METHOD, SYSTEMS AND DEVICES FOR IMPROVED SENSORS FOR CONTINUOUS GLUCOSE MONITORING

Description

FIELD

[0001] The present technology is generally related to sensor technology, including sensors used for sensing a variety of physiological parameters, e.g., glucose concentration.BACKGROUND

[0002] Over the years, a variety of sensors have been developed for detecting and / or quantifying specific agents or compositions in a patient's blood, which enable patients and medical personnel to monitor physiological conditions within the patient's body. Illustratively, subjects may wish to monitor blood glucose levels in a subject's body on a continuing basis. Thus, glucose sensors have been developed for use in obtaining an indication of blood glucose levels in a diabetic patient. Such readings are useful in monitoring and / or adjusting a treatment regimen which typically includes the regular administration of insulin to the patient. Presently, a patient can measure his / her blood glucose ("BG") using a BG measurement device (i.e., glucose meter), such as a test strip meter, a continuous glucose measurement system (or a continuous glucose monitor), or a hospital BG test. BG measurement devices use various methods to measure the BG level of a patient, such as a sample of the patient's blood, a sensor in contact with a bodily fluid, an optical sensor, an enzymatic sensor, or a fluorescent sensor. When the BG measurement device has generated a BG measurement, the measurement is displayed on the BG measurement device. US 2019 / 0328297 A1 describes an example of a blood glucose monitoring technique.SUMMARY

[0003] The current invention is defined by the claims. Current continuous glucose measurement systems include subcutaneous (or short-term) sensors and implantable (or long-term) sensors. Sensors have been applied in a telemetered characteristic monitor system. A telemetered system using an electrochemical sensor includes a remotely located data receiving device, a sensor for producing signals indicative of a characteristic of a user, and a transmitter device for processing signals received from the sensor and for wirelessly transmitting the processed signals to the remotely located data receiving device. The data receiving device may be a characteristic monitor, a data receiver that provides data to another device, an RF programmer, a medication delivery device (such as an infusion pump), or the like. 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 an electrical wire connection, a characteristic monitoring system of the type described above is of practical use only after it has been calibrated based on the unique characteristics of the individual user.

[0004] Continuous glucose monitoring ("CGM") is largely adjunctive, meaning that the readings provided by a CGM device (including, e.g., an implantable or subcutaneous sensor) cannot be used without a reference value in order to make a clinical decision. The reference value, in turn, must be obtained from a finger stick using, e.g., a BG meter. The reference value is needed because there is a limited amount of information that is available from the sensor / sensing component. Generally, glucose measurements are based on interactions with one of three enzymes: hexokinase, glucose oxidase ("GOx") or glucose-1-dehydrogenase ("GDH"). Specifically, the only pieces of information that are currently provided by the sensing component for processing are the raw sensor value (i.e., the sensor current or Isig) and the counter voltage. Therefore, during analysis, if it appears that the raw sensor signal is abnormal (e.g., if the signal is decreasing), the only way one can distinguish between a sensor failure and a physiological change within the user / patient (i.e., glucose level changing in the body) is by acquiring a reference glucose value via a finger stick. However, the use of repeated finger sticks by a user / patient is painful and otherwise undesirable; therefore, methods, systems, and devices are described herein to minimize the amount of testing and / or calibrations necessary for CGM and improve their reliability through improvements to glucose oxidase ("GOx") sensors.

[0005] To further compound the hurdles faced by CGM devices, government agencies (e.g., the Federal Drug Administration ("FDA")) impose restrictions and requirements for the sensitivity of CGMs to various medications. For example, CGM devices are required to have minimal impact from exposure to acetaminophen (a commonly used treatment for minor pain relief) when orally taken by a user per the FDA iCGM special requirements. GOx is a standard enzyme for biosensors as it has a relatively higher selectivity for glucose. GOx is also easy to obtain, inexpensive, and can withstand greater extremes of pH, ionic strength, and temperature than many other enzymes, thus allowing less stringent conditions during the manufacturing process and relatively relaxed storage norms for use by lay biosensor users. However, traditional GOx sensors are impacted by the presence of acetaminophen, which could results in an error in an estimated BG based on the sensor glucose ("SG") signal. For example, a high dose of acetaminophen can generate analytical interference on electrochemical biosensors because acetaminophen is directly oxidized after diffusing across a porous membrane to the electrode surface, producing an interfering current that increases the glucose reading. Accordingly, methods, systems, and devices are described herein to further improve on the reliability of CGM devices. This done by providing two electrodes, one referred to as a working electrode which detects glucose by virtue of the presence of GOx, but which is susceptible to interference due to the presence of an interferant such as acetaminophen, and a second electrode, referred to as a background electrode, which does not have GOx, and hence only responds to the interferant. By comparing the signals from the working electrode and the background electrode the interference can be eliminated and a corrected more accurate measured SG signal can be calculated.

[0006] More particularly, the methods, systems, and devices describe a working electrode with a GOx layer and a background electrode in which has no GOx sensor. The background electrode, which may be formed as a metallization layer, may be composed of various materials. For example, the background electrode metal layer may 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 may be tuned to target various types of interferants. For example, a gold electrode and a voltage of 600mV may be used, while in another arrangement a carbon electrode and a voltage of 900mV may be used. In one embodiment, the working electrode and the background electrode may have the same operating potential. The system may subtract the two signals from one another to remove the signal originating at the background electrode. Accordingly, in this embodiment, the system may determine a difference in the signals between the working electrode and the background electrode. If acetaminophen is used by a user / patient, both the working electrode and the background electrode are affected. The working electrode which includes a GOx layer produces a signal according to the amount of glucose present. It however also produces a signal from the exposure to acetaminophen. The background electrode on the other hand does not have a GOx layer and therefore only produces a signal due to its exposure to acetaminophen. The difference in the signals between the working electrode and the background electrode is then used for calculating, generating, an adjusted a sensor glucose value. In some embodiments, the signal from the working electrode and the signal from the background electrode may be input as a parameter to a pre-determined mathematical model (e.g., external calibration model) in order 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 be operated at a lower Vset relative for the background electrode. For example, the working electrode may be operated at 400-500mV range while the background electrode is operated in the 500-600mV range. For example, calculating a sensor glucose value based on the different voltage potentials (Vset) for the working electrode and the background electrode as described above provides a more accurate measure of sensor glucose values, particularly in the presence of medication that produces an interfering current that increases a system reading. The values of the voltage potentials (Vset) may be stored by electronic circuitry (e.g., storage circuitry). By voltage potential is meant the voltage between that particular electrode and a reference electrode. Operating the background electrode at a higher potential can produce a larger signal, and hence a more accurate indication of the interference. It alternatively allows the background electrode to be made smaller for the same signal.

[0008] In some aspects, methods, systems, and devices for continuous 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 the user, wherein the second electrode does not have aGOx 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; receiving 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, which detects glucose and interference due to the ingestion of a medication by the user and the second signal, which detects only ingestion of the medication by the user. The system can thengenerate a corrected sensor glucose value by deducting the error signal due to the interference. It will be understood that although GOx is referred to in the arrangements discussed herein, any substance that catalyses oxidation-reduction reactions of glucose, and hence ultimately results in an electric current proportional to glucose concentration, can be used. Well known for this purpose are the three enzymes: hexokinase, glucose oxidase ("GOx") and glucose-1-dehydrogenase ("GDH").

[0009] Various other aspects, features, and advantages will be apparent through the detailed description and the drawings attached hereto. It is also to be understood that both the foregoing general description and the following detailed description are examples and not restrictive of the scope of the invention. As used in the specification and in the claims, the singular forms of "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In addition, as used in the specification and the claims, the term "or" means "and / or" unless the context clearly dictates otherwise. Additionally, as used in the specification "a portion," refers to a sub-part of, or the entirety of, a given item (e.g., data) unless the context clearly dictates otherwise.

[0010] The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques described in this disclosure will be apparent from the description and drawings, and from the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] A detailed description of embodiments of the invention will be made with reference to the accompanying drawings, wherein like numerals designate corresponding parts in the figures. FIG. 1 is a perspective view of a subcutaneous sensor insertion set and block diagram of a sensor electronics device. FIG. 2 illustrates a substrate having two sides, a first side which contains an electrode configuration and a second side which contains electronic circuitry. FIG. 3 illustrates a block diagram of a sensor electronics device and a sensor including a plurality of electrodes. FIG. 4 illustrates an alternative embodiment of the invention including a sensor and a sensor electronics device. FIG. 5 illustrates an electronic block diagram of the sensor electrodes and a voltage being applied to the sensor electrodes. FIG. 6 shows a flowchart of the steps involved in continuous glucose monitoring, in accordance with one or more embodiments. FIG. 7 shows a flowchart of the steps involved in continuous glucose monitoring, in accordance with one or more embodiments. FIG. 8 illustrates a unit sensor having a background electrode metal layer made of platinum. FIG. 9 illustrates a unity sensor having a background electrode metal layer made of gold. FIG. 10 illustrates a single sensor flex in a CGM device and a dual sensor flex in a CGM device. DETAILED DESCRIPTION

[0012] In the following description, reference is made to the accompanying drawings which form a part hereof and which illustrate several embodiments of the present inventions. It is understood that other embodiments may be utilized, and structural and operational changes may be made without departing from the scope of the present inventions.

[0013] The inventions herein are described below with reference to flowchart illustrations of methods, systems, devices, apparatus, and programming and computer program products. It will 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 (as can any menu screens described in the figures). These computer program instructions may be loaded onto a computer or other programmable data processing apparatus (such as a controller, microcontroller, or processor in a sensor electronics device) to produce a machine, such that the instructions which execute on the computer or other programmable data processing apparatus create instructions for implementing the functions specified in the flowchart block or blocks. These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instructions which implement the function specified in the flowchart block or blocks. The computer program instructions may 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 the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions specified in the flowchart block or blocks, and / or menus presented herein. Programming instructions may also be stored in and / or implemented via electronic circuitry (e.g., storage circuitry, processing circuitry), including integrated circuits (ICs) and Application Specific Integrated Circuits (ASICs) used in conjunction with sensor devices, apparatuses, and systems. The following terms and definitions may also be used herein: Term Definition BGBlood Glucose value in mg / dLtypically from a fingerstick reading. Assumed use is for a sensor calibrationCalibrated ModeSensor operation mode in which the algorithm expects to receive BG calibrations as part of regular operationCECalibration ErrorCF (or calFactor)Calibration Factor, sensor sensitivity to glucose used to calculate sensor glucose. Units are mg / dL / nACR (or cr)Calibration Ratio, sensitivity based on a single BG and IsigDiscardPacket flagged to be invalid based on Isig.early calibrationTemporary CF update on the packet following a BGEISElectrochemical Impedance Spectroscopy, Diagnostic capability to measure impedances at varying frequencies applied by the AFE ICfinal calibrationRefers to updates to CF and other variables which may occur 10-15 minutes after a BG entryfisigFiltered Isig, used in calibration and SG calculationGSTGlucose Sensor TransmitterGOxGlucose OxidaseinitializationSensor Initialization. This typically refers to data collection activities during sensor warm up periodInstant calibration errorCE check based on prior Isig, determines if a BG can be used for calibrationinvalid packetRefers to a packet being flagged as invalid. Packets flagged as invalid do not show SG to the user.Isig5-minute reading of sensor current in nA. Sometimes called "raw Isig"Isig11-minutereading of sensor current in nA. Sometimes called "1-minute Isig"Isig DipIsig Dip Calibration. Refers to logic which may adjust CF following a calibration on an abnormally low IsigMAX_CRMaximum acceptable CRMIN_CRMinimum acceptable CRNot Calibrated ModeSensor operation mode in which the algorithm does not expect to receive BG calibrations as part of regular operations. The algorithm can utilize BG calibrations if any is made available.Packet (or SC Packet or Isig Packet)Refers to the collection of variables calculated at the 5-minute interval, including Isig, sg, etc.SGSensor Glucose value in mg / dLVsetVoltage potential at the working or background electrode of a potentiostat electrochemical cell with respect to a reference electrode.

[0014] FIG. 1 is a perspective view of a subcutaneous sensor insertion set and a block diagram of a sensor electronics device. As illustrated in FIG. 1, a subcutaneous sensor set 10 is provided for subcutaneous placement of an active portion of a flexible sensor 12 (see, e.g., FIG. 2), or the like, at a selected site in the body of a user. The subcutaneous or percutaneous portion of the sensor set 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. Inside the cannula 16 is a sensing portion 18 of the sensor 12 to expose 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 to leave the cannula 16 with the sensing portion 18 and the sensor electrodes 20 in place at the selected insertion site.

[0015] In particular embodiments, the subcutaneous sensor set 10 facilitates accurate placement of a flexible thin film electrochemical sensor 12 of the type used for monitoring specific blood parameters representative of a user's condition. The sensor 12 monitors glucose levels in the body and may be used in conjunction with automated or semi-automated medication infusion pumps of the external or implantable type to control delivery of insulin to a diabetic patient, as described, e.g., in U.S. Pat. Nos. 4,562,751; 4,678,408; 4,685,903 or 4,573,994.

[0016] Particular embodiments of the flexible electrochemical sensor 12 are constructed in accordance with thin film mask techniques to include elongated thin film conductors embedded or encased between layers of a selected insulative material such as polyimide film or sheet, and membranes. The sensor electrodes 20 at a tip end of the sensing portion 18 are exposed through one of the insulative layers for direct contact with patient blood or other body fluids, when the sensing portion 18 (or active portion) of the sensor 12 is subcutaneously placed at an insertion site. The sensing portion 18 is joined to a connection portion 24 that terminates in conductive contact pads, or the like, which are also exposed through one of the insulative layers.

[0017] As is known in the art, the connection portion 24 and the contact pads are generally adapted for a direct wired electrical connection to a suitable monitor or sensor electronics device 100 for monitoring a user's condition in response to signals derived from the sensor electrodes 20. Further description of flexible thin film sensors of this general type are be found in U.S. Pat. No. 5,391,250, entitled METHOD OF FABRICATING THIN FILM SENSORS. The connection portion 24 may be conveniently connected electrically to the monitor or sensor electronics device 100 or by a connector block 28 (or the like) as shown and described in U.S. Pat. No. 5,482,473, entitled FLEX CIRCUIT CONNECTOR. Thus, in accordance with some embodiments, subcutaneous sensor sets 10 may be configured or formed to work with either a wired or a wireless characteristic monitor system.

[0018] The sensor electrodes 20 may be used in a variety of sensing applications and may be configured in a variety of ways. For example, the sensor electrodes 20 may be used in physiological parameter sensing applications in which some type of biomolecule is used as a catalytic agent. For example, the sensor electrodes 20 may be used in a glucose and oxygen sensor having a glucose oxidase (GOx) enzyme catalyzing a reaction with the sensor electrodes 20. The sensor electrodes 20, along with a biomolecule or some other catalytic agent, may be placed in a human body in a vascular or non-vascular environment. For example, the sensor electrodes 20 and biomolecule may be placed in a vein and be subjected to a blood stream or may be placed in a subcutaneous or peritoneal region of the human body.

[0019] The monitor 100 may also be referred to as a sensor electronics device 100. The monitor 100 may include a power source 110, a sensor interface 122, processing electronics 124, and data formatting electronics 128. The monitor 100 may be coupled to the sensor set 10 by a cable 102 through a connector that 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 an appropriate connector for direct connection to the connection portion 104 of the sensor set 10. The sensor set 10 may be modified to have the connector portion 104 positioned at a different location, e.g., on top of the sensor set to facilitate placement of the monitor 100 over the sensor set.

[0020] In one embodiment, the sensor interface 122, the processing electronics 124, and the data formatting electronics 128 are formed as separate semiconductor chips, however, alternative embodiments may combine the various semiconductor chips into a single, or multiple customized semiconductor chips. The sensor interface 122 connects with the cable 102 that is connected with the sensor set 10.

[0021] The power source 110 may be a battery. The battery can include three series silver oxide 357 battery cells. In alternative embodiments, different battery chemistries may be utilized, such as lithium-based chemistries, alkaline batteries, nickel metal hydride, or the like, and a different number of batteries may be used. The monitor 100 provides power to the sensor set via the power source 110, through the cable 102 and cable connector 104. In one embodiment, the power is a voltage provided to the sensor set 10. In another embodiment, the power is a current provided to the sensor set 10. In an embodiment, the power is a voltage provided at a specific voltage to the sensor set 10.

[0022] FIG. 2 illustrates an implantable sensor, and electronics for driving the implantable sensor in accordance with one embodiment. FIG. 2 shows a substrate 220 having two sides, a first side 222 of which contains an electrode configuration and a second side 224 of which contains electronic circuitry (e.g., storage circuitry, processing circuitry, etc.). As may be seen in FIG. 2, a first side 222 of the substrate comprises two electrode pairs consisting of a counter electrode - background electrode pair 244, 240, and a counter electrode - working electrode pair 246, 242, on opposite sides of a reference electrode 248. A second side 224 of the substrate comprises electronic circuitry. As shown, the electronic circuitry may be enclosed in a hermetically sealed casing 226, providing a protective housing for the electronic circuitry. This allows the sensor substrate 220 to be inserted into a vascular environment or other environment which may subject the electronic circuitry to fluids. By sealing the electronic circuitry in a hermetically sealed casing 226, the electronic circuitry may operate without risk of short circuiting by the surrounding fluids. Also shown in FIG. 2 are pads 228 to which the input and output lines of the electronic circuitry may be connected. The electronic circuitry itself may be fabricated in a variety of ways. According to an embodiment, the electronic circuitry may be fabricated as an integrated circuit using techniques common in the industry.

[0023] FIG. 3 illustrates a general block diagram of an electronic circuit having a first channel 310, 312, 314 for sensing an output of the working electrode of a sensor according to one embodiment. At least one pair of sensor electrodes 310 may interface to a data converter 312, the output of which may interface to a counter 314. The counter 314 may be controlled by control logic 316. The output of the counter 314 may connect to a line interface 318. The line interface 318 may be connected to input and output lines 320 and may also connect to the control logic 316. The input and output lines 320 may also be connected to a power rectifier 322.

[0024] The sensor electrodes 310 may be used in a variety of sensing applications and may be configured in a variety of ways. For example, the sensor electrodes 310 may be used in physiological parameter sensing applications in which some type of biomolecule is used as a catalytic agent. For example, the sensor electrodes 310 may be used in a glucose and oxygen sensor having a GOx enzyme catalyzing a reaction with the sensor electrodes 310. The sensor electrodes 310, along with a biomolecule or some other catalytic agent, may be placed in a human body in a vascular or non-vascular environment. For example, the sensor electrodes 310 and biomolecule may be placed in a vein and be subjected to a blood stream. To compensate for the effect of an interferant which also causes a signal in the first channel 310, 312, 314, there is provided a second identical channel (not shown in FIG. 3) which senses the output of the background electrode of the sensor. The background electrode does not have the biomolecule and hence is only influenced by the interferant. By comparing the channels the effect of the interferant can be calculated out.

[0025] FIG. 4 illustrates a block diagram of a sensor electronics device and a sensor including a plurality of electrodes according to an embodiment herein. FIG. 4 includes system 400. System 400 includes a sensor 355 and a sensor electronics device 360. The sensor 355 includes a counter electrode 365, a reference electrode 370, and a working electrode 375. The sensor electronics device 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 either a voltage, a current, or a voltage including a current) to the regulator 385. The regulator 385 transmits a regulated voltage to the sensor 355. In one embodiment, the regulator 385 transmits a voltage to the counter electrode 365 of the sensor 355.

[0026] The sensor 355 creates a sensor signal indicative of a concentration of a physiological characteristic being measured. For example, the sensor signal may be indicative of a blood glucose reading. In an embodiment utilizing subcutaneous sensors, the sensor signal may represent a level of hydrogen peroxide in a subject. In an embodiment where blood or cranial sensors are utilized, the amount of oxygen is being measured by the sensor and is represented by the sensor signal. In an embodiment utilizing implantable or long-term sensors, the sensor signal may represent a level of oxygen in the subject. 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 an embodiment, the sensor signal may be a voltage measured at the working electrode.

[0027] The signal processor 390 receives the sensor signal (e.g., a measured current or voltage) after the sensor signal is measured at the sensor 355 (e.g., the working electrode). 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 utilizing reference values. In one embodiment, the reference values are 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) or by circuitry (e.g., storage circuitry). The sensor measurements may be sent to a display / transmission device to be either displayed on a display in a housing with the sensor electronics or transmitted to an external device.

[0028] The sensor electronics device 360 may be a monitor which includes a display to display physiological characteristics readings. The sensor electronics device 360 may also be installed in a desktop computer, a pager, a television including communications capabilities, a laptop computer, a server, a network computer, a personal digital assistant (PDA), a portable telephone including computer functions, an infusion pump including a display, a glucose sensor including a display, and / or a combination infusion pump / glucose sensor. The sensor electronics device 360 may be housed in a blackberry, a network device, a home network device, or an appliance connected to a home network. The system 400 also includes a second signal processor (not shown) connected to a background electrode (not shown) in the sensor 355. The background electrode does not have the chemistry necessary to detect the analyte sensed at the the working electrode 375, and hence only detects interference. In the measurement processor 395 the signal due to interference is removed from the signal due to the analyte to produce a corrected more accurate analyte reading.

[0029] FIG. 4 also includes system 450. System 450 includes a sensor electronics device 360 and a sensor 355. The sensor includes a counter electrode 365, a reference electrode 370, and a working electrode 375. The sensor electronics device 360 includes a microcontroller 410 and a digital-to-analog converter (DAC) 420. The sensor electronics device 360 may also include a current-to-frequency converter (I / F converter) 430.

[0030] The microcontroller 410 includes software program code, which when executed, or programmable logic which, causes the microcontroller 410 to transmit a signal to the DAC 420, where the signal is representative of a voltage level or value that is to be applied to the sensor 355. The DAC 420 receives the signal and generates the voltage value at the level instructed by the microcontroller 410. In one embodiment, 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.

[0031] The sensor 355 may receive the voltage level or value. In one embodiment, the counter electrode 365 may receive the output of an operational amplifier which has as inputs the reference voltage and the voltage value from the DAC 420. The application of the voltage level causes the sensor 355 to create a sensor signal indicative of a concentration of a physiological characteristic being measured. In an embodiment, the microcontroller 410 may measure the sensor signal (e.g., a current value) from the working electrode. Illustratively, a sensor signal measurement circuit 431 may measure the sensor signal. In an embodiment, the sensor signal measurement circuit 431 may include a resistor and the current may be passed through the resistor to measure the value of the sensor signal. In an embodiment, the sensor signal may be a current level signal and the sensor signal measurement circuit 431 may be a current-to-frequency (I / F) converter 430. The current-to-frequency converter 430 may measure the sensor signal in terms of a current reading, convert it to a frequency-based sensor signal, and transmit the frequency-based sensor signal to the microcontroller 410. In some embodiments, the microcontroller 410 may be able to receive frequency-based sensor signals easier than non-frequency-based sensor signals. The microcontroller 410 receives the sensor signal, whether frequency-based or non-frequency-based, and determines a value for the physiological characteristic of a subject, such as a blood glucose level. The microcontroller 410 may include program code, which when executed or run, is able to receive the sensor signal and convert the sensor signal to a physiological characteristic value. In one embodiment, the microcontroller 410 may convert the sensor signal to a blood glucose level. In an embodiment, the microcontroller 410 may utilize measurements stored within an internal memory or by circuitry (e.g., storage circuitry) in order to determine the blood glucose level of the subject. In an embodiment, the microcontroller 410 may utilize measurements stored within a memory external to the microcontroller 410 or by circuitry to assist in determining the blood glucose level of the subject. The system 450 also includes a second sensor signal measurement circuit (not shown) connected to a background electrode (not shown) in the sensor 355. The background electrode does not have the chemistry necessary to detect the analyte sensed (e.g. blood glucose) at the the working electrode 375, and hence only detects interference. In the microcontroller 410 the signal due to interference is removed from the signal from the working electrode to produce a corrected more accurate analyte reading.

[0032] After the physiological characteristic value is determined by the microcontroller 410, the microcontroller 410 may store measurements of the physiological characteristic values for a number of time periods. For example, a blood glucose value may be sent to the microcontroller 410 from the sensor every second or five seconds, and the microcontroller may save sensor measurements for five minutes or ten minutes of BG readings. The microcontroller 410 may transfer the measurements of the physiological characteristic values to a display on the sensor electronics device 360. For example, the sensor electronics device 360 may be a monitor which includes a display that provides a blood glucose reading for a subject. In one embodiment, the microcontroller 410 may transfer the measurements of the physiological characteristic values to an output interface of the microcontroller 410. The output interface of the microcontroller 410 may transfer the measurements of the physiological characteristic values, e.g., blood glucose values, to an external device, e.g., an infusion pump, a combined infusion pump / glucose meter, a computer, a personal digital assistant, a pager, a network appliance, a server, a cellular phone, or any computing device.

[0033] FIG. 5 is a block diagram illustrating the sensor electrodes and electronics for applying voltages to the sensor electrodes according to an embodiment. The sensor shown in Figure 5 has four electrodes 510, comprising a counter electrode 535, a reference electrode 532, a working electrode 534a and a background electrode 534b. An operational amplifier 530 is connected with its output coupled to the counter electrode and its inverting input coupled to the reference electrode 532. The non-inverting input of the operational amplifier is coupled to a voltage source held at a set voltage Vset with reference to the working electrode. In operation the operational amplifier stabilizes the voltage between the reference electrode and the working electrode irrespective of the amount of current which flows in the working electrode. The working electrode 534a has a coating of GOx or other suitable biomolecule. In the presence of surplus oxygen the GOx catalyses the oxidation of any glucose present resulting ultimately in the generation of an electric current Isig, referred to below as a first signal, in the working electrode. Electric currents are also produced at the working electrode due to interferants such as acetaminophen. The background electrode 534b has no GOx layer (e.g., as discussed below in relation to FIGS. 8 and 9). Accordingly the background electrode only conducts a current Isig produced by the interferants, referred to below as a second signal. The system may then, from the second signal, detect ingestion of a medication by the user, and by a comparison of the first and second signals generate a sensor glucose value free from the influence of the interferant. In the embodiment illustrated in FIG. 5, the operational amplifier 530, may connect to sensor electrodes 510 through a circuit / electrode interface 538. The operational amplifier 530, utilizing feedback through the sensor electrodes, attempts to maintain a prescribed voltage (what the DAC may desire the applied voltage to be) between the reference electrode 532 and the working electrode 534 by adjusting the voltage at a counter electrode 536. Current may then flow from the counter electrode 536 to the working electrode 534. Such current may be measured to ascertain the electrochemical reaction between the sensor electrodes 510 and the biomolecule of the sensor that has been placed in the vicinity of the sensor electrodes 510 and used as a catalyzing agent.

[0034] It has been found that a potential difference of about 0.5 Volts, preferably 535mV between the working electrode and the reference electrode for GOx produces good results. If a different biomolecule is used instead of GOx other voltages may be more appropriate. For best results the potential difference between the background electrode and the reference electrode can be higher, for example 700 mV.

[0035] As discussed above, during initial implantation or insertion of the sensor 510, the sensor 510 may provide inaccurate readings due to the adjusting of the subject to the sensor and also electrochemical byproducts caused by the catalyst utilized in the sensor. A stabilization period is needed for many sensors in order for the sensor 510 to provide accurate readings of the physiological parameter of the subject. During the stabilization period, the sensor 510 does not provide accurate blood glucose measurements. Users and manufacturers of the sensors may desire to improve the stabilization timeframe for the sensor so that the sensors can be utilized quickly after insertion into the subject's body or a subcutaneous layer of the subject.

[0036] In previous sensor electrode systems, the stabilization period or timeframe was one hour to three hours. In order to decrease the stabilization period or timeframe and increase the timeliness of accuracy of the sensor, a sensor (or electrodes of a sensor) may be subjected to a number of pulses rather than the application of one pulse followed by the application of another voltage. for the second time period. In one embodiment, the first voltage may be 1.07 volts. In an embodiment, the first voltage may be 0.535 volts. In an embodiment, the first voltage may be approximately 0.7 volts.

[0037] FIG. 6 shows a flowchart of the steps involved in continuous glucose monitoring, in accordance with one or more embodiments. For example, process 600 may represent the steps taken by one or more devices as shown in FIGS. 1-5.

[0038] At step 602, process 600 (e.g., using circuitry described in FIGS. 1-5) activates a first electrode on a user, wherein the first electrode has a coating to Glucose Oxidase (GOx). For example, the system may activate a first electrode on a user (e.g., a patient), wherein the first electrode detects a current Isig due to the oxidation of any glucose present catalysed by the Glucose Oxidase (GOx) (the first electrode is a GOx sensor).

[0039] For example in some embodiments, a sensor may initiate a start-up procedure either based on a remotely received command, automatically (e.g., based another sensor detecting certain conditions), or from a user inputted command. In response to the sensor start up, a first and second electrode (e.g., corresponding to a working electrode and a background electrode). Additionally, the first and second electrode may undergo a current and / or voltage initialization sequence. These initialization sequences may differ based on whether or the electrode comprises the GOx sensor.

[0040] At step 604, process 600 (e.g., using circuitry described in FIGS. 1-5) activates a second electrode on the user. This is the background electrode and does not have a layer of GOx.

[0041] At step 606, process 600 (e.g., using circuitry described in FIGS. 1-5) sets a first voltage potential (Vset) for the first electrode. For example, the system may set, using the control circuitry, a first voltage potential (Vset) for the first electrode. For example, the first Vset may be in a range of 400-500 mV.

[0042] At step 608, process 600 (e.g., using circuitry described in FIGS. 1-5) sets a second Vset for the second electrode. For example, the system may set, using the control circuitry, a second voltage potential (Vset) for the second electrode. In some examples, the first Vset may be lower than the second Vset. For example, the second Vset may be in a range of 500-600 m V.

[0043] At step 610, process 600 (e.g., using circuitry described in FIGS. 1-5) receives a first signal from the first electrode. For example, the system may receive, using the control circuitry, a first signal from the first electrode. The first electrode may be a working electrode, and the system may receive a 5-minute reading of sensor current in nA, sometimes called "raw Isig," or other Isig value (e.g., as shown above).

[0044] At step 612, process 600 (e.g., using circuitry described in FIGS. 1-5) receive a second signal from the second electrode. For example, the system may receive, using the control circuitry, a second signal from the second electrode. The second electrode may be a background electrode, and the system may receive a 5-minute reading of sensor current in nA, sometimes called "raw lsig," or other Isig value (e.g., as shown above). It may be convenient to perform the steps 606, 608, 610, and 612 in a different order from that shown in FIG 6. For example it may be desired to set the first electrode potential step 606 and obtain the first signal step 610, before setting the second or background electrode potential at step 608 and obtaining the second signal at step 612.

[0045] At step 614, process 600 (e.g., using circuitry described in FIGS. 1-5) compares the first signal and the second signal to detect ingestion of a medication by the user. For example, the system may compare, using the control circuitry, the first signal and the second signal to detect ingestion of a medication by the user. For example, the medication (e.g., acetaminophen) may produce an interfering current that increases both the current at the working / first electrode and at the background / second electrode..

[0046] In some embodiments, comparing the first signal and the second signal to detect ingestion of a medication by the user further comprises one or more steps. For example, the system may determine a noise level for the second signal. The system may compare the noise level to a noise threshold. The system may calculate the 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 a sensor glucose value based on the first electrode using the Isig from the first electrode.

[0047] In another example, the system may determine a noise level for the second signal. The system may compare the noise level to a noise threshold. The system may 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 signal and the second signal. For example, the system may apply a scale factor to the Isig of the second electrode and apply a Scale factor to the Isig. In some embodiments, the scale factor may be a linear or non-linear multidimensional scale factor. The system may then determine a difference between the Isig of the first electrode and scaled Isig of the second electrode. The system may then calculate a sensor glucose value in mg / dL based on the difference between the Isig of the first electrode and scaled Isig of the second electrode. The sensor glucose value may then be used to display a value to the user.

[0048] The normalized values are scaled using scaling functions, specific to the environmental or physiological factor under consideration, and the scaled values are combined to generate an aggregate value. In one embodiment, the combination may be obtained by multiplying the different scaled values together. In other embodiments, the aggregation may be achieved by determining a mean value or selecting the maximum of the available values.

[0049] It is noted that the threshold values, or ranges, for the above-mentioned parameters may depend on various factors, including the specific sensor and / or electrode design. Nevertheless, in one embodiment, typical ranges for some of the above-mentioned parameters may be, e.g., as follows: Bound threshold for 1 kHz real impedance = [0.3e+4 2e+4]; Bound threshold for 1kHz imaginary impedance = [-2e+3, 0]; Bound threshold for 0.105Hz real impedance = [2e+4 7e+4], Bound threshold for 0. 105Hz imaginary impedance = [-2e+5 -0.25e+5]; and Bound threshold for Nyquist slope = [2 5]. Noise may be calculated, e.g., using second order central difference method where, if noise is above a certain percentage (e.g., 30%) of median value for each variable buffer, it is considered to be out of noise bound.

[0050] It should also be noted that, in further embodiments, in determining whether data should be blanked, or the sensor terminated, the logic may also consider, in addition to the above-mentioned thresholds, sudden increases in impedance by, e.g., comparing impedance derivatives to historical derivatives. Moreover, the algorithm may incorporate noise-based blanking or termination, depending on the duration of high noise-low sensor signal combination. In this regard, prior methodologies included termination of the sensor after three (3) consecutive 2-hour windows of high noise and low sensor signal. However, in order to prevent unreliable data from being displayed to the user, embodiments employ noise-based blanking, wherein the algorithm stops calculating SG values after 2 consecutive 2-hour windows (i.e., at the start of the third consecutive window) involving high noise and low signal. In further aspects, the algorithm may allow further calculation and display of the calculated SG values after one hour of blanking, rather than two hours, where the sensor signal appears to have recovered. This is an improvement over methodologies that blank otherwise reliable data for longer periods of time.

[0051] At step 616, process 600 (e.g., using circuitry described in FIGS. 1-5) generates a sensor glucose value based on the comparison. In its simplest form the comparison comprises assessing the amount of signal from the working electrode that is due to the interferant and deducting that amount before calculating the glucose value. The amount of signal due to the interferant can readily be assessed as this is the signal from the background electrode, scaled to take into account any difference in the set voltage, or area of the electrodes. The comparison produces a corrected glucose value which can be displayed to the user. For example, the system may display the corrected sensor glucose value on a user interface and / or be used to adjust a glucose amount delivered to the user. As a further level of complexity in some embodiments there may be made an assessment of reliability of sensor glucose values, as well as estimation of sensor-data error direction, in order to provide users and automated insulin delivery systems--including those in closed-loop systems--an indicator of how reliable the system is when SG is displayed to the user. Depending on the reliability of sensor data, such automated systems are then able to assign a corresponding weight to the SG and make a determination as to how aggressively treatments should be provided to users. Additionally, the direction of error can also be used to inform users and / or the insulin delivery system in connection with SG being a "false low" or a "false high" value. The foregoing may be achieved by, e.g., detecting dips in sensor data during the first day (EIS dip detection), detecting sensor lag, and lower-frequency (e.g., 10Hz) impedance changes.

[0052] It is contemplated that the steps or descriptions of FIG. 6 may be used with any other embodiment of this disclosure. In addition, the steps and descriptions described in relation to FIG. 6 may be done in alternative orders or in parallel to further 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 any of the devices or equipment discussed in relation to FIGS. 2-4 could be used to perform one or more of the steps in FIG. 6.

[0053] FIG. 7 shows a flowchart of the steps involved in continuous glucose monitoring, in accordance with one or more embodiments. For example, process 700 may represent the steps taken by one or more devices as shown in FIGS. 1-5.

[0054] At step 702, process 700 (e.g., using circuitry described in FIGS. 1-5) receives a first and second signal (e.g., respective Isigs) from a first and second electrode (e.g., a working electrode and a background electrode). For example, the system may use one or more steps as described above in FIG. 6 to generate the Isigs.

[0055] At step 704, process 700 (e.g., using circuitry described in FIGS. 1-5) determines whether an adjustment of the value of the Isig from the working electrode is necessary. This is done by determining whether the Isig for a background electrode (e.g., the second electrode of FIG. 6) exceeds a noise threshold for the background electrode thereby indicating that there is a significant signal from an interferant such as Acetaminophen. In addition it can optionally be determined whether the working or background electrodehas a 0.1 Hz IMG EIS impedance ("EIS value") exceeding respective thresholds. For example, the effective resistance of an electric circuit or component to alternating current, arising from the combined effects of ohmic resistance and reactance of the EIS may be compared to a respective threshold.

[0056] EIS may be used in sensor systems where the sensor includes a single working electrode, as well those in which the sensor includes multiple (redundant) working electrodes. In one embodiment, EIS provides valuable information regarding the age (or aging) of the sensor. Specifically, at different frequencies, the magnitude and the phase angle of the impedance vary. Additionally, EIS may enable detection of sensor failure by detecting when the sensor's impedance drops below a low impedance threshold level indicating that the sensor may be too worn to operate normally. The system may then terminate the sensor before the specified operating life. Sensor impedance can also be used to detect other sensor failure (modes). For example, when a sensor goes into a low-current state (i.e., sensor failure) due to any variety of reasons, the sensor impedance may also increase beyond a certain high impedance threshold. If the impedance becomes abnormally high during sensor operation, due, e.g., to protein or polypeptide fouling, macrophage attachment or any other factor, the system may also terminate the sensor before the specified sensor operating life.

[0057] If process 700 determine that no adjustment is needed because neither criteria is met, process 700 proceeds to step 706. If process 700 determine that an adjustment is needed because one or both criteria are met, process 700 proceeds to step 710.

[0058] At step 706, process 700 (e.g., using circuitry described in FIGS. 1-5) calculates a 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.

[0059] At step 710, process 700 (e.g., using circuitry described in FIGS. 1-5) determines if the Isig from the background electrode (e.g., the second electrode of FIG. 6 above) is greater than a 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 for the background electrode is greater, process 700 proceeds to step 714. If the Isig for the background electrode is not greater, process 700 proceeds to step 712. Failure to exceed the threshold at step 710 corresponds to a positive detection of interference, but insufficient confidence that the background electrode Isig can be used to compensate for the interference at the Isig at the working electrode to produce a more reliable sensor glucose SG value. Steps 710 and 712 are optional and process 700 may continue to step 714 from the YES branch of step 704.

[0060] At step 712, process 700 (e.g., using circuitry described in FIGS. 1-5) blanks the sensor glucose value to the user for a given amount of time and returns to step 702, whereup the process 700 repeats with the next values of the working electrode Isig and the background electrode Isig. It should also be noted that in determining whether data should be blanked, or the sensor terminated, the logic may also consider, in addition to the above-mentioned thresholds, sudden increases in impedance by, e.g., comparing impedance derivatives to historical derivatives. Moreover, the algorithm may incorporate noise-based blanking or termination, depending on the duration of high noise-low sensor signal combination. In this regard, prior methodologies included termination of the sensor after three (3) consecutive 2-hour windows of high noise and low sensor signal. However, in order to prevent unreliable data from being displayed to the user, embodiments employ noise-based blanking, wherein the algorithm stops calculating SG values after 2 consecutive 2-hour windows (i.e., at the start of the third consecutive window) involving high noise and low signal. In further aspects, the algorithm may allow further calculation and display of the calculated SG values after one hour of blanking, rather than two hours, where the sensor signal appears to have recovered. This is an improvement over methodologies that blank otherwise reliable data for longer periods of time.

[0061] At step 714, process 700 (e.g., using circuitry described in FIGS. 1-5) determines a new Isig value for the working electrode using a pre-determined mathematical model (e.g., as shown by the formula at step 714). For example, the new value is the difference between the Isig value for the working electrode and a weighted Isig for the background electrode and optionally a weighted EIS value. It has been found that the 0.1 Hz imaginary impedence at the working electrode correlates well with Acetaminophen interference and can be used to establish confidence in the value obtained from the difference between the weighted Isigs. In the simplest case the new value is the difference between the Isig value for the working electrode and a weighted Isig value for the background electrode. Process 700 may then proceed to step 716 and calculate a new sensor glucose value based on the new Isig value for the working electrode for subsequent display to the user at step 708.. Following the display step the process 700 starts again at step 702 using the next next values of the working electrode Isig and the background electrode Isig.

[0062] It is contemplated that the steps or descriptions of FIG. 7 may be used with any other embodiment of this disclosure. In addition, the steps and descriptions described in relation to FIG. 7 may be done in alternative orders or in parallel to further 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 any of the devices or equipment discussed in relation to FIGS. 2-4 could be used to perform one or more of the steps in FIG. 7.

[0063] FIG. 8 illustrates a unity sensor having a background electrode metal layer made of platinum. As shown in FIG. 8, the sensor may comprise a conductor trace (e.g., gold) surrounded by an insulating material (e.g., polyimide). The sensor shown in FIG. 8 includes a counter electrode, background electrode, reference electrode, working electrode, and may include other electrodes. Each electrode may comprise 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 catalysing the reduction-oxidation reaction of glucose thereby producing a current in the electrode in response to the presence of glucose. The background electrode (e.g., comprising platinum in this embodiment) may be distinguished from the working electrode in that the background electrode does not include GOx or other glucose reduction-oxidation catalyst. Optionally each electrode may be coated in a glucose limiting membrane. A unity sensor such as shown in FIG. 8 may be included in a CGM device (e.g., as discussed in relation to FIG. 10). Although the sise and position of the electrodes on the substrate is optional, in FIG 8 the background electrode is smaller than the working electrode and is positioned on the opposite side of the reference electrode from the working electrode.

[0064] FIG. 9 illustrates a unity sensor with the same structure as that shown in FIG 8 except that the background electrode metal layer is made of gold. As shown in FIG. 9, the sensor may comprise a conductor trace (e.g., gold) surrounded by an insulating material (e.g., polyimide). The sensor includes a counter electrode, background electrode, reference electrode, working electrode, and optionally other electrodes. Each electrode may comprise 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 catalysing the reduction-oxidation reaction of glucose thereby producing a current in the electrode in response to the presence of glucose. The background electrode (e.g., comprising gold in this embodiment) may be distinguished from the working electrode in that the background electrode may not include the GOx or catalyst. Optionally each electrode may be coated in a glucose limiting membrane. A unity sensor such as shown in FIG. 9 may be included in a CGM device (e.g., as discussed in relation to FIG. 10).

[0065] FIG. 10 illustrates a single sensor flex 1002 in a CGM device 1000 and a dual sensor flex 1052 in a CGM device 1050. Single sensor flex 1002 (e.g., as shown in FIG. 8) may include a counter electrode 1004, background electrode 1006, reference electrode 1008, working electrode 1010, and / or other electrodes. The dual sensor flex 1052 includes two sensor flexes (e.g., as shown in FIG. 9) in CGM device 1050. For example, one sensor of dual sensor flex 1052 may include a counter electrode 1056, reference electrode 1058, working electrode 1060, and / or other electrodes, while the other sensor of dual sensor flex 1052 may include a background electrode 1054 and / or other electrodes. As shown in FIG. 10, the two sensor flexes in the dual sensor flex may be placed back-to-back in CGM device 1050. In manufacture, GOx may be deposited onto the working electrodes 1010 and 1060 shown in FIG. 10. Instead of GOx, a different enzyme of interest for example hexokinase, or glucose-1-dehydrogenase ("GDH") may be deposited onto one or more of the working electrodes. A glucose limiting membrane (GLM) may be deposited on top of the GOx (or other enzyme) layer. In manufacturing processes the GOx (or other enzyme) may be deposited onto several electrodes including the working and background electrodes and then removed from electrodes such as the background electrode where it is not required, resulting in a structure in which the GOx, or other enzyme remains only on the working electrode, but not on other electrodes. In some embodiments, the deposited layers may not be deposited solely above the electrodes. For example, the GLM layer may extend from one electrode to another.

[0066] The above-described embodiments of the present disclosure are presented for purposes of illustration and not of limitation, and the present disclosure is limited only by the claims which follow. Furthermore, it should be noted that the features and limitations described in any one embodiment may be applied to any other embodiment herein, and flowcharts or examples relating to one embodiment may be combined with any other embodiment in a suitable manner, done in different orders, or done in parallel. In addition, the systems and methods described herein may be performed in real time. It should also be noted that the systems and / or methods described above may be applied to, or used in accordance with, other systems and / or methods.

Claims

1. A method for continuous glucose monitoring in the presence of interference caused by a medication, comprising: activating a first electrode on a user wherein the first electrode has a layer of a catalyst promoting a reaction with the glucose detectable as an electrical current in the electrode; activating a second electrode on the user which does not have the catalyst; setting the first electrode to a first voltage potential (Vset1); setting the second electrode to a second voltage potential (Vset2); wherein the first voltage potential (Vset1) is lower than the second voltage potential (Vset2); receiving a first signal from the first electrode, the first signal having a first part due to the detection of glucose and a second part due to interference due to the medication; receiving a second signal from the second electrode, the second signal being due to the interference due to the medication; distinguishing between the first part of the signal from the first electrode and the second part by comparing the first signal and the second signal; and further comprising - determining a 0.1 Hz imaginary EIS Impedance of the first electrode and / or the second electrode - comparing the determined 0.1 Hz imaginary EIS Impedance to a respective threshold (704), - in response to the 0.1 Hz imaginary EIS Impedance not exceeding the respective threshold, calculating the sensor glucose value based on the first signal from the first electrode (706), wherein in response to the 0.1 Hz imaginary EIS Impedance exceeding the respective threshold: - determining a new value for the first signal based at least in part on the 0.1 Hz imaginary EIS impedance (714), - calculating the sensor glucose value based on the new value for the first signal (716).

2. The method of claim 1, wherein the catalyst is Glucose Oxidase (GOx).

3. The method of any of claims 1 to 2, wherein the distinguishing and generating comprise inputing the first signal and the second signal as parameters in a pre-determined mathematical model for adjusting the sensor glucose value.

4. The method of any of claims 1 to 2, further comprising: determining a noise level for the second signal; comparing the noise level to a noise threshold; and in response to the noise level not exceeding the noise threshold to assume that the second part of the signal from the first electrode is zero.

5. The method of any of claims 1 to 2, wherein, the comparing of the first signal and the second signal comprises: calculating the first part of the signal from the first electrode as a weighted difference between the first signal and the second signal.

6. A system for continuous glucose monitoring by performing the method in accordance with any of claims 1 to 5 comprising: the first electrode having the layer of the catalyst; the second electrode not having the catalyst; and processing circuitry configured to perform the said method.

7. The system of claim 6 wherein the first electrode is of platinum.

8. The system of claim 6 or 7 wherein the second electrode is of gold.

9. The system of any of claims 6 to 8, wherein the first electrode and the second electrode are located on separate sensors in a device.

10. The system of claim 9, wherein the separate sensors are sensor flexes.

11. The system of claim 10, wherein the two sensor flexes are placed back-to-back, particularly wherein the two sensor flexes face in opposite directions.

12. The system of claim 11, wherein the first electrode on a first of the flexes faces in one of the directions and the second electrode on a second of the flexes faces in the other direction.

13. A non-transitory computer-readable media for continuous glucose monitoring comprising instructions that, when executed by the system according to any of claims 6-12, cause operations comprising the method according to any of claims 1 to 5.