Continuous analyte monitoring system with microneedle array

Abstract

Described herein are variations of analyte monitoring systems that include analyte monitoring devices. For example, an analyte monitoring device can include an implantable microneedle array for measuring one or more analytes (e.g., glucose), for example, in a continuous manner. The microneedle array can include, for example, at least one microneedle including a tapered distal portion having an insulated distal tip and an electrode on a surface of the tapered distal portion proximal to the insulated distal tip. At least some of the microneedles can be electrically isolated such that one or more electrodes are individually addressable.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Patent Application No. 63 / 058,275, filed July 29, 2020, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates generally to the field of analyte monitoring, such as continuous glucose monitoring. Background Technology

[0004] Diabetes is a chronic disease in which the body cannot produce or properly use insulin, a hormone that regulates blood sugar. Insulin can be administered to people with diabetes to help regulate their blood sugar levels; however, blood sugar levels must still be carefully monitored to ensure the timing and dosage are appropriate. If the condition is not properly managed, people with diabetes may suffer from various complications caused by hyperglycemia (high blood sugar levels) or hypoglycemia (low blood sugar levels).

[0005] Glucose monitors help people with diabetes manage their condition by measuring blood glucose levels in a blood sample. For example, a diabetic patient obtains a blood sample by pricking their finger into a sampling device, transferring the sample to a test strip containing a suitable reagent that reacts with the blood sample, and then uses a glucose monitor to analyze the test strip to measure the glucose level in the blood sample. However, patients using this procedure typically only have their glucose levels measured at discrete moments, which may not be able to detect hyperglycemia or hypoglycemia in a timely manner. A newer type of glucose monitor is the continuous glucose monitoring (CGM) device, which includes a percutaneously implantable electrochemical sensor for continuously detecting and quantifying blood glucose levels via an alternative measurement of glucose levels in the subcutaneous interstitial fluid. However, traditional CGM devices also have weaknesses, including tissue damage caused by insertion and signal delay (e.g., due to the time required for the glucose analyte to diffuse from the capillary source to the sensor). These weaknesses also lead to several drawbacks, such as pain experienced by the patient when the electrochemical sensor is inserted, and limited accuracy of glucose measurements, especially when blood glucose levels change rapidly. Therefore, a new and improved analyte monitoring system is needed. Summary of the Invention

[0006] In some variations, the microneedle array for sensing the analyte may include multiple microneedles (e.g., solid microneedles). Each microneedle may include a tapered distal portion having an insulated distal apex, and an electrode on the surface of the tapered distal portion, wherein the electrode is located proximal to the insulated distal apex.

[0007] In some variations, the method for monitoring a user may include approaching the user's bodily fluids with an analyte monitoring device and quantifying one or more analytes in the bodily fluids using the analyte monitoring device, wherein the analyte monitoring device may include a plurality of solid microneedles. In some variations, at least one microneedle may include a tapered distal portion having an insulated distal apex, and an electrode on the surface of the tapered distal portion, wherein the electrode is located proximal to the insulated distal apex.

[0008] In some variations, the microneedle array for sensing the analyte may include a plurality of solid microneedles, wherein at least one microneedle includes a tapered distal portion having an insulated distal apex, and an electrode on the surface of the tapered distal portion, wherein the distal end of the electrode is offset from the distal apex.

[0009] In some variations, the method of sterilizing the analyte monitoring device may include exposing the analyte monitoring device to a sterilizing agent gas, wherein the analyte monitoring device includes a wearable housing, a microneedle array extending from the housing and including an analyte sensor, and an electronic system disposed within the housing and electrically coupled to the microneedle array. The analyte monitoring device may be exposed to the sterilizing agent gas for a duration sufficient to complete sterilization of the analyte monitoring device.

[0010] In some variations, the microneedle array for an analyte monitoring device may include multiple sensing microneedles (e.g., solid microneedles), each sensing microneedle comprising a tapered distal portion and a body portion, the tapered distal portion including a working electrode configured to sense the analyte, and the body portion providing a conductive connection to the working electrode. The body portion of each sensing microneedle may be insulated, such that each working electrode is individually addressable and electrically isolated from each other working electrode in the microneedle array.

[0011] In some variations, the microneedle array for a wearable analytical monitoring device may include at least one microneedle comprising a pyramidal body portion having a non-circular (e.g., octagonal base) and a tapered distal portion extending from the body portion and including an electrode, wherein the distal portion includes a flat surface offset from the distal apex of the at least one microneedle.

[0012] In some variations, the method for monitoring a user may include using an integrated analyte monitoring device comprising a single microneedle array to approach the user’s dermal interstitial fluid at multiple sensor locations and quantifying one or more analytes in the dermal interstitial fluid using multiple working electrodes in the microneedle array, wherein each working electrode is individually addressable and electrically isolated from each other working electrode in the analyte monitoring device.

[0013] In some variations, the wearable analyte monitoring device may include a wearable housing and a microneedle array. The microneedle array may extend outward from the housing and includes at least one microneedle configured to measure one or more analytes in the body of the user wearing the housing. The housing may include a user interface configured to convey information indicating the measurement results of one or more analytes.

[0014] In some variations, methods for monitoring a user may include measuring one or more analytes in the user's body using a wearable analyte monitoring device, the wearable analyte monitoring device including a wearable housing and one or more analyte sensors, and conveying information indicating the measurement results of one or more analytes through a user interface on the housing. Attached Figure Description

[0015] Figure 1 A schematic diagram of an analyte monitoring system with a microneedle array is depicted.

[0016] Figure 2A A schematic diagram of the analyte monitoring equipment is shown.

[0017] Figure 2B A schematic diagram depicting the microneedle insertion depth in an analyte monitoring device is shown.

[0018] Figures 3A-3C The top, side, and bottom perspective views of the analyte monitoring equipment are depicted respectively. Figure 3D Depicting an adhesive layer Figure 3A A partial exploded view of the analyte monitoring equipment shown. Figure 3E Depicting Figure 3A An exploded view of the analyte monitoring equipment shown.

[0019] Figure 3F-3I Top perspective view, bottom perspective view, side view and exploded view of the sensor assembly in the analyte monitoring device are depicted respectively.

[0020] Figure 3J A transparent side view of the sensor assembly in the analyte monitoring device is depicted.

[0021] Figures 4A-4E The perspective view, side view, bottom view, side sectional view, and top transparent perspective view of the analyte monitoring equipment are depicted respectively.

[0022] Figure 5A A schematic diagram of the microneedle array is depicted. Figure 5B Depicting Figure 5A An illustrative diagram of the microneedles in the microneedle array depicted in the image.

[0023] Figure 6A schematic diagram of a microneedle array for sensing a variety of analytes is depicted.

[0024] Figure 7A A side sectional view of a columnar microneedle with a tapered distal end is depicted. Figure 7B and 7C They are Figure 7A Perspective and detailed views of the microneedle embodiment shown.

[0025] Figure 8 A schematic diagram of a columnar microneedle with a tapered distal end is depicted.

[0026] Figure 9 A side sectional view of a columnar microneedle with a tapered distal end is depicted.

[0027] Figure 10 A schematic diagram of a columnar microneedle with a tapered distal end is depicted.

[0028] Figure 11A A side sectional view of a pyramidal microneedle with a tapered distal end is depicted. Figure 11B It is a description Figure 11A An image of a perspective view of one embodiment of the microneedle shown. Figure 11C It is a description including similar Figure 11B An image of an exemplary variant of the microneedle array shown.

[0029] Figure 12 A schematic diagram of a pyramidal microneedle with a tapered distal end is depicted.

[0030] Figure 13A A schematic diagram of a pyramidal microneedle with a tapered distal end and an asymmetric cut surface is depicted. Figure 13B It is a description Figure 13A An image of an exemplary variant of the microneedle shown.

[0031] Figure 13C-13E Explanation Figure 13A The forming process of the pyramidal microneedle shown.

[0032] Figure 14A A schematic diagram of a columnar-pyramidal microneedle with a tapered distal end is depicted. Figure 14B Depicting Figure 14A A detailed view of the distal portion of the microneedle depicted in the image.

[0033] Figures 15A-15D A schematic diagram illustrating the formation of conductive paths within a microneedle array is shown.

[0034] Figures 16A-16C Schematic diagrams depicting the layered structures of the working electrode, counter electrode, and reference electrode are shown respectively.

[0035] Figure 16D-16FSchematic diagrams depicting the layered structures of the working electrode, counter electrode, and reference electrode are shown respectively.

[0036] Figure 16G-16I Schematic diagrams depicting the layered structures of the working electrode, counter electrode, and reference electrode are shown respectively.

[0037] Figure 17 A schematic diagram of the microneedle array configuration is depicted.

[0038] Figure 18A and 18B Perspective views and orthographic views of exemplary variations of a carrier sheet including a microneedle array are depicted, respectively.

[0039] Figure 19A-19J Schematic diagrams depicting different variations of the microneedle array configuration are provided.

[0040] Figure 20 A schematic diagram of a low-profile battery holder is shown.

[0041] Figure 21 An illustrative flowchart depicts a method for sterilizing analyte monitoring equipment.

[0042] Figure 22 A schematic diagram of a sterilization apparatus that can be used for ethylene oxide sterilization is shown.

[0043] Figure 23 An illustrative variation of the ethylene oxide sterilization protocol is described.

[0044] Figures 24A-24C Exemplary data depicting the feasibility of recommending ethylene oxide sterilization of analyte monitoring equipment are presented.

[0045] Figure 25 This is a schematic diagram of the electronic circuitry that enables the analyte monitoring device to be activated after the microneedle array is inserted into the skin.

[0046] Figure 26 This is a diagram illustrating the pairing between an analytical monitoring device and a mobile computing device that executes a mobile application.

[0047] Figure 27A and 27B Schematic diagrams of the microneedle array and the microneedles are shown respectively. Figure 27C-27F A detailed partial view of an exemplary variant of the microneedle is depicted.

[0048] Figure 28A and 28B An illustrative variation of the microneedle is described.

[0049] Figure 29A and 29B A schematic diagram of the microneedle array configuration is depicted.

[0050] Figure 30A and 30B A schematic diagram of the microneedle array configuration is depicted.

[0051] Figure 31A and 31B A schematic diagram depicts the housing of an analyte monitoring device, including a user interface with indicator light elements.

[0052] Figures 32A-32C A schematic diagram depicts the illumination pattern in an analyte monitoring device used to indicate analyte measurement data.

[0053] Figures 33A-33D A schematic diagram depicts the illumination pattern in an analyte monitoring device used to indicate analyte measurement data.

[0054] Figures 34A-34C A schematic diagram depicts the illumination pattern in an analyte monitoring device used to indicate analyte measurement data.

[0055] Figure 35A and 35B A schematic diagram depicts the illumination patterns in an analytical monitoring device used to indicate device information (e.g., operating status and / or fault mode). Detailed Implementation

[0056] Non-limiting examples of aspects and variations of the invention are described herein and illustrated in the accompanying drawings.

[0057] As generally described herein, an analyte monitoring system may include an analyte monitoring device worn by a user and comprising one or more sensors for monitoring at least one analyte. For example, the sensors may include one or more electrodes configured to perform electrochemical detection of at least one analyte. The analyte monitoring device may transmit sensor data to an external computing device for storage, display, and / or analysis of the sensor data. For example, as... Figure 1As shown, the analyte monitoring system 100 may include an analyte monitoring device 110 worn by a user, and the analyte monitoring device 110 may be a continuous analyte monitoring device (e.g., a continuous glucose monitoring device). The analyte monitoring device 110 may include, for example, a microneedle array including at least one electrochemical sensor for detecting and / or measuring one or more analytes in the user's bodily fluids. In some variations, the analyte monitoring device may be applied to the user using a suitable applicator 160, or it may be applied manually. The analyte monitoring device 110 may include one or more processors for analyzing 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 executing mobile applications to process sensor data (e.g., displaying data, analyzing data trends, etc.) and / or the mobile computing device 102 may provide appropriate alerts or other notifications related to the sensor data and / or its analysis. It should be understood that, although in some variations, mobile computing device 102 can perform sensor data analysis locally / in-place, other computing devices may alternatively or additionally analyze sensor data remotely and / or communicate information related to such analysis with mobile computing device 102 (or other suitable user interface / user interface) for display to the user. Furthermore, in some variations, mobile computing device 102 may be configured to transmit sensor data and / or the analysis of sensor data via network 104 to one or more storage devices 106 (e.g., a server) for archiving data and / or other suitable information relevant to the user of the analyte monitoring device.

[0058] The analyte monitoring device described herein features improved characteristics beneficial 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 to help minimize changes in sensor response over time during storage and operation of the analyte monitoring device. Furthermore, compared to conventional continuous analyte monitoring devices, the analyte monitoring device described herein has a shorter warm-up time, enabling the sensor to quickly provide a stable sensor signal after implantation, and a short response time, enabling the sensor to quickly provide a stable sensor signal after changes in analyte concentration within the user's body. Moreover, as described in further detail below, the analyte monitoring device described herein can be applied and function at multiple different wearing sites, providing a painless sensor insertion for the user. Other characteristics such as biocompatibility, sterilizability, and mechanical integrity are also optimized in the analyte monitoring device described herein.

[0059] Although the analyte monitoring systems described herein may be referred to in relation to glucose monitoring (e.g., in users with type 1 or type 2 diabetes), it should be understood that such systems may be additionally or alternatively configured to sense and monitor other suitable analytes. Suitable target analytes for detection, as described further in detail below, may include, for example, glucose, ketones, lactate, and cortisol. One target analyte may be monitored, or multiple target analytes may be monitored simultaneously (e.g., in the same analyte monitoring device). For example, monitoring of other target analytes may monitor other indicators such as stress (e.g., by detecting elevated cortisol and glucose) and ketoacidosis (e.g., by detecting elevated ketones).

[0060] The following sections provide further details on various aspects of example variations of analyte monitoring systems and their usage methods.

[0061] Analyte monitoring equipment

[0062] like Figure 2AAs shown, in some variations, the analyte monitoring device 110 may generally include a housing 112 and a microneedle array 140 extending outwardly from the housing. The housing 112 may be, for example, a wearable housing configured to be worn on a user's skin such that the microneedle array 140 extends at least partially into the user's skin. For example, the housing 112 may include an adhesive, making the analyte monitoring device 110 a skin-adhesive patch that is simple and direct to apply to the user. The microneedle array 140 may be configured to puncture the user's skin and includes one or more electrochemical sensors (e.g., electrodes) configured to measure one or more target analytes that are accessible after the microneedle array 140 punctures the user's skin. In some variations, the analyte monitoring device 110 may be integrated or self-contained as a single unit, and this unit may be disposable (e.g., for use for a period of time and to be replaced by another analyte monitoring device 110).

[0063] Electronic system 120 may be at least partially arranged within housing 112 and includes various electronic components, such as sensor circuitry 124 configured to perform signal processing (e.g., biasing and readout of electrochemical sensors, converting analog signals from electrochemical sensors into digital signals, etc.). Electronic system 120 may also include at least one microcontroller 122 for controlling analyte monitoring device 110, at least one communication module 126, at least one power supply 130, and / or other various suitable passive circuitry 127. Microcontroller 122 may be configured, for example, to: interpret digital signals output from sensor circuitry 124 (e.g., by executing programming routines in firmware); perform various suitable algorithms or mathematical transformations (e.g., calibration, etc.); and / or route processed data to and / or from communication module 124. In some variations, communication module 126 may include a suitable wireless transceiver (e.g., a Bluetooth transceiver, etc.) for data communication with external computing device 102 via one or more antennas 128. For example, communication module 126 may be configured to provide one-way and / or two-way data communication with external computing device 102, which is paired with analyte monitoring device 110. Power supply 130 may provide power to analyte monitoring device 110, for example, to the electronic system. Power supply 130 may include a battery or other suitable power source, and in some variations may be rechargeable and / or replaceable. Passive circuitry 127 may include various passive circuits (e.g., resistors, capacitors, inductors, etc.) that provide interconnections between other electronic components, etc. For example, passive circuitry 127 may be configured to perform noise reduction, biasing, and / or other purposes. In some variations, the electronic components in electronic system 120 may be arranged on one or more printed circuit boards (PCBs), which may be rigid, semi-rigid, or flexible. Further details of electronic system 120 will be described below.

[0064] In some variations, the analyte monitoring device 110 may also include one or more additional sensors 150 to provide additional information that may be relevant to user monitoring. For example, the analyte monitoring device 110 may also include at least one temperature sensor (e.g., a thermistor) configured to measure skin temperature, thereby enabling temperature compensation of sensor measurements obtained from the microneedle array electrochemical sensor.

[0065] In some variations, the microneedle array 140 in the analyte monitoring device 110 can be configured to puncture the user's skin. For example... Figure 2BAs shown, when the device 110 is worn by a user, the microneedle array 140 can extend into the user's skin, such that electrodes on the distal regions of the microneedles remain in the dermis. Specifically, in some variations, the microneedles can be designed to penetrate the skin and enter the upper dermal regions (e.g., the papillary dermis and the upper reticular dermis) to allow the electrodes to access the intercellular fluid surrounding the cells in these layers. For example, in some variations, the microneedles may have a height typically 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 ends of the electrodes on the microneedles are located at positions 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.

[0066] Compared to conventional continuous analyte monitoring devices (such as CGM devices) that include sensors typically implanted in the subcutaneous tissue or fat layer of the skin at a depth of about 8 to 10 mm below the skin surface, the analyte monitoring device 110 has a shallower microneedle insertion depth of about 0.25 mm (allowing the electrodes to be implanted in the upper dermal region of the skin). These benefits include proximity to the dermal interstitial fluid containing one or more target analytes for detection, which is advantageous at least because measurements of at least some types of analytes in the dermal interstitial fluid have been found to be highly correlated with blood measurements. For example, glucose measurements using electrochemical sensors that contact the dermal interstitial fluid have been found to be advantageously highly linearly correlated with blood glucose measurements. Therefore, glucose measurements based on the dermal interstitial fluid are highly representative of blood glucose measurements.

[0067] Furthermore, due to the shallow insertion depth of the microneedles in the analyte monitoring device 110, the time delay for analyte detection is reduced compared to conventional continuous analyte monitoring devices. This shallow insertion depth brings the sensor surface very close (e.g., within a few hundred micrometers or less) to the dense and well-perfused capillary bed of the dermal reticular layer, resulting in negligible diffusion hysteresis from the capillaries to the sensor surface. Diffusion time and diffusion distance are determined according to t = x 2The 2D correlation is used, where t is the diffusion time, x is the diffusion distance, and D is the mass diffusivity of the analyte of interest. Therefore, positioning the analyte sensing element at twice the distance from the analyte source in the capillaries results in a fourfold diffusion delay time. Consequently, conventional analyte sensors residing in poorly vascularized adipose tissue in the subdermis result in significantly greater diffusion distances from the vascular system in the dermis, leading to considerably larger diffusion delays (e.g., typically 5–20 minutes). In contrast, the shallower microneedle insertion depth of the analyte monitoring device 110 benefits from the low diffusion delay from the capillaries to the sensor, thereby reducing time delays in analyte detection and providing more accurate results in real-time or near real-time. For example, in some embodiments, the diffusion delay can be less than 10 minutes, less than 5 minutes, or less than 3 minutes.

[0068] Furthermore, when the microneedle array is located in the upper dermal region, the lower dermis beneath it exhibits a very high level of vascularization and perfusion to support dermal metabolism, thereby enabling temperature regulation (through vasoconstriction and / or vasodilation) and providing a barrier function to help stabilize the sensing environment around the microneedles. Another advantage of the shallower insertion depth is that the upper dermal layer lacks pain receptors, thus reducing pain when the microneedle array punctures the user's skin and providing a more comfortable, minimally invasive user experience.

[0069] Therefore, the analyte monitoring device and method described herein can improve the continuous monitoring of one or more target analytes for a user. For example, as mentioned above, the analyte monitoring device can be applied simply and directly, which improves ease of use and user compliance. Furthermore, analyte measurement of dermal interstitial fluid can provide highly accurate analyte detection. Moreover, compared to conventional continuous analyte monitoring devices, the insertion of microneedle arrays and their sensors is less invasive and less painful for the user. Other advantages of the analyte monitoring device and method will be further described below.

[0070] shell

[0071] As described above, the analyte monitoring device may include a housing. The housing may at least partially enclose or encapsulate other components of the analyte monitoring device (e.g., electronic components), for example, to protect these components. For instance, the housing may be configured to help prevent dust and moisture from entering the analyte monitoring device. In some variations, an adhesive layer may allow the housing to adhere to a user's surface (e.g., skin) while allowing a microneedle array to extend outward from the housing and into the user's skin. Furthermore, in some variations, the housing may typically include rounded edges or corners and / or a low profile to prevent damage and reduce interference with clothing, etc., worn by the user.

[0072] For example, such as Figures 3A-3EAs shown, an example variant of the analyte monitoring device 300 may include a housing 310 and a microneedle array 330, the housing 310 being configured to at least partially surround other various internal components of the device 300, and the microneedle array 330 extending outward from the skin-facing surface (e.g., the underside) of the housing 310.

[0073] For example, housing 310 may include one or more rigid or semi-rigid protective housing components, which may be connected together by suitable fasteners (such as mechanical fasteners), mechanical interlocks or mating features and / or engineering fits. For example, as Figure 3E As shown, the housing may include a housing cover 310a and a housing base 310b, wherein the cover 310a and the base 310b may be secured together using one or more threaded fasteners (e.g., fasteners engaging threaded holes in the upper and / or lower housing portions). The cover 310a and the base 310b may include rounded / rounded edges and corners, and / or other damage-resistant features. When joined together, the cover 310a and the base 310b may form an internal volume that houses other internal components, such as a device printed circuit board 350 (PCB), a sensor assembly 320, and / or other components, such as a gasket 312. For example, the internal components arranged in the internal volume may be arranged in a compact, low-profile stack, such as... Figure 3E As shown. Although Figure 3E A housing 310 comprising multiple housing components is shown, but in some variations, housing 310 may include a single component defining an internal volume for accommodating internal device components. In some embodiments, housing 310 may be filled with a suitable potting compound (e.g., epoxy resin) to reduce harmful environmental impacts such as temperature, humidity, pressure, and light.

[0074] In addition, the analyte monitoring device 300 may include an adhesive layer 340 configured to attach the housing 310 to a user's surface (e.g., skin). The adhesive layer 340 may be attached to the skin-facing side of the housing 310, for example, via a double-sided adhesive pad 344. Figure 3D As illustrated in the variant depicted. Alternatively, the adhesive layer 340 can be directly attached to the skin-facing side of the housing 310 using one or more suitable fasteners (e.g., adhesive, mechanical fasteners, etc.). The adhesive layer 340 can be protected by a release liner, which the user removes before application to the skin to expose the adhesive. In some variants, the analyte monitoring device may include a feature that allows the analyte to be detected from the skin. Obtained 1504XL TM Double-sided adhesive and 4076 TMSkin-facing adhesives. These materials were chosen for their: breathability, abrasion resistance, average water vapor transmission rate (MWVTR), biocompatibility, compatibility with sensor sterilization methods / strategies, appearance, durability, tackiness, and ability to maintain said tackiness during sensor wear.

[0075] In some variations, the periphery of the adhesive layer 340 may extend further than the periphery or outer periphery of the housing 310 (e.g., to increase the adhesion surface area, improve retention stability, or enhance adhesion to the user's skin). Furthermore, in some variations, the adhesive layer 340 may include an opening 342 that allows the outwardly extending microneedle array 330 to pass through. The opening 342 may closely / closely externally / definite the shape of the microneedle array 330, such as... Figure 3C As shown (e.g., a square opening that closely corresponds in size and shape to a square microneedle array), or another suitable size and shape having a larger coverage area than the microneedle array (e.g., a circular opening larger than a square microneedle array).

[0076] although Figures 3A-3E The housing 310 shown is hexagonal and generally prismatic; however, it should be understood that in other variations, the housing 310 can be any suitable shape. For example, in other variations, the housing can be generally prismatic and have an elliptical (e.g., circular), triangular, rectangular, pentagonal, or other suitable shaped base. As another example, Figures 4A-4C An example variant of the analyte monitoring device 400, including a dome-shaped housing 410, is shown. Although Figures 4A-4C The dome-shaped shell 410 shown is typically circular, but in other variations, the dome-shaped shell may have a base that has another suitable elliptical or polygonal shape.

[0077] Similar to housing 310, housing 410 may include an internal volume configured to at least partially enclose other components of the analyte monitoring device 400. For example, such as Figure 4D As shown in the cross-sectional view, the housing 410 may include a dome-shaped cover 410a coupled to the base 410b to form an internal volume in which the device PCB 450 and the sensor assembly having a microneedle array 430 can be arranged. Furthermore, the housing 410 may be configured to be coupled to a surface via an adhesive layer 440, and the microneedle array 430 may extend outward from the housing and beyond the adhesive layer 440. Additionally, as... Figure 4D and 4E As shown, the adhesive layer 440 may extend beyond the outer periphery of the housing 410.

[0078] user interface

[0079] In some variations, the analyte monitoring system can directly provide user status, analyte monitoring device status, and / or other suitable information on the analyte monitoring device via a user interface (e.g., a display, indicator light, etc., as described below). Therefore, in some variations, this information can be provided directly by the analyte monitoring device, compared to analyte monitoring systems that can only transmit information to a separate peripheral device (e.g., a mobile phone, etc.) that then communicates the information to the user. Advantageously, in some variations, this user interface on the analyte monitoring device can reduce the need for the user to continuously maintain a separate peripheral device for monitoring user status and / or analyte monitoring device status (which may be impractical due to cost, inconvenience, etc.). Furthermore, the user interface on the analyte monitoring device can reduce the risk associated with communication loss between the analyte monitoring device and a separate peripheral device, such as the user's inaccurate understanding of their current analyte level (e.g., leading the user to believe their analyte level is high when it is actually low, which could, for example, lead the user to administer inaccurate doses of medication or refuse medical intervention when it is necessary).

[0080] Furthermore, this ability to communicate information to users directly through the analyte monitoring device itself without relying on separate peripheral devices reduces or eliminates the need to maintain compatibility between the analyte monitoring device and such peripheral devices when upgrading separate peripheral devices (e.g., replacing with a new device model or other hardware, running a new version of the operating system or other software, etc.).

[0081] Therefore, in some variations, the housing may include a user interface, such as an interface that provides information visually, audibly, and / or tactilely, to provide information about the user's status and / or the status of the analyte monitoring device, and / or other suitable information. Examples of user status that can be conveyed via the user interface include information representing analyte measurements in the user's data (e.g., below a predetermined target analyte measurement threshold or range, within a predetermined target analyte measurement range, above a predetermined target analyte measurement threshold or range, an increase or decrease in the analyte measurement over time, the rate of change of the analyte measurement, other information related to trends in the analyte measurement, other suitable alarms associated with the analyte measurement, etc.). Examples of analyte monitoring device status that can be conveyed via the user interface include device operating modes (e.g., associated with device warm-up status, analyte monitoring status, battery status such as low power), device error status (e.g., operational errors, pressure-induced sensor attenuation, malfunctions, failure modes, etc.), device power status, device lifespan status (e.g., expected end of sensor life), connectivity status between the device and the mobile computing device, etc.

[0082] In some variations, the user interface may be enabled or "on" by default to convey this information, at least when the analyte monitoring device is performing analyte measurements or is powered on, thus helping to ensure that the user has continuous access to information. For example, user interface elements may communicate not only through displays or indicator lights (e.g., as described below) to alert the user or recommend remedial measures, but also when the user and / or device are in normal working order. Therefore, in some variations, the user does not need to perform an action to initiate a scan to understand their current analyte measurement level, and this information is always readily available to the user. However, in some variations, the user may perform an action to temporarily deactivate the user interface (e.g., similar to a "sleep" button) for a predetermined period of time (e.g., 30 minutes, 1 hour, 2 hours, etc.), after which the user interface is automatically reactivated, or until a second action is performed to reactivate the user interface.

[0083] In some variations, the user interface of the casing may include a display configured to visually convey information. The display may include, for example, a screen (e.g., an LCD screen, an organic light-emitting diode (OLED) display, an electrophoretic display, an electrochromic display, etc.) configured to display alphanumeric text (e.g., numbers, letters, etc.), symbols, and / or appropriate graphics to convey information to the user. For example, the display may include numerical information, textual information, and / or graphics (e.g., diagonal lines, arrows, etc.) such as information about the user's status and / or the status of the analyte monitoring device. For example, the display may include textual or graphical representations of analyte measurement levels, trends, and / or recommendations (e.g., physical activity, reduced dietary intake, etc.).

[0084] As another example, the display on the housing may include one or more indicator lights (e.g., including light-emitting diodes, organic light-emitting diodes, lasers, electroluminescent materials or other suitable light sources, waveguides, etc.), which may be controlled to be in one or more predetermined light emission modes to convey different states and / or other suitable information. The indicator lights may be controlled to emit light in multiple colors (e.g., red, orange, yellow, green, blue, and / or purple, etc.) or only in one color. For example, the indicator lights may include multi-color LEDs. As another example, the indicator lights may include a transparent or translucent material (e.g., acrylic) surrounding one or more different colored light sources (e.g., LEDs), such that the different colored light sources can be selectively activated to illuminate the indicator lights in selected colors. Activation of the light sources may occur simultaneously or sequentially. The indicator lights may have any suitable form (e.g., protruding from the body of the housing, flush with the body of the housing, recessed from the body of the housing, etc.) and / or shape (e.g., circular or other polygonal, annular, elongated strip, etc.). In some variations, the indicator light may have a pinhole size and / or shape to present the same light intensity as a larger light source, but with significantly lower power requirements, which can help save onboard power in analyte monitoring equipment.

[0085] Indicator lights on a display can be illuminated in one or more different ways to convey different kinds of information. For example, an indicator light can be selectively illuminated or turned off to convey information (e.g., "on" indicates one state, and "off" indicates another state). Additionally or alternatively, an indicator light can be illuminated with a selected color or intensity to convey information (e.g., illuminating with a first color or intensity to indicate a first state, and illuminating with a second color or intensity to indicate a second state). Additionally or alternatively, an indicator light can be illuminated with a selected time pattern to convey information (e.g., illuminating with a first time pattern to indicate a first state, and illuminating with a second time pattern to indicate a second state). For example, an indicator light can be selectively illuminated in one of a plurality of predetermined time patterns, which differ in aspects such as illumination frequency (e.g., repeating illumination at a fast or slow frequency), regularity (e.g., periodic repetition versus intermittent illumination), duration of "on", duration of "off", rate of change of luminous intensity, and busy / idle status (e.g., the ratio of "on" time to "off" time), wherein each predetermined time pattern can indicate its respective state.

[0086] Additionally or alternatively, in some variations, the display may include multiple indicator lights that can be collectively illuminated according to one or more predetermined spatial and / or temporal patterns, in one or more predetermined lighting modes or sequences. For example, in some variations, some or all of the indicator lights arranged on the display may be illuminated synchronously or sequentially to indicate a specific state. Thus, a selected subset of the indicator lights (e.g., the spatial arrangement of the illuminated indicator lights) and / or the manner in which they are illuminated (e.g., lighting sequence, illumination rate, etc.) can indicate a specific state. Additionally or alternatively, multiple indicator lights may be illuminated simultaneously or sequentially to increase the diversity of the color palette. For example, in some variations, red, green, and blue LEDs may be rapidly and sequentially illuminated to create the impression of white light for the user.

[0087] It should also be understood that one or more of the above-mentioned illumination modes can be combined in any suitable manner (e.g., combinations of different colors, intensities, brightness, luminance, contrast, time, position, etc.) to convey information. Additionally or alternatively, an ambient light sensor can be incorporated into the device body to enable dynamic adjustment of the light level in the indicator light to compensate for ambient light conditions and help save power. In some variations, the ambient light sensor can be used in conjunction with a dynamic sensor (e.g., as described further below) to further determine the appropriate time period for the analyte monitoring device to enter a power-saving mode or reduce power. For example, detecting darkness and no movement of the analyte monitoring device can indicate that the wearer is asleep, which can trigger the analyte monitoring device to enter a power-saving mode or reduce power.

[0088] Figure 31A An example variant of an analyte monitoring device 3100 is shown, including a user interface 3120 with multiple indicator lights (3122, 3124a-3124c). Indicator lights 3120 can be selectively illuminated, for example, to indicate device status (e.g., operating mode, error status, power status, lifespan status, etc.). Although indicator lights 3122 are in the shape of symbols (e.g., signs), it should be understood that in other variants, indicator lights 3122 can have any suitable shape (e.g., text, other geometric shapes, etc.). Indicator lights 3124a-3124c can be selectively illuminated to indicate user status (e.g., information representing analyte measurement results). Although indicator lights 3124a-3124c are linear elements extending across the user interface (e.g., a chord across a circular display), it should be understood that in other variants, indicator lights 3124a-3124c have other suitable shapes (e.g., wavy lines, circles, etc.). In some variants, a one-dimensional array of indicator lights of any suitable shape can be arranged on the housing (e.g., arranged in rows, columns, arcs, etc.). Alternatively, the housing may comprise a multidimensional array of indicator lights of any suitable shape.

[0089] Furthermore, in some variations, the indicator light may include icons (e.g., symbols) that indicate analyte information (e.g., an upward arrow indicating an upward trend in analyte measurement levels, a downward arrow indicating a downward trend in analyte measurement levels), analyte monitoring device status (e.g., an exclamation mark indicating a device malfunction), and / or other suitable information. Additionally or alternatively, illustrations in the indicator light may be used to convey suggestions to the user, such as behavioral recommendations. The advantage of illustrations may be, for example, that they convey suggestions to the user in a more general or language-agnostic way (e.g., eliminating the need for language translation to adapt the device to different geographic regions or user preferences). For example, as... Figure 31B As shown, in some variations, in the case of glucose monitoring, the user interface for the analyte monitoring device 3100' may include a runner icon 3126 to indicate that the user should engage in physical activity. As another example, a food icon 3128 may indicate that the user should consume food (or, in combination with an "X" icon 3130, indicate that the user should limit food intake). As another example, a beverage icon 3132 may indicate that the user should consume fluids such as water (or, in combination with an "X" icon 3134, indicate that the user should limit fluid intake). As another example, a star icon 3136 may indicate positive reinforcement (e.g., indicating that the analyte measurement level has successfully remained within the normal or target range over a predetermined time period). However, it should be understood that behavioral recommendations may vary based on indications associated with the monitored analyte. For example, in some variations where the analyte monitoring device is additionally or alternatively used to monitor cortisol, elevated cortisol levels (and / or elevated glucose levels) may be associated with increased user stress. Therefore, in some of these variations, analyte monitoring devices may include appropriate icons to indicate to users suggestions for reducing exposure to stressful stimuli, meditation, etc., in order to avoid adverse health effects caused by stress.

[0090] exist Figure 31A and 31B In the variant shown, each of the indicator lights 3124a-3124c can be illuminated exclusively to indicate different analyte measurements (e.g., within the target range, below the target range, significantly below the target range, above the target range, significantly above the target range, etc.). Furthermore, the indicator lights 3124a-3124c can be arranged adjacent to each other so that they can be selectively illuminated in a progressive sequence to convey trend information about the analyte measurement (e.g., a progressive lighting sequence in a first direction corresponding to an increase in the analyte measurement, a progressive lighting sequence in a second direction corresponding to a decrease in the analyte measurement, a progressive lighting rate in the first or second direction corresponding to the rate of increase or decrease in the analyte measurement, etc.). See below for reference. Figures 33A-33DFurther describe examples of this progressive lighting sequence / order. Although in Figure 31A and 31B The diagram shows one device status indicator 3120 and three user status indicators 3124a-3124c; however, it should be understood that in other variations, the analyte monitoring device may include any suitable number of indicators, such as one, two, three, four, five, or more device status indicators, and one, two, three, four, five, or more user status indicators. Further details regarding example operation of the user interface 3120 in conveying device and / or user status are described below (see, for example, reference...). Figures 32A-32C 33A-33D, 34A-34C and 35A-35B).

[0091] microneedle array

[0092] like Figure 5A As illustrated in the schematic diagram, in some variations, the microneedle array 510 for sensing one or more analytes may include one or more microneedles 510 protruding from a substrate surface 502. For example, the substrate surface 502 may be generally flat, and one or more microneedles 510 may extend perpendicularly from the flat surface. Typically, as... Figure 5B As shown, the microneedle 510 may include a body portion 512 (e.g., a shaft) and a tapered distal portion 514 configured to puncture a user's skin. In some variations, the tapered distal portion 514 may terminate at an insulated distal apex 516. The microneedle 510 may also include an electrode 520 on the surface of the tapered distal portion. In some variations, electrode-based measurements may be performed at the interface between the interstitial fluid in the body and the electrode (e.g., across the entire outer surface of the microneedle). In some variations, the microneedle 510 may have a solid core (e.g., a solid body portion), but in some variations, the microneedle 510 may include one or more lumens that can be used for, for example, 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.

[0093] The microneedle array 500 may be formed at least partially from a semiconductor (such as silicon) substrate and includes various material layers applied and shaped using various suitable microelectromechanical systems (MEMS) fabrication techniques (such as deposition and etching techniques), as further described below. Similar to a typical integrated circuit, the microneedle array can be reflow soldered onto a circuit board. Furthermore, in some variations, the microneedle array 500 may include a three-electrode arrangement comprising a working (sensing) electrode, a reference electrode, and a counter electrode, having an electrochemical sensing coating (including biorecognition elements such as enzymes) capable of detecting target analytes. In other words, the microneedle array 500 may include at least one microneedle 510 containing a working electrode, at least one microneedle 510 containing a reference electrode, and at least one microneedle 510 containing a counter electrode. Further details of these types of electrodes will be described in further detail below.

[0094] In some variations, the microneedle array 500 may include a plurality of insulated microneedles, such that the electrode on each of the plurality of microneedles is individually addressable / accessible and electrically isolated from all other electrodes on the microneedle array. This ultimate individual addressability of the microneedle array 500 allows for better control over the function of each electrode, as each electrode can be probed individually. For example, the microneedle array 500 can be used to provide multiple independent measurements of a given target analyte, which improves the sensing reliability and accuracy of the device. Furthermore, in some variations, the electrodes of the multiple microneedles can be electrically connected to generate enhanced signal levels. As another example, the same microneedle array 500 can be additionally or alternatively interrogated to simultaneously measure multiple analytes, thereby providing a more comprehensive assessment of physiological states. For example, as... Figure 6 As illustrated in the schematic diagram, the microneedle array may include a 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 can be configured to detect any suitable number and variety of analytes (e.g., 1, 2, 3, 4, 5, or more, etc.). Suitable target analytes for detection may include, for example, glucose, ketones, lactates, and cortisol. For example, in some variations, ketones may be detected in a manner similar to that described in U.S. Patent Application No. 16 / 701,784, which is incorporated herein by reference in its entirety. Therefore, the individual electrical addressing capability of the microneedle array 500 provides greater control and flexibility to the sensing capabilities of the analyte monitoring device.

[0095] In some variations of the microneedle (e.g., a microneedle with a working electrode), electrode 520 may be located proximal to the insulated distal vertex 516 of the microneedle. In other words, in some variations, electrode 520 does not cover the vertex of the microneedle. Instead, electrode 520 may be offset from the vertex or tip of the microneedle. Electrode 520 located proximal to or offset from the insulated distal vertex 516 of the microneedle advantageously provides more accurate sensor measurements. For example, this arrangement prevents the electric field from concentrating at the microneedle vertex 516 during manufacturing, thereby avoiding non-uniform electrodeposition of sensing chemicals on the electrode surface 520, which could lead to erroneous sensing.

[0096] As another example, placing electrode 520 off-center from the microneedle apex can further improve sensing accuracy by reducing unwanted signal artifacts and / or erroneous sensor readings caused by stress during microneedle insertion. The distal apex of the microneedle is the first area penetrated into the skin and is therefore subjected to the greatest stress due to mechanical shearing phenomena accompanying skin tearing or cutting. If electrode 520 is placed on the apex or tip of the microneedle, this mechanical stress may cause delamination of the electrochemical sensing coating on the electrode surface and / or result in a small but disruptive amount of tissue being delivered to the active sensing portion of the electrode when the microneedle is inserted. Therefore, placing electrode 520 sufficiently off-center from the microneedle apex can improve sensing accuracy. For example, in some variations, the distal edge of electrode 520 may be located at least about 10 μm (e.g., about 20 μm to about 30 μm) from the distal apex or tip of the microneedle, as measured along the longitudinal axis of the microneedle.

[0097] The body portion 512 of the microneedle 510 may also include a conductive path extending between the electrode 520 and a back-side electrode or other electrical contacts (e.g., disposed on the back side of the microneedle array substrate). The back-side electrode may be soldered to a circuit board, enabling electrical communication with the electrode 520 via the conductive path. For example, during use, an in vivo sensed current (within the dermis) measured at the working electrode is interrogated by the back-side electrical contacts, and the conductive path facilitates an electrical connection between the back-side electrical contacts and the working electrode. In some variations, this conductive path may be facilitated by metal passing through the interior of the microneedle body portion (e.g., shaft) between the proximal and distal ends of the microneedle. Alternatively, in some variations, the conductive path may be provided by the entire body portion formed of a conductive material (e.g., doped silicon). In some of these variations, the entire substrate on which the microneedle array 500 is constructed may be conductive, and each microneedle 510 in the microneedle array 500 may be electrically isolated from adjacent microneedles 510, as described below. For example, in some variations, each microneedle 510 in the microneedle array 500 can be electrically isolated from adjacent microneedles 510, wherein the insulating barrier comprises an electrically insulating material (e.g., a dielectric material, such as silicon dioxide) surrounding a conductive path extending between the electrode 520 and the back-side electrical contact. For example, the body portion 512 may include an insulating material that forms a sheath around the conductive path, thereby preventing electrical continuity between the conductive path and the substrate. Other example variations of the structure capable of achieving electrical isolation between microneedles will be described in more detail below.

[0098] This electrical isolation between the microneedles in the microneedle array allows for individual addressing of the sensors. This individual addressing capability advantageously enables independent and parallel measurements between sensors, as well as dynamic reconfiguration of sensor assignments (e.g., for different analytes). In some variations, the electrodes in the microneedle array can be configured to provide redundant analyte measurements, an advantage over conventional analyte monitoring devices. For example, redundancy can improve performance by increasing device reliability and / or accuracy by reducing the likelihood of complete failure (e.g., averaging multiple analyte measurements for the same analyte, which reduces the impact of extremely high or low sensor signals on the determination of analyte levels).

[0099] In some variations, as described in further detail below for various variations of microneedles, the microneedle array can be formed at least in part using suitable semiconductor and / or MEMS fabrication techniques and / or mechanical cutting or dicing. This process, for example, facilitates the large-scale, low-cost fabrication of microneedle arrays. For instance, in some variations, the microneedle array can be formed at least in part using the technique described in U.S. Patent Application No. 15 / 913,709, which is incorporated herein by reference in its entirety.

[0100] microneedle structure

[0101] This article describes several example variations of microneedle structures that combine one or more of the microneedle features of the microneedle arrays in the aforementioned analyte monitoring devices.

[0102] In some variations, the microneedle may have a generally columnar body and a tapered distal portion with electrodes. For example, Figures 7A-7C An exemplary variant of the microneedle 700 extending from the substrate 702 is shown. Figure 7A This is a schematic side sectional view of the Microneedle 700, and Figure 7B This is a perspective view of the Microneedle 700. Figure 7C This is a detailed perspective view of the distal portion of the Microneedle 700. (See image.) Figure 7B and 7C As shown, the microneedle 700 may include a columnar body portion 712, a tapered distal portion 714 terminating at an insulated distal apex 716, and an annular electrode 720 comprising a conductive material (e.g., Pt, Ir, Au, Ti, Cr, Ni, etc.) disposed on the tapered distal portion 714. Figure 7A As shown, the annular electrode 720 may be located near (or offset from or spaced apart from) the distal vertex 716. For example, the electrode 720 may be electrically isolated from the distal vertex 716 via a distal insulating surface 715a comprising an insulating material (e.g., SiO2). In some variations, the electrode 720 may also be electrically isolated from the columnar body portion 712 via a second distal insulating surface 715b. The electrode 720 may be electrically connected to a conductive core 740 (e.g., a conductive path) extending along the body portion 712 to a back-side electrical contact 730 (e.g., made of a Ni / Au alloy) or other electrical bonding area in or on the substrate 702. For example, the body portion 712 may comprise a conductive core material (e.g., highly doped silicon). Figure 7A As shown, in some variations, an insulating sleeve 713 comprising an insulating material (e.g., SiO2) may be disposed around the body portion 712 (e.g., around its perimeter) and extend at least partially through the substrate 702. Thus, the insulating sleeve 713 may, for example, help prevent electrical contact between the conductive core 740 and the surrounding substrate 702. The insulating sleeve 713 may further extend over the entire surface of the body portion 712. The upper and / or lower surfaces of the substrate 702 may also include a layer composed of a substrate insulator 704 (e.g., SiO2). Thus, the insulation provided by the insulating sleeve 713 and / or the substrate insulator 704 may at least partially contribute to the electrical isolation of the microneedle 700, enabling the microneedle 700 to be individually addressed within the microneedle array. Furthermore, in some variations, the insulating sleeve 713 extending over the entire surface of the body portion 712 may be used to increase the mechanical strength of the microneedle 700 structure.

[0103] The microneedle 700 can be formed at least partially by a suitable MEMS fabrication technique, such as plasma etching, also known as dry etching. For example, in some variations, the insulating protective sleeve 713 surrounding the body portion 712 of the microneedle can be fabricated by first forming a trench in the silicon substrate from the back side of the substrate using deep reactive ion etching (DRIE), and then filling the trench with a SiO2 / polysilicon (poly-Si) / SiO2 sandwich structure by low-pressure chemical vapor deposition (LPCVD) or other suitable processes. In other words, the insulating protective sleeve 713 can passivate the surface of the body portion 712 of the microneedle and continue as a buried feature in the substrate 702 near the proximal portion of the microneedle. By primarily comprising a silicon compound, the insulating protective sleeve 713 can provide good filling and adhesion to adjacent silicon walls (e.g., the walls of the conductive core 740, the walls of the substrate 702, etc.). The sandwich structure of the insulating protective sleeve 713 can further help to provide a good match with the adjacent silicon in terms of coefficient of thermal expansion (CTE), thereby advantageously reducing defects, cracks and / or other thermally induced weaknesses in the insulating structure 713.

[0104] The tapered distal portion can be formed from the front side of the substrate by isotropic dry etching, and the body portion 712 of the microneedle 700 can be fabricated by DRIE. The front metal electrode 720 can be deposited and patterned on the distal portion by specialized photolithography (e.g., electron beam evaporation), which allows metal to be deposited in the desired annular region to obtain the electrode 720 without coating the distal vertex 716. Furthermore, the Ni / Au back-side electrical contact 730 can be deposited by suitable MEMS fabrication techniques (e.g., sputtering).

[0105] The microneedle 700 can have any suitable size. For example, in some variations, the microneedle 700 can have a height of about 300 μm to about 500 μm. In some variations, the distal conical portion 714 can have a apex angle of about 60 degrees to about 80 degrees and a apex diameter of about 1 μm to about 15 μm. In some variations, the surface area of ​​the annular electrode 720 can be about 9,000 μm². 2 Approximately 11,000 μm 2 Or approximately 10,000 μm 2 . Figure 8 Various sizes of exemplary variations of columnar microneedles with tapered distal portions and annular electrodes, similar to the microneedle 700 described above, are shown.

[0106] Figure 9Another example variant of the microneedle 900 is shown, having a generally columnar body portion. Except as described below, the microneedle 900 can be similar to the microneedle 700 as described above. For example, similar to the microneedle 700, the microneedle 900 may include a columnar body portion 912 and a tapered distal portion 914 terminating at an insulated distal apex 916. The microneedle 900 may also include an annular electrode 920 comprising a conductive material and disposed on the tapered distal portion 914 at a location proximal to (or offset from or spaced apart from) the distal apex 916. Other elements of the microneedle 900 have similar reference numerals to those of the corresponding elements of the microneedle 700.

[0107] However, compared to the microneedle 700, the microneedle 900 can have a sharper tip at the distal apex 916 and an improved insulating protective sheath 913. For example, the distal apex 916 can have a sharper apex angle (e.g., an apex angle of about 25 degrees to about 45 degrees) and a apex radius of less than about 100 nanometers, which provides a sharper microneedle profile that can penetrate the skin more easily, at lower speeds, with less energy, and / or with less trauma. Furthermore, compared to the insulating protective sheath 713 (e.g., ... Figure 7A As shown, the improved insulating sheath 913 can extend only through the substrate 902, compared to (where it extends through the substrate 702 and along the height of the microneedle body portion 712), allowing the interlayer structure filling the trench (e.g., produced by DRIE as described above) to form a buried feature only within the substrate. While the sidewalls of the microneedle 900 are in Figure 9 As shown, it extends approximately orthogonally to the substrate surface. However, it should be understood that because the improved insulating protective sleeve 913 does not need to extend the entire height of the microneedle body portion 712, in some variations, the sidewalls of the microneedle 900 may be at a non-orthogonal angle relative to the substrate (e.g., the sidewalls may have a slight positive taper of about 1 degree to about 10 degrees, or about 5 degrees to about 10 degrees).

[0108] In some variations, the remainder of the microneedle surface 900 (excluding the annular electrode 920) may include an insulating material extending from the substrate insulator 904. For example, a layer of insulating material (e.g., SiO2) may extend from the front surface of the substrate 902 to provide a body portion insulator 918, and may further extend upwards to the proximal edge of the electrode 920, such as... Figure 9As shown. Another area of ​​insulating material can similarly cover the distal edge of electrode 920 and insulate the distal vertex 916. This area of ​​insulating material and / or an improved insulating sheath 913 can help prevent electrical contact between the conductive core 940 and the surrounding substrate 902. Thus, similar to microneedles 700, microneedles 900 can remain electrically insulated for individual addressing within the microneedle array. In some variations, the process of forming microneedles 900 can result in higher yields and / or provide lower production costs compared to the process of forming microneedles 700.

[0109] The microneedle 900 can have any suitable size. For example, in some variations, the microneedle 900 can include a height of about 400 μm to about 600 μm or about 500 μm. In some variations, the distal tapered portion 914 can have a tip angle of about 25 degrees to about 45 degrees and a tip radius of less than about 100 nm. Furthermore, the microneedle can have an axial diameter of about 160 μm to about 200 μm. Figure 10 Various other sizes of exemplary variants of columnar microneedles with tapered distal portions and annular electrodes, similar to the microneedle 900 described above, are shown.

[0110] Figures 27A-27F Another example variant of the microneedle 2700 is shown, which has a generally columnar body portion. Except as described below, the microneedle 2700 can be similar to the microneedle 700 as described above. For example, as... Figure 27B As shown, similar to microneedle 700, microneedle 2700 may include a cylindrical body portion 2712 and a tapered distal portion disposed on a cylinder 2713 and terminating at an insulated distal apex 2716. The cylinder 2713 may be insulated and have a smaller diameter than the cylindrical body portion 2712. Microneedle 2700 may also include an annular electrode 2720 comprising a conductive material and disposed on the tapered distal portion at a location proximal to (or offset from or spaced apart from) the distal apex 2916. Figures 27A-27F Other components of the microneedle 2700 shown have similar reference numerals to the corresponding components of the microneedle 700.

[0111] However, the electrode 2720 on the microneedle 2700 may include a tip contact trench 2722. This contact trench may be configured to facilitate the establishment of an ohmic contact between the electrode 2720 and the underlying conductive core 2740 of the microneedle. In some variations, the shape of the tip contact trench 2722 may include an annular groove formed in the surface of the conductive core 2740 (e.g., entering / exiting into the body portion of the microneedle, or otherwise contacting a conductive path in the body portion), such that when the electrode 2720 material is deposited onto the conductive core 2740, the electrode 2720 with the tip contact trench 2722 may have a stepped profile when viewed from the side. The tip contact trench 2722 can advantageously help provide error tolerance to ensure contact between the electrode 2720 and the underlying conductive core 2740. Any other microneedle variations described herein may also have similar tip contact trenches to help ensure contact between the electrode (e.g., which may be a working electrode, reference electrode, counter electrode, etc.) and the conductive path within the microneedle.

[0112] Figure 28A and 28B Various other sizes of example variants of columnar microneedles with a tapered distal portion and an annular electrode, similar to the microneedle 2700 described above, are shown. For example, Figure 28A and 28B The variant of the microneedle shown may have a tapered distal portion, which typically has a cone angle of about 80 degrees (or about 78 degrees to about 82 degrees, or about 75 degrees to about 85 degrees) and a cone diameter of about 140 μm (or about 133 μm to about 147 μm, or about 130 μm to about 150 μm). The cone of the tapered distal portion may be arranged on a cylinder such that the total combined height of the cone and cylinder is about 110 μm (or about 99 μm to about 116 μm, or about 95 μm to about 120 μm). The annular electrode on the tapered distal portion may have an outer diameter or base diameter of about 106 μm (or about 95 μm to about 117 μm, or about 90 μm to about 120 μm) and an inner diameter of about 33.2 μm (or about 30 μm to about 36 μm, or about 25 μm to about 40 μm). Measured along the slope of the distal portion of the cone, the length of the annular electrode can be approximately 57 μm (or approximately 55 μm to approximately 65 μm), and the total surface area of ​​the electrode can be approximately 12,700 μm. 2 (or approximately 12,500 μm) 2 Approximately 12,900 μm 2 or approximately 12,000 μm 2 Approximately 13,000 μm 2 ).like Figure 28BAs shown, the electrode may also have a tip contact groove extending around the central region of a cone surrounding the distal conical portion, wherein the contact / contact groove may have a width of about 11 μm (or about 5 μm to about 50 μm, about 10 μm to about 12 μm, or about 8 μm to about 14 μm) and a groove depth of about 1.5 μm (or about 0.1 μm to about 5 μm, or about 0.5 μm to about 1.5 μm, or about 1.4 μm to about 1.6 μm, or about 1 μm to about 2 μm). The microneedle has an insulated distal apex with a diameter of about 5.5 μm (or about 5.3 μm to about 5.8 μm, or about 5 μm to about 6 μm).

[0113] In some variations, the microneedle may have a generally pyramidal body and a cone-shaped distal portion with electrodes. For example, Figure 11A An exemplary variant of the microneedle 1100 is shown, having a generally pyramidal body portion 1112 and a tapered distal portion 1114 extending from the body portion 1112. The microneedle 1100 may also include an annular electrode 1120 disposed on the tapered distal portion 1114 and located proximal to an insulated distal apex 1116. The electrode 1120 may be electrically coupled to a back-side electrical contact 1130 via a conductive path through a conductive core 1140 of the microneedle. Similar to the above reference... Figure 9 The described microneedle 900, microneedle 1100 may include an insulating protective sleeve 1113 arranged around the base of the body portion 1112 and extending through the substrate 1102 to provide electrical insulation around the microneedle 1100 (e.g., for individual addressing) and help prevent electrical contact between the conductive core 1140 and the surrounding substrate 1102. However, with Figure 9 In contrast to the insulating sleeve 913 shown, the insulating sleeve 1113 may be offset from the base of the microneedle 1100. For example, the sleeve may be offset from the location where the base of the microneedle 1100 meets the substrate 1102 to which it is attached by about 10 μm to about 400 μm, about 10 μm to about 300 μm, about 10 μm to about 200 μm, or about 10 μm to about 100 μm from the point where it meets the substrate 1102 to which it is attached. In some variations, the insulating sleeve may include a filler material including parylene, Si3N4, and SiO2, which can provide a low thermal stress and chemical and water-resistant insulating material. An additional body portion of the insulator 1118 may extend from the front surface of the substrate 1102 to the proximal edge of the electrode 1120. Another region of the insulating material may extend from the distal edge of the electrode 1120 and insulate the distal vertex 1116.

[0114] like Figure 11BAs shown, in some variations, the microneedle 1100 with a pyramidal body portion 1112 may include a polygonal base, but the base may have any suitable shape (e.g., circular). The pyramidal body portion 1112 may include a plurality of planar / planar facets, each planar facet extending from the corresponding polygonal base of the microneedle. In some variations, the planar facets may include anisotropically etched... <311> Planar facets are used to increase the mechanical strength (e.g., compressive and shear strength) and / or increase the electrode surface area of ​​the microneedle 1110 relative to a cone with a non-planar facet surface. For example, the microneedle 1110 may have an octagonal base with anisotropic etching. <311> The planar facets increase mechanical strength and enhance the metallization surface of the microneedles 1110 for the electrode surface.

[0115] Microneedles 1100 can be formed at least partially using suitable MEMS fabrication techniques. For example, the pyramidal structure of the microneedles can be formed by timing anisotropic wet etching of a silicon wafer substrate. To form the annular electrode surface, metal deposition can be performed on the distal conical portion of the microneedle using, for example, the dedicated photolithography technique described above with respect to electrode 720, wherein the distal vertices 1116 are not coated. However, compared to the process for forming microneedles 700 described above, most of the process for forming microneedles 1100 does not involve expensive RIE techniques, thereby significantly reducing manufacturing costs. Furthermore, in some variations, the process for forming microneedles 1100 may include mechanical cutting, bulk micromachining, or other cutting techniques to shape the microneedles 1100 into a pyramidal body, instead of utilizing the dry etching process described above with respect to microneedles 700. Moreover, this technique can be performed on a large scale to form, for example, Figure 11C The diagram shows multiple microneedles 1110 arranged in an array.

[0116] The microneedle 1100 can have any suitable size. For example, in some variations, the microneedle 1100 can have a height of about 400 μm to about 600 μm or about 500 μm. In some variations, the distal tapered portion 714 can have a tip angle / apex angle of about 30 degrees to about 50 degrees or about 40 degrees, which can provide a good balance between the sharpness of skin puncture and the photolithographic processability of the inclined surface on which the electrode 1120 will be disposed.

[0117] Figure 12Various dimensions of example variants of a pyramidal microneedle are shown, the pyramidal microneedle having a tapered distal portion having planar facets and electrodes disposed on at least a portion of the planar facets. While in some variants the electrodes may be annular or quasi-annular (because all planar facets on the pyramidal microneedle can include metallized surfaces for electrodes), it should be understood that, alternatively, in some variants only a portion of the planar facets on the pyramidal microneedle (e.g., one, two, three, four, five, six, or seven planar facets of a pyramidal microneedle having an octagonal base and eight planar facets extending distally from the octagonal base) may include metallized surfaces.

[0118] In some variations, besides microneedles, they can also have... Figure 13A and 13B In addition to the asymmetrical shape shown, pyramidal microneedles can be similar to those described above for... Figure 11A The microneedles described above. For example, in... Figure 13A In some variations shown, the microneedle 1300 may have a non-circular or polygonal (e.g., square, octagonal) base, but may taper in a radially asymmetrical manner. For example, the microneedle 1300 may include at least one cut surface 1350 (e.g., a planar surface) offset from the distal vertex 1316 of the microneedle (i.e., not extending through the central z-axis defined from the base of the microneedle 1300 to the distal vertex 1316). The insulated distal vertex 1316 may remain intact so as not to impair the surface area to be metallized for use as an electrode. In some variations, the cut surface 1350 may be at a non-orthogonal angle relative to the base of the microneedle (and / or the surface of the substrate 1302), such as... Figure 13A As shown. For example, in some variations, the cutting surface may be configured to produce a sharp, asymmetrical distal tip at the distal vertex 1316 with an angle of less than about 50 degrees, less than 40 degrees, less than about 30 degrees, or less than about 20 degrees. Alternatively, in some variations, the cutting surface 1350 may be perpendicular to or orthogonal to the base of the microneedle (and / or the surface of the substrate 1302).

[0119] Additional or alternative land, such as Figure 13A As shown, example variations of the asymmetric microneedle 1300 may have a polygonal (e.g., octagonal) base, but include various bevels that taper / taper at different angles. Figure 13AAs shown, the body portion 1316 of the microneedle 1300 may have a first cone angle (A) and a second cone angle (B) measured relative to the base of the body portion (and / or the surface of the base 1302). The second cone angle (B) may be greater than the first cone angle (A), such that the microneedle has a sharper puncture tip extending from a stable, mechanically strong base. For example, in some variations, the first cone angle (A) may be about 10 degrees to about 30 degrees, about 15 degrees to about 25 degrees, or about 20 degrees. Additionally, in some variations, the second cone angle (B) may be about 60 degrees to about 80 degrees, about 65 degrees to about 75 degrees, or about 70 degrees.

[0120] Figure 13C-13E A series of steps in forming an example variant of a pyramidal microneedle with an asymmetric cut surface are described. For example... Figure 13C As shown, a symmetrical pyramidal microneedle with two cone angles can be formed using an anisotropic wet etching process. The two cone angles of the microneedle may include, for example, a first cone angle of approximately 20 degrees located near the base of the microneedle, and a second cone angle of approximately 70 degrees located distal to the first cone angle, thereby forming a progressively inclined surface (e.g., along the planar facets of the pyramidal microneedle). Figure 13D As shown, the cutting blade can be applied at an angle offset from the distal apex of the microneedle, thereby forming a cutting surface similar to the cutting surface 1350 described above. This cutting surface can result in / leave a reduced microneedle base diameter (e.g., approximately 150 μm to approximately 190 μm, or approximately 170 μm), resulting in minimal tissue damage. Figure 13E As shown, the final microneedle (with an offset cutting surface) is asymmetrical, but has a complete, sharp distal vertex.

[0121] Related to the above Figure 11A Similar to the pyramidal microneedle 1100, the mechanical strength of the microneedle 1300 derives at least in part from the anisotropic etching. <311> Planar and pyramidal shapes. However, asymmetrical pyramidal microneedles with asymmetrical cut surfaces may be advantageous because they reduce longitudinal shear forces compared to symmetrical microneedles of similar dimensions but lacking asymmetrical cuts. Furthermore, using such asymmetrical cut surfaces allows for sharper (e.g., more pointed) distal microneedle tips. Although the cut surface 135° is in Figure 13A The image shows the microneedle positioned at a non-orthogonal angle relative to its base. However, alternatively, as described above, in some variations, the cutting surface 1350 may be substantially orthogonal or perpendicular to the base of the microneedle (and / or the surface of the substrate 1302), which may further reduce longitudinal shear forces in the microneedle.

[0122] In some variations, the microneedle may be similar to the microneedle described above, except that it may include a columnar body portion and a tapered distal portion. For example, as... Figure 14AAs shown, the columnar-pyramidal microneedle 1400 may include a columnar body portion 1412 extending from a polygonal (e.g., octagonal) base beyond a non-conductive substrate 1402, such as intrinsic (undoped) silicon. Furthermore, the columnar-pyramidal microneedle 1400 may include a tapered distal portion 1414 having a pyramidal shape with multiple planar facets. For example, the columnar-pyramidal microneedle 1400 may include a tapered distal portion 1414 having a pyramidal shape with eight facets extending from the octagonal columnar body portion 1412. However, the pyramidal shape may have any suitable number of planar facets (e.g., one, two, three, four, five, six, seven, nine, or more). The annular electrode 1420 may be formed on all planes of the pyramidal distal portion 1414, or only on a portion of these planar facets (e.g., on one, two, three, four, five, six, or seven facets), which may include metallized surfaces for the electrode. Similar to the above description, the columnar body portion 1412 may include a conductive core comprising a conductive material that serves as a conductive path for signals to and from the electrode 1420. The columnar body portion 1412 may also include an insulating material 1418 that may extend along the body portion 1412 and extend to the proximal edge of the electrode 1420 (or slightly overlap with the proximal edge of the electrode 1420). The distal apex 1416 may or may not be covered by a similar insulating material.

[0123] In some variations, the distal conical portion 1414 can be related to the above. Figure 11A-11C , Figure 12 and / or Figures 13A-13E Similarly, the distal conical portion 1414 can be formed using an anisotropic wet etching technique. Electrodes 1420 can be formed on the distal conical portion 1414 using photolithography, electrodeposition, or other suitable techniques. The distal conical portion 1414 can then be protected with an etch-resistant material, while the body portion 1412 is formed from the substrate using dry etching (e.g., DRIE) or other suitable processes.

[0124] The columnar and pyramidal combination of the microneedle 1400 offers numerous advantages. Similar to what was described above, the distal conical portion 1414 and the apex 1416, due to... <311> The wet etching process produces planar and pyramidal shapes with high mechanical strength. Furthermore, because the substrate is formed of a non-conductive material, the insulating "protective sleeve" described above is unnecessary for electrically isolating the microneedles, simplifying manufacturing and reducing costs. The absence of the insulating sleeve also allows for material continuity within the substrate, resulting in better mechanical integrity of the entire microneedle array structure.

[0125] Although the columnar-pyramidal microneedles 1400 described above comprise a non-conductive substrate, it should be understood that in certain variations, the columnar-pyramidal microneedles may include a conductive core extending from a conductive substrate (e.g., doped silicon). For example, in some variations, the columnar body portion 1412 may be similar to that described above. Figures 7A-7C and Figure 8-10 The columnar main body portion (e.g., may include an insulating protective sleeve for electrically isolated microneedles, etc.)

[0126] In some variations of the microneedle array comprising one or more microneedles 1400, conductive paths may be formed in a non-conductive substrate to facilitate communication / connection with the electrode 1420. For example, as described above, the body portion 1412 of each microneedle may include a conductive core comprising a conductive material. This conductive material may extend between the electrode 1420 and the substrate 1402. Figure 15D As shown, the microneedle array may include one or more connectors 1510 made of a conductive material (e.g., gold, aluminum), each connector being coupled / connected to a back-side electrical contact 1530 for further sensor communication. In some variations, such as Figures 15A-15D As shown, one or more connectors 1510 may extend laterally along the surface of the substrate and then be connected to the back electrical contacts 1530 through conductive vias 1520 within the substrate.

[0127] Further details of the example variant of the microneedle array configuration are described in more detail below.

[0128] electrode

[0129] As described above, each microneedle in a microneedle array may include an electrode. In some variations, multiple different types of electrodes may be included between the microneedles in the microneedle array. For example, in some variations, the microneedle array can be used as an electrochemical cell that can be operated electrolytically with three types of electrodes. In other words, the microneedle array may include at least one working electrode, at least one counter electrode, and at least one reference electrode. Thus, the microneedle array may include three different electrode types, but one or more of each electrode type can form a complete system (e.g., the system may include multiple different working electrodes). Furthermore, multiple different microneedles may be electrically connected to form an effective electrode type (e.g., a single working electrode may be formed by two or more connected microneedles having working electrode sites). Each of these electrode types may include a metallization layer and may include one or more coatings or layers on the metallization layer, which helps to facilitate the function of the electrode.

[0130] Typically, the working electrode is the electrode where the oxidation and / or reduction reaction of interest occurs to detect the analyte of interest. The function of the counter electrode is to maintain the electrons required for the electrochemical reaction at the working electrode by providing or accumulating current. The function of the reference electrode is to provide a reference potential for the system; that is, the potential of the working electrode when biased is referenced to the reference electrode. A fixed, time-varying, or at least controlled potential relationship is established between the working and reference electrodes, and within practical constraints, no current flows out of or into the reference electrode. Furthermore, to achieve this three-electrode system, the analyte monitoring device may include a suitable potentiostat or electrochemical simulation front end to maintain a fixed potential relationship between the working and reference electrodes within the electrochemical system (through an electronic feedback mechanism), while allowing the counter electrode to dynamically oscillate to the potential required to maintain the redox reaction of interest.

[0131] working electrode

[0132] As described above, the working electrode is the electrode where the oxidation and / or reduction reactions of interest occur. In some variations, sensing can be performed at the interface between the working electrode and the interstitial fluid in the body (e.g., on the entire outer surface of the microneedle). In some variations, the working electrode may include an electrode material and a biorecognition layer in which a biorecognition element (e.g., an enzyme) is immobilized on the working electrode to facilitate the quantification of selective analytes. In some variations, the biorecognition layer may also function as an interference barrier layer and may help prevent the direct oxidation (or reduction) of endogenous and / or exogenous substances at the electrode.

[0133] The redox current detected at the working electrode can be correlated with the detection concentration of the analyte of interest. This is because, assuming a steady-state, diffusion-limited system, the redox current detected at the working electrode follows the Cottrell relation:

[0134]

[0135] Where n is the stoichiometric number of electrons that mitigate the redox reaction, F is the Faraday constant, A is the electrode surface area, D is the diffusion coefficient of the analyte of interest, C is the concentration of the analyte of interest, and t is the duration for which the system is biased by a potential / applied bias voltage. Therefore, the current detected on the working electrode is linearly proportional to the analyte concentration.

[0136] Furthermore, since the detected current is a direct function of the electrode surface area A, the surface area of ​​the electrode can be increased to improve the sensor's sensitivity (e.g., amperes per mole of analyte). For example, multiple individual working electrodes can be grouped into an array consisting of two or more components to increase the total effective sensing surface area. Additionally or alternatively, for redundancy, multiple working electrodes can operate as parallel sensors to obtain multiple independent measurements of the concentration of the analyte of interest. The working electrode can operate either as an anode (where the analyte is oxidized on its surface) or as a cathode (where the analyte is reduced on its surface).

[0137] Figure 16A A schematic diagram depicting a set of exemplary layers of a working electrode 1610 is provided. For example, as described above, in some variations, the working electrode 1610 may include electrode material 1612 and a biorecognition layer comprising a biorecognition element. Electrode material 1612 facilitates the electrocatalytic detection of an analyte or the reaction product of an analyte and a biorecognition element. Electrode material 1612 also provides an ohmic contact and transmits an electrical signal from the electrocatalytic reaction to processing circuitry. In some variations, electrode material 1612 may include platinum, such as... Figure 16A As shown. However, electrode material 1612 may alternatively include, for example, palladium, iridium, rhodium, gold, ruthenium, titanium, nickel, carbon, doped diamond, or other suitable catalytic and inert materials.

[0138] In some variations, the electrode material 1612 may be coated with a highly porous electrocatalytic layer, such as a platinum black layer 1613, which can increase the electrode surface area to improve sensitivity. Additionally or alternatively, the platinum black layer 1613 can enable the electrocatalytic oxidation or reduction of the products of the biorecognition reaction facilitated by the biorecognition layer 1614. However, in some variations, the platinum black layer 1613 can be removed (e.g., as shown in the original text). Figure 16D and 16G (As shown). If the platinum black layer 1613 is absent, the electrode can achieve electrocatalytic oxidation or reduction of biorecognition reaction products.

[0139] A biometric layer 1614 may be disposed on electrode material 1612 (or platinum black layer 1613, if present) and used to immobilize and stabilize the biometric element, which facilitates selective analyte quantification over extended time periods. In some variations, the biometric element may include an enzyme, such as an oxidase. As an exemplary variation for a glucose monitoring system, the biometric element may include glucose oxidase, which converts glucose into an electroactive product (i.e., hydrogen peroxide) detectable on the electrode surface in the presence of oxygen. Specifically, the redox equations associated with this exemplary variation are glucose + oxygen → hydrogen peroxide + gluconolactone (mediated by glucose oxidase); hydrogen peroxide → water + oxygen (mediated by applying an oxidation potential to the working electrode).

[0140] However, in other variants, the biorecognition element may additionally or alternatively contain another suitable oxidase or redox enzyme, such as lactate oxidase, alcohol oxidase, β-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbic acid oxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, uricase oxidase, urease, and / or xanthine oxidase.

[0141] In some variations, the biorecognition element can be crosslinked with an amine condensation carbonyl chemical, which helps stabilize the biorecognition element within the biorecognition layer 1614. As further described below, in some variations, crosslinking of the biorecognition element can lead to compatibility of the microneedle array with ethylene oxide (EO) sterilization, allowing the entire analyte monitoring device (including sensing elements and electronics) to be exposed to the same sterilization cycle, thereby simplifying the sterilization process and reducing manufacturing costs. For example, the biorecognition element can be crosslinked with glutaraldehyde, formaldehyde, glyoxal, malondialdehyde, succinate, and / or other suitable substances. In some variations, the biorecognition element can be crosslinked with this amine condensation carbonyl chemical to form crosslinked biorecognition element aggregates. These crosslinked biorecognition element aggregates, having at least a threshold molecular weight, can then be embedded in a conductive polymer. By embedding only those aggregates with the threshold molecular weight, any uncrosslinked enzymes can be screened out and will not be incorporated into the biorecognition layer. Therefore, only aggregates with the desired molecular weight can be selected for use in conductive polymers to help ensure that the biorecognition layer includes only sufficiently stable cross-linked enzyme entities, thereby contributing to better overall suitability of the biorecognition layer for EO sterilization without loss of sensing performance. In some variants, only cross-linked aggregates with a molecular weight at least twice that of glucose oxidase can be embedded in the conductive polymer.

[0142] In some variations, the conductive polymer can be selectively permeable to enhance the robustness of the biorecognition layer against cyclic hermaphroditic electroactive substances (e.g., ascorbic acid, vitamin C, etc.), whose fluctuations can adversely affect sensor sensitivity. Such selectively permeable conductive polymers in the biorecognition layer can also provide greater resistance to interstitial fluid interference (e.g., acetaminophen) that could affect sensor accuracy. The conductive polymer can become selectively permeable, for example, by removing excess charge carriers through an oxidative electropolymerization process or by neutralizing these charge carriers with a counterion dopant, thereby transforming the conductive polymer into a non-conductive form. These oxidatively polymerized conductive polymers exhibit selective permeability, thus repelling ions with charge polarities similar to the dopant ions (net positive or negative), or by pore size exclusion due to the dense and compact form of the conductive polymer.

[0143] Furthermore, in some variations, conductive polymers can exhibit self-sealing and / or self-healing properties. For example, conductive polymers can undergo oxidative electropolymerization, during which the conductive polymer may lose its conductivity as the thickness of the conductive polymer deposited on the electrode increases, until the lack of sufficient conductivity leads to a reduction in the deposition of additional conductive polymer. In the event of minor physical damage to the conductive polymer (e.g., during use), the polymer backbone can reassemble to neutralize free charges, thereby reducing the total surface energy of the molecular structure, which can manifest as self-sealing and / or self-healing properties.

[0144] In some variations, the working electrode may also include a diffusion restriction layer 1615 disposed on the biorecognition layer 1614. The diffusion restriction layer 1615 can be used to limit the flux of the analyte of interest, thereby reducing the sensor's sensitivity to fluctuations in endogenous oxygen. For example, the diffusion restriction layer 1615 can reduce the concentration of the analyte of interest, making it a limiting reactant for aerobic enzymes. However, in some variations (e.g., if the biorecognition element is not aerobic), the diffusion restriction layer 1615 can be removed.

[0145] In some variations, the working electrode may also include a hydrophilic layer 1616, which provides a biocompatible interface to, for example, reduce foreign body reactions. However, in some variations, the hydrophilic layer 1616 may be removed (e.g., where the diffusion-limiting layer has a hydrophilic portion to serve this purpose), for example, as... Figure 16D and 16G As shown.

[0146] Reverse electrode

[0147] As described above, a counter electrode is an electrode that supplies / pulls or receives / fills the electrons (through current) required to sustain the electrochemical reaction at the working electrode. The number of counter electrode components can be increased in the form of a counter electrode array to increase the surface area so that the current-carrying capacity of the counter electrode does not limit the redox reaction at the working electrode. Therefore, it may be desirable for the counter electrode area to be excessive relative to the working electrode area to circumvent current-carrying capacity limitations. If the working electrode operates as the anode, the counter electrode will act as the cathode, or vice versa. Similarly, if the oxidation reaction occurs at the working electrode, the reduction reaction occurs at the counter electrode, or vice versa. Unlike the working electrode or reference electrode, the counter electrode is allowed to dynamically swing to the potential required to sustain the redox reaction of interest at the working electrode.

[0148] like Figure 16B As shown, the counter electrode 1620 may include an electrode material 1622 similar to electrode material 1612. For example, like electrode material 1612, electrode material 1622 in the counter electrode 1620 may include noble metals such as gold, platinum, palladium, iridium, carbon, doped diamond, and / or other suitable catalytic and inert materials.

[0149] In some variations, the counter electrode 1620 may have few or no additional layers on the electrode material 1622. However, in some variations, the counter electrode 1620 may benefit from an increased surface area to increase the amount of current it can support. For example, the counter electrode material 1622 may be textured or otherwise roughened to increase the surface area of ​​the electrode material 1622 to enhance its ability to draw or sink currents. Additionally or alternatively, the counter electrode 1620 may include a platinum black layer 1624, which may increase the electrode surface area as described above with respect to some variations of the working electrode. However, in some variations of the counter electrode, the platinum black layer may be removed (e.g., as...). Figure 16E (As shown). In some variations, the counter electrode may also include a hydrophilic layer that provides a biocompatible interface to, for example, reduce foreign body reactions.

[0150] Additional or alternative land, in Figure 16H In some variations shown, the counter electrode 1620 may include a diffusion confinement layer 1625 (e.g., disposed on the electrode). The diffusion confinement layer 1625 may be, for example, similar to the one referenced above. Figure 16A The diffusion confinement layer 1615 is described.

[0151] Reference electrode

[0152] As described above, the reference electrode is used to provide a reference potential for the system; that is, the working electrode is biased at a potential reference to the reference electrode. A fixed or at least controlled potential relationship can be established between the working electrode and the reference electrode, and within practical limitations, no current flows into or out of the reference electrode.

[0153] like Figure 16C As shown, the reference electrode 1630 may include an electrode material 1632 similar to electrode material 1612. In some variations, like electrode material 1612, electrode material 1632 in the reference electrode 1630 may include a metal salt or metal oxide, which serves as a stabilizing redox agent coupled to a well-known electrode potential. For example, the metal salt may include, for example, silver-silver chloride (Ag / AgCl), and the metal oxide may include iridium oxide (IrO). x / Ir₂O₃ / IrO₂). In other variations, noble metal and inert metal surfaces can be used as quasi-reference electrodes, including gold, platinum, palladium, iridium, carbon, doped diamond, and / or other suitable catalytic and inert materials. Furthermore, in some variations, the reference electrode 1630 can be textured or otherwise roughened to enhance adhesion / attachment to any subsequent layers. Such a subsequent layer on the electrode material 1632 may include a platinum black layer 1634. However, in some variations, the platinum black layer can be removed (e.g., as shown in the image). Figure 16F and 16I (As shown).

[0154] In some variations, the reference electrode 1630 may also include a redox pair layer 1636, which primarily comprises a surface-fixed solid redox pair with a stable thermodynamic potential. For example, the reference electrode may operate at a stable standard thermodynamic potential relative to a standard hydrogen electrode (SHE). High stability of the electrode potential can be achieved by employing a redox system having a constant (e.g., buffered or saturated) concentration of each participant in the redox reaction. For example, the reference electrode may comprise saturated Ag / AgCl (E = +0.197 V vs. SHE) or IrOx (E = +0.177 V vs. SHE, pH = 7.00) in the redox pair layer 1636. Other examples of the redox pair layer 1636 may comprise a suitable conductive polymer having dopant molecules, such as those described in U.S. Patent Publication No. 2019 / 0309433, which is incorporated herein by reference in its entirety. In some variations, the reference electrode may be used as a half-cell for constructing a complete electrochemical cell.

[0155] Additional or alternative land, in Figure 16IIn some variations shown, the reference electrode 1630 may include a diffusion confinement layer 1635 (e.g., disposed over the electrode and / or redox couple layer). The diffusion confinement layer 1635 may be, for example, similar to the one described above. Figure 16A The diffusion confinement layer 1615 is described.

[0156] Exemplary electrode layer formation

[0157] The working electrode, counter electrode, and reference electrode layers can be applied to microneedle arrays and / or functionalized using appropriate methods, such as those described below.

[0158] In the pretreatment step of the microneedle array, the microneedle array can be plasma-cleaned in an inert gas (e.g., an inert gas generated by radio frequency, such as argon) plasma environment to make the material surfaces, including the electrode materials (e.g., the electrode materials 1612, 1622, and 1632 mentioned above), more hydrophilic and chemically reactive. This pretreatment is used not only for the physical removal of organic debris and contaminants but also for cleaning and preparing the electrode surfaces to enhance the adhesion of subsequently deposited films to their surfaces.

[0159] working electrode

[0160] Anodizing: To construct the working electrode after the pretreatment step, the electrode material 1612 can be anodized using galvanoanalysis. This involves subjecting the electrode components assigned for the function of the working electrode to a fixed high anodic potential (e.g., in the range of +1.0V to +1.3V relative to an Ag / AgCl reference electrode) for an appropriate amount of time (e.g., approximately 30 seconds to approximately 10 minutes) in a moderately strong acid solution (e.g., 0.1-3M H₂SO₄). During this process, a thin and stable natural oxide layer can be formed on the electrode surface. Any trace contaminants can also be removed due to the low pH value present on the electrode surface.

[0161] In an alternative embodiment using the coulomb method, anodizing may continue until a specified amount of charge (measured in coulombs) has been passed. An anodic potential may be applied as described above; however, the duration of this process may be varied until the specified amount of charge has been passed.

[0162] Activation: Following the anodizing process, the working electrode components can be subjected to a cyclic scanning potential waveform during activation using cyclic voltammetry. During activation (which may occur in moderately strong acid solutions (e.g., 0.1–3 MH₂SO₄)), the applied potential may vary over time as a suitable function (e.g., a sawtooth function). For example, the voltage can be linearly scanned between cathode values ​​(e.g., in the range of -0.3 V to -0.2 V relative to an Ag / AgCl reference electrode) and anode values ​​(e.g., in the range of +1.0 V to -1.3 V relative to an Ag / AgCl reference electrode) using an alternating function (e.g., 15–50 linear scan segments). The scan rate of this waveform can be in the range of 1 mV / s to 1000 mV / s. It should be noted that the current peak appearing during the anodic scan (scanning to the positive end) corresponds to the oxidation of the chemical substance, while the current peak appearing during the subsequent cathode scan (scanning to the negative end) corresponds to the reduction of the chemical substance.

[0163] Functionalization of the Biorecognition Layer: Following the activation process, the working electrode components can be functionalized using the biorecognition layer 1614 as described above. Assuming the working electrode assembly of the microneedle array has undergone the above steps, the applied potential can vary over time as a sawtooth function. For example, the voltage can be linearly scanned between a cathode value (e.g., 0.0V relative to an Ag / AgCl reference electrode) and an anode value (e.g., +1.0V relative to an Ag / AgCl reference electrode) using a replacement function (e.g., 10 linear scan segments). In an exemplary variant, in an aqueous solution composed of cross-linked biorecognition elements (e.g., enzymes, such as glucose oxidase) and monomeric precursors of a conductive polymer, the scan rate of this waveform can be taken in the range of about 1 mV / s to about 10 mV / s. During this process, a thin film (e.g., about 10 nm to about 1000 nm) of the biorecognition layer can be formed (e.g., electrodeposited or electropolymerized) on the surface of the working electrode, the film containing a polymer with dispersed cross-linked biorecognition elements. In some variations, the conductive polymer may include one or more of aniline, pyrrole, acetylene, phenylene, phenylene vinylene, phenylene diamine, thiophene, 3,4-ethylenedioxythiophene, and aminophenol boronic acid. As described above, the biometric layer imparts selective sensing capabilities for the analyte of interest.

[0164] In some variations, the surface of the working electrode may be electrochemically roughened to enhance the adhesion of the biorecognition layer to the surface of the 1612 electrode material (and / or the platinum black layer). The roughening process may include cathodic treatment (e.g., cathodic deposition, a subset of electroanalysis), wherein the electrode is subjected to a fixed cathodic potential (e.g., in the range of -0.4 V to +0.2 V relative to an Ag / AgCl reference electrode) for a period of time (e.g., 5 seconds to 10 minutes) in an acidic solution (e.g., 0.01–100 mM H₂PtCl₆) containing the desired metal cation dissolved therein. Alternatively, the electrode is subjected to a fixed cathodic potential (e.g., in the range of about -0.4 V to about +0.2 V relative to an Ag / AgCl reference electrode) until a specific amount of charge (e.g., 0.1 mC–100 mC) is passed through an acidic solution (e.g., 0.01–100 mM H₂PtCl₆) containing the desired metal cation dissolved therein. In this process, a thin, porous metal layer can be formed on the electrode surface, thereby significantly increasing the electrode surface area. Additionally or alternatively, in some variations as described above, platinum metal can be deposited on the electrode to form or deposit a platinum black layer 1613.

[0165] Functionalization of the diffusion confinement layer: Following the functionalization of the biometric layer, in some variations, the working electrode components can be functionalized with a diffusion confinement layer. Assuming the working electrode assembly of the microneedle array has undergone the steps described above, the diffusion confinement layer can be applied using one or more of the following methods, and this diffusion confinement layer can be a thin film with a thickness of about 100 nanometers to about 10,000 nanometers.

[0166] In some variations, a diffusion-limiting layer can be applied via a spraying method, in which an atomized polymer formulation (dispersed in water or a solvent) is applied to the microneedle array device in a controlled environment setting, using a specified spray pattern and duration. This produces a thin film with the desired thickness and porosity required to limit the diffusion of the analyte of interest into the biorecognition layer.

[0167] In some variations, a diffusion-confining layer can be applied via plasma-induced polymerization, where a plasma source generates a gas discharge that provides energy to activate crosslinking reactions within a gaseous, atomized, or liquid monomer precursor (e.g., vinylpyridine). This transforms the monomer precursor into a polymer coating that can be deposited to a specific thickness on a microneedle array, resulting in a thin film with the desired thickness and porosity required to confine the diffusion of the analyte of interest to the biorecognition layer 1614.

[0168] In addition, in some variations, a diffusion confinement layer can be applied by electrophoresis or dielectrophoresis deposition, such as the example technique described in U.S. Patent No. 10,092,207, the entire contents of which are incorporated herein by reference.

[0169] Reverse electrode

[0170] Anodizing: In some variations, the counter electrode material can be anodized using current analysis, wherein the electrode components allocated for the counter electrode function are subjected to a fixed high anodic potential or an appropriate amount of time in a moderately strong acid solution. Exemplary parameters and other details of the counter electrode anodizing process can be similar to those described above for the working electrode. Similarly, the counter electrode anodizing can also be performed using the coulometric method as described above.

[0171] Activation: In some variations, after the anodizing process, during the activation process using cyclic voltammetry, the counter electrode component may undergo a cyclically scanned potential waveform. In some variations, the activation process can be similar to the activation process of the working electrode described above.

[0172] Roughening: In addition, in some variations, the surface of the counter electrode may be electrochemically roughened to enhance the current receiving or current supply capability of the electrode assembly. The electrochemical roughening process can be similar to the process described above for the working electrode. Additionally or alternatively, in some variations as described above, platinum metal may be deposited on the electrode to form or deposit a platinum black layer 1623.

[0173] Reference electrode

[0174] Anodizing: Similar to the working electrode and counter electrode described above, the reference electrode can be anodized using current analysis, wherein the electrode component assigned to the counter electrode function is subjected to a fixed high anodic potential or an appropriate amount of time in a moderately strong acid solution. Exemplary parameters and other details of the anodizing process for the counter electrode can be similar to those described above for the working electrode. Similarly, the anodizing of the counter electrode can be performed.

[0175] Activation: Following the anodizing process, the reference electrode components can be subjected to cyclic scanning potential waveforms during activation using cyclic voltammetry. In some variations, the activation process can be similar to the activation process for the working electrode described above.

[0176] Functionalization: Following the activation process, the reference electrode components can be functionalized. Assuming the reference electrode of the microneedle array has undergone the steps described above, a fixed anodic potential (e.g., in the range of +0.4V to +1.0V relative to an Ag / AgCl reference electrode) can be applied in an aqueous solution for a specific suitable duration (e.g., about 10 seconds to about 10 minutes). Alternatively, the reference electrode is subjected to a fixed anodic potential (e.g., in the range of about +0.4V to about +1.0V relative to an Ag / AgCl reference electrode) until a specific amount of charge (e.g., 0.01mC to 10mC) passes through the aqueous solution. In some variations, the aqueous solution may include a monomeric precursor of a conductive polymer and a charged dopant counterion or material carrying an opposite charge (e.g., poly(styrene sulfonate)). During this process, a thin film of the conductive polymer (e.g., about 10 nm to about 10,000 nm) with dispersed counterions or materials can be formed on the surface of the reference electrode. This produces a surface-fixed solid-state redox pair with a stable thermodynamic potential. In some variations, the conductive polymer may include one or more of aniline, pyrrole, acetylene, phenylene, phenylene vinylene, phenylene diamine, thiophene, 3,4-ethylenedioxythiophene, and aminophenol boronic acid.

[0177] In some alternative embodiments, a natural iridium oxide film (e.g., IrO2, Ir2O3, or IrO4) can be electrochemically grown on the iridium electrode surface during the oxidation process. As mentioned above, this also produces a stable redox pair.

[0178] Furthermore, in some variations, the reference electrode surface may be electrochemically roughened to enhance the adhesion of the surface-fixed redox pairs. The electrochemical roughening process can be similar to the process described above for the working electrode. Additionally or alternatively, in some variations as described above, platinum metal may be deposited on the electrode to form or deposit a platinum black layer 1633.

[0179] Other features and techniques used to form the reference electrode may be similar to those described in U.S. Patent Publication No. 2019 / 0309433, which is incorporated above by reference.

[0180] Microneedle array configuration

[0181] Multiple microneedles can be arranged in a microneedle array (e.g., any microneedle variant described herein, each of which may have a working electrode, counter electrode, or reference electrode as described above). Considerations for configuring the microneedles include factors such as the insertion force required to insert the microneedle array into the skin, optimization of electrode signal levels and other performance aspects, manufacturing costs, and complexity.

[0182] For example, a microneedle array may include multiple microneedles spaced apart at a predetermined interval (the distance between the center of a microneedle and the center of its nearest adjacent microneedle). In some variations, the microneedles may be spaced sufficiently to distribute the force applied to the user's skin (e.g., to avoid a "bed of nails" effect) to allow the microneedle array to penetrate the skin. As the interval increases, the force required to insert the microneedle array tends to decrease, while the puncture depth tends to increase. However, it has been found that the interval only begins to affect the insertion force at low values ​​(e.g., less than about 150 μm). Therefore, in some variations, the microneedles in the microneedle array may have a interval 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 interval 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 can be arranged in a periodic grid, and the spacing can be uniform across all directions and all regions of the microneedle array. Alternatively, the spacing measured along different axes (e.g., the X and Y directions) can vary, and / or some regions of the microneedle array may include smaller spacing while other regions may include larger spacing.

[0183] Furthermore, to achieve more consistent punctures, microneedles can be equidistant from each other (e.g., the same spacing in all directions). For this purpose, in some variations, the microneedles in the microneedle array can be as follows: Figure 17 The hexagonal configuration shown is illustrated. Alternatively, the microneedles in the microneedle array can be arranged in a rectangular array (e.g., a square array), or in another suitable symmetrical arrangement.

[0184] Another consideration in determining the microneedle array configuration is the overall signal level provided by the microneedles. Typically, the signal level of each microneedle in the array is the same across all the microneedle elements. However, the signal level can be enhanced by electrically interconnecting multiple microneedles in the array. For example, an array with a large number of electrical connections is expected to produce a greater signal strength (and therefore improved accuracy) compared to an array with fewer microneedles. However, a larger number of microneedles on the carrier increases the carrier cost (assuming constant spacing) and requires greater force and / or speed for insertion into the skin. Conversely, a smaller number of microneedles on the carrier reduces carrier cost and allows for insertion into the skin with reduced applied force and / or speed. Furthermore, in some variations, a lower number of microneedles on the carrier reduces the total coverage area of ​​the carrier, which can result in less unwanted localized edema and / or erythema. Therefore, in some variations, methods such as... Figure 17 The microneedle array shown includes 37 microneedles or Figure 29A and 29BThe microneedle array shown achieves a balance between these factors by including seven microneedles. However, in other variations, the array may have fewer microneedles (e.g., about 5 to about 35, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 100, about 10 to about 30, about 15 to about 25, etc.) or more microneedles (e.g., more than 37, more than 40, more than 45, etc.).

[0185] Furthermore, as described in further detail below, in some variations, only a subset of the microneedles in the microneedle array may be active / effective during operation of the analyte monitoring device. For example, a portion of the microneedles in the microneedle array may be inactive / ineffective (e.g., no electrode read signals from microneedles that have never been active). In some variations, a portion of the microneedles in the microneedle array may be activated at some point during operation and remain active / effective for the remaining operational life of the device. Additionally, in some variations, a portion of the microneedles in the microneedle array may be additionally or alternatively deactivated at some point during operation and remain inactive / ineffective for the remaining operational life of the device.

[0186] When considering the characteristics of microneedle array carriers, the carrier size is a function of the number of microneedles and the spacing between them. Manufacturing cost is also a consideration, as a smaller carrier size will help reduce costs because the number of carriers that can be formed from a single wafer of a given area will increase. Furthermore, due to the relative fragility of the substrate, a smaller carrier size is less prone to brittle fracture.

[0187] Furthermore, in some variations, microneedles at the periphery of the microneedle array (e.g., near the edge or boundary of the carrier, near the edge or boundary of the housing, near the edge or boundary of the adhesive layer on the housing, along the outer boundary of the microneedle array, etc.) may be found to have better performance (e.g., sensitivity) because they have better penetration compared to microneedles at the center of the microneedle array or the carrier. Therefore, in some variations, the working electrode can be arranged mostly or entirely on the microneedles located at the periphery of the microneedle array to obtain more accurate and / or precise analyte measurements.

[0188] Figure 17 A schematic diagram depicts 37 microneedles arranged in an example variant of the microneedle array. For example, the 37 microneedles can be arranged in a hexagonal array, wherein the inter-center spacing between the center of each microneedle and the center of its immediate neighbor in any direction is about 750 μm (or about 700 μm to about 800 μm, or about 725 μm to about 775 μm). Figure 18A Depicting including Figure 17A schematic diagram of an exemplary variant of the carrier sheet for the microneedle device shown. Example dimensions of the microneedle array and carrier sheet (e.g., approximately 4.4 mm × approximately 5.0 mm) are as follows. Figure 18B As shown.

[0189] Figure 29A and 29B A schematic perspective view depicts seven microneedles 2910 arranged in an example variant of the microneedle array 2900. The seven microneedles 2910 are arranged in a hexagonal array on a substrate 2902. Figure 29A As shown, electrode 2920 is disposed on the distal portion of microneedle 2910 extending from the first surface of substrate 2902. Figure 29B As shown, the proximal portion of the microneedle 2910 is electrically connected to a corresponding back-side electrical contact 2930 on a second surface of the substrate 2902 opposite to the first surface of the substrate 2902. Figure 30A and 30B A schematic plan view and side view of a microneedle array similar to the microneedle array 2900 are depicted. (See attached diagram.) Figure 30A and 30B As shown, seven microneedles are arranged in a hexagonal array, wherein the center-to-center spacing between the center of each microneedle and the center of its immediate neighbor in any direction is approximately 750 μm. In other variations, the center-to-center spacing can be, for example, from approximately 700 μm to approximately 800 μm, or from approximately 725 μm to approximately 775 μm. The microneedles may have an outer diameter of approximately 170 μm (or from approximately 150 μm to approximately 190 μm, or from approximately 125 μm to approximately 200 μm) and a height of approximately 500 μm (or from approximately 475 μm to approximately 525 μm, or from approximately 450 μm to approximately 550 μm).

[0190] Furthermore, the microneedle array described herein offers a high degree of configurability regarding the placement of the working electrode, counter electrode, and reference electrode within the microneedle array. Electronic systems can facilitate this configurability.

[0191] In some variations, the microneedle array may include two or more groups of electrodes distributed symmetrically or asymmetrically within the array, each group having the same or different number of electrode components depending on signal sensitivity and / or redundancy requirements. For example, electrodes of the same type (e.g., working electrodes) may be distributed in the microneedle array in a bilaterally symmetrical or radially symmetrical manner. Figure 19AA variant of the microneedle array 1900A is depicted, comprising two symmetrical groups of seven working electrodes (WE), labeled "1" and "2". In this variant, the two working electrode groups are distributed in a bilaterally symmetrical manner within the microneedle array. The working electrodes are typically arranged between a central region occupied by three reference electrodes (RE) and a peripheral region occupied by twenty counter electrodes (CE). In some variants, each of the two working electrode groups may include seven working electrodes electrically connected to each other (e.g., to enhance sensor signals). Alternatively, only a portion of one or both working electrode groups may include multiple electrodes electrically connected to each other. Alternatively, a working electrode group may include independent working electrodes not electrically connected to other working electrodes. Furthermore, in some variants, the working electrode groups may be distributed in an asymmetrical or random configuration within the microneedle array.

[0192] As another example, Figure 19B A variant of the microneedle array 1900B is depicted, comprising four symmetrical groups of three working electrodes (WE), labeled "1", "2", "3", and "4". In this variant, the four working electrode groups are distributed radially symmetrically within the microneedle array. Each working electrode group is adjacent to one of the two reference electrode (RE) components in the microneedle array and arranged symmetrically. The microneedle array also includes counter electrodes (CE) arranged around the outer periphery of the microneedle array, but two electrodes that are inactive / invalid or can be used for other features or operating modes occupy two vertices of a hexagon.

[0193] In some variations, only a portion of the microneedle array may include effective electrodes. For example, Figure 19C A variant of the microneedle array 1900C is depicted, featuring 37 microneedles and a reduced number of active electrodes, including four bilaterally symmetrically arranged working electrodes (labeled "1", "2", "3", and "4"), twenty-two counter electrodes, and three reference electrodes. The remaining eight electrodes in the microneedle array are inactive / invalid. Figure 19C In the microneedle array shown, each working electrode is surrounded by a set of counter electrodes. Two such clusters of working and counter electrodes are separated by a row of three reference electrodes.

[0194] As another example, Figure 19D A variant of the microneedle array 1900D is depicted, which has 37 microneedles and a reduced number of active electrodes, including four bilaterally symmetrically arranged working electrodes (labeled “1”, “2”, “3”, and “4”), twenty counter electrodes, and three reference electrodes, wherein the remaining ten electrodes in the microneedle array are inactive electrodes.

[0195] As another example, Figure 19E A variant of the microneedle array 1900E is depicted, featuring 37 microneedles and a reduced number of effective electrodes, including four working electrodes (labeled "1", "2", "3", and "4"), eighteen counter electrodes, and two reference electrodes. The remaining thirteen electrodes in the microneedle array are inactive / inactive. These inactive electrodes are positioned along a portion of the periphery of the entire microneedle array, thus reducing the effective size and shape of the effective microneedle arrangement to a smaller hexagonal array. In the effective microneedle arrangement, the four working electrodes are typically arranged radially symmetrically, and each working electrode is surrounded by a set of counter electrodes.

[0196] Figure 19F Another example variant of the microneedle array 1900F is depicted, featuring 37 microneedles and a reduced number of effective electrodes, including four working electrodes (labeled "1", "2", "3", and "4"), two counter electrodes, and one reference electrode. The remaining thirty electrodes in the microneedle array are inactive / invalid. The invalid electrodes are arranged in two layers around the perimeter of the entire microneedle array, thereby reducing the effective size and shape of the effective microneedle arrangement to a smaller hexagonal array centered on the reference electrode. In the effective microneedle arrangement, the four working electrodes are arranged symmetrically on both sides, and the two counter electrodes are equidistant from the central reference electrode.

[0197] Figure 19G Another example variant of the microneedle array 1900G is depicted, featuring 37 microneedles and a reduced number of effective electrodes. Besides including a counter electrode and two reference electrodes, and the smaller hexagonal effective microneedle array centered on the counter electrode, the effective electrodes in the microneedle array 1900G are arranged in a manner consistent with... Figure 19F The microneedle array shown is arranged in a similar manner to the 1900F. In the effective microneedle arrangement, the four working electrodes are arranged symmetrically on both sides, and the two reference electrodes are equidistant from the central counter electrode.

[0198] Figure 19H Another example variant of the microneedle array 1900H with seven microneedles is depicted. This microneedle arrangement includes two microneedles assigned as independent working electrodes (1 and 2), a counter electrode group consisting of four microneedles, and a single reference electrode. The arrangement of both the working and counter electrodes is bilaterally symmetrical, and they are equidistant from the central reference electrode. Furthermore, the working electrodes are arranged as far away from the center of the microneedle array as possible (e.g., on the outer periphery of the carrier or array) to take advantage of locations where higher sensitivity and overall performance are expected for the working electrodes.

[0199] Figure 19IAnother example variant of the microneedle array 1900I with seven microneedles is depicted. The microneedle arrangement comprises: four microneedles assigned to two independent groups (1 and 2), each group containing two working electrodes; a counter electrode group consisting of two microneedles; and a single reference electrode. The arrangement of the working electrodes and the counter electrode is bilaterally symmetrical, and they are equidistant from the central reference electrode. Furthermore, the working electrodes are arranged as far away from the center of the microneedle array as possible (e.g., arranged on the outer periphery of the carrier sheet or array) to take advantage of locations where the working electrodes are expected to have higher sensitivity and overall performance.

[0200] Figure 19J Another example variant of the microneedle array 1900J with seven microneedles is depicted. The microneedle arrangement comprises four microneedles assigned as independent working electrodes (1, 2, 3, and 4), a counter electrode group consisting of two microneedles, and a single reference electrode. The arrangement of the working electrodes and counter electrodes is bilaterally symmetrical, and they are equidistant from the central reference electrode. Furthermore, the working electrodes are arranged as far away from the center of the microneedle array as possible (e.g., on the outer periphery of the carrier sheet or array) to take advantage of locations where higher sensitivity and overall performance are expected for the working electrodes.

[0201] Although Figure 19A-19J Exemplary variations of microneedle array configurations are illustrated, but it should be understood that these figures are not limiting, and other microneedle configurations (including different numbers and / or distributions of working electrodes, counter electrodes, and reference electrodes, as well as different numbers and / or distributions of effective electrodes and ineffective electrodes, etc.) may be applicable to other variations of microneedle arrays.

[0202] preheating

[0203] Many implanted electrochemical sensors require a "warm-up" time, or the time it takes for the sensor to reach a stable signal value after implantation. This process originates from physiology and sensor kinetics. However, various aspects of the analyte monitoring device described herein are configured to mitigate factors contributing to warm-up time, thereby allowing the analyte monitoring device described herein to have significantly shorter warm-up times compared to conventional CGM systems. For example, the analyte monitoring device described herein can have warm-up times of approximately 30 minutes or less (e.g., approximately 10 minutes to approximately 30 minutes, approximately 15 minutes to approximately 30 minutes, approximately 20 minutes to approximately 30 minutes, approximately 25 minutes to approximately 30 minutes), approximately 45 minutes or less, approximately 60 minutes or less, approximately 90 minutes or less, or approximately 120 minutes or less. In some variations, the analyte monitoring device can be calibrated during a calibration phase following the warm-up phase.

[0204] Wound response: For example, sensor implantation can cause a wound response (due to disruption of tissue localization, tissue displacement, and tissue damage). The larger the sensor, or the deeper it is implanted, the greater the wound response. Therefore, there are compelling reasons to miniaturize sensors to induce a reduced wound response, which would result in faster warm-up.

[0205] Protein Adsorption: Furthermore, foreign body reactions are immediately triggered upon sensor implantation. These reactions involve a complex biochemical cascade designed to encapsulate the foreign body with cellular material. After implantation, hydrophobic surfaces readily and rapidly adsorb endogenous proteins; this is known as biofouling. Hydrophilic surfaces, on the other hand, resist biofouling due to their high water content. Human serum albumin (HSA) is the dominant protein in the dermal interstitial fluid, accounting for approximately 60% of total proteins, and maintains a negative charge at physiological pH. When the sensor is polarized to a positive potential (as in some variations of analyte monitoring devices), endogenous HSA undergoes electrical drift and charge attraction towards the sensor's positive (working) electrode. This increases the tendency for biofouling on the sensor surface. This is the fundamental principle behind implementing hydrophilic diffusion-limiting layers or external biocompatible layers to effectively conceal the sensor from being identified as a foreign body, as described further in detail above.

[0206] As described herein, the analyte monitoring device reduces the impact of the aforementioned physiological factors on warm-up time, for example, due to the following: the shallower implantation of the implant, the minimization of the volume of the displaced tissue (e.g., approximately two orders of magnitude lower than current CGM systems, such as approximately 1 / 1000 to approximately 1 / 100 times the volume of the displaced tissue, or approximately 1 / 600 to approximately 1 / 200 times the volume of the displaced tissue in current CGM systems), the minimization of trauma to the tissue during implantation, and the absence of a deeper vascular system penetrating into the dermal reticular layer, which, when disturbed, could trigger a greater wound response, thus accelerating the encapsulation of the implant, as is the case with competing thread-implanted CGM systems.

[0207] Reaching Equilibrium: One example of the impact of sensor dynamics on warm-up time involves reaching equilibrium. When used in a new environment, electrochemical sensors require a certain amount of time to reach equilibrium. This is typically related to the establishment of thermodynamic equilibrium due to the adsorption of ions on the surface layer of the electrode. Since the reference electrode in most implantable electrochemical sensors does not employ an internally filled solution with a redox pair that is sealed and isolated from the rest of the electrochemical cell, this reference electrode must reach equilibrium with its surrounding environment in order to establish a stable reference potential.

[0208] Hydration of the sensor layer: The electrode sensor layer must be immersed in an aqueous environment to function properly. The resulting hydration process activates the polymer layer and biorecognition elements of the electrode, allowing them to rearrange and return to their natural active tertiary structures, which are the primary reason for their activity or unique properties. This process is often referred to as sensor "wetting" and allows the medium in which sensing operations occur to insert the sensor layer to a sufficient extent.

[0209] Decay of the non-Faraday response: The bias / biasing (applied voltage) of the electrochemical sensor will cause the formation of a double layer of ions on the electrode surface. This process requires a limited amount of time due to the charging of the adsorbed material on the electrode surface. This creates a double-layer capacitance. The non-Faraday time constant is equal to the product of the double-layer capacitance and the solution resistance. Typically, the non-Faraday response (current) decays to a negligible level much faster than other physical phenomena, and it is usually not the rate-limiting step in the preheating process. Once the non-Faraday response decays to a negligible level, the Faraday response appears, reflecting the electrochemical / redox reaction of interest.

[0210] As described herein, analyte monitoring devices can, for example, be attributed to the implementation of thin membrane layers (approximately 10 nm–5000 nm; this allows these layers to hydrate faster than competing implantable CGM systems) to reduce the impact of sensor dynamics on warm-up time. Furthermore, due to the small size of the electrodes described herein (e.g., the geometric surface area of ​​the working electrode), the non-Radial response occurs over a shorter duration (due to reduced double-layer capacitance and thus reduced double-layer charging). In some variations, a high-potential (e.g., >0.75 V) bias for a defined period after device application to the skin can further accelerate sensor burn-in or warm-up to achieve balanced and stable signal levels.

[0211] Signal delay

[0212] Typically, implanted electrochemical sensors also experience delays or signal delays when they acquire stable signal values ​​after changes in analyte levels. This signal delay is a function of various factors. At high levels, the delay is a function of three distinct effects: (1) diffusion hysteresis (the amount of time required for analyte molecules to diffuse from the capillary (source) to the sensor surface), (2) diffusion constraints imposed on the sensor by the sensor's membrane / layer structure, and (3) algorithmic processing of the data (averaging, filtering, signal denoising, and other signal processing measures), which generally result in group delays. However, the aspects of the analyte monitoring device described herein minimize these factors that cause signal delays, resulting in faster response times for analyte measurements.

[0213] As described above, a significant advantage of the analyte monitoring device presented herein is the sensor placement. Because the electrode surface is implanted very close (e.g., within a few hundred micrometers or less) to the dense and well-perfused capillary bed of the dermal reticular layer, diffusion hysteresis is negligible. This is a significant advantage over conventional analyte sensors, which are located in poorly vascularized adipose tissue beneath the dermis, resulting in considerable diffusion distances from the dermal vasculature and the consequent diffusion delays (e.g., typically 5–20 minutes).

[0214] Furthermore, because the film deposited on the electrode sensor surface is achieved using an electrodeposition method, the film thickness can be controlled to a highly precise degree. For example, the electrodeposition method forming the sensor surface enables the consistent and controlled production of thin film layers, which reduces diffusion hysteresis. Moreover, the spatial positioning of the thin film layer relative to the sensing electrode allows for thinner films with lower diffusion resistance, further reducing delays / wait times caused by analytes diffusing from another film surface to the biometric layer.

[0215] Furthermore, the high level of redundancy (parallel channels for analyte measurement) provided by the microneedle array allows for higher fidelity measurements and reduces reliance on algorithms that interpolate sensor readings, thereby minimizing latency or waiting time.

[0216] Electronic systems

[0217] Such as the analytical monitoring device 110 Figure 2A As illustrated, the electronic system 120 can be integrated within the housing 112, thus allowing it to be combined with sensing elements (e.g., a microneedle array) as part of a single unit. This contrasts with conventional CGM systems that typically integrate components into multiple physically separate units. Further details of an example variant of the electronic system 120 are described below.

[0218] PCB

[0219] In some variations, the analyte monitoring device may include one or more printed circuit boards (PCBs). For example, the analyte monitoring device may include at least one PCB in a sensor assembly 320 and at least one device PCB 350, the sensor assembly 320 including an array of microneedles, such as... Figure 3E As shown.

[0220] For example, such as Figure 3F-3IAs shown, sensor assembly 320 may include sensor support printed circuit board (PCB) 322 coupled to connection printed circuit board (PCB) 324. Microneedle array 330 may be attached to sensor support PCB 322 (e.g., FR-4, PTFE, Rogers 4350B), for example, by a soldering process incorporating an epoxy underfill for mechanical strength. In some variations, an epoxy skirt may be deposited along the edge of silicon microneedle array 330 to mitigate sharp edges from the aforementioned silicon dicing process. The epoxy may also provide a transition from the silicon substrate edge of the microneedle array silicon to the edge of PCB 322. Alternatively, this epoxy may be replaced or supplemented by rubber gaskets or the like.

[0221] like Figure 3J As shown, the sensor support PCB 322 serves as a support, at least partially defining the desired distance the microneedle array 330 extends from the housing 310. Therefore, the support height of the sensor support PCB 322 can be selected to help ensure that the microneedle array 330 is properly inserted into the user's skin. During needle insertion, the bottom surface of the housing 310 acts as a stop for needle insertion. If the sensor support PCB 322 has a reduced height, and its lower surface is flush with or nearly flush with the bottom surface of the housing, the housing 310 will prevent the microneedle array 330 from fully inserting into the skin. However, increasing the support height may result in greater pressure on the skin from the microneedle array during microneedle insertion, which could lead to skin irritation and / or erythema (skin redness).

[0222] The sensor mount PCB 322 can be secured to the housing 310 and / or within a stack inside the housing, for example, using suitable fasteners. Figure 3H-3J As shown, the sensor support PCB 322 (with micro-needle array 330) can be connected to the first side of the connecting PCB 324, while the opposite second side of the connecting PCB 324 can be connected to the interposer PCB connector 326. Figure 3J As shown, the interposer PCB connector 326 can be communicatively coupled to the device PCB 350, for example, for signal processing as described below. Therefore, signals from the microneedle array 330 can be transmitted to the device PCB via the sensor mount PCB 322, the connection PCB 324, and the interposer PCB connector 326. However, in some variations, the analyte monitoring device may include fewer PCBs. For example, in some variations, the sensor assembly 320 may omit the sensor mount PCB 322, allowing the microneedle array 330 to be directly electrically connected to the connection PCB 324 (or directly to the device PCB 350).

[0223] Additionally or alternatively, in some variations, at least one printed circuit board in sensor assembly 320 may include or be coupled to one or more additional sensors combined with microneedle array 330. For example, sensor assembly 320 may include a temperature sensor (e.g., a thermistor, resistance temperature detector, thermocouple, bandgap reference, non-contact temperature sensor, etc.). In some variations, temperature measurement may be performed additionally or alternatively by one or more electrodes in the microneedle array that are insensitive to the analyte.

[0224] In some variations, the thickness of the sensor mount PCB 322 may be from about 0.05 inches to about 0.15 inches, or from about 0.093 inches to about 0.127 inches. In some variations, the sensor mount PCB 322 may include one or more conductive substrate vias configured to route / guide electrical signals from the front surface of the PCB to the rear surface of the PCB. In some variations, the sensor mount PCB 322 may include a semiconductor (e.g., silicon) with conductive substrate vias configured to route / guide electrical signals from the front surface of the semiconductor to the rear surface of the semiconductor. In other variations, the microneedle array 330 may be directly mounted to the PCB 324 without the sensor mount PCB 322.

[0225] Simulated front end

[0226] In some variations, the electronic system of the analyte monitoring device may include an analog front end. The analog front end may include sensor circuitry (e.g., such as…). Figure 2A The sensor circuit 124 shown converts analog current measurements into digital values ​​that can be processed by a microcontroller. For example, the analog front-end can include a programmable analog front-end suitable for electrochemical sensors. For instance, the analog front-end can include MAX30131, MAX30132, or MAX30134 components (with 1, 2, and 4 channels, respectively) available from Maxim Integrated (San Jose, CA), which are ultra-low-power programmable analog front-ends for electrochemical sensors. The analog front-end can also include AD5940 or AD5941 devices available from Analog Devices (Norwood, MA), which are high-precision impedance and electrochemical front-ends. Similarly, the analog front-end can also include the LMP91000, available from Texas Instruments (Dallas, TX), a configurable analog front-end regulator for low-power chemical sensing applications. The analog front-end can provide bias and a complete measurement path, including an analog-to-digital converter (ADC). Ultra-low power allows for continuous biasing of the sensor to maintain accuracy and fast response when measurements need to be taken over extended periods (e.g., 7 days) using a body-worn, battery-powered device.

[0227] In some variations, the analog front-end device can be compatible with two-terminal and three-terminal electrochemical sensors, for example, to enable DC current measurement, AC current measurement, and electrochemical impedance spectroscopy (EIS) measurement capabilities. Furthermore, the analog front-end may include an internal temperature sensor and a programmable reference voltage source, supporting external temperature monitoring and an external reference voltage source, and integrating bias and power supply voltage monitoring to ensure safety and compliance.

[0228] In some variations, the analog front end may include a multichannel regulator to multiplex sensor inputs and process multiple signal channels. For example, the analog front end may include a multichannel regulator, such as the multichannel regulator described in U.S. Patent No. 9,933,387, the entire contents of which are incorporated herein by reference.

[0229] In some variations, the analog front-end and peripheral electronics can be integrated into an application-specific integrated circuit (ASIC), which can help reduce costs. In some variations, this integration scheme may include a microcontroller.

[0230] microcontroller

[0231] In some variations, the electronic system of the analyte monitoring device may include at least one microcontroller (e.g., such as...). Figure 2A (See controller 122). The microcontroller may include, for example, a processor with integrated flash memory. In some variations, the microcontroller in the analyte monitoring device may be configured to perform analysis to correlate sensor signals with analyte measurements (e.g., glucose measurements). For example, the microcontroller may execute programming routines in firmware to interpret digital signals (e.g., from an analog front end), perform any relevant algorithms and / or other analyses, and route processed data to and / or from a communication module. Keeping the analysis on the analyte monitoring device may, for example, enable the analyte monitoring device to broadcast / transmit analyte measurement results in parallel to multiple devices (e.g., mobile computing devices such as smartphones or smartwatches, therapeutic delivery systems such as insulin pens or pumps, etc.) while ensuring that each connected device has the same information.

[0232] In some variations, the microcontroller can be configured to enable and / or deactivate the analyte monitoring device under one or more detection conditions. For example, the device can be configured to power on the analyte monitoring device after the microneedle array is inserted into the skin. This can, for example, enable power-saving features where the battery is disconnected until the microneedle array is placed in the skin, at which point the device can begin transmitting sensor data. Such features can, for example, help improve the shelf life of the analyte monitoring device and / or simplify the analyte monitoring device-external device pairing process for users.

[0233] Figure 25A schematic diagram of an example circuit variant enabling the aforementioned analyte monitoring device upon insertion is shown. Typically, after penetrating the stratum corneum and positioning the electrode at the distal tip of the microneedle component in a highly electrolyzed dermal interstitial fluid, the resistance of “Sensor_Detect” decreases significantly, thereby activating the p-channel MOSFET Q401. Once Q401 is turned on, the battery voltage VBAT flows to VDD_IN, powering the device. When the microcontroller powers on, its first procedure is to set “Pwr_Detect” high, thereby pulling the gate of Q401 low via Q402 to keep the device powered. This is done to mitigate the possibility of the microneedle not maintaining contact with the skin. If the device falsely activates, a high resistance should appear on “Sensor_Detect”, and the microprocessor can pull “Pwr_Detect” low, thereby cutting off the device power (and disabling the device). Other example variants of the structure and method for enabling and / or disabling the analyte monitoring device are described in U.S. Patent Application No. 16 / 051,398, which is incorporated herein by reference in its entirety.

[0234] Additionally or alternatively, the microcontroller may be configured to actively confirm insertion of the microneedle array into the skin based on sensor measurements performed on the microneedle array. For example, after two or more microneedles in the microneedle array are considered to have been inserted into the skin, a fixed or time-varying potential or current may be applied to these microneedles. The measurement results (e.g., potential or current values) of the signals generated between the electrodes of the inserted microneedles are measured and then compared with known reference values ​​to confirm successful insertion of the microneedle array into the skin. Reference values ​​may include, for example, voltage, current, resistance, conductance, capacitance, inductance, and / or impedance. Other exemplary variations of the structures and methods for enabling and / or deactivating analyte monitoring devices are described in further detail in U.S. Patent Application No. 16 / 051,398, which is incorporated herein by reference.

[0235] In some variations, microcontrollers can utilize 8-bit, 16-bit, 32-bit, or 64-bit data structures. Suitable microcontroller architectures include... and The architecture, and flash memory, can be embedded in the microcontroller or external to it for appropriate data storage. In some variations, the microcontroller can be a single-core microcontroller, while in others it can be a multi-core (e.g., dual-core) microcontroller, which allows for flexible architectures to optimize power and / or performance within the system. For example, the cores in the microcontroller can include similar or different architectures. For instance, in an example variation, the microcontroller could be a dual-core microcontroller comprising a first core with a high-performance and high-power architecture, and a second core with a low-performance and low-power architecture. The first core can act as the "master" because it can be used to handle higher-performance functions (e.g., sensor measurements, algorithm calculations, etc.), while the second core can be used to perform lower-performance functions (e.g., background routines, data transfers, etc.). Thus, the different cores of the microcontroller can operate with different duty cycles / idle times optimized for their respective functions (e.g., the second core for lower-performance functions can operate with a higher duty cycle), thereby improving overall power efficiency. Additionally or alternatively, in some variations, the microcontroller can include embedded analog circuitry, for example, for interfacing / connecting with additional sensors and / or microneedle arrays. In some variants, the microcontroller can be configured to operate using a power supply of 0.8V–5V, such as 1.2V–3V.

[0236] Communication module

[0237] In some variations, the electronic system of the analyte monitoring device may include at least one communication module (e.g., such as...). Figure 2AThe communication module 126 shown is, for example, a wireless communication module that communicates with one or more devices. For example, the communication module may include a wireless transceiver integrated into the microcontroller device. However, the electronic system may additionally or alternatively include a communication module separate from the microcontroller device. In some variations, the communication module may communicate via a wireless network (e.g., via Bluetooth, NFC, WiFi, RFID, or any type of cable-free data transmission). For example, devices may communicate directly with each other in paired connections (1:1 relationship, i.e., point-to-point transmission) or in a centrally radiating or broadcast connection (“one-to-many” or 1:m relationship, i.e., multipoint transmission). As another example, devices may communicate with each other via mesh network connections (e.g., “many-to-many”, or m:m relationship, or point-to-point (ad-hoc)), such as via a Bluetooth mesh network. Wireless communication can use any of a variety of communication standards, protocols, and technologies, including but not limited to Global System for Mobile Communications (GSM), Enhanced Data GSM Environment (EDGE), High-Speed ​​Downlink Packet Access (HSDPA), High-Speed ​​Uplink Packet Access (HSUPA), Evolution, Data-Only (EV-DO), HSPA, HSPA+, Dual-Cell HSPA (DC-HSPDA), Long Term Evolution (LTE), Near Field Communication (NFC), Wideband Code Division Multiple Access (W-CDMA), Code Division Multiple Access (CDMA), Time Division Multiple Access (TDMA), Bluetooth, Wi-Fi (e.g., IEEE 802.11a, IEEE 802.11b, IEEE 802.11g, IEEE 802.11n, etc.), or any other suitable communication protocol. Some wireless network deployments may combine networks from multiple cellular networks or use a mix of cellular, Wi-Fi, and satellite communications. In an example variant, the communication module may include a wireless transceiver integrated into a microcontroller and a Bluetooth Low Energy compatible radio compliant with the Bluetooth Special Interest Group 5.0 specification.

[0238] The communication module may also include or be coupled to one or more antennas (e.g., such as...). Figure 2A Antenna 128 is shown. For example, the electronic system may include a chip antenna mounted on a PCB, or an antenna directly implemented on a PCB, which can provide better range while reducing cost and complexity. In some variations, the user wearing the analyte monitoring device 110 can act as an antenna (e.g., antenna 128). For example, the antenna input / output section 128 of the communication module 126 can be electrically connected to a single microneedle or multiple microneedles inserted into the wearer's skin (e.g., similar to...). Figure 2BThe microneedle array 140 shown is an example. This can increase the effective cross-sectional area of ​​the antenna, provide sufficient impedance matching between the antenna input / output and free space of the communication module, and / or help improve operating parameters such as antenna gain, antenna diversity, omnidirectionality, and receiver sensitivity / transmitter efficiency of the communication module.

[0239] The device can enter and exit the range of the communication module for connection and reconnection, enabling users to seamlessly connect and transfer information between devices. In some variants, the microcontroller on each analyte monitoring device may have a unique serial number, which allows for the tracking of specific analyte monitoring devices during production and / or field use.

[0240] Additional sensors

[0241] As described above, in some variations, in addition to the microneedle array, the analyte monitoring device may include one or more sensors. For example, the analyte monitoring device may include one or more temperature sensors configured to measure skin temperature, thereby enabling temperature compensation for the analyte sensor. For example, in some variations, the temperature sensor (e.g., a thermistor, RTD, semiconductor junction, bimetallic sensor, thermopile sensor) may be coupled to the device PCB within the housing, such that the temperature sensor is positioned near the skin-facing portion or bottom of the housing 112. The housing may be thinned to reduce thermal resistance and improve heat transfer, thereby increasing measurement accuracy. Additionally or alternatively, a thermally conductive material may thermally couple the surface-mount temperature sensor to the user's skin. In variations where the temperature sensor is coupled to the device PCB near the microneedle array carrier substrate, the thermally conductive material may, for example, be molded into a skirt to soften the sharp edges of the carrier and wrap around the edges of the carrier and along the surface of the main PCB.

[0242] In some variations, temperature sensors can be used to develop glucose interpolation characteristics based on the measured current and prior sensitivity (e.g., nA / mM or pA / mg / dL). Under constant temperature conditions, the current characteristics can be modeled by the following relationship: y = m G [G], where y is the measured current, m G [G] is the glucose sensitivity, while [G] is the interpolated glucose concentration. In some cases, such as when introducing a channel b that is insensitive to the analyte, the background signal can be introduced into the above equation: y = m G [G]+b. Introducing measurements from a temperature sensor, the current characteristic can be expressed by the following equation: y=m G [G]+m T [T]+b, where m THere, T is the temperature sensitivity (e.g., pA / ℃), and b is the background signal (e.g., pA). In other operating conditions, the current characteristics are modeled by the following relationship: y = m1[G][T] + b, where m1 is a priori determined weighting factor. In other operating scenarios, the current characteristics can be modeled as the convolution of temperature and glucose: y = {m... T [T]+m2}[G]+b, where m2 is a priori determined weighting factor. In other operating conditions, the current characteristic is provided by the following relationship: y={m G [G]+m2}[T][G]+b. Under other operating conditions, the current characteristics are given by the following nonlinear relationship: y={m G2 [G] 2 +m G [G]}[T]+b, where m G2 It is a nonlinear weighting factor. Under other operating conditions, the current characteristics are given by the following Gaussian relationship: y = m G [G]exp{-([T]–[T OPT ]) 2 / (2σ 2 )}+b, where T OPT It is the optimal temperature for the enzyme's maximum catalytic conversion, and σ is the operating temperature range of the enzyme.

[0243] In some variations, the analyte monitoring device may include at least one microneedle with electrodes configured to function as an analyte-insensitive channel (e.g., a glucose-insensitive channel) with known temperature sensitivity, which can be used to compensate for temperature. For example, an advantage of using a glucose-insensitive channel includes proximity to the glucose sensor (e.g., resulting in smaller errors from thermal gradients) and cost (e.g., by reducing external components and the specialized process of thermally coupling the sensor to the skin). In some variations, the analyte monitoring device may include both the analyte-insensitive channel and a thermistor, with algorithms utilizing information from both. Additionally or alternatively, the analyte monitoring device may include an additional sensor measuring ambient temperature, which can also be used in temperature compensation algorithms.

[0244] In some variations, the analyte-insensitive channel can be used for differential measurements and / or to subtract the background noise level from the analyte-sensitive channel to improve signal fidelity and / or signal-to-noise ratio. The analyte-insensitive channel may be sensitive to common-mode signals that also occur in the analyte-sensitive channel (e.g., endogenous and pharmacological interferences, pressure attenuation, etc.).

[0245] Additionally or alternatively, in some variations, the analyte monitoring device may include at least one kinetic sensor / motion sensor. The motion sensor may include, for example, an accelerometer, gyroscope, and / or inertial measurement unit to capture position, displacement, trajectory, velocity, acceleration, and / or device orientation values. For example, such measurements can be used to infer the wearer's physical activity (e.g., steps, vigorous exercise) over a finite duration. Additionally or alternatively, in some variations, the motion sensor may be employed to detect interactions between the wearer and the analyte monitoring device (e.g., touch or tap). For example, touch or tap detection may be used to mute or pause notifications, alerts, and alarms; control wirelessly connected mobile computing devices; or enable / disable a user interface (e.g., an embedded display or indicator light) on the analyte monitoring device. Touches or taps may be performed in a defined sequence and / or for a predetermined duration (e.g., at least 3 seconds, at least 5 seconds) to trigger certain actions (e.g., deactivating / activating the display or indicator light). Additionally or alternatively, in some variations, such as when restricted motion or activity (e.g., without significant acceleration) is detected for at least a predetermined period of time (e.g., 15 minutes, 30 minutes, 45 minutes, 1 hour, or other suitable time) as measured by a motion sensor, the analyte monitoring device may enter a power-saving mode.

[0246] Additionally or alternatively, in some variations, the analyte monitoring device may include at least one real-time clock (RTC). The RTC can be used to track absolute time (e.g., Coordinated Universal Time, UTC, or local time) while the analyte monitoring device is in storage or during use. In some variations, synchronization with absolute time may be performed after the analyte monitoring device has been manufactured. The RTC can be used to time-stamp analyte measurements (e.g., glucose measurements) during operation of the analyte monitoring device to create a time-series dataset that is transmitted to connected peripheral devices (e.g., mobile computing devices), cloud storage, or other suitable data storage devices, for later viewing, for example, by users (e.g., wearers of the analyte monitoring device), their support networks, or their healthcare providers.

[0247] power supply

[0248] like Figure 2A As shown, the analyte monitoring device may include one or more power sources 130 (such as batteries) within a housing 112, configured to power other components. For example, the analyte monitoring device may include an AgO battery, which has high energy density and is more environmentally friendly than lithium batteries. In some variations, primary (e.g., non-rechargeable) batteries may be used. Furthermore, in some variations, secondary (e.g., rechargeable) batteries may be used. However, any suitable power source may be used, including lithium-based batteries.

[0249] In some variations, low-profile mounts or brackets can be used to connect power to the device PCB, reducing the overall height of the electronics and thus minimizing the height or profile of the analyte monitoring device. For example, while conventional battery holders use a conductive metal with spring force to apply force to the top side of the battery, in some variations, laterally mounted battery holders can contact the sides of the battery to complete the circuitry. For example, as... Figure 20 As shown, the horizontally mounted battery holder 2020 may include an arc-shaped clamp that clamps or otherwise contacts the side of the battery without increasing the vertical volume. The battery holder 2020 may also include one or more mounting holes for attachment to a device PCB via one or more suitable fasteners (and / or may be attached to a device PCB in any suitable manner). In some variations, the dimensions and / or shape of the housing may be determined with suitable tolerances to apply a vertical or downward force toward the device PCB on the battery, thereby maintaining contact between the battery and the PCB.

[0250] Applicator

[0251] In some variations, the analyte monitoring device can be applied manually. For example, a user can remove the protective film from the adhesive layer and manually press the device onto the desired wearing site on his or her skin. Additionally or alternatively, such as Figure 1 As shown, in some variations, a suitable applicator 160 can be used to apply the analyte monitoring device to the skin. The applicator 160 may be configured, for example, to push the analyte monitoring device 110 toward the user's skin, such that the microneedle array 140 of the analyte monitoring device 110 can be inserted into the skin (e.g., to a desired target depth).

[0252] kit

[0253] In some variations, some or all components of the analyte monitoring system may be provided in a kit / set (e.g., for users, clinicians, etc.). For example, a kit may include at least one analyte monitoring device 110 and / or at least one applicator 160. In some variations, a kit may include multiple analyte monitoring devices 110, which can form a supply of analyte monitoring devices sufficient for a predetermined time period (e.g., one week, two weeks, three weeks, one month, two months, three months, six months, one year, etc.). The kit may include any suitable ratio of applicators to analyte monitoring devices (e.g., 1:1, less than 1:1, greater than 1:1). For example, the kit may include the same number of applicators as the analyte monitoring devices, for example, if each applicator is for single use and configured to be discarded after use when the corresponding analyte monitoring device is applied to the user. As another example, the kit may include a smaller number of applicators than the number of analyte monitoring devices in the kit (e.g., one applicator for every two or three analyte monitoring devices), for example, if the applicator is intended to be reused to apply to multiple analyte monitoring devices, or if multiple analyte monitoring devices are loaded into a single applicator for repeated application. As another example, the kit may include a larger number of applicators than the number of analyte monitoring devices in the kit (e.g., two applicators for each analyte monitoring device) to provide additional or redundant applicators in case of applicator loss or damage.

[0254] In some variations, the kit may also include user manuals for operating the analyte monitoring device and / or applicator (e.g., instructions for manually or by applicator applying the analyte monitoring device, instructions for pairing the analyte monitoring device with one or more peripheral devices (e.g., computing devices such as mobile phones, etc.).

[0255] Sterilization of analyte monitoring equipment

[0256] As described above, the analyte monitoring device 110 (as described herein) differs from other CGM devices, at least in that the sensing elements (e.g., microneedle arrays) and electronics are integrated into a single unit. One advantage of this integration is that the user does not need to perform any assembly of the analyte monitoring device 110. However, there are some sterilization-related challenges in achieving this integration.

[0257] Traditional CGM devices and similar electrochemical sensors are typically sterilized using processes incompatible with the electronics. For example, traditional electrochemical sensors use gamma radiation or electron beam radiation to sterilize the sensing element. However, the bosons or fermions associated with these sterilization processes can interfere with the operation of the electronics. Therefore, typically, the electronic components must be sterilized separately, requiring the end user to perform some assembly of the device, or the electronic components are simply not sterilized, which can lead to contamination problems.

[0258] In contrast, the aforementioned sensor technology is configured to be compatible with sterilization methods suitable for sensing elements and electronics. In some variations, as described above, the working electrodes in the microneedle array may include a biorecognition layer comprising cross-linked biorecognition elements. For example, the biorecognition elements may be cross-linked with amine condensation carbonyl chemicals, which helps bridge the amine groups, thereby contributing to the stability of the biorecognition elements within the biorecognition layer. For example, the biorecognition elements may include enzymes (e.g., glucose oxidase) cross-linked with glutaraldehyde, formaldehyde, glyoxal, malondialdehyde, succinate, and / or other suitable substances, and then embedded in the conductive polymer described above.

[0259] The cross-linked structure described above results in an enzyme that is sufficiently stable to withstand gaseous sterilization methods, such as ethylene oxide (EO) sterilization, with surprisingly minimal impact on the sensing element's sensing performance. Therefore, because the electronics can undergo EO sterilization, in some variations, the analyte monitoring device 110 is uniquely and advantageously configured to withstand an "integrated" sterilization process, in which the electronics and sensing element are fully integrated into a single unit and sterilized simultaneously as a single unit without damaging any set of components.

[0260] Therefore, in some variations, the method of sterilizing the analyte monitoring device may include exposing the analyte monitoring device to a sterilizing agent gas, wherein the analyte monitoring device includes a housing (e.g., a wearable housing), a microneedle array extending from the housing and including an analyte sensor, and an electronic system disposed within the housing and electrically connected to the microneedle array. The analyte monitoring device is exposed to the sterilizing agent gas for a residence time sufficient to sterilize the analyte monitoring device. In some variations, the analyte monitoring device may be sterilized to 10... -6 The level of sterility assurance (SAL) (i.e., the probability of no more than one surviving microorganism in 1,000,000 sterilization devices).

[0261] Figure 21An exemplary variant of a method 2100 for sterilizing an analyte monitoring device is shown. The method 2100 may include, for example, inserting the analyte monitoring device into a chamber suitable for sterilization 2110, pretreating the analyte monitoring device 2120, exposing the analyte monitoring device to a sterilizing agent gas 2130, and ventilating the analyte monitoring device 2140.

[0262] Figure 22 A schematic diagram of an example variant of a sterilization system comprising a chamber (or series of chambers) suitable for sterilizing analyte monitoring equipment is depicted. For example, the sterilization system may include at least one chamber for performing a pretreatment process, at least one chamber for the sterilization process, and / or at least one chamber for a ventilation process. In some variants, the same chambers may be used for two or more of these processes in method 2100.

[0263] Therefore, for example, the analyte monitoring device can be placed in a pretreatment chamber for pretreatment process 2120. As described above, the analyte monitoring device can be placed in the chamber as an integrated device including both electrochemical sensing elements and electronic components.

[0264] Pretreatment can be used to heat and humidify analyte monitoring equipment to a stable temperature and moisture content before it enters the sterilization chamber. This helps ensure the consistency and reliability of the sterilization process, regardless of environmental conditions. Figure 23 As shown, the pretreatment analyte monitoring device may include reducing the pressure in the chamber to a vacuum setpoint (e.g., 1.0 psia). The vacuum may be built up gradually, for example at a rate of approximately 2 psia / min or other suitable rate. Furthermore, pretreatment may include setting additional environmental conditions for each setpoint at a predetermined residence time. For example, as... Figure 23 As shown, after the pressure is reduced to the vacuum setpoint, vapor can be injected into the chamber to establish temperature, relative humidity, and / or humidity at predetermined setpoints. For example, in one embodiment, the temperature within the chamber can be set in the range of about 35 degrees Celsius to about 40 degrees Celsius, or about 38 degrees Celsius, which may be suitable to avoid denaturation of biorecognition elements (e.g., enzymes) by higher heat during pretreatment. As another example, the relative humidity can be set to about 45% to about 55% (or about 51%). The temperature, relative humidity, and vacuum setpoints can be maintained for predetermined residence times, such as about 90 minutes to about 180 minutes, about 100 minutes to about 160 minutes, about 110 minutes to about 140 minutes, or about 120 minutes, or other suitable times. After the residence time has elapsed, the chamber can be evacuated and / or the treated analyte monitoring device can be removed and placed in a sterilization chamber.

[0265] like Figure 21As shown, after pretreating the analyte monitoring device, the method may include exposing the analyte monitoring device to a sterilizing agent gas 2130, such as ethylene oxide (EO). In some variations, EO may be introduced into the sterilization chamber at a gas concentration of about 425 mg / L to about 475 mg / L or about 450 mg / L. Figure 23 As shown, during sterilization, the pressure in the sterilization chamber can be set to approximately 5 psia to approximately 6 psia, or to a sterilizing agent setpoint of approximately 5.3 psia. In some variations, at least approximately 97% of the air must be purged from the chamber before the EO gas is introduced. Additionally or optionally, a series of local vacuums can be established in the chamber, followed by a series of nitrogen (N2) injections to remove sufficient air from the chamber. Similar to the temperature during pretreatment, the chamber temperature during sterilization can be set to approximately 35°C to approximately 40°C, or approximately 38°C. With the introduction of EO, the temperature can be increased to the setpoint. After the EO gas is introduced into the chamber, the analyte monitoring device can maintain exposure to the EO gas for a suitable sterilizing agent residence time or exposure time. Suitable sterilizing agent residence times can be, for example, about 90 minutes to about 180 minutes, about 100 minutes to about 160 minutes, about 110 minutes to about 140 minutes, or about 120 minutes, or other suitable time periods sufficient to sterilize the analyte monitoring device. It should be understood that in some variations, an increase in temperature during EO exposure may reduce the necessary EO residence time (e.g., empirically, the EO residence time decreases by about half for every 10°C increase in temperature). After the sterilizing agent residence time, the chamber may undergo vacuum / air circulation to remove the EO from the chamber.

[0266] like Figure 21 As shown, method 2100 may include ventilating the analyte monitoring device 2140. Ventilating the analyte monitoring device allows for the additional removal of any residual gases from the device (e.g., prior to packaging and storage), because EO is flammable and any residual EO on the device after sterilization may be highly toxic. In some variations, ventilation may be performed at room temperature. Figure 23 As shown, ventilation can continue for a predetermined time, sufficient to allow for complete degassing. For example, the ventilation process can last from at least about 4 hours to 24 hours, such as about 12 hours. In other variations, the ventilation process can last for at least about 12 hours, at least about 15 hours, or at least 24 hours, etc.

[0267] Example

[0268] A feasibility assessment was conducted on an EO sterilization cycle for sterilizing analyte monitoring equipment (e.g., the analyte monitoring equipment described herein). Briefly, pretreatment was performed at 38°C for two hours. This was followed by exposure to EO gas at 38°C for two hours. After EO exposure, samples were aerated at ambient temperature for at least 12 hours to remove the EO gas. Detailed information on the EO exposure protocol is shown in Table 1.

[0269] <![CDATA[ Sterilization setpoints ]]> EO gas concentration 450 mg / L (100% EO) temperature 38℃ relative humidity 51％ initial vacuum 1.0 psia EO gas residence time 120 minutes Steam residence time 120 minutes Ventilation setpoint temperature Ambient temperature time 12 hours (minimum) <![CDATA[ Post-vacuum ]]> 3.5psia <![CDATA[ Detox A ]]> Initial steam flushing 3.7psia Initial steam flushing residence time 0 minutes Steam Pulse 3.7psia Steam pulse residence time 5 minutes vacuum 3.5psia Steam flushing 3.7psia Steam flushing residence time 0 <![CDATA[ Detox B ]]> Steam Pulse 3.7psia Steam pulse residence time 5 minutes vacuum 3.5psia Steam flushing 3.7psia Steam pulse residence time 0 minutes <![CDATA[ Air washing ]]> 11.0-2.0 psia (5 total)

[0270] Table 1. Examples of EO Exposure Protocols

[0271] To test the stability of the sensing chemistry after exposure to EO, six functionalized microneedle sensors were subjected to EO sterilization cycles. In this example, the sensor chemistry using amide crosslinking with glucose oxidase was evaluated in this feasibility study. Figure 24 shows the retained sensitivity of the six sensors after exposure to ethylene oxide (EO), as well as three sensors used as negative controls (untreated (DNP)). Overall, all six sensors exposed to EO remained sensitive to glucose after treatment. The average percentage of retained sensitivity was 75%.

[0272] The operational stability of the three sensors exposed to EO was then tested over seven days in PBS containing 6 mM glucose. The sensors were stored in solution, and sensitivity was measured by calibrating the sensors daily. The summary results of the operational stability tests are as follows: Figure 24B As shown, the sensor remained stable during the test. No data was obtained on days 5 and 6 due to instrument error. This trend is similar to that observed with sensors sterilized using gamma radiation.

[0273] In addition, three sensors exposed to the EO were used to test storage stability. Figure 24C The average sensitivity was shown on day 0 (before exposure to EO), day 14, and day 28. The sensor was stored in a dry environment at 37°C from day 14 to day 28. The average sensitivity remained at 92% from day 14 to day 28 of dry storage. This demonstrates the potential of using ethylene oxide sterilization and storing the sensor after exposure to ethylene oxide.

[0274] Therefore, the crosslinked sensor chemistry was found to be sufficiently stable to EO exposure, indicating that it is feasible to use an EO process to sterilize analyte monitoring devices with sensing elements incorporating crosslinked sensor chemistry. Furthermore, the chemical properties after EO exposure remained stable during seven days of active operation, as well as during dry storage.

[0275] In some variants, the sensor can be decoupled from the electronics and sterilized using other suitable methods, including gamma-ray / particle-based radiation or electron beam radiation with sufficient acceleration potential. The sterilization dosage (e.g., duration and particle energy) can be controlled to achieve a satisfactory level of sterility, including a sterility assurance level (SAL) less than 1E-6. In some variants, the electronics do not require sterilization because they do not come into contact with broken or damaged skin surfaces. In this variant, the electronics can be coupled to the sensor before the entire system is applied to the user's skin.

[0276] Use of Analyte Monitoring System

[0277] The following outlines various aspects of the use and operation of the analyte monitoring system, including the analyte monitoring equipment and peripheral devices.

[0278] Application of analyte monitoring equipment

[0279] As described above, the analyte monitoring device is applied to the user's skin, allowing the microneedle array within the device to penetrate the skin. The electrodes of the microneedle array are located in the superficial dermis to access the interdermal fluid. For example, in some variations, the microneedle array may be geometrically configured to penetrate the outer layer of skin, the stratum corneum, through the epidermis, and remain within the papillary or reticular dermis. The sensing area of ​​the electrode, confined to the distal extent of each microneedle component of the array (as described above), can be configured to remain and remain situated within the papillary or reticular dermis after application to ensure adequate exposure to the circulating interdermal fluid (ISF) without the risk of bleeding or undue influence on nerve endings.

[0280] In some variations, the analyte monitoring device may include a wearable shell or patch with an adhesive layer configured to adhere to the skin and hold the microneedle array in place. While the analyte monitoring device can be applied manually (e.g., by removing a protective film from the adhesive layer and manually pressing the patch onto the skin at the desired wearing location), in some variations, a suitable applicator can be used to apply the analyte monitoring device to the skin.

[0281] The analyte monitoring device can be applied to any suitable location, but in some variations, it may be necessary to avoid anatomical areas with thick skin or calluses (e.g., palms and soles) or areas undergoing significant curvature (e.g., olecranon or patella). Suitable wearing sites may include, for example, the arms (e.g., upper arm, lower arm), shoulders (e.g., above the deltoid), back of the hands, neck, face, scalp, trunk (e.g., back, such as the chest area, lumbar area, sacral area, etc., or in the chest or abdomen), hips, legs (e.g., thighs, calves, etc.), and / or the top of the feet.

[0282] As described above, in some variations, the analyte monitoring device may be configured to automatically activate upon insertion and / or confirm correct skin insertion. Details of these features are described above. In some variations, the method for performing such activation and / or confirmation may be similar to that described in U.S. Patent Application No. 16 / 051,398, which is incorporated herein by reference.

[0283] Pairing with peripheral devices

[0284] In some variations, the analyte monitoring device may be paired with at least one peripheral device, enabling the peripheral device to receive broadcast or otherwise transmitted data, including measurement data, from the analyte monitoring device. Suitable peripheral devices include, for example, mobile computing devices capable of executing mobile applications (e.g., smartphones, smartwatches).

[0285] Additionally or alternatively, the analyte monitoring device may be paired (or otherwise combined) with a therapeutic delivery device (e.g., an insulin pen or pump). For example, the analyte monitoring device may be combined with a therapeutic delivery device in a manner similar to that described in U.S. Patent Applications Nos. 62 / 823,628 and 62 / 862,658, each of which is incorporated herein by reference in its entirety. Studies have shown that users of insulin delivery devices with intelligent algorithm-controlled dosing devices maintain a normal blood glucose range (i.e., healthy blood glucose levels) >95% of the time when CGM is available. The ability of the analyte monitoring device to communicate directly with the insulin delivery device (i.e., without the need for an intermediary smartphone) allows users to significantly increase the time within the range by eliminating the time when CGM is unavailable (during the warm-up or replacement of the analyte monitoring device). This feature also allows users to wear multiple analyte monitoring devices that simultaneously detect different analytes and input the data into the same mobile application.

[0286] As described above, pairing can be accomplished via a suitable wireless communication module (e.g., implementing Bluetooth). In some variations, pairing can occur after the analyte monitoring device is applied and inserted into the user's skin (e.g., after the analyte monitoring device is activated). Additionally or alternatively, pairing can occur before the analyte monitoring device is applied and inserted into the user's skin.

[0287] Therefore, paired mobile devices or other devices can receive broadcast or transmitted data from the analyte monitoring device. Peripheral devices can display, store, and / or transmit measurement data to users and / or healthcare providers and / or support networks. Furthermore, in some variations, the paired mobile or wearable devices perform algorithmic processing on the data to improve signal fidelity, accuracy, and / or calibration, etc. In some variations, measurement data and / or other user information can be additionally or alternatively transmitted and / or stored via a network (e.g., a cloud network).

[0288] As an example, in some variations, mobile computing devices or other computing devices (e.g., smartphones, smartwatches, tablets, etc.) can be configured to run a mobile application that provides an interface displaying estimated glucose values, trend information, and historical data. While the following description specifically mentions glucose as the target analyte, it should be understood that the characteristics and processes described below regarding glucose can be similarly applied to applications involving other types of analytes.

[0289] In some variations, mobile applications can use the Bluetooth frame of a mobile computing device to scan for analyte monitoring devices. For example... Figure 26 As shown, the analyte monitoring device can be immediately powered on or initialized upon application to the skin, and the analyte monitoring device can begin the application process. The mobile application can then connect to the analyte monitoring device and initiate sensor measurements. In cases where the mobile application detects multiple analyte monitoring devices, it can detect the one closest to it and / or can request user confirmation (e.g., via the user interface on the mobile device) to disambiguate the issue. In some variations, the mobile application can also connect to multiple analyte monitoring devices simultaneously. This can be useful, for example, to replace sensors that have reached the end of their lifespan.

[0290] In some variations, Low Energy TM The BLE (Browser-Loop Electron) protocol can be used for connectivity. For example, sensors can implement customized BLE peripheral profiles for analyte monitoring systems. Once a standard, secure BLE connection is established between the analyte monitoring device and a smartphone, smartwatch, or tablet running a mobile app, data can be exchanged. The BLE connection can be maintained permanently for the sensor's lifetime. If the connection is lost for any reason (e.g., weak signal), the analyte monitoring device can resume advertising itself, and the mobile app can re-establish the connection at the earliest possible time (i.e., when within range / physical proximity).

[0291] In some variants, one or more additional security layers can be implemented on top of the BLE connection to ensure authorized access, including a combination of one or more technologies such as password protection, shared secrets, encryption, and multi-factor authentication.

[0292] The mobile app guides users to activate a new analyte monitoring device. Once the process is complete, the analyte monitoring device no longer requires the mobile app to operate and record measurements. In some variations, a smart insulin delivery device connected to the analyte monitoring device can be authorized from the mobile app to receive glucose readings directly from the sensor. Additionally or alternatively, an auxiliary display device such as a smartwatch can be authorized from the mobile app to receive glucose readings directly from the sensor.

[0293] Furthermore, in some variations, mobile applications can additionally or alternatively assist in calibrating analyte monitoring equipment. For example, the analyte monitoring equipment can indicate a calibration request to the mobile application, and the mobile application can request calibration input from the user to calibrate the sensor.

[0294] Sensor Measurement

[0295] Once the analyte monitoring device is plugged in and preheated, and any calibrations are complete, it is ready to provide sensor measurements of the target analyte. The target analyte (and any necessary cofactors) diffuses from the biological environment, through a biocompatible layer and a diffusion-limiting layer on the working electrode, to the biorecognition layer, which includes the biorecognition element. In the presence of the cofactor (if applicable), the biorecognition element can convert the target analyte into an electroactive product.

[0296] A bias voltage / potential can be applied between the working electrode and the reference electrode of the analyte monitoring device, and current can flow from the counter electrode to maintain a fixed potential relationship between the working and reference electrodes. This results in the oxidation or reduction of the electroactive product, causing current to flow between the working and counter electrodes. The current value is proportional to the rate of the redox reaction at the working electrode, and specifically, according to the Cottrell relationship as described further above, to the concentration of the analyte of interest.

[0297] Current can be converted into a voltage signal using a transimpedance amplifier, and then quantized into a digital bit stream using an analog-to-digital converter (ADC). Alternatively, current can be directly quantized into a digital bit stream using a current-mode ADC. The digital representation of the current can be processed in an embedded microcontroller within the analyte monitoring device and relayed to a wireless communication module for broadcasting or transmission (e.g., to one or more peripheral devices). In some variations, the microcontroller can perform additional algorithmic processing on the data to improve signal fidelity, accuracy, and / or calibration, etc.

[0298] In some variations, a digital representation of a current or sensor signal can be correlated with an analyte measurement result (e.g., a glucose measurement result) via an analyte monitoring device. For example, a microcontroller can execute programmed routines in firmware to interpret the digital signal and perform any relevant algorithms and / or other analyses. Analysis on the analyte monitoring device can, for example, enable the device to broadcast analyte measurement results to multiple devices in parallel, while ensuring that each connected device has the same information. Therefore, typically, a user's target analyte (e.g., glucose) value can be estimated and stored within the analyte monitoring device and transmitted to one or more peripheral devices.

[0299] Data exchange can be initiated by a mobile application or by an analyte monitoring device. For example, when new analyte data becomes available, the analyte monitoring device can notify the mobile application of the new analyte data. The update frequency can vary, for example, from about 5 seconds to about 5 minutes, and the update frequency can depend on the type of data. Additionally or alternatively, the mobile application can request data from the analyte monitoring device (e.g., if the mobile application identifies gaps in the data it has collected, such as due to disconnection).

[0300] If the mobile app is not connected to the analyte monitoring device, it may be unable to receive data from the sensor electronics. However, the electronics in the analyte monitoring device can store each actual and / or estimated analyte data point. When the mobile app reconnects to the analyte monitoring device, it can request the data it missed during the disconnection, and the electronics on the analyte monitoring device can also transmit that set of data (e.g., backfilling).

[0301] Typically, mobile applications can be configured to provide the display of real-time or near real-time analyte measurement data, such as on the display of a mobile computing device running the application. In some variations, the mobile application can communicate through a user interface providing analysis of the analyte measurements, such as warnings, alerts, trend insights, etc., to notify the user of analyte measurement results requiring attention or follow-up action (e.g., high analyte value, low analyte value, high rate of change, analyte value exceeding a preset range, etc.). In some variations, the mobile application may additionally or alternatively facilitate communication of measurement data to the cloud for storage and / or archiving for later retrieval.

[0302] Explaining the user interface of the analytical material monitoring equipment

[0303] In some variations, information related to analyte measurement data and / or analyte monitoring equipment can be conveyed through the user interface of the analyte monitoring equipment. In other variations, the user interface of the analyte monitoring equipment can be used to convey information to the user as a supplement to or alternative to conveying information via peripheral devices (e.g., mobile applications on computing devices). Therefore, users and / or those around them can easily and intuitively view the analyte monitoring equipment itself to assess analyte measurement data (e.g., the status of analyte measurement results, such as current and / or trend levels of analyte measurement values) and / or equipment status without needing to view a separate device (e.g., a peripheral device or other device located away from and communicating with the analyte monitoring equipment). This availability of information directly on the analyte monitoring equipment itself also allows users and / or those around them to be alerted more quickly to any problems (e.g., analyte measurement values ​​above or below target ranges, and / or analyte measurement values ​​increasing or decreasing at alarming rates), enabling users to take appropriate corrective action more quickly.

[0304] For example, Figures 32A-32C An example variant of an analyte measurement device 3200 is depicted, including a user interface 3220 with multiple indicator lights, including indicator lights 3224a-3224c, which can be selectively illuminated to convey user status (e.g., information related to the user's analyte measurement results). The user interface 3220 may be similar to, for example, the one described above. Figure 31A and / or Figure 31B The user interface 3120 is described. Although the user interface 3220 includes three indicator lights 3224a-3224c, it should be understood that in some variations, the user interface 3220 may include any suitable number of lights, including fewer than three (e.g., one, two) or more than three (e.g., four, five, six or more).

[0305] Indicator lights 3224a-3224c can be arranged sequentially, and their relative positions help the user intuitively understand the information conveyed by the user interface. For example, the three indicator lights 3224a-3224c can be illuminated to generally indicate three progressive levels (or ranges) of the analyte measurement: the lowest indicator light 3224a can be illuminated to generally indicate the lowest analyte measurement among the three levels, the middle indicator light 3224b can be illuminated to generally indicate the analyte measurement in the middle of the three levels, and the highest indicator light 3224c can be illuminated to generally indicate the highest analyte measurement among the three levels. In an exemplary variant, the lowest indicator light 3224a can be illuminated to indicate the analyte measurement within the target range (…). Figure 32A The central indicator light 3224b can be illuminated to indicate analyte measurements above the target range. Figure 32B), and the highest indicator light 3224c can be illuminated to indicate analyte measurements significantly above the target range ( Figure 32C In another exemplary variant, the lowest indicator light 3224a may be illuminated to indicate analyte measurements below the target range, the middle indicator light 3224b may be illuminated to indicate analyte measurements within the target range, and the highest indicator light 3224c may be illuminated to indicate analyte measurements above the target range.

[0306] The threshold for the target range can be any suitable value. For example, in some variations of glucose monitoring, an analyte measurement is considered to be within the target range if it is in the range of approximately 70 mg / dL to approximately 180 mg / dL (or in the range of approximately 80 mg / dL or approximately 60 mg / dL to approximately 170 mg / dL or approximately 190 mg / dL, etc.), and is considered to be below the target range if it is below approximately 70 mg / dL (or below approximately 80 mg / dL, or below approximately 60 mg / dL, etc.). The different thresholds for "above" and "significantly above" the target range can have any suitable values. For example, in some variations, an analyte measurement is considered “above” the target range if it is above a first predetermined threshold (e.g., above a threshold of about 180 mg / dL for hyperglycemia determination in glucose monitoring, or above a threshold in the range of about 170 mg / dL to about 200 mg / dL for hyperglycemia determination in glucose monitoring), and is considered “significantly above” the target range if it is above a first predetermined threshold by a predetermined amount (e.g., percentage), such as at least 33% above a first predetermined threshold (the first predetermined threshold is, for example, a value of >240 mg / dL for extreme hyperglycemia determination in glucose monitoring), or at least about 25% above a first predetermined threshold, at least about 30% above a first predetermined threshold, at least 35% above a first predetermined threshold, or at least 40% above a first predetermined threshold, or above another suitable second predetermined threshold by a predetermined amount.

[0307] Furthermore, the thresholds used to determine whether an analyte measurement is within, below, "above," or "significantly above" the target range (or other characteristics of the analyte measurement) can be static or dynamic, and / or can vary based on user information (e.g., historical measurements and / or trends or other historical data (e.g., average or expected analyte measurements or relative to average or expected rates of change for the user at a specific time)). Additionally, it should be understood that while user interface 3220 includes three sequentially arranged indicator lights, in other variations, the user interface on the housing of the analyte monitoring device may include fewer (e.g., two) or more (e.g., four, five, six, or more) indicator lights that can be similarly individually illuminated to indicate analyte measurement results (e.g., each indicator light corresponding to a general relative level of the analyte measurement).

[0308] In some variations, different illumination colors and / or timings of one or more indicator lights 3224a-3224c may additionally or alternatively enable the user to easily distinguish the level of each analyte measurement. For example, when the analyte measurement is within the target range, the appropriate indicator light may illuminate in a first color (e.g., blue), while when the analyte measurement is outside the target range, the appropriate indicator light may illuminate in a different color (e.g., white for below the target range, orange for above the target range). As another example, when the analyte measurement is within the target range, the appropriate indicator light may illuminate in a first timing pattern (e.g., a long, gentle pulse duration), while when the analyte measurement is outside the target range, the appropriate indicator light may illuminate in a different timing pattern (e.g., a short, flashing pulse duration). For example, a shorter pulse duration may help to better attract the user's attention and / or more intuitively convey the alarm when the analyte measurement is below, above, or significantly above the target range. In some variations, higher frequency of illumination can be associated with higher alarm levels (e.g., significantly below or significantly above the target range).

[0309] Figures 33A-33DTable 2 illustrates different illumination modes used in example methods of the user interface 3220 of the analyte monitoring device. The exact parameter values ​​for these illumination modes are not limiting and are included as example variations for illustrative purposes only. For example, in the "below target range" illumination mode, the illumination color can be any suitable color, and / or the illumination time / lamp "on" time can be about 0.1 to 1 second, about 0.2 to 0.5 seconds, or about 0.3 seconds, and / or the lamp "off" time / lamp "closed" time can be about 0.5 to about 5 seconds, or about 1 to about 4 seconds, or about 2 to about 4 seconds, or about 3 seconds; and / or the ratio between illumination time and lamp "off" time can be about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, and / or other suitable illumination parameters. As another example, in the "within target range" lighting mode and / or the "above target range" lighting mode, the lighting color can be any suitable color, and / or the lighting time can be approximately 0.1 seconds to approximately 3 seconds, approximately 0.5 seconds to approximately 2 seconds, or approximately 1 second, and / or the off-light mode can be approximately 0.5 seconds to approximately 5 seconds, or approximately 1 second to approximately 4 seconds, or approximately 2 seconds to approximately 4 seconds, or approximately 3 seconds; and / or the ratio between the lighting time and the off-light time can be approximately 0.1, approximately 0.2, approximately 0.3, approximately 0.4, approximately 0.5, and / or other suitable lighting parameters. As another example, in the "significantly above target range" mode, the lighting color can be any suitable color, and / or the lighting time can be approximately 0.2 seconds to 2 seconds, approximately 0.5 seconds to approximately 1.5 seconds, or approximately 0.8 seconds, and / or the off-light time can be approximately 0.5 seconds to approximately 5 seconds, or approximately 1 second to approximately 4 seconds, or approximately 2 seconds to approximately 4 seconds, or approximately 3 seconds, and / or other suitable lighting parameters. In addition, in other variations, it is possible to use fewer or more illumination patterns to indicate the level of analyte measurements.

[0310]

[0311] Table 2. Example illumination patterns used to indicate analyte measurements

[0312] Additionally or alternatively, in some variations, indicator lights 3224a-3224c may illuminate in a progressive sequence to indicate the trend of analyte measurements over time. For example, as Figure 34AAs shown, the progressive lighting sequence of indicator lights 3224a-3224c in the first direction, from lower to higher indicator lights (e.g., indicator light 3224a followed by indicator light 3224b, then indicator light 3224c), can visually indicate a trend of increasing analyte measurements. In some variations, the progressive lighting sequence can have any suitable lighting color. In some variations, this ascending sequence of indicator lights can be of suitable color to indicate that the current analyte measurement is within the target range and is increasing, or that the current analyte measurement is above the target range and is increasing. For example, Figure 34A A gradual illumination, starting with a first color (e.g., blue), is displayed to indicate that the current analyte measurement is within the target range and is increasing. Figure 34B A gradual increase in a second color (e.g., orange) is shown to indicate that the current analyte measurement is above (or significantly above) the target range and is rising. As another example, a gradual increase in a third color (e.g., white) can indicate that the current analyte measurement is below (or significantly below) the target range and is rising.

[0313] As another example, such as Figure 34C As shown, the progressive lighting sequence of indicator lights 3224a-3224c in a second direction (e.g., the direction opposite to the first direction), from higher to lower indicator lights (e.g., indicator light 3224c, followed by indicator light 3224b, followed by indicator light 3224a), visually indicates the decreasing trend of the analyte measurement value. Similar to the above regarding... Figure 34A and 34B As described, this progressive lighting sequence of the indicator light can be an appropriate color to indicate that the current analyte measurement is decreasing (e.g., a first color (e.g., blue) progressive lighting indicates that the current analyte measurement is within the target range and is decreasing, a second color (e.g., orange) progressive lighting indicates that the current analyte measurement is above (or significantly above) the target range and is decreasing, and a third color (e.g., white) progressive lighting indicates that the current analyte measurement is below (or significantly below) the target range and is decreasing).

[0314] It should be understood that other variations of the illumination gradient sequence can be used to similarly indicate trends in analyte measurements. For example, a one-dimensional array of indicator lights (e.g., arranged in rows, columns, arcs, etc.) can be illuminated in a gradient sequence from the first end of the array to the second end to indicate an upward trend in analyte measurements, and from the second end of the array to the first end to indicate a downward trend in analyte measurements. For example, the illumination gradient sequence can be characterized as from left to right, from right to left, from top to bottom, from bottom to top, clockwise, counterclockwise, etc. Furthermore, it should be understood that although user interface 3220 includes three sequential indicator lights, in other variations, the user interface on the housing of the analyte monitoring device may include fewer (e.g., two) or more (e.g., four, five, six, or more) indicator lights that can be similarly illuminated in a gradient sequence to indicate upward and / or downward trends in analyte measurements.

[0315] In some variations, the lighting of adjacent indicator lights may be interspersed by off-light cycles within each rising or falling sequence of indicator lights. Furthermore, in some variations, the rate of transition between indicator lights can indicate the rate of change of the analyte measurement. For example, the faster the indicator lights transition from lower to higher levels, the faster the rate of change (and potentially, the user needs to be more urgent or more focused on the trend). Additionally or alternatively, each rising or falling sequence of indicator lights may be separated by an end-of-sequence off-light time to help distinguish between rising and falling sequences. The end-of-sequence off-light time may be longer than the off-light time within each sequence. In some variations, the beginning or end of each rising or falling sequence of lights may be additionally or alternatively demarcated in any suitable manner (e.g., all lights are lit simultaneously at the beginning or end of the rising or falling sequence).

[0316] Table 3 illustrates different illumination patterns used in example methods for indicating trends in analyte measurements in the user interface 3220 of the analyte monitoring device. The exact parameter values ​​for these illumination patterns are not limiting and are included as example variations for illustrative purposes only. For example, in a progressive sequence of illumination (e.g., for any more suitable illumination pattern), the illumination color can be any suitable color; and / or the illumination time can be about 0.1 seconds to 1 second, about 0.2 seconds to 0.5 seconds, or about 0.3 seconds; and / or the off-light time between adjacent indicator lights can be about 0.05 seconds to about 1 second, about 0.1 seconds to about 0.5 seconds, or about 0.18 seconds; and / or the ratio between the illumination time and the off-light time can be about 1, about 1.5, or about 2; and / or the end of the sequence can be indicated by the off-light time of about 2 seconds to about 5 seconds, or about 3 seconds. Furthermore, in other variations, fewer or more illumination patterns are possible for indicating trends in analyte measurements.

[0317]

[0318] Table 3. Example lighting patterns used to indicate trends in analyte measurements

[0319] Additionally or alternatively, indicator light 3222 may be selectively illuminated to convey device status. Similar to the description above, the illuminated color and / or timing may vary in a predetermined manner to indicate different device states. Statuses may include, for example, warm-up period notifications, end-of-life notifications, sensor failure status notifications, sensor failure mode (e.g., incorrect insertion) notifications, low battery notifications, and / or device error notifications. Furthermore, any suitable number of indicator lights may be illuminated individually and / or together (e.g., sequentially or simultaneously) to indicate different device states. For example, as... Figure 35A As shown, the user interface including indicator light 3222 can be illuminated in a first illumination mode (e.g., a first illumination color such as white and / or a first-time illumination mode) to indicate a device "wait" mode. The wait mode may, for example, correspond to a device warm-up period (as described elsewhere herein), or the detection of temporary errors (e.g., detection of sensor attenuation caused by pressure). As another example, such as... Figure 35B As shown, the user interface including indicator light 3222 can be illuminated in a second illumination mode (e.g., a second illumination color such as red and / or a second time illumination mode) to indicate the device's "end of life" mode (e.g., determining the end of a predetermined wear period, detecting a permanent error, etc., as described below).

[0320] Table 4 illustrates different illumination modes used in example methods for indicating device status in the user interface of the analyte monitoring device. The exact parameter values ​​for these illumination modes are not limiting and are included as example variations for illustrative purposes only. For example, in the "Wait" illumination mode, the illumination color can be any suitable color; and / or the illumination time can be from about 0.1 seconds to about 3 seconds, from about 0.5 seconds to about 2 seconds, or about 1 second; and / or the off mode can be from about 0.5 seconds to about 5 seconds, or from about 1 second to about 4 seconds, or from about 2 seconds to about 4 seconds, or about 3 seconds; and / or the ratio between the illumination time and the off time can be about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, and / or other suitable illumination parameters. As another example, in the "end of life" illumination mode, the illumination color can be any suitable color; and / or the illumination time can be about 0.01 seconds to about 1 second, about 0.01 seconds to about 0.5 seconds, about 0.01 seconds to about 0.3 seconds, about 0.01 seconds to about 0.1 seconds, or about 0.04 seconds; and / or the illumination time can be about 1 second to about 10 seconds, about 3 seconds to about 8 seconds, or about 6 seconds; and / or the ratio between the illumination time and the illumination time can be about 0.3, about 0.2, about 0.1, about 0.05, about 0.01, or less than about 0.01, and / or other suitable illumination parameters. Although only two illumination modes are shown, in some variations, the analyte monitoring device may have fewer or more illumination modes, for example, for each of the states described above (e.g., a first illumination mode for the device warm-up phase, a second illumination mode for detecting temporary errors, a third illumination mode for determining the end of the device's life, a fourth illumination mode for detecting permanent errors, etc.).

[0321] Equipment status Attached Figure Light up the color Light duration t (on) Lights off time t (off) wait Figure 35A White 1 second 3 seconds End of life Figure 35B red 0.04 seconds 6 seconds

[0322] Table 4. Example lighting patterns used to indicate device status

[0323] In some variations, photodiodes, phototransistors, photodetectors, or other suitable ambient light sensors can be used to measure the illuminance of the environment surrounding the device. Ambient light measurements can be used, for example, to trigger adjustments to the brightness of the user interface (e.g., dimming it) to conserve battery power in power-saving mode, improve contrast in various lighting scenarios, and / or reduce the device's visibility to others. For example, an analyte monitoring device can enter a power-saving mode in response to a measurement from an ambient light sensor indicating that there is substantially no ambient light (e.g., sufficiently dark at least for a predetermined period of time), such as when the device is placed under the wearer's clothing or when the wearer is sleeping in a dark environment. In these cases, power-saving mode may be useful because indicator lights may have limited utility when they are hidden and out of the wearer's field of vision (e.g., under clothing) or might be perceived as a disturbance (e.g., during sleep). In response to an indication from an ambient light sensor that the measurement results show exposure to ambient light (e.g., sufficient brightness for at least a predetermined period of time), the analyte monitoring device can then exit power-saving mode and increase the brightness of the user interface accordingly.

[0324] Additional system functions

[0325] In some variations, the mobile application helps users manage the lifespan and replacement of the analyte monitoring device. For example, the mobile application can stop data display when the analyte monitoring device's wear period has expired. In some variations, the analyte monitoring device can have a longer lifespan compared to conventional CGM devices. For example, the analyte monitoring device described herein can have a wear period (e.g., expected lifespan) of at least 3 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, or at least 12 days, 5 to 10 days, 10 to 14 days, etc., without significant performance loss.

[0326] Additionally or alternatively, the mobile application can provide users with configurable warnings informing them that the wear period is about to expire. This allows users to apply a new analyte monitoring device when the current one is still valid but nearing its expiration date. Furthermore, the new analyte monitoring device can be warmed up (typically from approximately 30 minutes to approximately 2 hours) while the old unit continues to transmit analyte measurements. The old analyte monitoring device can then be removed upon expiration. The new analyte monitoring device can then become the primary sensor transmitting analyte measurement results to the mobile application. This provides uninterrupted coverage of analyte measurement results. Additionally, readings from the old analyte monitoring device can be used for calibration or algorithmic improvements to enhance the accuracy of the new analyte monitoring device.

[0327] In some variations, analyte monitoring devices may have a unique serial number contained within a microcontroller (e.g., located in the electronic system). This serial number allows the sensor to be tracked throughout its use, from manufacturing to the final product. For example, historical data on sensor devices, including manufacturing and customer usage, can be transferred and stored in a cloud database. This enables the tracking and inference of various parameters, such as sensor performance metrics and improvements tailored to individual users, as well as sensor batches; allows for very rapid tracking of defective sensor batches from field data to manufacturing or supplier issues; and enables the personalization of health monitoring features for individual users, among other things.

[0328] In some variants, the system can track the inventory of analytical monitoring devices from warehousing to purchase transactions and product usage, enabling the system to help users fulfill orders promptly (e.g., ensuring users are not without analytical monitoring devices). Additionally or alternatively, as the use of monitoring devices is tracked, fulfillment can be automated and timely delivery to the user's residence can help ensure uninterrupted sensor supply (e.g., "on-time" delivery). This can be integrated with virtual or e-pharmacies, fulfillment centers, and / or web-based sales portals (such as Amazon). TM )connect.

[0329] Through the portal, the cloud infrastructure also allows users to view their real-time and historical blood glucose data / trends and share that data with caregivers, their healthcare providers, support networks, and / or other appropriate individuals.

[0330] List of implementation plans

[0331] Implementation Scheme I-1. A microneedle array for sensing analytes, comprising:

[0332] A plurality of solid microneedles, wherein at least one microneedle comprises:

[0333] A cone-shaped distal portion with an insulating distal apex; and

[0334] An electrode on the surface of the distal portion of the cone, wherein the electrode is located near the distal apex of the insulation.

[0335] Implementation Scheme I-2. The microneedle array according to Implementation Scheme I-1, wherein the electrode is a working electrode configured to sense at least one analyte, and the at least one microneedle includes a biometric layer disposed above the working electrode, wherein the biometric layer includes biometric elements.

[0336] Implementation Scheme I-3. The microneedle array according to Implementation Scheme I-2, wherein the biometric element includes an enzyme.

[0337] Implementation Scheme I-4. The microneedle array according to Implementation Scheme I-3, wherein the enzyme is an oxidoreductase.

[0338] Implementation Scheme I-5. The microneedle array according to Implementation Scheme I-4, wherein the oxidoreductase is at least one selected from lactate oxidase, alcohol oxidase, β-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbic acid oxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, uricase, and xanthine oxidase.

[0339] Implementation Scheme I-6. The microneedle array according to Implementation Scheme I-4, wherein the oxidoreductase is glucose oxidase.

[0340] Implementation Scheme I-7. The microneedle array according to Implementation Scheme I-2, wherein the biometric element is cross-linked with an amine condensation carbonyl chemical substance.

[0341] Implementation Scheme I-8. The microneedle array according to Implementation Scheme I-7, wherein the amine condensation carbonyl chemical substance is at least one of formaldehyde, glyoxal, malondialdehyde, and succinaldehyde.

[0342] Implementation Scheme I-9. The microneedle array according to Implementation Scheme I-7, wherein the amine condensation carbonyl chemical is glutaraldehyde.

[0343] Implementation Scheme I-10. The microneedle array according to Implementation Scheme I-2, wherein the at least one microneedle comprises at least one of a diffusion restriction layer and a hydrophilic layer disposed above the biometric layer.

[0344] Implementation Scheme I-11. The microneedle array according to Implementation Scheme I-2, wherein the microneedle array includes at least one microneedle having a counter electrode, the counter electrode being configured to pull current or sink current to maintain the electrochemical reaction on the working electrode.

[0345] Implementation Scheme I-12. The microneedle array according to Implementation Scheme I-2, wherein the microneedle array includes at least one microneedle having a reference electrode configured to provide a reference potential to the working electrode.

[0346] Implementation Scheme I-13. The microneedle array according to Implementation Scheme I-12 further includes a conductive polymer disposed on the reference electrode.

[0347] Implementation Scheme I-14. The microneedle array according to Implementation Scheme I-13, wherein the conductive polymer includes a dopant.

[0348] Implementation Scheme I-15. The microneedle array according to Implementation Scheme I-13, wherein the reference electrode comprises a metal oxide having a stable electrode potential.

[0349] Implementation Scheme I-16. The microneedle array according to Implementation Scheme I-15, wherein the metal oxide comprises iridium oxide.

[0350] Implementation Scheme I-17. The microneedle array according to Implementation Scheme I-13, wherein the reference electrode comprises a metal salt having a stable electrode potential.

[0351] Implementation Scheme I-18. The microneedle array according to Implementation Scheme I-17, wherein the metal salt comprises silver chloride.

[0352] Implementation Scheme I-19. The microneedle array according to Implementation Scheme I-1, wherein the entire electrode is located on the conical distal portion of the at least one microneedle.

[0353] Implementation Scheme I-20. The microneedle array according to Implementation Scheme I-1, wherein the electrode includes a catalytic surface.

[0354] Implementation Scheme I-21. The microneedle array according to Implementation Scheme I-20, wherein the catalytic surface comprises at least one of platinum, palladium, iridium, rhodium, gold, ruthenium, titanium, nickel, carbon, and doped diamond.

[0355] Implementation Scheme I-22. The microneedle array according to Implementation Scheme I-20, wherein the at least one microneedle comprises platinum black disposed above the electrode.

[0356] Implementation Scheme I-23. The microneedle array according to Implementation Scheme I-1, wherein the distal end of the electrode is offset from the distal vertex by an offset distance of at least about 10 μm, wherein the offset distance is measured along the longitudinal axis of the at least one microneedle.

[0357] Implementation Scheme I-24. The microneedle array according to Implementation Scheme I-1, wherein the electrodes are annular.

[0358] Implementation Scheme I-25. The microneedle array according to Implementation Scheme I-1, wherein a portion of the working electrode is recessed into the distal portion of the cone.

[0359] Implementation Scheme I-26. The microneedle array according to Implementation Scheme I-1, wherein the electrode is located only on one segment of the distal portion of the cone.

[0360] Implementation Scheme I-27. The microneedle array according to Implementation Scheme I-1 further includes an electrical contact, wherein the at least one microneedle includes a body portion that provides a conductive path between the electrical contact and the electrode.

[0361] Implementation Scheme I-28. The microneedle array according to Implementation Scheme I-27, wherein the main body portion is formed of a conductive material.

[0362] Implementation Scheme I-29. The microneedle array according to Implementation Scheme I-27, wherein the main body portion includes an embedding path.

[0363] Implementation Scheme I-30. The microneedle array according to Implementation Scheme I-27, wherein the main body portion is insulated.

[0364] Implementation Scheme I-31. The microneedle array according to Implementation Scheme I-27, wherein the main body portion has a circular, square or octagonal base.

[0365] Implementation Scheme I-32. The microneedle array according to Implementation Scheme I-27, wherein at least one segment of the main body is columnar.

[0366] Implementation Scheme I-33. The microneedle array according to Implementation Scheme I-27, wherein at least one segment of the main body is pyramidal.

[0367] Implementation Scheme I-34. The microneedle array according to Implementation Scheme I-33, wherein at least a portion of the main body portion has a first cone angle measured relative to the base of the main body portion, and the distal vertex has a second cone angle measured relative to the base, wherein the second cone angle is greater than the first cone angle.

[0368] Implementation Scheme I-35. The microneedle array according to Implementation Scheme I-34, wherein at least one of the main body portion and the distal portion of the microneedle is radially asymmetrical.

[0369] Implementation Scheme I-36. The microneedle array according to Implementation Scheme I-35, wherein the distal conical portion includes a flat surface offset from the distal apex of the at least one microneedle.

[0370] Implementation Scheme I-37. The microneedle array according to Implementation Scheme I-1, wherein each of the plurality of microneedles comprises:

[0371] A cone-shaped distal portion with an insulating distal apex; and

[0372] An electrode on the surface of the distal portion of the cone, wherein the electrode is located near the distal apex of the insulation.

[0373] Implementation Scheme I-38. The microneedle array according to Implementation Scheme I-1, wherein the microneedles of the plurality of microneedles are electrically insulated from each other.

[0374] Implementation Scheme I-39. The microneedle array according to Implementation Scheme I-38, wherein the microneedle array is configured to detect a variety of analytes.

[0375] Implementation Scheme I-40. The microneedle array according to Implementation Scheme I-1, wherein the microneedles of the plurality of microneedles are arranged in a periodic grid pattern.

[0376] Implementation Scheme I-41. The microneedle array according to Implementation Scheme I-40, wherein the periodic grid comprises a rectangular array.

[0377] Implementation Scheme I-42. The microneedle array according to Implementation Scheme I-40, wherein the periodic grid comprises a hexagonal array.

[0378] Implementation Scheme I-43. The microneedle array according to Implementation Scheme I-40, wherein the microneedles in the periodic grid are spaced apart by a distance of about 200 μm to about 800 μm.

[0379] Implementation Scheme I-44. The microneedle array according to Implementation Scheme I-40, wherein the microneedles in the periodic grid are uniformly spaced.

[0380] Implementation Scheme I-45. The microneedle array according to Implementation Scheme I-1, wherein the plurality of microneedles includes at least one delivery microneedle having an inner cavity.

[0381] Implementation Scheme I-46. The microneedle array according to Implementation Scheme I-1, wherein the at least one microneedle is configured to puncture the user's skin and sense analytes in the interstitial fluid of the user's dermis.

[0382] Implementation Scheme I-47. An analyte monitoring system comprising the microneedle array described in Implementation Scheme I-1 and a wearable housing, wherein the microneedle array extends outward from the housing.

[0383] Implementation Scheme I-48. The system according to Implementation Scheme I-47, wherein the at least one microneedle extends from the housing such that the distal end of the electrode is located at a position less than about 5 mm from the housing.

[0384] Implementation Scheme I-49. The system according to Implementation Scheme I-48, wherein the at least one microneedle extends from the housing such that the distal end of the electrode is located at a position less than about 1 mm from the housing.

[0385] Implementation Scheme I-50. The system according to Implementation Scheme I-47, wherein the housing encapsulates an electronic system, the electronic system including at least one of a processor and a wireless communication module.

[0386] Implementation Scheme I-51. The system according to Implementation Scheme I-50, wherein the electronic system includes a wireless communication module, and the system further includes a software application to be paired with the wireless communication module that can be executed on a mobile computing device.

[0387] Implementation Scheme I-52. The system according to Implementation Scheme I-47, wherein the housing includes one or more indicator lights configured to convey status information.

[0388] Implementation Scheme I-53. The system according to Implementation Scheme I-52, wherein at least one of the indicator lights is configured to be selectively illuminated according to an illumination pattern corresponding to the state of the analyte measurement result.

[0389] Implementation Scheme I-54. The system according to Implementation Scheme I-53, wherein at least one of the indicator lights is configured to be selectively illuminated to convey the current analyte measurement level.

[0390] Implementation Scheme I-55. The system according to Implementation Scheme I-53, wherein the user interface includes a plurality of indicator lights configured to be selectively illuminated in a progressive sequence to convey trends in analyte measurements.

[0391] Implementation Scheme I-56. The system according to Implementation Scheme I-55, wherein the plurality of indicator lights are configured to be selectively illuminated in a first progressive sequence along a first direction to convey an upward trend in analyte measurements, and are further configured to be selectively illuminated in a second progressive sequence along a second direction to convey a downward trend in analyte measurements.

[0392] Implementation Scheme I-57. The system according to Implementation Scheme I-52, wherein the user interface is further configured to convey information indicating the status of the analyte monitoring device.

[0393] Implementation Scheme I-58. The system according to Implementation Scheme I-47 further includes an adhesive configured to attach the housing to a user's skin.

[0394] Implementation Scheme I-59. The system according to Implementation Scheme I-47 further includes an applicator configured to apply at least a portion of the analyte monitoring system to the user's skin.

[0395] Implementation Scheme I-60. The system according to Implementation Scheme I-47, wherein the analyte monitoring system is a skin adhesion patch.

[0396] Implementation Scheme I-61. The system according to Implementation Scheme I-47, wherein the plurality of microneedles includes at least one delivery microneedle having an inner lumen.

[0397] Implementation Scheme I-62. The system according to Implementation Scheme I-47, wherein the plurality of microneedles includes at least one solid microneedle, the solid microneedle including a coating containing a therapeutic substance.

[0398] Implementation Scheme I-63. The system according to Implementation Scheme I-62, wherein the therapeutic substance comprises at least one of insulin, glucagon, metformin, acetaminophen, acetylsalicylic acid, isobutylphenylpropionic acid, levodopa, statins, hydrocodone, opioids, nonsteroidal anti-inflammatory drugs, anesthetics, analgesics, anticonvulsants, antidepressants, antipsychotics, sedatives, relaxants, hormones, antibacterial agents, and antiviral agents.

[0399] Implementation Scheme I-64. A method for monitoring users, comprising:

[0400] Using analytical monitoring devices close to a user's bodily fluids; and

[0401] Use analyte monitoring equipment to quantify one or more analytes in body fluids.

[0402] The analyte monitoring device includes a plurality of solid microneedles, wherein at least one microneedle comprises:

[0403] A cone-shaped distal portion with an insulating distal apex; and

[0404] Electrodes on the surface of the distal portion of the cone, wherein the electrodes are located near the insulated distal apex.

[0405] Implementation Scheme I-65. The method according to Implementation Scheme I-64, wherein the body fluid includes the user's dermal interstitial fluid.

[0406] Implementation Scheme I-66. The method according to Implementation Scheme I-64, wherein the one or more analytes comprise glucose.

[0407] Implementation Scheme I-67. A microneedle array for sensing analytes, comprising:

[0408] Multiple solid microneedles, wherein at least one microneedle comprises:

[0409] A cone-shaped distal portion with an insulating distal apex; and

[0410] An electrode on the surface of the distal portion of the cone, wherein the distal end of the electrode is offset from the distal apex.

[0411] Implementation Scheme I-68. The microneedle array according to Implementation Scheme I-67, wherein the electrode is a working electrode configured to sense at least one analyte, and the at least one microneedle includes a biometric layer disposed above the working electrode, wherein the biometric layer includes biometric elements.

[0412] Implementation Scheme I-69. The microneedle array according to Implementation Scheme I-68, wherein the biometric element includes glucose oxidase.

[0413] Implementation Scheme I-70. The microneedle array according to Implementation Scheme I-67, wherein the distal end of the electrode is offset from the distal vertex by an offset distance of at least about 10 μm, wherein the offset distance is measured along the longitudinal axis of the at least one microneedle.

[0414] Implementation Scheme I-71. The microneedle array according to Implementation Scheme I-67, wherein the electrodes are annular.

[0415] Implementation scheme I-72. The microneedle array according to implementation scheme I-67, wherein, in at least one microneedle, a portion of the working electrode is recessed into the distal conical portion.

[0416] Implementation Scheme I-73. The microneedle array according to Implementation Scheme I-67, wherein the electrode is located only on one segment of the distal portion of the cone.

[0417] Implementation Scheme I-74. The microneedle array according to Implementation Scheme I-67 further includes an electrical contact, wherein the at least one microneedle includes a body portion that provides a conductive path between the electrical contact and the electrode.

[0418] Implementation Scheme I-75. The microneedle array according to Implementation Scheme I-67, wherein each of the plurality of microneedles comprises:

[0419] A cone-shaped distal portion with an insulating distal apex; and

[0420] An electrode on the surface of the distal portion of the cone, wherein the electrode is located near the distal apex of the insulation.

[0421] Implementation Scheme I-76. The microneedle array according to Implementation Scheme I-67, wherein the microneedle array includes a plurality of working electrodes, wherein each working electrode is individually addressable and electrically isolated from each other working electrode in the analyte monitoring device.

[0422] Implementation Scheme I-77. The microneedle array according to Implementation Scheme I-76, wherein the microneedle array is configured to detect a variety of analytes.

[0423] Implementation Scheme I-78. The microneedle array according to Implementation Scheme I-67, wherein the microneedles of the plurality of microneedles are arranged in a hexagonal array.

[0424] Implementation Scheme I-79. The microneedle array according to Implementation Scheme I-67, wherein the at least one microneedle is configured to puncture the user's skin and sense analytes in the interstitial fluid of the user's dermis.

[0425] Implementation Scheme I-80. An analyte monitoring system comprising the microneedle array described in Implementation Scheme I-67 and a wearable housing, wherein the microneedle array extends outward from the housing.

[0426] Implementation Scheme I-81. The system according to Implementation Scheme I-80, wherein the at least one microneedle extends from the housing such that the distal end of the electrode is located at a position less than about 5 mm from the housing.

[0427] Implementation Scheme I-82. The system according to Implementation Scheme I-80, wherein the housing encapsulates an electronic system including a wireless communication module, and the system further includes a software application to be paired with the wireless communication module that can be executed on a mobile computing device.

[0428] Implementation Scheme I-83. The system according to Implementation Scheme I-80, wherein the housing includes a user interface, the user interface including one or more indicator lights configured to convey status information.

[0429] Implementation Scheme I-84. The system according to Implementation Scheme I-83, wherein at least one of the indicator lights is configured to be selectively illuminated according to an illumination pattern corresponding to the state of the analyte measurement result.

[0430] Implementation Scheme I-85. The system according to Implementation Scheme I-83, wherein the analyte monitoring system includes a skin adhesion patch.

[0431] Implementation Scheme I-86. A method for sterilizing analyte monitoring equipment, the method comprising:

[0432] The analyte monitoring device is exposed to a sterilizing agent gas, wherein the analyte monitoring device includes a wearable housing, a microneedle array extending from the housing and including an analyte sensor, and an electronic system disposed within the housing and electrically coupled to the microneedle array.

[0433] The analyte monitoring device is exposed to sterilizing agent gas for a duration sufficient to complete the sterilization of the analyte monitoring device.

[0434] Implementation Scheme I-87. The method according to Implementation Scheme I-86, wherein the sterilizing agent gas is suitable for oxidative sterilization.

[0435] Implementation Scheme I-88. The method according to Implementation Scheme I-87, wherein the sterilizing agent gas includes ethylene oxide.

[0436] Implementation Scheme I-89. The method according to Implementation Scheme I-86, wherein the analyte sensor includes electrodes.

[0437] Implementation Scheme I-90. The method according to Implementation Scheme I-89, wherein the analyte sensor includes a biometric layer disposed above the electrode, wherein the biometric layer includes biometric elements.

[0438] Implementation Scheme I-91. The method according to Implementation Scheme I-90, wherein the biometric element includes an enzyme.

[0439] Implementation Scheme I-92. The method according to Implementation Scheme I-91, wherein the enzyme is an oxidoreductase.

[0440] Implementation Scheme I-93. The method according to Implementation Scheme I-92, wherein the oxidoreductase is at least one selected from lactate oxidase, alcohol oxidase, β-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbic acid oxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, uricase, and xanthine oxidase.

[0441] Implementation Scheme I-94. The method according to Implementation Scheme I-92, wherein the oxidoreductase is glucose oxidase.

[0442] Implementation Scheme I-95. The method according to Implementation Scheme I-90, wherein the biometric element is cross-linked with an amine condensation carbonyl chemical substance.

[0443] Implementation Scheme I-96. The method according to Implementation Scheme I-95, wherein the amine condensation carbonyl chemical substance is at least one of formaldehyde, glyoxal, malondialdehyde, and succinaldehyde.

[0444] Implementation Scheme I-97. The method according to Implementation Scheme I-95, wherein the amine condensation carbonyl chemical is glutaraldehyde.

[0445] Implementation Scheme I-98. The method according to Implementation Scheme I-90, wherein the biometric layer is formed at least in part by cross-linking the biometric elements to form cross-linked biometric element aggregates, and embedding the cross-linked biometric element aggregates in a conductive polymer.

[0446] Implementation Scheme I-99. The method according to Implementation Scheme I-98, wherein embedding the cross-linked biometric element aggregate includes embedding only cross-linked biometric element aggregates having at least a threshold molecular weight.

[0447] Implementation Scheme I-100. The method according to Implementation Scheme I-86, wherein exposing the analyte monitoring device to a sterilizing agent gas comprises injecting the sterilizing agent gas into a compartment containing the analyte monitoring device and heating the compartment to a sterilization temperature.

[0448] Implementation Scheme I-101. The method according to Implementation Scheme I-100, wherein the sterilization temperature is below about 45 degrees Celsius and the residence time is at least about 2 hours.

[0449] Implementation Scheme I-102. The method according to Implementation Scheme I-86 further includes pretreating the analyte monitoring device before exposing it to sterilizing agent gas, wherein pretreating the analyte monitoring device includes exposing it to vapor.

[0450] Implementation Scheme I-103. A microneedle array for an analyte monitoring device, the microneedle array comprising:

[0451] A plurality of solid sensing microneedles, wherein each sensing microneedle comprises:

[0452] The distal portion of the cone includes a working electrode configured to sense the analyte; and

[0453] The main body portion provides a conductive connection to the working electrode.

[0454] The body portion of each sensing microneedle is insulated, such that each working electrode is individually addressable and electrically isolated from each other working electrode in the microneedle array.

[0455] Implementation Scheme I-104. The microneedle array according to Implementation Scheme I-103, wherein at least one sensing microneedle includes a biometric layer disposed above a working electrode, wherein the biometric layer includes biometric elements.

[0456] Implementation Scheme I-105. The microneedle array according to Implementation Scheme I-104, wherein the biometric element includes an enzyme.

[0457] Implementation Scheme I-106. The microneedle array according to Implementation Scheme I-105, wherein the enzyme is an oxidoreductase.

[0458] Implementation Scheme I-107. The microneedle array according to Implementation Scheme I-106, wherein the oxidoreductase is at least one selected from lactate oxidase, alcohol oxidase, β-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbic acid oxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, uricase, and xanthine oxidase.

[0459] Implementation Scheme I-108. The microneedle array according to Implementation Scheme I-106, wherein the oxidoreductase is glucose oxidase.

[0460] Implementation Scheme I-109. The microneedle array according to Implementation Scheme I-104, wherein the biometric element is cross-linked with an amine condensation carbonyl chemical substance.

[0461] Implementation Scheme I-110. The microneedle array according to Implementation Scheme I-109, wherein the amine condensation carbonyl chemical substance is at least one of formaldehyde, glyoxal, malondialdehyde, and succinaldehyde.

[0462] Implementation Scheme I-111. The microneedle array according to Implementation Scheme I-109, wherein the amine condensation carbonyl chemical is glutaraldehyde.

[0463] Implementation Scheme I-112. The microneedle array according to Implementation Scheme I-104, wherein the at least one sensing microneedle includes at least one of a diffusion restriction layer and a hydrophilic layer disposed above the biometric layer.

[0464] Implementation Scheme I-113. The microneedle array according to Implementation Scheme I-103, wherein the microneedle array further includes at least one microneedle having a counter electrode configured to pull current or sink current to maintain an electrochemical reaction on the working electrode of the at least one sensing microneedle.

[0465] Implementation Scheme I-114. The microneedle array according to Implementation Scheme I-103, wherein the plurality of microneedles includes at least one microneedle having a reference electrode configured to provide a reference potential to the working electrode.

[0466] Implementation Scheme I-115. The microneedle array according to Implementation Scheme I-114 further includes a conductive polymer disposed on a reference electrode.

[0467] Implementation Scheme I-116. The microneedle array according to Implementation Scheme I-115, wherein the conductive polymer includes a dopant.

[0468] Implementation Scheme I-117. The microneedle array according to Implementation Scheme I-114, wherein the reference electrode comprises a metal oxide having a stable electrode potential.

[0469] Implementation Scheme I-118. The microneedle array according to Implementation Scheme I-117, wherein the metal oxide comprises iridium oxide.

[0470] Implementation Scheme I-119. The microneedle array according to Implementation Scheme I-114, wherein the reference electrode comprises a metal salt having a stable electrode potential.

[0471] Implementation Scheme I-120. The microneedle array according to Implementation Scheme I-119, wherein the metal salt comprises silver chloride.

[0472] Implementation Scheme I-121. The microneedle array according to Implementation Scheme I-103, wherein in at least one sensing microneedle, the tapered distal portion includes an insulated distal vertex, and the working electrode is located proximal to the insulated distal vertex.

[0473] Implementation Scheme I-122. The microneedle array according to Implementation Scheme I-121, wherein the distal end of the working electrode is offset from the distal vertex by an offset distance of at least about 10 μm, wherein the offset distance is measured along the longitudinal axis of the at least one sensing microneedle.

[0474] Implementation scheme I-123. The microneedle array according to implementation scheme I-103, wherein, in at least one sensing microneedle, a portion of the working electrode is recessed into the distal portion of the cone.

[0475] Implementation Scheme I-124. An analyte monitoring device comprising a microneedle array according to Implementation Scheme I-103 and a wearable housing, wherein the microneedle array extends outwardly from the housing.

[0476] Implementation Scheme I-125. The analyte monitoring device according to Implementation Scheme I-124, wherein the housing includes one or more indicator lights configured to convey status information.

[0477] Implementation Scheme I-126. The analyte monitoring device according to Implementation Scheme I-124, wherein the housing encapsulates an electronic system, the electronic system including at least one of a processor and a wireless communication module.

[0478] Implementation Scheme I-127. The analyte monitoring device according to Implementation Scheme I-126, wherein the analyte monitoring device is a skin adhesion patch.

[0479] Implementation Scheme I-128. A microneedle array for a wearable analyte monitoring device, wherein the microneedle array comprises:

[0480] At least one microneedle, said at least one microneedle comprising:

[0481] A pyramidal main body with a non-circular base; and

[0482] The tapered distal portion extending from the main body and including the electrode,

[0483] The distal portion includes a flat surface offset from the distal vertex of the at least one microneedle.

[0484] Implementation Scheme I-129. The microneedle array according to Implementation Scheme I-128, wherein at least a portion of the main body portion has a first cone angle measured relative to the base, and the distal vertex has a second cone angle measured relative to the base, wherein the second cone angle is greater than the first cone angle.

[0485] Implementation scheme I-130. The microneedle array according to implementation scheme I-128, wherein the second cone angle is about 65 degrees to about 75 degrees.

[0486] Implementation Scheme I-131. The microneedle array according to Implementation Scheme I-130, wherein the first cone angle is about 15 degrees to about 25 degrees.

[0487] Implementation scheme I-132. The microneedle array according to implementation scheme I-128, wherein the flat surface forms an angle of about 75 degrees to 85 degrees with respect to the base.

[0488] Implementation scheme I-133. The microneedle array according to implementation scheme I-128, wherein the distal conical portion includes an insulated distal apex.

[0489] Implementation Scheme I-134. An analyte monitoring device comprising a microneedle array according to Implementation Scheme I-128 and a wearable housing, wherein the microneedle array is configured to extend outwardly from the housing.

[0490] Implementation Scheme I-135. The analyte monitoring device according to Implementation Scheme I-134, wherein the analyte monitoring device is a patch.

[0491] Implementation Scheme I-136. A method for monitoring users, comprising:

[0492] Use an integrated analyte monitoring device, including a single microneedle array, to monitor the interdermal fluid close to the user at multiple sensor locations;

[0493] Multiple working electrodes in a microneedle array are used to quantify one or more analytes in dermal interstitial fluid, wherein each working electrode is individually addressable and electrically isolated from each other working electrode in the analyte monitoring device.

[0494] Implementation Scheme I-137. The method according to Implementation Scheme I-136, wherein quantifying one or more analytes includes quantifying multiple analytes in the dermal interstitial fluid using the plurality of working electrodes.

[0495] Implementation Scheme I-138. The method according to Implementation Scheme I-136, wherein the microneedle array includes a plurality of sensing microneedles, each sensing microneedle including its own working electrode.

[0496] Implementation Scheme I-139. The method according to Implementation Scheme I-138, wherein at least one sensing microneedle includes a biometric layer disposed above a working electrode, wherein the biometric layer includes an enzyme.

[0497] Implementation Scheme I-140. The method according to Implementation Scheme I-139, wherein the at least one microneedle comprises at least one of a diffusion restriction layer and a hydrophilic layer disposed above the biometric layer.

[0498] Implementation Scheme I-141. The method according to Implementation Scheme I-136, wherein the microneedle array includes at least one microneedle having a counter electrode configured to pull current or sink current to maintain an electrochemical reaction on at least one working electrode.

[0499] Implementation Scheme I-142. The method according to Implementation Scheme I-136, wherein the plurality of microneedle arrays include at least one microneedle having a reference electrode configured to provide a reference potential to at least one working electrode.

[0500] Implementation Scheme I-143. The method according to Implementation Scheme I-142 further includes a conductive polymer disposed on the reference electrode.

[0501] Implementation Scheme I-144. The method according to Implementation Scheme I-143, wherein the conductive polymer includes a dopant.

[0502] Implementation Scheme I-145. The method according to Implementation Scheme I-142, wherein the reference electrode comprises a metal oxide having a stable electrode potential.

[0503] Implementation Scheme I-146. The method according to Implementation Scheme I-145, wherein the metal oxide comprises iridium oxide.

[0504] Implementation Scheme I-147. The method according to Implementation Scheme I-142, wherein the reference electrode comprises a metal salt having a stable electrode potential.

[0505] Implementation Scheme I-148. The method according to Implementation Scheme I-147, wherein the metal salt comprises silver chloride.

[0506] Implementation Scheme I-149. The method according to Implementation Scheme I-136 further includes conveying status information indicating the quantification of one or more analytes.

[0507] Implementation Scheme I-150. The method according to Implementation Scheme I-149, wherein the microneedle array extends outward from the wearable housing, and conveying status information includes conveying status information via a user interface on the housing.

[0508] Implementation Scheme I-151. The method according to Implementation Scheme I-150, wherein the communication of status information includes selectively illuminating one or more indicator lights on the housing according to an illumination pattern corresponding to the status of the analyte measurement result or the status of the integrated analyte monitoring device.

[0509] Implementation Scheme I-152. The method according to Implementation Scheme I-150, wherein the communication of status information includes activating a display corresponding to the status of analyte measurement results or the status of an integrated analyte monitoring device.

[0510] Implementation Scheme I-153. A wearable analytical substance monitoring device, comprising:

[0511] Wearable case; and

[0512] A microneedle array extending outward from the housing and including at least one microneedle configured to measure one or more analytes in the body of a user wearing the housing.

[0513] The housing includes a user interface configured to convey information indicating measurement results of the one or more analytes.

[0514] Implementation Scheme I-154. The device according to Implementation Scheme I-153, wherein the user interface includes one or more indicator lights configured to be selectively illuminated according to an illumination pattern corresponding to the status of the analyte measurement result or the status of the integrated analyte monitoring device.

[0515] Implementation Scheme I-155. The device according to Implementation Scheme I-154, wherein at least one of the indicator lights is configured to be selectively illuminated to convey the current analyte measurement level.

[0516] Implementation Scheme I-156. The device according to Implementation Scheme I-154, wherein the user interface includes a plurality of indicator lights configured to be selectively illuminated in a progressive sequence to convey trends in analyte measurements.

[0517] Implementation Scheme I-157. The device according to Implementation Scheme I-156, wherein the plurality of indicator lights are configured to be selectively illuminated in a first progressive sequence along a first direction to convey an upward trend in analyte measurements.

[0518] Implementation Scheme I-158. The device according to Implementation Scheme I-156, wherein the plurality of indicator lights are configured to be selectively illuminated in a second progressive sequence along a second direction to convey a decreasing trend in analyte measurements.

[0519] Implementation Scheme I-159. The device according to Implementation Scheme I-153, wherein the user interface is further configured to convey information indicating the status of the analyte monitoring device.

[0520] Implementation Scheme I-160. The device according to Implementation Scheme I-153, wherein the user interface includes a display screen.

[0521] Implementation Scheme I-161. The device according to Implementation Scheme I-153, wherein the analyte monitoring device is a skin adhesion patch.

[0522] Implementation Scheme I-162. The device according to Implementation Scheme I-153, wherein the at least one microneedle includes a tapered distal portion having an insulated distal apex and an electrode on the surface of the tapered distal portion, wherein the electrode is located proximal to the insulated distal apex.

[0523] Implementation Scheme I-163. The device according to Implementation Scheme I-153, wherein the microneedle array includes a plurality of working electrodes, wherein each working electrode is individually addressable and electrically isolated from each other working electrode in the analyte monitoring device.

[0524] Implementation Scheme I-164. A method for monitoring users, comprising:

[0525] Use a wearable analyte monitoring device that includes a wearable shell and one or more analyte sensors to measure one or more analytes in the user's body;

[0526] The user interface on the casing conveys information indicating the measurement results of the one or more analytes.

[0527] Implementation Scheme I-165. The method according to Implementation Scheme I-164, wherein conveying information includes illuminating one or more indicator lights on the housing according to an illumination pattern corresponding to the state of the analyte measurement result.

[0528] Implementation Scheme I-166. The method according to Implementation Scheme I-165, wherein the information communication includes selectively illuminating at least one indicator light to communicate the current analyte measurement level.

[0529] Implementation Scheme I-167. The method according to Implementation Scheme I-166, wherein the information communication includes communicating the current analyte measurement level based on the color of the illuminated indicator light, the position of the illuminated indicator light, or both the color of the illuminated indicator light and the position of the illuminated indicator light.

[0530] Implementation Scheme I-168. The method according to Implementation Scheme I-165, wherein the information communication includes selectively illuminating a plurality of indicator lights on the housing in a progressive sequence to communicate trends in analyte measurement values.

[0531] Implementation Scheme I-169. The method according to Implementation Scheme I-168, wherein the information communication includes selectively illuminating the plurality of indicator lights in a first progressive sequence along a first direction to communicate an upward trend in analyte measurements.

[0532] Implementation Scheme I-170. The method according to Implementation Scheme I-168, wherein the information communication includes selectively illuminating the plurality of indicator lights in a second progressive sequence along a second direction to communicate a decreasing trend in analyte measurements.

[0533] Implementation Scheme I-171. The method according to Implementation Scheme I-164 further includes conveying information indicating the status of the analyte monitoring device via a user interface.

[0534] Implementation Scheme I-172. The method according to Implementation Scheme I-164 further includes using the analyte monitoring device to approach the user's dermal interstitial fluid at multiple sensor locations, wherein quantifying one or more analytes includes quantifying one or more analytes in the dermal interstitial fluid.

[0535] Implementation Scheme I-173. The method according to Implementation Scheme I-164, wherein the analyte monitoring device includes a microneedle array, the microneedle array including a plurality of working electrodes, wherein each working electrode is individually addressable and electrically isolated from each other working electrode in the analyte monitoring device.

[0536] For purposes of explanation, specific terminology has been used in the foregoing description to provide a comprehensive understanding of the invention. However, it will be apparent to those skilled in the art that specific details are not required to practice the invention. Therefore, for purposes of illustration and description, the foregoing description presents specific embodiments of the invention. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed; obviously, many modifications and variations are possible in light of the foregoing teachings. The embodiments were chosen and described to explain the principles of the invention and its practical application, and thus enable others skilled in the art to utilize the invention and various embodiments with various modifications to suit a particular intended use. The following claims and their equivalents are intended to define the scope of the invention.

Claims

1. A microneedle array for sensing analytes, comprising: A plurality of solid microneedles, wherein at least one microneedle comprises: The columnar main body; A tapered distal portion located on the distal side of the columnar main body, the tapered distal portion having an insulated distal apex; and A ring electrode on the surface of the distal portion of the cone, wherein the ring electrode is located near the distal apex of the insulation.

2. The microneedle array according to claim 1, wherein, The annular electrode is a working electrode configured to sense at least one analyte, and the at least one microneedle includes a biometric layer disposed above the working electrode, wherein the biometric layer includes biometric elements.

3. The microneedle array according to claim 2, wherein, The biometric element includes enzymes.

4. The microneedle array according to claim 3, wherein, The enzyme in question is an oxidoreductase.

5. The microneedle array according to claim 4, wherein, The oxidoreductase is at least one of lactate oxidase, alcohol oxidase, β-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbic acid oxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, uricase oxidase, urease, and xanthine oxidase.

6. The microneedle array according to claim 4, wherein, The oxidoreductase is glucose oxidase.

7. The microneedle array according to claim 2, wherein, The biometric element is cross-linked with an amine condensation carbonyl chemical substance.

8. The microneedle array according to claim 7, wherein, The amine condensation carbonyl chemical substance is at least one of formaldehyde, glyoxal, malondialdehyde, and succinaldehyde.

9. The microneedle array according to claim 7, wherein, The amine condensation carbonyl chemical is glutaraldehyde.

10. The microneedle array according to claim 2, wherein, The at least one microneedle includes at least one of a diffusion restriction layer and a hydrophilic layer disposed above the biometric layer.

11. The microneedle array according to claim 2, wherein, The microneedle array includes at least one microneedle with a counter electrode configured to pull or sink current to maintain the electrochemical reaction on the working electrode.

12. The microneedle array according to claim 2, wherein, The microneedle array includes at least one microneedle having a reference electrode configured to provide a reference potential to the working electrode.

13. The microneedle array of claim 12 further comprises a conductive polymer disposed on the reference electrode.

14. The microneedle array according to claim 13, wherein, The conductive polymer includes a dopant.

15. The microneedle array according to claim 13, wherein, The reference electrode comprises a metal oxide having a stable electrode potential.

16. The microneedle array according to claim 15, wherein, The metal oxide includes iridium oxide.

17. The microneedle array according to claim 13, wherein, The reference electrode comprises a metal salt having a stable electrode potential.

18. The microneedle array according to claim 17, wherein, The metal salt includes silver chloride.

19. The microneedle array according to claim 1, wherein, The entire annular electrode is located on the distal conical portion of the at least one microneedle.

20. The microneedle array according to claim 1, wherein, The annular electrode includes a catalytic surface.

21. The microneedle array according to claim 20, wherein, The catalytic surface includes at least one of platinum, palladium, iridium, rhodium, gold, ruthenium, titanium, nickel, carbon, and doped diamond.

22. The microneedle array according to claim 20, wherein, The at least one microneedle includes platinum black disposed above the annular electrode.

23. The microneedle array according to claim 1, wherein, The distal end of the annular electrode is offset from the distal vertex by at least 10 μm, wherein the offset distance is measured along the longitudinal axis of the at least one microneedle.

24. The microneedle array according to claim 1, wherein, A portion of the annular electrode is recessed into the distal portion of the cone.

25. The microneedle array of claim 1, further comprising an electrical contact, wherein the at least one microneedle includes a body portion providing a conductive path between the electrical contact and the annular electrode.

26. The microneedle array according to claim 25, wherein, The main body is formed of a conductive material.

27. The microneedle array according to claim 25, wherein, The main body includes the embedding path.

28. The microneedle array according to claim 25, wherein, The main body is insulated.

29. The microneedle array according to claim 25, wherein, The main body has a circular, square, or octagonal base.

30. The microneedle array according to claim 1, wherein, Each of the plurality of microneedles includes: The columnar main body; A tapered distal portion located on the distal side of the columnar main body, the tapered distal portion having an insulated distal apex; and A ring electrode on the surface of the distal portion of the cone, wherein the ring electrode is located near the distal apex of the insulation.

31. The microneedle array according to claim 1, wherein, The microneedles in the plurality of microneedles are electrically insulated from each other.

32. The microneedle array according to claim 31, wherein, The microneedle array is configured to detect a variety of analytes.

33. The microneedle array according to claim 1, wherein, The microneedles among the plurality of microneedles are arranged in a periodic grid pattern.

34. The microneedle array according to claim 33, wherein, The periodic grid comprises a rectangular array.

35. The microneedle array according to claim 33, wherein, The periodic grid comprises a hexagonal array.

36. The microneedle array according to claim 33, wherein, The microneedles in the periodic grid are spaced 200 μm to 800 μm apart.

37. The microneedle array according to claim 33, wherein, The microneedles in the periodic grid are evenly spaced.

38. The microneedle array according to claim 1, wherein, The plurality of microneedles includes at least one delivery microneedle having an inner lumen.

39. The microneedle array according to claim 1, wherein, The at least one microneedle is configured to puncture the user's skin and sense analytes in the interstitial fluid of the user's dermis.

40. An analyte monitoring system comprising a microneedle array according to claim 1 and a wearable housing, wherein, The microneedle array extends outward from the outer shell.

41. The system according to claim 40, wherein, The at least one microneedle extends from the housing, such that the distal end of the annular electrode is located less than 5 mm from the housing.

42. The system according to claim 41, wherein, The at least one microneedle extends from the housing, such that the distal end of the annular electrode is located less than 1 mm from the housing.

43. The system according to claim 40, wherein, The housing encapsulates an electronic system, which includes at least one of a processor and a wireless communication module.

44. The system according to claim 43, wherein, The electronic system includes a wireless communication module, and the system also includes a software application that can be executed on a mobile computing device and is to be paired with the wireless communication module.

45. The system according to claim 40, wherein, The housing includes a user interface configured to convey status information via one or more indicator lights.

46. ​​The system according to claim 45, wherein, At least one of the one or more indicator lights is configured to be selectively illuminated according to an illumination pattern corresponding to the state of the analyte measurement result.

47. The system according to claim 46, wherein, At least one of the one or more indicator lights is configured to be selectively illuminated to convey the current analyte measurement level.

48. The system according to claim 46, wherein, The user interface includes multiple indicator lights configured to be selectively illuminated in a progressive sequence to convey trends in analyte measurements.

49. The system according to claim 48, wherein, The plurality of indicator lights are configured to be selectively illuminated in a first progressive sequence along a first direction to convey an upward trend in analyte measurements, and are also configured to be selectively illuminated in a second progressive sequence along a second direction to convey a downward trend in analyte measurements.

50. The system according to claim 45, wherein, The user interface is also configured to convey information indicating the status of the analyte monitoring equipment.

51. The system of claim 40 further includes an adhesive configured to attach the housing to a user's skin.

52. The system of claim 40 further includes an applicator configured to apply at least a portion of the analyte monitoring system to a user's skin.

53. The system according to claim 40, wherein, The analyte monitoring system is a skin-adhesive patch.

54. The system according to claim 40, wherein, The plurality of microneedles includes at least one delivery microneedle having an inner lumen.

55. The system according to claim 40, wherein, The plurality of microneedles includes at least one solid microneedle, the solid microneedle including a coating containing a therapeutic substance.

56. The system according to claim 55, wherein, The therapeutic substances include at least one of the following: insulin, glucagon, metformin, acetaminophen, acetylsalicylic acid, isobutylphenylpropionic acid, levodopa, statins, hydrocodone, opioids, nonsteroidal anti-inflammatory drugs, anesthetics, analgesics, anticonvulsants, antidepressants, antipsychotics, sedatives, relaxants, hormones, antibacterial agents, and antiviral agents.

57. A microneedle array for sensing analytes, comprising: A plurality of solid microneedles, wherein at least one microneedle comprises: A tapered distal portion located distal to the columnar body portion of the at least one microneedle, the tapered distal portion having an insulated distal apex; and A ring electrode is attached to the surface of the distal portion of the cone, wherein the ring electrode is located near the distal apex of the insulation.

58. The microneedle array according to claim 57, wherein, The annular electrode is a working electrode configured to sense at least one analyte, and the at least one microneedle includes a biometric layer disposed above the working electrode, the biometric layer including biometric elements.

59. The microneedle array according to claim 58, wherein, The biometric element includes glucose oxidase.

60. The microneedle array according to claim 58, wherein, The microneedle array includes at least one microneedle with a counter electrode configured to pull or sink current to maintain the electrochemical reaction on the working electrode.

61. The microneedle array according to claim 58, wherein, The microneedle array includes at least one microneedle having a reference electrode configured to provide a reference potential to the working electrode.

62. The microneedle array according to claim 57, wherein, The distal edge of the annular electrode is offset from the distal vertex by at least 10 μm, wherein the offset distance is measured along the longitudinal axis of the at least one microneedle.

63. The microneedle array according to claim 57, wherein, A portion of the annular electrode overlaps with an annular contact groove defined by an annular groove formed in the surface of the distal portion of the cone.

64. The microneedle array of claim 57 further includes an electrical contact, wherein the columnar body portion provides a conductive path between the electrical contact and the annular electrode.

65. The microneedle array according to claim 64, wherein, The columnar body portion is formed of a conductive material and / or the columnar body portion includes an embedded path.

66. The microneedle array according to claim 57, wherein, The columnar main body is insulated.

67. The microneedle array according to claim 57, wherein, Each of the plurality of microneedles includes: A tapered distal portion located on the far side of the columnar main body, the tapered distal portion having an insulated distal apex; and The annular electrode on the surface of the distal portion of the cone, The ring electrode includes a proximal edge and a distal edge. The distal edge of the ring electrode is located near the proximal edge of the distal vertex of the insulation.

68. The microneedle array according to claim 67, wherein, The ring electrode is a working electrode, a counter electrode, or a reference electrode.

69. The microneedle array according to claim 57, wherein, The microneedle array includes multiple working electrodes, each of which is individually addressable and electrically isolated from each other working electrode in the microneedle array.

70. The microneedle array according to claim 57, wherein, The microneedle array is configured to detect a variety of analytes.

71. The microneedle array according to claim 57, wherein, The microneedles are arranged in a hexagonal array.

72. The microneedle array according to claim 57, wherein, The solid microneedles extend from the semiconductor substrate.

73. The microneedle array according to claim 57, wherein, The annular electrode includes a proximal edge and a distal edge, the distal edge being located proximal to the proximal edge of the distal vertex of the insulation.

74. The microneedle array according to claim 73, wherein, The distal portion of the cone also includes a proximal insulating surface, wherein the distal edge of the proximal insulating surface is located proximal to the proximal edge of the annular electrode.

75. An analyte monitoring system, comprising an analyte monitoring device, the analyte monitoring device comprising: The microneedle array according to claim 57; and Wearable case The microneedle array extends outward from the outer shell.

76. The system according to claim 75, wherein, The at least one microneedle extends from the housing such that the distal edge of the annular electrode is located less than 1 mm from the housing.

77. The system according to claim 75, wherein, The analyte monitoring device is a skin adhesion patch.

78. The system according to claim 75, wherein, The plurality of microneedles include a plurality of working electrodes, wherein each working electrode is individually addressable and electrically isolated from each other working electrode in the analyte monitoring device.

79. A microneedle array for sensing analytes, comprising: Semiconductor substrate; A plurality of solid microneedles extending from the semiconductor substrate, wherein at least one of the microneedles is configured to sense an analyte in the user's dermal interstitial fluid, and includes: The columnar main body; A cone-shaped distal portion with an insulating distal apex; and An annular working electrode on the surface of the distal conical portion, wherein the working electrode includes a proximal edge and a distal edge, and is located only on a segment of the surface of the distal conical portion of the microneedle, wherein the distal edge of the working electrode is located proximal to the proximal edge of the insulated distal apex.

80. The microneedle array according to claim 79, wherein, The microneedle includes a biometric layer disposed above the working electrode, wherein the biometric layer includes biometric elements.

81. The microneedle array according to claim 80, wherein, The biometric element includes glucose oxidase.

82. The microneedle array according to claim 80, wherein, The microneedle array includes at least one microneedle with a counter electrode configured to pull or sink current to maintain the electrochemical reaction on the working electrode.

83. The microneedle array according to claim 80, wherein, The microneedle array includes at least one microneedle having a reference electrode configured to provide a reference potential to the working electrode.

84. The microneedle array according to claim 79, wherein, The distal edge of the working electrode is offset from the distal vertex by an offset distance of at least 10 μm, wherein the offset distance is measured along the longitudinal axis of the at least one microneedle.

85. The microneedle array according to claim 79, wherein, A portion of the working electrode covers an annular contact groove defined by an annular groove formed in the surface of the distal portion of the cone.

86. The microneedle array of claim 79, further comprising an electrical contact located on the back side of the semiconductor substrate, wherein the columnar body portion of at least one of the plurality of microneedles provides a conductive path between the electrical contact and the working electrode.

87. The microneedle array according to claim 86, wherein, The columnar main body is formed of a conductive material.

88. The microneedle array according to claim 86, wherein, The columnar main body includes embedded conductive paths.

89. The microneedle array according to claim 86, wherein, The columnar main body is insulated.

90. The microneedle array according to claim 79, wherein, The plurality of microneedles also includes one or more additional microneedles, each of the one or more additional microneedles comprising: A cone-shaped distal portion with an insulating distal apex; The columnar main body; and The annular electrode on the surface of the distal portion of the cone, The annular electrode includes a proximal edge and a distal edge, and is located only on a segment of the surface of the distal conical portion of the microneedle, wherein the distal edge of the annular electrode is located proximal to the proximal edge of the distal apex of the insulation, and The ring electrode is a working electrode, a counter electrode, or a reference electrode.

91. The microneedle array according to claim 79, wherein, The microneedle array includes multiple working electrodes, each of which is individually addressable and electrically isolated from each other working electrode in the microneedle array.

92. The microneedle array according to claim 91, wherein, The microneedle array is configured to detect a variety of analytes.

93. The microneedle array according to claim 79, wherein, The multiple microneedles are arranged in a square or hexagonal array.

94. The microneedle array according to claim 79, wherein, The distal portion of the cone also includes a proximal insulating surface, wherein the distal edge of the proximal insulating surface is located proximal to the proximal edge of the working electrode.

95. An analyte monitoring system, comprising: Analyte monitoring equipment, the analyte monitoring equipment includes: The microneedle array according to claim 79; and Wearable case The microneedle array extends outward from the outer shell.

96. The system according to claim 95, wherein, At least one of the plurality of microneedles extends from the housing, such that the distal end of the working electrode is located less than 1 mm from the housing.

97. The system according to claim 95, wherein, The housing encapsulates an electronic system including a wireless communication module, and the system further includes a software application that is to be paired with the wireless communication module and can be executed on a mobile computing device.

98. The system according to claim 95, wherein, The housing includes a user interface, which includes one or more indicator lights configured to convey status information.

99. The system according to claim 98, wherein, At least one of the one or more indicator lights is configured to be selectively illuminated according to an illumination mode corresponding to the state of the analyte measurement result, or according to the state of the analyte monitoring device, or according to both an illumination mode corresponding to the state of the analyte measurement result and the state of the analyte monitoring device.

100. The system according to claim 98, wherein, At least one of the one or more indicator lights is configured to be selectively illuminated to convey the current analyte measurement level.

101. The system according to claim 98, wherein, The user interface includes multiple indicator lights configured to be selectively illuminated in a progressive sequence to convey trends in analyte measurements.

102. The system according to claim 101, wherein, The plurality of indicator lights are configured to be selectively illuminated in a first progressive sequence along a first direction to convey an upward trend in analyte measurements, and are also configured to be selectively illuminated in a second progressive sequence along a second direction to convey a downward trend in analyte measurements.

103. The system according to claim 98, wherein, The user interface is also configured to convey information indicating the status of the analyte monitoring device.

104. The system according to claim 95, wherein, The analyte monitoring device is a skin-adhesive patch.

105. The system according to claim 95, wherein, The plurality of microneedles includes a plurality of working electrodes, wherein each working electrode is located on a corresponding microneedle among the plurality of microneedles, wherein each working electrode is individually addressable and electrically isolated from each other working electrode in the analyte monitoring device.

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