System and method for intelligent bias voltage for insulin interference compensation

Abstract

An analyte sensor configured to compensate for insulin interference includes a working electrode including an analyte sensing molecule disposed on the working electrode, the analyte sensing molecule configured to generate a signal when exposed to an analyte; a processor; and a memory. The memory includes instructions that, when executed by the processor, cause the sensor to: obtain an indication from the pump that a bolus is delivered; in response to delivery of the bolus, determining at least one of a first electrochemical impedance spectroscopy (EIS) parameter value or a first conductivity value in response to exposure of the working electrode to the analyte; and determining the presence of one or more interferents based on at least one of the first EIS parameter value or the first conductivity value.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 63 / 565,754, filed on March 15, 2024. Technical Field

[0003] The present disclosure relates generally to continuous glucose monitoring (CGM), and more particularly to analytical sensors and methods for improving interferent rejection and longevity. Background Art

[0004] Analyte sensors, such as biosensors, include devices that use biological elements to convert a chemical analyte in a matrix into a detectable signal. There are many types of biosensors for a wide variety of analytes, including amperometric glucose sensors used for glucose level control in diabetes.

[0005] A typical glucose sensor works based on the following chemical reaction:

[0006] , Formula 1; and

[0007] , Formula 2.

[0008] Glucose oxidase catalyzes the reaction between glucose and oxygen to produce gluconic acid and hydrogen peroxide (H2O2) (Equation 1). The hydrogen peroxide reacts electrochemically, as shown in Equation 2, and the current is measured by a potentiostat. These reactions, which occur in a variety of redox enzymes known in the art, are used in many sensor designs.

[0009] A common problem with analyte sensors is that they can electrochemically react not only with the analyte being measured (or byproducts of enzymatic reactions with the analyte), but also with other electroactive chemical species not intended to be measured, causing the signal intensity to increase due to these "interfering species" or "interferants." Typically, such interfering species are compounds with oxidation or reduction potentials that overlap with the analyte being measured (or byproducts of enzymatic reactions with the analyte). For example, in conventional amperometric glucose oxidase-based glucose sensors, in which the sensor measures hydrogen peroxide, interfering species such as acetaminophen, ascorbate, and urate are known to obscure the true analyte signal, resulting in decreased sensor sensitivity or lifetime.

[0010] Another common problem is that analyte sensors are less sensitive when insulin is injected near the sensor. There is room for improvement in the design of analyte sensors to improve sensitivity near insulin boluses. Summary of the Invention

[0011] The present disclosure relates to analytical sensors and methods for improved interferent rejection and lifetime.

[0012] According to various aspects of the present disclosure, an analyte sensor configured to compensate for insulin interference includes a working electrode, a processor, and a memory. The working electrode includes an analyte-sensing molecule disposed on the working electrode, the analyte-sensing molecule configured to generate a signal when exposed to an analyte. The working electrode is biased at a first bias voltage value. The memory includes instructions that, when executed by the processor, cause the sensor to: obtain an indication from a pump that a bolus was delivered at a time point; in response to the delivery of the bolus, determine at least one of a first electrochemical impedance spectroscopy (EIS) parameter value or a first conductivity value in response to the working electrode being exposed to the analyte; and determine the presence of an interferent based on at least one of the first EIS parameter value or the first conductivity value.

[0013] In one aspect of the present disclosure, the instructions, when executed by the processor, may further cause the analyte sensor to adjust the bias voltage of the working electrode from the first bias voltage value to a second bias voltage value in response to determining the presence of the interferent.

[0014] In another aspect of the present disclosure, the second bias voltage value may be lower than the first bias voltage value.

[0015] In another aspect of the present disclosure, the instructions, when executed by the processor, may also cause the analyte sensor to: determine at least one of a second EIS parameter value or a second conductivity value in response to exposure of the electrode to the analyte; and determine that the amount of the interferent present is below a threshold amount based on at least one of the second EIS parameter value or the second conductivity value.

[0016] In another aspect of the present disclosure, the instructions, when executed by the processor, may further cause the analyte sensor to adjust a bias voltage of the working electrode in response to determining that the interferent is present in an amount below a threshold amount.

[0017] In yet another aspect of the present disclosure, adjusting the bias voltage of the working electrode in response to the interferent being below a threshold amount may include ramping the bias voltage down.

[0018] In one aspect of the present disclosure, the first bias voltage may be within a range where the insulin excipient is oxidized.

[0019] In another aspect of the present disclosure, determining that the analyte value exceeds a threshold value may be based on obtaining a bolus size value from the pump.

[0020] In another aspect of the present disclosure, the instructions, when executed by the processor, may also cause the analyte sensor to: obtain a signal indicative of an analyte value from the working electrode prior to delivery of the bolus, determine that the analyte value exceeds a predetermined threshold; and cause the pump to deliver the bolus in response to the analyte value exceeding the predetermined threshold.

[0021] In another aspect of the present disclosure, the instructions, when executed by the processor, may further cause the analyte sensor to: prior to delivery of the bolus, obtain input from a user to cause the pump to deliver the bolus; and cause the pump to deliver the bolus in response to the input. The input may include a bolus size.

[0022] According to aspects of the present disclosure, a processor-implemented method of compensating for insulin interference of an analyte sensor is shown. The method includes: obtaining an indication from a pump that a bolus was delivered at a time point; in response to the delivery of the bolus, determining at least one of a first electrochemical impedance spectroscopy (EIS) parameter value or a first conductivity value in response to exposure of a working electrode of the analyte sensor to an analyte; and determining the presence of an interferent based on at least one of the first EIS parameter value or the first conductivity value.

[0023] In another aspect of the present disclosure, the method may further include adjusting a bias voltage of the working electrode from a first bias voltage value to a second bias voltage value in response to the presence of the interferent.

[0024] In another aspect of the present disclosure, the second bias voltage value may be lower than the first bias voltage value.

[0025] In yet another aspect of the present disclosure, the method may further include: determining at least one of a second EIS parameter value or a second conductivity value in response to exposure of the electrode to the analyte; and determining that the interferent is below a threshold amount based on at least one of the second EIS parameter value or the second conductivity value.

[0026] In one aspect of the present disclosure, the method may further include adjusting a bias voltage of the working electrode in response to the interferent being below a threshold amount.

[0027] In yet another aspect of the present disclosure, adjusting the bias voltage of the working electrode in response to the interferent being below a threshold amount may include ramping the bias voltage down.

[0028] In one aspect of the present disclosure, the bias voltage may be within a range where the insulin excipient is oxidized.

[0029] In yet another aspect of the present disclosure, determining that the analyte value exceeds a threshold value may be based on obtaining a bolus size value from the pump.

[0030] In another aspect of the present disclosure, the method may further include, prior to delivery of the bolus: obtaining a signal indicative of an analyte value from the working electrode; determining that the analyte value exceeds a predetermined threshold; and causing the pump to deliver the bolus in response to the analyte value exceeding the predetermined threshold.

[0031] According to aspects of the present disclosure, one or more non-transitory processor-readable media store instructions that, when executed by one or more processors, cause at least one of: obtaining an indication from a pump that a bolus was delivered; in response to the delivery of the bolus, determining at least one of a first electrochemical impedance spectroscopy (EIS) parameter value or a first conductivity value in response to exposure of a working electrode of an analyte sensor to an analyte; and determining the presence of an interferent based on at least one of the first EIS parameter value or the first conductivity value.

[0032] The details of one or more aspects of the present disclosure are set forth in the following drawings and the description. Other features, objects, and advantages of the technology described in this disclosure will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Various aspects of the disclosure will be described in detail with reference to the drawings, wherein like numerals represent corresponding parts throughout the figures.

[0034] Figure 1 shows a perspective view of a subcutaneous sensor insertion set and a block diagram of analyte sensor electronics according to one or more aspects;

[0035] Figure 2 A substrate having a first side and a second side, the first side including an electrode configuration and the second side including electronic circuitry according to one or more aspects is shown;

[0036] Figure 3 A block diagram illustrating an electronic circuit for sensing an output of an analyte sensor according to one or more aspects is shown;

[0037] Figure 4 shows a block diagram of analyte sensor electronics and a sensor including a plurality of electrodes according to one or more aspects;

[0038] Figure 5 An alternative aspect including a sensor and sensor electronics according to one or more aspects is shown;

[0039] Figure 6 is a flow chart of a method for compensating for insulin interference of an analyte sensor according to aspects of the present disclosure;

[0040] Figure 7 is a graph showing polymerization of phenol on bare platinum according to aspects of the present disclosure;

[0041] Figure 8 is a graph showing ferricyanide (FeCN) cyclic voltammetry (CV) to verify phenol film formation according to aspects of the present disclosure;

[0042] Figure 9 is a graph illustrating ferricyanide CV characterization of the effect of applied bias voltage on phenol poisoning of bare platinum according to one or more aspects of the present disclosure;

[0043] Figure 10 is a graph illustrating a first exemplary bias voltage according to one or more aspects of the present disclosure;

[0044] Figure 11 is a graph illustrating a second exemplary bias voltage according to one or more aspects of the present disclosure;

[0045] Figure 12 is a graph illustrating a third exemplary bias voltage according to one or more aspects of the present disclosure;

[0046] Figure 13 is a graph illustrating a fourth exemplary bias voltage according to one or more aspects of the present disclosure;

[0047] Figure 14 is a graph illustrating a fifth exemplary bias voltage according to one or more aspects of the present disclosure;

[0048] Figure 15 is a graph illustrating exemplary insulin excipient concentration profiles according to one or more aspects of the present disclosure;

[0049] Figure 16A and Figure 16B is a model for illustrating a subcutaneous insulin depot for 5U bolus injection according to one or more aspects of the present disclosure;

[0050] Figure 17A and Figure 17B is a model for subcutaneous injection of insulin depot showing a 10U bolus according to one or more aspects of the present disclosure;

[0051] Figure 18 is a table showing working electrode depth and time at phenol concentrations according to one or more aspects of the present disclosure;

[0052] 19A to 19C is a computed tomography (CT) image of various boluses in tissue according to one or more aspects of the present disclosure; and

[0053] Figure 20The present invention shows the use of conductivity and / or electrochemical impedance spectroscopy (EIS) to adjust the Figure 1 Graph of the sensor's bias voltage. DETAILED DESCRIPTION

[0054] In the following description, reference is made to the accompanying drawings which form a part hereof and which illustrate several aspects of the present disclosure. It is understood that other aspects may be utilized and structural and operational changes may be made without departing from the scope of the present disclosure.

[0055] Various aspects are described below with reference to flowchart illustrations of methods, systems, apparatuses, devices, processor-executable products, processor-executable instructions, and programming products and computer program products. It should be understood that each block of the flowchart illustrations, as well as combinations of blocks in the flowchart illustrations, can be implemented by programming instructions, including computer program instructions (e.g., any menu screens depicted in the illustrations). These computer program instructions can be loaded onto a computer or other programmable data processing device (such as a controller, microcontroller, or processor in a sensor electronics device) to produce a machine, such that the instructions executed on the computer or other programmable data processing device 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 memory that can direct the computer or other programmable data processing device to function in a specific manner, such that the instructions stored in the computer-readable memory produce an article of manufacture that includes 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 device to cause execution of a series of operational steps on the computer or other programmable device to produce a computer-implemented process, such that the instructions executed on the computer or other programmable device provide steps for implementing the functions specified in one or more flowchart blocks and / or the menus presented herein. Programming instructions may also be stored in and / or implemented by electronic circuits, including integrated circuits (ICs) and application specific integrated circuits (ASICs) used in conjunction with sensor devices, apparatuses, and systems.

[0056] In diabetes treatment, it is known that components of insulin can interact with glucose sensors when infused nearby. These interactions can interfere with the sensitivity of the sensor. The disclosed technology provides the benefit of leveraging communication between the insulin pump and the sensor to adjust the bias voltage of the sensor electrodes for more accurate readings.

[0057] Figure 1 is a perspective view of a subcutaneous sensor insertion set and a block diagram of sensor electronics according to various aspects of the present disclosure. Figure 1As shown, a subcutaneous sensor assembly 10 is provided for attaching the active portion of the analyte sensor 12 (e.g., see Figure 2 ) or the like, is placed subcutaneously at a selected site in the user's body. The subcutaneous or percutaneous portion of the sensor group 10 includes a hollow slotted insertion needle 14 and a cannula 16. The needle 14 is used to facilitate quick and easy subcutaneous placement of the cannula 16 at the subcutaneous insertion site. The sensing portion 18 of the analyte sensor 12 is inside the cannula 16, and the sensing portion is used to expose one or more sensor electrodes 20 to the user's body fluids through a window 22 formed in the cannula 16. In one aspect of the present disclosure, the one or more sensor electrodes 20 may include a counter electrode, a reference electrode, and one or more working electrodes. After insertion, the insertion needle 14 is removed, leaving the cannula 16 and the sensing portion 18 and the sensor electrodes 20 in place at the selected insertion site.

[0058] In certain aspects, the subcutaneous sensor set 10 facilitates precise placement of a flexible, thin-film electrochemical analyte sensor 12 of a type used to monitor a specific blood parameter indicative of a user's condition. The analyte sensor 12 monitors glucose levels within the body and can be used in conjunction with an external or implantable automatic or semi-automatic drug infusion pump of the type described in, for example, U.S. Patent Nos. 4,562,751; 4,678,408; 4,685,903; or 4,573,994, the entire contents of which are incorporated herein by reference, to control insulin delivery to a diabetic patient.

[0059] Certain aspects of the flexible analyte sensor 12 are constructed according to thin-film shielding technology, comprising an elongated thin-film conductor embedded or coated between layers of a selected insulating material (such as a polyimide film or sheet) and the membrane. When the sensing portion 18 (or active portion) of the analyte sensor 12 is subcutaneously placed at the insertion site, the sensor electrode 20 at the tip of the sensing portion 18 is exposed through one of the insulating layers for direct contact with the patient's blood or other bodily fluid. The sensing portion 18 is bonded to a connecting portion 24 that terminates in a conductive contact pad, etc., which is also exposed through one of the insulating layers. In alternative aspects, other types of implantable sensors may be used, such as chemical-based sensors, optical-based sensors, etc.

[0060] As is known in the art, the connecting portion 24 and contact pads are generally adapted for direct wired electrical connection to a suitable monitor or sensor electronics 100 to monitor a user's condition in response to signals derived from the sensor electrodes 20. Further description of this general type of flexible film sensor can be found, for example, in U.S. Patent No. 5,391,250, which is incorporated herein by reference. The connecting portion 24 can be conveniently electrically connected to the monitor or sensor electronics 100, or via a connector block 28 (or the like) as shown and described, for example, in U.S. Patent No. 5,482,473, which is also incorporated herein by reference. Thus, according to aspects of the present disclosure, the subcutaneous sensor set 10 can be configured or formed to operate with either a wired or wireless characteristic monitoring system.

[0061] 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 acts as a catalyst. For example, the sensor electrode 20 can be used in an oxygen-independent glucose sensor.

[0062] Sensor electrodes 20, along with biomolecules or some other catalyst, can be placed in a vascular or non-vascular environment within the human body. For example, sensor electrodes 20 and biomolecules can be placed in a vein and exposed to blood flow, or can be placed in the subcutaneous or peritoneal areas of the human body.

[0063] 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 may be coupled to the sensor group 10 via a cable 102 via a connector that is electrically coupled to the connector block 28 of the connection portion 24. In alternative aspects, the cable 102 may be omitted. In this aspect of the disclosure, the monitor 100 may include an appropriate connector for connecting directly to the connection portion 104 of the sensor group 10. The sensor group 10 may be modified to position the connector portion 104 at a different location, such as on top of the sensor group 10, to facilitate placement of the monitor 100 above the sensor group 10.

[0064] In various aspects of the present disclosure, the sensor interface 122, processing electronics 124, and data formatting electronics 128 are formed as separate semiconductor chips, however, alternative aspects may combine the various semiconductor chips into a single or multiple custom semiconductor chips. The sensor interface 122 is connected to the cable 102, which is connected to the sensor group 10.

[0065] The power source 110 can be a battery. The battery can include three silver oxide cells connected in series. In alternative aspects, different battery chemistries can be utilized, such as lithium-based chemistries, alkaline batteries, nickel metal hydride, etc., and different numbers of batteries can be used. The monitor 100 provides power to the sensor group via the power source 110 through the cable 102 and the cable connector 104. In one aspect of the present disclosure, power is the voltage provided to the sensor group 10. In one aspect of the present disclosure, power is the current provided to the sensor group 10. In one aspect of the present disclosure, power is the voltage provided to the sensor group 10 at a specific voltage.

[0066] Figure 2 An implantable analyte sensor and electronics for driving the implantable analyte sensor according to one aspect of the present disclosure are shown. Figure 2 A substrate or flexible member 220 is shown having two sides; a first side 222 containing an electrode configuration and a second side 224 containing electronic circuitry. Figure 2 As shown, the first side 222 of the substrate includes two counter electrode-working electrode pairs 240, 242, 244, 246 on opposite sides of a reference electrode 248. The second side 224 of the substrate includes the electronic circuitry. As shown, the electronic circuitry can be enclosed in a hermetically sealed housing 226, thereby providing a protective casing for the electronic circuitry. This allows the sensor substrate 220 to be inserted into a vascular environment or other environment where the electronic circuitry may be subjected to fluids. By sealing the electronic circuitry in the hermetically sealed housing 226, the electronic circuitry can operate without the risk of being shorted by the surrounding fluid. Similarly, as shown in FIG. Figure 2 As shown, pads 228 are connected to the input and output lines of the electronic circuit. The electronic circuit itself can be manufactured in a variety of ways. According to one aspect of the present disclosure, the electronic circuit can be manufactured as an integrated circuit using techniques commonly used in the industry.

[0067] Figure 3 A general block diagram of an electronic circuit for sensing the output of an analyte sensor according to aspects of the present disclosure is shown. At least one pair of sensor electrodes 310 can be connected to a data converter 312, the output of which can be connected to a counter electrode 314. The counter electrode 314 can be controlled by control logic 316. The output of the counter electrode 314 can be connected to a line interface 318. The line interface 318 can be connected to input and output lines 320 and can also be connected to the control logic 316. The input and output lines 320 can also be connected to a power rectifier 322.

[0068] The sensor electrode 310 can be used in a variety of sensing applications and can be configured in a variety of ways. For example, the sensor electrode 310 can be used in physiological parameter sensing applications where a certain type of biomolecule is used as a catalyst. For example, the sensor electrode 310 can be used in an oxygen-independent glucose sensor having boric acid viologen (oBBV) that binds to glucose. The sensor electrode 310, along with the oBBV and / or dye ( Figure 8 ) can be placed in a vascular or non-vascular environment within the human body. For example, the sensor electrode 310 and the biomolecule can be placed in a vein and subjected to blood flow.

[0069] Figure 4 A block diagram of an analyte sensor electronics and a sensor including multiple electrodes according to one aspect of the present disclosure is shown. A sensor assembly or system 350 includes an analyte sensor 355 and sensor electronics 360. The analyte sensor 355 includes a counter electrode 365, a reference electrode 370, and a working electrode 375. The 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. The power supply 380 provides power (in the form of a voltage, current, or a voltage including a current) to the regulator 385. The regulator 385 transmits a regulated voltage to the analyte sensor 355. In one aspect of the present disclosure, the regulator 385 transmits a voltage to the counter electrode 365 of the analyte sensor 355.

[0070] The analyte sensor 355 generates a sensor signal that indicates the concentration of the physiological property being measured. For example, the sensor signal can indicate a blood glucose reading. The sensor signal can be measured at the working electrode 375. In one aspect of the present disclosure, the sensor signal can be a current measured at the working electrode. In another aspect of the present disclosure, the sensor signal can be a voltage measured at the working electrode.

[0071] After measuring a sensor signal at the analyte sensor 355 (e.g., a working electrode), the sensor signal (e.g., a measured current or voltage) is received by the signal processor 390. The signal processor 390 processes the sensor signal and generates a processed sensor signal. The measurement processor 395 receives the processed sensor signal and calibrates the processed sensor signal using a reference value. In one aspect of the present disclosure, the reference value is stored in a reference memory and provided to the measurement processor 395. The measurement processor 395 generates sensor measurements. The sensor measurements may be stored in a measurement memory (not shown). The sensor measurements may be sent to a display / transmission device for display on a display in the housing along with the sensor electronics, or transmitted to an external device.

[0072] Sensor electronics 360 may be a monitor that includes a display to show physiological characteristic readings. Sensor electronics 360 may also be installed in a desktop computer, a pager, a television including communication capabilities, a laptop computer, a server, a network computer, a personal digital assistant (PDA), a portable phone including computer functionality, an infusion pump including a display, and / or a combination infusion pump / analyte sensor. Sensor electronics 360 may be housed in a cellular phone, a smartphone, a network appliance, a home network appliance, and / or other equipment connected to a home network.

[0073] Figure 5 An alternative aspect including an analyte sensor and sensor electronics according to one aspect of the present disclosure is shown. A sensor set or sensor system 400 includes sensor electronics 360 and an analyte sensor 355. Analyte sensor 355 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.

[0074] The microcontroller 410 includes software program code or programmable logic that, when executed, causes the microcontroller 410 to transmit a signal to the DAC 420, wherein the signal represents a voltage level or value to be applied to the analyte sensor 355. The DAC 420 receives the signal and generates a voltage value at the level indicated by the microcontroller 410. In various aspects of the present disclosure, the microcontroller 410 may change the representation of the voltage level in the signal frequently or infrequently. Illustratively, the 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.

[0075] The analyte sensor 355 can receive a voltage level or value. In one aspect of the present disclosure, the counter electrode 365 can receive the output of an operational amplifier having a reference voltage and a voltage value from the DAC 420 as inputs. Application of the voltage level causes the analyte sensor 355 to generate a sensor signal indicative of the concentration of the physiological characteristic being measured. In one aspect of the present disclosure, the microcontroller 410 can measure the sensor signal (e.g., a current value) from the working electrode. Illustratively, the sensor signal can be measured by the sensor signal measurement circuit 431. In one aspect of the present disclosure, the sensor signal measurement circuit 431 can include a resistor, and current can flow through the resistor to measure the value of the sensor signal. In one aspect of the present disclosure, the sensor signal can be a current level signal, and the sensor signal measurement circuit 431 can be a current-to-frequency (I / F) converter 430. The I / F converter 430 can measure the sensor signal represented by the current reading, convert the sensor signal into a frequency-based sensor signal or an electrochemical impedance spectroscopy (EIS) signal, and transmit the frequency-based sensor signal or EIS signal to the microcontroller 410. Those skilled in the art will understand how to implement and apply EIS. Various aspects of EIS signals are described in U.S. Patent Application Publication No. US2013 / 0060105A1, the entire contents of which are incorporated herein by reference. In various aspects of the present disclosure, microcontroller 410 may be able to more easily receive frequency-based sensor signals than non-frequency-based sensor signals. Microcontroller 410 receives the sensor signal (whether frequency-based or non-frequency-based) and determines a value of a physiological characteristic of a subject, such as blood glucose level. Microcontroller 410 may include program code that, when executed or run, is capable of receiving the sensor signal and converting the sensor signal into a value of the physiological characteristic.

[0076] In one aspect of the present disclosure, microcontroller 410 can convert sensor signals into blood glucose levels. When converting sensor signals into blood glucose values, microcontroller 410 can use one or more models, which are specific ways to calculate blood glucose values ​​using sensor signals. In some aspects, microcontroller 410 can utilize measurements stored in internal memory (e.g., sensor signals and electrochemical impedance spectroscopy (EIS) signals from analyte sensor 355) to determine the subject's blood glucose level. In some aspects, microcontroller 410 can utilize measurements stored in memory external to microcontroller 410 to assist in determining the subject's blood glucose level.

[0077] After the microcontroller 410 determines the physiological characteristic value, it may store the physiological characteristic value measurement for a number of time periods. For example, a blood glucose (BG) value may be sent from the sensor to the microcontroller 410 every second or every five seconds, and the microcontroller may store the sensor measurement for five or ten minutes after the BG reading. The microcontroller 410 may transmit the physiological characteristic value measurement to a display on the sensor electronics 360. For example, the sensor electronics 360 may be a monitor that includes a display that provides a subject's blood glucose reading. In one aspect of the present disclosure, the microcontroller 410 may transmit the physiological characteristic value measurement to an output interface of the microcontroller 410. The output interface of the microcontroller 410 may transmit the physiological characteristic value measurement, such as the BG value, to an external device, such as an infusion pump 530, a combination infusion pump / glucose meter, a computer, a personal digital assistant, a pager, a network appliance, a server, a cell phone, or any other computing device.

[0078] Figure 6 It is compensation Figure 1 Flowchart of a processor-implemented method 600 for detecting insulin interference with an analyte sensor 12. The method 600 may be performed by Figure 1 The sensor electronics 100 or Figure 4 and Figure 5 The sensor electronics 360 are implemented.

[0079] Typically, analyte sensors apply a bias voltage to the working electrode to adjust the sensitivity of the analyte measurement. The bias voltage is within the range where the insulin excipient oxidizes (e.g., 300 mV to 600 mV). This can cause the delivery of a bolus (e.g., insulin) to interfere with the accuracy of the sensor's measurements.

[0080] At block 602, the processor causes the analyte sensor 12 (eg, from the pump 530 ( Figure 5 )) obtains an indication that a bolus is to be delivered. For example, prior to delivery of a bolus, the processor may cause the analyte sensor to obtain a signal indicative of an analyte value from the working electrode, determine that the analyte value exceeds a predetermined threshold, and cause pump 530 to deliver the bolus in response to the analyte value exceeding the predetermined threshold. In various aspects, the analyte sensor may obtain the size of the bolus from the pump. For example, pump 530 may transmit to the sensor the size of the bolus to be delivered at a specific time point (e.g., 5 U).

[0081] In another example, prior to delivery of the bolus, the processor may cause the analyte sensor to obtain input from the user to cause the pump to deliver the bolus and cause the pump to deliver the bolus in response to the input. The input may include the size of the bolus.

[0082] At block 604, the pump 530 prepares to deliver a bolus at a point in time. In various aspects, the processor may cause a sensor to obtain an indication from the pump that a bolus is delivered at a particular point in time.

[0083] In various aspects, the processor can cause the sensor to obtain a signal from the working electrode in response to the delivery of the bolus.The signal can be processed to generate an electrochemical impedance spectroscopy (EIS) parameter value and / or a conductivity value.

[0084] At block 606, if the analyte value exceeds the predetermined threshold, the processor causes the sensor 12 to reduce or switch off the bias voltage on the working electrode. The operations of block 606 will be described in more detail below.

[0085] At block 608, the processor causes the sensor 12 to generate an electrochemical impedance spectroscopy (EIS) parameter value and / or a conductivity value in response to the working electrode being exposed to the analyte. In various aspects, the processor determines the presence of an interferent (e.g., insulin) based on at least one of the first EIS parameter value or the first conductivity value. An interferent is a substance that interferes with the analytical procedure and produces an incorrect result.

[0086] Blocks 606 and 608 are performed iteratively. For example, if the EIS or conductivity measurement still indicates the presence of an interferent, the processor causes the sensor to reduce the bias voltage of the working electrode. Thus, the sensor can adjust the bias voltage of the working electrode from a first bias voltage value to a second bias voltage value in response to the presence of an interferent. The second bias voltage value is lower than the first bias voltage value. For example, the bias voltage of the working electrode can be adjusted by ramping or stepping the bias voltage down to a lower value. Other aspects of this adjustment will be discussed in conjunction with Figures 10 to 14 Provide a description.

[0087] At box 610, sensor 12 no longer detects the presence of the interferent. For example, time has passed and insulin has dropped to a sufficiently low value so that it does not interfere with the accuracy of the measurement result of sensor 12 signal. For example, sensor 12 may determine a second EIS parameter value and / or a second conductivity value in response to the electrode being exposed to the analyte. Based on at least one of the second EIS parameter value or the second conductivity value, sensor 12 may determine the absence of the interferent, or determine that the interferent is below a threshold amount. In various aspects, the processor may cause sensor 12 to adjust the bias voltage of the working electrode in response to the absence of the interferent. For example, the processor may remeasure the EIS parameter value to test for the presence or absence of insulin. Sensor 12 may determine that there is no insulin based on the EIS parameter value. For example, the threshold amount may be lower than the amount that causes the working electrode to lose more than about 1% of its measurement sensitivity and / or accuracy.

[0088] In various aspects, the sensor 12 may provide one or more shapes / curves of adjusted bias voltage, which will be discussed below in conjunction with Figures 10 to 14 For example, the user interface may display one or more curves. In another aspect, the one or more curves may be selected by the sensor 12 based on at least one of the type or model of the sensor 12 or the bolus dose indicated by the pump 530.

[0089] about Figure 7 and Figure 8 , shows the use of chronoamperometry in Figure 1 The current versus time of electropolymerization of phenol on the bare platinum electrode (Pt) of the sensor Figure 7 ) and voltage versus time ( Figure 8 ). 8 mM phenol in PBS (phosphate-buffered saline) was prepared at 37°C and stirred at approximately 200 rpm for approximately 15 hours using chronoamperometry for electropolymerization. PBS was used as an exemplary indicator. The disappearance of the red oxidation peak in the FeCN cyclic voltammetry (CV) curve confirmed the blocking behavior of phenol on the platinum electrode at a bias potential of 570 mV. The FeCN CV red oxidation peak appears identical to that of a clean platinum electrode, and immersion of the platinum electrode in a phenol solution with a 0 mV applied voltage confirmed that phenol poisoning does not occur at 0 mV. Here, phenol was used as an example in place of insulin.

[0090] Figure 9 is a graph showing current versus voltage, which shows the effect of applied bias voltage on the Figure 1 Ferricyanide CV characterization of the effect of phenol poisoning on bare platinum (Pt) sensors. An electropolymerization method using 8 mM phenol in PBS at approximately 37°C with stirring at approximately 200 rpm was used for approximately 2 hours using chronoamperometry. A red oxidation peak was visible at the working electrode below approximately 300 mV.

[0091] Figure 10 is a graph showing a first exemplary bias voltage. During the period of time when the disturbance occurs, the bias voltage is ramped down to a lower voltage. As the sensor signal returns to normal, the bias voltage is configured to slowly ramp back up to normal.

[0092] Figure 11 is a graph showing a second exemplary bias voltage. During the period of time when the disturbance occurs, the bias voltage is stepped down to a lower voltage. As the sensor signal returns to normal, the bias voltage is configured to step back to normal.

[0093] Figure 12is a graph showing a third exemplary bias voltage. During the period of time when the disturbance occurs, the bias voltage is ramped down to 0 mV. As the sensor signal returns to normal, the bias voltage is configured to slowly ramp back up to normal.

[0094] Figure 13 is a graph showing a fourth exemplary bias voltage. During the period when the disturbance occurs, the bias voltage is stepped down to 0 mV. As the sensor signal returns to normal, the bias voltage is configured to slowly ramp back up to normal.

[0095] Figure 14 is a graph showing a fifth exemplary bias voltage. During the period of time when interference occurs, the bias voltage is stepped down to 0 mV. As the sensor signal returns to normal, the bias voltage is configured to step back to normal.

[0096] Figure 15 Computational fluid dynamics (CFD) models of the concentration profiles of exemplary insulin excipients are shown. Figure 16A and Figure 16B A CFD model is shown. Figure 16B The graph above shows the decay of insulin excipient concentration as a function of the distance of the working electrode from the cannula tip for a 5 U bolus. The X-axis is distance and the Y-axis is the magnitude of the concentration ( Figure 16B ).

[0097] Figure 17A and Figure 17B is a model for a subcutaneous insulin depot showing a 10U bolus. For a 10U bolus, the insulin excipient concentration decays as a function of the distance from the working electrode to the cannula tip. The X-axis is distance, and the Y-axis is the magnitude of the concentration ( Figure 17B ).

[0098] Figure 18 TABLE 1 is a table showing working electrode depth versus time for phenol concentrations. Phenol concentration percentages for bolus volumes of 5U, 10U, and 25U after various time periods are shown.

[0099] 19A to 19C It is a CT image of various boluses in tissue. Figure 19A A 25 U bolus injection into the tissue is shown. The working electrode of sensor 12 ( Figure 1 ) and the cannula tip can be seen within insulin deposits in the tissue. Figure 19B A 10 U bolus is shown, showing significantly smaller insulin deposits in the tissue. Figure 19C A 5 U bolus in the tissue is shown.

[0100] Figure 20 is shown using conductivity and / or EIS to adjust Figure 1Graph of the sensor's bias voltage.

[0101] It should be understood that the various aspects disclosed herein may be combined in combinations different from those specifically presented in the description and drawings. It should also be understood that, depending on the example, certain actions or events in any of the processes or methods described herein may be performed in a different order, added, combined, or omitted entirely (e.g., not all described actions or events may be required to perform these techniques). In addition, although for clarity, certain aspects of the present disclosure are described as being performed by a single module or unit, it should be understood that the techniques of this disclosure may be performed by a combination of units or modules associated with, for example, the servers and computing devices described above.

[0102] Although the above description relates to specific aspects of the present disclosure, it should be understood that many modifications can be made without departing from the spirit of the present disclosure. Additional steps and changes to the order of the algorithm can be performed while still implementing the key teachings of the present disclosure. Therefore, the appended claims are intended to cover this modification that falls within the true scope and spirit of the present disclosure. Therefore, the various aspects of the current disclosure should be considered illustrative rather than restrictive in all aspects, and the scope of the present disclosure is indicated by the appended claims rather than the foregoing description. Unless the context otherwise indicates, any aspect disclosed herein may be combined with any other one or more aspects disclosed herein. All changes within the meaning and scope of the equivalents of the claims are intended to be encompassed within said meaning and scope.

Claims

1. An analyte sensor configured to compensate for insulin interference, the analyte sensor comprising: a working electrode comprising an analyte-sensing molecule disposed on the working electrode, the analyte-sensing molecule configured to generate a signal when exposed to an analyte, wherein the working electrode is biased at a first bias voltage value; processor; and a memory comprising instructions that, when executed by the processor, cause the sensor to: obtaining an indication from the pump that the bolus was delivered; In response to delivery of the bolus, determining at least one of a first electrochemical impedance spectroscopy (EIS) parameter value or a first conductivity value in response to exposure of the working electrode to the analyte; as well as The presence or absence of an interferent is determined based on at least one of the first EIS parameter value or the first conductivity value.

2. The analyte sensor of claim 1 , wherein the instructions, when executed by the processor, further cause the analyte sensor to: A bias voltage of the working electrode is adjusted from the first bias voltage value to a second bias voltage value in response to determining the presence of the interferent. The analyte sensor of claim 2 , wherein the second bias voltage value is lower than the first bias voltage value.

4. The analyte sensor of claim 2, wherein the instructions, when executed by the processor, further cause the analyte sensor to: determining at least one of a second EIS parameter value or a second conductivity value in response to exposure of the electrode to the analyte; and The interferent is determined to be present in an amount below a threshold amount based on at least one of the second EIS parameter value or the second conductivity value.

5. The analyte sensor of claim 4, wherein the instructions, when executed by the processor, further cause the analyte sensor to: The bias voltage of the working electrode is adjusted in response to determining that the interferent is present in an amount below the threshold amount. 6 . The analyte sensor of claim 5 , wherein adjusting the bias voltage of the working electrode in response to the interferent being below the threshold amount comprises ramping the bias voltage down.

7. The analyte sensor of claim 2, wherein the first bias voltage is within a range where an insulin excipient is oxidized.

8. The analyte sensor of claim 1, wherein determining that the analyte value exceeds a threshold is based on obtaining a size value of the bolus from the pump.

9. The analyte sensor of claim 1 , wherein the instructions, when executed by the processor, further cause the analyte sensor to: Prior to the delivery of the bolus: obtaining said signal indicative of an analyte value from said working electrode; determining that the analyte value exceeds a predetermined threshold; and The pump is caused to deliver the bolus in response to the analyte value exceeding the predetermined threshold.

10. The analyte sensor of claim 1 , wherein the instructions, when executed by the processor, further cause the analyte sensor to: Prior to the delivery of the bolus: obtaining input from a user to cause the pump to deliver the bolus, wherein the input includes a bolus size; and The pump is caused to deliver the bolus in response to the input.

11. A processor-implemented method of compensating an analyte sensor for insulin interference, the method comprising: obtaining an indication from the pump that a bolus was delivered at a point in time; responsive to said delivery of said bolus, determining at least one of a first electrochemical impedance spectroscopy (EIS) parameter value or a first conductivity value responsive to exposure of a working electrode of an analyte sensor to an analyte; as well as The presence of an interferent is determined based on at least one of the first EIS parameter value or the first conductivity value.

12. The processor-implemented method of claim 11 , further comprising: A bias voltage of a working electrode is adjusted from a first bias voltage value to a second bias voltage value in response to the presence of the interferent.

13. The processor-implemented method of claim 12, wherein the second bias voltage value is lower than the first bias voltage value.

14. The processor-implemented method of claim 12, further comprising: determining at least one of a second EIS parameter value or a second conductivity value in response to exposure of the electrode to the analyte; as well as The interferent is determined to be below a threshold amount based on at least one of the second EIS parameter value or the second conductivity value.

15. The processor-implemented method of claim 14, further comprising: The bias voltage of the working electrode is adjusted in response to the interferent being below the threshold amount.

16. The processor-implemented method of claim 15, wherein adjusting the bias voltage of the working electrode in response to the interferent being below the threshold amount comprises ramping the bias voltage down.

17. The processor-implemented method of claim 12, wherein the bias voltage is within a range for oxidation of an insulin excipient.

18. The processor-implemented method of claim 11, wherein determining that the analyte value exceeds the threshold is based on obtaining a size value of the bolus from the pump.

19. The processor-implemented method of claim 11 , further comprising: Prior to the delivery of the bolus: obtaining said signal indicative of an analyte value from said working electrode; determining that the analyte value exceeds a predetermined threshold; as well as The pump is caused to deliver the bolus in response to the analyte value exceeding the predetermined threshold.

20. One or more non-transitory processor-readable media storing instructions that, when executed by one or more processors, cause at least the following steps to be performed: obtaining an indication from the pump that the bolus was delivered; In response to the delivery of the bolus, determining at least one of a first electrochemical impedance spectroscopy (EIS) parameter value or a first conductivity value responsive to exposure of a working electrode of an analyte sensor to an analyte; and The presence of an interferent is determined based on at least one of the first EIS parameter value or the first conductivity value.

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