Methods, systems, and devices for continuous glucose monitoring using improved sensors.

Abstract

This invention discloses methods, systems, and apparatus for continuous glucose monitoring. More specifically, these methods, systems, and apparatus describe a working electrode with a GOx sensor and a background electrode, wherein the background electrode does not have a GOx sensor. The system can then compare a first signal and a second signal to detect the user's drug intake. The system can generate a sensor blood glucose value based on the comparison.

Description

Technical Field

[0001] This technology as a whole relates to sensor technology, including sensors for sensing various physiological parameters (e.g., blood glucose concentration). Background Technology

[0002] Over the years, various sensors have been developed for the detection and / or quantification of specific reagents or compositions in a patient's blood, enabling patients and healthcare professionals to monitor physiological conditions within the patient's body. Illustratively, subjects may wish to continuously monitor their blood glucose levels. Therefore, blood glucose sensors have been developed to obtain indications of blood glucose levels in patients with diabetes. Such readings are suitable for monitoring and / or adjusting treatment regimens that typically involve the regular administration of insulin to the patient. Currently, patients can measure their blood glucose (“BG”) using BG measuring devices (i.e., blood glucose meters), such as test strips, continuous glucose measurement systems (or continuous glucose monitors), or hospital BG tests. BG measuring devices use various methods to measure a patient's BG levels, such as blood samples from the patient, sensors in contact with bodily fluids, optical sensors, enzyme sensors, or fluorescence sensors. When a BG measuring device has generated a BG measurement result, the result is displayed on the BG measuring device. Summary of the Invention

[0003] Current continuous glucose measurement systems include subcutaneous (or short-term) sensors and implantable (or long-term) sensors. These sensors are used in telemetry characteristic monitoring systems. Telemetry systems using electrochemical sensors include a remotely located data receiving device, a sensor for generating signals indicative of user characteristics, and a transmitter device for processing the signals received from the sensor and wirelessly transmitting the processed signals back to the remotely located data receiving device. The data receiving device can be a characteristic monitor, a data receiver providing data to another device, an RF programmer, a drug delivery device (such as an infusion pump), etc. Regardless of whether the data receiving device (e.g., a glucose monitor), the transmitter device, and the sensor (e.g., a glucose sensor) communicate wirelessly or via wired connections, the characteristic monitoring systems of the above types are only practically useful after calibration based on the unique characteristics of an individual user.

[0004] Continuous glucose monitoring (“CGM”) is largely ancillary, meaning that clinical decisions cannot be made using readings provided by CGM devices (including, for example, implantable or subcutaneous sensors) without a reference value. The reference value, in turn, must be obtained from finger prick using, for example, a BG meter. The reason for needing a reference value is the limited amount of information available from the sensor / sensing component. Generally, glucose measurement is based on interaction with one of three enzymes: hexokinase, glucose oxidase (“GOx”), or glucose-1-dehydrogenase (“GDH”). Specifically, currently, only a few pieces of information are provided by the sensing component for processing: the raw sensor value (i.e., sensor current or Isig) and the reverse voltage. Therefore, during analysis, if the raw sensor signal appears abnormal (e.g., if the signal is decreasing), the only way to distinguish sensor malfunction from physiological changes in the user / patient's body (i.e., changes in glucose levels) is by obtaining a reference glucose value via finger prick. However, repeated finger pricking by users / patients is painful and otherwise undesirable; therefore, this article describes methods, systems, and devices for minimizing the amount of testing and / or calibration required for CGM and improving the reliability of such testing and / or calibration by improving glucose oxidase (“GOx”) sensors.

[0005] To further mitigate the obstacles faced by CGM devices, government agencies (e.g., the Federal Drug Administration (“FDA”) impose restrictions and requirements on the sensitivity of CGMs to various drugs. For example, under the FDA iCGM Specific Requirements, CGM devices are required to be minimally affected by acetaminophen exposure when the user orally ingests acetaminophen (a common treatment for mild pain relief). GOx is a standard enzyme used in biosensors due to its relatively high selectivity for glucose. GOx is also readily available, inexpensive, and tolerant of more extreme pH, ionic strength, and temperature conditions compared to many other enzymes, allowing for less stringent manufacturing conditions and relatively relaxed storage specifications for use by novice biosensor users. However, conventional GOx sensors are affected by the presence of acetaminophen, which can lead to errors in the estimated BG based on the sensor glucose (“SG”) signal. For example, high doses of acetaminophen can cause analytical interference to electrochemical biosensors because acetaminophen is directly oxidized after diffusing across the porous membrane to the electrode surface, generating interfering currents that increase glucose readings. Therefore, this paper describes methods, systems, and devices for further improving the reliability of CGM devices. This is accomplished by providing two electrodes: one electrode, called the working electrode, detects glucose by virtue of the presence of GOx, but is susceptible to interference from interfering substances such as acetaminophen; the second electrode, called the background electrode, does not have GOx and therefore only responds to interfering substances. By comparing the signals from the working electrode and the background electrode, interference can be eliminated, and a more accurate, calibrated SG signal can be calculated.

[0006] More specifically, these methods, systems, and apparatuses describe a working electrode having a GOx layer and a background electrode having no GOx sensor. The background electrode, which can be formed as a metallized layer, can be made of various materials. For example, the background electrode metallization layer can be made of platinum, gold, or another material. In one example, the working electrode is made of platinum, and the background electrode is made of gold. In some embodiments, the electrode material and the applied voltage can be tuned to target various types of interference. For example, a gold electrode and a voltage of 600 mV can be used, while in another arrangement, a carbon electrode and a voltage of 900 mV can be used. In one embodiment, the working electrode and the background electrode can have the same operating potential. The system can subtract the two signals from each other to remove the signal originating from the background electrode. Thus, in this embodiment, the system can determine the difference in signal between the working electrode and the background electrode. If the user / patient uses acetaminophen, both the working electrode and the background electrode are affected. The working electrode, including the GOx layer, generates a signal based on the amount of glucose present. However, it also generates a signal for exposure to acetaminophen. On the other hand, the background electrode does not have a GOx layer and therefore generates a signal solely due to its exposure to acetaminophen. The difference in signals between the working electrode and the background electrode is then used to calculate and generate an adjusted sensor glucose value. In some embodiments, the signals from the working electrode and the background electrode can be input as parameters into a predetermined mathematical model (e.g., an external calibration model) to adjust the sensor glucose value.

[0007] The working electrode and the background electrode may have different voltage potentials (Vset) for the working electrode and the background electrode. The working electrode may operate at a lower Vset relative to the background electrode. For example, the working electrode may operate in the range of 400mV-500mV, while the background electrode may operate in the range of 500mV-600mV. For example, as described above, calculating the sensor glucose value based on the different voltage potentials (Vset) of the working electrode and the background electrode provides a more accurate measure of the sensor glucose value, especially in the presence of drugs that generate interfering currents that increase system readings. The value of the voltage potential (Vset) may be stored by electronic circuitry (e.g., a storage circuit). Voltage potential refers to the voltage between a particular electrode and a reference electrode. Operating the background electrode at a higher potential produces a larger signal, thus providing a more accurate indication of interference. Alternatively, the background electrode may be made smaller for the same signal.

[0008] In some aspects, methods, systems, and apparatuses for continuous blood glucose monitoring are described. For example, the system may activate a first electrode on a user, wherein the first electrode is configured to detect glucose, for example, by the presence of a glucose oxidase (GOx) layer. The system may activate a second electrode on the user, wherein the second electrode does not have a GOx layer. The system may set a first voltage potential (Vset) for the first electrode. The system may set a second voltage potential (Vset) for the second electrode; receive a first signal from the first electrode. The system may receive a second signal from the second electrode. The system may compare the first signal with the second signal, which detects glucose and interference due to the user's ingestion of medication, and the second signal, which detects only the user's ingestion of medication. The system can then generate a calibrated sensor glucose value by deriving an error signal due to interference. It should be understood that although GOx is mentioned in the arrangements discussed herein, any substance that catalyzes the redox reaction of glucose and thus ultimately produces a current proportional to the glucose concentration can be used. Three enzymes are well known for this purpose: hexokinase, glucose oxidase (“GOx”), and glucose-1-dehydrogenase (“GDH”).

[0009] Various other aspects, features, and advantages will become apparent from the detailed description and accompanying drawings. It should also be understood that the foregoing general description and the following detailed description are examples and not limitations on the scope of the invention. As used in the specification and claims, the singular forms “a,” “an,” and “described” include plural indicators unless the context clearly indicates otherwise. Furthermore, as used in the specification and claims, the term “or” means “and / or” unless the context clearly indicates otherwise. Additionally, as used in the specification, “a portion” means a sub-part or the whole of a given item (e.g., data) unless the context clearly specifies otherwise.

[0010] Details of one or more aspects of this disclosure are set forth in the following drawings and description. Other features, objectives, and advantages of the technology described in this disclosure will be apparent from the specification, drawings, and claims. Attached Figure Description

[0011] Embodiments of the present invention will be described in detail with reference to the accompanying drawings, wherein similar numbers denote corresponding parts in the drawings.

[0012] Figure 1 This is a perspective view of the subcutaneous sensor insertion assembly and a block diagram of the sensor electronics.

[0013] Figure 2 A substrate with two sides is shown, the first side containing an electrode configuration and the second side containing electronic circuitry.

[0014] Figure 3A block diagram of a sensor electronics device and a sensor containing multiple electrodes is shown.

[0015] Figure 4 An alternative embodiment of the present invention, including a sensor and sensor electronics, is shown.

[0016] Figure 5 An electronic block diagram showing the sensor electrodes and the voltage applied to the sensor electrodes is shown.

[0017] Figure 6 A flowchart is shown illustrating the steps involved in continuous glucose monitoring according to one or more embodiments.

[0018] Figure 7 A flowchart is shown illustrating the steps involved in continuous glucose monitoring according to one or more embodiments.

[0019] Figure 8 A unit sensor with a background electrode metal layer made of platinum is shown.

[0020] Figure 9 A single sensor with a background electrode metal layer made of gold is shown.

[0021] Figure 10 The single-sensor flexible component and the dual-sensor flexible component in the CGM device are shown. Detailed Implementation

[0022] In the following description, reference is made to the accompanying drawings, which form a part of the description and illustrate several embodiments of the invention. It should be understood that other embodiments may be utilized, and structural and operational changes may be made, without departing from the scope of the invention.

[0023] The invention is described below with reference to flowchart illustrations of methods, systems, apparatuses, devices, and programming products and computer program products. It should be understood that each block of the flowchart illustrations, and combinations of blocks in the flowchart illustrations, can be implemented by programming instructions, including computer program instructions (such as any menu screens shown in the illustrations). These computer program instructions can be loaded onto a computer or other programmable data processing apparatus (such as a controller, microcontroller, or processor in sensor electronics) to produce a machine, such that instructions executing on the computer or other programmable data processing apparatus produce instructions for implementing the functions specified in one or more flowchart blocks. These computer program instructions can also be stored in a computer-readable storage medium that directs the computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable storage medium produce an article of writing containing instructions for implementing the functions specified in one or more flowchart blocks. The computer program instructions can also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer-implemented process, such that instructions executing on the computer or other programmable apparatus provide steps for implementing the functions specified in one or more flowchart blocks, and / or menus presented herein. Programming instructions may also be stored in and / or implemented via electronic circuits (e.g., storage circuits, processing circuits), including integrated circuits (ICs) and application-specific integrated circuits (ASICs) used in conjunction with sensor devices, equipment, and systems. The following terms and definitions may also be used herein:

[0024]

[0025]

[0026] Figure 1 This is a perspective view of the subcutaneous sensor insertion assembly and a block diagram of the sensor electronics. (Example) Figure 1 As shown, a subcutaneous sensor assembly 10 is provided for housing a flexible sensor 12 (see example...). Figure 2The active portion of the sensor assembly 10 is placed subcutaneously at a selected site on the user's body. The subcutaneous or percutaneous portion of the sensor assembly 10 includes a hollow, slotted insertion needle 14 and a cannula 16. The needle 14 facilitates quick and easy subcutaneous placement of the cannula 16 at the subcutaneous insertion site. The sensing portion 18 of the sensor 12 is located inside the cannula 16, and this sensing portion exposes one or more sensor electrodes 20 to the user's bodily fluids through a window 22 formed in the cannula 16. In one embodiment, the one or more sensor electrodes 20 may include a counter electrode, a reference electrode, one or more working electrodes, and a background electrode. After insertion, the insertion needle 14 is withdrawn, leaving the cannula 16, the sensing portion 18, and the sensor electrodes 20 in place at the selected insertion site.

[0027] In a particular embodiment, the subcutaneous sensor array 10 facilitates precise placement of a flexible thin-film electrochemical sensor 12, which belongs to the type used to monitor specific blood parameters indicative of a user's condition. Sensor 12 monitors glucose levels in the body and can be used in conjunction with external or implantable automated or semi-automated drug infusion pumps to control insulin delivery to diabetic patients, as described, for example, in U.S. Patent Nos. 4,562,751; 4,678,408; 4,685,903 or 4,573,994.

[0028] A particular embodiment of the flexible electrochemical sensor 12 is constructed according to thin-film shielding technology, comprising an elongated thin-film conductor embedded or covered between a selected insulating material (e.g., a polyimide film or sheet) and the membrane. When the sensing portion 18 (or active portion) of the sensor 12 is placed subcutaneously at the insertion site, the sensor electrode 20 at the tip of the sensing portion 18 is exposed through one of the insulating layers to directly contact the patient's blood or other bodily fluids. The sensing portion 18 engages with a connection portion 24 terminating in a conductive contact pad, etc., which is also exposed through one of the insulating layers.

[0029] As is known in the art, the connection portion 24 and the contact pad are generally suitable for direct wired electrical connection to a suitable monitor or sensor electronics 100 to monitor the user's condition in response to a signal received from the sensor electrodes 20. Further description of this general type of flexible thin-film sensor can be found in U.S. Patent No. 5,391,250 entitled "METHOD OF FABRICATING THIN FILMSENSORS". The connection portion 24 can be conveniently electrically connected to the monitor or sensor electronics 100, or connected via a connector block 28 (or the like) as shown and described in U.S. Patent No. 5,482,473 entitled "FLEX CIRCUIT CONNECTOR". Therefore, according to embodiments of the invention, the subcutaneous sensor assembly 10 can be configured or formed to work with a wired or wireless characteristic monitoring system.

[0030] The sensor electrode 20 can be used in a variety of sensing applications and can be configured in a variety of ways. For example, the sensor electrode 20 can be used in physiological parameter sensing applications where a certain type of biomolecule is used as a catalyst. For example, the sensor electrode 20 can be used in glucose and oxygen sensors having glucose oxidase (GOx) that catalyzes the reaction with the sensor electrode 20. The sensor electrode 20, together with the biomolecule or some other catalyst, can be placed in the human body in vascular or non-vascular environments. For example, the sensor electrode 20 and the biomolecule can be placed in a vein and subjected to blood flow, or they can be placed subcutaneously or in the peritoneum of the human body.

[0031] The monitor 100 may also be referred to as sensor electronics 100. The monitor 100 may include a power supply 110, a sensor interface 122, processing electronics 124, and data formatting electronics 128. The monitor 100 can be coupled to the sensor assembly 10 via a connector through a cable 102, which is electrically coupled to the connector block 28 of the connection portion 24. In an alternative embodiment, the cable may be omitted. In this embodiment, the monitor 100 may include a suitable connector for direct connection to the connection portion 104 of the sensor assembly 10. The sensor assembly 10 may be modified to position the connector portion 104 at a different location, such as above the sensor assembly, to facilitate placing the monitor 100 above the sensor assembly.

[0032] In one embodiment, the sensor interface 122, processing electronics 124, and data formatting electronics 128 are formed as a single semiconductor chip; however, alternative embodiments may combine various semiconductor chips into a single or multiple custom semiconductor chips. The sensor interface 122 is connected to a cable 102, which is connected to the sensor assembly 10.

[0033] Power source 110 may be a battery. The battery may include three silver oxide 357 battery cells connected in series. In alternative embodiments, different battery chemistry, such as lithium-based chemistry, alkaline batteries, nickel metal hydride, etc., may be used, and different numbers of batteries may be used. Monitor 100 provides power to the sensor assembly via power source 110 through cable 102 and cable connector 104. In one embodiment, the power is the voltage supplied to sensor assembly 10. In another embodiment, the power is the current supplied to sensor assembly 10. In one embodiment, the power is the voltage supplied to sensor assembly 10 at a specific voltage.

[0034] Figure 2 An implantable sensor according to one embodiment and electronic devices for driving the implantable sensor are shown. Figure 2A substrate 220 with two sides is shown, wherein a first side 222 contains an electrode configuration, and a second side 224 contains electronic circuitry (e.g., storage circuitry, processing circuitry, etc.). Figure 2 As can be seen, the first side 222 of the substrate includes two electrode pairs located opposite to the reference electrode 248. These two electrode pairs consist of a reverse electrode-background electrode pair 244, 240 and a reverse electrode-working electrode pair 246, 242. The second side 224 of the substrate includes electronic circuitry. As shown, the electronic circuitry can be encapsulated in a hermetically sealed housing 226, thus providing a protective enclosure for the electronic circuitry. This allows the sensor substrate 220 to be inserted into a vascular environment or other environments where the electronic circuitry may be exposed to fluids. By sealing the electronic circuitry in the hermetically sealed housing 226, the electronic circuitry can operate without the risk of short-circuiting by the surrounding fluids. Figure 2 Pad 228 is also shown for connecting input and output lines of electronic circuitry. The electronic circuitry itself can be manufactured in various ways. According to one embodiment, the electronic circuitry can be manufactured as an integrated circuit using techniques common in industry.

[0035] Figure 3 A general block diagram of electronic circuitry according to one embodiment, comprising first channels 310, 312, 314 for outputs of working electrodes for sensing sensors, is shown. At least one pair of sensor electrodes 310 may be connected to a data converter 312, the output of which may be connected to a counter 314. The counter 314 may be controlled by control logic 316. The output of the counter 314 may be connected to a line interface 318. The line interface 318 may be connected to input and output lines 320, and also to the control logic 316. The input and output lines 320 may also be connected to a power rectifier 322.

[0036] Sensor electrode 310 can be used in a variety of sensing applications and can be configured in a variety of ways. For example, sensor electrode 310 can be used in physiological parameter sensing applications where a certain type of biomolecule is used as a catalyst. For example, sensor electrode 310 can be used in glucose and oxygen sensors having a GOx enzyme that catalyzes the reaction with sensor electrode 310. Sensor electrode 310, together with biomolecules or some other catalyst, can be placed in vascular or non-vascular environments in the human body. For example, sensor electrode 310 and biomolecules can be placed in a vein and subjected to blood flow. To compensate for the effects of interferences that also cause signal interference in the first channels 310, 312, 314, a second identical channel (the output of the background electrode of the sensing sensor) is provided. Figure 3 (Not shown in the image). The background electrode does not contain biomolecules and is therefore only affected by interfering substances. The effect of interfering substances can be calculated by comparing the channels.

[0037] Figure 4A block diagram of a sensor electronics device and a sensor including multiple electrodes according to an embodiment of the present invention is shown. Figure 4 The system includes system 400. System 400 includes sensor 355 and sensor electronics 360. Sensor 355 includes a reverse electrode 365, a reference electrode 370, and a working electrode 375. Sensor electronics 360 includes a power supply 380, a regulator 385, a signal processor 390, a measurement processor 395, and a display / transmission module 397. Power supply 380 provides power (in the form of voltage, current, or voltage including current) to regulator 385. Regulator 385 transmits a regulated voltage to sensor 355. In one embodiment, regulator 385 transmits voltage to the reverse electrode 365 of sensor 355.

[0038] Sensor 355 generates a sensor signal indicating the concentration of the measured physiological characteristic. For example, the sensor signal may indicate a blood glucose reading. In embodiments utilizing a subcutaneous sensor, the sensor signal may represent the level of hydrogen peroxide in the subject's body. In embodiments utilizing a blood or cranial sensor, the amount of oxygen is measured by the sensor and represented by a sensor signal. In embodiments utilizing an implantable or long-term sensor, the sensor signal may represent the level of oxygen in the subject's body. The sensor signal is measured at the working electrode 375. In one embodiment, the sensor signal may be a current measured at the working electrode. In one embodiment, the sensor signal may be a voltage measured at the working electrode.

[0039] After measuring a sensor signal at sensor 355 (e.g., the working electrode), signal processor 390 receives the sensor signal (e.g., the measured current or voltage). Signal processor 390 processes the sensor signal and generates a processed sensor signal. Measurement processor 395 receives the processed sensor signal and calibrates the processed sensor signal using a reference value. In one embodiment, the reference value is stored in a reference memory and provided to measurement processor 395. Measurement processor 395 generates sensor measurement values. Sensor measurement values ​​may be stored in measurement memory (not shown) or stored by circuitry (e.g., storage circuitry). Sensor measurement values ​​may be sent to a display / transmission device for display on a monitor within a housing along with the sensor electronics, or transmitted to an external device.

[0040] Sensor electronics 360 can be a monitor including a display to show physiological characteristic readings. Sensor electronics 360 can also be installed in a desktop computer, pager, television with communication capabilities, laptop computer, server, network computer, personal digital assistant (PDA), portable telephone with computer functionality, infusion pump with display, glucose sensor with display, and / or a combination of infusion pump / glucose sensor. Sensor electronics 360 can be housed in a Blackberry mobile phone, network device, home network device, or appliance connected to a home network. System 400 also includes a second signal processor (not shown) connected to a background electrode (not shown) in sensor 355. The background electrode does not contain the chemical substances necessary to detect the analyte sensed at working electrode 375, and therefore only detects interference. In measurement processor 395, the signal caused by interference is removed from the signal caused by the analyte to produce a corrected, more accurate analyte reading.

[0041] Figure 4 It also includes system 450. System 450 includes sensor electronics 360 and sensor 355. The sensor includes a counter electrode 365, a reference electrode 370, and a working electrode 375. Sensor electronics 360 includes a microcontroller 410 and a digital-to-analog converter (DAC) 420. Sensor electronics 360 may also include a current-to-frequency converter (I / F converter) 430.

[0042] The microcontroller 410 includes software program code or programmable logic that, when executed, causes the microcontroller 410 to transmit signals to the DAC 420, wherein the signals represent voltage levels or values ​​to be applied to the sensor 355. The DAC 420 receives the signals and generates voltage values ​​at the levels indicated by the microcontroller 410. In one embodiment, the microcontroller 410 may frequently or infrequently change the representation of the voltage level in the signal. Illustratively, a signal from the microcontroller 410 may instruct the DAC 420 to apply a first voltage value for one second and a second voltage value for two seconds.

[0043] Sensor 355 may receive a voltage level or value. In one embodiment, counter electrode 365 may receive the output of an operational amplifier having a reference voltage and a voltage value from DAC 420 as inputs. The application of the voltage level causes sensor 355 to generate a sensor signal indicating the concentration of the measured physiological characteristic. In one embodiment, microcontroller 410 may measure the sensor signal (e.g., a current value) from the working electrode. Illustratively, sensor signal measurement circuitry 431 may measure the sensor signal. In one embodiment, sensor signal measurement circuitry 431 may include a resistor, and current may flow through the resistor to measure the value of the sensor signal. In one embodiment, the sensor signal may be a current level signal, and sensor signal measurement circuitry 431 may be a current-to-frequency (I / F) converter 430. Current-to-frequency converter 430 measures the sensor signal as a current reading, converts the sensor signal into a frequency-based sensor signal, and transmits the frequency-based sensor signal to microcontroller 410. In some embodiments, microcontroller 410 may be able to receive frequency-based sensor signals more easily than non-frequency-based sensor signals. Microcontroller 410 receives sensor signals, whether frequency-based or non-frequency-based, and determines values ​​of a subject's physiological characteristics, such as blood glucose levels. Microcontroller 410 may include program code that, when executed or run, is capable of receiving sensor signals and converting them into physiological characteristic values. In one embodiment, microcontroller 410 may convert sensor signals into blood glucose levels. In one implementation, microcontroller 410 may utilize measurements stored in internal memory or by circuitry (e.g., storage circuitry) to determine a subject's blood glucose level. In another implementation, microcontroller 410 may utilize measurements stored in external memory or by circuitry to aid in determining a subject's blood glucose level. System 450 also includes a second sensor signal measurement circuitry (not shown) connected to a background electrode (not shown) in sensor 355. The background electrode does not contain the chemicals necessary to detect the analyte (e.g., blood glucose) sensed at working electrode 375, and therefore only detects interference. In microcontroller 410, signals caused by interference are removed from the signal from the working electrode to produce a corrected, more accurate analyte reading.

[0044] After determining the physiological characteristic value, the microcontroller 410 can store the measured value of the physiological characteristic value over several time periods. For example, the blood glucose value can be sent from the sensor to the microcontroller 410 every second or every five seconds, and the microcontroller can save the sensor measurement value for five or ten minutes after the BG is read. The microcontroller 410 can transmit the measured value of the physiological characteristic value to a display on the sensor electronics 360. For example, the sensor electronics 360 can be a monitor that includes a display providing the subject's blood glucose reading. In one embodiment, the microcontroller 410 can transmit the measured value of the physiological characteristic value to an output interface of the microcontroller 410. The output interface of the microcontroller 410 can transmit the measured value of the physiological characteristic value, such as the glucose value, to an external device, such as an infusion pump, a combination infusion pump / glucose meter, a computer, a personal digital assistant, a pager, a network device, a server, a cellular phone, or any computing device.

[0045] Figure 5 This is a block diagram illustrating a sensor electrode and an electronic device for applying a voltage to the sensor electrode according to one embodiment. Figure 5 The sensor shown has four electrodes 510, including a counter electrode 535, a reference electrode 532, a working electrode 534a, and a background electrode 534b. An operational amplifier 530 is configured such that its output is coupled to the counter electrode and its inverting input is coupled to the reference electrode 532. The non-inverting input of the operational amplifier is coupled to a voltage source that maintains a set voltage Vset relative to the reference working electrode. In operation, the operational amplifier stabilizes the voltage between the reference electrode and the working electrode regardless of the amount of current flowing in the working electrode. The working electrode 534a has a coating of GOx or other suitable biomolecules. In the presence of excess oxygen, GOx catalyzes the oxidation of any glucose present, ultimately generating a current Isig in the working electrode, hereinafter referred to as the first signal. A current is also generated at the working electrode due to interfering substances such as acetaminophen. The background electrode 534b does not have a GOx layer (e.g., as described below regarding...). Figure 8 and Figure 9 (As discussed). Therefore, the background electrode only conducts the current Isig generated by the interfering substance, hereinafter referred to as the second signal. The system can then detect the user's drug intake from the second signal and generate a sensor glucose value unaffected by the interfering substance by comparing the first signal with the second signal. Figure 5In the illustrated embodiment, operational amplifier 530 is connected to sensor electrode 510 via circuit / electrode interface 538. Operational amplifier 530 utilizes feedback from the sensor electrode to attempt to maintain a predetermined voltage (the voltage the DAC may expect to be applied) between reference electrode 532 and working electrode 534 by adjusting the voltage at counter electrode 536. Current can then flow from counter electrode 536 to working electrode 534. This current can be measured to determine the electrochemical reaction between sensor electrode 510 and the biomolecules placed near sensor electrode 510 and acting as a catalyst.

[0046] It has been found that a potential difference of approximately 0.5 volts, preferably 535 mV, between the working electrode and the reference electrode for GOx produces good results. Other voltages may be more suitable if different biomolecules are used instead of GOx. For optimal results, a higher potential difference, such as 700 mV, can be used between the background electrode and the reference electrode.

[0047] As discussed above, during the initial implantation or insertion of sensor 510, the sensor 510 may provide inaccurate readings due to the subject's adjustment to the sensor and electrochemical byproducts generated by the catalyst used in the sensor. Many sensors require a settling period in order for sensor 510 to provide accurate readings of the subject's physiological parameters. During the settling period, sensor 510 does not provide accurate blood glucose measurements. Sensor users and manufacturers may wish to improve the sensor's settling timeframe so that the sensor can be rapidly utilized after insertion into the subject's body or subcutaneous layer.

[0048] In previous sensor electrode systems, the settling period or time frame was one to three hours. To shorten the settling period or time range and improve the timeliness of sensor accuracy, the sensor (or its electrodes) can be subjected to multiple pulses, rather than applying one pulse followed by another voltage in a second time period. In one embodiment, the first voltage may be 1.07 volts. In another embodiment, the first voltage may be 0.535 volts. In yet another embodiment, the first voltage may be approximately 0.7 volts.

[0049] Figure 6 A flowchart illustrating the steps involved in continuous glucose monitoring according to one or more embodiments is shown. For example, process 600 may represent a process as follows: Figures 1-5 The steps taken by one or more of the devices shown.

[0050] At step 602, process 600 (e.g., using...) Figures 1-5The circuit described herein activates a first electrode on the user, wherein the first electrode has a coating of glucose oxidase (GOx). For example, the system can activate a first electrode on the user (e.g., a patient), wherein the first electrode detects a current Isig (the first electrode is a GOx sensor) caused by the oxidation of any glucose catalyzed by glucose oxidase (GOx).

[0051] For example, in some implementations, the sensor may initiate a startup procedure automatically based on a remotely received command (e.g., based on certain conditions detected by another sensor) or according to a user-input command. In response to sensor startup, a first electrode and a second electrode (e.g., corresponding to a working electrode and a background electrode) are activated. Additionally, the first and second electrodes may undergo a current initialization sequence and / or a voltage initialization sequence. These initialization sequences may vary depending on whether the electrodes include a GOx sensor.

[0052] At step 604, process 600 (e.g., using...) Figures 1-5 The circuit described herein activates a second electrode on the user. This second electrode is a background electrode and does not have a GOx layer.

[0053] At step 606, process 600 (e.g., using...) Figures 1-5 The circuit described herein sets the first voltage potential (Vset) of the first electrode. For example, the system can use a control circuit to set the first voltage potential (Vset) of the first electrode. For example, the first Vset can be in the range of 400mV-500mV.

[0054] At step 608, process 600 (e.g., using...) Figures 1-5 The circuit described herein sets the second Vset of the second electrode. For example, the system can use a control circuit to set the second voltage potential (Vset) of the second electrode. In some examples, the first Vset may be lower than the second Vset. For example, the second Vset may be in the range of 500mV-600mV.

[0055] At step 610, process 600 (e.g., using...) Figures 1-5 The circuit described herein receives a first signal from the first electrode. For example, the system may use control circuitry to receive the first signal from the first electrode. The first electrode may be a working electrode, and the system may receive a 5-minute sensor current reading in nA, sometimes referred to as the “raw Isig” or other Isig values ​​(e.g., as shown above).

[0056] At step 612, process 600 (e.g., using...) Figures 1-5The circuit described herein receives a second signal from the second electrode. For example, the system may use control circuitry to receive the second signal from the second electrode. The second electrode may be a background electrode, and the system may receive a 5-minute sensor current reading in nA, sometimes referred to as the "raw Isig" or other Isig values ​​(e.g., as shown above). It can be conveniently compared with... Figure 6 The steps 606, 608, 610, and 612 are executed in different sequences as shown. For example, it may be desirable to set the second or background electrode potential at step 608 and to set the first electrode potential at step 606 and obtain the first signal at step 612, before step 606 and step 610.

[0057] At step 614, process 600 (e.g., using...) Figures 1-5 The circuit described herein compares a first signal with a second signal to detect the user's ingestion of the drug. For example, the system may use control circuitry to compare the first and second signals to detect the user's ingestion of the drug. For example, the drug (e.g., acetaminophen) may generate an interfering current that increases the current at both the working / first electrode and the background / second electrode.

[0058] In some implementations, comparing the first signal with the second signal to detect drug intake by the user further includes one or more steps. For example, the system may determine the noise level of the second signal. The system may compare the noise level with a noise threshold. The system may calculate a sensor glucose value based on the second signal in response to the noise level not exceeding the noise threshold. For example, the system may calculate the sensor glucose value based on the first electrode using the Isig from the first electrode.

[0059] In another example, the system can determine the noise level of the second signal. The system can compare the noise level to a noise threshold. The system can calculate the sensor glucose value based on a modified first signal, wherein the modified first signal is based on a weighted difference between the first and second signals. For example, the system can apply a scaling factor to the Isig of the second electrode and apply the scaling factor to the Isig. In some embodiments, the scaling factor can be a linear or non-linear multidimensional scaling factor. The system can then determine the difference between the Isig of the first electrode and the scaled Isig of the second electrode. The system can then calculate the sensor glucose value in mg / dL based on the difference between the Isig of the first electrode and the scaled Isig of the second electrode. The sensor glucose value can then be used to display the value to the user.

[0060] The normalized values ​​are scaled using a scaling function specific to the environmental or physiological factors under consideration, and the scaled values ​​are combined to generate an aggregated value. In one embodiment, the combination can be obtained by multiplying the different scaled values ​​together. In other embodiments, aggregation can be achieved by determining the mean or selecting the maximum value available.

[0061] It should be noted that the thresholds or ranges of the above parameters can depend on various factors, including specific sensor and / or electrode designs. However, in one embodiment, typical ranges for some of the above parameters may be, for example, as follows: threshold for the real part of impedance at 1 kHz = [0.3e+4 2e+4]; threshold for the imaginary part of impedance at 1 kHz = [-2e+3, 0]; threshold for the real part of impedance at 0.105 Hz = [2e+4 7e+4]; threshold for the imaginary part of impedance at 0.105 Hz = [-2e+5 -0.25e+5]; and threshold for the Nyquist slope = [2 5]. Noise can be calculated, for example, using a second-order central difference method, where noise is considered to exceed the noise threshold if it exceeds a certain percentage (e.g., 30%) of the median of each variable buffer.

[0062] It should also be noted that in another implementation, when determining whether to blank data or terminate the sensor, in addition to the thresholds mentioned above, the logic can also consider sudden increases in impedance, for example, by comparing the impedance derivative with historical derivatives. Furthermore, depending on the duration of the high-noise-low sensor signal combination, the algorithm can incorporate noise-based blanking or termination. In this regard, previous methods involved terminating the sensor after three (3) consecutive 2-hour windows of high noise and low sensor signals. However, to prevent unreliable data from being displayed to the user, the implementation employs noise-based blanking, where the algorithm stops calculating the SG value after two consecutive 2-hour windows involving high noise and low signals (i.e., at the start of the third consecutive window). In other respects, the algorithm can allow for further calculation and display of the calculated SG value after one hour instead of two hours of blanking, provided the sensor signal appears to have recovered. This is an improvement over methods that blank otherwise reliable data over longer periods.

[0063] At step 616, process 600 (e.g., using...) Figures 1-5The circuit described herein generates a sensor glucose value based on a comparison. In its simplest form, the comparison involves assessing the amount of signal from the working electrode caused by interference, deriving that amount, and then calculating the glucose value. The amount of signal caused by interference can be readily assessed since it is a signal from a background electrode, which can be scaled to account for any differences in set voltage or electrode area. The comparison produces a corrected glucose value, which can be displayed to the user. For example, the system can display the corrected sensor glucose value on a user interface and / or adjust the amount of glucose delivered to the user. Due to further complexity, in some embodiments, a reliability assessment of the sensor glucose value and an estimate of the direction of error in the sensor data can be performed to provide an indicator of the system's reliability to the user and the automated insulin delivery system (including those in closed-loop systems) when the SG is displayed to the user. Depending on the reliability of the sensor data, such an automated system can then be able to assign corresponding weights to the SG and make a determination on how aggressively to deliver treatment to the user. Additionally, the direction of error can also be used to inform the user and / or the insulin delivery system that the SG is a "false low" or "false high" value. The above objectives can be achieved, for example, by detecting a sudden drop in sensor data during the first day (EIS drop detection), detecting sensor hysteresis, and low-frequency (e.g., 10 Hz) impedance changes.

[0064] expected Figure 6 The steps or descriptions herein may be used in conjunction with any other embodiments of this disclosure. Furthermore, regarding... Figure 6 The steps and descriptions described may be performed in an alternative order or in parallel to further achieve the objectives of this disclosure. For example, each of these steps may be performed in any order or in parallel or substantially simultaneously to reduce lag or increase the speed of the system or method. Furthermore, it should be noted that regarding… Figures 2-4 Any device or equipment discussed may be used to perform Figure 6 One or more steps in the process.

[0065] Figure 7 A flowchart illustrating the steps involved in continuous glucose monitoring according to one or more embodiments is shown. For example, process 700 may represent a process as follows: Figures 1-5 The steps taken by one or more of the devices shown.

[0066] At step 702, process 700 (e.g., using...) Figures 1-5 The circuit described above receives a first signal and a second signal (e.g., corresponding Isig) from a first electrode and a second electrode (e.g., a working electrode and a background electrode). For example, the system can use the circuit described above. Figure 6 The steps described above are used to generate Isig.

[0067] At step 704, process 700 (e.g., using...) Figures 1-5 The circuit described herein determines whether the value of Isig from the working electrode needs to be adjusted. This is done by determining the background electrode (e.g., Figure 6 The Isig of the second electrode exceeds the noise threshold of the background electrode, thus indicating the presence of a significant signal from an interfering substance such as acetaminophen. Alternatively, it can be optionally determined whether the working or background electrode has a 0.1 Hz IMG EIS impedance (“EIS value”) exceeding the corresponding threshold. For example, the effective resistance of a circuit or component to alternating current, resulting from the combined effect of ohmic resistance and the reactance of EIS, can be compared to the corresponding threshold.

[0068] EIS can be used in sensor systems where the sensor contains a single working electrode, as well as sensor systems where the sensor contains multiple (redundant) working electrodes. In one embodiment, EIS provides valuable information about the sensor's lifetime (or aging). Specifically, it shows the magnitude of impedance and phase angle changes at different frequencies. Additionally, EIS can detect sensor failure by detecting when the sensor's impedance drops below a low impedance threshold level, indicating that the sensor may be excessively worn and unable to operate properly. The system can then terminate the sensor before its specified operating life. Sensor impedance can also be used to detect other sensor failure (modes). For example, when a sensor enters a low-current state (i.e., sensor failure) for various reasons, the sensor impedance may also increase to exceed a certain high impedance threshold. If the impedance becomes abnormally high during sensor operation, for example due to protein or peptide contamination, macrophage attachment, or any other factor, the system can also terminate the sensor before its specified operating life.

[0069] If process 700 determines that no adjustment is needed due to non-compliance with criteria, process 700 proceeds to step 706. If process 700 determines that adjustment is needed due to compliance with one or two criteria, process 700 proceeds to step 710.

[0070] At step 706, process 700 (e.g., using...) Figures 1-5 The circuit described herein calculates the sensor glucose value from the working electrode based on the Isig from the working electrode, and displays the value to the user at step 708.

[0071] At step 710, process 700 (e.g., using...) Figures 1-5 The circuit described herein) determines the signal from the background electrode (e.g., the upper electrode). Figure 6The system checks whether the Isig of the second electrode is greater than the weighted background electrode noise threshold. For example, to determine the weighted background electrode noise threshold, the system may apply a safety factor to the background electrode noise threshold. If the Isig of the background electrode is larger, process 700 proceeds to step 714. If the Isig of the background electrode is not larger, process 700 proceeds to step 712. The failure to exceed the threshold at step 710 corresponds to positive detection of interference, but the background electrode Isig can be used to compensate for interference under the Isig at the working electrode to produce a more reliable sensor glucose SG value with insufficient confidence. Steps 710 and 712 are optional, and process 700 may continue from the "Yes" branch of step 704 to step 714.

[0072] At step 712, process 700 (e.g., using...) Figures 1-5 The circuit described herein blanks the sensor glucose value to the user for a given amount of time and returns to step 702, wherein process 700 is repeated with the next value of the working electrode Isig and the background electrode Isig. It should also be noted that, in determining whether to blank the data or terminate the sensor, in addition to the thresholds mentioned above, the logic can also consider sudden increases in impedance, for example, by comparing the impedance derivative with historical derivatives. Furthermore, depending on the duration of the high noise-low sensor signal combination, the algorithm may incorporate noise-based blanking or termination. In this regard, the previous method involved terminating the sensor after three (3) consecutive 2-hour windows of high noise and low sensor signals. However, to prevent unreliable data from being displayed to the user, the implementation employs noise-based blanking, wherein the algorithm stops calculating the SG value after two consecutive 2-hour windows involving high noise and low signals (i.e., at the start of the third consecutive window). In other respects, the algorithm may allow further calculation and display of the calculated SG value after one hour instead of two hours of blanking, provided that the sensor signal appears to have recovered. This is an improvement over the method of blanking otherwise reliable data over a longer period of time.

[0073] At step 714, process 700 (e.g., using...) Figures 1-5The circuit described herein uses a predetermined mathematical model (e.g., as shown in the equation at step 714) to determine a new Isig value for the working electrode. For example, the new value is the difference between the Isig value of the working electrode and the weighted Isig and optionally weighted EIS values ​​of the background electrode. It has been found that the imaginary part of the 0.1 Hz impedance at the working electrode is closely related to acetaminophen interference and can be used to establish confidence in the value obtained from the difference between the weighted Isig values. In the simplest case, the new value is the difference between the Isig value of the working electrode and the weighted Isig value of the background electrode. Process 700 can then proceed to step 716 and calculate a new sensor glucose value based on the new Isig value of the working electrode for later display to the user at step 708. After the display step, process 700 restarts at step 702 using the next values ​​of the working electrode Isig and the background electrode Isig.

[0074] After consideration, Figure 7 The steps or descriptions herein may be used in conjunction with any other embodiments of this disclosure. Furthermore, in combination with... Figure 7 The described steps and descriptions may be performed in an alternative order or in parallel to further illustrate the purposes of this disclosure. For example, each of these steps may be performed in any order or in parallel or substantially simultaneously to reduce lag or increase the speed of the system or method. Furthermore, it should be noted that regarding... Figures 2-4 Any device or equipment discussed may be used to perform Figure 7 One or more steps in the process.

[0075] Figure 8 A single sensor with a background electrode metal layer made of platinum is shown. (Example) Figure 8 As shown, the sensor may include a conductor trace (e.g., gold) surrounded by a thermally insulating material (e.g., polyimide). Figure 8 The sensor shown includes a counter electrode, a background electrode, a reference electrode, and a working electrode, and may include other electrodes. Each electrode may include platinum, gold, and / or other materials. For example, the reference electrode may include silver or silver chloride, and the working electrode may include GOx or some other substance capable of catalyzing the reductive oxidation of glucose, thereby generating a current in the electrode in response to the presence of glucose. The background electrode (e.g., in this embodiment, comprising platinum) may differ from the working electrode in that the background electrode does not include GOx or other glucose reductive oxidation catalysts. Optionally, each electrode may be coated with a glucose-limited thin film. Figure 8 The single sensor shown may be included in the CGM device (e.g., as per [reference]). Figure 10 (As discussed). Although the size and location of the electrodes on the substrate are optional, in Figure 8 In this configuration, the background electrode is smaller than the working electrode and is positioned on the side of the reference electrode opposite to the working electrode.

[0076] Figure 9 It shows having with Figure 8 The single sensor shown has the same structure, except that the background electrode metal layer is made of gold. Figure 9 As shown, the sensor may include a conductive trace (e.g., gold) surrounded by an insulating material (e.g., polyimide). The sensor includes a counter electrode, a background electrode, a reference electrode, a working electrode, and optionally other electrodes. Each electrode may include platinum, gold, and / or other materials. For example, the reference electrode may include silver or silver chloride, and the working electrode may include GOx or some other substance capable of catalyzing the reductive oxidation of glucose, thereby generating a current in the electrode in response to the presence of glucose. The background electrode (e.g., in this embodiment, comprising gold) may differ from the working electrode in that the background electrode may not include GOx or a catalyst. Optionally, each electrode may be coated with a glucose-limiting thin film. Figure 9 The single sensor shown may be included in the CGM device (e.g., as per [reference]). Figure 10 (As discussed).

[0077] Figure 10 The single-sensor flexible element 1002 in CGM device 1000 and the dual-sensor flexible element 1052 in CGM device 1050 are shown. The single-sensor flexible element 1002 (e.g., as...) Figure 8 (As shown) may include a reverse electrode 1004, a background electrode 1006, a reference electrode 1008, a working electrode 1010, and / or other electrodes. The dual-sensor flexible element 1052 includes two sensor flexible elements (e.g., such as...) located in the CGM device 1050. Figure 9 (As shown). For example, one sensor of the dual-sensor flexible member 1052 may include a counter electrode 1056, a reference electrode 1058, a working electrode 1060, and / or other electrodes, while the other sensor of the dual-sensor flexible member 1052 may include a background electrode 1054 and / or other electrodes. Figure 10 As shown, the two sensor flexible components in the dual-sensor flexible component can be placed back-to-back in the CGM device 1050. During manufacturing, GOx can be deposited onto... Figure 10The working electrodes 1010 and 1060 are shown. Instead of GOx, different enzymes of interest, such as hexokinase or glucose-1-dehydrogenase (“GDH”), can be deposited onto one or more of these working electrodes. A glucose restriction film (GLM) can be deposited on top of the GOx (or other enzyme) layer. During fabrication, GOx (or other enzymes) can be deposited onto several electrodes, including working and background electrodes, and then removed from electrodes where it is not needed, such as the background electrode, resulting in a structure where the GOx or other enzyme remains only on the working electrode and not on the other electrodes. In some embodiments, the deposited layer may not only be deposited on top of the electrodes. For example, the GLM layer may extend from one electrode to another.

[0078] The embodiments described above are presented for illustrative purposes and not for limitation, and this disclosure is limited only by the appended claims. Furthermore, it should be noted that the features and limitations described in any embodiment can be applied to any other embodiment herein, and flowcharts or examples associated with one embodiment can be combined with any other embodiment in a suitable manner, in a different order, or in parallel. Moreover, the systems and methods described herein can be performed in real time. It should also be noted that the above systems and / or methods can be applied to other systems and / or methods or used in conjunction with other systems and / or methods.

[0079] Referring to the following implementation schemes will provide a better understanding of this technology:

[0080] 1. A method for continuous glucose monitoring, the method comprising: activating a first electrode on a user; activating a second electrode on the user; setting the first electrode to a first voltage potential (Vset); setting the second electrode to a second voltage potential (Vset); receiving a first signal from the first electrode; receiving a second signal from the second electrode; comparing the first signal with the second signal to detect drug intake by the user; and generating a sensor glucose value based on the comparison.

[0081] 2. The method according to embodiment 1, wherein the drug generates an interfering current that increases the glucose reading at the first electrode.

[0082] 3. The method according to any one of embodiments 1-2 further includes: storing the first voltage potential (Vset) of the first electrode, wherein the first electrode detects glucose oxidase (GOx); storing the second voltage potential (Vset) of the second electrode, wherein...

[0083] The second electrode does not detect GOx; and the first Vset is lower than the second Vset.

[0084] 4. The method according to any one of embodiments 1-3 further includes: inputting the first signal and the second signal as parameters into a predetermined mathematical model for adjusting the glucose value of the sensor.

[0085] 5. The method according to any one of embodiments 1-4 further includes: selecting the material of the first electrode, the material of the second electrode, or the applied voltage based on the analyte.

[0086] 6. The method according to any one of embodiments 1-5, wherein the first electrode and the second electrode are located on a single sensor or a separate sensor in the device.

[0087] 7. The method according to any one of embodiments 1-6, wherein comparing the first signal with the second signal to detect the user's intake of the drug comprises: determining the noise level of the second signal; comparing the noise level with a noise threshold; and calculating a sensor glucose value based on the second signal in response to the noise level not exceeding the noise threshold.

[0088] 8. The method according to any one of embodiments 1-7, wherein comparing the first signal with the second signal to detect the user's intake of the drug comprises: determining the noise level of the second signal; comparing the noise level with a noise threshold; and calculating the sensor glucose value based on the modified first signal, wherein the modified first signal is based on a weighted difference between the first signal and the second signal.

[0089] 9. A tangible, non-transitory, machine-readable medium storing instructions that, when executed by a data processing apparatus, cause the data processing apparatus to perform operations including those according to any one of embodiments 1-8.

[0090] 10. A system comprising: one or more processors; and a memory storing instructions that, when executed by the processors, cause the processors to perform operations including those according to any one of embodiments 1-8.

[0091] 11. A system comprising a method for performing any one of embodiments 1-8.

[0092] The following paragraphs define further embodiments of the invention according to another aspect of the invention shown herein, and also form part of this disclosure.

[0093] Paragraph 1. An implantable electrode array for a continuous glucose sensor, comprising:

[0094] Substrate;

[0095] A reference electrode, which is supported on the substrate;

[0096] The working electrode is supported by the substrate and carries a catalyst layer that can catalyze a reaction with glucose, which induces a current in the working electrode that is proportional to the glucose concentration when there is a voltage potential between the working electrode and the reference electrode.

[0097] Background electrode, which is supported by the substrate and has no material layer;

[0098] Both the working electrode and the background electrode are located near the reference electrode, so that when implanted in vivo and maintained at a corresponding voltage potential difference (Vref) with the reference electrode, they form a corresponding electrochemical cell. The catalyst is preferably an oxidoreductase, such as glucose oxidase.

[0099] Paragraph 2. The electrode array according to paragraph 1, wherein the working electrode is platinum and the background electrode is a non-platinum material.

[0100] Paragraph 3. The electrode array according to paragraph 1 or 2, wherein the background electrode is gold.

[0101] Paragraph 4. The electrode array according to any one of paragraphs 1 to 3, wherein the working electrode has a larger area than the background electrode.

[0102] Paragraph 5. The electrode array according to any one of paragraphs 1 to 4 further comprises: a counter electrode system supported by the substrate in the vicinity of the reference electrode, and for applying a servo control voltage to the electrochemical cells to stabilize the corresponding potentials on the working electrode and the background electrode relative to the reference electrode.

[0103] Paragraph 6. The electrode array according to any one of paragraphs 1 to 5 further includes: a glucose limiting film covering the electrode.

[0104] Paragraph 7. An electrode array according to any one of paragraphs 1 to 6, wherein the substrate is polyimide.

[0105] Paragraph 8. An electrode array according to any one of paragraphs 1 to 7, wherein the substrate has gold traces connected to the electrodes.

[0106] Paragraph 9. An electrode array according to any one of paragraphs 1 to 8, wherein the substrate includes two parallel flexible members facing different, preferably opposite, directions, wherein a counter electrode, the reference electrode, and the working electrode located on a first flexible member of the flexible members face one of these directions, and a background electrode located on a second flexible member of the flexible members faces the other direction.

[0107] Paragraph 10. An electrode array according to any one of paragraphs 1 to 8, wherein the electrodes are arranged in a line on the substrate, wherein the reference electrode is physically located between the background electrode and the working electrode.

[0108] Paragraph 11. A method of manufacturing an electrode array according to any one of claims 1 to 10, comprising: forming an electrode on a substrate; depositing the catalyst on the electrode; and removing the catalyst from all electrodes except the working electrode.

[0109] Paragraph 12. A continuous glucose monitor, comprising: an electrode array according to any one of paragraphs 1 to 10; and

[0110] A circuit connected to the electrode array to maintain the working electrode and the background electrode at corresponding voltage potentials (Vref) relative to the reference electrode;

[0111] A circuit connected to the working electrode to measure the current (We Isig) flowing in the working electrode;

[0112] A circuit connected to the background electrode to measure the current (Be Isig) flowing in the background electrode;

[0113] A processor, in response to a measured current, distinguishes between a portion of the current flowing in the working electrode attributable to glucose and a portion of the current flowing in the working electrode attributable to interference effects by comparing the current flowing in the working electrode (WeIsig) with the current flowing in the background electrode (BeIsig), and is configured to calculate a glucose concentration from the portion of the current flowing in the working electrode attributable to glucose detection; and

[0114] Optionally, a display is connected to receive and display the calculated glucose concentration.

[0115] Paragraph 13. The continuous glucose monitor according to paragraph 12, wherein the processor is configured to analyze the current (Be Isig) flowing in the background electrode as noise, and if the level of the noise is below a first threshold, calculate the glucose concentration from the entire current flowing in the working electrode.

[0116] Paragraph 14. The continuous glucose monitor according to paragraph 12 or 13, wherein the processor is configured to analyze the current (Be Isig) flowing in the background electrode as noise, and if the noise is higher than a second threshold, calculate the glucose concentration from the weighted difference between the level of the current (We Isig) flowing in the working electrode and the level of the current (Be Isig) flowing in the background electrode.

[0117] Paragraph 15. The continuous glucose monitor according to any one of paragraphs 12 to 14 further includes: circuitry configured to perform one or both of the following:

[0118] a) Perform EIS on the working electrode, and if the imaginary part of the impedance at 0.1 Hz exceeds the threshold impedance, modify the measured value of the current (We Isig) flowing in the working electrode by a weighting factor based on the impedance before calculating the glucose concentration using the current (We Isig).

[0119] b) If the level of the current (Be Isig) flowing in the background electrode is between the first threshold and the second threshold, then blanking of the display is performed.

Claims

1. A system for continuous glucose monitoring, comprising: One or more processors; as well as One or more processor-readable media storing instructions that, when executed by the one or more processors, cause the system to perform the following operations: Activate the working electrode of a subcutaneously placed glucose sensor, the working electrode being configured to generate a first sensor current; Activate the background electrode of the subcutaneously placed glucose sensor, the background electrode being configured to generate a second sensor current; This causes multiple pulses to be applied to the working electrode and the background electrode to stabilize the glucose sensor; The working electrode is set to a first voltage potential, wherein the working electrode includes a glucose oxidase sensor, and the first sensor current generated by the working electrode is affected by the glucose oxidase sensor being exposed to a drug ingested by the user; The background electrode is set to a second voltage potential greater than the first voltage potential, the background electrode having a metallization layer, wherein the second sensor current generated by the background electrode is only affected by the background electrode being exposed to the drug ingested by the user; Receive the first sensor current from the working electrode; Receive the second sensor current from the background electrode; The glucose value of the sensor is generated based on the current of the first sensor. Determine the electrochemical impedance spectroscopy (EIS) impedance value of the background electrode; The first sensor current and the second sensor current are input into the mathematical model, wherein if the second sensor current exceeds the noise threshold for the background electrode, the mathematical model calculates the new value of the first sensor current as the difference between the first sensor current and the sum of the weighted second sensor current and the weighted electrochemical impedance spectroscopy impedance value of the background electrode. as well as The glucose value of the sensor is adjusted based on the new value of the first sensor current calculated by the mathematical model.

2. The system of claim 1, wherein the glucose sensor includes a first flexible sensor configured for subcutaneous placement within a user's body and a second flexible sensor disposed separately from the first flexible sensor and configured for subcutaneous placement within the user's body.

3. The system according to claim 2, wherein the working electrode is disposed on the first flexible sensor of the glucose sensor, and the background electrode is disposed on the second flexible sensor of the glucose sensor.

4. The system according to claim 3, wherein, An anti-electrode and a reference electrode are disposed on the first flexible sensor.

5. The system according to claim 4, wherein, A glucose limiting film is disposed on at least one of the counter electrode, the reference electrode, the background electrode, and the working electrode.

6. A method for continuous glucose monitoring, comprising: The working electrode of a subcutaneously placed glucose sensor is activated using a control circuit, the working electrode being configured to generate a first sensor current. The control circuit is used to activate the background electrode of the subcutaneously placed glucose sensor, which is configured to generate a second sensor current. The control circuitry is used to cause multiple pulses to be applied to the working electrode and the background electrode to stabilize the glucose sensor. The control circuit is used to set the working electrode to a first voltage potential, wherein the working electrode includes a glucose oxidase sensor, and the first sensor current generated by the working electrode is affected by the glucose oxidase sensor being exposed to a drug ingested by the user. The control circuit is used to set the background electrode to a second voltage potential greater than the first voltage potential. The background electrode has a metallization layer, wherein the second sensor current generated by the background electrode is only affected by the background electrode being exposed to the drug ingested by the user. The control circuit is used to receive the first sensor current from the working electrode; The control circuit is used to receive the second sensor current from the background electrode; The control circuit is used to generate the sensor glucose value based on the current of the first sensor. Determine the electrochemical impedance spectroscopy (EIS) impedance value of the background electrode; The first sensor current and the second sensor current are input into the mathematical model, wherein if the second sensor current exceeds the noise threshold for the background electrode, the mathematical model calculates the new value of the first sensor current as the difference between the first sensor current and the sum of the weighted second sensor current and the weighted electrochemical impedance spectroscopy impedance value of the background electrode. as well as The glucose value of the sensor is adjusted based on the new value of the first sensor current calculated by the mathematical model.

7. The method of claim 6, wherein the drug ingested by the user generates an interfering current that increases the glucose reading at the working electrode.

8. The method of claim 6, further comprising selecting the material of the working electrode, the material of the background electrode, or the applied voltage based on the analyte.

9. The method according to claim 6, wherein: The glucose sensor includes a first flexible sensor and a second flexible sensor disposed separately from the first flexible sensor. The working electrode, the counter electrode, and the reference electrode are disposed on the first flexible sensor, and The background electrode is disposed on the second flexible sensor.

10. A non-transitory computer-readable medium for continuous glucose monitoring, comprising: Instructions that, when executed by one or more processors, cause operation comprising the method according to any one of claims 6 to 9.

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