface of the electrode (320) that would result in failure detection.

[0035] As another example, positioning the electrode (320) offset from the apex of the microneedle further improves detection accuracy by reducing undesirable signal artifacts and / or false sensor readings caused by stress during microneedle insertion. The distal apex of the microneedle is the site that first penetrates the skin and receives the greatest stress caused by mechanical shear phenomena associated with tearing or cutting of the skin. If the electrode (320) is positioned at the apex or tip of the microneedle, this mechanical stress can cause the electrochemical sensing coating on the electrode surface to peel off when the microneedle is inserted, and / or cause a small but interfering amount of tissue to be transferred to the active sensing portion of the electrode. Therefore, detection accuracy can be improved by positioning the electrode (320) sufficiently offset from the apex of the microneedle. For example, in some variations, the distal edge of the electrode (320) may be located at least about 10 µm (e.g., about 20 µm to about 30 µm) from the distal apex or tip of the microneedle when measured along the longitudinal axis of the microneedle.

[0036] The body portion (312) of the microneedle (310) may further include an electrically conductive path extending between the electrode (320) and the rear electrode or other electrical contact (e.g., arranged on the back surface of the substrate of the microneedle array). The rear electrode may be soldered to the circuit board to enable electrical communication with the electrode (320) through the conductive path. For example, the in vivo (inside the dermis) sensing current measured at the working electrode during use is irradiated by the rear electrical contact, and the electrical connection between the rear 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 penetrating the interior of the microneedle body portion (e.g., shaft) between the proximal and distal ends of the microneedle. Alternatively, in some variations, the conductive path may be provided by the entire body portion formed of a conductive material (e.g., doped silicon). In some of these variations, the complete substrate on which the microneedle array (300) is constructed may be electrically conductive, and each microneedle (310) of the microneedle array (300) may be electrically insulated from adjacent microneedles (310) as described below. For example, in some variations, each microneedle (310) of the microneedle array (300) may be electrically insulated from adjacent microneedles (310) by an insulating barrier comprising an electrical insulating material (e.g., a dielectric material such as silicon dioxide) surrounding a conductive path extending between the electrode (320) and the rear electrical contact. For example, the body portion (312) may include an insulating material that forms a covering around the conductive path to prevent electrical communication between the conductive path and the substrate. Other exemplary variations of the structure enabling electrical insulation between microneedles are described in more detail below.

[0037] This electrical isolation between the microneedles of the microneedle array enables the sensors to be individually addressable. This individual addressing capability advantageously allows not only independent simultaneous measurements between sensors but also dynamic reconfiguration of sensor assignments (e.g., to different analytes). In some variations, the electrodes of the microneedle array can be configured to provide redundant analyte measurements, which is an advantage over conventional analyte monitoring devices. For example, redundancy can improve performance by enhancing accuracy (e.g., averaging multiple analyte measurements for the same analyte to reduce the influence of extremely high or low sensor signals on analyte level determination) and / or improving device reliability by reducing the possibility of complete failure.

[0038] In some variations, as described in more detail below along with each various variation of the microneedle, the microneedle array may be formed at least partially by suitable semiconductor and / or MEMS manufacturing techniques and / or mechanical cutting or dicing. Such processes may be advantageous, for example, in enabling cost-effective large-scale manufacturing of the microneedle array.

[0039] In some variations, the microneedle may have a generally cylindrical body portion and a tapered distal portion having an electrode. For example, FIGS. 5a through 5c illustrate exemplary variations of a microneedle (500) extending from a substrate (502). FIG. 5a is a side cross-sectional view of a schematic diagram of the microneedle (500), FIG. 5b is a perspective view of the microneedle (500), and FIG. 5c is a detailed perspective view of the distal portion of the microneedle (500). As illustrated in FIGS. 5b and 5c, the microneedle (500) may include a cylindrical body portion (512), a tapered distal portion (514) ending at an insulated distal apex (516), and an annular electrode (520) comprising a conductive material (e.g., Pt, Ir, Au, Ti, Cr, Ni, etc.) and disposed on the tapered distal portion (514). As illustrated in FIG. 5a, the annular electrode (520) may be positioned close to (or offset or spaced apart from) the distal apex (516). For example, the electrode (520) may be electrically insulated from the distal apex (516) by a distal insulating surface (515a) comprising an insulating material (e.g., SiO2). In some variations, the electrode (520) may also be electrically insulated from the cylindrical body portion (512) by a second distal insulating surface (515b). The electrode (520) may be electrically connected to a conductive core (540) (e.g., a conductive path) passing through a rear electrical contact (530) (e.g., made of a Ni / Au alloy) or another electrical pad inside or on the substrate (502) along the body portion (512). For example, the body portion (512) may comprise a conductive core material (e.g., highly doped silicon). As shown in FIG. 5a, in some variations, an insulating moat (513) comprising an insulating material (e.g., SiO2) may be arranged around the body portion (512) (e.g., around the perimeter) and may extend at least partially through the substrate (502).Accordingly, the insulating moat (513) may help prevent electrical contact, for example, between the conductive core (540) and the surrounding substrate (502). The insulating moat (513) may extend further over the surface of the body portion (512). The upper and / or lower surface of the substrate (502) may also include a substrate insulating layer (504) (e.g., SiO2). Thus, the insulator provided by the insulating moat (513) and / or the substrate insulator (504) may contribute at least partially to the electrical insulation of the micro-needles (500), enabling the individual addressing of the micro-needles (500) within the micro-needle array. Additionally, in some variations, the insulating moat (513) extending over the surface of the body portion (512) may function to increase the mechanical strength of the micro-needle (500) structure.

[0040] The micro-needle (500) can be formed at least partially by a suitable MEMS manufacturing technique, such as plasma etching, also known as dry etching. For example, in some variations, the insulating moat (513) around the body portion (512) of the micro-needle can be created by first forming a trench in the silicon substrate by deep reactive ion etching (DRIE) from the back of the substrate, and then filling the trench to have a sandwich structure of SiO2 / polycrystalline silicon (poly-Si) / SiO2 by low-pressure chemical vapor deposition (LPCVD) or other suitable process. That is, the insulating moat (513) can passivate the surface of the body portion (512) of the micro-needle and continue as a buried feature in the substrate (502) near the proximal portion of the micro-needle. By including most silicon compounds, the insulating moat (513) can provide good filling and adhesion to adjacent silicon walls (e.g., conductive core (540), substrate (502), etc.). The sandwich structure of the insulating moat (513) can further help provide an excellent match in coefficient of thermal expansion (CTE) with adjacent silicon, thereby advantageously reducing defects, cracks, and / or other thermally induced weaknesses of the insulating moat (513).

[0041] The tapered distal portion can be formed from the front surface of the substrate by isotropic dry etching, and the body portion (512) of the micro-needle (500) can be formed from DRIE. The front metal electrode (520) can be deposited and patterned on the distal portion by special lithography (e.g., electron beam evaporation) that allows metal deposition on the desired annular region of the electrode (520) without coating the distal vertex (516). Additionally, the rear electrical contact portion (530) of Ni / Au can be deposited by a suitable MEMS manufacturing technique (e.g., sputtering).

[0042] The micro-needle (500) may have any suitable dimensions. As an example, the micro-needle (500) may have a height of about 300 μm to about 500 μm in some variations. In some variations, the tapered distal portion (514) may have a tip angle between about 60 and about 80 degrees and a apex diameter between about 1 μm and about 15 μm. In some variations, the surface area of ​​the annular electrode (520) is about 9,000 μm 2 to about 11,000 μm 2 , or about 10,000 μm 2 It may include.

[0043] As described above, each microneedle of the microneedle array may include an electrode. In some variations, multiple distinct types of electrodes may be included between the microneedles of the microneedle array. For example, in some variations, the microneedle array may function as an electrochemical cell capable of operating in an electrolytic manner using three types of electrodes. That is, the microneedle array may include at least one working electrode, at least one counter electrode, and at least one reference electrode. Thus, the microneedle array may include three distinct electrode types, but one or more of each electrode type may form a complete system (for example, the system may include multiple distinct working electrodes). Additionally, multiple distinct microneedles may be electrically connected to form an effective electrode type (for example, a single working electrode may be formed from two or more connected microneedles having working electrode portions). Each of these electrode types may include a metallization layer and may include one or more coatings or layers on the metallization layer that help facilitate the function of the electrode.

[0044] Generally, the working electrode is the electrode where the oxidation and / or reduction reaction of interest takes place for the detection of the analyte of interest. The counter electrode functions to source (provide) or sink (accumulate) electrons through the current required to sustain the electrochemical reaction at the working electrode. The reference electrode functions to provide a reference potential for the system. That is, the potential to which the working electrode is biased is based on 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 actual limits, no current is generated from or sinks to the reference electrode. Additionally, to implement such a three-electrode system, the analyte monitoring device may include a suitable potentiostat or electrochemical analog front end to maintain a fixed potential relationship between the working electrode and reference electrode conditions within the electrochemical system (via an electronic feedback mechanism) and simultaneously allow the counter electrode to dynamically swing to the potential required to sustain the redox reaction of interest.

[0045] working electrode

[0046] As described above, the working electrode is the electrode where the oxidation and / or reduction reaction of interest takes place. In some variations, sensing may be performed at the interface between the working electrode and the interstitial fluid located within the body (e.g., on the outer surface of the entire microneedle). In some variations, the working electrode may comprise a biorecognition layer and an electrode material in which a biorecognition element (e.g., an enzyme) is immobilized on the working electrode to facilitate selective analyte quantification. In some variations, the biorecognition layer may also function as an interference blocking layer and may help prevent endogenous and / or exogenous paper from being directly oxidized (or reduced) at the electrode.

[0047] The redox current detected at the working electrode may be correlated with the detected 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 Cottrell relation shown below.

[0048]

[0049] Here, n is the stoichiometric number of electrons relaxing 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 that the system is biased to the potential. Therefore, the current detected at the working electrode is linearly proportional to the analyte concentration.

[0050] 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 sensitivity of the sensor (e.g., amperes per mole of analyte). For example, multiple single working electrodes can be grouped into an array of two or more components to increase the total effective sensing surface area. Additionally, or alternatively, to obtain 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 electrodes can be operated as an anode (to allow the analyte to be oxidized at the surface) or a cathode (to allow the analyte to be reduced at the surface).

[0051] FIG. 6a illustrates a schematic diagram of an exemplary set of layers for a working electrode (610). For example, as described above, in some variations, the working electrode (610) may comprise a biometric layer comprising an electrode material (612) and a biometric element. The electrode material (612) functions to facilitate the electrocatalytic detection of an analyte or the reaction product of 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 a processing circuit. In some variations, the electrode material (612) may comprise platinum as shown in FIG. 6a. However, the electrode material (612) may alternatively comprise, for example, palladium, iridium, rhodium, gold, ruthenium, titanium, nickel, carbon, doped diamond, or other suitable catalyst and inert materials.

[0052] 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 for enhanced sensitivity. Additionally or alternatively, the platinum black layer (613) may enable electrocatalytic oxidation or reduction of the biorecognition reaction product facilitated by the biorecognition layer (614). However, in some variations, the platinum black layer (613) may be omitted (e.g., as illustrated in FIG. 6d and 6g). The electrode may enable electrocatalytic oxidation or reduction of the biorecognition reaction product in the absence of the platinum black layer (613).

[0053] The biorecognition layer (614) may be arranged on the electrode material (612) (or the platinum black layer (613) if present) and functions to immobilize and stabilize biorecognition elements that facilitate selective analyte quantification over extended time periods. 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 a glucose oxidase that converts blood glucose into an electroactive product (i.e., hydrogen peroxide) detectable on the electrode surface in the presence of oxygen. Specifically, the redox equation associated with this exemplary variation is as follows: Glucose + Oxygen → Hydrogen peroxide + Gluconolactone (mediated by glucose oxidase); Hydrogen peroxide → Water + Oxygen (mediated by applying an oxidation potential to the working electrode).

[0054] However, in other variations, the biorecognition element additionally or alternatively includes other suitable oxidases or redoxases such as lactate oxidase, alcohol oxidase, beta-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbic acid oxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, urate oxidase, urease, and / or xanthine oxidase.

[0055] In some variations, the biometric element may be cross-linked with an amine-condensed carbonyl species that can help stabilize the biometric element within the biometric layer (614). As further described below, in some variations, the cross-linking of the biometric element may make the microneedle array compatible with ethylene oxide (EO) sterilization, which allows the entire analyte monitoring device (including the sensing element and electronic device) to be exposed to the same sterilization cycle, thereby simplifying the sterilization process and lowering manufacturing costs. For example, the biometric element may be cross-linked with glutaraldehyde, formaldehyde, glyoxal, malonaldehyde, succinaldehyde, and / or other suitable species. In some variations, the biometric element may be cross-linked with these amine-condensed carbonyl species to form a cross-linked biometric element assembly. A cross-linked biometric element assembly having at least a critical molecular weight may be embedded in a conducting polymer. By embedding only aggregates having a critical molecular weight, any uncrosslinked enzymes can be blocked and not incorporated into the biorecognition layer. Therefore, only aggregates with a desired molecular weight can be selected for use in the conductive polymer, which helps ensure that only sufficiently stabilized crosslinked enzyme entities are included in the biorecognition layer and thus contributes to a biorecognition layer that is generally more suitable for EO sterilization without loss of sensing performance. In some variations, only crosslinked aggregates having a molecular weight that is at least twice the molecular weight of glucose oxidase can be embedded in the conductive polymer.

[0056] In some variations, the conductive polymer may be permselective to contribute to the robustness of the biorecognition layer against circulating androgynous electroactive species (e.g., ascorbic acid, vitamin C, etc.), and variations thereof may negatively affect the sensitivity of the sensor. Such permselective conductive polymers in the biorecognition layer may be more robust against pharmacological interference from interstitial fluid (e.g., acetaminophen), which can affect sensor accuracy. The conductive polymer may become permselective by modifying the conductive polymer into a non-conductive form, for example, by removing excess charge carriers through an oxidative electropolymerization process or by neutralizing these charge carriers with a counter-ion dopant. Since such oxidatively-polymerized conductive polymers exhibit permselective permeability, they may reject ions with charge polarities similar to the dopant ion (pure positive or negative) or reject them through size exclusion due to the dense and compact form of the conductive polymer.

[0057] Furthermore, in some variations, conductive polymers may exhibit self-sealing and / or self-healing properties. For example, conductive polymers may undergo oxidative electropolymerization, during which the conductive polymer may lose conductivity as the thickness of the polymer deposited on the electrode increases until the deposition of additional conductive polymer is reduced due to insufficient conductivity. If the conductive polymer sustains minor physical damage (e.g., during use), the polymer backbone may reassemble to neutralize free charges, thereby lowering the total surface energy of the molecular structure, which may manifest as self-sealing and / or self-healing properties.

[0058] In some variations, the working electrode may further include a diffusion limiting layer (615) arranged on top of the biorecognition layer (614). The diffusion limiting layer (615) may function to limit the flux of the analyte of interest to reduce the sensitivity of the sensor to endogenous oxygen fluctuations. For example, the diffusion limiting layer (615) may attenuate the concentration of the analyte of interest to become a limiting reactant for aerobic enzymes. However, in some variations (e.g., when the biorecognition element is not aerobic), the diffusion limiting layer (615) may be omitted.

[0059] In some variations, the working electrode may additionally include a hydrophilic layer (616) that provides a biocompatible interface to reduce foreign body reactions, for example. However, in some variations, the hydrophilic layer (616) may be omitted, for example as shown in FIG. 6d and 6g (for example, if the diffusion-limiting layer expresses a hydrophilic moiety for this purpose).

[0060] Counter electrode

[0061] As explained above, the counter electrode is an electrode that sources or sinks electrons (via current) necessary to sustain the electrochemical reaction at the working electrode. The number of counter electrode components can be increased in the form of a counter electrode array to enhance the surface area so that the current carrying capacity of the counter electrode does not limit the redox reaction at the working electrode. Therefore, it may be desirable for the counter electrode area to exceed the working electrode area to bypass current carrying capacity limitations. If the working electrode operates as an anode, the counter electrode acts as a 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 or reference electrode, the counter electrode can dynamically swing to the potential required to sustain the redox reaction of interest at the working electrode.

[0062] As illustrated in FIG. 6b, the counter electrode (620) may include an electrode material (622) similar to the electrode material (612). For example, like the electrode material (612), the electrode material (622) of the counter electrode (620) may include precious metals such as gold, platinum, palladium, iridium, carbon, doped diamond, and / or other suitable catalysts and inert materials.

[0063] In some variations, the counter electrode (620) may have little to no additional layer on the electrode material (632). However, in some variations, the counter electrode (620) may benefit from an increased surface area to increase the amount of current it can support. For example, the counter electrode material (632) may be surface-treated or otherwise roughened in a way that increases the surface area of ​​the electrode material (632) for improved current sourcing or sinking ability. Additionally, or alternatively, the counter electrode (620) may include a layer of platinum black (624), which may increase the electrode surface as described above for some variations of the working electrode. However, in some variations of the counter electrode, the layer of platinum black may be omitted (e.g., as shown in FIG. 6e). In some variations, the counter electrode may additionally include a hydrophilic layer that provides a biocompatible interface to reduce foreign body reactions, for example.

[0064] Additionally or as an alternative, in some variations as illustrated in FIG. 6h, the counter electrode (620) may include a diffusion limiting layer (625) (e.g., arranged on top of the electrode). The diffusion limiting layer (625) may be similar to the diffusion limiting layer (615) described above in relation to FIG. 6a, for example.

[0065] reference electrode

[0066] As explained above, the reference electrode functions to provide a reference potential to the system. That is, the potential to which the working electrode is biased is based on the reference electrode. A fixed or at least controlled potential relationship can be formed between the working electrode and the reference electrode, and within actual limits, current is not sourced from or sunk into the reference electrode.

[0067] As illustrated in FIG. 6c, the reference electrode (630) may comprise an electrode material (632) similar to the electrode material (612). In some variations, like the electrode material (612), the electrode material (632) of the reference electrode (630) may comprise a metal salt or a metal oxide, which serves as a stable redox coupled with a well-known electrode potential. For example, the metal salt may comprise silver-silver chloride (Ag / AgCl), and the metal oxide may comprise iridium oxide (IrOx / Ir2O3 / IrO2). In other variations, noble metal and inert metal surfaces may function as quasi-reference electrodes and may comprise gold, platinum, palladium, iridium, carbon, doped diamond, and / or other suitable catalysts and inert materials. Additionally, in some variations, the reference electrode (630) may be surface-treated or otherwise roughened in a manner that improves adhesion to any subsequent layer. This subsequent layer on the electrode material (632) may include a layer of platinum black (634). However, in some variations, the layer of platinum black may be omitted (e.g., as shown in FIG. 6f and 6i).

[0068] In some variations, the reference electrode (630) may further comprise a redox bonding layer (636), which comprises a surface-fixed solid-state redox couple having a stable thermodynamic potential. For example, the reference electrode may operate at a standard thermodynamic potential that is stable relative to the standard hydrogen electrode (SHE). High stability of the electrode potential can be achieved by using a redox system having a constant concentration (e.g., buffered or saturated) of each participant in the redox reaction. For example, the reference electrode may comprise a saturated Ag / AgCl (E = +0.197 V vs. SHE) or IrOx (E = +0.177 V vs. SHE, pH = 7.00) in the redox bonding layer (636). Other examples of the redox bonding layer (636) may comprise a suitable conductive polymer having a dopant molecule as described in U.S. Patent Publication No. 2019 / 0309433, the entirety of which is incorporated herein by reference. In some variations, the reference electrode can be used as a half cell to form a complete electrochemical cell.

[0069] Additionally or as an alternative, in some variations as illustrated in FIG. 6i, the reference electrode (630) may include a diffusion limiting layer (635) (e.g., arranged over the electrode and / or redox-coupled layer). The diffusion limiting layer (635) may be similar to the diffusion limiting layer (615) described above in relation to FIG. 6a, for example.

[0070] Exemplary electrode layer formation

[0071] Various layers of working electrodes, counter electrodes, and reference electrodes can be applied to a microneedle array using an appropriate process as described below and / or functionalized, etc.

[0072] In the pretreatment step of the micro-needle array, the micro-needle array is plasma-cleaned in an inert gas (e.g., RF-generated inert gas such as argon) plasma environment to render the surface of the material containing the electrode material (e.g., the electrode material described above (612, 622, 632)) so that it can become more hydrophilic and chemically reactive. This pretreatment functions not only to physically remove organic residues and contaminants but also to clean and prepare the electrode surface to improve the adhesion of the film subsequently deposited on the surface.

[0073] A plurality of microneedles (e.g., any microneedle variant described herein, each of which may have a working electrode, a counter electrode, or a reference electrode as described above) may be arranged in a microneedle array. Considerations for the method of configuring the microneedles include factors such as the desired insertion force for penetrating the skin with the microneedle array, optimization of electrode signal levels and other performance aspects, manufacturing costs, and complexity.

[0074] For example, a microneedle array may include multiple microneedles spaced apart by a predetermined pitch (the distance from the center of one microneedle to the center of the nearest neighbor microneedle). In some variations, the microneedles may be spaced apart by a sufficient pitch to distribute the force applied to the user's skin to make the microneedle array penetrate the skin (e.g., to avoid the "bed of nails" effect). As the pitch increases, the force required to insert the microneedle array tends to decrease, and the penetration depth tends to increase. However, it is known that the pitch begins to affect the insertion force only at low values ​​(e.g., less than about 150 μm). Therefore, in some variations, the microneedles of the microneedle array may have a pitch of at least 200 μm, at least 300 μm, at least 400 μm, at least 500 μm, at least 600 μm, at least 700 μm, or at least 750 μm. For example, the pitch may be about 200 µm to about 800 µm, about 300 µm to about 700 µm, or about 400 µm to about 600 µm. In some variations, the microneedles may be arranged in a periodic grid, and the pitch may be uniform in all directions across all regions of the microneedle array. Alternatively, the pitch may differ when measured along different axes (e.g., X, Y directions) and / or some regions of the microneedle array may have a smaller pitch while other regions may have a larger pitch.

[0075] Additionally, for more consistent penetration, the micro-needles can be spaced equidistant from each other (e.g., have the same pitch in all directions). To this end, in some variations, the micro-needles of the micro-needle array can be arranged in a hexagonal configuration as shown in FIG. 7. Alternatively, the micro-needles of the micro-needle array can be arranged in a rectangular array (e.g., a square array) or in other suitable symmetrical ways.

[0076] Another consideration for determining the configuration of a microneedle array is the overall signal level provided by the microneedle. Generally, the signal level of each microneedle does not vary depending on the total number of microneedle elements within the array. However, the signal level can be enhanced by electrically interconnecting multiple microneedles within the array. For example, an array with a large number of electrically connected microneedles is expected to generate greater signal strength (and thus increased accuracy) than an array with fewer microneedles. However, creating a larger number of microneedles on a die increases die costs (given a constant pitch) and requires greater force and / or speed for insertion into the skin. In contrast, creating a smaller number of microneedles on a die can reduce die costs and enable insertion into the skin with reduced application force and / or speed. Additionally, in some variations, creating a smaller number of microneedles on a die can reduce the overall footprint area of ​​the die, which may result in less unwanted localized edema and / or erythema. Accordingly, in some variations, a balance between these factors can be achieved with a microneedle array comprising 37 microneedles as shown in FIG. 7, or a microneedle array comprising 7 microneedles as shown in FIG. 8a and 8c. However, in other variations, there may be fewer microneedles in the array (e.g., between about 5 and about 35, about 5 and about 30, about 5 and about 25, about 5 and about 20, about 5 and about 15, about 5 and about 100, about 10 and about 30, about 15 and about 25, etc.), or there may be more microneedles in the array (e.g., more than 37, more than 40, more than 45, etc.).

[0077] Additionally, as described in more detail below, in some variations, only a subset of the microneedles of the microneedle array may be activated during the operation of the analyte monitoring device. For example, some of the microneedles in the microneedle array may be inactive (e.g., no signal is read from the electrodes of the inactive microneedles). In some variations, some of the microneedles in the microneedle array may be activated at a specific time during operation and remain active for the remainder of the device's operating life. Furthermore, in some variations, some of the microneedles in the microneedle array may be deactivated at a specific time during operation, either additionally or alternatively, and remain inactive for the remainder of the device's operating life.

[0078] When considering the characteristics of dies for microneedle arrays, the die size is a function of the number of microneedles and the pitch of the microneedle array. Manufacturing cost is also a consideration, as smaller die sizes contribute to lower costs because the number of dies that can be formed on a single wafer within a given area increases. Additionally, smaller die sizes are less susceptible to brittle fracture due to the relative fragility of the substrate.

[0079] In addition, in some variations, it was found that microneedles located around 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.) exhibit better performance (e.g., sensitivity) due to better penetration compared to microneedles located at the center of the microneedle array or die. Therefore, in some variations, the working electrode is positioned largely or entirely on the microneedles located around the microneedle array to obtain more accurate and / or precise analyte measurements.

[0080] FIG. 7 illustrates an exemplary schematic diagram of 37 micro-needles arranged as an exemplary variation of a micro-needle array. The 37 micro-needles may be arranged in a hexagonal array having a needle center-to-center pitch of about 750 μm (or about 700 μm to about 800 μm, or about 725 μm to about 775 μm) between the center of each micro-needle and the center of the micro-needle immediately adjacent in any direction.

[0081] FIGS. 8a and 8b illustrate perspective views of an exemplary schematic diagram of seven micro-needles (810) arranged as an exemplary variation of a micro-needle array (800). The seven micro-needles (810) are arranged in a hexagonal array on a substrate (802). As shown in FIG. 8a, electrodes (820) are arranged on the distal portions of the micro-needles (810) extending from the first surface of the substrate (802). As shown in FIG. 8b, the proximal portions of the micro-needles (810) are conductively connected to respective rear electrical contacts (830) on the second surface of the substrate (802) opposite the first surface of the substrate (802). FIGS. 8c and 8d illustrate a top view and a side view of an exemplary schematic diagram of a micro-needle array similar to the micro-needle array (800). As illustrated in FIGS. 8c and 8d, seven micro-needles are arranged in a hexagonal array having a needle center-to-center pitch of about 750 μm between the center of each micro-needle and the center of its immediate neighbor in any direction. In other variations, the needle center-to-center pitch may be, for example, about 700 μm to about 800 μm, or about 725 μm to about 775 μm. The micro-needles may have an approximate outer shaft diameter of about 170 μm (or about 150 μm to about 190 μm, or about 125 μm to about 200 μm) and a height of about 500 μm (or about 475 μm to about 525 μm or about 450 μm to about 550 μm).

[0082] Additionally, the microneedle array described herein may have a high degree of configurability with respect to the positions in which the working electrode(s), counter electrode(s), and reference electrode(s) are located within the microneedle array. Such configurability may be facilitated by an electronic system.

[0083] 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 featuring the same or different number of electrode components depending on requirements for signal sensitivity and / or redundancy. For example, electrodes of the same type (e.g., working electrodes) may be distributed bilaterally or radially symmetrically within the microneedle array. For example, FIG. 9a depicts a variation of the microneedle array (900A) comprising two symmetrical groups of seven working electrodes (WE) with two working electrode groups labeled "1" and "2". In this variation, the two working electrode groups are distributed symmetrically within the microneedle array. The working electrodes are typically arranged between the central region of three reference electrodes (RE) and the outer region of twenty counter electrodes (CE). In some variations, each of the two working electrode groups may include seven working electrodes electrically connected between them (e.g., to enhance sensor signals). Alternatively, only a portion of one or both of the working electrode groups may include multiple electrodes electrically connected among themselves. As yet another alternative, the working electrode group may include a standalone working electrode that is not electrically connected to other working electrodes. Additionally, in some variations, the working electrode groups may be distributed in a microneedle array in an asymmetric or random configuration.

[0084] As another example, FIG. 9b depicts a variation of a microneedle array (900B) comprising four symmetric groups of three working electrodes (WE) along with four working electrode groups labeled "1", "2", "3", and "4". In this variation, 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) components of the microneedle array and is arranged symmetrically. The microneedle array also includes counter electrodes (CE) arranged around the perimeter of the microneedle array, except for two electrodes at the hexagonal vertices that may be inactive or used for other functions or modes of operation.

[0085] In some variations, only a portion of the microneedle array may contain active electrodes. For example, FIG. 9c illustrates a variation of a microneedle array (900C) having a reduced number of active electrodes, comprising 37 microneedles and 4 working electrodes (indicated as "1", "2", "3", and "4") arranged in a left-right symmetrical arrangement, 22 counter electrodes, and 3 reference electrodes. The remaining 8 electrodes of the microneedle array are deactivated. In the microneedle array illustrated in FIG. 9c, each working electrode is surrounded by a group of counter electrodes. These two groups of working electrode and counter electrode clusters are separated by three rows of reference electrodes.

[0086] As another example, FIG. 9d illustrates a variation of a microneedle array (900D) having a reduced number of active electrodes, comprising 37 microneedle and 4 working electrodes (indicated as "1", "2", "3" and "4") in a left-right symmetrical arrangement, 20 counter electrodes and 3 reference electrodes, wherein the remaining 10 electrodes of the microneedle array are inactive.

[0087] As another example, FIG. 9e illustrates a variation of a microneedle array (900e) having a reduced number of active electrodes, comprising 37 microneedles and 4 working electrodes (labeled "1", "2", "3", and "4"), 18 counter electrodes, and 2 reference electrodes. The remaining 13 electrodes of the microneedle array are deactivated. Since the deactivated electrodes are located along a portion of the perimeter of the entire microneedle array, the effective size and shape of the active microneedle array are reduced to a smaller hexagonal array. Within the active microneedle array, the 4 working electrodes are generally arranged in a radially symmetrical arrangement, and each working electrode is surrounded by a group of counter electrodes.

[0088] FIG. 9f illustrates another exemplary variation of a microneedle array (900F) having a reduced number of active electrodes, comprising 37 microneedles and 4 working electrodes (labeled "1", "2", "3", and "4"), 2 counter electrodes, and 1 reference electrode. The remaining 30 electrodes of the microneedle array are deactivated. The deactivated electrodes are arranged in two layers around the perimeter of the entire microneedle array, reducing the effective size and shape of the active microneedle array to a smaller hexagonal array centered on the reference electrode. Within the active microneedle array, the 4 working electrodes are arranged symmetrically, and the counter electrodes are equidistant from the central reference electrode.

[0089] FIG. 9g illustrates another exemplary variation of a microneedle array (900G) having 37 microneedles and a reduced number of active electrodes. Except that the microneedle array (900G) includes one counter electrode and two reference electrodes, and a smaller hexagonal array of active microneedles is located at the center of the counter electrode, the active electrodes of the microneedle array (900G) are arranged in a manner similar to that of the microneedle array (900F) shown in FIG. 9f. Within this active microneedle array, the four working electrodes are arranged symmetrically, and the reference electrode is equidistant from the central counter electrode.

[0090] FIG. 9h illustrates a microneedle array (900H) of another exemplary variation having seven microneedles. This microneedle array includes two microneedles designated as independent working electrodes (1 and 2), a counter electrode consisting of four microneedles, and a single reference electrode. There is left-right symmetry in the arrangement of the counter electrode and working electrodes, which are equidistant from the central reference electrode. Additionally, the working electrodes are arranged as far as possible from the center of the microneedle array (e.g., on the die or around the array) to utilize a position where the working electrodes are expected to have greater sensitivity and overall performance.

[0091] FIG. 9i illustrates a microneedle array (900I) of another exemplary variation having seven microneedles. This microneedle array includes four microneedles designated as two independent groups (1 and 2) of two working electrodes each, a counter electrode consisting of two microneedles, and a single reference electrode. There is left-right symmetry in the arrangement of the counter electrode and working electrodes at equidistant distances from the central reference electrode. Additionally, the working electrodes are arranged as far as possible from the center of the microneedle array (e.g., on the die or around the array) to utilize a position where the working electrodes are expected to have greater sensitivity and overall performance.

[0092] FIG. 9j illustrates another exemplary variant of a microneedle array (900J) having seven microneedles. This microneedle array includes four microneedles designated as independent working electrodes (1, 2, 3, 4), a counter electrode consisting of two microneedles, and a single reference electrode. There is left-right symmetry in the arrangement of the counter electrode and working electrodes at equidistant distances from the central reference electrode. Additionally, the working electrodes are arranged as far as possible from the center of the microneedle array (e.g., on the die or around the array) to utilize a position where the working electrodes are expected to have greater sensitivity and overall performance.

[0093] FIGS. 9a through 9j illustrate exemplary variations of microneedle array configurations, but it should be understood that these figures are not limiting and other microneedle configurations (including working electrodes, counter electrodes, and reference electrodes of different numbers and / or distributions, and active electrodes and inactive electrodes of different numbers and / or distributions) may be suitable in other variations of the microneedle array.

[0094] Analog front end

[0095] In some variations, the electronic system of the analyte monitoring device may include an analog front end. The analog front end may include a sensor circuit (e.g., a sensor circuit (124) as shown in FIG. 2a) that converts analog current measurements into digital values ​​that can be processed by a microcontroller. The analog front end may include a programmable analog front end suitable for use with, for example, an electrochemical sensor. For example, the analog front end may include a MAX30131, MAX30132, or MAX30134 component (each including 1, 2, and 4 channels, respectively) available from Maxim Integrated (San Jose, California), which is an ultra-low power programmable analog front end for use with an electrochemical sensor. The analog front end may also include an AD5940 or AD5941 component available from Analog Devices (Norwood, Massachusetts), which is a high-precision, impedance, and electrochemical front end. Similarly, the analog front end may include the LMP91000, available from Texas Instruments (Dallas, Texas), a configurable analog front-end potentiometer for low-power chemical sensing applications. The analog front end may provide a biasing and complete measurement path including an analog-to-digital converter (ADC). The ultra-low power may allow for continuous biasing of the sensor to maintain accuracy and fast response when measurements are required for extended periods (e.g., 7 days) using a battery-operated wearable device.

[0096] In some variations, the analog front-end device may be compatible with both two- and three-terminal electrochemical sensors, such as enabling DC current measurement, AC current measurement, and electrochemical impedance spectroscopy (EIS) measurement functions. Additionally, the analog front-end may include an internal temperature sensor and a programmable reference voltage, support external temperature monitoring and external reference sources, and integrate voltage monitoring of bias and supply voltages for safety and compliance.

[0097] In some variations, the analog front end may include a multi-channel potentiometer for multiplexing sensor inputs and processing multiple signal channels. For example, the analog front end may include a multi-channel potentiometer such as that described in U.S. Patent No. 9,933,387, the entirety of which is incorporated herein by reference.

[0098] In some variations, analog front-ends and peripheral electronics can be integrated, for example, into an Application-Specific Integrated Circuit (ASIC), which can help reduce costs. In some variations, these integrated solutions may include the microcontrollers described below.

[0099] Microcontroller

[0100] In some variations, the electronic system of the analyte monitoring device may include at least one microcontroller (e.g., the controller (122) shown in FIG. 2a). The microcontroller may include, for example, a processor with integrated flash memory. In some variations, the microcontroller of the analyte monitoring device may be configured to perform an analysis that correlates sensor signals with analyte measurements (e.g., blood glucose measurements). For example, the microcontroller may execute routines programmed in the firmware to interpret digital signals (e.g., from an analog front end), perform any relevant algorithms and / or other analyses, and route the processed data to / from a communication module. Maintaining analyte monitoring device onboard analysis ensures that, for example, the analyte monitoring device can broadcast analyte measurement(s) 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.) and simultaneously ensures that each connected device has the same information.

[0101] In some variations, the microcontroller may be configured to enable and / or disable the analyte monitoring device under one or more detected conditions. For example, the device may be configured to power the analyte monitoring device when the microneedle array is inserted into the skin. This may enable a power-saving feature where the battery is disconnected, for example, until the microneedle array is placed within the skin, at which point the device may begin broadcasting sensor data. This feature may help, for example, improve the storage life of the analyte monitoring device and / or simplify the analyte monitoring device-external device pairing process for the user.

[0102] An aspect of the present invention relates to the detection of failure and diagnosis related to the detection of failure in a microneedle array-based analyte monitoring device, such as an analyte monitoring device (110). An electrochemical sensor configured to measure one or more target analytes (e.g., an electrode of the analyte monitoring device (110)) may experience various failures during the use of the analyte monitoring device (110). The failure may be a failure of one or more aspects of the analyte monitoring device (110) in which the failure affects the operation of the analyte monitoring device (110). Examples of failures include degradation of the electrode membrane (e.g., cracking, delamination, and / or other damage to the membrane structure and / or surface affecting detection), degradation of the biorecognition element (e.g., inactivation and / or denaturation), physiological response to the implantation of the microneedle array (e.g., foreign body response, encapsulation, protein attachment, or collagen formation occurring in response to the insertion of the electrode-forming microneedle), improper placement or insertion of the microneedle array (e.g., the electrode-forming microneedle is not placed at a sufficient depth for analyte detection), pressure attenuation (e.g., pressure applied to the analyte monitoring device (110), and external environmental influence (e.g., external influence on the electronic devices of the analyte monitoring device (110). Failures may affect the electrical and / or electrochemical behavior of the analyte monitoring device (110) and, consequently, may result in errors and / or instability in the measurement of the target analyte or analytes. In some cases, such as in the case of pressure attenuation, the failure may be transient. In other cases, the failure may permanently affect the operation of the analyte monitoring device (110).

[0103] Some faults can be detected by monitoring current consumption. For example, the value of the sensing current at the working electrode of the analyte monitoring device (110) can indicate and / or correlate some faults. In such cases, if the sensing current exhibits extreme, irregular, and / or unexpected behavior or patterns, the fault can be determined based on the characteristics of the behavior or pattern exhibited by the sensing current. The extreme, irregular, and / or unexpected behavior or pattern of the sensing current may be characterized by a rapid rate of change that is or could be non-physiologically possible. High noise may also affect the behavior or pattern of the sensing current.

[0104] However, other failures may not affect the sensing current while still affecting the electrical and / or electrochemical behavior of the analyte monitoring device (110). Alternative or additional variables are therefore required to provide insight into and verify changes in the electrical and / or electrochemical behavior of the analyte monitoring device (110). The voltage of the counter electrode is an example of a variable that provides such insight and verification. Thus, failures can be detected by monitoring the voltage of the counter electrode.

[0105] Although various types of failures as described above may occur, a failure is generally characterized by whether the analyte monitoring device (110) can recover from the failure (e.g., whether the failure is transient) or whether the analyte monitoring device (110) is damaged and must cease operation (e.g., whether the failure is permanent). Such characterization can be achieved and a response to the failure determined by monitoring the counter electrode voltage and, in some variations, by monitoring how the counter electrode voltage corresponds to or correlates with the sensing current. The response to the failure may be in the form of an operating mode for operating the analyte monitoring device. For example, if the failure is transient, the operating mode may include blanking and / or ignoring the sensing data while the failure is occurring. In this situation, the sensing data is inaccurate and is not reported to the user or utilized for operational purposes. If the failure 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.

[0106] In some variations, the counter electrode voltage is monitored to identify one or more characteristics that may serve as an indication of failure. Characteristics indicating failure may include the rate of change of the counter electrode voltage and / or a compliance lower limit of the counter electrode voltage. These characteristics can be described by considering the relationship between the counter electrode potential and the current of the working electrode. That is, as further described herein, the counter electrode voltage dynamically fluctuates or adjusts to the potential required to sustain the redox reaction at the working electrode. Thus, the counter electrode voltage can be considered as the voltage required to support the current level of the working electrode (e.g., the sensing current). As the sensing current fluctuates or changes, the counter electrode voltage also fluctuates or changes in a corresponding or reciprocal manner. If the sensing current experiences a rapid rate of change, the counter electrode voltage responds with a rapid rate of change. The correspondence or correlation between the sensing current and the counter electrode voltage can be defined as having the same but opposite rate of change (or nearly the same but opposite rate of change (e.g., a maximum difference of about 5% between the rates of change)). If the sensing current changes at a specified rate, the counter electrode voltage also changes in the opposite direction at a specified rate. Then, the rate of change of the counter electrode voltage serves as an indicator of the rate of change of the sensing current. A sensing current exhibiting a rapid rate of change is non-physiologically possible or possible. Therefore, by monitoring the counter electrode voltage, the physiological viability of the sensing current can be determined. Since a rapid rate of change is not physiologically possible, such a change serves to indicate that there is a problem with the device. In some variations, the rapid rate of change of the counter electrode voltage can be defined as approximately 0.10 V / min. In some variations, the rapid rate of change of the counter electrode voltage can be defined between approximately 0.05 V / min and approximately 0.15 V / min. For example, in some variations, the rapid rate of change of the counter electrode voltage is approximately 0.05 V / min, approximately 0.It can be defined as 0.6 V / min, approx. 0.07 V / min, approx. 0.08 V / min, approx. 0.09 V / min, approx. 0.10 V / min, approx. 0.11 V / min, approx. 0.12 V / min, approx. 0.13 V / min, approx. 0.14 V / min, or approx. 0.15 V / min. The rapid rate of change of the sensing current may be associated with the rate of change of the analyte being measured. In the case of blood glucose, the rapid rate of change may be approximately 4 mg / dL / min. In some variations, the rapid rate of change of blood glucose may be between approximately 3.5 mg / dL / min and approximately 6 mg / dL / min.

[0107] The lower compliance limit of the counter electrode voltage can be defined as the lowest level to which the counter electrode voltage can swing. The counter electrode voltage may also have an upper compliance limit, which is the highest level to which the counter electrode can swing. If the counter electrode voltage swings toward the lower compliance limit, this can serve as an indication that a failure has occurred, as the sensing current has reached a physiologically improbable high magnitude.

[0108] Accordingly, a counter electrode voltage that experiences a rate of change that meets or exceeds a critical rate of change and / or meets a critical compliance limit serves as an indication that there is a failure within the analyte monitoring device (110). In some variations, when it is identified that the rate of change of the counter electrode voltage meets or exceeds a critical rate of change and / or that the counter electrode voltage meets a critical compliance limit, the characteristics or parameters of the counter electrode voltage may be compared with the characteristics or parameters of the sensing current to determine whether the failure is transient or permanent. The comparison may include a determination of the correspondence or correlation between the counter electrode voltage and the sensing current.

[0109] In some variations, the counter electrode voltage corresponding to the sensing current exhibits pressure-induced signal attenuation such that the counter electrode voltage changes at the same rate of change as the sensing current. This pressure-induced signal attenuation may occur as external pressure is applied to the analyte monitoring device (110) and may be characterized as a transient failure. When the external pressure is removed, the analyte monitoring device (110) operates as intended.

[0110] In some variations, a change in counter electrode voltage corresponding to a change in sensing current, such that the correspondence is maintained and coupled with the counter electrode voltage that satisfies the compliance lower limit, indicates a change in the physiological environment surrounding the sensor and / or the sensor surface. In other variations, a counter electrode voltage that satisfies the compliance lower limit regardless of the sensing current indicates a change in the physiological environment and / or the sensor surface. In this scenario, the counter electrode voltage does not need to be correlated with the sensing current. Changes in the physiological environment surrounding the sensor and changes in the sensor surface can be examples of permanent failure.

[0111] In some variations, a change in counter electrode voltage deviating from a change in sensing current, which causes the counter electrode voltage and sensing current to change differently in conjunction with the rapid rate of change of the counter electrode voltage, may indicate an external influence on the electronics of the analyte monitoring device. Such external influence may be an example of permanent failure.

[0112] When the correlation between the counter electrode voltage and the sensing current is determined, the analyte monitoring device (110) (e.g., controller) responds by applying an operating mode corresponding to the fault. For example, an operating mode is applied to a micro-needle array-based analyte monitoring device based on the characteristics of the identified counter electrode voltage and the correspondence between the counter electrode voltage and the sensing current.

[0113] In some variations, the operating mode includes a change in counter electrode voltage corresponding to a change in sensing current, and ignoring the sensing current when the rate of change of the counter electrode voltage exceeds a threshold rate of change. As described herein, this may indicate pressure-induced signal attenuation. If pressure-induced signal attenuation is removed from the counter electrode voltage and sensing current (e.g., if the rate of change of the counter electrode voltage does not exceed a threshold rate of change), the sensing current is not ignored because the fault has been resolved.

[0114] In some variations, the operating mode includes stopping the application of potential between the working electrode and the reference electrode when a change in the counter electrode voltage corresponds to a change in the sensing current and the lower compliance limit of the counter electrode voltage meets the threshold compliance limit. When the threshold compliance limit is reached, it indicates a permanent failure, and the bias potential is removed and operation is stopped.

[0115] In some variations, the operating mode includes a step of stopping the application of potential between the working electrode and the reference electrode when the change in the counter electrode voltage deviates from the change in the sensing current and the rate of change of the counter electrode voltage exceeds a critical rate of change. This indicates a permanent failure, and the bias potential is removed and operation is stopped.

[0116] As further described in this specification, the reference electrode functions to provide a reference potential for a three-electrode electrochemical system implemented by the analyte monitoring device (110). The potential to which the working electrode is biased is based on 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 actual limits, no current is supplied from or sinks to the reference electrode. To implement such a three-electrode electrochemical system, the analyte monitoring device (110) includes a potentiometer or an electrochemical analog front end (e.g., an analog front end) to maintain a fixed potential relationship between the working electrode and the reference electrode within the three-electrode electrochemical system, while allowing the counter electrode to dynamically swing to the potential required to maintain the redox reaction of interest. Biasing the electrochemical system with a potentiometer or analog front end to establish a potential relationship between the working electrode and the reference electrode drives a redox reaction at the working electrode and causes the counter electrode to sink current in the oxidation process or source current in the reduction process to sustain the redox reaction at the working electrode. The magnitude of the current is proportional to the magnitude of the redox reaction occurring at the working electrode and the impedance or resistance between the working electrode and the counter electrode. Biasing the electrochemical system generates 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 electrode and the counter electrode.

[0117] The voltage of the counter electrode is adjusted to the potential to balance the redox reaction occurring at the working electrode when maintained at the potential relative to the reference electrode. If a failure occurs in one or more aspects of the analyte monitoring device (110) that affects the operation of the analyte monitoring device (110), the voltage of the counter electrode is modulated and reflects the impedance accumulated between the working electrode and the counter electrode. By monitoring the voltage of the counter electrode, the impedance indication between the working electrode and the counter electrode can be determined. The three-electrode electrochemical system of the analyte monitoring device (110) can be modeled as an electrical network or system including an electrical component for correlating the voltage of the counter electrode with the impedance or resistance between the working electrode and the counter electrode, which is correlated with one or more conditions, including types of failure. By associating or characterizing the impedance with specific conditions, including failures of the three-electrode electrochemical system, the voltage value can be correlated with one or more failures.

[0118] FIG. 10 illustrates a potentiometer circuit (1000) of an analyte monitoring device (110). The potentiometer circuit (1000) may be part of a sensor circuit (124) illustrated and described with reference to FIG. 2a. The potentiometer circuit (1000) includes an electrochemical cell (1010) connecting the working electrode and the counter electrode of a three-electrode electrochemical system.

[0119] FIG. 11 illustrates a Randles equivalent circuit (1100) representing the electrochemical cell (1010) illustrated in FIG. 10a. The Randles equivalent circuit (1100) has a solution resistance R s (Uncompensated resistance R u or R Ω Also called), charge transfer resistance R ct and double layer capacitance C between the counter electrode (1120) and the working electrode (1110) dl Includes. Solution resistance R sis the charge transfer resistance R ct and double-layer capacitance C dl It is in series with a parallel combination of. The Randles equivalent circuit (1100) connects the terminals between the counter electrode (1120) and the working electrode (1110). Solution resistance R s represents the degree of ohmic contact between the counter electrode (1120) and the working electrode (1110), and may represent the electrolyte content / ionic strength of the medium in which the analyte monitoring device (110) is operating (e.g., the fluid in which the electrodes of the microneedle array are located, e.g., interstitial fluid). Charge transfer resistance R ct represents the magnitude of the electrochemical reaction occurring at the working electrode (1110). Double layer capacitance C dl It indicates the surface shape and components of the working electrode (1110) (e.g., the composition and configuration of the surface of the working electrode (1110)).

[0120] The Randles equivalent circuit (1100) of the electrochemical cell (1010) of the analyte monitoring device (110) simplifies the redox reaction occurring within the electrochemical cell (1010). By modeling the electrochemical cell (1010) with the Randles equivalent circuit (1100), the solution resistance R s , charge transfer resistance R ct , double-layer capacitance C dl Contributions from 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 case of DC, C dl If assumed to have an infinite impedance such as ω→0, the voltage of the counter electrode (1120) is the total resistive component of the system (e.g., R s +R ct Provides an evaluation for ). In another extreme case, as ω→∞, C dlapproaches a negligibly small impedance and R ct is bypassed. This can be realized as an impulse or unit step function applied to the counter electrode (1120), R s Allows for the quantification of only.

[0121] In the DC case (ω→0), the voltage of the counter electrode (1120) is predicted to swing to more extreme values ​​relative to the compliance voltage of the potentiometer, as additional current must be sourced or sank to maintain a fixed potential relationship between the working electrode and the reference electrode. This is manifested through a counter electrode voltage moving away from the voltage set at the working electrode (1110). In extreme cases, the voltage of the counter electrode (1120) approaches the compliance voltage, or the maximum voltage provided by the circuit driving the counter electrode. In the Randles equivalent circuit, the representation of this mode of operation is the solution resistance R s Charge transfer resistance R that tends to approach the value of ct In the case of DC, this indicates that one or more of the following failures are occurring: a short circuit between the working electrode and the counter electrode, failure of the reference electrode's ability to maintain a stable thermodynamic potential, a compromise regarding the diffusion limiting membrane, or a steady increase in the porosity of the sensing layer contained within the analyte selection sensor.

[0122] The counter electrode voltage approaches the voltage value maintained by the working electrode (1110) in a scenario where the current requirement to maintain a fixed potential relationship between the working electrode and the reference electrode tends toward a negligible value (e.g., a negligible value of current flow through the system, i→0). In the Randles equivalent circuit, the representation of this mode of operation is a charge transfer resistance R that tends toward infinity. ctIn the case of DC, this is an indication that one or more of the following are occurring: improper sensor insertion, improper access to viable anatomical compartments, partial or total occlusion of the sensor causing degradation product diffusion to be attenuated (e.g., due to biofouling / protein adsorption / collagen formation / encapsulation), and failure of the reference electrode's function to maintain a stable thermodynamic potential.

[0123] The measurement of voltage at the counter electrode can be achieved by a potentiometer, an electrochemical analog front end, or a converter such as a voltage-sensing or current-sensing analog-to-digital converter (ACD).

[0124] In some cases, as illustrated in the measurement circuit (1200) of FIG. 12, a buffer (1210) and a filter (1220) (e.g., a low-pass filter) may provide separation from the converter (1230) to isolate components from the counter electrode included in the electrochemical sensor (1240). In some implementations, a differential amplifier, a transimpedance amplifier, or a finite gain amplifier may be incorporated. The filter (1220) may be positioned before the converter (1230) to reduce interference from high frequency, low frequency, both high frequency and low frequency, and / or band-limited signals with the measurement of the counter electrode voltage.

[0125] 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 evaluate and / or determine the fault. An analog-to-digital converter can electrically communicate with the working electrode. In some embodiments, a galvanostat is integrated to establish a desired current relationship between the working electrode and the counter electrode.

[0126] A scenario in which the voltage of the counter electrode approaches the voltage of the working electrode indicates that the impedance or resistance value of the analyte sensor has decreased to a low level according to Ohm's law (v = Zi, where Z is the cumulative impedance of the analyte sensor). This indicates that one or more of the following failures are occurring: a short circuit between the working electrode and the counter electrode, failure of the reference electrode's function in maintaining a stable thermodynamic potential, a compromise regarding the diffusion limiting membrane, or a steady increase in the porosity of the sensing layer contained within the analyte selection sensor. The counter electrode voltage approaches the working electrode voltage in a situation where the counter electrode voltage swings in the positive direction to support the current level of the working electrode (e.g., sensing current).

[0127] An increase in the difference between the counter electrode voltage and the working electrode voltage indicates that the impedance or resistance value of the analyte sensor has increased to a very large value. This indicates that one or more of the following are occurring: improper sensor insertion, partial or total occlusion of the sensor causing analyte diffusion to attenuate (e.g., due to biological contamination / protein adsorption / collagen formation / encapsulation), or a failure of the reference electrode's function in maintaining a stable thermodynamic potential. An increase in the difference between the counter electrode voltage and the working electrode voltage occurs when the counter electrode voltage swings in the negative direction to support the sensing current.

[0128] Therefore, in some cases, voltage is measured at the working electrode and the counter electrode to identify failures. The voltage value of the counter electrode is dynamically adjusted to support the specified current requirements of the analyte sensor, as shown in Fig. 13a. Fig. 13a shows an electrochemical cell using both Nyquist and Bode plot formulas. The Bode plot shows the amplitude and phase response of the electrochemical cell.

[0129] FIG. 13b is a Nyquist plot of an electrochemical cell showing the real (Re{Z}) and imaginary (Im{Z}) components of the electrochemical impedance as the radian frequency ω changes. According to the Randles equivalent circuit model, (1) when the radian frequency approaches ∞, the solution resistance (R s / R Ω ) can be inferred, and (2) as the radian frequency approaches 0, the solution resistance R s Charge transfer resistance (R) coupled with ct The imaginary component of the impedance is achieved as zero in the two cases where ) can be inferred. By perturbing the electrochemical cell at both frequency extremes, the real (resistive) component of the electrochemical cell can be fully characterized. Assuming the electrochemical cell is purely capacitive, the double-layer capacitance C is obtained through semicircular interpolation between the Im{Z}→0 intersection points. dl It can calculate.

[0130] FIGS. 14-17 is an exemplary plot showing the relationship between the current and the corresponding counter electrode voltage under different fault conditions, illustrating the operational relationship between the sensing current and the counter electrode voltage. The exemplary plot can be used to provide an indication of the change in sensor impedance between the counter electrode and the working electrode.

[0131] FIG. 14 includes a sensing current plot (1410) and a corresponding counter electrode voltage plot (1420) over time. During normal operation (e.g., before points 1411, 1421 and between points 1413, 1423 and points 1414, 1424), as the sensor current changes, the counter electrode voltage changes at the same or nearly the same but opposite rate of change, which is visually shown as a mirrored response in the plots (1410 and 1420). During normal operation where no fault is present, the rate of change of the counter electrode voltage and the rate of change of the sensing current may be nearly the same or substantially the same. For example, there may be a difference of up to about 5% between the rates of change. In some variations, there may be a difference of up to 10% between the rates of change. The difference between the rate of change of the counter electrode voltage and the rate of change of the sensing current may vary within a nearly the same or substantially the same range of up to 5% or, in some cases, up to 10% during normal operation.

[0132] Faults are indicated at points 1421, 1422, 1423, 1424, and 1425 of the counter electrode voltage, corresponding to points 1411, 1412, 1413, 1414, and 1415 of the sensing current, respectively. Faults at points 1421, 1422, 1423, 1424, and 1425 indicate pressure-induced signal attenuation and are identified by deviations in the correspondence between the counter electrode voltage and the sensing current. As shown in plots (1410 and 1420), at fault, the counter electrode voltage corresponds to a sensing current having the same or nearly the same rate of change. For example, the rates of change may differ by up to 5%, and in some cases up to 10%.

[0133] FIG. 15 (similar to FIG. 14) includes a current plot (1510) and a corresponding counter electrode voltage plot (1520) over time. During normal operation (e.g., before points 1511, 1521 and between points 1511, 1521 and points 1512, 1522), as the sensor current changes, the counter electrode voltage changes at the same but opposite rate of change, which is visually displayed in the plot as a mirrored response. During normal operation where no fault is present, the rate of change of the counter electrode voltage and the rate of change of the sensed current may be nearly identical or substantially identical. For example, there may be a difference of up to about 5% between the rates of change. In some variations, there may be a difference of up to 10% between the rates of change. The difference between the rate of change of the counter electrode voltage and the rate of change of the sensed current may vary within a nearly identical or substantially identical range of up to 5% or, in some cases, up to 10% during normal operation.

[0134] Faults are indicated at points 1521, 1522, 1523, and 1524 of the counter electrode voltage, corresponding to points 1511, 1512, 1513, and 1514 of the sensing current, respectively. Faults at points 1521, 1522, 1523, and 1524 indicate pressure-induced signal attenuation and are identified by deviations in the correspondence between the counter electrode voltage and the sensing current. As shown in plots (1510 and 1520), at fault, the counter electrode voltage corresponds to a sensing current having the same or nearly the same rate of change. For example, the rates of change may differ by up to 5%, and in some cases up to 10%.

[0135] FIG. 16 includes a current plot (1610) and a corresponding counter electrode voltage plot (1620) over time. During normal operation (e.g., point 1621, prior to 1611), as the sensor current changes, the counter electrode voltage changes at the same or nearly the same but opposite rate of change, which is visually displayed in the plots (1610 and 1620) as a mirrored response. During normal operation where no fault is present, the rate of change of the counter electrode voltage and the rate of change of the sensed current may be nearly or substantially the same. For example, there may be a difference of up to about 5% between the rates of change. In some variations, there may be a difference of up to 10% between the rates of change. The difference between the rate of change of the counter electrode voltage and the rate of change of the sensed current may vary within a nearly or substantially the same range of up to 5% or, in some cases, up to 10% during normal operation.

[0136] At point (1621), the counter electrode voltage reaching the compliance lower limit indicates a failure. Point (1621) may correspond to a previous current spike at point (1611) of the sensor current, but in some cases, there may not be a clear correlation between the counter electrode voltage and the sensing current. A failure at 1621 based on the reached compliance lower limit indicates a change in the physiological environment surrounding the sensor or a change in the sensor surface.

[0137] FIG. 17 includes a current plot (1710) and a corresponding counter electrode voltage plot (1720) over time. Points (1721 and 1722) indicating failures due to the indicated rapid rate of change are indicated on the counter electrode voltage and are not related to the current of the analyte monitoring device as illustrated. Since the current does not experience significant fluctuations or unexpected deformations, points (1721 and 1722) indicate failures not related to the current of the analyte monitoring device and are instead correlated with external environmental influences, such as external influences on the electronics of the analyte monitoring device.

[0138] FIG. 18 illustrates an exemplary schematic diagram of a fault detection and diagnosis system (1800) for monitoring counter electrode voltage and working electrode voltage according to the described implementation. An embodiment of the fault detection and diagnosis system (1800) may be integrated into an analyte monitoring device (110). As described herein, an analog front end (1840) is included to maintain 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 maintain the redox reaction of interest at the working electrode. A converter (1815) coupled to the working electrode (1810) is optionally provided to convert the working electrode voltage. A converter (1825) coupled to the counter electrode (1820) is provided to convert the counter electrode voltage. In some cases, one converter may be provided to and coupled to the working electrode (1810) and the counter electrode (1820), respectively, to convert the voltage. The converter (1815), converter (1825) and / or a single converter may be an analog-to-digital converter.

[0139] The digitized voltage signal is transmitted to a controller (1822) coupled to each converter. In some cases, the controller (122) shown in FIG. 2a and described by reference thereto may incorporate the operating mode 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 the modes described herein, the controller (1822) (and / or controller (122)) processes the counter electrode voltage, the sensing current, and optionally the working electrode voltage to identify the fault and the associated operating mode. The controller (1822) may provide a command or correction signal to the 3-electrode electrochemical system and may provide an output (1824) to warn the user of the fault and optionally the operating mode. The output (1824) may be provided to the user interface of the analyte monitoring device and / or communicated to a remote device and / or a remote server (e.g., wirelessly via short-range communication, Bluetooth, or other wireless protocols).

[0140] In some variations, one or more working electrodes are integrated and used to detect analytes. For example, in the microneedle array configurations (900H, 900I, and / or 900J) shown in FIGS. 9h, 9i, and 9j, one or more working electrodes and one or more counter electrodes are integrated. In variations where one or more counter electrodes are integrated, the counter electrodes are shorted together so that a single accumulated counter electrode voltage is monitored when the counter electrodes shorted together act as a single counter electrode.

[0141] When using one or more working electrodes, each additional working electrode generates a separate sensing current. In some variations, the correlation between the counter electrode voltage and each working electrode sensing current can be determined. Since each working electrode is located on a separate individual microneedle of the microneedle array, failures may not be consistent across working electrodes. For example, electrode membrane degradation and biorecognition element degradation may vary across multiple working electrodes. Additionally, regarding improper placement or insertion, in some cases, working electrodes may experience different insertion depths, to the extent that one or more working electrodes are sufficiently inserted while others are not. Pressure attenuation may also affect working electrodes differently in some cases. Therefore, based on the differences that may occur across the entire microneedle array, it may be useful to separately monitor and analyze the counter electrode voltage for each working electrode sensing current. Separate monitoring and analysis can serve to provide indications of failure in one or more working electrodes. In some variations, once a failure is identified, the corresponding operating mode is applied.

[0142] If one or more faults are identified and the faults are different, the operating mode that stops the application of potential between the working electrode and the reference electrode takes precedence over the operating mode that blanks and / or ignores the detection data. In some variations, if a fault is detected in one working electrode but one or more additional working electrodes operate according to normal operation (e.g., no fault is detected), the applied potential at the working electrode indicating the fault may be stopped while allowing operation to continue using the remaining working electrodes. In some variations, a minimum number of working working electrodes may be defined so that the operation of the analyte monitoring device continues when the number of working working electrodes meets or exceeds a minimum number.

[0143] In some variations, the combined sensing current is based on the working electrode sensing currents being combined. For example, the sensing currents from each working electrode may be averaged to form a combined sensing current. The combined sensing current may be used in conjunction with the counter electrode voltage as described herein to determine the failure and operating mode of the analyte monitoring device.

[0144] Additional details regarding the Randles equivalent model are provided. The impedance Z of the Randles equivalent model is expressed by the following relationship:

[0145]

[0146] Extending this relationship to express impedance as a function of radian frequency ω, we get the following:

[0147]

[0148] In the DC case (frequency 0), the impedance is given as follows:

[0149]

[0150] In the AC case (high frequency extreme), the impedance is given as follows:

[0151]

[0152] Mathematical Equation 2 can be rewritten as follows:

[0153]

[0154] The real and imaginary components of the impedance provided in Equation 5 can be easily identified as follows:

[0155]

[0156]

[0157] If you re-enter:

[0158]

[0159] The amplitude response of the system is given as follows:

[0160]

[0161] Accordingly, the phase response is calculated:

[0162]

[0163] Current i supported by electrochemical reaction CELL This can be calculated by applying Kirchhoff's voltage law to the Randall cell:

[0164]

[0165] Counter electrode voltage V CE It can be calculated by re-formulating the above relationship.

[0166]

[0167] The current can be positive or negative depending on the configuration of the potentiometer and whether the electrochemical reaction is undergoing oxidation or reduction. In the provided model and current operation equation, it is assumed that the current flows from the counter electrode (maintained at the highest potential) through the electrochemical cell to the working electrode, which is maintained at a lower potential (e.g., relative to ground). This model assumes a reduction reaction (e.g., current flows to the working electrode and acts as an electron source). Alternatively, the counter electrode may be maintained at a lower potential than the working electrode (during oxidation), causing current to flow from the working electrode to the counter electrode. In this case, the working electrode acts as an electron sink.

[0168] In the case of DC:

[0169]

[0170] Given R s and R ct About V CE is i CELL Tracks the finite charge transfer resistance R ct In the case of, it is as follows:

[0171]

[0172] This is the compliance voltage limit of the potentiometer. In this scenario, there is no ohmic connection between the counter electrode and the working electrode. Similarly:

[0173]

[0174] am.

[0175] This represents the ideal operating conditions of an electrochemical system. This is achieved by operating in a medium with sufficient electrolyte / ionic strength (e.g., a buffer solution or the wearer's physiological fluid). Similarly, a finite resistance R s In the case of:

[0176]

[0177] am.

[0178] In other words, the current i passing through the electrochemical cell CELL Due to this infinite charge transfer resistance, as it approaches zero, the counter electrode voltage will approach the working electrode voltage. A practical representation of this is to completely passivate the working electrode surface so that no current flows. Thus, an ideal double-layer capacitor is formed. When the charge transfer resistance approaches zero:

[0179]

[0180] am.

[0181] The current passing through the electrochemical cell remains constant during the charge transfer process (e.g., as in an electrolysis reaction). Instead, a counter electrode tracks the current flowing through the electrochemical cell (assuming that the solution resistance / electrolyte content remains constant throughout the electrolysis).

[0182] In the case of AC, since the frequency tends to approach extreme values:

[0183]

[0184] am.

[0185] The current passing through an electrochemical cell remains constant during the charge transfer process (e.g., as in an electrolysis reaction). Similarly, in the case of DC, the frequency tends to approach zero:

[0186]

[0187] This is equal to mathematical formula 13.

[0188] Exemplary Examples

[0189] Example I-1. As an analyte monitoring device based on a microneedle array:

[0190] A working electrode comprising an electrochemical sensing coating configured to generate a sensing current indicating a redox reaction of an analyte on the surface of the working electrode, wherein the working electrode is positioned on the surface of a first microneedle of a microneedle array.

[0191] A reference electrode located on the surface of the upper portion of the second micro-needle of the above micro-needle array;

[0192] A counter electrode located on the surface of the distal portion of the third micro-needle of the above micro-needle array;

[0193] An analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode, and to allow the potential of the counter electrode to swing so as to maintain the redox reaction at the working electrode;

[0194] As a controller communicating with the above analog front end,

[0195] Monitoring the counter electrode voltage at the above counter electrode;

[0196] Identifying the characteristics of the counter electrode voltage that satisfy or exceed a threshold value;

[0197] In response to identifying the characteristics of the counter electrode voltage exceeding the above threshold, the correlation between the counter electrode voltage and the sensing current is determined;

[0198] Based on the characteristics of the counter electrode voltage and the correlation, an operating mode is applied to the microneedle array-based analyte monitoring device.

[0199] The above controller configured to do so;

[0200] A microneedle array-based analyte monitoring device characterized by including

[0201] Example I-2. A microneedle array-based analyte monitoring device according to Example I-1, characterized in that the characteristics of the counter electrode voltage include one or more of the rate of change of the counter electrode voltage or the compliance lower limit of the counter electrode voltage.

[0202] Example I-3. A microneedle array-based analyte monitoring device according to Example I-2, characterized in that the change in counter electrode voltage and the change in sensing current represent the correlation between the counter electrode voltage and the sensing current.

[0203] Example I-4. An analyte monitoring device based on a microneedle array, wherein, in Example I-3, the operating mode includes a step of ignoring the sensing current when the change in the counter electrode voltage corresponds to the change in the sensing current and the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0204] Example I-5. A microneedle array-based analyte monitoring device according to Example I-4, wherein the controller is further configured to stop the operating mode of the step of ignoring the sensing current in response to a subsequent determination that the rate of change of the counter electrode voltage has not exceeded the threshold rate of change.

[0205] Example I-6. A microneedle array-based analyte monitoring device according to Example I-3, wherein the operating mode includes the step of stopping the application of potential between the working electrode and the reference electrode when the compliance lower limit of the counter electrode voltage satisfies a critical compliance limit.

[0206] Example I-7. A microneedle array-based analyte monitoring device according to Example I-3, wherein the operating mode includes the step of stopping the application of potential between the working electrode and the reference electrode when the change in the counter electrode voltage deviates from the change in the sensing current and the rate of change in the counter electrode voltage exceeds a threshold rate of change.

[0207] Example I-8. In Example I-1,

[0208] Each of the one or more additional working electrodes generates a respective sensing current;

[0209] Includes more,

[0210] A microneedle array-based analyte monitoring device characterized in that the controller is further configured to determine the correlation between the counter electrode voltage and the respective sensing current in response to identifying the characteristics of the counter electrode voltage that exceeds the threshold value.

[0211] Example I-9. A microneedle array-based analyte monitoring device according to Example I-8, wherein the operating mode is further based on the correlation between the counter electrode voltage and the respective sensing current.

[0212] Example I-10. A microneedle array-based analyte monitoring device according to Example I-9, characterized in that the sensing current at the working electrode and the respective sensing currents at one or more additional working electrodes are combined to determine a combined correlation.

[0213] Example I-11.

[0214] A step of monitoring a counter electrode voltage at a counter electrode of a microneedle array-based analyte monitoring device, wherein the counter electrode is located on the surface of a distal portion of a first microneedle of the microneedle array;

[0215] A step of identifying the characteristics of the counter electrode voltage that satisfy or exceed a threshold value;

[0216] In response to the step of identifying the characteristics of the counter electrode voltage exceeding the threshold value, a step of determining the correlation between the sensing current occurring on the surface of the working electrode of the microneedle array-based analyte monitoring device and the counter electrode voltage; and

[0217] A step of applying an operating mode to the micro-needle array-based analyte monitoring device based on the characteristics of the counter electrode voltage and the correlation above;

[0218] Includes,

[0219] The above working electrode comprises an electrochemical sensing coating configured to generate a sensing current indicating a redox reaction of an analyte on the surface of the above working electrode, and the above working electrode is positioned on the surface of the distal portion of a second microneedle of a microneedle array;

[0220] A method characterized by further comprising a reference electrode located on the surface of the distal portion of a third microneedle of the microneedle array, and an analog front end configured to allow the potential of the counter electrode to swing in order to maintain a fixed potential relationship between the working electrode and the reference electrode and to maintain the redox reaction at the working electrode.

[0221] Example I-12. A method in which, in Example I-11, 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.

[0222] Example I-13. A method according to Example I-12, wherein the change in the counter electrode voltage and the change in the sensing current represent a correlation between the counter electrode voltage and the sensing current.

[0223] Example I-14. The method of Example I-13, wherein the operating mode comprises the step of ignoring the sensing current when the change of the counter electrode voltage corresponds to the change of the sensing current and the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0224] Example I-15. A method in Example I-14, wherein the operating mode of the step of ignoring the sensing current is interrupted in response to a subsequent determination that the rate of change of the counter electrode voltage does not exceed the threshold rate of change.

[0225] Example I-16. A method according to Example I-13, wherein the operating mode comprises the step of stopping the application of potential between the working electrode and the reference electrode when the compliance lower limit of the counter electrode voltage satisfies a critical compliance limit.

[0226] Example I-17. A method according to Example I-13, wherein the operating mode comprises the step of stopping the application of potential between the working electrode and the reference electrode when the change of the counter electrode voltage deviates from the change of the sensing current and the rate of change of the counter electrode voltage exceeds a threshold rate of change.

[0227] Example I-18. In Example I-11, the microneedle array-based analyte monitoring device further comprises one or more additional working electrodes, each of the one or more additional working electrodes generates a respective sensing current;

[0228] The above method is characterized by further including a step of determining the correlation between the counter electrode voltage and each of the sensing currents in response to a step of identifying the characteristics of the counter electrode voltage that exceeds the threshold value.

[0229] Example I-19. A method according to Example I-18, wherein the operating mode is further based on the correlation between the counter electrode voltage and the respective sensing current.

[0230] Example I-20. A method according to Example I-19, characterized in that the sensing current at the working electrode and the respective sensing currents at one or more additional working electrodes are combined to determine a combined correlation.

[0231] The foregoing description uses specific nomenclature to provide a complete understanding of the invention for illustrative purposes. However, it will be apparent to those skilled in the art that specific details are not required to practice the invention. Accordingly, the foregoing description of specific embodiments of the invention is provided for illustrative and illustrative purposes only. It is not intended to limit the invention to its complete or disclosed exact form. Clearly, many modifications and variations are possible in light of the foregoing teachings. The embodiments have been selected and described to illustrate the principles of the invention and their practical applications, thereby enabling those skilled in the art to utilize various embodiments with various modifications suitable for the invention and the specific use being considered. The claims below and their equivalents are intended to define the scope of the invention.

Claims

Claim 1 An analyte monitoring device based on a microneedle array, comprising: an electrochemical sensing coating configured to generate a sensing current indicating a redox reaction of an analyte on the surface of a working electrode, said working electrode located on the surface of a distal portion of a first microneedle of the microneedle array; a reference electrode located on the surface of a distal portion of a second microneedle of the microneedle array; a counter electrode located on the surface of a distal portion of a third microneedle of the microneedle array; an analog front end configured to maintain a fixed potential relationship between the working electrode and the reference electrode and to allow the potential of the counter electrode to swing to maintain the redox reaction at the working electrode; and a controller communicating with said analog front end. Monitoring the counter electrode voltage at the above counter electrode; Identifying the characteristics of the counter electrode voltage that satisfy or exceed a threshold value; In response to identifying the characteristics of the counter electrode voltage exceeding the above threshold, determining the correlation between the counter electrode voltage and the sensing current; and A microneedle array-based analyte monitoring device characterized by including the controller configured to apply an operating mode to the microneedle array-based analyte monitoring device based on the characteristics and correlation of the counter electrode voltage.

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