Apparatus and method for probing sensor operation for continuous analyte sensing and automatic calibration - Patent Application 20070122997

Abstract

To provide an improved apparatus and method for field calibration of a CGM sensor.SOLUTION: Apparatus and methods are operative to probe the condition of a sensor either initially, at any point thereafter or continuously during a continuous sensor operation for measuring an analyte in a bodily fluid (such as performed by, e.g., a continuous glucose monitoring (CGM) sensor). Results of the probe may include calibration indices determined from electrical signals obtained during the probe. The calibration index may indicate whether the field adjustment of the sensor calibration should be carried out initially and / or at random checkpoints. Probing potential modulation parameters also may be used during analyte calculations to reduce the effects of lot-to-lot sensitivity variations, sensitivity drift during monitoring, temperature, interferents, and / or the like. Other aspects are disclosed.SELECTED DRAWING: Figure 20

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 801,592, filed February 5, 2019, entitled "APPARATUS AND METHODS FOR PROBING SENSOR OPERATION OF CONTINUOUS ANALYTE SENSING AND AUTO-CALIBRATION," which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates to continuous sensor monitoring of analytes in bodily fluids. [Background technology]

[0003] Continuous analyte sensing in in vivo or in vitro samples, such as continuous glucose monitoring (CGM), has become a routine sensing operation in the medical device field, and more specifically, in diabetes care. For example, for biosensors that measure analytes in whole blood samples with discrete sensing, such as by pricking a finger to obtain a blood sample, the temperature of the sample and the hematocrit of the blood sample can be major sources of error. However, for sensors placed in a non-whole blood environment with a relatively constant temperature, such as sensors used in continuous in vivo sensing operations, other sources of sensor error can exist. Summary of the Invention [Problem to be solved by the invention]

[0004] Therefore, improved apparatus and methods for field calibration of CGM sensors are desirable. [Means for solving the problem]

[0005] According to aspects of the present disclosure, an apparatus and method are provided that can probe a sensor for its sensitivity or operating conditions, extract a sensitivity index for the sensor's operating conditions, and provide a field calibration other than a factory calibration, if necessary.

[0006] In some embodiments, a method is provided for compensating for errors in continuous glucose monitoring (CGM) measurements, the method comprising: providing a CGM device including a sensor, a memory, and a processor; applying a constant voltage potential to the sensor and measuring a primary current signal resulting from the constant voltage potential; and storing the measured primary current signal in memory; between measurements of the primary current signal, applying a probe potential modulation sequence to the sensor and measuring a probe potential-modulated current signal resulting from the probe potential modulation sequence; and storing the measured probe potential-modulated current signal in memory; and using the primary current signal and a plurality of measured probe potential-modulated current signals associated with the primary current signal to determine a glucose value for each primary current signal.

[0007] In some embodiments, the method includes the steps of: creating a prediction equation based on a plurality of probe potential-modulated current signals measured for a reference CGM sensor in response to a probe potential modulation sequence applied to the reference CGM sensor before or after a primary current signal is measured for the reference CGM sensor; providing a CGM device including a sensor, a memory, and a processor; storing the prediction equation in the memory of the CGM device; and, when executed by the processor, causing the CGM device to (a) apply a constant voltage potential to the sensor and measure a resulting primary current signal from the constant voltage potential and store the measured primary current signal in memory; and (b) measure a primary current signal. A method of making a continuous glucose monitoring (CGM) device is provided, comprising: (c) applying a probe potential modulation sequence to a sensor between measurements of the current signals, measuring probe potential modulated current signals resulting from the probe potential modulation sequence, and storing the measured probe potential modulated current signals in memory; (d) storing computer program code in the memory of the CGM device that causes the computer program code to: (a) for each primary current signal, use the primary current signal, a plurality of measured probe potential modulated current signals associated with the primary current signal, and a stored prediction equation to determine a glucose value; and (e) communicate the determined glucose value to a user of the CGM device.

[0008] In some embodiments, a continuous glucose monitoring (CGM) device is provided that includes a wearable portion having a sensor configured to generate a current signal from interstitial fluid, a processor, a memory coupled to the processor, and a transmitter circuit coupled to the processor. The memory includes a prediction equation based on a primary current signal generated by application of a constant voltage potential applied to a reference sensor and a plurality of probe potential-modulated current signals generated by application of a probe potential-modulation sequence applied between primary current signal measurements. The memory also includes computer program code stored in the memory that, when executed by the processor, causes the CGM device to (a) measure and store the primary current signal using the sensor and the memory of the wearable portion, (b) measure and store a plurality of probe potential-modulated current signals associated with the primary current signal, (c) use the primary current signal, the plurality of probe potential-modulated current signals, and the stored prediction equation to calculate a glucose value, and (d) communicate the glucose value to a user of the CGM device.

[0009] In some embodiments, a method is provided for determining an analyte concentration during continuous monitoring measurements, comprising: inserting a biosensor subcutaneously into a subject, the biosensor including a counter electrode, a reference electrode, and a working electrode having a chemical composition configured to oxidize an analyte at a point of interest; applying a constant voltage to the working electrode having the chemical composition to generate a continuous current from the working electrode; sensing and storing in memory a primary current signal from the working electrode; applying a probe potential modulation sequence to the working electrode after sensing each primary current signal and sensing and storing in memory a probe potential-modulated current generated in response to the probe potential modulation sequence; collecting the primary current signals and a probe potential-modulated current generated after the primary current signals; and using the collected primary current signals and the probe potential-modulated current to calculate an analyte value.

[0010] In some embodiments, a method is provided for probing the state of a continuous analyte monitoring (CAM) sensor and calibrating the sensor based thereon, the method comprising applying an operating voltage to the CAM sensor, probing the state of the CAM sensor by applying at least one voltage step higher than the operating voltage and at least one voltage step lower than the operating voltage, measuring an output voltage of the CAM sensor in response to the probing, calculating a calibration index via a ratio of the output currents, and calibrating the CAM sensor based on the calibration index.

[0011] In some embodiments, a continuous analyte monitoring (CAM) sensor device is provided that includes a management unit including a wireless transmitter / receiver that communicates with a wireless transmitter coupled to an on-body sensor, the management unit further comprising a processor, memory, and software, wherein the processor and software operate to (a) apply an operating voltage to the on-body sensor, (b) probe a state of the on-body sensor by applying at least one voltage step above the operating voltage and at least one voltage step below the operating voltage, (c) measure an output current of the on-body sensor in response to the probe, (d) calculate a calibration index via a ratio of the output currents, and (e) calibrate the on-body sensor based on the calibration index.

[0012] In some embodiments, a method of applying probe potential modulation during continuous analyte monitoring to determine an analyte concentration is provided, comprising applying a constant operating voltage to an analyte sensor during continuous sensor operation; applying at least one probe potential modulation step different from the constant operating voltage in each cycle of the continuous sensor operation; measuring a primary current from the constant operating voltage in each cycle and at least one companion probe potential modulation current in each cycle as a function of the analyte concentration; and determining the analyte concentration from the primary current and the at least one companion probe potential modulation current from the at least one probe potential modulation step.

[0013] In some embodiments, a continuous analyte monitoring (CAM) device is provided that includes a wearable portion having a sensor configured to be subcutaneously inserted into a subject and to generate a current signal from interstitial fluid, a processor, and a memory coupled to the processor. The memory includes computer program code stored therein that, when executed by the processor, causes the CAM device to: (a) apply a constant voltage to the sensor to generate a primary current from the sensor; (b) sense and store in the memory the primary current signal generated in response to the constant voltage; (c) apply a probe potential modulation sequence to the sensor while sensing the primary current signal, and sense and store in the memory a probe potential modulation current generated in response to the probe potential modulation sequence; and (d) use the primary current signal and the probe potential modulation current to calculate an analyte value over a time period of at least one week. The CAM does not use field calibration during the time period.

[0014] Still other aspects, features, and advantages of these and other embodiments of the present disclosure may become readily apparent from the following detailed description, the appended claims, and the accompanying drawings, wherein: Accordingly, the drawings and descriptions herein are to be regarded as illustrative in nature, and not as restrictive.

[0015] The drawings described below are for illustrative purposes and are not necessarily drawn to scale. The drawings are not intended to limit the scope of the disclosure in any way. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a graph of applied voltage E0 versus time for a continuous glucose monitoring (CGM) sensor in accordance with one or more embodiments of the present disclosure. [Figure 2] 1 is a graph of the output current of a CGM sensor versus time, in accordance with one or more embodiments of the present disclosure. [Figure 3] 10 is a graph of varying CGM sensor input potential modulation steps versus time during an initial probing period, in accordance with one or more embodiments of the present disclosure. [Figure 4] 10 is a graph of varying CGM sensor input potential modulation steps versus time during an intermediate probing period, in accordance with one or more embodiments of the present disclosure. [Figure 5A] 1 is a graph of the current-voltage relationship at and near the redox plateau of a redox species (mediator) in accordance with one or more embodiments of the present disclosure. [Figure 5B] 5 is a graph of an exemplary current-time relationship for the current before, during, and after the probe voltage modulation shown in FIGS. 3 and 4, in accordance with one or more embodiments of the present disclosure. [Figure 6A] FIG. 1 is a block diagram of a CGM sensor device according to one or more embodiments. [Figure 6B] FIG. 1 is a block diagram of a CGM sensor device according to one or more embodiments. [Figure 7A] 1 is a graph of applied voltage E0 versus time for a continuous glucose monitoring (CGM) sensor in accordance with one or more embodiments of the present disclosure. [Figure 7B] 1A-1C illustrate exemplary sequences of probe potential modulations that may be used in embodiments provided herein, showing stepped probe potential modulations. [Figure 7C] 1A-1C illustrate exemplary sequences of probe potential modulations that may be used in embodiments provided herein, showing one step-down / up probe potential modulation in two consecutive sequences. [Figure 7D] 10A-10C illustrate exemplary sequences of probe potential modulations that may be used in embodiments provided herein, showing asymmetric step probe potential modulations. [Figure 7E] 10A-10C illustrate exemplary sequences of probe potential modulations that may be used in embodiments provided herein, showing linear scan / triangular probe potential modulation. [Figure 7F] FIG. 10 illustrates an exemplary sequence of probing potential modulations that may be used in embodiments provided herein, showing a one-step potential modulation followed by a direct step back to a constant operating potential. [Figure 8A]7C is an exemplary graph of working electrode (WE) current versus time generated by the probe potential modulation of FIG. 7B during a first cycle of the probe potential modulation, according to embodiments provided herein. [Figure 8B] 8B is a graph of WE current versus time showing the decay of the probe voltage-modulated current of FIG. 8A over the first 6 hours after probe. [Figure 9A] 7D is an exemplary graph of working electrode (WE) current versus time generated by the probe potential modulation of FIG. 7C in response to three consecutive cycles of probe potential modulation at a constant glucose concentration, according to embodiments provided herein. [Figure 9B] 7C is a graph of WE currents in response to the probe voltage modulation of FIG. 7C taken on seven different days (Day 1-Day 7) at a constant glucose concentration. [Figure 10] 10 is a graph of working electrode current versus probe potential modulation time, according to an exemplary embodiment. [Figure 11A] 1 is a graph of working electrode current versus time showing the temporal response current of a CGM sensor with probe potential modulation (ppm) and without probe potential modulation (nppm) in response to different glucose concentrations at different acetaminophen concentrations as background signals, according to embodiments provided herein. [Figure 11B] FIG. 11B is a graph of predicted glucose concentration versus time for the WE current of FIG. 11A based on simple multivariate regression. [Figure 11C] 1 is a graph of WE current versus glucose solution concentration showing a linear response line at four levels of acetaminophen (ppm) with probe potential modulation as described herein. [Figure 11D] FIG. 11D is a graph of predicted glucose concentration based on the WE current of FIG. 11C (determined using probe potential modulation) versus glucose solution concentration. [Figure 11E] 1 is a graph of WE current versus glucose solution concentration showing a linear response line at four levels of acetaminophen without probe potential modulation (nppm). [Figure 11F]FIG. 11C is a graph of predicted glucose concentration based on the WE current of FIG. 11E (determined without using probe potential modulation) versus glucose solution concentration. [Figure 11G] FIG. 10 shows initial probe voltage-modulated current correlations for a background acetaminophen level of 0.2 mg / dL, according to embodiments provided herein. [Figure 11H] FIG. 10 shows terminal probe potential modulated current correlations for a background acetaminophen level of 0.2 mg / dL, according to embodiments provided herein. [Figure 12A] 1 is a graph of working electrode current versus time for three sensors that underwent probing potential modulation (sensors ppm-1, ppm-2, and ppm-3) and one sensor that did not undergo probing potential modulation (sensor nppm-1), according to embodiments provided herein. [Figure 12B] FIG. 10 shows working electrode current versus glucose concentration for three sensors (ppm −1 , ppm −2 , ppm −3 ) at day 7, according to embodiments provided herein. [Figure 12C] FIG. 10 illustrates working electrode current versus glucose concentration for one sensor (sensor ppm −1 ) at days 1, 7, and 14, according to embodiments provided herein. [Figure 12D] FIG. 10 shows the working electrode (primary current) of three sensors with temperature fluctuations during a portion of the 9th day of long-term monitoring according to embodiments provided herein. [Figure 13A] FIG. 10 shows output glucose values ​​over a 17 day period, where the use of probe potential modulation reduced the difference in glucose values ​​and increased overall glucose accuracy, according to embodiments provided herein. [Figure 13B] FIG. 10 illustrates the improvement of three glucose response lines for different sensors through the use of probing potential modulation, according to embodiments provided herein. [Figure 13C] FIG. 10 illustrates the elimination of nonlinear characteristics during warm-up through the use of probing potential modulation, according to embodiments provided herein. [Figure 13D]10A-10C illustrate the reduction of temperature effects through the use of probing potential modulation, according to embodiments provided herein. [Figure 13E] 10A-10C illustrate the reduction of sensitivity effects between different sensors through the use of probing potential modulation, according to embodiments provided herein. [Figure 13F] 10A-10C illustrate the reduction of sensitivity effects between different sensors through the use of probing potential modulation, according to embodiments provided herein. [Figure 14A] FIG. 1 is a high-level block diagram of an exemplary CGM device according to embodiments provided herein. [Figure 14B] FIG. 1 is a high-level block diagram of another exemplary CGM device according to embodiments provided herein. [Figure 15] FIG. 1 is a side schematic view of an exemplary glucose sensor according to embodiments provided herein. [Figure 16] 1 is a flowchart of an exemplary method for compensating for errors in continuous glucose monitoring (CGM) measurements, according to embodiments provided herein. [Figure 17] 1 is a flowchart of an exemplary method of making a continuous glucose monitoring (CGM) device according to embodiments provided herein. [Figure 18] 1 is a flowchart of an exemplary method for determining an analyte concentration during a continuous monitoring measurement according to embodiments provided herein. [Figure 19] 1 is a flowchart of an exemplary method for probing the state of a continuous analyte monitoring (CAM) sensor and calibrating the sensor based thereon, according to embodiments provided herein. [Figure 20] 1 is a flowchart of an exemplary method for determining an analyte concentration from a continuous analyte monitoring (CAM) sensor and calibrating the sensor based thereon, according to embodiments provided herein. DETAILED DESCRIPTION OF THE INVENTION

[0017] Reference will now be made in detail to the exemplary embodiments of the present disclosure, which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. Features of the various embodiments described herein may be combined with each other unless noted otherwise.

[0018] The terms "voltage," "potential," and "voltage potential" are used interchangeably. "Current," "signal," and "current signal" are also used interchangeably, as are "continuous analyte monitoring" and "continuous analyte sensing." As used herein, probe potential modulation refers to a periodic, intentional change to a constant voltage potential applied to a sensor during continuous analyte sensing, such as the application of a probe potential step, pulse, or other potential modulation to the sensor. A primary data point or primary current refers to a measurement of a current signal generated in response to an analyte at a constant voltage potential applied to the sensor during continuous analyte sensing. A probe potential modulation (ppm) current refers to a measurement of a current signal generated in response to a probe potential modulation applied to a sensor during continuous analyte sensing. A reference sensor refers to a sensor used to generate a primary data point and ppm current (e.g., a primary current and ppm current that are then stored in a continuous analyte monitoring (CAM) device and measured for purposes of determining a predictive equation used during continuous analyte sensing to determine analyte concentration) in response to a reference glucose concentration, for example, represented by a BGM reading.

[0019] For sensors deployed in non-whole-blood environments with relatively constant temperatures, such as sensors used in continuous in-vivo sensing operations, sensor errors may be related to the short-term and long-term sensitivity of the sensor and subsequent calibration methods. There are several issues / challenges associated with such continuous sensing operations: (1) long break-in (warm-up) times, (2) factory or field calibration, and (3) sensitivity changes during continuous sensing operations. These issues / challenges appear to be related to sensor sensitivity as manifested in the initial decay (break-in / warm-up time), sensitivity changes due to the sensor's sensitivity to the environment during sensor manufacturing, and the environment / conditions in which the sensor is subsequently deployed.

[0020] According to one or more embodiments of the present disclosure, the devices and methods operate to probe an initial starting condition of continuous sensor operation for a sample analyte and to probe the sensor condition at any subsequent time during the continuous sensing operation of the sensor. The results of the probing sequence may include a calibration indicator determined from the electrical signal obtained from the probing sequence that indicates whether in-situ adjustment of the sensor's calibration at any of the initial and / or random checkpoints is required. In some embodiments, the output of the probing method and its calibration indicator may internally provide in-situ calibration for the continuous sensor operation (and / or, in embodiments described below, the probing method may reduce and / or eliminate the need for in-situ calibration).

[0021] The embodiments described herein include systems and methods for applying a probing potential modulation to a constant voltage applied to an analyte sensor. The terms voltage, potential, and voltage potential are used interchangeably herein.

[0022] Methods are provided for formulating parameters for predictive equations that can be used to continuously and accurately determine analyte concentrations from analyte sensors. Additionally, methods and apparatus are provided for determining analyte concentrations through the use of a probe potential modulation (ppm) self-sufficient signal (e.g., working electrode current resulting from application of a probe potential modulation). Such methods and apparatus may (1) overcome the effects of different background interference signals, (2) smooth out or eliminate the effects of different sensor sensitivities, (3) reduce warm-up time at the beginning of a (long-term) continuous monitoring process, (4) compensate for sensor sensitivity changes over the continuous monitoring process, and / or (5) enable analyte concentration determination while compensating for temperature effects on the sensor output current. These and other embodiments are described below with reference to FIGS. 1-20.

[0023] For continuous glucose monitoring (CGM) biosensors, which typically operate at a constant applied voltage, the current from the mediator is measured continuously as a result of the enzymatic oxidation of the target analyte glucose. In practice, the current is typically measured or sensed every 3 to 15 minutes or another regular interval, even though it is referred to as continuous. When a CGM sensor is first inserted / implanted into a user, there is an initial break-in period that can last from 30 minutes to several hours. Once a CGM sensor has been broken in, its sensitivity may still change for a variety of reasons. Therefore, it is necessary to sense the sensor's operating condition during this initial break-in period and after the break-in period to identify any changes in its sensitivity.

[0024] CGM sensor operation begins with an applied voltage E0 after the CGM sensor is inserted / implanted subcutaneously into the user. This voltage E0 typically lies on the redox plateau of the mediator. For the natural mediator of oxygen production by the enzyme glucose oxidase, the oxidation plateau of hydrogen peroxide (HO) (the oxidation product of the enzymatic reaction) ranges from approximately 0.5 to 0.8 volts relative to an Ag / AgCl reference electrode in a medium with a chloride concentration of approximately 100 to 150 mM. The operating potential of the glucose sensor can be set within the plateau region, between 0.55 and 0.7 volts. Figure 1 illustrates such a fixed potential (applied voltage) E0, and Figure 2 illustrates typical behavior of the sensor output current in the initial and steady states with decay, as the sensor records the up / down changes in glucose during deployment. Specifically, Figure 1 shows a graph 100 of the working electrode voltage versus time during continuous sensing operation, and Figure 2 shows a graph 200 of the working electrode current versus time.

[0025] Figure 1 also shows the location in time of the initial and intermediate probes using probe potential modulation. Exemplary probe potential modulations are further shown in Figures 3 and 4. The probe potential modulations and their adjacent cluster potential steps may be further defined as follows:

[0026] Probe Potential: For the initial probe of the sensor condition / environment, in some embodiments, the probe may begin 0-5 minutes after sensor insertion and initial applied voltage. Other initial probe start times may also be used. In some embodiments, the probe potential modulation may include at least one forward potential step from a base potential E0. That is, the forward step potential E1 is higher than E0 and is less than ΔE 1,0 =E1 - E0 > 0, which is on the order of 0.05 to 0.3 volts. The probe potential modulation is ΔE 2,0 It may also include at least one reverse potential step E2, such that ΔE = E2 - E0 and is on the order of -0.05 to -0.5 volts, i.e., E2 is significantly lower than E1 and E0, where ΔE 2,1 =E2-E1<0 and ΔE 2,0 =E2-E0<0.

[0027] 5A and 5B show an exemplary relative potential step (graph 500A) and typical current behavior during the backward / forward potential step described above (graph 500B). Potential E2 is designed to set the mediator in a partially reduced state. The ratio of the end-of-potential-step currents, i 1,t / i 2,t may provide an assessment of the condition and sensitivity of the sensor, i.e., 1,t (Similarly, i 0,t , i 3,t ) provides the diffusion-limited current from the oxidation of the reduced state of the mediator, and i 2,t provides a response current related to sensor sensitivity. Additional potential steps may include a forward potential step E3 above E0 but below E1, and another reverse potential step from E3 back to E0. This probe potential sequence is designed to have minimal perturbation to ongoing current monitoring at fixed potential E0 after the final probe potential step returns to E0. After the probe potential modulation, normal current recording frequency may resume.

[0028] Probe Periods and Rest Periods: In some embodiments, the timing of a probe sequence including multiple probe potential modulations (potential steps in this example) can be on the order of 5 to 100 seconds, where each potential step can have a duration of 1 to 20 seconds with equal or unequal step sizes for the individual steps. This probe period can be separated by rest periods of, for example, 1 to 30 minutes. An example of such a probe scheme can be represented by a 30-second probe period for a 15-minute probe cycle and 3 to 5 probe groups separated by 14.5-minute rest periods. Long-term sensor response currents can be measured as frequently as every 1 to 15 minutes, while the current sampling interval for the probe potential modulations can be on the order of 0.1 to 5 seconds, depending on the step duration of the probe potential modulations.

[0029] Current decay constants of probe potential modulation: Exemplary probe potential modulation positions and their typical current decay behavior within those potential steps are shown in Figures 5A and 5B. The probe potential modulation (PPM) current is generally

[0030]

number

[0031] is proportional to the magnitude of the step potential by, where ΔE is the potential step and R S is the solution resistance between the working electrode and the reference electrode or combined reference / counter electrode, and C d is the capacitance of the electrode surface and t is the time after the initial step potential. ΔE / R S After an initial current spike characterized by S C d )). Thus, if ΔE>0, the step potential current is positive, and if ΔE<0, the step potential current is negative. Such behavior is shown in Figure 5B for four potential steps. For each probing potential modulation, there is a decay characteristic of the sensor electrode, the enzyme / membrane encapsulation, and the sensor environment. This decay is given by the decay constant

[0032]

number

[0033] where i n,0 is E n (n=1,2,3,...) denotes the initial current of the step, i n,t denotes the final current of the step at time t for each potential step. The decay is 1,t / i 1,0 , i 2,t / i 2,0 , i 3,t / i 3,0 , and i 4,t / i 4,0 It can also be defined by the ratio of i n,0 is the initial step current, and i n,tis the final step current at time t for each potential step. These decay constants may reflect changes in sensor sensitivity or changes in the enzyme / membrane state of the sensor during the break-in period.

[0034] Ratio of potential step end currents: The potential step end currents from E0, E1, and E3 should be close to each other after sufficient current decay. This occurs because E0, E1, and E3 are in the redox plateau due to diffusion-limited current. However, because E2 is in a region of current much lower than the diffusion-limited current in the redox plateau, the potential step end current for E2 can be significantly smaller than those from E0, E1, and E3. In particular, i 1,t / i 2,t The ratio of i to i may indicate the relative sensitivity of the sensor at nearby times. 3,t / i 2,t These ratios and the i from the factory calibration 1,t / i 2,t and i 3,t / i 2,t A comparison of the average ratio of E to the operating potential E can provide the relative sensitivity of the sensor and, therefore, the basis for field calibration. This ratio can also provide the sensor state at various stages. Thus, factory calibration can be based not only on the sensor's response curve (e.g., a set of slope and intercept calibration constants, coefficients of a polynomial relating the sensor current signal to analyte concentration, etc.), but also on calibration indices obtained from probe potential modulation. While slope and intercept calibration constants can be obtained only with in vitro administration of a reference concentration of analyte, the calibration indices described herein can be generated via in vivo potential modulation (or other types of probe potential modulation) using potential steps above and below the operating potential E and added to the factory calibration as additional calibration elements. For example, in some embodiments, the calibration constants can include multiple sets of slopes and intercepts, and calibration indices can be correlated with different sets of slopes and intercepts. These constants and indices can be stored in the sensor system's memory for field calibration during sensor operation.

[0035] Initial Probe: If the probe regime is applied every 15 minutes, then during the return to normal applied voltage E, the first hour provides four different sets of indices characteristic of the sensor, and different calibration constants can be applied to predict glucose concentrations within such a short period. As the probe indices generated from four consecutive probe potential modulations change over the break-in time, even if the general current behavior is still decaying, an initial decay current trend can be established to predict subsequent current behavior and thus provide a glucose determination based on the probe indices trend and the factory calibration constant. This approach can help reduce the overall sensor break-in / warm-up time from approximately 3 hours to 1 hour in some embodiments. The initial probe can be performed at other time intervals (e.g., less than every 15 minutes or more than every 15 minutes, so that fewer or more than four different sets of indices characteristic of the sensor can be obtained).

[0036] Intermediate Probe: In some embodiments, probe potential modulations may be applied periodically daily to provide an anchor for the long-term monitoring current. For example, one or more sets of probe potential modulations may be applied when the sensor is in a relatively low fluctuation state. If the probe index generated from the probe potential modulations indicates a change in sensor sensitivity, a sensitivity adjustment may be applied to correct for the change. This is a step of in-situ calibration (internal calibration).

[0037] Sensor System Intelligence: The probe potential modulation scheme may be applied routinely, such as initially, or periodically. The application of the probe potential modulation may use some built-in intelligence (e.g., software running on the microprocessor of the CGM sensor's management unit) to initiate the potential modulation and perform calculations of metrics to be used for in-situ sensor calibration.

[0038] 6A and 6B illustrate a CGM device 600 according to one or more embodiments. The CGM device 600 includes a management unit 602 having a wireless transmitter / receiver unit 604 and a wireless transmitter 605 coupled to an on-body sensor 607 received in a sensor pad 609 attachable to a user's body 611 (e.g., torso). The wireless transmitter 605 transmits sensor readings and other data to the wireless transmitter / receiver unit 604. The management unit 602 is inserted into the user's body 611 via known means, such as the use of a cannula, needle, or sensor component 613 (e.g., an analyte sensor), an insertion set, or the like, and interfaces with the on-body sensor 607 to enable substantially continuous sensing of glucose levels in the user's interstitial fluid. The management unit 602 has a housing 606, a display screen 608 that displays glucose readings and / or trends, and a user interface 610 that may include a number of buttons for controlling various functions of the management unit 602. 6B, management unit 602 also includes antenna 612, processor 614 (which may be, for example, a microprocessor), memory 616, software 618, rechargeable battery 620, battery charger 622, analog interface 624, and cable connector 626. Processor 614, memory 616, and software 618 are operable to probe CGM sensors (e.g., on-body sensors 607) for their sensitivity and operating status, extract and store sensitivity metrics related to the operating status of the CGM sensors, and perform on-site calibration adjustments, as needed, of CGM device 600 as described above.

[0039] The embodiments described herein use probe potential modulation as a periodic perturbation to a constant voltage potential applied to a working electrode of a subcutaneous biosensor during a continuous sensing operation (e.g., for monitoring a biological sample analyte such as glucose). While the previous embodiments describe the use of probe potential modulation during an initial time period after sensor insertion and during an intermediate time period, probe potential modulation can be used during other time periods. For example, during a continuous sensing operation such as continuous glucose monitoring, the sensor working electrode current is typically sampled every 3-15 minutes (or some other frequency) for glucose value determination. These current measurements represent the primary current and / or primary data points used for analyte determination during the continuous sensing operation. In some embodiments, a periodic cycle of probe potential modulation can be used after each primary current measurement such that a self-contained group of currents accompanies each primary data point with information about the status and / or condition of the sensor / electrode.

[0040] The probing potential modulation can include one or more steps at a potential different from the constant voltage potential normally used during continuous analyte monitoring. For example, the probing potential modulation can include a first potential step above or below the constant voltage potential, a first potential step above or below the constant voltage potential and then a potential step back to the constant voltage potential, a series of potential steps above and / or below the constant voltage potential, a voltage step, a voltage pulse, pulses of the same or different duration, a square wave, a sine wave, a triangular wave, or any other potential modulation.

[0041] As described, conventional biosensors used in continuous analyte sensing operate by applying a constant potential to the sensor's working electrode (WE). Under these conditions, the current from the WE is recorded periodically (e.g., every 3–15 minutes or at some other time interval). In this way, the biosensor generates a current that is due solely to changes in analyte concentration, not to changes in the applied potential. That is, there is no non-steady-state current associated with the application of different potentials. While this approach simplifies continuous sensing operations, the current signal in the data stream from the application of a constant potential to the sensor provides minimal information about the sensor status / condition. That is, the sensor current signal from the application of a constant potential to the sensor provides little information related to issues associated with long-term continuous sensor monitoring, such as lot-to-lot sensitivity variations, long warm-up times due to initial signal decay, changes in sensor sensitivity over the long-term monitoring process, and influences from fluctuating background interference signals.

[0042] Embodiments described herein include systems and methods for applying a probe potential modulation to a constant voltage applied to an analyte sensor. Methods are provided for formulating parameters for a predictive equation that can be used to continuously and accurately determine analyte concentration from an analyte sensor. Additionally, methods and systems are provided for determining analyte concentration through the use of a probe potential modulation (ppm) self-contained signal. Such methods and systems may enable analyte concentration determination while (1) overcoming the effects of different background interference signals, (2) smoothing or eliminating the effects of different sensor sensitivities, (3) reducing warm-up time at the beginning of a (long-term) continuous monitoring process, (4) compensating for sensor sensitivity changes over the continuous monitoring process, and / or (5) compensating for the effects of temperature on the sensor output current. These and other embodiments are described below with reference to FIGS. 7A-19.

[0043] FIG. 7A illustrates a graph of applied voltage E versus time for a continuous glucose monitoring (CGM) sensor according to one or more embodiments of the present disclosure. Exemplary times are shown where primary data point measurements are taken and subsequent probe potential modulations are applied. As shown in FIG. 7A, the constant voltage potential E applied to the working electrode of the analyte sensor may be approximately 0.55 volts in this example. Other voltage potentials may also be used. FIG. 7A illustrates an example of a typical cycle of primary data points taken at a constant applied voltage. Primary data points are data points measured or sampled at regular intervals, such as 3-15 minutes, during continuous glucose monitoring and used to calculate a user's glucose level. A primary data point may be, for example, the working electrode current measured for the analyte sensor during continuous analyte monitoring. While FIG. 7A does not illustrate the primary data points, it does indicate the time and voltage at which each primary data point is measured. For example, circle 702 in Figure 7A represents the time / voltage (3 minutes / 0.55 volts) at which a first primary data point (e.g., a first working electrode current) is measured for a sensor biased at a voltage of E. Similarly, circle 704 in Figure 7A represents the time / voltage (6 minutes / 0.55 volts) at which a second primary data point (e.g., a second working electrode current) is measured for a sensor biased at a voltage of E.

[0044] 7B, 7C, 7D, 7E, and 7F show exemplary sequences of probe potential modulation that may be used according to embodiments provided herein. The triangles above the potential profiles indicate the time at which the probe potential modulation current is measured, as an example of this embodiment. For example, FIG. 7B shows a stepped probe potential modulation, FIG. 7C shows a single step down / up probe potential modulation in two consecutive sequences, FIG. 7D shows an asymmetric step probe potential modulation, FIG. 7E shows a linear scan / triangle probe potential modulation, and FIG. 7F shows a one-step potential modulation followed by a direct step back to a constant operating potential, respectively. Other probe potential modulation types may also be used. In these figures, "primary voltage" refers to the constant applied potential under normal sensor operation, "primary data" refers to the timing of primary data points (e.g., current signals) recorded periodically as indicative of analyte concentration, "probe voltage" refers to the probe potential modulation potential applied as a perturbation to the primary / constant applied potential, and "probe data" refers to the timing of the current signal generated by the probe potential modulation and recorded at a specified sampling rate. While Figures 7B-7E show four or more steps of probe potential modulation, it will be understood that fewer or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) probe potential modulation steps may be used.

[0045] The probe potential modulation can be applied before or after the primary data points are measured. In the embodiment of Figures 7B-7E, the probe potential modulation is applied to the sensor immediately after each primary data point is measured (e.g., after the primary data points are measured at 3 minutes, 6 minutes, 9 minutes, etc.).

[0046] Exemplary primary data points and probe potential modulations are now described. While primarily described with respect to voltage pulses or voltage steps, it will be understood that other types of probe potential modulations may be used, as previously discussed. Referring to FIG. 7A, 0.55 V is applied to the working electrode of an analyte sensor (e.g., a glucose sensor having a chemical composition such as glucose oxidase to oxidize / convert glucose to a product such as HO) relative to a reference electrode such as Ag / AgCl. Other sensor types and / or electrode materials may also be used. The continuous current through the working electrode is measured periodically at a fixed sampling frequency of 3 minutes as the primary data point / current signal. Other sampling frequencies may also be used.

[0047] After each primary data point is measured, a probe potential modulation may be applied to the working electrode, e.g., to probe the status and / or condition of the sensor / electrode. In the embodiment of FIGS. 7B-7F, the probe potential modulation described below is applied after each primary data point is measured. Specifically, in FIGS. 7B-7F, a probe potential modulation is used after a primary data point is measured at 3 minutes (circle 702) and 6 minutes (circle 704). Similar probe potential modulation may be used after each primary data point is measured (e.g., 0 minutes, 3 minutes, 6 minutes, 9 minutes, 12 minutes, 15 minutes, 18 minutes, etc.). As mentioned above, in other embodiments, a probe potential modulation may be applied before measuring a primary data point (e.g., assuming that a primary data point has not been measured until the probe potential modulation current has decayed). In some embodiments, a probe potential modulation may be applied before and after measuring a primary data point.

[0048] Referring to Figure 7B, after each primary data point is measured, six voltage steps (steps 1-6) may be used. In the illustrated embodiment, each step lasts 6 seconds, and the resulting working electrode current signal is measured every 2 seconds (resulting in three current signal measurements per potential step). Other steps in voltage, step duration, and / or sampling rate may also be used.

[0049] Step 1: 0.55V=>0.6V

[0050] Step 2: 0.6V=>0.45V

[0051] Step 3: 0.45V=>0.3V

[0052] Step 4: 0.3V=>0.45V

[0053] Step 5: 0.45V=>0.6V

[0054] Step 6: 0.6V=>0.55V

[0055] Following step 6, the constant voltage of 0.55 V is resumed until the next primary data point is measured and the probe potential modulation sequence is repeated.

[0056] Referring to Figure 7C, after each primary data point is measured, six voltage steps (steps 1-6) may be used. In the illustrated embodiment, each step lasts 6 seconds, and the resulting working electrode current signal is measured every 2 seconds (resulting in three current signal measurements per potential step). Other steps in voltage, step duration, and / or sampling rate may also be used.

[0057] Step 1: 0.55V=>0.6V

[0058] Step 2: 0.6V=>0.25V

[0059] Step 3: 0.25V=>0.6V

[0060] Step 4: 0.6V=>0.45V

[0061] Step 5: 0.45V=>0.6V

[0062] Step 6: 0.6V=>0.55V

[0063] Following step 6, the constant voltage of 0.55 V is resumed until the next primary data point is measured and the probe potential modulation sequence is repeated.

[0064] Referring to Figure 7D, after each primary data point is measured, four voltage steps (Steps 1-4) may be used. In the illustrated embodiment, each step lasts 6 seconds, and the resulting working electrode current signal is measured every 2 seconds (resulting in three current signal measurements per potential step). Other steps in voltage, step duration, and / or sampling rate may also be used.

[0065] Step 1: 0.55V=>0.65V

[0066] Step 2: 0.65V=>0.35V

[0067] Step 3: 0.35V=>0.6V

[0068] Step 4: 0.6V=>0.55V

[0069] Following step 4, the constant voltage of 0.55 V is resumed until the next primary data point is measured and the probe potential modulation sequence is repeated.

[0070] Referring to Figure 7E, after each primary data point is measured, six linearly varying voltage steps (steps 1-6) can be used. In the illustrated embodiment, each step lasts 6 seconds, and the resulting working electrode current signal is measured every 2 seconds (resulting in three current signal measurements per potential step). Other steps in voltage, step duration, and / or sampling rate can also be used.

[0071] Step 1: Linear scan from 0.55V to 0.6V, scan rate 0.00833V / sec

[0072] Step 2: Linear scan from 0.6V to 0.25V, scan rate 0.05833V / sec

[0073] Step 3: Linear scan from 0.25V to 0.6V, scan rate 0.05833V / sec

[0074] Step 4: Linear scan from 0.6V to 0.45V, scan rate 0.025V / sec

[0075] Step 5: Linear scan from 0.45V to 0.6V, scan rate 0.025V / sec

[0076] Step 6: Linear scan from 0.6V to 0.55V, scan rate 0.00833V / sec

[0077] Following step 6, the constant voltage of 0.55 V is resumed until the next primary data point is measured and the probe potential modulation sequence is repeated.

[0078] For the above example of probing potential modulation, other timing and / or applied voltages may also be used. For example, other potential step sequences for different biosensor mediators may be devised.

[0079] Referring to FIG. 7F, one potential modulation step is applied to the working electrode, followed by a direct return to the original constant voltage of 0.55V.

[0080] FIG. 8A is an exemplary graph of working electrode (WE) current versus time generated by the probe potential modulation of FIG. 7B during the first cycle of probe potential modulation, according to embodiments provided herein. In this example, a CGM glucose sensor was placed in a 100 mg / dL glucose solution. FIG. 8B is a graph of WE current versus time showing the decay of the probe potential modulation current of FIG. 8A over the first 6 hours. A sample rate of 1 s / point was used throughout. FIG. 8B provides an overview of all probe potential modulation (PPM) currents, where the outer contours of the profiles show clear decay behavior, indicating that the PPM currents embed information about the decay nature of the sensor current after sensor insertion and activation. Because the PPM currents embed information about the decay of the sensor current, they can be used as self-contained information to correct for the transient nature of sensor sensitivity. Instead of waiting for the sensor to reach a meta-steady state, the warm-up time can then be shortened, as shown below.

[0081] FIG. 9A is an exemplary graph of working electrode (WE) current versus time generated by the probe potential modulation of FIG. 7C in response to three consecutive cycles of probe potential modulation, according to embodiments provided herein. In this example, a CGM glucose sensor was placed in a 100 mg / dL glucose solution. FIG. 9B is a graph of WE current in response to the probe potential modulation of FIG. 7C taken on seven different days (Day 1 through Day 7). A sample rate of 1 s / point was used throughout. Similar WE current responses are observed on Day 1 and throughout Days 1 through 7.

[0082] As seen in the two examples in Figures 8A, 8B, 9A, and 9B above, in some embodiments, the current signals in the probed and non-probe potential-modulated regions can be measured at a fixed sampling rate, such as 1 second per point. In other embodiments, different sampling rates can be used. For example, primary data points can be measured at a slower sample rate of 1, 2, 3, 5, 10, or 15 minutes, and the probe potential-modulated current can be measured at a sample rate of 0.5, 1, 2, 3, or 5 seconds within each potential step. To reduce random signal noise, the primary data points can be further measured as the average of multiple signals at a constant applied voltage within a close time range of periodic sample times (e.g., every 3 minutes), such as 60, 30, 20, 10, or 5 seconds. The same can be done for the probe potential-modulated current within 0.1, 0.2, or 0.5 seconds of the periodic sample time (e.g., every 1 second), depending on the AD conversion speed. Other sample rates and / or sampling schemes can also be used.

[0083] 8A, 8B, 9A, and 9B, it can be seen that the magnitude of the probe potential-modulated current ("ppm" or "PPM" current) is substantially greater than the steady-state current (non-probe or "nppm" or "NPPM" current measured without the probe potential modulation perturbation). Without wishing to be bound by theory, the goal of the probe potential modulation is to briefly create a perturbed output current to obtain sensor status / condition information while measuring the primary data point without the effects of the probe potential modulation. That is, the primary data point is measured when the WE current returns to the flat current profile generated at the constant voltage E0. It is hypothesized that there is a wealth of information regarding the status / condition of the sensor / electrode embedded within the ppm current generated by the probe potential modulation. As previously mentioned, the probe potential modulation can be applied before or after the primary data point is measured. In some embodiments, the probe potential-modulated output current can be generated on at least one side of the flat current profile measured as the primary data point. In other embodiments, the probe potential modulated output currents can be generated on either side of a flat current profile measured as the primary data points. In yet other embodiments, negative and positive probe potential modulated output currents can be generated on either side of a flat current profile measured as the primary data points.

[0084] Explanation of Probing Potential Modulated Current FIG. 10 shows a graph of working electrode current versus probe potential modulation time, according to an exemplary embodiment. Referring to FIG. 10, the probe potential modulation step used to generate the working electrode current of FIG. 10 is the following sequence: a forward step from a fixed / constant voltage (e.g., 0.55 volts), followed by two reverse steps, followed by two forward steps, and finished with a small reverse step to facilitate a return to a constant potential (e.g., 0.55 volts), similar to the probe potential modulation step of FIG. 7B. The probe potential modulation output current may follow the primary current or primary data points recorded at a constant potential of 0.55 volts during one cycle (e.g., as described with reference to FIG. 7B). The probe potential modulation (ppm) output current and the non-probe (nppm) output current (e.g., the current from a constant potential without probe potential modulation) are labeled in FIG. 10. In the illustrated embodiment, both ppm and nppm currents are measured at the same sampling rate of 2 seconds per point (resulting in three current signal measurements per voltage step: i11, i12, i13, i21, i22, i23, etc.). Other sampling rates may also be used. In the figures, i10, i11, i12, i13, i21, i22, i23, etc. may be written as i1.0, i1.1, i1.2, i2.1, i2.2, i2.3, etc.

[0085] The probe potential modulation is applied periodically (e.g., after a primary data point is measured) as a potential perturbation to the constant potential applied to the working electrode, so that each primary data point can be accompanied by a group of ppm currents. In some embodiments, the period for applying the probe potential modulation can vary from 1 minute to several hours, and in some embodiments, from about 3 to 15 minutes, over which periodic analyte concentrations are reported. In one particular embodiment, the period for applying the probe potential modulation is 3 minutes (e.g., after each primary data point is measured at 3-minute intervals). The minimum time between primary data points can be set, for example, based on how quickly the output current from the constant potential stabilizes after each probe potential modulation cycle.

[0086] As an example, the improvement in accuracy through the use of probe potential modulation is demonstrated with a data set from an in vitro laboratory study in which a CGM sensor was immersed in a glucose solution with four different levels of acetaminophen representing background signals: 0.2 mg / dL, 0.6 mg / dL, 1.2 mg / dL, and 1.8 mg / dL. These four levels of acetaminophen were used to simulate different background signals from interfering species using acetaminophen as a surrogate for oxidizable species at 0.55 V, and then to simulate results corrected for the effects of the different background signals using PPM current. An acetaminophen concentration of 0.2 mg / dL is considered equivalent to a normal level of interfering background signal, while 0.6 mg / dL is considered a high level. Acetaminophen concentrations of 1.2 mg / dL and 1.8 mg / dL are considered very high levels. For each level of background acetaminophen, one linearity run was performed at five levels of glucose concentration: 50, 100, 200, 300, and 450 mg / dL.

[0087] FIG. 11A is a graph of working electrode current versus time showing the time response current (primary data points) of a CGM sensor with probe potential modulation (ppm) (curve 1102) and without probe potential modulation (nppm) (curve 1104) for the sample described above, according to embodiments provided herein. The graph shows that the current profile of the primary data points with ppm behaves similarly to the current profile of the primary data points without ppm, except that the sensors used have different sensitivities. This behavior again indicates that probe potential modulation does not affect the primary data points, but provides additional information regarding the state / changes of the sensor, as described further below. FIG. 11B is a graph of predicted glucose concentration versus time for the WE current of FIG. 11A based on simple multivariate regression. FIG. 11C is a graph of WE current versus glucose solution concentration showing a linear response line at four levels of acetaminophen with probe potential modulation (ppm) as described herein. FIG. 11D is a graph of predicted glucose concentration versus glucose solution concentration based on the WE current of FIG. 11C (determined using probe potential modulation). FIG. 11E is a graph of WE current versus glucose solution concentration showing linear response lines at four levels of acetaminophen without probe potential modulation (nppm). FIG. 11F is a graph of predicted glucose concentration versus glucose solution concentration based on the WE current of FIG. 11E (determined without using ppm current). Linear regression equations are shown progressively from the lower to the upper lines in FIGS. 11C, 11D, 11E, and 11F for four lines corresponding to four levels of acetaminophen (AA), with increasing intercepts representing the effect from increasing acetaminophen levels.

[0088] Table 1 summarizes the response lines (slope and intercept) from Figures 11C, 11D, 11E, and 11F for the primary data points and calculated glucose for the sensors with and without PPM. Output glucose values ​​for the probe potential modulation (PPM) and non-PPM methods are calculated from a prediction equation (described below) derived from data for all four levels of acetaminophen.

[0089] [Table 1]

[0090] Table 1 shows that the average response slopes of the two sensors may vary due to individual sensor sensitivity during manufacturing, but the effect of added acetaminophen (AA) as an interfering background substance results in a significant increase in the intercept. The effect on the intercept, while large, is similar for both the PPM and non-PPM data sets. When using PPM current as part of the input to the glucose prediction equation, the correlation of output glucose to reference glucose (represented by the slope, also known as the "correlation slope") approaches 1, which is expected. When the prediction equation is based on data from levels 1 and 2, the maximum effect of added acetaminophen is within ±6 mg / dL. This level of effect on output glucose is within the range of other factors; i.e., this effect is very small compared to the effects of other factors, such as daily sensitivity changes. On the other hand, the correlation slope of output glucose for the non-PPM data is reduced by at least 10% and is less than 1 due to the overall weighting effect of low and high acetaminophen currents. That is, when drawing a statistical mean line across the four data sets (acetaminophen levels 1, 2, 3, and 4), the correlation slope is affected by the elevated intercept from the level 4 acetaminophen data set. The large effect of added acetaminophen cannot be removed without additional information such as PPM current. Thus, the maximum effect on output glucose when PPM current is not used is an error of up to 80 mg / dL, which translates to 110% at 70 mg / dL glucose and 80% at 100 mg / dL glucose.

[0091] Primary data point profiles recorded over a 3-minute period are shown in Figure 11A at five glucose levels in each of the four acetaminophen backgrounds. For the probe potential modulation (ppm) data from the probe potential modulation, only the primary data points are shown (in the same format as the non-probe potential modulation (nppm) data points). That is, for the ppm data in Figure 11A, only the constant operating voltage-generated current response to acetaminophen and glucose stimulation is shown. The two sensors are shown to have different sensitivities, which are related to the individual sensor sensitivities at the time of manufacture, rather than to the PPM and non-PPM methods. Additionally, the effect of background acetaminophen, increasing from a typical level of 0.2 mg / dL to a maximum level of 1.8 mg / dL, is seen at glucose levels as low as 50 mg / dL. The two data sets, probe potential modulation (ppm) data and non-probe potential modulation (nppm) data, were analyzed with simple multivariate regression to derive predictive equations for probe potential modulation (ppm) and non-probe potential modulation (nppm) data, using glucose concentration as the target and primary data point, and, when ppm data were present, 18 ppm currents (three per voltage step) following the primary data point as regression inputs. Statistical software, such as Minitab software available from Minitab, LLC, State College, PA, can be used for regression analysis.

[0092] For the probe potential modulation (ppm) data, the effect of increasing background acetaminophen was most evident in the intercepts of the response lines for the four linear runs, as shown in Figure 11C, with only a slight effect on the slope observed. However, the predicted glucose plot in Figure 11D shows the four lines effectively collapsing into a single line, where the prediction equation incorporates multiple probe potential modulation (ppm) currents. Meanwhile, the effect of different background acetaminophen levels cannot be overcome with the primary data points alone (without probe potential modulation), and the four separate lines in the glucose signal response in Figure 11E are transformed into four separate lines of predicted glucose in Figure 11F. This comparison demonstrates that the probe potential modulation current provides a wealth of information for correcting for the effects of background signal fluctuations, while the current from a constant applied voltage is highly susceptible to background signal fluctuations.

[0093] For the non-probe potential modulation (nppm) data, the primary data points alone cannot overcome the substantial changes in background acetaminophen concentration, thus yielding output glucose values ​​with significant influence from background interfering species. For the probe potential modulation (ppm) data, there is a group of probe potential modulation (ppm) currents accompanying each primary data point. Review of the glucose prediction equation by regression indicates that 11 of the 19 inputs (primary data points from the applied constant voltage and 18 probe potential modulation (ppm) currents) were significantly selected in the glucose prediction equation. The significant probe potential modulation (ppm) currents were from voltage steps 1–5. Therefore, these probe potential modulation (ppm) currents are self-contained information currents with subtle correlations to various influences on the sensor and / or working electrode output current. These probe potential modulation (ppm) currents then help formulate a prediction equation for glucose that corrects for the different background signals from the four levels of acetaminophen.

[0094] Exemplary prediction equations based on simple or multivariate regression are provided below. In these equations, the primary current is labeled i10. The primary current is the current in response to a constant voltage potential applied to the working electrode. The primary current is typically measured, for example, before the application of any probe potential modulation. That is, in some embodiments, a probe potential modulation is applied to the working electrode after the primary current is measured. Any number of probe potential modulation steps (e.g., 1, 2, 3, 4, 5, 6, etc.) can be applied. The application of probe potential modulation steps causes a nonlinear response in the working electrode current, which can be measured multiple times (e.g., 2, 3, 4, or more) with varying response currents, as previously described with reference to Figures 7B-7E. In the prediction equations provided below, the probe potential modulation current is labeled ixy, where x indicates the voltage step and y indicates the position (e.g., time) within the voltage step at which the current is measured. For example, i11 is the first of three currents recorded during the first voltage step, i13 is the third of three currents recorded during the first voltage step, and i63 is the third of three currents recorded during the sixth voltage step. As mentioned above, i10 is the primary current, or the current measured at time 0 before the probe potential modulation is applied.

[0095] For non-probe potential modulation (nppm) data, where only the primary data point current is used, the nppm prediction formula G_ref_nppm is based on a simple regression in equation (3) below: That is, there is only one signal, i10, available to represent glucose. Even if additional data signals are measured in the time between primary data points (when ppm data is measured), the current following i10 still contains the same information as i10 because only a constant voltage of 0.55 V is used. (3)G_ref_nppm(mg / dL)=-43.147657+6.14967*i10

[0096] For probe potential modulation (ppm) data, where both primary data point currents and probe potential modulation currents are used, the currents generated at different potential modulation steps differ from the generally constant output current from the constant operating voltage used to measure the primary data points. These ppm currents correlate with i10 in various ways. As examples of these correlations, as provided in the Methods, two graphs of the correlation between the initial and final potential modulation currents for a background acetaminophen level of 0.2 mg / dL are shown in Figures 11G and 11H. These subtle relationships are incorporated into the glucose prediction equation, G_ref_ppm, in Equation (4) by multivariate regression. (4)G_ref_ppm(mg / dL)=39.07108-11.663917*i11+18.212602*i13-9.318668*i21+13.896986*i22-9.51 9628*i23-1.947934*i31+13.389696*i32-12.395404*i33-2.851515*i41+9.183032*i42-2.944314*i51

[0097] Note that equations (3) and (4) are merely examples: other prediction equations may also be used.

[0098] In another example, three CGM sensors underwent long-term (17-day) stability monitoring with probe potential modulation applied periodically every 3 minutes, along with a CGM sensor in the same monitoring run without probe potential modulation. Three linearity runs were performed at time 0 (immediately after the start of the 17-day run), day 7, and day 14. At times other than the linearity runs, the CGM sensors were exposed to a constant 450 mg / dL glucose solution. Raw current profiles of primary data points for the four sensors are shown in Figure 12A, which shows a graph of working electrode current versus time for three sensors with probe potential modulation (sensors ppm-1, ppm-2, and ppm-3) and one sensor without probe potential modulation (sensor nppm-1). It can be seen that the three sensors with probe potential modulation (ppm) and the sensor without probe potential modulation (nppm) temporarily track each other as the working electrode current moves up and down. Relative sensitivity is maintained throughout the entire 17-day monitoring period. This plot of ppm and nppm current shows that there is no long-term adverse effect of probe potential modulation on the primary current (the current resulting from the constant operating voltage used to generate the primary data points).

[0099] There are at least four factors that can contribute to error in the determined glucose concentration or affect accuracy: (1) initial sensor current decay or warm-up time, which initially limits the sensor system's ability to report accurate analyte concentrations; (2) individual sensor sensitivity between different sensors or different lots of sensors; (3) changes in sensor sensitivity over the monitoring period; and (4) changes in background signal due to ingestion of interfering substances, such as acetaminophen medication.

[0100] The three sensors using probe potential modulation had different sensitivities with three different sets of calibration constants (slope and intercept) to accurately determine glucose values ​​when only primary data information was available. The three sensor sensitivities (slope_1 = 0.107, Slope_2 = 0.1532, Slope_3 = 0.1317) varied by as much as 50% from low to high, representing significant sensitivity variation. For example, Figure 12B shows the working electrode current versus glucose concentration for three sensors (ppm-1, ppm-2, ppm-3) at day 7 according to an embodiment provided herein. Conventional methods of factory calibration link sensitivity during release testing to sensor performance, such as by lot constants, for glucose calculations. If there is any sensitivity change, such as a current signal moving up or down, the factory-assigned calibration constants (slope and intercept) will introduce error into the determined glucose concentration.

[0101] An initial decay in sensor current is a natural tendency of CGM sensors and prevents glucose readings from being reported until later, e.g., 1, 2, or 3 hours or more after sensor insertion (see, e.g., FIG. 2). This initial rest period is called the warm-up time of the CGM sensor. If this warm-up time could be shortened, the CGM system could provide glucose readings in a reasonably short time, such as 30 minutes, or even 15, 10, or 5 minutes after insertion.

[0102] The change in sensitivity over the monitoring time can be seen, for example, in Figure 12C, which shows working electrode current versus glucose concentration for one of the sensors (sensor ppm-1) at days 1, 7, and 14 according to embodiments provided herein. As shown in Figure 12C, the sensitivity of the sensor changes (e.g., decreases) over time.

[0103] The sensor current also depends on the temperature, as shown in FIG. 12D, which shows the working electrode (primary current) of the three sensors with temperature fluctuations during the 9-day portion of the long-term monitoring.

[0104] Because the probe potential modulation (ppm) current contains sensor information, issues of sensitivity differences, initial warm-up time, and sensitivity changes during monitoring can be overcome to provide more accurately determined analyte concentrations. For example, a predictive glucose equation can be derived using input parameters such as the probe potential modulation current and the primary data point current, e.g., using multivariate regression. (The following examples use voltage potential steps, but it will be understood that other types of probe potential modulation may be used as well.) For the example provided in FIG. 12A , the input parameters may be of the following types (defined below): (1) primary data point current i10 and probe potential modulation currents i11-i63, (2) temperature cross-terms i10T of primary data point currents and temperature cross-terms i11T-i63T of probe potential modulation (ppm) currents, (3) probe potential modulation (ppm) current ratios R1, R2, R3, R4, R5, and R6 within each potential step for six steps in the probe potential modulation sequence, (4) x-type parameters, (5) y-type parameters, (6) z-type parameters, and / or (7) cross-terms of additional parameters. These terms are defined as follows:

[0105] Probe current: Probe potential-modulated current i11, i12, i13, ..., i61, i62, i63, where the first digit (x) in the ixy format indicates the potential step and the second digit (y) indicates the current measurement taken after application of the potential step (e.g., the first, second, or third measurement).

[0106] R parameters: These ratios are calculated by dividing the final ppm current by the first ppm current within one potential step. For example, R1 = i13 / i11, R2 = i23 / i21, R3 = i33 / i31, R4 = i43 / i41, R5 = i53 / i51, and R6 = i63 / i61.

[0107] x-type parameters: The general form of this type of parameter is given by dividing the terminal ppm current of the later potential step by the terminal ppm current of the earlier potential step. For example, the parameter x61 is determined by i63 / i13, where i63 is the terminal ppm current of step 6 and i13 is the terminal ppm current of step 1 in the three recorded currents per step. In addition, x61=i63 / i13, x62=i63 / i23, x63=i63 / i33, x64=i63 / i43, x65=i63 / i53, x51=i53 / i13, x52=i53 / i23, x53=i53 / i33, x54=i53 / i43, x41=i43 / i13, x42=i43 / i23, x43=i43 / i33, x31=i33 / i13, x32=i33 / i23, and x21=i23 / i13.

[0108] y-type parameters: The general form of this type of parameter is given by dividing the final ppm current of a later potential step by the first ppm current of the earlier potential step. For example, the parameter y is determined by i / i, where i is the final ppm current of step 6 and i is the first ppm current of step 1 in the three recorded currents per step. In addition, y61=i63 / i11, y62=i63 / i21, y63=i63 / i31, y64=i63 / i41, y65=i63 / i51, y51=i53 / i11, y52=i53 / i21, y53=i53 / i31, y54=i53 / i41, y41=i43 / i11, y42=i43 / i21, y43=i43 / i31, y31=i33 / i11, y32=i33 / i21, and y21=i23 / i11.

[0109] Z-type parameters: The general form of this type of parameter is given by dividing the first ppm current of a later potential step by the final ppm current of an earlier potential step. For example, the parameter z61 is determined by i61 / i13, where i61 is the first ppm current of step 6 and i13 is the final ppm current of step 1 of the three recorded currents per step. In addition, z61 = i61 / i13, z62 = i61 / i23, z63 = i61 / i33, z64 = i61 / i43, z65 = i61 / i53, z51 = i51 / i13, z52 = i51 / i23, z53 = i51 / i33, z54 = i51 / i43, z41 = i41 / i13, z42 = i41 / i23, z43 = i41 / i33, z31 = i31 / i13, z32 = i31 / i23, and z21 = i21 / i13.

[0110] Temperature Cross Terms: Temperature cross terms are calculated by multiplying other parameters by the temperature at which the underlying currents are measured, e.g., R1T = (i13 / i11)*T, y61T = (i63 / i11)*T, etc.

[0111] Other types of parameters such as ppm current differences or relative differences, or ratios of intermediate ppm currents that carry equivalent or similar information may also be used.

[0112] To demonstrate the feasibility of overcoming issues of different sensor sensitivities, initial warm-up times, sensitivity changes over time, and different background signals due to uptake of different amounts of interfering substances, the above parameters, along with their temperature cross-terms, are used as inputs to a multivariate regression in a simple form. Additional terms / parameters may be provided in the regression analysis.

[0113] Equation 5 below shows the regression equation for predicting glucose using ppm data (ppm-1, ppm-2, ppm-3) from three sensors over 17 days of longitudinal monitoring with three linearity runs in Figures 12A-12D. In addition to the subtle relationships between the individual ppm currents shown in Figures 11G and 11H, different ratio parameters previously defined can also be selected and incorporated into the prediction equation. The selected parameters in the equation resulting from this multivariate regression are the probe current and related parameters, also known as "self-sufficient information" parameters, that are not available when only a constant voltage potential is used. The parameters and / or coefficients in Equation 5 are merely examples. Other numbers and / or types of parameters and / or coefficients may also be used. (5)G_ref(mg / dL)=-3428.448+27.64708*i10-19.990456*i11+5.820128*i13-1.933492*i21+5.18382*i31-5.131074*i32-3.451613*i33+5.493953*i41+23.541526*i43+.41852*i51-1.125275*i10T+.673867*i11T+.196962*i21T-.202042*i31T+.271105*i32T-.102746*i41T-0.047134*i42T-.889602*i43T+.06569*i52T-.374561*i63T+2158.6*R1+5210.274*R3+3880.969*x62+195.9686*x51+2939.115*x53+500.49*x54+2519.018*x42-2445.111*z53-320.966*z41+9593.727*y64+4002.55*y53-2736.6*y54-11649.06*y41-43811.72*y43+978*y31-66.3105*R4T+62.13563*x61T-170.8194*x62T+19.64226*x52T-75.8533*x53T-61.46921*x42T+10.023384*z52T+72.26341*z53T-5.7766*z54T-4.099989*z41T+16.754378*z32T-18.354153*z21T+309.6468*y61T-1538.808*y65T+83.124865*y51T

[0114] The regression results after applying Equation 5 to the data in Figures 12A-12D can be further demonstrated in the improved glucose accuracy in Figures 13A-13F. Corresponding to the three sensors ppm-1, ppm-2, and ppm-3 (each with different sensitivity) in Figure 12A, Figure 13A shows output glucose values ​​over a 17-day period, where the probe potential modulation signal fed into the predictive equation for glucose determination (Equation 5) reduced the differences in glucose values ​​and improved overall glucose accuracy. In addition, wrinkles in the current profile due to sensitivity changes and temperature effects over the 17 days of monitoring are smoothed. Comparing Figures 12B and 13B, Figure 13B shows three glucose response lines for sensors ppm-1, ppm-2, and ppm-3. The three sensors, with widely different sensitivities, produce glucose output lines that essentially overlap each other, further demonstrating the smoothing of sensitivity differences among the three sensors. Where sensors ppm-1, ppm-2, and ppm-3 represent three different released sensor lots from manufacturing and have sensitivities ranging from center to ±25%, the methods provided herein using ppm current for correction demonstrate that these methods can accommodate different sensor sensitivities and provide highly accurate CGM glucose determinations without having to rely on factory or field calibration.

[0115] Additionally, comparing Figures 12C and 13C, unlike the initial nonlinear behavior due to the slow warm-up time of 30–40 minutes in Figure 12C, the output glucose values ​​shown in Figure 13C at 50 mg / dL initial glucose do not exhibit nonlinear characteristics as they are eliminated by regression, making the initial start-up time for providing accurate glucose readings as early as 5–10 minutes. The temperature effect shown in Figure 12D is shown to be eliminated in Figure 13D, and the glucose profiles from the three sensors ppm-1, ppm-2, and ppm-3 are substantially overlapping. The effect of smoothing out sensitivity differences and reducing warm-up time can be further seen in Figure 13E (raw currents at the start of monitoring) and Figure 13F (glucose calculated by the prediction formula in Equation 5 using input from ppm currents). A steady-state glucose concentration profile is generated in approximately 1 hour, and the glucose profiles of the three sensors quickly align.

[0116] In summary, using probe potential modulation (ppm) as described herein provides sufficient self-contained information (providing a reduced warm-up time) to accommodate sensitivity differences between different sensor lots, sensitivity changes over the continuous monitoring time period, background variations due to interfering species at different levels, and nonlinear effects on the glucose signal immediately after insertion and activation. This can be achieved without factory and / or field calibration using ppm signals.

[0117] 14A shows a high-level block diagram of an exemplary CGM device 1400 according to embodiments provided herein. While not shown in FIG. 14A , it should be understood that various electronic components and / or circuits are configured to be coupled to a power source, such as, but not limited to, a battery. The CGM device 1400 includes a bias circuit 1402 that can be configured to be coupled to a CGM sensor 1404. The bias circuit 1402 can be configured to apply a bias voltage, such as a continuous DC bias, to the analyte-containing fluid via the CGM sensor 1404. In this exemplary embodiment, the analyte-containing fluid can be human interstitial fluid, and the bias voltage can be applied to one or more electrodes 1405 (e.g., a working electrode, a background electrode, etc.) of the CGM sensor 1404.

[0118] The bias circuit 1402 may also be configured to apply a probe potential modulation sequence such as that shown in Figures 7B-7E or another probe potential modulation sequence to the CGM sensor 1404. For example, the probe potential modulation sequence may be applied for an initial and / or intermediate time period as described above with reference to Figures 1-6, or may be applied for each primary data point as described above with reference to Figures 7A-13F. The probe potential modulation sequence may be applied, for example, before, after, or both before and after the measurement of a primary data point.

[0119] In some embodiments, the CGM sensor 1404 may include two electrodes, and a bias voltage and probe potential modulation may be applied across the electrode pair. In such cases, current may be measured via the CGM sensor 1404. In other embodiments, the CGM sensor 1404 may include three electrodes, such as a working electrode, a counter electrode, and a reference electrode. In such cases, a bias voltage and probe potential modulation may be applied between the working electrode and the reference electrode, and current may be measured, for example, via the working electrode. The CGM sensor 1404 includes chemicals that react with the glucose-containing solution, which affects the concentration of charge carriers and the time-dependent impedance of the CGM sensor 1404. Exemplary chemicals include glucose oxidase, glucose dehydrogenase, etc. In some embodiments, a mediator such as ferricyanide or ferrocene may be used.

[0120] The continuous bias voltage generated and / or applied by bias circuit 1402 can be, for example, in the range of about 0.1 to 1 volt relative to the reference electrode. Other bias voltages can also be used. Exemplary probe potential modulation values ​​are described above.

[0121] The probe potential modulated (ppm) and non-probe potential modulated (nppm) currents through the CGM sensor 1404 in the analyte-containing fluid in response to the probe potential modulation and constant bias voltage are measured as amperometric measurements (I meas ) circuit 1406 (also referred to as a current sensing circuit). The current measurement circuit 1406 may be configured to sense and / or record (e.g., using a suitable current-to-voltage converter (CVC)) an amperometric signal having a magnitude indicative of the magnitude of the current transmitted from the CGM sensor 1404. In some embodiments, the current measurement circuit 1406 may include a resistor having a known nominal value and a known nominal accuracy (e.g., in some embodiments, 0.1% to 0.5%, or even less than 0.1%) through which the current transmitted from the CGM sensor 1404 passes. The voltage developed across the resistor of the current measurement circuit 1406 represents the magnitude of the current and is used to generate an amperometric signal (or raw glucose signal SignalRaw ) is sometimes called.

[0122] In some embodiments, the sample circuit 1408 may be coupled to the current measurement circuit 1406 and configured to sample the current measurement signal and generate digitized time-domain sample data (e.g., a digitized glucose signal) representing the current measurement signal. For example, the sample circuit 1408 may be any suitable A / D converter circuit configured to receive the analog current measurement signal and convert it into a digital signal having a desired number of bits as an output. The number of bits output by the sample circuit 1408 may be 16 in some embodiments, although more or fewer bits may be used in other embodiments. In some embodiments, the sample circuit 1408 may sample the current measurement signal at a sampling rate ranging from about 10 samples per second to 1000 samples per second. Faster or slower sampling rates may also be used. For example, sampling rates of about 10 kHz to 100 kHz may be used, and downsampling may be used to reduce the signal-to-noise ratio. Any suitable sampling circuit may be used.

[0123] 11A , the processor 1410 may be coupled to the sampling circuit 1408 and may further be coupled to a memory 1412. In some embodiments, the processor 1410 and the sample circuit 1408 are configured to communicate directly with each other via a wired path (e.g., via a serial or parallel connection). In other embodiments, the coupling of the processor 1410 and the sample circuit 1408 may be via the memory 1412. In this configuration, the sample circuit 1408 writes digital data to the memory 1412, and the processor 1410 reads digital data from the memory 1412.

[0124] The memory 1412 may store therein one or more prediction equations 1414 (e.g., Equation 5) for use in determining glucose values ​​based on primary data points (nppm current) and probe potential modulation (ppm) currents (from the current measurement circuit 1406 and / or sample circuit 1408). For example, in some embodiments, two or more prediction equations, each for use with a different segment (time period) of CGM collected data, may be stored in the memory 1412. In some embodiments, the memory 1412 may include prediction equations based on a primary current signal (e.g., ppm-1, ppm-2, and / or ppm-3 in FIG. 12A ) generated by application of a constant voltage potential applied to a reference sensor and multiple probe potential modulation current signals generated by application of a probe potential modulation sequence applied between primary current signal measurements.

[0125] Additionally or alternatively, the memory 1412 may store therein a calibration index calculated based on the probe potential modulation current for use during field calibration as previously described.

[0126] The memory 1412 may also store a plurality of instructions therein. In various embodiments, the processor 1410 may be a computational resource such as, but not limited to, a microprocessor, a microcontroller, an embedded microcontroller, a digital signal processor (DSP), a field programmable gate array (FPGA) configured to function as a microcontroller, or the like.

[0127] In some embodiments, the instructions stored in memory 1412, when executed by processor 1410, may include instructions that cause processor 1410 to (a) cause CGM device 1400 to measure current signals (e.g., primary current signals and probe potential modulation current signals) from interstitial fluid (via bias circuit 1402, CGM sensor 1404, current measurement circuit 1406, and / or sample circuit 1408), (b) store the current signals in memory 1412, (c) calculate calibration indicators and / or prediction formula parameters, such as ratios (and / or other relationships) of currents from different pulses, voltage steps, or other voltage changes in a probe potential modulation sequence, (d) use the calculated prediction formula parameters to calculate a glucose value (e.g., concentration) using the prediction formula, (e) calculate a calibration indicator, (f) communicate the glucose value to a user, and / or (f) perform an on-site calibration based on the calculated calibration indicator.

[0128] The memory 1412 may be any suitable type of memory, such as, but not limited to, one or more of volatile memory and / or nonvolatile memory. Volatile memory may include, but is not limited to, static random access memory (SRAM) or dynamic random access memory (DRAM). Nonvolatile memory may include, but is not limited to, electrically programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), flash memory (e.g., in either a NOR or NAND configuration, and / or in either a stacked or planar arrangement, and / or in any type of single-level cell (SLC), multi-level cell (MLC), or combined SLC / MLC arrangement), resistive memory, filament memory, metal oxide memory, phase-change memory (such as chalcogenide memory), or magnetic memory. The memory 112 may be packaged, for example, as a single chip or multiple chips. In some embodiments, the memory 112 may be embedded within an integrated circuit, such as, for example, an application-specific integrated circuit (ASIC), along with one or more other circuits.

[0129] As noted above, memory 1412 may have a plurality of instructions that, when executed by processor 1410, cause processor 1410 to perform various actions specified by one or more of the stored instructions. Memory 1412 may further have a portion reserved for one or more “scratchpad” storage areas that may be used for read or write operations by processor 1410 responsive to execution of one or more of the instructions.

[0130] 14A , bias circuit 1402, CGM sensor 1404, current measurement circuit 1406, sample circuit 1408, processor 1410, and memory 1412 containing prediction equation 1414 may be located within a wearable sensor portion 1416 of CGM device 1400. In some embodiments, wearable sensor portion 1416 may include a display 1417 for displaying information such as glucose concentration information (without the use of external equipment). Display 1417 may be any suitable type of human-perceivable display, such as, but not limited to, a liquid crystal display (LCD), a light-emitting diode (LED) display, or an organic light-emitting diode (OLED) display.

[0131] Still referring to FIG. 14A , the CGM device 1400 may further include a portable user device portion 1418. A processor 1420 and a display 1422 may be disposed within the portable user device portion 1418. The display 1422 may be coupled to the processor 1420. The processor 1420 may control text or images shown by the display 1422. The wearable sensor portion 1416 and the portable user device portion 1418 may be communicatively coupled. In some embodiments, the communicative coupling of the wearable sensor portion 1416 and the portable user device portion 1418 may be by wireless communication via transmitter and / or receiver circuitry, such as, for example, transmit / receive circuit TxRx 1424a in the wearable sensor portion 1416 and transmit / receive circuit TxRx 1424b in the portable user device 1418. Such wireless communication may be by any suitable means, including, but not limited to, a standards-based communication protocol, such as the Bluetooth® communication protocol. In various embodiments, wireless communication between the wearable sensor portion 1416 and the portable user device portion 1418 may alternatively be by near field communication (NFC), radio frequency (RF) communication, infrared (IR) communication, or optical communication. In some embodiments, the wearable sensor portion 1416 and the portable user device portion 1418 may be connected by one or more wires.

[0132] Display 1422 may be any suitable type of human-perceivable display, such as, but not limited to, a liquid crystal display (LCD), a light emitting diode (LED) display, or an organic light emitting diode (OLED) display.

[0133] 14B, an exemplary CGM device 1450 is shown that is similar to the embodiment shown in FIG. 14A but has a different division of components. In the CGM device 1450, the wearable sensor portion 1416 includes a bias circuit 1402 coupled to the CGM sensor 1404 and a current measurement circuit 1406 coupled to the CGM sensor 1404. The portable user device portion 1418 of the CGM device 1450 includes a sample circuit 1408 coupled to a processor 1420 and a display 1422 coupled to the processor 1420. The processor 1420 is further coupled to a memory 1412 that may include a prediction equation 1414 stored therein. In some embodiments, the processor 1420 in the CGM device 1450 may also perform the functions described above, for example, performed by the processor 1410 of the CGM device 1400 of FIG. 14A. The wearable sensor portion 1416 of the CGM device 1450 may be smaller, lighter, and therefore less invasive than the CGM device 1400 of FIG. 14A because it does not include the sample circuit 1408, processor 1410, memory 1412, etc. Other component configurations may also be used. For example, in a variation of the CGM device 1450 of FIG. 14B, the sample circuit 1408 may remain on the wearable sensor portion 1416 (such that a portable user device 1418 receives the digitized glucose signal from the wearable sensor portion 1416).

[0134] FIG. 15 is a side schematic view of an exemplary glucose sensor 1404 according to embodiments provided herein. In some embodiments, the glucose sensor 1404 may include a working electrode 1502, a reference electrode 1504, a counter electrode 1506, and a background electrode 1508. The working electrode may include a conductive layer coated with a chemical that reacts with a glucose-containing solution in a reduction-oxidation reaction (affecting the concentration of charge carriers and the time-dependent impedance of the CGM sensor 1404). In some embodiments, the working electrode may be formed from platinum or surface-roughened platinum. Other working electrode materials may also be used. Exemplary chemical catalysts (e.g., enzymes) for the working electrode 1502 include glucose oxidase, glucose dehydrogenase, etc. The enzyme component may be immobilized on the electrode surface by a crosslinker such as glutaraldehyde. An outer membrane layer may be applied to the enzyme layer to protect the entire internal components, including the electrode and enzyme layer. In some embodiments, a mediator such as ferricyanide or ferrocene may be used. Other chemical catalysts and / or mediators may also be used.

[0135] In some embodiments, the reference electrode 1504 may be formed from Ag / AgCl. The counter electrode 1506 and / or counter electrode 1508 may be formed from a suitable conductor, such as platinum, gold, or palladium. Other materials may also be used for the reference, counter, and / or background electrodes. In some embodiments, the background electrode 1508 may be identical to the working electrode 1502, but lacking the chemical catalyst and mediator. The counter electrode 1506 may be separated from the other electrodes by a separation layer 1510 (e.g., polyimide or another suitable material).

[0136] Although described primarily with respect to determining glucose concentrations during continuous glucose monitoring, it will be understood that the embodiments described herein may be used with other continuous analyte monitoring systems (e.g., cholesterol, lactate, uric acid, alcohol, or other analyte monitoring systems). For example, one or more predictive equations similar to Equation 5 may be developed for any analyte to be monitored through the use of probe potential-modulated output currents and their associated cross terms. Similarly, probe potential-modulated output currents may be measured for other analytes and used to calculate calibration indices for use during field calibration.

[0137] FIG. 16 is a flowchart of an exemplary method for compensating for errors during continuous glucose monitoring (CGM) measurements according to embodiments provided herein. Method 1600 includes providing a CGM device including a sensor, memory, and a processor (block 1602), such as, for example, the wearable sensor portion 1416 of FIG. 14A. Method 1600 also includes applying a constant voltage potential to the sensor (block 1604), measuring a primary current signal resulting from the constant voltage potential (block 1606), and storing the measured primary current signal in memory (block 1608). As described with reference to FIG. 7A, the constant voltage potential may be applied to a working electrode of an analyte sensor. In response to the constant voltage potential, a primary current signal may be generated by the sensor, measured, and stored in memory (e.g., memory 412).

[0138] During measurement of the primary current signals, method 1600 includes applying a probe potential modulation sequence to the sensor (block 1610), measuring a probe potential-modulated current signal resulting from the probe potential modulation sequence (block 1612), and storing the measured probe potential-modulated current signal in memory (block 1614). For example, FIGS. 7B-7C show exemplary probe potential modulation sequences that may be applied during primary current signal measurement, resulting in a probe potential-modulated current that may be measured and stored in memory. For each primary current signal, method 1600 may include using the primary current signal and multiple measured probe potential-modulated current signals associated with the primary current signal to determine a glucose value (block 1616). In some embodiments, as previously described, a predictive equation similar to Equation 5 may be used to calculate a glucose value based on the primary current signal and a probe potential-modulated current measured after (and / or before) each primary current signal. A probe potential-modulated current used in conjunction with a primary current signal to determine a glucose or other analyte value may be referred to as "associated" with the primary current signal. For example, a probe potential-modulated current measured before or after a primary current signal may be associated with the primary current signal (when used to calculate a glucose or other analyte value).

[0139] 17 is a flowchart of an exemplary method 1700 of making a continuous glucose monitoring (CGM) device according to embodiments provided herein. Method 1700 includes creating a predictive equation based on a plurality of probe potential-modulated current signals measured for a reference CGM sensor in response to probe potential-modulation sequences applied to the reference CGM sensor before or after a primary current signal is measured for the reference CGM sensor (block 1702). For example, the reference CGM sensor may include one or more CGM sensors used to generate primary data points and ppm currents in response to reference glucose concentrations represented by BGM readings (e.g., primary currents and ppm currents measured for purposes of determining the predictive equations that are then stored within the CGM device and used during continuous glucose monitoring).

[0140] Method 1700 also includes providing a CGM device including a sensor, a memory, and a processor (block 1704); storing a prediction equation in the memory of the CGM device (1706); and storing computer program code in the memory of the CGM device (block 1708), which, when executed by the processor, causes the CGM device to (a) apply a constant voltage potential to the sensor and measure a primary current signal resulting from the constant voltage potential and store the measured primary current signal in memory; (b) apply a probe potential modulation sequence to the sensor between measurements of the primary current signals and measure a probe potential-modulated current signal resulting from the probe potential modulation sequence and store the measured probe potential-modulated current signal in memory; (c) use, for each primary current signal, the primary current signal, a plurality of measured probe potential-modulated current signals associated with the primary current signal, and the stored prediction equation to determine a glucose value; and (d) communicate the determined glucose value to a user of the CGM device.

[0141] 18 is a flowchart of an exemplary method 1800 for determining an analyte concentration during continuous glucose monitoring according to embodiments provided herein. Method 1800 includes subcutaneously inserting a biosensor into a subject, the biosensor including a counter electrode, a reference electrode, and a working electrode having a chemical composition configured to oxidize an analyte (block 1802), applying a constant voltage to the working electrode having a chemical composition to generate a continuous current flow from the working electrode (block 1804), sensing and storing in memory a primary current signal from the working electrode (block 1806), applying a probe potential modulation sequence to the working electrode after sensing each primary current signal and sensing and storing in memory a probe potential modulation current generated in response to the probe potential modulation sequence (block 1808), collecting the primary current signals and a probe potential modulation current generated after the primary current signal (block 1810), and using the collected primary current signals and the probe potential modulation current to calculate an analyte value (block 1812).

[0142] 19 is a flowchart of an exemplary method 1900 for probing the state of a continuous analyte monitoring (CAM) sensor and calibrating the sensor based thereon, according to embodiments provided herein. Method 1900 includes applying an operating voltage to the CAM sensor (block 1902), probing the state of the CAM sensor by applying at least one voltage potential step above the operating voltage and at least one voltage potential step below the operating voltage (block 1904), measuring an output current of the CAM sensor in response to the probing (block 1906), calculating a calibration index via a ratio of the output currents (block 1908), and calibrating the CAM sensor based on the calibration index (block 1910).

[0143] FIG. 20 is a flowchart of an exemplary method 2000 for applying probe potential modulation during continuous analyte monitoring for determining analyte concentration, according to embodiments provided herein. Method 2000 includes applying a constant operating voltage to an analyte sensor during continuous sensor operation (block 2002). For example, a constant voltage potential, such as 0.55 volts or another suitable value, can be applied to the working electrode of the sensor. Block 2004 includes providing at least one probe potential modulation step that differs from the constant operating voltage in each cycle of continuous sensor operation. For example, as shown in FIGS. 7B-7F, a probe potential modulation sequence of voltage steps can be applied to the working electrode of the sensor to generate a probe potential modulation current. Block 2006 includes measuring a primary current from the constant operating voltage in each cycle and at least one companion probe potential modulation current in each cycle in response to the analyte concentration. For example, following each measurement of a primary data point (e.g., a current signal caused by a constant operating voltage), a probe potential-modulated current may be generated by application of a probe potential modulation sequence, and these probe potential-modulated currents may be measured (as "companion" probe potential-modulated currents to the primary data point). Block 2008 includes determining the analyte concentration from the primary current and at least one companion probe potential-modulated current from at least one probe potential modulation step.

[0144] In some embodiments, determining the analyte concentration may include accommodating a sensor sensitivity variation of at least ±25% from the center sensitivity of the manufacturing release without factory calibration. That is, large sensitivity variations between sensors may be accommodated using ppm current without the use of factory calibration. Further, in some embodiments, determining the analyte concentration may include accommodating the effect of a change in background signal by at least a factor of five. For example, the analyte concentration may be accurately determined by using ppm current despite a five-fold change in background interference signal, as previously described with reference to FIGS. 11A-11F.

[0145] In some embodiments, determining the analyte concentration may include accommodating day-to-day sensitivity variations without field calibration. For example, the analyte concentration may be accurately determined despite day-to-day sensitivity variations by using ppm current (without field calibration), as described with reference to FIGS. 13A-13D. Similarly, in some embodiments, determining the analyte concentration may include determining the analyte concentration with a warm-up time of 30 minutes or less, as previously described (e.g., see FIG. 12C).

[0146] As mentioned above, while primarily described with respect to determining glucose concentrations during continuous glucose monitoring, it will be understood that the embodiments described herein may be used with other continuous analyte monitoring systems (e.g., cholesterol, lactate, uric acid, alcohol, or other analyte monitoring systems). For example, in some embodiments, a continuous analyte monitoring (CAM) device may be provided that includes a wearable portion (e.g., wearable sensor portion 1416) having a sensor configured to be inserted subcutaneously into a subject and generate a current signal from interstitial fluid, a processor (e.g., processor 1410), and a memory (e.g., memory 412) coupled to the processor. The memory may include computer program code stored therein that, when executed by the processor, causes the CAM device to (a) apply a constant voltage to the sensor to generate a primary current from the sensor, (b) sense and store in memory the primary current signal generated in response to the constant voltage, (c) apply a probe potential modulation sequence to the sensor while sensing the primary current signal, and sense and store in memory the probe potential modulation current generated in response to the probe potential modulation sequence, and (d) use the primary current signal and the probe potential modulation current to calculate an analyte value over a time period of at least one week (e.g., 7-14 days). In some embodiments, by using the probe potential modulation current, the CAM device does not need to use in-situ calibration at any point during continuous analyte monitoring (e.g., no fingerstick or in-situ calibration for 7-14 days), such as to accommodate changes in sensor sensitivity due to different levels of interferents or changes in background signal. In some embodiments, by using the probe potential modulation current, the CAM device may have a warm-up time of 30 minutes or less, and in some cases 5-15 minutes or less. Similarly, in some embodiments, the use of a probe potential modulation current may eliminate the need for the CAM device to be factory calibrated (eg, to account for lot-to-lot variations).

[0147] The foregoing description discloses exemplary embodiments of the present disclosure. Modifications of the above-disclosed devices and methods that fall within the scope of the present disclosure will be readily apparent to those skilled in the art. Thus, while the present disclosure has been disclosed in connection with exemplary embodiments, it should be understood that other embodiments may be within the scope of the present disclosure as defined by the following claims. [Explanation of symbols]

[0148] 100, 200, 500A, 500B graph 600 CGM equipment 602 Management Unit 604 Wireless Transmitter / Receiver Unit 605 Wireless Transmitter 606 Housing 607 On-body Sensor 608 Display screen 609 Sensor Pad 610 User Interface 611 User's Body 612 Antenna 613 Sensor Components 614 processor 616 memory 618 Software 620 Rechargeable Battery 622 Battery Charger 624 Analog Interface 626 Cable Connector 702,704 yen 1102,1104 curve 1400 CGM devices 1402 bias circuit 1404 CGM sensor, glucose sensor 1405 Electrode 1406 Current measurement (I meas ) circuit, current measurement circuit 1408 Sample Circuit 1410 processor 1412 memory 1414 Prediction Formula 1416 Wearable sensor part 1417 Display 1418 Portable user device part, portable user device 1420 processor 1422 Display 1424a, 1424b transmit / receive circuit TxRx 1450 CGM devices 1502 Working electrode 1504 Reference electrode 1506 Counter electrode 1508 Background electrode 1510 Separation tank

Claims

1. 1. A method of probing a condition of a continuous analyte monitoring sensor and calibrating the continuous analyte monitoring sensor based thereon, the method comprising: applying an operating voltage to the continuous analyte monitoring sensor; performing a probe of the condition of the continuous analyte monitoring sensor by applying a first voltage potential step above the operating voltage and a second voltage potential step below the operating voltage; measuring an output current of the continuous analyte monitoring sensor in response to the probing using an end-of-potential-step current; calculating a ratio of the output currents as a calibration index; calibrating the continuous analyte monitoring sensor based on a comparison of the calibration index and a ratio of end-of-potential-step currents from a factory calibration; A method comprising:

2. The operating voltage is E 0 and the first voltage potential step above the operating voltage is E 1 and E 1 -E 0 2. The method of claim 1, wherein is between 0.05 and 0.3 volts.

3. The operating voltage is E 0 and the second voltage potential step less than the operating voltage is E 2 and E 2 -E 0 2. The method of claim 1, wherein is between −0.05 volts and −0.5 volts.

4. 10. The method of claim 1, wherein the second voltage potential step less than the operating voltage is selected to set a mediator of the continuous analyte monitoring sensor to a partially reduced state.

5. The method described in claim 1, wherein the step of calculating the ratio of the output current as the calibration index includes a step of determining the ratio of a first output current generated by the first voltage potential step higher than the operating voltage to a second output current generated by the second voltage potential step lower than the operating voltage.

6. 6. The method of claim 5, wherein the first output current is generated at a first end of the first voltage potential step above the operating voltage and the second output current is generated at a second end of the second voltage potential step below the operating voltage.

7. 10. The method of claim 1, further comprising applying a third voltage potential step equal to or greater than the operating voltage after the second voltage potential step below the operating voltage, and applying a fourth voltage potential step below the operating voltage after the third voltage potential step above the operating voltage.

8. 10. The method of claim 1, further comprising storing the calibration index in a memory of a continuous analyte monitoring device that employs the continuous analyte monitoring sensor for use during one or more subsequent field calibrations.

9. The method of claim 1 , wherein the continuous analyte monitoring sensor is a continuous glucose monitoring sensor.

10. 1. A continuous analyte monitoring sensor device comprising: a management unit including a wireless transmitter / receiver in communication with a wireless transmitter coupled to an on-body sensor, the management unit further comprising a processor, memory, and software, the processor and the software: Applying an operating voltage to the on-body sensor; performing a probe of the state of the on-body sensor by applying a first voltage potential step above the operating voltage and a second voltage potential step below the operating voltage; measuring an output current of the on-body sensor in response to the probing using a potential step end current; calculating a ratio of said output currents as a calibration index; Calibrating the on-body sensor based on a comparison of the calibration index and a ratio of potential step end currents from a factory calibration. A continuous analyte monitoring sensor device that operates as follows:

11. The operating voltage is E 0 and the first voltage potential step above the operating voltage is E 1 and E 1 -E 0 11. The continuous analyte monitoring sensor device of claim 10, wherein is between 0.05 and 0.3 volts.

12. The operating voltage is E 0 and the second voltage potential step less than the operating voltage is E 2 and E 2 -E 0 11. The continuous analyte monitoring sensor device of claim 10, wherein is between -0.05 and -0.5 volts.

13. 11. The continuous analyte monitoring sensor apparatus of claim 10, wherein the second voltage potential step less than the operating voltage is selected to set a mediator of the on-body sensor to a partially reduced state.

14. 11. The continuous analyte monitoring sensor device of claim 10, wherein the processor and software operate to calculate a ratio of a first output current produced by the first voltage potential step above the operating voltage to a second output current produced by the second voltage potential step below the operating voltage.

15. 15. The continuous analyte monitoring sensor apparatus of claim 14, wherein the first output current is generated at a first end of the first voltage potential step above the operating voltage, and the second output current is generated at a second end of the second voltage potential step below the operating voltage.

16. 11. The continuous analyte monitoring sensor device of claim 10, wherein the processor and software operate to apply a third voltage potential step above the operating voltage after the second voltage potential step below the operating voltage, and to apply a fourth voltage potential step below the operating voltage after the third voltage potential step above the operating voltage.

17. 11. The continuous analyte monitoring sensor device of claim 10, wherein the processor and software operate to store the calibration indicator in the memory of the continuous analyte monitoring sensor device for use during one or more subsequent field calibrations.

18. 11. The continuous analyte monitoring sensor device of claim 10, wherein the on-body sensor is a continuous glucose monitoring sensor.

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