Methods, systems, and devices for continuous analyte monitoring

Abstract

Embodiments of the disclosure generally relates to systems and methods for real time continuous monitoring of glucose. More specifically, the embodiments of the disclosure relate to a device for continuous glucose monitoring (COM), that includes subcutaneous electrochemical sensor, electronics, and algorithms to improve ease of manufacture, use, and more importantly, the welfare of people with diabetes.

Description

INTERNATIONAL PATENT APPLICATIONMETHODS, SYSTEMS, AND DEVICESFOR CONTINUOUS ANALYTE MONITORINGRELATED APPLICATIONS

[0001] The subject disclosure claims benefit of and priority to U.S. provisional patent application no. 63 / 612,343 filed on December 19, 2023, the entire disclosure of which is herein incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The embodiments of the disclosure generally relate to systems and methods for real time continuous monitoring of glucose. More specifically, the embodiments of the disclosure relate to a device for continuous glucose monitoring (CGM), that includes subcutaneous electrochemical sensor, electronics, and algorithms to improve ease of use and welfare of people with diabetes.BACKGROUND

[0003] Continuous glucose monitoring (CGM) systems play a critical role in diabetes management by enabling real-time tracking of glucose levels. Current CGM technologies, however, often face challenges related to accuracy, calibration, longevity, and interference from non-glucose analytes. These challenges often result in substantial costs during manufacturing, or else provide sub-optimal products to end-users. This invention addresses at least one and / or other challenge by introducing an advanced sensing system utilizing multi - electrode electrochemical configuration and real-time signal processing algorithms.SUMMARY OF THE DISCLOSURE

[0004] In some embodiments of the present disclosure, a system for continuously monitoring glucose concentration (hereinafter "CGM system" or "system") in the subcutaneous tissue is provided. In some embodiments, the system includes a skin adhered sensor patch that comprises an electronic assembly having a battery, a processor, and a bi-directional communication with a monitor and a planar probe ("sensor", or "electrochemical sensor") for insertion within a subject. The planar probe includes a side A and a side B. The electrochemical sensor can comprise, in some embodiments, a plurality of working electrodes, a reference electrode, and a counter electrode.

[0005] The processor has access to computer instructions which when operated thereon, cause the processor to determine glucose concentration based on information (which in some embodiments, are one or more signals) generated by the planar probe.

[0006] In some embodiments, each working electrode includes a base sheet, a conductive metal layer, and one of multiple glucose sensitive enzymes (and in some embodiments, at least one), other analytes sensitive enzymes, or inactive enzymes. Each working electrode is coated or not coated with glucose limiting membrane (GLM) or any other analyte limiting membrane. In some embodiments, all electrodes that are coated with GLM are positioned on one side of the planar probe.

[0007] In some embodiments, each triad of working electrode, reference electrode, and counter electrode form an electrochemical cell (EC). To this end, each electrochemical cell generates an electrical current (j) by enzymatic oxidizing of glucose (or another analyte) by a glucose (analyte) sensitive enzyme deposited on the working electrode.

[0008] In some embodiments, a plurality of electrochemical cells is provided, e.g., EC-1, EC- 2, EC-3 ... EC-n, which generate currents j1, j2, J3, ... jn, respectively. The processor receives these current signals from one or more electrochemical cells, analyses the signals (in some embodiments, via a glucose determination algorithm), and provides output - i.e., a glucose concentration (g).

[0009] In some embodiments, the processor receives current signals from two (2) electrochemical cells (EC 1, comprising a working electrode with glucose sensitive enzyme and GLM, and EC 2, comprising a working electrode with the same enzyme without GLM), analyses the signals (in some embodiments, using a dedicated algorithm) and provides output (glucose level(s)). In some such embodiments, the glucose levels are accurate immediatelyafter insertion and throughout use time, and in some embodiments, include a short warm-up time and / or a short step response time. In some such embodiments, the glucose concentration is not dependent on calibration.

[0010] In some embodiments, the electrochemical cells include a working electrode with glucose sensitive enzyme, a working electrode with inactive glucose sensitive enzyme, and other working electrodes with other glucose sensitive enzymes and other analyte sensitive enzymes. Analysis of signals concomitantly received from multiple electrochemical cells provides glucose readings that are insensitive to interference. Analysis of signals received from each electrochemical cell having a working electrode with analyte (non-glucose) sensitive enzyme provides real time (or substantially real-time) readings of analytes concentration.

[0011] In some embodiments, the additional information provided by one or more additional electrodes (EC-2, EC-3, EC-n) is used to provide real-time calibration. An algorithm is used to process the signal from a non-coated electrode with predictable characteristics, low production variance, and a non-linear response, to provide data aiding in the accurate real-time calibration of the primary glucose-sensitive electrode EC-1. The algorithm uses the statistical information about the electrodes, as measured per batch in production, to estimate the specific calibration parameters of the primary electrode.

[0012] The signal from additional electrode EC-2 is represented as the time series yEc-2(i) where i is the time index. The signal demonstrates a relationship with glucose concentration according to:

[0013] Where Cgiucoseis the concentration of glucose in the bulk solution where the electrode is present, and is the interesting signal to measure; CLEC-2 and bEC-2 are constants describing the linear relationship of the signal received at EC-2 and the activity of the enzyme; f() is a non-linear function of the form:

[0014] The function f() is a description of enzyme activity, where C is the concentration of the substrate; V is the max activity level of the enzyme and Kmis the Michaelis constant.

[0015] These constants (aEC-2, bEc-2, V, and Km) are estimated during production of the sensor according to measurements while the sensor is tested by exposure to different glucose levels.

[0016] The relationship [1] holds during the first few hours of operation while the enzyme is intact and does not experience degradation as a result of excess activity. Using the knowledge of the constants it is possible to estimate the glucose concentration

[0017] The signal from the EC-1 electrode is represented by a the time series ygc-iCO where i is the time index. The signal demonstrates a linear relationship with glucose concentration according to:

[0018] Where i is the time index; is the glucose concentration in the bulk solution;andareconstants describing the linear relationship of the signal received atEC-1 and the glucose concentration Given the estimated signal the constantsand shall be estimations of using a linear regression such as leastsquares estimation. Once the linear constants are estimated, for the duration of the sensor activity, the estimated glucose is given by:

[0019] In some embodiments, the additional information provided by one or more additional electrodes (EC-2, EC-3, EC-n...) is used to reduce the required warm up time of the sensor. An algorithm is used to process the signal from a non-coated electrode with a fast warm up time to provide glucose information in the first few hours of operations while estimating system coefficients to provide accurate calibration for the primary electrode EC-1.

[0020] In these embodiments, the solution for calibration coefficients for calculation of glucose by signal EC-1 is done according to the same procedure of

[0009] , However, during the first few hours of the sensor activity, the glucose levels are calculated according to the signal received from the one or more additional electrodes (EC-2, EC-3, . . .) per equation [1] and [2]

[0021] In some embodiments, the additional information provided by one or more additional electrodes (EC -2, EC-3, . . .) is used to improve the sensor response time. An algorithm is used to process the signal from a non-coated electrode with a fast response time, while the signals from the primary electrode and the additional electrodes are used to calculate respective calibration coefficients.

[0022] In these embodiments, the signal received from the one or more additional electrodes (EC-2, EC-3, ...) represents well the average glucose value, over a long time period of >30minutes. However, the signal has a slow response time and therefore does not reflect well a fast rising or fast falling glucose scenario. Therefore, the momentary glucose levels are calculated from a combination of the signals received from EC-1 and EC-2 (EC-3, EC-n).

[0023] Similar to the embodiments disclosed above, the glucose concentration at any given time can be given by:

[0024] Where Cgiucoseis the concentration of glucose in the bulk solution where the electrode is present and is the interesting signal to measure; f() is a non-linear function of the form [2], However, different than [1], aEC-2and bEC-2are constants that are calculated in real-time from the relationship between the average signal received by EC-1 and the average of the signal received by EC -2. This estimation of the calibration constants of EC-2 is performed given the constraint:

[0025] Where the average is taken over the same time duration. A duration which is significantly larger than the response time of EC-1 electrode.

[0026] In some embodiments, the additional information provided by one or more additional electrodes (EC-2, EC-3, . . .) is used to improve the sensor specificity by subtraction of signals correlating to interferences. An algorithm is used to process the signals from additional electrodes, which are not sensitive to glucose, but are sensitive to interferences, estimate the effect of the interferences and subtract from the signal of the primary glucose-sensitive electrode.

[0027] In these embodiments, the electrode EC-1 includes an enzyme based sensing layer, while an additional electrode (EC -2, EC-3, . . .) is constructed from an in-activated sensing layer (manufactured by applying inactive enzyme instead of active enzyme into the formulation of EC-1) or else is constructed from a replacement material to the enzyme layer that does not contain enzyme, but otherwise provides the same fluid dynamics properties of the sensing layer (characterized by diffusion parameters and mass transfer coefficient). All Electrodes (EC-1, EC -2, EC-3, ...) are otherwise produced in a similar fashion, i.e., covered by the same membranes for diffusion limiting and biocompatibility purposes.

[0028] The interference species that react electrochemically with the working electrode and do not interact with the enzyme, shall produce a signal similar in both active enzyme electrode EC-1 as well as in-active enzyme electrode (EC-2, EC-3, . . .). It is therefore possible to reduce the effect of these species on the glucose signal by subtracting the signal measured at the additional electrode from the signal of EC-1.

[0029] Manufacturing parameters may cause minor differences in gain properties of the measured interferences (e.g., the signal is directly proportional to electrode area which will include manufacturing variance). It is possible to estimate the gain difference between EC-1 and the additional electrode by calculating the correlation of the two signals, and account for this gain in the subtraction.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG. 1 shows a CGM system that includes a sensor patch and a monitor, according to some embodiments;

[0031] FIG. 2 shows a cross-section view of a skin adhered sensor patch and a subcutaneous electrochemical sensor, according to some embodiments, where glucose that oxidized on the sensor is converted to gluconic acid and a generated electrical current is conducted to the PCB / A;

[0032] FIGs. 3a-f show an exploded view of a sensor patch according to some embodiments, where the sensor patch 3a-b includes electronic assembly 3c and probe assembly 3d, and the probe assembly includes a probe 3e having a contacts plate and a tip (magnified view 3f).

[0033] FIG. 4a-b show detailed views of an electronic assembly 4a and a probe assembly 4b according to some embodiments;

[0034] FIG. 5a-e show a view of a probe for a continuous glucose monitoring system, illustrating a top-level view, side A (5a), and side B (5b), spatial view (5c), and cross section views of electrodes (5d-e), according to some embodiments;

[0035] FIGs. 6a-e shows a production process of electrodes on side A of a planar probe - adhesion of 2ndpolyimide sheets (top level view 6a) to 1stpolyimide sheet (cross section view - 6b), electrodes base sheet and conductive layer (cross section view 6c), deposition of enzyme (bio-dotting) 6d, and coating of GLM 6e, according to some embodiments;

[0036] FIGs. 7a-e shows a top-level view, a side A (7a) and a side B (7b), a spatial view (7c), and cross section views of the electrodes (7d-e), for a planar probe according to some embodiments;

[0037] FIGs. 8a-e shows a production process of electrodes on side A of a planar probe - adhesion of 2ndpolyimide sheets (top level view 8a) to 1stpolyimide sheet (cross section view - 8b), electrodes base sheet and conductive layer (cross section view 8c), deposition of enzymes (bio-dotting) 8d, and GLM coating 8e, according to some embodiments;

[0038] FIGs. 9a-c shows a calibration curve of electrochemical cells - typical calibration curve of a single electrochemical cell (9a), different calibration curves (1 and 2) of 2 electrochemical cells of 2 sensors from same lot (9b), calibration curves of a single electrochemical cell without GLM (9c- 1) and with GLM (9c-2) according to some embodiments;

[0039] FIG. 10 a characteristic stability curve after insertion of a sensor without GLM (line 1) and with GLM (line 2), according to some embodiments;

[0040] FIG. 11 shows a step addition test (chronoamperometry) of a single electrochemical cell for a probe for glucose monitoring, at day 1 (11-1) and day 13 (11-2), where response time is the distance between diamonds, according to some embodiments;

[0041] FIG. 12 shows a step addition test (chronoamperometry) of a single electrochemical cell for a probe for glucose monitoring, at day 1, 5, 9, and 16 (12-1, 2, 3, and 4), where response time is the distance between diamonds, according to some embodiments;

[0042] FIG. 13 shows a step addition test (chronoamperometry) of a single electrochemical cell (working electrode without GLM) for a probe for glucose monitoring, at days 1, 5, 9, and 16 (FIGs. 12-1, 2, 3, and 4), according to some embodiments; and

[0043] FIG. 14 shows a step addition test (chronoamperometry) of a calibrated electrochemical cell (working electrode with GLM) for a probe for glucose monitoring, at day 1 (14-1) and day 11 (14-2), after implementing an algorithm that considers signals from another electrochemical cell (working electrode without GLM), according to some embodiments.DETAILED DESCRIPTION

[0044] FIG. 1 shows a CGM system 200 that is configured for continuously measuring real time glucose levels. The system 200, in some embodiments, includes a sensor patch 1 and amonitor 2. Glucose readings can be transmitted from the sensor patch 1 to the monitor 2 and presented on a monitor screen. The sensor patch 1, in some embodiments, includes an adhesive 21 and a sensing probe tip 10 ("sensor"). FIG. 2 shows a cross section view according to some embodiments of the sensor patch 1 that is adhered to the skin 100 with the adhesive 21 and includes a probe tip 10 and a printed circuit board assembly (PCB / A) 24 having a processor. Probe tip 10 is configured for insertion within sub-cutaneous tissue 300 of a subject and can include electrodes 50 and 70 provided on one or both sides of the probe tip 10. Electrodes 50 and 70 ("working electrodes") can be coated with enzyme and collect electrons (i.e., electrical current) that are generated by enzymatic oxidation of glucose.

[0045] In some embodiments, the processor has computer instructions operating thereon for determining glucose concentration based on input signals (which can also be referred to as information) and output the result (or provide to another device, e.g., monitor 2, for display to a person (e.g., the subject) or otherwise an indication thereof.

[0046] In some embodiments, glucose within the subcutaneous tissue 300 is oxidized to gluconic acid by a glucose specific enzyme and the generated electrons are conducted, via the prob tip 10, to the PCB / A 24. Accordingly, given a non-linear correlation between glucose concentration and the generated current, an algorithm operating on PCB / A 24 processor converts the current (signal) to glucose readings. In some embodiments, the enzyme is glucose specific, oxygen independent, cellobiose dehydrogenase (CDH), and electrons are transferred from the enzyme to the electrode. Alternatively, the enzyme can be oxygen dependent (e.g., glucose oxidase (GOX), glucose dehydrogenase (GDH), and electrons are transferred from the enzyme to the electrode by soluble or solid mediators - e.g., hydrogen peroxide, and / or a conductive polymer, respectively.

[0047] FIGs. 3a-f shows an exploded view of a sensor patch 1 according to some embodiments. The sensor patch 1 (FIGs. 3a-b) includes an electronic assembly 20 (FIG. 3c) and probe assembly (30) (FIG. 3d) which are removably connected with a locker 11. The electronic assembly includes electronic adhesive ("adhesive") 21, chassis 22, battery 23, PCB / A 24, and electronic cover 25. The PCB / A includes a processor and computer instructions which at least include instructions for an algorithm for analyzing signals (electrical current) received from the sensor. The probe assembly 30 can include carrier 31, carrier adhesive 32, and and / or probe 40 (in some embodiments, one and / or another of the foregoing). Probe 40 can include a tip 10, a contacts plate 41, a trace 42, a contact 43, and electrodes 50 and 80 (in some embodiments, one and / or another of the foregoing). Electrical current generated on electrodesof probe tip 10 (FIG. 3f) (sensor) can be conducted via traces 42 to contacts plate 41 (FIG. 3e) and to PCB / A 24.

[0048] FIGs. 4a-b shows an electronic assembly 20 (FIG. 4a) and a probe assembly 30 (FIG. 4b) according to some embodiments. Electronic assembly 20 is configured to measure current generated by the probe assembly 30 (e.g., signals corresponding to generated current), store and analyze the data, and transmit information / data to the monitor 2 (e.g., via Bluetooth Low Energy (BLE), for example). Electronic assembly 20, in some embodiments, includes electronic cover 25, chassis 22, PCB / A 24, battery 23, and electronic adhesive 21 (in some embodiments, one and / or another of the foregoing). PCB / A can include a processor and computer instructions operable thereon corresponding to one or more algorithms (e.g., for determining analyte / glucose concentration). Electronic assembly 20 can be installed on top of probe assembly 30, where the Probe assembly 30 is configured to oxidize glucose and conduct generated electrical current from the electrodes to the electronic assembly 20. Probe assembly 30 can include probe 40, carrier 31, and carrier adhesive 32.

[0049] FIGs. 5a-e and FIGs. 6a-c show a configuration of the probe 40 (FIG. 5) and probe production process (FIG. 6), according to some embodiments. This configuration includes one electrochemical cell (EC) with 3 electrodes - a working electrode, a reference electrode, and a counter electrode. FIGs. 5a-b shows the probe 40 before folding as Probe 40, in some embodiments, is planar and can include a contacts plate 41 and a tip 10. In some embodiments, the probe 40 is made of a nonconductive polyimide sheet. Electrodes 50 (working electrode) and 80 (reference electrode), traces 42, and contacts 43 can be located on one side (Side A) of the probe tip 10. Electrode 90, traces 42, and contacts 43 can be located on the other side (Side B) of the probe tip 10. Electrodes 50, 80, and 90, traces 42, and contacts 43 are configured to be electrically conductive (i.e., gold, platinum) and are deposited and shaped via any known process. In one configuration, gold is sputtered, and shape is formed by etching. FIG. 5c shows the probe 40 after folding, the contact plate 41 is perpendicular to the tip 10.

[0050] FIG. 5d-e show cross section views of Side A electrodes 50 (working) and 80 (reference). Working electrode 50 can include polyimide base sheet 51, gold layer 52, enzyme layer 53, glucose limiting layer (GLM) 54, and biocompatible layer 55 (and in some embodiments, different combinations thereof). Reference electrode 80 can include polyimide base sheet 51, gold layer 52, Ag / AgCl layer 53, glucose limiting layer (GLM) 54, and biocompatible layer 55 (and in some embodiments, combinations thereof). FIG. 5e shows a transverse cross-sectional view of Side B counter electrode 90. The counter electrode 90 caninclude polyimide base 51, gold 52, and biocompatible layer 55 (and in some embodiments, combinations thereof).

[0051] FIGs. 6a-e show an exemplary production process for electrodes on Side A of probe tip 10 according to some embodiments. Accordingly, gold nanoparticles are sputtered on a first polyimide base sheet 51 and etched into the shape of electrodes, traces 42, and contacts 43 (FIG. 5a). A second polyimide sheet with openings (FIG. 6a, top view) is attached to the first polyimide sheet (FIG. 6b). FIG. 6c shows a longitudinal cross section view of tip 10 with 2 openings for the working electrode 50 and counter electrode 80. FIG. 6d shows the deposition (bio-dotting) of enzyme layer 53 on working electrode 50, and FIG. 6e shows the deposition of the glucose limiting membrane (GLM) 54. A first stage of a production process of counter electrode 90 on Side B of prob tip (not shown) is like that of Side A (polyimide base sheet and shaped gold layer). At a later stage, Side A and Side B can be coated with a biocompatible layer 55 (FIG. 5d-e). In some embodiments, if the working electrode 50 is driven to a positive potential, relative to the reference electrode 80, an oxidation reaction can occur at the working electrode 50. Accordingly, the electrochemical (amperometric) glucose sensor can continuously measure current resulting from the oxidation of glucose. In some embodiments, current is measured between the working electrode 50 and the counter electrode 90, at a constant potential, applied between the working electrode 50 and reference electrode 80 (amperometry). Enzyme 53 is configured to catalyze the oxidation reaction of glucose to gluconic acid, where two electrons are produced per glucose molecule. These electrons reduce the working electrode.

[0052] FIGs. 7a-e and FIGs. 8a-e show a probe 40 design (FIG. 7) and probe production process (FIG. 8), according to some embodiments. In such embodiments, probe tip 10 includes more than one working electrode. In some embodiments, the probe tip 10 can include five (5) electrodes: 3 working electrodes - working electrode-1 50, working electrode-2 60, and working electrode-3 70, reference electrode 80, and counter electrode 90. This configuration can address functionality such as calibration, response time, warm-up time, and interference (and in some embodiments, one or more of such functionality). In some embodiments, tip 10 (sensor) can include 4 electrodes: 2 working (working electrode 50 and 60, or working electrodes 50 and 70), reference electrode 80, and counter electrode 90.

[0053] FIGs. 7a-b show probe 40 before folding, according to some embodiments. Accordingly, Probe 40 is planar and includes a contacts plate 41 and a tip 10. In some such embodiments, the probe 40 can be made of a nonconductive polyimide sheet. Workingelectrode-1 50, working electrode-2 60, reference electrode 80, traces 42, and contacts 43 can be located on one side (Side A) of the probe tip 10. Working electrode-3 70, counter electrode 90, traces 42, and contacts 43 can be located on the other side (Side B) of the probe tip 10. Electrodes 50, 60, 70, 80, and 90, traces 42, and contacts 43 can be electrically conductive (e.g., gold) and deposited (e.g., sputtering of gold nanoparticles) and shaped at any known in the art process (e.g., etching). FIG. 7c shows probe 40 after folding, the contact plate 41 being perpendicular to the tip 10.

[0054] FIGs. 7d-e show transverse, cross sectional views of Side A (FIG. 7d) and Side B (FIG. 7e) of electrodes: Side A - working electrode- 1 50, working electrode-2 60 and reference electrode 80, Side B - working electrode-3 70 and counter electrode 90. FIG. 7d shows transverse cross section views of Side A of prob tip. Working electrode-1 50 includes polyimide base sheet 51, gold layer 52, enzyme layer 53, glucose limiting layer (GLM) 54, and biocompatible layer 55. Working electrode-2 includes polyimide base sheet 51, gold layer 52, inactive enzyme layer 61, glucose limiting layer (GLM) 54, and biocompatible layer 55. Reference electrode 80 can include polyimide base sheet 51, gold layer 52, Ag / AgCl layer 53, glucose limiting layer (GLM) 54, and biocompatible layer 55. FIG. 7c shows transverse cross- sectional view of Side B of probe tip 10. Working electrode-3 70 can include polyimide base sheet 51, gold layer 52, enzyme layer 61, and biocompatible layer 55 (no GLM layer). In some embodiments, working electrode-3 70 can be covered with GLM. The counter electrode 90 can include polyimide base 51, gold 52, and biocompatible layer 55.

[0055] FIGs. 8a-e show a production process of electrodes on Side A of probe tip 10, according to some embodiments. Gold nanoparticles can be sputtered on a first polyimide base sheet 51 and etched to the shape of electrodes, traces 42, and contacts 43 (see FIGs. 7a-b). A second polyimide sheet 51 with openings (Figure 8a, top view) can be attached to a first polyimide sheet (FIG. 8b). FIG. 8c shows a longitudinal cross-sectional view of tip 10 with 3 openings for the working electrode- 1 50, working electrode-2, 60, and counter electrode 80. FIG. 8d shows the deposition of enzyme layer 53 (working electrode- 1 50) and inactive enzyme layer 61 (working electrode-260). FIG. 8e shows the deposition of the glucose limiting membrane (GLM) 54 on the 3 electrodes of Side A of prob tip 10 - working electrode- 1 50, working electrode-260, and reference electrode 80. At a later stage, probe tip 10 can be covered with biocompatible layer 55. In some embodiments, the probe tip 10 (sensor) can include one or more working electrodes (n electrodes) including working electrodes with enzymes thatoxidize glucose (e.g., CDH, GDH, GOX, etc.), inactive enzymes, no enzyme, and enzymes that oxidize additional analytes (e.g., lactate dehydrogenase).Exemplary System Embodiments

[0056] In some embodiments, a CGM system can be based on a concomitant operation of one or more electrochemical cells (EC) (in some embodiments, a plurality of ECs). Each electrochemical cell can include a triad of electrodes: a working electrode, a reference electrode, and a counter electrode. In each electrochemical cell, the working electrode can be at least one of a plurality of working electrodes, and in some embodiments, at least two working electrodes, and some embodiments three or more working electrodes: working electrode- 1, working electrode-2, working electrode-3, working electrode-4, working electrode-5.... working electrode-n, the one or more combinations of working electrodes can correspond to electrochemical cells EC-1, EC-2, EC-3, EC-4, EC-5. . . .EC-n).

[0057] In some embodiments, working electrode- 1 can include glucose sensitive enzyme (A) layer and a GLM layer, working electrode-2 can include inactive glucose sensitive enzyme (A) layer and GLM layer, working electrode-3 can include glucose sensitive enzyme layer, but lacks a GLM layer, working electrode-4 can lack an enzyme layer and lack a GLM layer, working electrode-5 can include another glucose sensitive enzyme (B) layer and a GLM layer. Other working electrodes may include other glucose sensitive enzymes (C, D, E...n), other analyte specific enzymes, and / or other analyte specific inactive enzymes. In some embodiments, a plurality of electrodes (and in some embodiments, a majority of electrodes, and in some embodiments, all electrodes) are covered by a biocompatible layer. The concomitant operation of one or more electrochemical cells can provide, in some embodiments, one or more of (or all of), automatic calibration (EC-1 and EC3), short warm-up time (EC-1 and EC-3), short step response time (EC-1 and EC-3), and high specificity to glucose (minimal interaction with interferences) (EC-1, EC -2, and EC-5). In some embodiments, the system can include additional multiple electrochemical cells that continuously measure concentration of non-glucose analytes.Exemplary Calibration Embodiments

[0058] In some embodiments, an electrochemical sensor measures a “raw” current signal via an enzymatic electrochemical reaction in electrochemical cell. The correlation between glucose levels and current (which may be referred to a "calibration curve") is not linear as at a highglucose level the enzyme reaches saturation (which may be referred to an "enzyme kinetics"). The calibration curve of a specific electrochemical cell depends on multiple parameters, one of which is the amount of enzyme deposited and GLM characteristics (composition and thickness). Variability in these parameters can lead to production "in lot" and "between lot" differences in the calibration curve of a single electrochemical cell. Enzyme deposition process is precise but a predominant cause of variability between electrochemical cells is the GLM layer. The GLM layer reduces glucose flux (i.e., a thicker layer, higher reduction), provides longer sensor stability (less enzyme degradation), and flattens the calibration curve (make it linear). However, GLM coating processes (spray, slot, or spin coating) are imprecise which can lead to variability in GLM thickness and homogeneity.

[0059] FIGs. 9a-c shows calibration curves, each curve shows a typical response of a single electrochemical cell (generated current) to different glucose concentrations (X axis - glucose, Y axis - current). FIG. 9a shows a typical calibration curve of a single electrochemical cell without GLM on the working electrode. FIG. 9b shows an example of two calibration curves (FIG. 9b-l and FIG. 9b-2) of two electrochemical cells. FIG. 9c shows a calibration curve of a single electrochemical cell without GLM (FIG. 9c-l) and calibration curve of the same single electrochemical cell with GLM (FIG. 9c-2). In factory calibration, each sensor's electrochemical cell can be calibrated in solutions of different glucose concentration ("wet calibration"), but it is an expensive and time-consuming process. In some embodiments, the sensor is designed to eliminate wet factory calibration. Accordingly, the sensor includes 2 electrochemical cells having 2 working electrodes - working electrode-1 with GLM and working electrode-3 without GLM (FIG. 7), a reference electrode, and a counter electrode, corresponding to electrochemical cells EC-1 and EC-3. A calibration curve of EC-3 (working electrode-3 with no GLM) is highly repetitive because enzyme deposition is precise and correlation between glucose and current is predictable. Accordingly, EC-3 can be used for providing accurate glucose readings during the first day of use and for calibration of EC-1. EC- 1 provides accurate readings during the remaining days of on-body sensor use.

[0060] The general case of EC-1 calibration based on EC-3 signals is the following:The calibration curves formulas of EC-3 (Figure 9c-2) and EC-1 (Figure 9c-l) are:

[0061] Where g is glucose concentration, y1(gi) and y2(gi) are signals (currents) of EC-3 (no GLM) and EC-1 (GLM), respectively, k and k2, are the sensitivity of EC -3 and EC-1, respectively, i is the index of the time-series signal received from the electrochemical cells. In EC-3, the function f(x), is a non-linear due to inherent enzyme kinetics (Figure 9c-l). Typically, f(x) is related to specific enzyme kinetics, such as Michaelis-Menten kinetics, and diffusion dynamics of the electrochemical cell (EC -3). The function can be mathematically modelled or numerically extracted from a lab characterization. In EC-1, a function ( ) is not present in the signal y2because the correlation between glucose and current is linear (Figure 9c-2). An algorithm is used to estimate the value k2from series of values y thatare received from EC-3 and EC-1, respectively. Where i, is the index of the time-series signal received from the electrochemical cells. The means and probability distributions of kltk2, are known from lab characterization of the electrochemical cells, and can serve as the estimation prior. The functionf(x) , is also known as detailed above. These provide constraints for the algorithm to find the likely solution of k2. Once the value k2, is known, calculating the glucose concentration from the measured signal of EC-1 is straightforward.

[0062] In some embodiments, a gradient descent optimization algorithm can be used (via computer instructions operable on a processor) to estimate the constants whereas themean values of is used as an initialization condition, and the error function is thedifference between the calculated glucose value received from EC-1 and EC-3.Exemplary Warm-up time Embodiments

[0063] In some embodiments, warm-up time can be defined as time to receive accurate glucose readings after sensor insertion. Warm-up time can be relatively long (approximately 1-2 hours), predominately due to slow diffusion of electrolytes (required for electrochemical cell) through the GLM layer. FIG. 10 shows a characteristic stability curve after insertion of sensor without GLM (line 1) and with GLM (line 2), black dots indicate a warm-up time, approximately 600 seconds (10 minutes) and 6000 seconds (100 minutes), respectively. In some embodiments, the sensor is designed to shorten the warm-up time. The sensor includes 2 electrochemical cells having 2 working electrodes - working electrode-3 without GLM and working electrode- 1 with GLM, a reference electrode, and a counter electrode, corresponding to electrochemical cells EC-3 and EC-1, respectively. Accordingly, accurate glucose readings are taken from EC-3 (no GLM) after sensor insertion and EC-3 stabilization (Figure 10-1, 10 minutes). Afterstabilization of EC-1 (with GLM, Figure 10-2, approximately 2 hours), glucose readings are taken from EC-1 during the remaining days of on -body sensor use.Exemplary Step response time Embodiments

[0064] In some embodiments, a step response time (t90) is defined as the time required for an electrochemical cell (EC) to reach 90% of the final value at the output (electrical current) in the event of an abrupt change (step) in glucose concentration. In some embodiments, a short step response time provides accurate real time glucose readings and is crucial for accurate treatment (insulin) decisions. In an electrochemical cell with working electrode coated with GLM, step response time is elongated over time, predominately due to enzyme inhibition of accumulated by-products (e.g., gluconic acid). FIG. 11 shows an example of a step addition test (using chronoamperometry) of a single electrochemical cell (working electrode with GLM) on day 1 (FIG. 11-1) and day 13 (FIG. 11-2). The response time (t90) on day 1 (approximately 200 seconds) and day 13 (approximately 2000 seconds) is shown at two (2) abrupt steps in glucose concentration (distance between diamonds).

[0065] FIG. 12 shows another step addition test of a single electrochemical cell (working electrode with GLM) at various days - day 1 (FIG. 12-1), day 16 (FIG. 12-2), sensor sensitivity remains stable, however, response time increased over time (distance between diamonds). FIG. 13 shows an example of a step addition test (chronoamperometry) of a single electrochemical cell (working electrode without GLM) on days 1, 5, 9, 16 (FIGs. 12-1, 2, 3, 4), the response time (t90, time between diamonds) remains at approximately 200 seconds in all days. However, sensitivity generally declines over days because without GLM, enzyme activity rapidly deteriorates. In some embodiments, the sensor is designed to maintain a short step response time over the entire on-body use time. The sensor includes electrochemical cells having 2 working electrodes - working electrode-3 without GLM and working electrode- 1 with GLM, a reference electrode, and a counter electrode, corresponding to electrochemical cells EC-3 and EC-1. The processor concomitantly receives signals from EC-3 and EC-1 and uses a real-time calibration algorithm to adjust the readings of EC-1 according to readings from EC-3.

[0066] In some embodiments, the calibration algorithm (operable via computer instructions on a processor) utilizes the following scheme:1. A non-linear approximation of the signal from EC-3 and model fitting the EC-3 signal (current) to a linear function (described above). Initial calibration constant is set in production and the output signal is initially used on-body.2. EC-3 and EC-1 signals are passed through a low pass filter with a large time constant (could be in the order of a few hours); and3. A new calibration constant is calculated according to the ratio between EC-1 and EC-3 signals as calculated after the low pass filter.

[0067] EC-3 and EC-1 contain the same low frequency information because the GLM acts as a first order low pass filter. Accordingly, the application of a low pass filter with a time constant of a few hours on both EC-3 and EC-1 should produce a similar signal. The difference between these signals should only reflect the difference in sensitivity of the two electrochemical cells. The sensitivity of EC-1 (working electrode with GLM) is relatively low but remains constant over time. The sensitivity of EC-3 (working electrode without GLM) is initially high but rapidly declines. Once the ratio between the signals of the 2 electrochemical cells is calculated, the appropriate calibration factor that corresponds to the sensitivity of EC-3 can be calculated. The calibrated signal of EC-3 demonstrates both stability over time as well as fast response time.

[0068] FIG. 14 shows a step addition test (chronoamperometry) of the dual electrode configuration, utilizing the algorithm mentioned above. The signal of EC-3 is calibrated according to EC-1. The resulting signal using the algorithm shows stability in sensitivity as well as a fast response time (FIG. 14-1 day 1, FIG. 14-2 day 11).Exemplary Interference Embodiments

[0069] Interferences are non-glucose analytes that could oxidize / reduced at the working electrode either non-specific by working electrode metal (e.g., gold layer) or specific by working electrode enzyme. Both non-specific and specific interactions generate false signals. In some embodiments, the sensor is designed to minimize interference related to non-specific oxidation / reduction of non-glucose analytes. Accordingly, the system can include 2 electrochemical cells having 2 working electrodes - working electrode-1, active enzyme, and working electrode-2, inactive enzyme (Figure 7), a reference electrode, and a counter electrode, corresponding to electrochemical cells EC-1 and EC-2. Working el ectrode- 1 and working electrode-2 are preferably identical in all parameters (in some embodiments, one or more of,and in some embodiments a plurality of, and in some embodiments all of: effective area, thickness of enzyme, GLM, and biocompatible layer, etc.), however, the enzyme on working electrode-2 is inactive. Signals concomitantly received from EC-1 and EC-2 can be collected and processed by a compensation algorithm. The difference in signals received from EC-1 and EC -2 reflects the effect of the interfering analyte and the algorithm is a simple subtraction of the two signals. In some embodiments, if working electrode-1 and working electrode-2 are not identical (production process variability), the compensation algorithm includes a correlation constant. The correlation constant k is calculated according to the measured sensitivities SEC-2 of the two electrochemical cells EC-1 and EC -2, respectively:The glucose signal g with interference reduction can then be calculated using the measured currents of the two electrochemical cells EC-1 and EC -2, respectively:

[0070] In some embodiments, the sensor is designed to minimize interference related to specific oxidation / reduction of non-glucose analytes (interaction with the enzyme). Accordingly, the system can include two (2) or more electrochemical cells having working electrodes corresponding to 2 or more electrochemical cells. In a two (2) electrode configuration, the sensor includes 2 electrochemical cells having 2 working electrodes- working electrode- 1 with active enzyme A, working electrode-5 with active enzyme B, a reference electrode, and a counter electrode, corresponding to electrochemical cells EC-1 and EC-5, respectively. Enzyme B could be any enzyme that oxidizes glucose and is different from Enzyme A (e.g., glucose oxidase, glucose dehydrogenase, etc.). If the effect of interference on enzyme A and enzyme B is known, the difference between EC-1 and EC-5 reflects the effect of the interfering analyte. The calculation of the glucose concentration is done using EC-1, and EC-5 signals is x, z, respectively. The known sensitivity of EC-1 and EC-5 to an interference is kx, and kzrespectively:

[0071] In some embodiments, the CGM system is designed to minimize interference related to both non-specific (non-enzyme related) and specific (enzyme related) oxidation / reduction ofnon-glucose analytes. In such embodiments, the sensor includes 3 electrochemical cells having 3 working electrodes - 1) working electrode- 1, active enzyme A, 2) working electrode-2, inactive enzyme, 3) working electrode-5, active enzyme B, a reference electrode, and a counter electrode, corresponding to electrochemical cells EC-1, EC-2, and EC-5.Exemplary Non-glucose analyte monitoring Embodiments

[0072] In some embodiments, the CGM system can be configured to measure the concentration of non-glucose analytes (e.g., lactate, beta-hydroxybutyrate, etc.). In such embodiments, the system includes two (2) or more electrochemical cells having two (2) or more working electrodes, each working electrode includes either glucose specific enzyme (A, B, C, etc.), non- glucose specific enzymes (A, B, C, etc.), inactive enzyme, or no enzyme (bare metal), a reference electrode, and a counter electrode, corresponding to electrochemical cells EC-1, EC- 2, EC- 3. . . .EC-n.Examples:

[0073] The following are examples according to one and / or another of the embodiments supported by the subject disclosure:Example 1 : An on-body, continuous analyte monitoring system for continuous monitoring of analyte of an individual including an electronics assembly comprising a processor computerinstructions accessible for running thereon or running thereon including computer-instructions for determining analyte concentration, and a subcutaneous sensor comprising at least two electrochemical cells (ECs), each electrochemical cell including a reference electrode, a counter electrode, and one of at least two (2) working electrodes including a working electrode including an enzyme (EC-1) and an analyte limiting membrane (EC-1), and a working electrode including an enzyme only (EC-3), where EC-3 and EC-1 generate currents corresponding to analyte concentrationrespectively, the computerinstructions for determining analyte concentration are configured to cause the processor to determine analyte concentration g, such thatis derived from EC-3 current, EC-3 sensitivity , and a non-linear enzyme kinetics function ,and EC-1sensitivity is derived from the determined analyte concentration and EC-1 current, and the system is configured to calibrate g substantially in real-time.Example 2: The system of Example 1, where EC-3 is configured for calibrating a signal of EC-1.Example 3 : A continuous analyte concentration monitoring (CGM) system including a skin sensor patch (SSP) comprising an electronic assembly; having a battery, a processor, computer instructions operable on the processor to operate the SSP, including at least one algorithm for performing CGM, and a transceiver, a planar probe having a first side A and a second side B for insertion within subcutaneous tissue of a subject, and a wireless monitor, where the planar probe includes a plurality of electrochemical cells (ECs) each including a plurality of working electrodes, a reference electrode, and a counter electrode, each working electrode includes a base substrate, a conductive metal layer, and a plurality of enzymes including at least one analyte sensitive enzyme, at least one analyte sensitive enzyme, and / or optionally, at least one inactive enzyme, at least some of the working electrodes of the ECs includes an analyte limiting membrane (GLM) (“an analyte limiting membrane”) coated on one side of the planar electrode, each EC generates an electrical current (j) by enzymatic oxidizing of an analyte (analyte) by an analyte (analyte) sensitive enzyme, each electrical current comprising an EC signal for a respective EC, and the processor is configured to process the EC signals using the at least one algorithm to generate an output comprising an analyte concentration (g) of the subject using the SSP.Example 4: The system of Example 3, where the plurality of ECs comprises a first EC and a second EC, the first EC comprising a working electrode including an analyte sensitive enzyme and a GLM, and the second EC comprising a working electrode including an analyte sensitive enzyme and lacks a GLM.Example 5: The system of example 3, where the plurality of ECs comprise a first EC, a second EC, and a third EC, and where the first EC comprises a working electrode including a first analyte sensitive enzyme, a second EC comprises a working electrode including a first inactive analyte sensitive enzyme, a third EC comprising a plurality of working electrodes, each including at least one other analyte sensitive enzymes different from the first analyte sensitive enzyme and at least one other analyte sensitive enzyme different from the first inactive analyte sensitive enzyme, and analysis of signals concomitantly received from the ECs provides analyte readings that are insensitive to interferences.Example 6: A continuous analyte monitoring system including an electronics assembly including a processor, computer-instructions accessible for running thereon or running thereon including computer-instructions for determining analyte concentration, and a subcutaneoussensor comprising at least two electrochemical cells (ECs), each electrochemical cell including a reference electrode, a counter electrode, and one of at least two (2) working electrodes including a working electrode including an enzyme (EC-1) and an analyte limiting membrane (EC-1), and a working electrode including an enzyme only (EC-3), where EC-3 and EC-1 generate currents jEC-^andjEC-i corresponding to analyte concentrationgrespectively, the computer-instructions for determining analyte concentration are configured to cause the processor to determine analyte concentration is determined from EC-3 during an initial time period, and determined from EC-1 after the initial time period during a body -use time, and the system is configured to include a warm of time of between 1 and 60 minutes.Example 7: The analyte sensor of the system of Example 6, where the two electrodes are configured to overcome delayed warm up.Example 8: A continuous analyte monitoring system for continuous monitoring of analyte that has a short response time for the entire on-body use period, including an electronics assembly comprising a processor computer-instructions accessible for running thereon or running thereon including computer-instructions for determining analyte concentration, and a subcutaneous sensor comprising at least two electrochemical cells (ECs), each electrochemical cell including a reference electrode, a counter electrode, and one of at least two (2) working electrodes including a working electrode including an enzyme (EC-1) and an analyte limiting membrane (EC-1), and a working electrode including an enzyme only (EC- 3), where EC-3 and EC-1 generate currentscorresponding to analyte concentrationg, respectively, the computer-instructions for determining analyte concentration are configured to cause the processor to determine an average analyte concentrationgover a predetermined time period is determined from EC-1 average currentover time and EC- 1 sensitivity , EC-3 sensitivityis derived from analyte concentration 3 ,and EC-3 average current over time, and a non-linear enzyme kineticsfunction :and t e SyStem configured to include a response time of between 1 and 300 seconds.Example 9: The analyte sensor of the system of Example 8, where EC-3 is configured for overcoming the slow response time of EC-1.Example 10: A continuous analyte monitoring system for continuous monitoring of analyte that is not susceptible to interferences, including an electronics assembly comprising aprocessor computer-instructions accessible for running thereon or running thereon including computer-instructions for determining analyte concentration, and a subcutaneous sensor comprising at least two electrochemical cells (ECs), each electrochemical cell including a reference electrode, a counter electrode, and one of three working electrodes including a working electrode having an analyte-sensitive enzyme A (EC-1), a working electrode having an inactive analyte-sensitive enzyme A (EC-2), and a working electrode having an analytesensitive enzyme B (EC-5), where each of the working electrodes EC-1, EC-2, and EC-5 include a respective current signal comprising, respectively, the sensitivity of EC-1 and EC-5 to interference corresponds to respectively, and the computerinstructions are configured to cause the processor to determine analyte g concentration g according toExample 11 : A calibration method for calibrating a sensing electrode of a continuous analyte monitor, such as analyte, lactate, etc., including a-priory provided statistical information about one or more electrodes corresponding to a particular batch production, the statistical information being used to estimate one or more calibration parameters of a primary sensing electrode EC-1; as well as calibration parameters and non-linearity of a secondary sensing electrode EC-2, processing one or more signals from EC-1 to provide an accurate estimation of the analyte concentration, and processing one or more signals from a non-coated electrode EC -2 for aiding in the accurate real-time calibration of EC-1.Example 12: The method of Example 11, further including estimating a plurality of coefficients for determining analyte concentration and relationships of the one or more signals from EC-2.Example 13: The method of Examples 11 or 12, where the one or more signals from EC-2 is represented as a time series.Example 14: The method of claim 13, where the time series corresponds to:and where: i is the time index, is the concentration of analyte in the bulk solutionwhere EC-2 is present, comprise coefficients corresponding to a linearrelationship of the one or more signals of EC-2 and activity of the enzyme, respectively, and f() is a non-linear function of the formExample 15: The method of Example 14, where the function f() corresponds to enzyme activity, where C is the concentration of the substrate, V is the max activity level of the enzyme, and Kmis the Michaelis constant.Example 16: The method of any of Examples 11-13, where the one or more signals from EC- 1 is represented as a time series.Example 17: The method of Example 16, where the time series corresponds to:wherein: i is the time index,is the analyteconcentration in the bulk solution, and comprise coefficients correspondingto a linear relationship of the signal received at EC-1 and the analyte concentration.Example 18: The method of Example 17, where the coefficients areestimations of using a linear regression.Example 19: The method of Example 18, where upon estimating the coefficients, for a duration of sensor activity, an estimate of analyte corresponds to:Example 20: The method of any of Examples 11-19, where transient analyte levels are calculated from a combination of one or more signals received from each of EC-1 and EC-2 (optionally up to EC-n).Example 21 : The method of any of Examples 11 -20, where analyte concentration at any given time corresponds to: where: is theconcentration of analyte in the bulk solution where the EC-1 is present, and f() is a non-linear function of the formExample 22: The method of any of Examples 11-21, where comprisecoefficients estimated in real-time from a relationship between the average signal received by EC-1 and the average of the signal received by EC-2.Example 23 : The method of Example 22, where the estimation of the average signal of the andcoefficients of EC -2 correspond to:and the average is taken over the same time duration for each of EC-1 and EC-2.Example 24: The method according to any of Examples 21-23, where one or more signals and determined estimations is provided by one or more additional electrodes up to EC-n electrodes.Example 25: The method of Example 24, where a specificity of the EC-1 electrode is increased by use of the one or more signals of the one or more additional EC-n electrodes.Example 26: The method of Example 25, where the specificity of the EC-1 electrode is increased by subtraction of the one or more signals correlating to interferences.Example 27: The method of any of Examples 24-26, where the one or more additional EC-n electrodes are not sensitive to analyte.Example 28: The method of any of Examples 24-26, where the one or more additional EC-n electrodes are sensitive to interferences.Example 29: The method of any of Examples 26 and 28, where an effect of the interferences is subtracted from the one or more signals of EC-1 electrode.Example 30: A continuous analyte sensor comprising at least a first electrode and a second electrode, where: the first electrode (EC-1) includes a covering comprising an analyte limiting membrane (GLM); and at least one second electrode (EC-2) configured without a GLM covering and configured for calibrating a signal of EC 1.Example 31 : An analyte sensor including at least two electrodes including a first electrode with an active enzyme and a second electrode with inactive enzyme, optionally the at least two electrodes include one or more additional electrodes each of which includes a different variant enzyme, the sensor being configured so as to suppress the interference of signals.Example 32: The system, method, or sensor according to any of Examples 1-31, where the analyte comprises glucose.General Considerations for at least some Embodiments

[0074] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means, steps, components, and / or structures for performing the function of the embodiments (and elements thereof) disclosed herein, and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, amounts, dimensions, materials, steps, and configurations described herein are meant to be merely an example and that the actual parameters, amounts, dimensions, materials, steps, and configurations will depend upon thespecific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is therefore to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of claims supported by the subject disclosure and equivalents thereto, and inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are also directed to each individual feature, device, system, article, material, kit, step, function / functionality, and method described herein. In addition, any combination of two or more such features, devices, systems, articles, materials, kits, steps, functions / functionality, and methods, if such features, systems, articles, materials, kits, steps, functions / functionality, and methods are not mutually inconsistent, is included within the inventive scope of the present disclosure and considered embodiments (thus, any one or more, and in many instances any combination of two or more, features can be pursued as claimed subject matter for patent protection).

[0075] In addition, the disclosure can include other innovations not presently expressly described, but rather, implicitly or inherently disclosed. Applicant reserves all rights in such innovations, including the right to claim such embodiments, file additional applications, continuations, continuations-in-part, divisionals, and / or the like thereof. As such, it should be understood that advantages, embodiments, examples, functional, features, logical, operational, organizational, structural, topological, and / or other aspects of the disclosure are not to be considered limitations on the disclosure as defined by the embodiments or limitations on equivalents to the embodiments. Depending on the particular desires and / or characteristics of an individual and / or enterprise user, database configuration and / or relational model, data type, data transmission and / or network framework, syntax structure, and / or the like, various embodiments of the technology disclosed herein can be implemented in a manner that enables a great deal of flexibility and customization as described herein and is supportive for claimed subject matter.

[0076] Embodiments disclosed herein may also be combined with one or more additional features, components, materials, parameters, as well as complete systems, devices, and / or methods, to yield yet other embodiments and inventions. Moreover, some embodiments, may be distinguishable from the prior art by specifically lacking one and / or another feature disclosed in the particular prior art reference(s); i.e., claims to some embodiments of the subject disclosure are distinguishable from the prior art by including one or more negative limitations(i.e., expressly reciting that the claimed embodiment does not include one or more specific elements found in the prior art).

[0077] Also, as noted, various inventive concepts may be embodied as one or more methods, of which one or more examples have been provided. The acts performed as part of the method(s) may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0078] Any and all references to publications or other documents, including but not limited to, patents, patent applications, articles, webpages, books, etc., presented anywhere in the present application, are herein incorporated by reference in their entirety. Moreover, all definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0079] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0080] Accordingly, the indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” The terms “can” and “may” are used interchangeably in the present disclosure, and indicate that the referred to element, component, structure, function, functionality, objective, advantage, operation, step, process, apparatus, system, device, result, or clarification, has the ability to be used, included, or produced, or otherwise stand for the proposition indicated in the statement for which the term is used (or referred to) for a particular embodiment(s).

[0081] The phrase "and / or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and / or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B(optionally including other elements); etc.

[0082] As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of' "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0083] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and / or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0084] In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0085] The term “automatic” and “automatically” are used herein to modify actions that occur without direct input or prompting by an external source such as a user. Automatically occurring actions can occur periodically, sporadically, in response to a detected event (e.g., a user logging in), or according to a predetermined schedule.

[0086] The term “determining” encompasses a wide variety of actions and, therefore, “determining” can include calculating, computing, processing, deriving, investigating, looking up (e.g., looking up in a table, a database or another data structure), ascertaining and the like. Also, “determining” can include receiving (e.g., receiving information), accessing (e.g., accessing data in a memory) and the like. Also, “determining” can include resolving, selecting, choosing, establishing and the like.

[0087] The phrase “based on” does not mean “based only on,” unless expressly specified otherwise. In other words, the phrase “based on” describes both “based only on” and “based at least on.”

[0088] Some embodiments and / or methods described herein can be performed by software (executed on hardware), hardware, or a combination thereof. Hardware modules can include, for example, a general-purpose processor, a field programmable gate array (FPGA), and / or an application specific integrated circuit (ASIC). To this end, one or more of the aspects and embodiments described herein can be conveniently implemented using one or more machines (e.g., one or more computing devices that are utilized as a user computing device for an electronic document, one or more server devices, such as a document server, etc.) programmed according to the teachings of the present specification. In some embodiments, such a machine can be provided on as wholly or partially part of a processor of a sensor patch.

[0089] Examples of a computing device include, but are not limited to, an electronic book reading device, a computer workstation, a terminal computer, a server computer, a handheld device (e.g., a tablet computer, a smartphone, etc.), a web appliance, a network router, a network switch, a network bridge, any machine capable of executing a sequence of instructions that specify an action to be taken by that machine, and any combinations thereof. In one example, a computing device can include and / or be included in a kiosk. As noted in at least some embodiments, the computing device can comprise a processor on a sensor patch for analyte monitoring.

[0090] The term “processor” should be interpreted broadly to encompass a general -purpose processor, a central processing unit (CPU), a microprocessor, a digital signal processor (DSP), a controller, a microcontroller, a state machine and so forth. Under some circumstances, a“processor” can refer to an application specific integrated circuit (ASIC), a programmable logic device (PLD), a field programmable gate array (FPGA), etc. The term “processor” can refer to a combination of processing devices, e.g., a combination of a DSP and a microprocessor, multiple microprocessors, one or more microprocessors in conjunction with a DSP core or any other such configuration.

[0091] The term “memory” should be interpreted broadly to encompass any electronic component capable of storing electronic information. The term memory can refer to various types of processor-readable media such as random-access memory (RAM), read-only memory (ROM), non-volatile random-access memory (NVRAM), programmable read-only memory (PROM), erasable programmable read only memory (EPROM), electrically erasable PROM (EEPROM), flash memory, magnetic or optical data storage, registers, etc. Memory is said to be in electronic communication with a processor if the processor can read information from and / or write information to the memory. Memory that is integral to a processor is in electronic communication with the processor.

[0092] Appropriate software coding can readily be prepared by skilled programmers based on the teachings of the present disclosure. Aspects, implementations and embodiments (each term can be used interchangeably) discussed above employing software and / or software modules can also include appropriate hardware for assisting in the implementation of the machine executable instructions of the software and / or software module.

[0093] Such software can be a computer program product that employs a machine-readable storage medium. A machine-readable storage medium can be any medium that is capable of storing and / or encoding a sequence of instructions for execution by a machine (e.g., a computing device) and that causes the machine to perform any one of the methodologies and / or embodiments described herein. Examples of a machine-readable storage medium include, but are not limited to, a magnetic disk, an optical disc (e.g., CD, CD-R, DVD, DVD-R, etc.), a magneto-optical disk, a read-only memory "ROM" device, a random-access memory "RAM" device, a magnetic card, an optical card, a solid-state memory device, an EPROM, an EEPROM, and any combinations thereof. A machine-readable medium, as used herein, is intended to include a single medium as well as a collection of physically separate media, such as, for example, a collection of compact discs or one or more hard disk drives in combination with a computer memory. As used herein, a machine-readable storage medium does not include transitory forms of signal transmission.

[0094] Such software can also include information (e.g., data) carried as a data signal on a datacarrier, such as a carrier wave. For example, machine-executable information can be included as a data-carrying signal embodied in a data carrier in which the signal encodes a sequence of instruction, or portion thereof, for execution by a machine (e.g., a computing device) and any related information (e.g., data structures and data) that causes the machine to perform any one of the methodologies and / or embodiments described herein.

[0095] The terms “instructions” and “code” should be interpreted broadly to include any type of computer-readable statement(s). For example, the terms “instructions” and “code” can refer to one or more programs, routines, sub-routines, functions, procedures, etc. “Instructions” and “code” can comprise a single computer-readable statement or many computer-readable statements.

[0096] The term “modules” can be, for example, distinct but interrelated units from which a program may be built up or into which a complex activity may be analyzed. A module can also be an extension to a main program dedicated to a specific function. A module can also be code that is added in as a whole or is designed for easy reusability.

[0097] Some embodiments described herein relate to a computer storage product with a non- transitory computer-readable medium (also can be referred to as a non-transitory processor- readable medium) having instructions or computer code thereon for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not include transitory propagating signals per se (e.g., a propagating electromagnetic wave carrying information on a transmission medium such as space or a cable). The media and computer code (also can be referred to as code) can be those designed and constructed for the specific purpose or purposes. Examples of non-transitory computer-readable media include, but are not limited to, magnetic storage media such as hard disks, floppy disks, and magnetic tape; optical storage media such as Compact Disc / Digital Video Discs (CD / DVDs), Compact Disc-Read Only Memories (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; carrier wave signal processing modules; and hardware devices that are specially configured to store and execute program code, such as Application-Specific Integrated Circuits (ASICs), Programmable Logic Devices (PLDs), Read-Only Memory (ROM) and Random-Access Memory (RAM) devices. Other embodiments described herein relate to a computer program product, which can include, for example, the instructions and / or computer code discussed herein.

Claims

What is currently claimed:

1. A calibration method for calibrating a sensing electrode of a continuous analyte monitor, such as analyte, lactate, etc., comprising: a-priory provided statistical information about one or more electrodes corresponding to a particular batch production, the statistical information being used to estimate one or more calibration parameters of a primary sensing electrode EC-1, as well as calibration parameters and non-linearity of a secondary sensing electrode EC- 2; processing one or more signals from EC-1 to provide an accurate estimation of the analyte concentration; and processing one or more signals from a non-coated electrode EC-2 for aiding in the accurate real-time calibration of EC-1.

2. The method of claim 1, further comprising estimating a plurality of coefficients for determining analyte concentration and relationships of the one or more signals from EC-2.

3. The method of claim 1, wherein the one or more signals from EC-2 is represented as a time series.

4. The method of claim 2, wherein the one or more signals from EC-2 is represented as a time series.

5. The method of claim 3, wherein the time series corresponds to:wherein: i is the time index;Cgiuco.se is the concentration of analyte in the bulk solution where EC-2 is present;aEC-2and bEC-2comprise coefficients corresponding to a linear relationship of the one or more signals of EC-2 and activity of the enzyme, respectively; and f() is a non-linear function of the form:

6. The method of claim 4, wherein the time series corresponds to:wherein: i is the time index;Cglucoseis the concentration of analyte in the bulk solution where EC-2 is present; aEC-2 and bEC-2comprise coefficients corresponding to a linear relationship of the one or more signals of EC-2 and activity of the enzyme, respectively; and f() is a non-linear function of the form:

7. The method of claim 5, wherein: the function f() corresponds to enzyme activity, where C is the concentration of the substrate;V is the max activity level of the enzyme, and Kmis the Michaelis constant.

8. The method of claim 6, wherein: the function f c(o)rresponds to enzyme activity, where C is the concentration of the substrate;V is the max activity level of the enzyme, andKmis the Michaelis constant.

9. The method of claim 1, wherein the one or more signals form EC-1 is represented as a time series.

10. The method of claim 9, wherein the time series corresponds to: wherein:i is the time index; the analyte concentration in the bulk solution; andcomprise coefficients corresponding to a linear relationship ofthe signal received at EC-1 and the analyte concentration.

11. The method of claim 10, wherein the coefficients are estimations of using a linear regression.

12. The method of claim 11, wherein upon estimating the coefficients, for a duration of sensor activity, an estimate of analyte corresponds to:

13. The method of claim 1 , wherein one or more transient analyte levels are calculated from a combination of one or more signals received from each of EC-1 and EC-2.

14. The method of claim 1, wherein analyte concentration at any given time corresponds to:and wherein:Cglucose is the concentration of analyte in the bulk solution where the EC-1 is present; and f() is a non-linear function of the form:

15. The method of claim 1, wherein comprise coefficients estimated inreal-time from a relationship between the average signal received by EC-1 and the average of the signal received by EC-2.

16. The method of claim 15, wherein: the estimation of the average signal of the coefficients of EC-2correspond to: andthe average is taken over the same time duration for each of EC-1 and EC -2.

17. The method according to claim 14, wherein one or more signals and determined estimations are provided by one or more additional electrodes up to EC-n electrodes.

18. The method according to claim 15, wherein one or more signals and determined estimations are provided by one or more additional electrodes up to EC-n electrodes.

19. The method according to claim 16, wherein one or more signals and determined estimations are provided by one or more additional electrodes up to EC-n electrodes.

20. The method of claim 17, wherein a specificity of the EC-1 electrode is increased by use of the one or more signals of the one or more additional EC-n electrodes.

21. The method of claim 18, wherein a specificity of the EC-1 electrode is increased by use of the one or more signals of the one or more additional EC-n electrodes.

22. The method of claim 19, wherein a specificity of the EC-1 electrode is increased by use of the one or more signals of the one or more additional EC-n electrodes.

23. The method of claim 20, wherein the specificity of the EC-1 electrode is increased by subtraction of the one or more signals correlating to interferences.

24. The method of claim 21, wherein the specificity of the EC-1 electrode is increased by subtraction of the one or more signals correlating to interferences.

25. The method of claim 22, wherein the specificity of the EC-1 electrode is increased by subtraction of the one or more signals correlating to interferences.

26. The method of claim 17, wherein the one or more additional EC-n electrodes are not sensitive to analyte.

27. The method of claim 18, wherein the one or more additional EC-n electrodes are not sensitive to analyte.

28. The method of claim 19, wherein the one or more additional EC-n electrodes are not sensitive to analyte.

29. The method of claim 17, wherein the one or more additional EC-n electrodes are sensitive to interferences.

30. The method of claim 18, wherein the one or more additional EC-n electrodes are sensitive to interferences.

31. The method of claim 19, wherein the one or more additional EC-n electrodes are sensitive to interferences.

32. The method of claim 25, wherein an effect of the interferences is subtracted from the one or more signals of EC-1 electrode.

33. The method of claim 27, wherein an effect of the interferences is subtracted from the one or more signals of EC-1 electrode.

34. The method of claim 29, wherein an effect of the interferences is subtracted from the one or more signals of EC-1 electrode.

35. The method of claim 30, wherein an effect of the interferences is subtracted from the one or more signals of EC-1 electrode.

36. The method of claim 31, wherein an effect of the interferences is subtracted from the one or more signals of EC-1 electrode

Images