Detection and calibration of interferents in analyte monitoring systems

Abstract

A sensor, system, and method for detecting and calibrating the effect of an analyte sensor on an analyte indicator. The analyte indicator may have a first detectable characteristic that varies with analyte concentration and its effect on the analyte indicator (e.g., degradation). The analyte sensor may further include an interferent indicator having a second detectable characteristic (e.g., absorbance) that varies with its effect on the analyte indicator. The analyte sensor may generate (i) an analyte measurement based on the first detectable characteristic of the analyte indicator and (ii) an interferent measurement based on the second detectable characteristic of the interferent indicator. The analyte sensor may be part of a system that also includes a transceiver. The transceiver may calculate the analyte level using the analyte measurement and the interferent measurement.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 483,432, filed February 6, 2023, and U.S. Provisional Application Serial No. 63 / 414,394, filed October 7, 2022, which are incorporated by reference in their entireties.

[0002] FIELD OF THE INVENTION

[0003] The present invention relates generally to the detection and calibration of interferents in analyte monitoring systems, which may include blood in a medium (e.g., interstitial fluid) and / or effects (e.g., oxidation-induced degradation) on an analyte indicator within the analyte monitoring system. [Background technology]

[0003]

[0004] Background Considerations

[0005] Analyte monitoring systems may be used to monitor analyte levels, such as analyte concentrations (e.g., glucose concentrations). One type of analyte monitoring system is a continuous analyte monitoring system. Continuous analyte monitoring systems measure analyte levels throughout the day and can be very useful in managing diseases such as diabetes.

[0004]

[0006] Some analyte monitoring systems include an analyte sensor, which may be implanted (fully or partially) in an animal and may contain an analyte indicator. Effects on the blood and / or analyte indicator in interstitial fluid adjacent to the analyte indicator may interfere with the accurate measurement of an analyte (e.g., glucose) by the analyte sensor. For example, the analyte sensor may lose sensitivity while implanted in the animal as a result of changes in sensitivity parameters (e.g., calibration constants). The change in sensitivity parameter may be due, for example, to degradation of the analyte indicator. Degradation may be caused, for example, by oxidation of the analyte indicator induced by reactive oxygen species (ROS) generated in cells. See, for example, U.S. Pat. No. 8,143,068, U.S. Pat. No. 9,427,181, and U.S. Patent Application Publication No. 2012 / 0238842, each of which is incorporated by reference in its entirety. The rate of in vivo sensitivity loss can be reduced, for example, by using oxidation-resistant indicator molecules, incorporating catalytic protection, and / or using membranes that catalyze the decomposition of reactive oxygen species (ROS). However, reducing the rate of in vivo sensitivity loss does not completely prevent sensitivity loss: gradual changes in sensitivity parameters over time may adversely affect analyte sensing accuracy and may require recalibration with a reference analyte measurement (e.g., a self-monitoring blood glucose measurement), which may be uncomfortable for the user and / or otherwise undesirable. Summary of the Invention

[0005]

[0007] The present invention overcomes the shortcomings of conventional systems by providing an analyte monitoring system capable of detecting and calibrating one or more interfering substances. In some embodiments, the one or more interfering substances may interfere with the accurate measurement of an analyte (e.g., glucose) in a medium (e.g., interstitial fluid). In some embodiments, the one or more interfering substances may include blood in the medium. In some embodiments, the one or more interfering substances may include an effect on an analyte indicator of an analyte sensor. In contrast to prior art systems that can only calibrate one or more interfering substances during recalibration using a reference analyte measurement, the analyte monitoring system may offer, among other advantages, the ability to calibrate one or more interfering substances without the need for a reference analyte measurement. In some embodiments, the analyte monitoring system may include an analyte sensor that measures one or more interfering substances using an interfering substance indicator. In some embodiments, the interfering substance indicator is not sensitive to the analyte. In some embodiments, the interfering substance indicator may have one or more properties that change depending on its effect on the analyte indicator (e.g., degradation by reactive oxygen species (ROS)). In some embodiments, the one or more properties of the interfering substance indicator may include absorbance, which changes depending on its effect on the analyte indicator. In some embodiments, one or more properties of the interferent indicator may include optical properties that change in response to their effect on the analyte indicator. In some embodiments, the interferent indicator may be used as a reference dye to measure and calibrate its effect on the analyte indicator. In some embodiments, the analyte monitoring system may calibrate the one or more interferents using empirical correlations established through laboratory testing.

[0006]

[0008] One aspect of the present invention may provide an analyte sensor for measuring an analyte in a living animal medium. The analyte sensor may include an analyte indicator, a degradation indicator, and a sensor element. The analyte indicator may have a first detectable characteristic that varies depending on (i) the amount or concentration of the analyte in the medium and (ii) the degree of degradation of the analyte indicator. The degradation indicator may have a second detectable characteristic that varies depending on the degree of degradation of the degradation indicator. The degree of degradation of the degradation indicator may correspond to the degree of degradation of the analyte indicator. The sensor element may be configured to generate (i) an analyte measurement based on the first detectable characteristic of the analyte indicator and (ii) a degradation measurement based on the second detectable characteristic of the degradation indicator.

[0007]

[0009] In some embodiments, the degree of degradation of the degradation indicator may be proportional to the degree of degradation of the analyte indicator. In some embodiments, the degradation of the analyte indicator may include reactive oxidizing species (ROS)-induced oxidation, and the degradation of the degradation indicator includes ROS-induced oxidation. In some embodiments, the analyte indicator may be a phenylboron-based analyte indicator. In some embodiments, the degradation indicator may be a phenylboron-based degradation indicator.

[0008]

[0010] In some embodiments, the analyte sensor may further comprise an indicator element including an analyte indicator and a degradation indicator. In some embodiments, the analyte indicator may comprise analyte indicator molecules distributed throughout the indicator element, and the degradation indicator may comprise degradation indicator molecules distributed throughout the indicator element. In some embodiments, the second detectable characteristic does not vary with the amount or concentration of the analyte in the medium.

[0009]

[0011] In some embodiments, the sensor element may comprise a first light source and a first photodetector. The first light source may be configured to emit a first excitation light to the analyte indicator. The first photodetector is configured to receive the first emitted light emitted by the analyte indicator and output an analyte measurement. The analyte measurement may be indicative of the amount of the first emitted light received by the first photodetector. In some embodiments, the sensor element may comprise a second light source and a second photodetector. The second light source may be configured to emit a second excitation light to the degradation indicator. The second photodetector may be configured to receive the second emitted light emitted by the degradation indicator and output a degradation measurement. The degradation measurement may be indicative of the amount of the second emitted light received by the second photodetector. In some embodiments, the first photodetector may be configured to receive the second excitation light reflected from the indicator element and output a first reference signal indicative of the amount of reflected second excitation light received by the first photodetector. In some embodiments, the sensor element may include a third photodetector configured to receive the first excitation light reflected from the indicator element and output a second reference signal indicative of the amount of reflected first excitation light received by the third photodetector.

[0010]

[0012] Another aspect of the present invention may provide a method that includes measuring an amount or concentration of an analyte in a medium using an analyte indicator of an analyte sensor. The method may include using a degradation indicator of the analyte sensor to measure a degree of degradation of the degradation indicator. The method may include receiving, using a sensor interface device of a transceiver, an analyte measurement indicative of the amount or concentration of analyte in the medium from the analyte sensor. The method may include receiving, using the sensor interface device of the transceiver, a degradation measurement indicative of a degree of degradation of the degradation indicator from the analyte sensor. The method may include calculating, using a controller of the transceiver, a degree of degradation of the analyte indicator of the analyte sensor based at least on the received degradation measurement. The method may include adjusting, using the controller of the transceiver, a conversion function based on the calculated degree of degradation of the analyte indicator. The method may include calculating, using the controller of the transceiver, an analyte level using the adjusted conversion function and the received analyte measurement. The method may include displaying the calculated analyte level.

[0011]

[0013] Yet another aspect of the present invention may provide an analyte monitoring system including an analyte sensor and a transceiver. The analyte sensor may include an analyte indicator, a degradation indicator, a sensor element, and a transceiver interface device. The analyte indicator may have a first detectable characteristic that varies depending on (i) the amount or concentration of the analyte in the medium and (ii) the degree of degradation of the analyte indicator. The degradation indicator may have a second detectable characteristic that varies depending on the degree of degradation of the degradation indicator. The sensor element may be configured to generate (i) an analyte measurement based on the first detectable characteristic of the analyte indicator and (ii) a degradation measurement based on the second detectable characteristic of the degradation indicator. The transceiver may include a sensor interface device and a controller. The controller may be configured to: (i) receive analyte measurements from the analyte sensor via the analyte sensor's transceiver interface device and sensor interface device; (ii) receive degradation measurements from the analyte sensor via the analyte sensor's transceiver interface device and sensor interface device; (iii) calculate a degree of degradation of an analyte indicator in the analyte sensor based on at least the received degradation measurements; (iv) adjust a conversion function based on the calculated degree of degradation of the analyte indicator; and (v) calculate an analyte level using the adjusted conversion function and the received analyte measurements.

[0012]

[0014] In some embodiments, the analyte sensor may further comprise an indicator element, which may include an analyte indicator and a degradation indicator. In some embodiments, the second detectable characteristic does not vary with the amount or concentration of the analyte in the medium.

[0013]

[0015] Yet another aspect of the present invention may provide an analyte monitoring system including an analyte indicator, an interferent indicator, a sensor element, and a controller. The analyte indicator may have a first detectable characteristic that varies in response to at least (i) the amount or concentration of the analyte in the medium and (ii) an effect on the analyte indicator. The interferent indicator may have an absorbance that varies in response to the effect on the analyte indicator. The sensor element may be configured to generate (i) an analyte measurement based on the first detectable characteristic of the analyte indicator and (ii) a reference measurement based on at least the absorbance of the interferent indicator. The controller may be configured to (i) calculate the effect on the analyte indicator based on at least the reference measurement, (ii) adjust a conversion function based on at least the calculated effect on the analyte indicator, and (iii) calculate the analyte level using the adjusted conversion function and the analyte measurement.

[0014]

[0016] In some embodiments, the effect on the analyte indicator may be degradation of the analyte indicator. In some embodiments, the system may further comprise an indicator element comprising an analyte indicator and an interferent indicator, wherein the analyte indicator may comprise analyte indicator molecules distributed throughout the indicator element, and the interferent indicator may comprise interferent indicator molecules distributed throughout the indicator element.

[0015]

[0017] In some embodiments, the sensor element comprises a first light source configured to emit a first excitation light to the analyte indicator and a signal light detector configured to receive the first emitted light emitted by the analyte indicator and output an analyte measurement, where the analyte measurement may be indicative of the amount of the first emitted light received by the signal light detector. In some embodiments, the sensor element may further comprise a second light source configured to emit a second excitation light to the interferent indicator. In some embodiments, the signal light detector may be further configured to receive an amount of the second excitation light and output a reference measurement, where the reference measurement may be indicative of the amount of the second excitation light received, where the amount of the second excitation light received may be indicative of the absorbance of the interferent indicator. In some embodiments, the sensor element may further comprise a reference light detector configured to receive an amount of the second excitation light and output a reference measurement, where the reference measurement may be indicative of the amount of the second excitation light received, where the amount of the second excitation light received may be indicative of the absorbance of the interferent indicator.

[0016]

[0018] In some embodiments, the sensor element may further comprise an interferent light detector configured to receive the second emitted light emitted by the interferent indicator and output an interferent measurement value indicative of the amount of the second emitted light received by the interferent light detector. In some embodiments, the second emitted light may vary in response to an effect on the analyte indicator. In some embodiments, the sensor element may comprise a first reference light detector configured to receive an amount of the first excitation light and output a first reference measurement value indicative of the amount of the first excitation light received. In some embodiments, the second emitted light emitted by the interferent indicator does not vary in response to the amount or concentration of analyte in the medium. In some embodiments, the processor may be configured to calculate an effect on the analyte indicator based at least on the reference measurement value and the interferent measurement value. In some embodiments, the processor may be configured to calculate the effect on the analyte indicator based at least on a ratio of the interferent measurement value to the reference measurement value.

[0017]

[0019] In some embodiments, the processor may be further configured to calculate the amount of blood in the medium. In some embodiments, the processor may be configured to adjust the conversion function based on at least the calculated effect on the analyte indicator and the calculated amount of blood in the medium. In some embodiments, the reference measurement value may be a second reference measurement value, and the sensor element may comprise a first light source, a second light source, a first reference light detector, and a signal light detector. In some embodiments, the first light source may be configured to irradiate the analyte indicator with a first excitation light, the second light source may be configured to irradiate the interferent indicator with a second excitation light, the first reference light detector may be configured to receive an amount of the first excitation light and output a first reference measurement value indicative of the amount of the received first excitation light, and the signal light detector may be configured to (i) receive the first emitted light emitted by the analyte indicator and output the analyte measurement value, and (ii) receive an amount of the second excitation light and output the second reference measurement value. In some embodiments, the analyte measurement may be indicative of the amount of first emission light received, and the second reference measurement may be indicative of the amount of second excitation light received.

[0018]

[0020] In some embodiments, the reference measurement value may be a second reference measurement value, and the sensor element comprises a first light source, a second light source, a first reference light detector, and a signal light detector. In some embodiments, the first light source may be configured to irradiate the analyte indicator with a first excitation light, the second light source may be configured to emit a second excitation light to the interferent indicator, the first reference light detector may be configured to receive an amount of the first excitation light and output a first reference measurement value indicative of the amount of first excitation light received, the signal light detector may be configured to receive the first emitted light emitted by the analyte indicator and output an analyte measurement value indicative of the amount of first emitted light received, and the second reference light detector may be configured to receive an amount of the second excitation light and output a second reference measurement value indicative of the amount of second excitation light received.

[0019]

[0021] In some embodiments, the processor may be configured to calculate the amount of blood in the medium based on at least the first reference measurement and the second reference measurement. In some embodiments, the processor may be configured to calculate the amount of blood in the medium based on at least a ratio of the first reference measurement to the second reference measurement. In some embodiments, the sensor element may include an interferent light detector configured to receive emitted light emitted by the interferent indicator and output an interferent measurement value indicative of the amount of emitted light received by the interferent light detector, and the processor may be configured to calculate the amount of blood in the medium based on at least the interferent measurement value.

[0020]

[0022] In some embodiments, the interferent indicator may have a second detectable property that changes depending on its effect on the analyte indicator, the sensor element may be further configured to generate an interferent measurement based on the second detectable property of the analyte indicator, and the processor may be configured to calculate the effect on the analyte indicator based on at least the reference measurement and the interferent measurement. In some embodiments, the processor may be configured to calculate the effect on the analyte indicator based on at least a ratio of the interferent measurement to the reference measurement.

[0021]

[0023] Yet another aspect of the invention may provide a method that includes using an analyte indicator to generate an analyte measurement indicative of an amount or concentration of an analyte in a medium, where the analyte measurement may vary depending on at least an effect on the analyte indicator. The method may include using an interferent indicator to generate a reference measurement indicative of an absorbance of the interferent indicator, where the absorbance may vary depending on the effect on the analyte indicator. The method may include calculating the effect on the analyte indicator based at least on the reference measurement. The method may include adjusting a conversion function based at least on the calculated effect on the analyte indicator. The method may include calculating the analyte level using the adjusted conversion function and the analyte measurement.

[0022]

[0024] In some embodiments, the effect on the analyte indicator may be degradation of the analyte indicator.

[0025] In some embodiments, generating an analyte measurement using the analyte indicator may include emitting a first excitation light to the analyte indicator and using a signal light detector configured to receive the first emitted light emitted by the analyte indicator and output an analyte measurement, where the analyte measurement may be indicative of an amount of the first emitted light received by the signal light detector. In some embodiments, generating a reference measurement using the interferent indicator may include emitting a second excitation light to the interferent indicator. In some embodiments, generating a reference measurement using the interferent indicator may further include receiving an amount of second excitation light using the signal light detector and outputting a reference measurement, where the reference measurement may be indicative of an amount of the second excitation light received, where the amount of the second excitation light received may be indicative of an absorbance of the interferent indicator. In some embodiments, the step of generating a reference measurement using the interferent indicator may further include receiving an amount of the second excitation light using a reference light detector and outputting a reference measurement, wherein the reference measurement may be indicative of the amount of the second excitation light received, and wherein the amount of the second excitation light received may be indicative of the absorbance of the interferent indicator.

[0023]

[0026] In some embodiments, the method may further include receiving a second emitted light emitted by the interferent indicator using an interferent light detector and outputting an interferent measurement value indicative of the amount of second emitted light received by the interferent light detector. In some embodiments, the second emitted light may vary depending on the effect on the analyte indicator. In some embodiments, the method may further include receiving an amount of the first excitation light using a first reference light detector and outputting a first reference measurement value indicative of the amount of first excitation light received. In some embodiments, the effect on the analyte indicator may be calculated based on at least the reference measurement value and the interferent measurement value. In some embodiments, the effect on the analyte indicator may be calculated based on at least the ratio of the interferent measurement value to the reference measurement value.

[0024]

[0027] In some embodiments, the method may further include calculating the amount of blood in the medium. In some embodiments, the conversion function may be adjusted based on at least the calculated effect on the analyte indicator and the calculated amount of blood in the medium. In some embodiments, the reference measurement value may be a second reference measurement value, and generating the analyte measurement value using the analyte indicator may include: emitting a first excitation light to the analyte indicator; receiving an amount of the first excitation light using a first reference light detector and outputting a first reference measurement value indicative of the amount of the first excitation light received; and receiving the first emitted light using a signal light detector and outputting the analyte measurement value. In some embodiments, the analyte measurement value may be indicative of the amount of the first emitted light received. In some embodiments, generating the reference measurement value using the interferent indicator may further include: emitting a second excitation light to the interferent indicator; receiving an amount of the second excitation light using a signal light detector and outputting the second reference measurement value. In some embodiments, the second reference measurement may indicate the amount of second excitation light received, and the amount of blood in the medium may be calculated based on at least the first reference measurement and the second reference measurement.

[0025]

[0028] In some embodiments, the reference measurement value may be a second reference measurement value, and generating the analyte measurement value using the analyte indicator may include: emitting a first excitation light to the analyte indicator; receiving an amount of the first excitation light using a first reference light detector and outputting a first reference measurement value indicative of the amount of first excitation light received; and receiving the first emitted light using a signal light detector and outputting the analyte measurement value. In some embodiments, the analyte measurement value may be indicative of the amount of first emitted light received. In some embodiments, generating the reference measurement value using the interferent indicator may further include: emitting a second excitation light to the interferent indicator; receiving an amount of the second excitation light using a second reference light detector and outputting a second reference measurement value. In some embodiments, the second reference measurement value may be indicative of the amount of second excitation light received. In some embodiments, the amount of blood in the medium may be calculated based on at least the first reference measurement value and the second reference measurement value.

[0026]

[0029] In some embodiments, the amount of blood in the medium may be calculated based on at least a ratio of the first reference measurement to the second reference measurement. In some embodiments, the method may further include receiving, using an interferent light detector, the emitted light emitted by the interferent indicator and outputting an interferent measurement indicative of the amount of emitted light received by the interferent light detector, and the amount of blood in the medium may be calculated based on at least the interferent measurement.

[0027]

[0030] Yet another aspect of the present invention may provide an analyte monitoring system. The system may include an indicator element including an analyte indicator and a degradation indicator. The analyte indicator may have a detectable characteristic that varies depending on at least the amount or concentration of the analyte in the medium. The system may include a first light source configured to emit a first excitation light to the analyte indicator. The system may include a second light source configured to emit a second excitation light to the degradation indicator. The system may include one or more photodetectors configured to (i) receive the emitted light emitted by the analyte indicator and output an analyte measurement indicative of the amount of emitted light received by the one or more photodetectors, and (ii) receive the second excitation light reflected from the indicator element and output a reference measurement indicative of the amount of reflected second excitation light received by the one or more photodetectors. The reference measurement indicates the opacity of the indicator element. The system may include a controller configured to (i) adjust a conversion function based on the reference measurement and (ii) calculate the analyte level using the adjusted conversion function and the analyte measurement.

[0028]

[0031] In some embodiments, the one or more light detectors may comprise (i) a signal light detector configured to receive the first emitted light and output an analyte measurement, and (ii) a reference light detector configured to receive the reflected second excitation light and output a reference measurement. In some embodiments, the one or more light detectors include (i) a signal light detector configured to receive the first emitted light and output an analyte measurement, and (ii) a reference light detector configured to receive the reflected second excitation light and output a reference measurement.

[0029]

[0032] In some embodiments, the emitted light may be a first emitted light, and the one or more photodetectors may be further configured to receive a second emitted light emitted by the degradation indicator and output a degradation measurement value indicative of the amount of the second emitted light received by the one or more photodetectors, and the controller may be further configured to calculate a degree of degradation of the analyte indicator based on at least the degradation measurement value, and the controller may be configured to adjust the conversion function based on the reference measurement value and the calculated degree of degradation of the analyte indicator.

[0030]

[0033] Yet another aspect of the present invention may provide a glucose monitoring method. The method may include using first measuring electronics in a first sensing area of ​​a glucose sensor to generate a first sensing area glucose measurement and a first sensing area degradation measurement for each of a plurality of time points over a 365-day period. The first measuring electronics may use a first analyte indicator of a first indicator element of the glucose sensor to generate the first sensing area glucose measurement and a first interferent indicator of the first indicator element of the glucose sensor to generate the first sensing area degradation measurement. The first sensing area glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate to the first indicator element. The first sensing area glucose measurement may change in response to degradation of at least the first interferent indicator, which may correspond to degradation of the first analyte indicator. The first sensing area degradation measurement may indicate degradation of the first interferent indicator. The method may include using second measurement electronics in a second sensing area of ​​the glucose sensor to generate a second sensing area glucose measurement and a second sensing area degradation measurement for each of a plurality of time points over 365 days. The second measurement electronics may use a second analyte indicator of a second indicator element of the glucose sensor to generate the second sensing area glucose measurement and a second interferent indicator of the second indicator element of the glucose sensor to generate the second sensing area degradation measurement. The second sensing area glucose measurement may indicate an amount or concentration of glucose in interstitial fluid proximate to the second indicator element. The second sensing area glucose measurement may change in response to degradation of at least the second interferent indicator, which may correspond to degradation of the second analyte indicator. The second sensing area degradation measurement may indicate degradation of the second interferent indicator. The method may include calculating a first sensing area glucose concentration using at least the first sensing area glucose measurement for each of a plurality of time points over 365 days. The method may include calculating a second sensing zone glucose concentration using at least the second sensing zone glucose measurements for each of a plurality of time points over a 365 day period.The method may include calculating, for each of a plurality of time points over the 365 days, a first weight for a first sensing area glucose concentration using at least a first sensing area degradation measurement. The method may include calculating, for each of a plurality of time points over the 365 days, a second weight for a second sensing area glucose concentration using at least a second sensing area degradation measurement. The method may include calculating, for each of a plurality of time points over the 365 days, a composite glucose concentration as a weighted average of at least the first sensing area glucose concentration and the second sensing area glucose concentration using at least the first weight and the second weight. The method may include displaying the calculated composite glucose concentration for each of the plurality of time points over the 365 days. The composite glucose concentrations for multiple time points over 365 days may have (a) an overall mean relative difference (MARD) vs. self-monitoring of blood glucose (SMBG) value of 10.4% or less and a 40 / 40% agreement rate of 98.5% or greater when the sensing zone glucose concentration calculation is calibrated using one SMBG value every 7 days for 365 days, or (b) an overall MARD vs. SMBG value of 10.3% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensing zone glucose concentration calculation is calibrated using two SMBG values ​​every 14 days for 365 days.

[0031]

[0034] In some embodiments, calculating the first sensing area glucose concentration may include adjusting a first conversion function using at least the first sensing area degradation measurement and calculating the first sensing area glucose concentration using at least the adjusted first conversion function and the first sensing area glucose measurement, and calculating the second sensing area glucose concentration includes adjusting a second conversion function using at least the second sensing area degradation measurement and calculating the second sensing area glucose concentration using at least the adjusted second conversion function and the second sensing area glucose measurement.

[0032]

[0035] In some embodiments, the method may include using a third measurement electronic circuit in a third sensing area of ​​the glucose sensor to generate a third sensing area glucose measurement and a third sensing area degradation measurement for each of a plurality of time points over a 365-day period. The third measurement electronic circuit may use a third analyte indicator of a third indicator element of the glucose sensor to generate the third sensing area glucose measurement and a third interferent indicator of a third indicator element of the glucose sensor to generate the third sensing area degradation measurement. The third sensing area glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate the third indicator element. The third sensing area glucose measurement may change in response to degradation of at least the third interferent indicator, which may correspond to degradation of the third analyte indicator. The third sensing area degradation measurement may indicate degradation of the third interferent indicator. The method may further include using fourth measurement electronics in a fourth sensing area of ​​the glucose sensor to generate a fourth sensing area glucose measurement and a fourth sensing area degradation measurement for each of a plurality of time points over the 365 days. The fourth measurement electronics may use a fourth analyte indicator of a fourth indicator element of the glucose sensor to generate the fourth sensing area glucose measurement and a fourth interferent indicator of a fourth indicator element of the glucose sensor to generate the fourth sensing area degradation measurement. The fourth sensing area glucose measurement may indicate an amount or concentration of glucose in interstitial fluid proximate the fourth indicator element. The fourth sensing area glucose measurement may change in response to degradation of at least the fourth interferent indicator, which may correspond to degradation of the fourth analyte indicator. The fourth sensing area degradation measurement may indicate degradation of the fourth interferent indicator. The method may also include calculating a third sensing area glucose concentration using at least the third sensing area glucose measurement for each of a plurality of time points over the 365 days. The method may include calculating a fourth sensing zone glucose concentration using at least a fourth sensing zone glucose measurement for each of a plurality of time points over a 365 day period.The method may include calculating a third weight for a third sensing area glucose concentration using at least a third sensing area degradation measurement for each of a plurality of time points over the 365 day period. The method may further include calculating a fourth weight for a fourth sensing area glucose concentration using at least a fourth sensing area degradation measurement for each of a plurality of time points over the 365 day period. The composite glucose concentration may be calculated as a weighted average of at least the first sensing area glucose concentration, the second sensing area glucose concentration, the third sensing area glucose concentration, and the fourth sensing area glucose concentration using the first weight, the second weight, the third weight, and the fourth weight.

[0033]

[0036] In some embodiments, calculating the first sensing area glucose concentration may include adjusting a first conversion function using at least the first sensing area degradation measurement and calculating the first sensing area glucose concentration using at least the adjusted first conversion function and the first sensing area glucose measurement, and calculating the second sensing area glucose concentration may include calculating a second sensing area glucose concentration using at least the second sensing area degradation measurement and adjusting a second conversion function and calculating the second sensing area glucose concentration using at least the adjusted second conversion function and the second sensing area glucose measurement. and calculating a glucose concentration, wherein calculating the third sensing area glucose concentration includes adjusting a third conversion function using at least the third sensing area degradation measurement and calculating the third sensing area glucose concentration using at least the adjusted third conversion function and the third sensing area glucose measurement; and calculating the fourth sensing area glucose concentration includes adjusting a fourth conversion function using at least the fourth sensing area degradation measurement and calculating the fourth sensing area glucose concentration using at least the adjusted fourth conversion function and the fourth sensing area glucose measurement.

[0034]

[0037] In some embodiments, the first indicator element and the third indicator element may be part of one indicator element, and the second analyte indicator and the fourth analyte indicator may be part of another indicator element. In some embodiments, the first measurement electronic circuit and the third measurement electronic circuit may be fabricated and / or implemented on a first substrate of the glucose sensor, and the second measurement electronic circuit and the fourth measurement electronic circuit may be fabricated and / or implemented on a second substrate of the glucose sensor.

[0035]

[0038] In some embodiments, the composite glucose concentrations for multiple time points over 365 days may have (a) an overall MARD vs. SMBG value of 10.2% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensing zone glucose concentration calculation is calibrated using one SMBG value every 7 days for 365 days, or (b) an overall MARD vs. SMBG value of 10.1% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensing zone glucose concentration calculation is calibrated using two SMBG values ​​every 14 days for 365 days.

[0036]

[0039] In some embodiments, the method may further include calibrating the calculation of the sensing zone glucose concentration using (a) one SMBG value every seven days for 365 days, or (b) two SMBG values ​​every 14 days for 365 days.

[0037]

[0040] In some embodiments, the measurement electronic circuits each comprise a first light source configured to emit a first excitation light and a signal light detector configured to receive the first emitted light and output a sensing-zone glucose measurement, where the sensing-zone glucose measurement may indicate an amount of the first emitted light received by the signal light detector. In some embodiments, the measurement electronic circuits each may further comprise a second light source configured to emit a second excitation light. In some embodiments, the measurement electronic circuits each may further comprise an interferent light detector configured to receive the second emitted light and output a sensing-zone degradation measurement, where the sensing-zone glucose measurement may indicate an amount of the second emitted light received by the signal light detector. In some embodiments, the signal light detector may further be configured to receive an amount of the second excitation light and output a sensing-zone degradation measurement, where the sensing-zone degradation measurement may indicate an amount of the second excitation light received. In some embodiments, the measuring electronic circuits may each further comprise a reference photodetector configured to receive a quantity of the second excitation light and output a sensing area degradation measurement value, which may indicate the amount of the second excitation light received.

[0038]

[0041] In some embodiments, the method may further include calibrating the calculation of the sensing zone glucose concentration using SMBG values ​​at an increased frequency during an initial 365-day period compared to the remainder of the 365-day period. In some embodiments, the initial period may be 14 days. In some embodiments, the increased frequency may be one SMBG value per day during the initial period. In some embodiments, the increased frequency may be one SMBG value every 12 hours during the initial period.

[0039]

[0042] Yet another aspect of the present invention may provide a glucose monitoring system including a glucose sensor and a controller. The glucose sensor may include a first indicator element including a first analyte indicator and a first interferent indicator, a second indicator element including a second analyte indicator and a second interferent indicator, a first sensing area, and a second sensing area. The glucose sensor may include first measurement electronics in the first sensing area. The first measurement electronics may be configured to generate a first sensing area glucose measurement and a first sensing area degradation measurement for each of a plurality of time points over a 365-day period. The first measurement electronics may be configured to use the first analyte indicator to generate the first sensing area glucose measurement and the first interferent indicator to generate the first sensing area degradation measurement. The first sensing area glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate to the first indicator element. The first sensing zone glucose measurement may change in response to degradation of at least a first interferent indicator, which may correspond to degradation of the first analyte indicator. The first sensing zone degradation measurement may indicate degradation of the first interferent indicator. The glucose sensor may include second measurement electronics in the second sensing zone. The first measurement electronics may be configured to generate a second sensing zone glucose measurement and a second sensing zone degradation measurement for each of a plurality of time points over a 365-day period. The second measurement electronics may be configured to use a second analyte indicator to generate the second sensing zone glucose measurement and a second interferent indicator to generate the second sensing zone degradation measurement. The second sensing zone glucose measurement may indicate an amount or concentration of glucose in interstitial fluid proximate to the second indicator element. The second sensing zone glucose measurement may change in response to degradation of at least a second interferent indicator, which may correspond to degradation of the second analyte indicator. The second sensing zone degradation measurements may be indicative of degradation of the second interferent indicator. The controller may be configured to calculate a first sensing zone glucose concentration using at least the first sensing zone glucose measurements for each of a plurality of time points over the 365 day period.The controller may be configured to calculate a second sensing area glucose concentration using at least the second sensing area glucose measurement for each of a plurality of time points over the 365 days. The controller may be configured to calculate a first weight for the first sensing area glucose concentration using at least the first sensing area degradation measurement for each of the plurality of time points over the 365 days. The controller may be configured to calculate a second weight for the second sensing area glucose concentration using at least the second sensing area degradation measurement for each of the plurality of time points over the 365 days. The controller may be configured to calculate a composite glucose concentration as a weighted average of at least the first sensing area glucose concentration and the second sensing area glucose concentration using at least the first weight and the second weight for each of the plurality of time points over the 365 days. The glucose monitoring system may be configured to display the calculated composite glucose concentration. The composite glucose concentrations for multiple time points over 365 days may have (a) an overall mean relative difference (MARD) vs. self-monitoring of blood glucose (SMBG) value of 10.4% or less and a 40 / 40% agreement rate of 98.5% or greater when the sensing zone glucose concentration calculation is calibrated using one SMBG value every 7 days for 365 days, or (b) an overall MARD vs. SMBG value of 10.3% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensing zone glucose concentration calculation is calibrated using two SMBG values ​​every 14 days for 365 days.

[0040]

[0043] In some embodiments, the controller may be configured to, in calculating the first sensing zone glucose concentration, adjust a first conversion function using at least the first sensing zone degradation measurement, and calculate the first sensing zone glucose concentration using at least the adjusted first conversion function and the first sensing zone glucose measurement. In some embodiments, the controller may be configured to, in calculating the second sensing zone glucose concentration, adjust a second conversion function using at least the second sensing zone degradation measurement, and calculate the second sensing zone glucose concentration using at least the adjusted second conversion function and the second sensing zone glucose measurement.

[0041]

[0044] In some embodiments, the glucose sensor may further comprise a third indicator element including a third analyte indicator and a third interferent indicator, a fourth indicator element including a fourth analyte indicator and a fourth interferent indicator, a third sensing region, and a fourth sensing region. In some embodiments, the glucose sensor may further comprise third measurement electronics in the third sensing region. The third measurement electronics may be configured to generate a third sensing region glucose measurement and a third sensing region degradation measurement for each of a plurality of time points over a 365-day period. The third measurement electronics may be configured to use the third analyte indicator to generate the third sensing region glucose measurement and the third interferent indicator to generate the third sensing region degradation measurement. The third sensing region glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate the third indicator element. The third sensing region glucose measurement may change in response to degradation of at least the third interferent indicator, which may correspond to degradation of the third analyte indicator. The third sensing zone degradation measurement may indicate degradation of the third interferent indicator. In some embodiments, the glucose sensor may further comprise a fourth measuring electronic circuit in the fourth sensing zone. The fourth measuring electronic circuit may be configured to generate a fourth sensing zone glucose measurement and a fourth sensing zone degradation measurement for each of a plurality of time points over a 365-day period. The fourth measuring electronic circuit may be configured to use a fourth analyte indicator to generate the fourth sensing zone glucose measurement and a fourth interferent indicator to generate the fourth sensing zone degradation measurement. The fourth sensing zone glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate the fourth indicator element. The fourth sensing zone glucose measurement may change in response to degradation of at least the fourth interferent indicator, which may correspond to degradation of the fourth analyte indicator. The fourth sensing zone degradation measurement may indicate degradation of the fourth interferent indicator. In some embodiments, the controller may be further configured to calculate a third sensing zone glucose concentration using at least the third sensing zone glucose measurements for each of a plurality of time points over the 365 day period.The controller may be further configured to calculate a fourth sensing zone glucose concentration using at least the fourth sensing zone glucose measurement for each of the plurality of time points over the 365 days. The controller may be further configured to calculate a third weight for the third sensing zone glucose concentration using at least the third sensing zone degradation measurement for each of the plurality of time points over the 365 days. The controller may be further configured to calculate a fourth weight for the fourth sensing zone glucose concentration using at least the fourth sensing zone degradation measurement for each of the plurality of time points over the 365 days. The composite glucose concentration may be calculated as a weighted average of at least the first sensing zone glucose concentration, the second sensing zone glucose concentration, the third sensing zone glucose concentration, and the fourth sensing zone glucose concentration using the first weight, the second weight, the third weight, and the fourth weight.

[0042]

[0045] In some embodiments, the controller may be configured to, in calculating a first sensing zone glucose concentration, adjust a first conversion function using at least the first sensing zone degradation measurement, and calculate the first sensing zone glucose concentration using at least the adjusted first conversion function and the first sensing zone glucose measurement. In some embodiments, the controller may be configured to, in calculating a second sensing zone glucose concentration, adjust a second conversion function using at least the second sensing zone degradation measurement, and calculate the second sensing zone glucose concentration using at least the adjusted second conversion function and the second sensing zone glucose measurement. In some embodiments, the controller may be configured to, in calculating a third sensing zone glucose concentration, adjust a third conversion function using at least the third sensing zone degradation measurement, and calculate the third sensing zone glucose concentration using at least the adjusted third conversion function and the third sensing zone glucose measurement. In some embodiments, the controller may be configured to adjust a fourth conversion function using at least the fourth sensing area degradation measurement in calculating the fourth sensing area glucose concentration, and to calculate the fourth sensing area glucose concentration using at least the adjusted fourth conversion function and the fourth sensing area glucose measurement.

[0043]

[0046] In some embodiments, the first indicator element and the third indicator element may be part of one indicator element, and the second indicator element and the fourth indicator element may be part of another indicator element. In some embodiments, the glucose sensor may further comprise a first substrate and a second substrate, and the first measurement electronic circuit and the third measurement electronic circuit may be fabricated and / or mounted on the first substrate, and the second measurement electronic circuit and the fourth measurement electronic circuit may be fabricated and / or mounted on the second substrate.

[0044]

[0047] In some embodiments, the composite glucose concentrations for multiple time points over 365 days may have (a) an overall MARD to SMBG value of 10.2% or less and a 40 / 40% agreement rate of 98.8% or greater when the calculations of the first sensing area glucose concentration, the second sensing area glucose concentration, the third sensing area glucose concentration, and the fourth sensing area glucose concentration are calibrated using one SMBG value every seven days for 365 days, or (b) an overall MARD to SMBG value of 10.1% or less and a 40 / 40% agreement rate of 98.8% or greater when the calculations of the first sensing area glucose concentration, the second sensing area glucose concentration, the third sensing area glucose concentration, and the fourth sensing area glucose concentration are calibrated using two SMBG values ​​every fourteen days for 365 days.

[0045]

[0048] In some embodiments, the controller may be further configured to calibrate the calculation of the sensing area glucose concentration using (a) one SMBG value every seven days for 365 days, or (b) two SMBG values ​​every 14 days for 365 days.

[0046]

[0049] In some embodiments, the measurement electronic circuits each comprise a first light source configured to emit a first excitation light and a signal light detector configured to receive the first emitted light and output a sensing-zone glucose measurement, where the sensing-zone glucose measurement may indicate an amount of the first emitted light received by the signal light detector. In some embodiments, the measurement electronic circuits each may further comprise a second light source configured to emit a second excitation light. In some embodiments, the measurement electronic circuits each may further comprise an interferent light detector configured to receive the second emitted light and output a sensing-zone degradation measurement, where the sensing-zone glucose measurement may indicate an amount of the second emitted light received by the signal light detector. In some embodiments, the signal light detector may further be configured to receive an amount of the second excitation light and output a sensing-zone degradation measurement, where the sensing-zone degradation measurement may indicate an amount of the second excitation light received. In some embodiments, the measuring electronic circuits may each further comprise a reference photodetector configured to receive a quantity of the second excitation light and output a sensing area degradation measurement value, which may indicate the amount of the second excitation light received.

[0047]

[0050] In some embodiments, the controller may be further configured to calibrate the calculation of the sensing area glucose concentration with SMBG values ​​at an increased frequency during an initial 365-day period compared to the remainder of the 365-day period. In some embodiments, the initial period may be 14 days. In some embodiments, the increased frequency may be one SMBG value per day during the initial period. In some embodiments, the increased frequency may be one SMBG value every 12 hours during the initial period.

[0048]

[0051] Further variations encompassed by the systems and methods are described in the detailed description below.

[0052] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various non-limiting aspects of the present invention, in which like reference numbers indicate identical or functionally similar elements. [Brief explanation of the drawings]

[0049] [Figure 1]

[0053] FIG. 1 is a schematic diagram illustrating an analyte monitoring system embodying aspects of the present invention. [Figure 2A]

[0054] 1 is a schematic diagram illustrating an analyte sensor embodying aspects of the present invention. [Figure 2B] 1 is a schematic diagram illustrating an analyte sensor embodying aspects of the present invention. [Figure 3]

[0055] FIG. 1 is a perspective view showing elements of an analyte sensor embodying aspects of the present invention. [Figure 4]

[0056] FIG. 1 is a schematic diagram illustrating a semiconductor substrate layout of an analyte sensor embodying aspects of the present invention. [Figure 5]

[0057] 1 is a chart showing a non-limiting example of a sensitivity ratio correlating an analyte indicator with an interferent indicator, embodying aspects of the present invention. [Figure 6]

[0058] 1 is a cross-sectional perspective view of a transceiver embodying aspects of the present invention; [Figure 7]

[0059] 1 is an exploded perspective view of a transceiver embodying aspects of the present invention; [Figure 8]

[0060] 1 is a schematic diagram of a transceiver embodying aspects of the present invention; [Figure 9]

[0061] 1 is a flow chart illustrating a process for detecting and calibrating changes in an analyte indicator, embodying aspects of the present invention. [Figure 10]

[0062] 1 is a schematic diagram illustrating a non-limiting example of the structure of an indicator element 106 embodying aspects of the present invention. [Figure 11] 1 is a schematic diagram illustrating a non-limiting example of the structure of an indicator element 106 embodying aspects of the present invention. [Figure 12] 1 is a schematic diagram illustrating a non-limiting example of the structure of an indicator element 106 embodying aspects of the present invention. [Figure 13]

[0063] 1 is a graph showing a correlation plot of the percentage interferents between an indicator and a reference dye, according to one non-limiting embodiment of the present invention. [Figure 14]

[0064] Figure 14A shows fluorometer measurements in 2 mM glucose and 50 uM hydrogen peroxide showing a decrease in fluorescence intensity of the indicator molecule (excitation wavelength 380 nm) and a concomitant increase in fluorescence intensity of Compound A (excitation wavelength 470 nm) at a 1:1 ratio of indicator molecule:Compound A, demonstrating the use of Compound A as a copolymerizable reference dye. Figure 14B shows fluorometer measurements in 2 mM glucose and 50 uM hydrogen peroxide showing a decrease in fluorescence intensity of the indicator molecule (excitation wavelength 380 nm) and a concomitant increase in fluorescence intensity of Compound A (excitation wavelength 470 nm) at a 1:1 ratio of indicator molecule:Compound A, demonstrating the use of Compound A as a copolymerizable reference dye. [Figure 15A]

[0065] 1 shows non-limiting examples of analyte indicator molecules of analyte indicators before and after degradation caused by reactive oxygen species (ROS) according to embodiments of the present invention. [Figure 15B]

[0066] 1 shows non-limiting examples of interferent indicator molecules of interferent indicators before and after degradation caused by ROS according to embodiments of the present invention. [Figure 16]

[0067] Figure 16A shows the white color of an unoxidized indicator element for an indicator element containing an interferent indicator embodying an embodiment of the present invention, and Figure 16B shows the yellow color of an oxidized indicator element for an indicator element containing an interferent indicator embodying an embodiment of the present invention. [Figure 17A]

[0068] 1 illustrates the decrease in intensity or amount of light emitted by an analyte indicator over time, according to an embodiment of the present invention. [Figure 17B]

[0069] 1 shows the increase in absorbance of an indicator element over time and the decrease in the intensity or amount of second excitation light reflected by the indicator element over time, according to an embodiment of the present invention. [Figure 18]

[0070] 1 is a graph showing experimental data from a clinical trial in which the analyte sensor 100 was subcutaneously implanted in a living human. [Figure 19A]

[0071] 1 is a graph showing the extinction coefficients of oxyhemoglobin and deoxyhemoglobin at different wavelengths. [Figure 19B] 1 is a graph showing the extinction coefficients of oxyhemoglobin, deoxyhemoglobin, methemoglobin, and bilirubin at different wavelengths. [Figure 20]

[0072] 1 is a flow chart illustrating a process for detecting and calibrating effects on an analyte indicator, embodying aspects of the present invention. [Figure 21A]

[0073] 1 shows chemical structures of analyte indicators according to some embodiments. [Figure 21B] 1 shows chemical structures of interferent indicators according to some embodiments. [Figure 22A]

[0074] 1 shows a perspective view of an analyte sensor including multiple sensing regions and multiple indicator elements according to some embodiments. [Figure 22B] 1 shows a top view, in which an analyte sensor includes multiple sensing regions and multiple indicator elements according to some embodiments. [Figure 23]

[0075] Similar degradation kinetics according to some embodiments demonstrates that as oxidation progresses, the analyte indicator emits a decrease in a first emitted light and the interferent indicator emits an increase in a second emitted light. [Figure 24]

[0076] Figure 24A shows optical and fluorescent images of an analyte sensor after local oxidation according to some embodiments, Figure 24B shows optical and fluorescent images of an analyte sensor after local oxidation according to some embodiments, Figure 24C shows optical and fluorescent images of an analyte sensor after local oxidation according to some embodiments, and Figure 24D shows optical and fluorescent images of an analyte sensor after local oxidation according to some embodiments. [Figure 25]

[0077] Figure 25A shows in vivo measurements from different sensing regions of the analyte sensor shown in Figures 22A and 22B according to some embodiments. Figure 25B shows in vivo measurements from different sensing regions of the analyte sensor shown in Figures 22A and 22B according to some embodiments. Figure 25C shows in vivo measurements from different sensing regions of the analyte sensor shown in Figures 22A and 22B according to some embodiments. Figure 25D shows in vivo measurements from different sensing regions of the analyte sensor shown in Figures 22A and 22B according to some embodiments. [Figure 26]

[0078] Figure 26A shows individual glucose concentrations calculated from the sensing areas of the analyte sensor 100 shown in Figures 22A and 22B, respectively, according to some embodiments. Figure 26B shows a composite glucose concentration calculated based on a weighted average of the individual glucose concentrations, according to some embodiments. [Figure 27]

[0079] 27A and 27B show the accuracy of glucose concentrations calculated by an analyte monitoring system over a 365-day period based on self-measured blood glucose readings, according to some embodiments. [Figure 28]

[0080] Figure 28A shows the normalized signals for regions 1-4 (i.e., sensing regions 2202a, 2202b, 2202c, and 2202d) of an analyte sensor over a 365-day period with calibration once every seven days, according to some embodiments. Figure 28B shows the individual weights for regions 1-4 (i.e., sensing regions 2202a, 2202b, 2202c, and 2202d) of an analyte sensor over a 365-day period with calibration once every seven days, according to some embodiments. [Figure 29]

[0081] 1 is a flow chart illustrating a glucose monitoring process embodying aspects of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0050]

[0082] FIG. 1 is a schematic diagram of an exemplary analyte monitoring system 50 embodying embodiments of the present invention. The analyte monitoring system 50 may be a continuous analyte monitoring system (e.g., a continuous glucose monitoring system). In some embodiments, the analyte monitoring system 50 may comprise one or more of an analyte sensor 100, a transceiver 101, and a display device 107. In some embodiments, the analyte sensor 100 may be a miniature, fully subcutaneously implantable sensor that measures the amount or concentration of an analyte (e.g., glucose) in a medium (e.g., interstitial fluid) of a living animal (e.g., a living human). However, this is not required, and in some alternative embodiments, the analyte sensor 100 may be a partially implantable (e.g., transcutaneous) sensor or a fully external sensor. In some embodiments, the transceiver 101 may be an externally worn transceiver (e.g., attached via an armband, wristband, waistband, or adhesive patch). In some embodiments, the transceiver 101 may remotely power and / or communicate with the sensor 100 to initiate and receive measurements (e.g., via near field communication (NFC)). However, this is not required, and in some alternative embodiments, the transceiver 101 may power and / or communicate with the analyte sensor 100 via one or more wired connections. In some non-limiting embodiments, the transceiver 101 may be a smartphone (e.g., an NFC-enabled smartphone). In some embodiments, the transceiver 101 may communicate information (e.g., one or more analyte measurements) wirelessly (e.g., via a Bluetooth™ communication standard, such as, but not limited to, Bluetooth Low Energy) to a handheld application running on the display device 107 (e.g., a smartphone).

[0051]

[0083] FIG. 2A is a schematic diagram illustrating an analyte sensor 100 embodying an embodiment of the present invention, and FIG. 3 is a perspective view illustrating elements of an analyte sensor 100 embodying an embodiment of the present invention. In some embodiments, the analyte sensor 100 may detect the presence, amount, and / or concentration of an analyte (e.g., glucose, oxygen, cardiac markers, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides). In some non-limiting embodiments, the analyte sensor 100 may be an optical sensor (e.g., a fluorometer). In some embodiments, the analyte sensor 100 may be a chemical sensor or a biochemical sensor. In some embodiments, the analyte sensor 100 may be a radio frequency identification (RFID) device. The analyte sensor 100 may be powered by a radio frequency (RF) signal from a transceiver 101.

[0052]

[0084] The analyte sensor 100 may be in communication with a transceiver 101. The transceiver 101 may be an electronic device that communicates with the analyte sensor 100 to power the analyte sensor 100 and / or receive measurement data (e.g., photodetector and / or temperature sensor measurements) from the analyte sensor 100. The measurement data may include one or more measurements from one or more photodetectors of the analyte sensor 100 and / or one or more measurements from one or more temperature sensors of the analyte sensor 100. In some embodiments, the transceiver 101 may calculate the analyte concentration from the measurement data received from the analyte sensor 100. However, it is not required that the transceiver 101 perform the analyte concentration calculation itself, and in some alternative embodiments, the transceiver 101 may instead communicate / relay the measurement data received from the analyte sensor 100 to another device (e.g., display device 107) for analyte concentration calculation. In other alternative embodiments, the analyte sensor 100 may perform the analyte concentration calculation and communicate the calculated analyte concentration to the transceiver 101.

[0053]

[0085] In some embodiments (e.g., embodiments in which the analyte sensor 100 is a fully implantable sensing system), the transceiver 101 may implement passive telemetry to communicate with the implantable analyte sensor 100 via an inductive magnetic link for power and / or data transfer. In some embodiments, as shown in FIG. 3, the analyte sensor 100 may include an inductive element 114, which may be, for example, a ferrite-based micro-antenna. In some embodiments, as shown in FIG. 3, the inductive element 114 may include a conductor 302 in the form of a coil and a magnetic core 304. In some non-limiting embodiments, the core 304 may be, for example, without limitation, a ferrite core. In some embodiments, the inductive element 114 may be connected to the analyte detection circuitry of the analyte sensor 100. For example, in some embodiments, if the analyte sensor 100 is an optical sensor, the inductive element 114 may be connected to the microfluorometer circuitry (e.g., an application specific integrated circuit (ASIC)) and associated optical detection system of the analyte sensor 100. In some embodiments, the analyte sensor 100 may not include a battery, and as a result, the analyte sensor 100 may rely on the transceiver 101 of the sensor system 105 to provide power to the analyte sensor 100 and a data link to communicate analyte-related data from the analyte sensor 100 to the transceiver 101. However, this is not required, and in some alternative embodiments, the analyte sensor 100 may include a battery.

[0054]

[0086] In some non-limiting embodiments, the analyte sensor 100 may be a passive, fully implantable, multi-site sensing system with a compact size. In the case of an analyte sensor 100 that is a fully implantable sensing system without a battery power source, the transceiver 101 may provide energy to power the analyte sensor 100 via a magnetic field. In some embodiments, the link of a magnetic transceiver-based sensing system may be considered a "weakly coupled transformer" type. The link of a magnetic transceiver-based sensing system may provide energy and a link for data transfer using amplitude modulation (AM). In some embodiments, data transfer occurs using AM, although alternative embodiments may use other types of modulation. The link of a magnetic transceiver-based sensor may have low power transfer efficiency and therefore may require a relatively high-power amplifier to energize the analyte sensor 100 over longer distances. In some non-limiting embodiments, the transceiver 101 and the analyte sensor 100 may communicate using short-range communication (e.g., 13.56 MHz, a frequency band that can achieve high penetration through the skin and is medically approved) for power transfer. However, this is not required and in other embodiments, different frequencies may be used to power and communicate with the analyte sensor 100.

[0055]

[0087] 7, the transceiver 101 may include an inductive element 103, such as a coil. The transceiver 101 may generate an electromagnetic wave or electrodynamic field (e.g., using the coil 103) to induce a current in the inductive element 114 of the analyte sensor 100, thereby powering the analyte sensor 100. The transceiver 101 may also communicate data (e.g., commands) to the analyte sensor 100. For example, in a non-limiting embodiment, the transceiver 101 may communicate data by modulating the electromagnetic wave used to power the analyte sensor 100 (e.g., by modulating the current through the coil of the transceiver 101). The modulation of the electromagnetic wave generated by the transceiver 101 may be detected / extracted by the analyte sensor 100. Additionally, the transceiver 101 may receive data (e.g., measurement information) from the analyte sensor 100. For example, in a non-limiting embodiment, the transceiver 101 may receive data by detecting modulation of the electromagnetic waves generated by the analyte sensor 100, e.g., by detecting modulation of the current flowing through the coil 103 of the transceiver 101.

[0056]

[0088] In some non-limiting embodiments, as shown in FIG. 2A , the analyte sensor 100 may comprise a sensor housing 102 (i.e., body, shell, capsule, or container), which may be rigid and biocompatible. In one non-limiting embodiment, the sensor housing 102 may be a silicone tube. However, this is not required, and in other embodiments, different materials and / or shapes may be used for the sensor housing 102. In some embodiments, the analyte sensor 100 may comprise a transmissive optical resonator. In some non-limiting embodiments, the transmissive optical resonator may be formed from a suitable optically transparent polymeric material, such as, for example, an acrylic polymer (e.g., polymethyl methacrylate (PMMA)). However, this is not required, and in other embodiments, different materials may be used for the transmissive optical resonator.

[0057]

[0089] 2A, the analyte sensor 100 may include an indicator element 106, such as, for example, a polymer graft or hydrogel, coated on, diffused, attached, implanted, or grown on or in at least a portion of the exterior surface of the sensor housing 102. In some non-limiting embodiments, the sensor housing 102 may include one or more notches or recesses, and the indicator element 106 may be disposed (partially or entirely) within the notch or recess. In some embodiments, the indicator element 106 may be porous, allowing an analyte (e.g., glucose) in the medium (e.g., interstitial fluid) to diffuse into the indicator element 106.

[0058]

[0090] In some embodiments, the indicator element 106 (e.g., a polymer graft or hydrogel) of the sensor 100 may include one or more of an analyte indicator 207 and an interferent indicator 209 (e.g., a degradation indicator). In some embodiments, the analyte indicator 207 may have one or more detectable properties (e.g., optical properties) that change depending on (i) the amount or concentration of analyte in proximity to the indicator element 106 and (ii) an effect on the analyte indicator 207 (e.g., a change to the analyte indicator 207). In some embodiments, the change to the analyte indicator 207 may include a degree of degradation of the analyte indicator 207. In some non-limiting embodiments, the degradation may be (at least in part) ROS-induced oxidation. In some embodiments, the analyte indicator 207 may include one or more analyte indicator molecules (e.g., fluorescent analyte indicator molecules), which may be distributed throughout the indicator element 106. In some non-limiting embodiments, the analyte indicator 207 may be a phenylboron-based analyte indicator. However, phenylboron-based analyte indicators are not required, and in some alternative embodiments, the analyte sensor 100 may include different analyte indicators, such as, but not limited to, glucose oxidase-based indicators, glucose dehydrogenase-based indicators, and glucose binding protein-based indicators.

[0059]

[0091] In some embodiments, the interferent indicator 209 may have one or more detectable properties (e.g., optical properties) that change in response to a change to the interferent indicator 209. In some embodiments, the interferent indicator 209 is insensitive to the amount of concentration of analyte proximate to the indicator element 106. That is, in some embodiments, the one or more detectable properties of the interferent indicator 209 do not change in response to the amount or concentration of analyte proximate to the indicator element 106. However, this is not required, and in some alternative embodiments, the one or more detectable properties of the interferent indicator 209 may change in response to the amount or concentration of analyte proximate to the indicator element 106.

[0060]

[0092] In some embodiments, the changes to the interferent indicator 209 may include a degree of degradation of the interferent indicator 209. In some embodiments, the degradation may be (at least in part) ROS-induced oxidation. In some embodiments, the interferent indicator 209 may include one or more interferent indicator molecules (e.g., fluorescent interferent indicator molecules), which may be distributed throughout the indicator element 106. In some non-limiting embodiments, the interferent indicator 209 may be a phenylboron-based interferent indicator. However, a phenylboron-based interferent indicator is not required, and in some alternative embodiments, the analyte sensor 100 may include a different interferent indicator, such as, for example, but not limited to, an amplex red-based interferent indicator, a dichlorodihydrofluorescein-based indicator, a dihydrorhodamine-based indicator, and a scopoletin-based interferent indicator.

[0061]

[0093] In some non-limiting embodiments, the interferent indicator molecule can be a fluorescent probe compound having an excitation wavelength of about 450 nm to about 550 nm, a Stokes shift of about 500 nm to about 650 nm, and a half-life of about 50 days to about 150 days. In some non-limiting embodiments, the interferent indicator molecule can be a compound of Formula I:

[0062]

number

[0063] wherein A″, B″, C″, A′, B′, C′, W′, X, Y′, and Z′ represent —CH, wherein the hydrogens are optionally and independently substituted with alkyl groups; R1 and R2 are independently selected from one or more vinyl groups, alkyl vinyl groups, acrylamide groups, methacrylamide groups, or other polymerizable groups.

[0064] Exemplary, non-limiting compounds include:

[0065]

number

[0066] In further non-limiting embodiments, interferent indicator molecules can include, for example, the following exemplary compounds:

[0067]

number

[0068] wherein A, B', C', D', E, F', G, H', I', and J represent -CH, and the hydrogens are optionally and independently substituted with alkyl groups.

[0094] The compounds may be synthesized using synthetic techniques known in the art, such as "Preparation and use of MitoPY1 for imaging hydrogen peroxide in mitochondria of live cells," Dickinson, et al. Nat Protoc. 2013 June;8(6):1249-1259, and U.S. Application Publication No. 2016 / 0312033 (Application Serial No. 15 / 135,788, Yang et al., October 27, 2016), the disclosures of which are incorporated herein by reference in their entireties.

[0069]

[0095] In some alternative embodiments, the molecules of interferent indicator 209 may be compounds having different formulae with excitation wavelengths of about 450 nm to about 550 nm, Stokes shifts of about 500 nm to about 650 nm, and half-lives of about 50 days to about 150 days.

[0070]

[0096] In some non-limiting embodiments, as shown in FIGS. 10-12, the indicator element 106 may include one or more polymer backbones 1002. In some non-limiting embodiments, the polymer backbone 1002 may be a polymer chain. In some embodiments, as shown in FIGS. 10 and 11, the indicator element 106 may include one or more analyte indicator molecules A and one or more interferent indicator molecules D. In some embodiments, as shown in FIGS. 10 and 11, the analyte indicator molecules A and the interferent indicator molecules D may be monomers individually polymerized into the polymer backbone 1002. In some non-limiting embodiments, the indicator element 106 may include the same number of analyte indicator molecules A and interferent indicator molecules D (see FIG. 10) or different numbers of analyte indicator molecules A and interferent indicator molecules D (see FIG. 11). In some embodiments, the ratio of analyte indicator molecule A to interferent indicator molecule D may be, for example, but not limited to, 1:1 as shown in FIG. 10, 2:1 as shown in FIG. 11, 1:2, 3:1, 5:1, 10:1, etc.

[0071]

[0097] 12 , one or more interferent indicator molecules D may be chemically bonded (e.g., via a covalent bond) to analyte indicator molecule A, and analyte indicator molecule A may be chemically bonded to polymer backbone 1002. In non-limiting alternative embodiments, analyte indicator molecule A and interferent indicator molecule D may be monomers, and analyte indicator molecule A may be polymerized into polymer backbone 1002. In some other alternative embodiments, one or more analyte indicator molecules A may be chemically bonded to interferent indicator molecule D, and interferent indicator molecule D may be chemically bonded to polymer backbone 1002. In non-limiting alternative embodiments, analyte indicator molecule A and interferent indicator molecule D may be monomers, and interferent indicator molecule D may be polymerized into polymer backbone 1002.

[0072]

[0098] In some embodiments, the analyte sensor 100 may indirectly measure changes in the analyte indicator 207 using an interferent indicator 209 that is sensitive to degradation by reactive oxygen species (ROS) but not the analyte. In some embodiments, the interferent indicator 209 may have one or more optical properties that change with the degree of oxidation and may be used as a reference dye to measure and calibrate the degree of oxidation of the analyte indicator. In some embodiments, the degree of degradation of the interferent indicator 209 may correspond to the degree of degradation of the analyte indicator 207. For example, in some non-limiting embodiments, the degree of degradation of the interferent indicator 209 may be proportional to the degree of degradation of the analyte indicator 207. In some non-limiting embodiments, the degree of degradation of the analyte indicator 207 may be calculated based on the degree of degradation of the interferent indicator 209. In some embodiments, the analyte monitoring system 50 may calibrate changes in the analyte indicator 207 using empirical correlations established through laboratory testing.

[0073]

[0099] 2A, the analyte sensor 100 may include one or more first light sources 108 that emit a first excitation light 329 over a wavelength range that interacts with the analyte indicator 207 in the indicator element 106. In some non-limiting embodiments, the first excitation light 329 may be ultraviolet (UV) light. In some embodiments, the analyte sensor 100 may include one or more light sources 227 that emit a second excitation light 330 over a wavelength range that interacts with the interferent indicator 209 in the indicator element 106. In some non-limiting embodiments, the second excitation light 330 may be blue light.

[0074]

[0100] 2A, the analyte sensor 100 may further comprise one or more photodetectors 224, 226, 228 (e.g., photodiodes, phototransistors, photoresistors, or other light-sensitive elements). In some embodiments, the analyte sensor 100 may comprise one or more signal photodetectors 224 sensitive to the first emitted light 331 (e.g., fluorescent light) emitted by the analyte indicator 207 of the indicator element 106, such that a signal generated by the photodetector 224 in response to the first emitted light 331 indicates the level of the first emitted light 331 of the analyte indicator 207 and, therefore, the amount of the analyte (e.g., glucose) of interest. In some non-limiting embodiments, the analyte sensor 100 may comprise one or more reference photodetectors 226 that may be sensitive to the first excitation light 329 that may be reflected from the indicator element 106, such that a signal generated by the photodetector 226 in response to the first excitation light 329 indicates the level of the reflected first excitation light 329. In some embodiments, the analyte sensor 100 may comprise one or more interferent photodetectors 228 sensitive to the second emitted light 332 (e.g., fluorescent light) emitted by the interferent indicator 209 of the indicator element 106, such that a signal generated by the interferent photodetector 228 in response to the second emitted light 332 indicates the level of the second emitted light 332 of the interferent indicator 209, and thus the amount of degradation (e.g., oxidation). In some non-limiting embodiments, the one or more signal photodetectors 224 may be sensitive to the second excitation light 330 that may be reflected from the indicator element 106. In this manner, the one or more signal photodetectors 224 may function as a reference photodetector when the one or more light sources 227 are emitting the second excitation light 330.

[0075]

[0101] However, it is not necessary for the one or more signal photodetectors 224 to function as the reference photodetector when the one or more light sources 227 are emitting the second excitation light 330. In some alternative embodiments, as shown in FIG. 2B , the analyte sensor 100 may include one or more second reference photodetectors 230 that function as the reference photodetector when the one or more light sources 227 are emitting the second excitation light 330. In some embodiments, the one or more second reference photodetectors 230 may be sensitive to the second excitation light 330 that may be reflected from the indicator element 106, such that a signal generated by the photodetector 230 in response to the second excitation light 330 indicates the level of the reflected second excitation light 330.

[0076]

[0102] In some embodiments, the first excitation light 329 may span a first wavelength range, and the second excitation light 330 may span a second wavelength range, which may be different from the first wavelength range. In some non-limiting embodiments, the first wavelength range and the second wavelength range do not overlap, but this is not required, and in some alternative embodiments, the first wavelength range and the second wavelength range may overlap. In some embodiments, the first emitted light 331 may span a third wavelength range, and the second emitted light 332 may span a fourth wavelength range, which may be different from the third wavelength range. In some non-limiting embodiments, the third wavelength range and the fourth wavelength range do not overlap, but this is not required, and in some alternative embodiments, the third wavelength range and the fourth wavelength range may overlap. In some embodiments, the first wavelength range and the third wavelength range may be different. In some non-limiting embodiments, the first wavelength range and the third wavelength range do not overlap, but this is not required, and in some alternative embodiments, the first wavelength range and the third wavelength range may overlap. In some embodiments, the second wavelength range and the fourth wavelength range may be different. In some non-limiting embodiments, the second wavelength range and the fourth wavelength range do not overlap, but this is not required, and in some alternative embodiments, the second wavelength range and the fourth wavelength range may overlap. In some embodiments, the second wavelength range and the third wavelength range may be different. In some non-limiting embodiments, the second wavelength range and the third wavelength range do not overlap, but this is not required, and in some alternative embodiments, the second wavelength range and the third wavelength range do not overlap.

[0077]

[0103] In some embodiments, one or more of the photodetectors 224, 226, 228, 230 may be covered by one or more filters that pass only a specific subset of wavelengths of light and reflect (or absorb) the remaining wavelengths. In some non-limiting embodiments, the one or more filters of one or more signal photodetectors 224 may pass only a subset of wavelengths corresponding to the first emission light 331 and / or the reflected second excitation light 330. In some non-limiting embodiments, the one or more filters of one or more reference photodetectors 226 may pass only a subset of wavelengths corresponding to the reflected first excitation light 329. In some non-limiting embodiments, the one or more filters of one or more interferent photodetectors 228 may pass only a subset of wavelengths corresponding to the second emission light 332. In some non-limiting embodiments in which the analyte sensor 100 includes one or more second reference photodetectors 230, one or more filters of the one or more second reference photodetectors 230 may pass only a subset of wavelengths corresponding to the reflected second excitation light 330.

[0078]

[0104] In some embodiments, the interferent indicator 209 may be used as a reference dye to measure and calibrate the degree of oxidation of the analyte indicator 207. In some embodiments, the analyte monitoring system 50 may calibrate changes in the analyte indicator 207 using an empirical correlation established through laboratory testing. FIG. 5 is a chart showing non-limiting examples of sensitivity ratios correlating the analyte indicator 207 and the interferent indicator 209. In some embodiments, the interferent indicator 209 may be more sensitive to oxidation than the analyte indicator 207, as indicated by a sensitivity ratio of 1 in FIG. 5. However, this is not required, and in some alternative embodiments, the interferent indicator 209 may be less sensitive to oxidation than the analyte indicator 207, as indicated by a sensitivity ratio of 2 in FIG. 5. In other alternative embodiments, the interferent indicator 209 and the analyte indicator 207 may be equally sensitive to oxidation.

[0079]

[0105] In some embodiments, as shown in FIG. 4 , substrate 112 may be a circuit board (e.g., a printed circuit board (PCB) or a flexible PCB) on which one or more of circuit components 111 (e.g., analog and / or digital circuit components) may be mounted or otherwise attached. However, in some alternative embodiments, substrate 112 may be a semiconductor substrate within which one or more of circuit components 111 are fabricated. For example, the fabricated circuit components may include analog and / or digital circuits. Also, in some embodiments in which substrate 112 is a semiconductor substrate, circuit components may be mounted or otherwise attached to the semiconductor substrate in addition to the circuit components fabricated therein. In other words, in some semiconductor substrate embodiments, some or all of circuit components 111, which may include discrete circuit elements, integrated circuits (e.g., application specific integrated circuits (ASICs)), and / or other electronic components (e.g., non-volatile memory), may be fabricated within the semiconductor substrate, with the remainder of circuit components 111 being fixed to the semiconductor substrate, thereby providing communication paths between the various fixed components.

[0080]

[0106] In some embodiments, the analyte sensor 100 may include one or more light sources 108, 227, one or more of which may be mounted to or fabricated within the substrate 112. In some embodiments, the analyte sensor 100 may include one or more light detectors 224, 226, 228, 230, one or more of which may be mounted to or fabricated within the substrate 112. In some non-limiting embodiments, one or more light sources 108, 227 may be mounted to the substrate 112, one or more light detectors may be fabricated within the substrate 112, and all or a portion of the circuit component 111 may be fabricated within the substrate 112.

[0081]

[0107] In some embodiments, one or more of the indicator element 106, light source 108, 227, photodetectors 224, 226, 228, 230, circuit component 111, and substrate 112 of the analyte sensor 100 can include some or all of the features described in one or more of U.S. patent application Ser. No. 13 / 761,839, filed February 7, 2013, U.S. patent application Ser. No. 13 / 937,871, filed July 9, 2013, U.S. application Ser. No. 13 / 650,016, filed October 11, 2012, and U.S. application Ser. No. 14 / 142,017, filed December 27, 2013, all of which are incorporated by reference in their entirety. Similarly, the structure, function, and / or features of the sensor housing 102, the analyte sensor 100, and / or the transceiver 101 may be as described in one or more of U.S. Application Serial Nos. 13 / 761,839, 13 / 937,871, 13 / 650,016, and 14 / 142,017. For example, the sensor housing 102 may have one or more hydrophobic, hydrophilic, opaque, and / or immune-blocking membranes or layers on its exterior.

[0082]

[0108] In some embodiments, the analyte sensor 100 may be a fully implantable sensor, as shown in FIG. 1 , although this is not required, and in some alternative embodiments, the analyte sensor 100 may be a transcutaneous sensing system with a wired connection to the transceiver 101. For example, in some alternative embodiments, the analyte sensor 100 may be located in or on (e.g., at the tip of) a percutaneous needle. In these embodiments, instead of communicating wirelessly using the inductive elements 103 and 114, the analyte sensor 100 and transceiver 101 may communicate using one or more wires connected between the transceiver 101 and the transceiver transceiver needle comprising the analyte sensor 100. As another example, in some alternative embodiments, the analyte sensor 100 may be located in a catheter (e.g., for intravenous blood glucose monitoring) and may communicate (wirelessly or using wires) with the transceiver 101.

[0083]

[0109] In some embodiments, the analyte sensor 100 may comprise a transceiver interface device. In some embodiments, the transceiver interface device may comprise an antenna (e.g., inductive element 114) of the analyte sensor 100. In some transcutaneous embodiments where a wired connection exists between the analyte sensor 100 and the transceiver 101, the transceiver interface device may include the wired connection.

[0084]

[0110] 6 and 7 are cross-sectional and exploded views, respectively, of a non-limiting embodiment of a transceiver 101 that may be included in the analyte monitoring system 50 shown in FIG. 1. As shown in FIG. 7, in some non-limiting embodiments, the transceiver 101 may include a graphic overlay 204, a front housing 206, a button 208, a printed circuit board (PCB) assembly 210, a battery 212, a gasket 214, an antenna 103, a frame 218, a reflector 216, a rear housing 220, an ID label 222, and / or a vibration motor 928. In some non-limiting embodiments, the vibration motor 928 may be attached to the front housing 206 or the rear housing 220 such that the battery 212 does not dampen the vibrations of the vibration motor 928. In non-limiting embodiments, the transceiver electronics may be assembled using standard surface mount device (SMD) reflow and soldering techniques. In one embodiment, the electronics and peripherals may be in a snap-together housing design, where the front housing 206 and the rear housing 220 snap together. In some embodiments, the entire assembly process may be performed in a single external electronics house. However, this is not required, and in alternative embodiments, the transceiver assembly process may be performed in one or more electronics houses, which may be internal, external, or a combination thereof. In some embodiments, the assembled transceiver 101 may be programmed and functionally tested. In some embodiments, the assembled transceiver 101 may be packaged in a final shipping container and prepared for sale.

[0085]

[0111] In some embodiments, the antenna 103 may be housed within the housings 206 and 220 of the transceiver 101, as shown in FIGS. 6 and 7. In some embodiments, the antenna 103 of the transceiver 101 may be small and / or planar, such that the antenna 103 fits within the small and lightweight housings 206 and 220 of the transceiver 101. In some embodiments, the antenna 103 may be rugged and able to withstand various impacts. In some embodiments, the transceiver 101 may be suitable for placement on the abdominal region, upper arm, wrist, or thigh of a patient's body, for example. In some non-limiting embodiments, the transceiver 101 may be suitable for attachment to the patient's body via a biocompatible patch. In some embodiments, the antenna 103 may be housed within the housings 206 and 220 of the transceiver 101, but this is not required, and in some alternative embodiments, part or all of the antenna 103 may be located outside the transceiver housing. For example, in some alternative embodiments, the antenna 103 may be wrapped around the user's wrist, arm, leg, or waist, such as the antenna described in U.S. Pat. No. 8,073,548, the entire contents of which are incorporated herein by reference.

[0086]

[0112] 8 is a schematic diagram of an external transceiver 101, according to a non-limiting embodiment. In some embodiments, the transceiver 101 may have a connector 902, such as a micro-universal serial bus (USB) connector. The connector 902 may allow for a wired connection to an external device, such as a personal computer (e.g., personal computer 109) or a display device 107 (e.g., a smartphone).

[0087]

[0113] The transceiver 101 may exchange data with an external device through the connector 902 and / or may receive power through the connector 902. The transceiver 101 may include a connector integrated circuit (IC) 904, such as a USB-IC, which may control the transmission and reception of data through the connector 902. The transceiver 101 may further include a charger IC 906 which may receive power through the connector 902 and charge a battery 908 (e.g., a lithium polymer battery). In some embodiments, the battery 908 may be rechargeable, may have a short recharge time, and / or may have a small size.

[0088]

[0114] In some embodiments, transceiver 101 may include one or more connectors in addition to (or as an alternative to) Micro-USB connector 904. For example, in an alternative embodiment, transceiver 101 may include a spring-loaded connector (e.g., a pogo-pin connector) in addition to (or as an alternative to) Micro-USB connector 904, and transceiver 101 may use the connection established via the spring-loaded connector for wired communication to a personal computer (e.g., personal computer 109) or display device 107 (e.g., a smartphone) and / or to receive power that may be used, for example, to charge battery 908.

[0089]

[0115] In some embodiments, the transceiver 101 may have a wireless communication IC 910, which enables wireless communication with external devices such as, for example, one or more personal computers (e.g., personal computer 109) or one or more display devices 107 (e.g., smartphones). In one non-limiting embodiment, the wireless communication IC 910 may employ one or more wireless communication standards to wirelessly transmit data. The employed wireless communication standard may be any suitable wireless communication standard, such as the ANT standard, the Bluetooth standard, or the Bluetooth Low Energy (BLE) standard (e.g., BLE 4.0). In some non-limiting embodiments, the wireless communication IC 910 may be configured to wirelessly transmit data at frequencies above 1 gigahertz (e.g., 2.4 or 5 GHz). In some embodiments, the wireless communication IC 910 may include an antenna (e.g., a Bluetooth antenna). In some non-limiting embodiments, the antenna of the wireless communication IC 910 may be entirely housed within the housing of the transceiver 101 (e.g., housings 206 and 220). However, this is not required, and in alternative embodiments, all or part of the antenna of the wireless communication IC 910 may be external to the transceiver housing.

[0090]

[0116] In some embodiments, the transceiver 101 may comprise a display interface device, which may enable communication by the transceiver 101 with one or more display devices 107. In some embodiments, the display interface device may comprise an antenna and / or connector 902 of a wireless communication IC 910. In some non-limiting embodiments, the display interface device may further comprise a wireless communication IC 910 and / or a connector IC 904.

[0091]

[0117] In some embodiments, the transceiver 101 may include a voltage regulator 912 and / or a booster 914. The battery 908 (via the booster 914) provides power to a radio frequency identification (RFID) reader IC 916, which uses the inductive element 103 to communicate information (e.g., commands) to the sensor 101 and receive information (e.g., measurement information) from the sensor 100. In some non-limiting embodiments, the sensor 100 and the transceiver 101 may communicate using near field communication (NFC) (e.g., at a frequency of 13.56 MHz). In the illustrated embodiment, the inductive element 103 is a planar antenna. In some non-limiting embodiments, the antenna may be flexible. However, as described above, the inductive element 103 of the transceiver 101 may be of any configuration that allows an appropriate electric field strength to be achieved when in sufficient physical proximity to the inductive element 114 of the sensor 100. In some embodiments, the transceiver 101 may include a power amplifier 918 for amplifying the signal transmitted by the inductive element 103 to the sensor 100 .

[0092]

[0118] In some embodiments, the transceiver 101 may include a peripheral interface controller (PIC) controller 920 and memory 922 (e.g., flash memory), which may be non-volatile and / or electronically erasable and / or rewritable. The PIC controller 920 may control the overall operation of the transceiver 101. For example, the PIC controller 920 may control the connector IC 904 or the wireless communication IC 910 to transmit data via wired or wireless communication and / or control the RFID reader IC 916 to communicate data via the inductive element 103. The PIC controller 920 may also control the processing of data received via the inductive element 103, the connector 902, or the wireless communication IC 910.

[0093]

[0119] In some embodiments, the transceiver 101 may comprise a sensor interface device, which may enable the transceiver 101 to communicate with the sensor 100. In some embodiments, the sensor interface device may comprise an inductive element 103. In some non-limiting embodiments, the sensor interface device may further comprise an RFID reader IC 916 and / or a power amplifier 918. However, in some alternative embodiments where a wired connection exists between the sensor 100 and the transceiver 101 (e.g., a transcutaneous embodiment), the sensor interface device may include a wired connection.

[0094]

[0120] In some embodiments, the transceiver 101 may include a display 924 (e.g., a liquid crystal display and / or one or more light emitting diodes) that the PIC controller 920 may control to display data (e.g., analyte concentration values). In some embodiments, the transceiver 101 may include a speaker 926 (e.g., a beeper) and / or a vibration motor 928, which may be activated, for example, when an alarm condition is met (e.g., detection of a hypoglycemic or hyperglycemic condition). The transceiver 101 may further include one or more additional sensors 930, which may include an accelerometer and / or a temperature sensor, which may be used in the processing performed by the PIC controller 920.

[0095]

[0121] 9 illustrates a non-limiting embodiment of an analyte monitoring process 950 that may be performed by the analyte monitoring system 50. In some embodiments, the process 950 may detect and calibrate the effect on the analyte indicator 207.

[0096]

[0122] In some embodiments, the process 950 may include a step 952 in which the analyte monitoring system 50 measures an analyte signal. In some embodiments, step 952 may include the transceiver 101 transmitting an analyte measurement command to the analyte sensor 100. In some embodiments, step 952 may include the analyte sensor 100, in response to receiving and decoding the analyte measurement command, emitting a first excitation light 329 to the indicator element 106 using the first light source 108. The analyte indicator 207 of the indicator element 106 may receive the first excitation light 329 and emit a first emitted light 331. The signal light detector 224 may receive the first emitted light 331 and generate an analyte measurement signal based on the amount of first emitted light 331 received by the signal light detector 224. In some embodiments, step 952 may include the analyte sensor 100 using the reference photodetector 226 to receive the first excitation light 329 reflected from the indicator element 106 and generating a reference signal indicative of the amount of reflected first excitation light 329 received by the reference photodetector 226.

[0097]

[0123] In some embodiments, the process 950 may include a step 954 in which the analyte monitoring system 50 measures an interferent signal. In some embodiments, step 954 may include the transceiver 101 transmitting an interferent measurement command to the analyte sensor 100. In some embodiments, step 954 may include the analyte sensor 100, in response to receiving and decoding the interferent measurement command, emitting a second excitation light 330 to the indicator element 106 using the second light source 227. The interferent indicator 209 of the indicator element 106 may receive the second excitation light 330 and emit a second emitted light 332. The interferent light detector 228 may receive the second emitted light 332 and generate an interferent measurement signal based on the amount of second emitted light 332 received by the interferent light detector 228. In some embodiments, step 954 may include the analyte sensor 100 receiving the second excitation light 330 reflected from the indicator element 106 using the signal photodetector 224 (and / or the second reference photodetector 230) and generating a reference signal indicative of the amount of reflected second excitation light 330 received by the signal photodetector 224 (and / or the second reference photodetector 230).

[0098]

[0124] In some alternative embodiments, step 954 may not include communicating an interferent measurement command to the analyte sensor 100, and the analyte sensor 100 may emit the second excitation light 330 to the indicator element 106 using the second light source 227 in response to receiving and decoding the analyte measurement command (rather than in response to receiving and decoding a separate interferent measurement command). In some alternative embodiments, steps 952 and 954 may be performed simultaneously, and the analyte sensor 100 may emit the first excitation light 329 and the second excitation light 330 to the indicator element 106 simultaneously using the first light source 108 and the second light source 227. In some alternative embodiments, step 954 may be performed before step 952.

[0099]

[0125] In some embodiments, the process 950 may include a step 956 in which the analyte monitoring system 50 calculates a change in the analyte indicator 207. In some embodiments, step 956 may include the transceiver 101 receiving sensor data from the analyte sensor 100. In some embodiments, the sensor data may include one or more of an analyte measurement, a first reference measurement, an interferent measurement, a second reference measurement, and a temperature measurement. In some embodiments, the analyte measurement may correspond to an amount of first emitted light 331 received by the signal light detector 224, the first reference measurement may correspond to an amount of reflected first excitation light 329 received by the reference light detector 226, the interferent measurement may correspond to an amount of second emitted light 332 received by the interferent light detector 228, and the second reference measurement may correspond to an amount of reflected second excitation light 330 received by the signal light detector 224. In some alternative embodiments, one or more of the analyte measurement and the first reference measurement may be received during step 952, and one or more of the interferent measurement and the second reference measurement may be received during step 954.

[0100]

[0126] In some embodiments, step 956 may include the transceiver 101 (e.g., the microcontroller 910 of the transceiver 101) determining, based on at least the received interferent measurements, a degree of degradation of the analyte indicator 207. In some non-limiting embodiments, step 956 may include the transceiver 101 determining (i) a degree of degradation of the interferent indicator 209 based on the received interferent measurements, and (ii) a degree of degradation of the analyte indicator 207 based on the determined degree of degradation of the interferent indicator 209. In some non-limiting embodiments, the transceiver 101 may additionally or alternatively use one or more previous interferent measurements and / or one or more previous determinations of the degree of degradation of the interferent indicator 209 to determine the degree of degradation of the analyte indicator 207.

[0101]

[0127] In some embodiments, the process 950 may include a step 958 in which the analyte monitoring system 50 calibrates the calculated change to the analyte indicator 207 and / or the calculated blood volume in the ISF. In some non-limiting embodiments, the transceiver 101 (e.g., the microcontroller 910 of the transceiver 101) may calibrate the calculated change to the analyte indicator 207 and / or the calculated blood volume in the ISF by adjusting a conversion function used to calculate the analyte level based on the analyte measurement. In some embodiments, adjusting the conversion function may include adjusting one or more parameters of the conversion function. In some embodiments, in step 958, the transceiver 101 may additionally or alternatively adjust the conversion function based on a first reference measurement that may be indicative of in vivo hydration and / or wound healing kinetics of the indicator element 106. In some embodiments, in step 958, the transceiver 101 may additionally or alternatively adjust the conversion function based on a second reference measurement that may be a measurement of the opacity of the indicator element 106 in the wavelength range of the first emitted light 331.

[0102]

[0128] In some embodiments, the process 950 may include a step 960 in which the analyte monitoring system 50 calculates the analyte level (e.g., the analyte concentration). In some embodiments, in step 960, the transceiver 101 (e.g., the microcontroller 910 of the transceiver 101) may calculate the analyte level using at least the adjusted conversion function and the analyte measurement. In some embodiments, the transceiver 101 may additionally calculate the analyte level using a temperature measurement.

[0103]

[0129] In some embodiments, the process 950 may include a step 962 in which the analyte monitoring system 50 displays the calculated analyte level. In some embodiments, in step 962, the transceiver 101 may display the analyte level on the display 924. In some embodiments, in step 962, the transceiver 101 may additionally or alternatively communicate the calculated analyte level to the display device 107, which may additionally or alternatively communicate the calculated analyte level.

[0104]

[0130] Example

[0131] Compound A was copolymerized with an indicator molecule on the hydrogel. The copolymerization method is described in U.S. Patent Nos. 7,060,503 (Colvin) and 9,778,190 (Huffstetler et al.), which are incorporated by reference in their entireties.

[0105]

number

[0106]

[0132] As shown in Figures 14A and 14B, initial characterization and subsequent oxidation studies were helpful in understanding the degradation kinetics of both the reference dye (Compound A) and the indicator. Initial fluorometer work was performed at a 1:1 ratio of indicator (TFM):Compound A, demonstrating the use of Compound A as a copolymerizable reference dye. The plots in Figures 14A and 14B show a decrease in fluorescence intensity of the indicator molecule (excitation wavelength 380 nm) and a simultaneous increase in fluorescence intensity of Compound A (excitation wavelength 470 nm) in 2 mM glucose and 50 μM hydrogen peroxide. TFM has the chemical name 9-[N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene sodium salt.

[0107]

[0133] In vivo testing using simulated sensors with a 1:1 ratio of indicator to Compound A copolymerized in a hydrogel and implanted in 18 female guinea pigs was conducted to evaluate Compound A's performance against in vivo oxidation and its correlation with indicator molecule degradation. Implantation was performed subcutaneously on the back of each guinea pig using the Senseonics Implantation Toolkit according to an implantation training file (two samples per guinea pig). Subjects were divided into three explant groups: 30, 60, and 90 days. Once explanted, the samples were cleaned and disinfected using ENZOL® enzyme detergent and glutaraldehyde solution. The explanted samples were then analyzed using a fluorometer to assess changes in Compound A fluorescence intensity and compare the relationship between the rate of Compound A intensity increase and the rate of indicator modulation loss.

[0108]

[0134] The in vitro test was performed as follows: Prior to the oxidation test, an initial modulation step of 0–18 cycles was performed to collect initial modulation data. A known concentration of hydrogen peroxide was used to intentionally partially oxidize the sensor. After partial oxidation, another modulation step of 0–18 cycles was performed, modulation data was collected, and the loss of modulation was recorded. This procedure was repeated for 3–5 cycles to further partially oxidize the same sensor, collecting modulation data for 0–18 cycles for each oxidation step. A correlation plot of the degradation rates of both the indicator and reference dye is shown in Figure 13.

[0109]

[0135] In explant analysis of the samples, the samples showed a strong correlation between in vitro and in vivo oxidized samples. This correlation is useful for determining the amount of modulation left in the signal channel by analyzing the amount of oxidation of the indicator dye, thereby reducing the number of calibrations that need to be performed.

[0110]

[0136] Further Aspects

[0137] In some embodiments, the intensity or amount of emitted light (e.g., first emitted light 331) emitted by the analyte indicator 207 may change (e.g., increase or decrease) as degradation of the analyte indicator 207 progresses. For example, FIG. 15A shows non-limiting examples of analyte indicator molecules of an analyte indicator 207 before and after degradation caused by reactive oxygen species (ROS). In some embodiments, as shown in FIG. 14A, the intensity or amount of emitted light (e.g., first emitted light 331) emitted by an analyte indicator 207 comprising the analyte indicator molecule shown in FIG. 15A may decrease as degradation of the analyte indicator 207 progresses over time.

[0111]

[0138] In some embodiments, the intensity or amount of emitted light (e.g., second emitted light 332) emitted by the interferent indicator 209 may change (e.g., increase or decrease) as degradation of the interferent indicator 209 progresses. In some embodiments, the degree of degradation of the interferent indicator 209 may correspond to the degree of degradation of the analyte indicator 207. Thus, in some embodiments, the degree of change in the intensity or amount of emitted light emitted by the interferent indicator 209 may correspond to the change in the intensity or amount of emitted light emitted by the analyte indicator 207. For example, FIG. 15B shows non-limiting examples of interferent indicator molecules of an interferent indicator 209 before and after degradation caused by ROS. In some embodiments, as shown in FIG. 14B, the intensity or amount of emitted light (e.g., second emitted light 332) emitted by an interferent indicator 209 including the analyte indicator molecule shown in FIG. 15B may increase as degradation of the interferent indicator 209 progresses over time. However, this is not required, and in some alternative embodiments, the intensity or amount of emitted light (e.g., second emitted light 332) emitted by the interferent indicator 209 may decrease as the interferent indicator 209 deteriorates over time.

[0112]

[0139] In some embodiments, in addition to (or as an alternative to) a change in the intensity or amount of emitted light (e.g., second emitted light 332) emitted by the interferent indicator 209 as degradation of the interferent indicator 209 progresses, the absorbance of the interferent indicator 209 may change (e.g., increase or decrease) as degradation of the interferent indicator 209 progresses. In some embodiments, the degree of degradation of the interferent indicator 209 may correspond to the degree of degradation of the analyte indicator 207. Thus, in some embodiments, the degree of change in absorbance of the interferent indicator 209 (e.g., as measured by the amount of second excitation light 330 reflected from and not absorbed by the indicator element 106) may correspond to a change in the intensity or amount of emitted light emitted by the analyte indicator 207. In some embodiments, the color of the interferent indicator 209 (and thus the color of the indicator element 106 containing the interferent indicator 209) may change as degradation (e.g., oxidation) of the interferent indicator 209 progresses. For example, in some embodiments, the color of the indicator element 106 may change from an unoxidized white, as shown in Figure 16A, to an oxidized yellow, as shown in Figure 16B. However, a change from white to yellow is not required, and in some alternative embodiments, a different color change may occur with degradation (e.g., white to yellow, white to orange, yellow to red, orange to brown, etc.). In some embodiments, a change in the color of the interferent indicator 209 (and thus the color of the indicator element 106 including the interferent indicator 209) may change the absorbance of the interferent indicator 209 (and thus the absorbance of the indicator element 106 including the interferent indicator 209).

[0113]

[0140] In some embodiments, as shown by FIG. 17A, the intensity or amount of emitted light 331 emitted by the analyte indicator 207 may decrease over time (e.g., as degradation, such as oxidation, of the analyte indicator 207 progresses). In some embodiments, as shown by the yellow line in FIG. 17B, the absorbance of the indicator element 106 may increase over time (e.g., as degradation, such as oxidation, of the interferent indicator 209 progresses). In some embodiments, as shown by the blue line in FIG. 17B, the intensity or amount of second excitation light 330 reflected by the indicator element 106 may decrease over time (e.g., as degradation, such as oxidation, of the interferent indicator 209 progresses). In some embodiments, as shown in FIGS. 17A and 17B, the increase in absorbance of the indicator element 106 and the decrease in the intensity or amount of second excitation light 330 reflected by the indicator element 106 may correspond to a decrease in the intensity or amount of emitted light 331 emitted by the analyte indicator 207.

[0114]

[0141] Figure 18 is a graph with experimental data from a clinical trial in which the analyte sensor 100 was subcutaneously implanted in a living human. The glucose signal region of Figure 18 shows an analyte measurement that indicates the amount of first emitted light 331 emitted by the analyte indicator 207 and received by the one or more signal light detectors 224 over time. As shown in Figure 18, the analyte measurement may fluctuate initially (e.g., during the wound healing period after implantation of the analyte sensor 100, when the amount of blood in the interstitial fluid adjacent to the sensor 100 may increase). Thereafter, the analyte measurement may decrease over time due to the progression of effects on the analyte indicator 207 (e.g., degradation of the analyte indicator 207).

[0115]

[0142] The UV reference region of Figure 18 shows a first reference measurement indicative of the amount of first excitation light 329 reflected by the indicator element 106 and received by the one or more first reference photodetectors 226 over time. As shown in Figure 18, the first reference measurement may fluctuate initially (e.g., during a wound healing period after implantation of the analyte sensor 100, when the amount of blood in the interstitial fluid proximate the sensor 100 may increase).

[0116]

[0143] The yellow oxidation indicator (YOI) region of FIG. 18 illustrates an interferent measurement that indicates the amount of second emitted light 332 emitted by the interferent indicator 209 and received by one or more interferent light detectors 228. In the experiment, the interferent measurement was discontinued after 10 days from the start, but was expected to increase over time as the interferent indicator 209 deteriorated. However, the experimental data from the in vitro oxidation test shows an increase in the intensity or amount of light emitted by the interferent indicator 209 over time as the interferent indicator 209 deteriorates. Furthermore, the experimental data from the in vitro oxidation test demonstrates that the increase in the intensity or amount of light emitted by the interferent indicator 209 over time corresponds to a decrease in the intensity or amount of light emitted by the analyte indicator 207 over time as the analyte indicator 207 deteriorates.

[0117]

[0144] The blue reference area in FIG. 18 illustrates a second reference measurement value indicative of the amount of second excitation light 330 reflected by the indicator element 106 and received by one or more photodetectors (e.g., one or more signal photodetectors 224 of FIG. 2A or one or more second reference photodetectors 230 of FIG. 2B) over time. As shown in FIG. 18, the second reference measurement value may fluctuate initially (e.g., during a wound healing period after implantation of the analyte sensor 100, when the amount of blood in the interstitial fluid proximate the sensor 100 may increase). Thereafter, the second reference measurement value may decrease over time as the absorbance of the interferent indicator 209 (and thus the absorbance of the indicator element 106 including the interferent indicator 209) increases (e.g., due to degradation, such as oxidation, of the interferent indicator 209). As shown in FIG. 18, the decrease in the second reference measurement value over time corresponds to a decrease in the analyte measurement value over time. Thus, the experimental data confirms that absorbance measurements of an indicator element 106 containing an interferent indicator 209 can be used to calculate the effect (e.g., degradation) of the indicator element 106 on the analyte indicator 207.

[0118]

[0145] 20 illustrates a non-limiting embodiment of a process 2000 that may be performed by the analyte monitoring system 50. In some embodiments, the process 2000 may detect and calibrate for effects on the analyte indicator 207. In some embodiments, the process 2000 may additionally or alternatively detect and calibrate for blood in a medium (e.g., interstitial fluid) proximate to the analyte indicator 207.

[0119]

[0146] In some embodiments, the process 2000 may include a step 2002 in which the analyte monitoring system 50 performs an analyte measurement. In some embodiments, step 2002 may include the analyte monitoring system 50 (e.g., the analyte sensor 100) using an analyte indicator 207 to generate an analyte measurement indicative of the amount or concentration of the analyte in the medium. In some embodiments, the analyte measurement may change in response to at least an effect on the analyte indicator 207. In some embodiments, the effect on the analyte indicator 207 may be degradation of the analyte indicator 207. In some embodiments, the degradation may include oxidation-induced degradation, such as, for example, degradation by reactive oxygen species (ROS).

[0120]

[0147] In some embodiments, generating the analyte measurement using the analyte indicator 207 in step 2002 may include emitting a first excitation light 329 to the analyte indicator 207 using one or more first light sources 108, and using a signal light detector 224 configured to receive a first emitted light 331 emitted by the analyte indicator 207 and output the analyte measurement. In some embodiments, the analyte measurement may be indicative of the amount of first emitted light 331 received by the signal light detector 224.

[0121]

[0148] In some embodiments, step 2002 may include the analyte monitoring system 50 (e.g., the analyte sensor 100) receiving, using one or more first reference light detectors 226, an amount of the first excitation light 329 and outputting a first reference measurement indicative of the amount of the received first excitation light 329. In some embodiments, the first excitation light 329 received by the first reference light detector 226 may be emitted by one or more first light sources 108 and reflected from a first analyte indicator 207.

[0122]

[0149] In some embodiments, step 2002 may include the transceiver 101 transmitting and the analyte sensor 100 receiving an analyte measurement command. In some embodiments, step 2002 may include the analyte sensor 100, in response to receiving and decoding the analyte measurement command, emitting a first excitation light 329 to the indicator element 106 using the first light source 108. The analyte indicator 207 of the indicator element 106 may receive the first excitation light 329 and emit a first emitted light 331. The signal light detector 224 may receive the first emitted light 331 and generate an analyte measurement signal based on the amount of first emitted light 331 received by the signal light detector 224. In some embodiments, the reference light detector 226 may receive the first excitation light 329 reflected from the indicator element 106 and generate a first reference measurement value.

[0123]

[0150] In some embodiments, process 2000 may include step 2004 in which the analyte monitoring system 50 measures the effect on the analyte indicator 207. In some embodiments, step 2004 may include the analyte monitoring system 50 (e.g., the analyte sensor 100) generating a second reference measurement using the interferent indicator 209. In some embodiments, the second reference measurement may be indicative of the absorbance of the interferent indicator 209. In some embodiments, the absorbance of the interferent indicator 209 may change in response to an effect (e.g., degradation) on the analyte indicator 207. In some embodiments, the second reference measurement generated in step 2004 may be additional to the first reference measurement, which may be generated in step 2002 and may be indicative of the amount of first excitation light 329 received by the one or more first reference light detectors 226. However, the second reference measurement may be generated in step 2004 even in embodiments in which a first reference measurement is not generated in step 2002.

[0124]

[0151] In some embodiments, generating a second reference measurement using the interferent indicator 209 in step 2004 may include emitting second excitation light 330 to the interferent indicator 209 using one or more second light sources 227. In some embodiments, generating a second reference measurement using the interferent indicator 209 may include receiving an amount of second excitation light 330 using one or more light detectors (e.g., one or more signal light detectors 224 shown in FIG. 2A or one or more second reference light detectors 230 shown in FIG. 2B) and outputting a second reference measurement. In some embodiments, the second reference measurement may be indicative of the amount of second excitation light 330 received, which may be indicative of the absorbance of the interferent indicator 209.

[0125]

[0152] In some embodiments, step 2004 (in addition to or as an alternative to generating the second reference measurement) may include the analyte monitoring system 50 (e.g., the analyte sensor 100) generating an interferent measurement using the interferent indicator 209. In some embodiments, generating the interferent measurement may include emitting a second excitation light 330 to the interferent indicator 209 using one or more second light sources 227. In some embodiments, generating the interferent measurement may include receiving a second emitted light 332 emitted by the interferent indicator 209 using an interferent light detector 228 and outputting an interferent measurement indicative of the amount of second emitted light 332 received by the interferent light detector 228. In some embodiments, the second emitted light 332 may change in response to an effect (e.g., degradation) on the analyte indicator 207.

[0126]

[0153] In some embodiments, step 2004 may include the transceiver 101 transmitting and the analyte sensor 100 receiving an interferent measurement command. In some embodiments, step 2004 may include the analyte sensor 100 measuring an effect on the analyte indicator 207 in response to receiving and decoding the interferent measurement command. In some embodiments, measuring the effect on the analyte indicator may include using the second light source 227 to emit a second excitation light 330 to the indicator element 106. The interferent indicator 209 of the indicator element 106 may receive the second excitation light 330 and emit a second emitted light 332. The interferent light detector 228 may receive the second emitted light 332 and generate an interferent measurement signal based on the amount of second emitted light 332 received by the interferent light detector 228. The signal photodetector 224 (and / or the second reference photodetector 230) may receive the second excitation light 330 reflected from the indicator element 106 and generate a second reference signal. In some alternative embodiments, step 2004 may not include the transceiver 101 transmitting and the analyte sensor 100 receiving the interferent measurement command, and the analyte sensor 100 may measure the effect on the analyte indicator 207 in response to receiving and decoding the analyte measurement command (instead of in response to receiving and decoding the interferent measurement command).

[0127]

[0154] In some embodiments, step 2002 may be performed before step 2004. In some alternative embodiments, steps 2002 and 2004 may be performed simultaneously, and the analyte sensor 100 may use the first light source 108 and the second light source 227 to simultaneously emit the first excitation light 329 and the second excitation light 330 to the indicator element 106. In some other alternative embodiments, step 2004 may be performed before step 2002.

[0128]

[0155] In some embodiments, the process 2000 may include step 2006 in which the analyte monitoring system 50 (e.g., the transceiver 101) calculates an effect on the analyte indicator 207 (e.g., the degree of degradation of the analyte indicator 207). In some embodiments, step 2006 may include the analyte sensor 100 transmitting and the transceiver 101 receiving sensor data. In some embodiments, the sensor data may include one or more of the analyte measurement, the first reference measurement, the interferent measurement, the second reference measurement, and the temperature measurement. In some alternative embodiments, step 2002 may include the analyte sensor 100 transmitting and the transceiver 101 receiving sensor data (e.g., the analyte measurement, the first reference measurement, and / or the temperature measurement), and / or step 2004 may include the analyte sensor 100 transmitting and the transceiver 101 receiving sensor data (e.g., the interferent measurement and / or the second reference measurement).

[0129]

[0156] In some embodiments, the analyte monitoring system 50 (e.g., the transceiver 101) may calculate the effect on the analyte indicator 207 in step 2006 based on at least one or more measurements generated in step 2004 (e.g., the second baseline measurement indicative of the absorbance of the interferent indicator 209 and / or the interferent measurement indicative of the emission of the interferent indicator 209). In some embodiments, the system 50 may calculate the effect on the analyte indicator 106 based on a change in the absorbance of the analyte indicator 106 that may be indicated by the second baseline measurement. In some embodiments, the system 50 may calculate the effect on the analyte indicator 207 based on a ratio of the interferent measurement to the second baseline measurement. In some embodiments, step 2006 may additionally or alternatively include the system 50 calculating the effect (e.g., the current effect) on the analyte indicator 207 using one or more previous interferent measurements and / or one or more previous calculations of the effect on the analyte indicator 207.

[0130]

[0157] In some embodiments, the process 2000 may include step 2008 in which the analyte monitoring system 50 (e.g., the transceiver 101) calculates the amount of blood in the medium (e.g., interstitial fluid (ISF)). In some embodiments, the amount of blood in the medium may be calculated in step 2008 based on a second reference measurement that may be indicative of the amount of second excitation light 330 received. In some embodiments, the second reference measurement may be indicative of the absorbance of the interferent indicator 209. In some embodiments, the amount of blood in the medium may additionally or alternatively be calculated based on a first reference measurement that may be indicative of the amount of first excitation light 329 received. In some embodiments, the amount of blood in the medium may be calculated in step 2008 based on at least a ratio of the first reference measurement to the second reference measurement. In some embodiments, the amount of blood in the medium may additionally or alternatively be calculated in step 2008 based on an interferent measurement that may be indicative of the amount of second emitted light 332 received.

[0131]

[0158] 19A is a graph showing the extinction coefficients of oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) at different wavelengths. FIG. 19B is a graph showing the extinction coefficients of oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), methemoglobin (MetHb), and bilirubin at different wavelengths. In some embodiments, in step 2008, the system 50 may calculate the volume of blood in a medium proximate to the analyte sensor 100 using the known extinction coefficients of one or more of oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), methemoglobin (MetHb), and bilirubin at one or more wavelengths of the first excitation light 329 (e.g., 380 nm) and the second excitation light 330 (e.g., 470 nm) along with one or more of the first and second reference measurements.

[0132]

[0159] In some embodiments, process 2000 may include step 2010, in which the analyte monitoring system 50 (e.g., transceiver 101) calibrates the effect on the analyte indicator 207 and / or the blood in the medium (e.g., ISF). In some embodiments, step 2010 may include the analyte monitoring system 50 (e.g., transceiver 101) adjusting a conversion function. In some embodiments, the conversion function may be used to calculate the analyte level based on the analyte measurement. In some embodiments, the conversion function may be adjusted in step 2010 based on the calculated effect on the analyte indicator 207 (e.g., calculated in step 2006). In some embodiments, the conversion function may additionally or alternatively be adjusted in step 2010 based on the calculated blood in the medium (e.g., calculated in step 2008). In some embodiments, adjusting the conversion function may include adjusting one or more parameters of the conversion function.

[0133]

[0160] In some embodiments, the process 2000 may include step 2012 in which the analyte monitoring system 50 (e.g., the transceiver 101) calculates the analyte level (e.g., the analyte concentration). In some embodiments, step 2012 may include the analyte monitoring system 50 (e.g., the transceiver 101) using the adjusted conversion function and the analyte measurement. In some embodiments, the system 50 may additionally calculate the analyte level using a temperature measurement.

[0134]

[0161] In some embodiments, the process 2000 may include a step 2014 in which the analyte monitoring system 50 displays the calculated analyte level. In some embodiments, to display the calculated analyte level in step 2014, the system 50 may display the analyte level on the display 924. In some embodiments, to display the calculated analyte level in step 2014, the system 50 may additionally or alternatively communicate the calculated analyte level to the display device 107, which may additionally or alternatively communicate the calculated analyte level.

[0135]

[0162] In some embodiments, the analyte sensor 100 of the analyte monitoring system 50 may be a fully implantable sensor and may utilize a fluorescent boronic acid glucose-binding moiety as the analyte indicator 207 for measuring glucose. In some embodiments, the binding affinity of this analyte indicator 207 may be specific for glucose, but may also be sensitive to oxidative deboronation via local reactive oxygen species (ROS) (e.g., hydrogen peroxide (HO)) present in the interstitial space. In some embodiments, the analyte sensor 100 may rely on calibration updates to assess the rate of oxidation by local in vivo concentrations of ROS. In some embodiments, utilizing an indicator element 106 including an interferent indicator 209 to measure ROS concentrations may allow for reduced calibration frequency.

[0136]

[0163] 22A and 22B, the analyte sensor 100 may include multiple sensing regions 2202 (e.g., sensing regions 2202a, 2202b, 2202c, and 2202d). In some embodiments, each sensing region 2202 may include measurement electronics (e.g., optical measurement electronics). In some embodiments, the optical measurement electronics in the multiple sensing regions 2202 of the analyte sensor 100 may be referred to as redundant optical measurement electronics (ROME). In some embodiments, the measurement electronics in each of the sensing regions 2202 may include one or more light sources (e.g., light sources 108 and 227) and / or one or more photodetectors (e.g., photodetectors 224, 226, 228, and / or 230). In some embodiments, the analyte sensor 100 may comprise a first and second substrate 112, and sensing areas 2202a and 2202c may be on the first substrate 112, and sensing areas 2202b and 2202d may be on the second substrate 112. In some embodiments, sensing areas 2202a and 2202c may be the long edge distal (LED) and long edge center (LEC) sensing areas, respectively, of the analyte sensor 100, and sensing areas 2202b and 2202d may be the short edge center (SEC) and short edge distal (SED) sensing areas, respectively, of the analyte sensor.

[0137]

[0164] In some embodiments, as shown in FIGS. 22A and 22B, the analyte sensor 100 may include one or more indicator elements 106 (e.g., indicator elements 106a and 106b), which may be, for example, one or more hydrogels on the sensor housing 102. In some embodiments, as shown in FIGS. 2A and 2B, the one or more indicator elements 106 may each include an analyte indicator 207 and an interferent indicator 209. In some embodiments, the analyte sensor 100 may measure the presence, amount, and / or concentration of an analyte (e.g., glucose, oxygen, cardiac marker, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides) using the analyte indicator 207. In some embodiments, the analyte sensor 100 may measure ROS-induced signal degradation using the interferent indicator 209. In some embodiments, the analyte indicator 207 and the interferent indicator 209 in one or more indicator elements 106 may be copolymerized into a single biocompatible hydrogel. In some embodiments, the analyte indicator 207 and the interferent indicator 209 may have negligible spectral overlap and may undergo similar degradation in vivo (e.g., similar degradation of boronic acids).

[0138]

[0165] In some embodiments, the analyte indicator 207 of one or more indicator elements 106 may be, for example, a TFM. In some embodiments, the analyte indicator 207 may have the chemical structure shown in FIG. 21A. In some embodiments, as shown in FIG. 21A, an analyte (e.g., glucose) may reversibly bind to the analyte indicator 202, and the analyte indicator 207 with the bound analyte may emit a first emitted light 331 (e.g., fluorescent light) when illuminated by a first excitation light 329, while the analyte indicator 207 with no bound analyte may emit no light (or emit only a small amount of light) when illuminated by the first excitation light 329. In some embodiments, as shown in FIG. 21B, oxidation of the interferent indicator 209 causes the interferent indicator 209 to emit a second emitted light 332 (e.g., when illuminated by a second excitation light 330). In some embodiments, oxidation of the interferent indicator 209 may additionally or alternatively change the absorbance of the interferent indicator 209 (e.g., the absorbance of the second excitation light 330 by the interferent indicator 209). In some embodiments, as shown in Figures 22A and 22B, one or more sensing regions 2202 (e.g., sensing regions 2202a and 2202c) may interact with the first indicator element 106a (e.g., emitting first excitation light 329 and second excitation light 330 and measuring first emitted light 331 and second emitted light 332 emitted by the first indicator element 106a), and one or more different sensing regions 2202 (e.g., sensing regions 2202b and 2202d) may interact with the second indicator element 106b.

[0139]

[0166] In some embodiments, the interferent indicators 209 in one or more indicator elements 106 may allow the analyte sensor 100 to be configured to measure in vivo signal degradation and signal changes due to ROS, which may reduce the frequency at which calibrations based on reference analyte measurements (e.g., finger blood glucose measurements) need to be performed.

[0140]

[0167] In some embodiments, the analyte sensor 100 may sense an analyte (e.g., glucose) in each of the multiple sensing regions 2202 (e.g., each of sensing regions 2202a-2202d). In some embodiments, the multiple sensing regions 2202 may be redundant sensing regions. In some embodiments, in each of the sensing regions 2202, the analyte indicator 207 may be excited by a first excitation light 329 emitted by the light source 108 (e.g., a UV LED), and the interferent indicator 209 may be excited by a second excitation light 330 emitted by the light source 227 (e.g., a blue LED). In some embodiments, the first excitation light 329 and the first emitted light 331 emitted by the analyte indicator 207 may be measured by one or more first reference photodetectors 226 (e.g., one or more UV filter-coated photodiodes) and one or more signal photodetectors 224 (e.g., one or more blue filter-coated photodiodes), respectively. In some embodiments, the second excitation light 330 may be measured by one or more signal photodetectors 224 (see FIG. 2A) or one or more second reference photodetectors 230 (see FIG. 2B), which may be, for example, one or more blue filter-coated photodiodes. In some embodiments, the second emitted light 332 emitted by the interferent indicator 209 may be measured by one or more interferent photodetectors 228 (e.g., one or more yellow filter-coated photodiodes).

[0141]

[0168] In some embodiments, as shown in FIGS. 22A and 22B , the analyte sensor 100 may include one or more drug-eluting polymer matrices 2204 on all or a portion of the exterior surface of the sensor housing 102. In some embodiments, one or more therapeutic agents may be dispersed within the one or more drug-eluting polymer matrices 2204. In some embodiments, the one or more therapeutic agents may inhibit or stop neutrophil ingress into the space in which the analyte sensor 100 is implanted, and thus inhibit or stop hydrogen peroxide generation and fibrous encapsulation. Accordingly, in some embodiments, the one or more therapeutic agents may reduce degradation of the one or more indicator elements 106 (e.g., indicator elements 106a and 106b). In some embodiments, the one or more therapeutic agents that may be dispersed within the drug-eluting polymer matrix 2204 may include, for example, one or more anti-inflammatory agents, such as nonsteroidal anti-inflammatory agents (e.g., acetylsalicylic acid (aspirin) and / or isobutylphenylpropanoic acid (ibuprofen)). In some embodiments, the one or more therapeutic agents dispersed within the drug-eluting polymer matrix may include one or more glucocorticoids. In some non-limiting embodiments, the one or more therapeutic agents may include one or more of dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclomethasone, fludrocortisone, their derivatives, and their analogs. In some embodiments, the one or more therapeutic agents may inhibit hydrogen peroxide production by neutrophils and macrophages.

[0142]

[0169] In vitro oxidation experiments were performed to examine the response of the analyte indicator 207 and the interferent indicator 209 to oxidation. As shown in FIG. 23, as oxidation progresses, the first emitted light 331 emitted by the analyte indicator 207 decreases, while the second emitted light 332 emitted by the interferent indicator 209 increases, with similar degradation kinetics. FIGS. 24A-24D show optical and fluorescent images of the analyte sensor 100 after localized oxidation. FIGS. 24A and 24B show brightfield images of the underlying sensor optics and the analyte sensor 100, respectively. FIG. 24C shows fluorescent imaging of the analyte indicator 207 with a local decrease in fluorescence due to localized oxidation near the bottom of the analyte indicator 207, and FIG. 24D shows fluorescent imaging of the interferent indicator 209 with a corresponding local increase in fluorescence due to localized oxidation near the bottom of the interferent indicator 209. Thus, the fluorescence imaging shown in Figures 24C and 24D shows that the decrease in first emitted light 331 emitted by the analyte indicator 207 due to local oxidation is spatially correlated with the increase in second emitted light 332 emitted by the interferent indicator 209.

[0143]

[0170] In a non-limiting example, a clinical feasibility evaluation was conducted in 10 adult patients with type 1 diabetes for up to 365 days after informed consent. Accuracy was evaluated against finger blood glucose monitoring during home use. Measurement results demonstrated the benefit of evaluating local oxidation to determine transient deboronation of the analyte indicator chemical. Figures 25A-25D show in vivo measurements from sensing areas 2202a, 2202c, 2202b, and 2202d, respectively, of the analyte sensor 100 shown in Figures 22A and 22B. In some embodiments, sensing areas 2202a and 2202c may be the long edge distal (LED) and long edge central (LEC) sensing areas, respectively, of the analyte sensor 100, and sensing areas 2202b and 2202d may be the short edge central (SEC) and short edge distal (SED) sensing areas, respectively, of the analyte sensor. As shown in FIGS. 25A-25D, the measurements may include measurements of first excitation light 329 and second excitation light 330, and first emitted light 331 and second emitted light 332.

[0144]

[0171] In some embodiments, the analyte sensor 100 shown in Figures 22A and 22B may combine an interferent indicator 209 used to measure oxidation with redundant sensing regions 2202a-2202d to obtain analyte values ​​using weighted averaging. In some embodiments, the analyte monitoring system 50 (e.g., the transceiver 101 of the analyte monitoring system 50) may incorporate the oxidation and analyte measurements into an analyte computational model that allows for reduced calibration frequency (e.g., calibration once a week after day 14). In some embodiments, the analyte monitoring system 50 may selectively utilize information (e.g., measurements) from sensing regions 2202 from a multi-analyte (e.g., glucose and oxidation) multi-site array to calculate glucose values. 22A and 22B (e.g., based on measurements of one or more of the first excitation light 329 and second excitation light 330, and the first emitted light 331 and second emitted light 332 from sensor region 2202), and FIG. 26B shows a composite glucose concentration calculated based on a weighted average of the individual glucose concentrations. In some embodiments, sensing regions 2202a and 2202c may be the long edge distal (LED) and long edge center (LEC) sensing regions, respectively, of the analyte sensor 100, and sensing regions 2202b and 2202d may be the short edge center (SEC) and short edge distal (SED) sensing regions, respectively, of the analyte sensor.

[0145]

[0172] In a non-limiting example, as shown in the table below, in a feasibility study of 10 subjects, the analyte monitoring system 50 having the analyte sensor 100 shown in Figures 22A and 22B had an overall mean relative difference (MARD) of 9.2% at 90 days and 9.3% at 180 days when calibrated once a week using finger blood glucose measurements as the reference.

[0146] [Table 1]

[0147]

[0173] 22A and 22B, the multiple sensing channels of the analyte sensor 100 allow for accurate measurement of glucose and also allow for assessment of oxidation of the indicator element 106. By detecting these multiple analytes (e.g., glucose and oxidation), calibration can be significantly reduced (e.g., to once every week or more) while maintaining accuracy for up to 365 days.

[0148]

[0174] In some embodiments, as described above, the analyte sensor 100 shown in Figures 22A and 22B may be a next-generation, long-term implantable sensor with redundant optical measurement electronics (ROME) and the ability to measure sensor degradation caused by foreign body reactions (FBR). In some embodiments, measuring sensor degradation caused by FBR may enable a reduced calibration algorithm (e.g., one calibration every seven days or two calibrations every 14 days instead of two calibrations per day). In a non-limiting example, a feasibility study was conducted to demonstrate the performance of an analyte monitoring system 50 including the analyte sensor 100 shown in Figures 22A and 22B for up to 365 days with a 7-day and 14-day calibration reduction scheme.

[0149]

[0175] In a non-limiting example, a feasibility study was conducted on 14 subjects fitted with a ROME sensor (e.g., the analyte sensor 100 shown in FIGS. 22A and 22B). Ten users were evaluated through 365 days and four users through 300 days after sensor implantation. A CGM model incorporating changes related to the sensor's FBR and redundant sensor functionality was utilized to calculate glucose relative to self-monitoring of blood glucose (SMBG) measurements. After an initial two-week period of twice-daily calibration, data were post-processed separately with two calibration schemes: one with one calibration every seven days and the other with two calibrations every 14 days (half a month). Accuracy was assessed relative to SMBG measurements.

[0150]

[0176] Feasibility studies showed that over 365 days, once-daily calibration yielded 9.2% MARD and 98.9% 40 / 40% agreement, while the calibration algorithm on day 7 yielded 10.4% MARD vs. SMBG with a 98.5% 40 / 40% agreement, and the calibration algorithm on day 14 yielded 10.3% MARD vs. SMBG with a 98.8% 40 / 40% agreement. A 1.4% increase in MARD and SMBG compared to venous blood measurements (e.g., YSI) has previously been demonstrated. The results of the feasibility studies are shown in Figures 27A and 27B. Figure 27A shows MARD vs. SMBG over 365 days for daily, weekly, and semi-monthly calibration schemes. Figure 27B shows the 15 / 15% agreement for daily, weekly, and semi-monthly calibration schemes. Feasibility study results showed that improvements in sensor chemistry and electronics could significantly reduce calibration frequency while maintaining clinical accuracy over one year of use as measured against SMBG.

[0151]

[0177] In some embodiments, as shown in FIGS. 22A and 22B , the analyte sensor 100 may include multiple sensing areas 2202 (e.g., sensing areas 2202a, 2202b, 2202c, and 2202d). In some embodiments, each sensing area 2202 may include measurement electronics (e.g., optical measurement electronics). In some embodiments, the optical measurement electronics in the multiple sensing areas 2202 of the analyte sensor 100 may be referred to as redundant optical measurement electronics (ROME). In some embodiments, the analyte sensor 100 may be a long-term implantable glucose sensor with redundant optical measurement electronics (ROME). In some embodiments, the analyte sensor 100 may bridge the benefits of both long life and significantly reduced calibration (cal) with the ability to measure sensor degradation caused by foreign body reaction (FBR) (e.g., using interferent indicators 209). In some embodiments, the analyte sensor 100 may comprise sensing regions 2202a, 2202b, 2202c, and 2202d, and each of the multiple sensing regions 2202 may comprise an individual channel that is sensitive to either glucose or degradation (e.g., a glucose measurement channel based on an analyte measurement signal output by the signal photodetector 224 indicative of the amount of first emitted light 331 emitted by the analyte indicator 207 upon excitation by a first excitation light 329 emitted by the first light source 108, and a degradation measurement channel based on an interferent measurement signal output by the interferent photodetector 228 indicative of the amount of second emitted light 332 emitted by the interferent indicator 209 upon excitation by a second excitation light 330 emitted by the second light source 227, and / or a second reference signal output by the signal photodetector 224 or the second reference photodetector 230 indicative of the amount of second excitation light 330 emitted by the second light source 227 and reflected by the indicator element 106).

[0152]

[0178] In a non-limiting example, a feasibility study was conducted to demonstrate the performance of an analyte monitoring system 50 including the analyte sensor 100 shown in FIGS. 22A and 22B for up to 365 days using reduced calibration schemes (a 7-day or weekly calibration scheme and a 14-day or semi-monthly calibration scheme). In the feasibility study, 14 subjects were implanted with the analyte sensor 100 shown in FIGS. 22A and 22B for 365 days. In some embodiments, the analyte monitoring system 50 may use a glucose monitoring model that incorporates changes associated with sensor foreign body response and may utilize redundant sensor capabilities to calculate glucose based on self-monitoring of blood glucose (SMBG) measurements. In some embodiments, the analyte monitoring system 50 may directly measure degradation of the analyte indicator 207 and model the degradation in a glucose algorithm from each of the sensing regions 2202a, 2202b, 2202c, and 2202d, and the results of the feasibility study indicate that this enables reduced calibration.

[0153]

[0179] In some embodiments, the analyte monitoring system 50 may use region-specific health metrics that assess noise, FBR degradation, and / or reference channel stability. In some embodiments, the analyte monitoring system 50 may combine health metrics to determine the quality of each of the sensing regions 2202a, 2202b, 2202c, and 2202d when calculating overall glucose, and selectively de-weight poorly performing regions (such as region 4 / sensing region 2202d in FIGS. 28A and 28B ), with feasibility testing showing this allows for further accuracy improvements and longer lifespan. FIGS. 28A and 28B show the normalized signal and individual weights, respectively, for regions 1-4 (i.e., sensing regions 2202a, 2202b, 2202c, and 2202d) of the analyte sensor 100 over 365 days with calibration once every seven days, resulting in a MARD of 6.9 and a 40 / 40 of 99.8. In a feasibility study, after an initial 2-week period of twice-daily calibration, data were post-processed separately with two calibration reduction schemes: (1) one calibration every 7 days and (2) two calibrations every 14 days (bimonthly) for the CGM-SMBG MARD. Agreement between the calibration schemes was assessed, as shown in the table below.

[0154] [Table 2]

[0155]

[0180] In a feasibility study, over a 365-day period, a 7-day calibration algorithm resulted in a CGM-SMBG MARD of 10.2% with a 40 / 40% agreement of 98.8%, while a 14-day calibration algorithm resulted in a MARD of 10.1% with a 40 / 40% agreement of 98.8%. SMBG-based MARD has previously been demonstrated to be up to approximately 1.4% higher than YSI-based MARD. Thus, the feasibility study results demonstrate that the sensor chemistry (e.g., interferent indicator 209) and electronic configuration (e.g., redundant sensing areas 2202a, 2202b, 2202c, and 2202d) of the analyte sensor 100 of the analyte monitoring system 50 allows for a significant reduction in calibration frequency while maintaining clinical accuracy over a one-year period of use measured against SMBG.

[0156]

[0181] 29 shows a non-limiting embodiment of a glucose monitoring process 2900 that may be performed by some embodiments of the analyte monitoring system 50 where the analyte monitoring system 50 is a glucose monitoring system and the analyte sensor 100 is a glucose sensor. In some embodiments, the process 2900 may detect and calibrate the effect on the analyte indicator 207. In some embodiments, the process 2900 may be performed for each of a plurality of time points over a 365-day period. In some embodiments, the plurality of time points over the 365-day period may be periodic. In some embodiments, the periodic plurality of time points may be, for example, without limitation, every 1 minute, every 2 minutes, every 3 minutes, every 5 minutes, every 10 minutes, or every 15 minutes.

[0157]

[0182] 29, glucose monitoring process 2900 may include step 2902 of generating a first sensing area glucose measurement and a first sensing area degradation measurement using first measuring electronics in a first sensing area (e.g., sensing area 2202a) of glucose sensor 100. In some embodiments, the first measuring electronics may use a first analyte indicator 207 of a first indicator element (e.g., a first portion of indicator element 106a) of glucose sensor 100 to generate the first sensing area glucose measurement and a first interferent indicator 209 of the first indicator element of glucose sensor 100 to generate the first sensing area degradation measurement. In some embodiments, the first sensing area glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate to the first indicator element. In some embodiments, the first sensing area glucose measurement may change in response to degradation of at least the first interferent indicator 209, which may correspond to degradation of the first analyte indicator 207. In some embodiments, the first sensing region degradation measurement may indicate degradation of the first interferent indicator 209 .

[0158]

[0183] 29, glucose monitoring process 2900 may include step 2904 of generating a second sensing area glucose measurement and a second sensing area degradation measurement using second measurement electronics in a second sensing area (e.g., sensing area 2202b) of the glucose sensor. In some embodiments, the second measurement electronics may use a second analyte indicator 207 of a second indicator element (e.g., a first portion of indicator element 106b) of glucose sensor 100 to generate the second sensing area glucose measurement and a second interferent indicator 209 of the second indicator element of glucose sensor 100 to generate the second sensing area degradation measurement. In some embodiments, the second sensing area glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate to the second indicator element. In some embodiments, the second sensing area glucose measurement may change in response to degradation of at least the second interferent indicator 209, which may correspond to degradation of the second analyte indicator 207. In some embodiments, the second sensing region degradation measurement may indicate degradation of the second interferent indicator 209 .

[0159]

[0184] 29, glucose monitoring process 2900 may include optional step 2906 of using third measurement electronics in a third sensing area (e.g., sensing area 2202c) of glucose sensor 100 to generate a third sensing area glucose measurement and a third sensing area degradation measurement. In some embodiments, the third measurement electronics may use a third analyte indicator 207 of a third indicator element (e.g., a second portion of indicator element 106a) of glucose sensor 100 to generate the third sensing area glucose measurement and a third interferent indicator 209 of the third indicator element of glucose sensor 100 to generate the third sensing area degradation measurement. In some embodiments, the third sensing area glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate the third indicator element. In some embodiments, the third sensing area glucose measurement may change in response to degradation of at least the third interferent indicator 209, which may correspond to degradation of the third analyte indicator 207. In some embodiments, the third sensing region degradation measurement may indicate degradation of the third interferent indicator 209.

[0160]

[0185] 29, glucose monitoring process 2900 may include optional step 2908 of generating a fourth sensing area glucose measurement and a fourth sensing area degradation measurement using fourth measurement electronics in a fourth sensing area (e.g., sensing area 2202d) of glucose sensor 100. In some embodiments, the fourth measurement electronics may use a fourth analyte indicator 207 of a fourth indicator element (e.g., a second portion of indicator element 106b) of glucose sensor 100 to generate the fourth sensing area glucose measurement and a fourth interferent indicator 209 of the fourth indicator element of glucose sensor 100 to generate the fourth sensing area degradation measurement. In some embodiments, the fourth sensing area glucose measurement may indicate the amount or concentration of glucose in interstitial fluid proximate the fourth indicator element. In some embodiments, the fourth sensing area glucose measurement may change in response to degradation of at least the fourth interferent indicator 209, which may correspond to degradation of the fourth analyte indicator 207. In some embodiments, the fourth sensing region degradation measurement may indicate degradation of the fourth interferent indicator 209.

[0161]

[0186] In some embodiments involving a first indicator element and a second indicator element, the first indicator element and the third indicator element may be different portions of one indicator element (e.g., indicator element 106). In some alternative embodiments involving a first indicator element and a second indicator element, the first indicator element and the third indicator element may be separate and distinct indicator elements (e.g., indicator elements 106a and 106b). In some embodiments involving a first indicator element, a second indicator element, a third indicator element, and a fourth indicator element, the first indicator element and the third indicator element may be different portions of one indicator element (e.g., indicator element 106a), and the second indicator element and the fourth indicator element may be different portions of another indicator element (e.g., indicator element 106b), as shown in Figures 22A and 22B. In some alternative embodiments including a first indicator element, a second indicator element, a third indicator element, and a fourth indicator element, the first indicator element, the second indicator element, the third indicator element, and the fourth indicator element may be separate and distinct indicator elements 106. In some further alternative embodiments including a first indicator element, a second indicator element, a third indicator element, and a fourth indicator element, the first indicator element, the second indicator element, the third indicator element, and the fourth indicator element may be different portions of one indicator element (e.g., indicator element 106).

[0162]

[0187] In some embodiments, as shown in Figures 22A and 22B, the first measurement electronic circuit and the third measurement electronic circuit may be fabricated and / or implemented on a first substrate 112 of the glucose sensor 100, and the second measurement electronic circuit and the fourth measurement electronic circuit may be fabricated and / or implemented on a second substrate 112 of the glucose sensor 100.

[0163]

[0188] 2A-4, 22A, and 22B, each of the measurement electronic circuits (e.g., the first measurement electronic circuit, the second measurement electronic circuit, the third measurement electronic circuit, and / or the fourth measurement electronic circuit) comprises a first light source 108 configured to emit a first excitation light 329 and a signal light detector 224 configured to receive the first emitted light 331 and output a sensing-zone glucose measurement, which may indicate the amount of first emitted light 331 received by the signal light detector. In some embodiments, each of the measurement electronic circuits may further comprise a second light source 227 configured to emit a second excitation light 330, as shown in FIGS. 2A-4, 22A, and 22B. 2A-4, 22A, and 22B, the measurement electronics may each further include an interferent photodetector 228 configured to receive second emitted light 332 and output a sensing-zone degradation measurement, where the sensing-zone glucose measurement may be indicative of the amount of second emitted light 332 received by the signal photodetector 228. In some embodiments, as shown in FIG. 2A, the signal photodetector 224 may further be configured to receive an amount of second excitation light 330 and output a sensing-zone degradation measurement, where the sensing-zone degradation measurement may be indicative of the amount of second excitation light 330 received. In some alternative embodiments, as shown in FIG. 2B, the measurement electronics may each further include a reference photodetector 230 configured to receive an amount of second excitation light 330 and output a sensing-zone degradation measurement, where the sensing-zone degradation measurement may be indicative of the amount of second excitation light 330 received.

[0164]

[0189] 29, glucose monitoring process 2900 may include step 2910 of calculating a first sensing area glucose concentration using at least the first sensing area glucose measurement. In some embodiments, calculating the first sensing area glucose concentration in step 2910 may include adjusting a first conversion function using at least the first sensing area degradation measurement, and calculating the first sensing area glucose concentration using at least the adjusted first conversion function and the first sensing area glucose measurement.

[0165]

[0190] 29, glucose monitoring process 2900 may include step 2912 of calculating a second sensing area glucose concentration using at least a second sensing area glucose measurement. In some embodiments, calculating the second sensing area glucose concentration in step 2912 may include adjusting a second conversion function using at least the second sensing area degradation measurement, and calculating the second sensing area glucose concentration using at least the adjusted second conversion function and the second sensing area glucose measurement.

[0166]

[0191] 29, glucose monitoring process 2900 may include an optional step 2914 of calculating a third sensing area glucose concentration using at least a third sensing area glucose measurement. In some embodiments, calculating the third sensing area glucose concentration in step 2914 may include adjusting a third conversion function using at least the third sensing area degradation measurement, and calculating the third sensing area glucose concentration using at least the adjusted third conversion function and the third sensing area glucose measurement.

[0167]

[0192] 29, glucose monitoring process 2900 may include an optional step 2916 of calculating a fourth sensing area glucose concentration using at least a fourth sensing area glucose measurement. In some embodiments, calculating the fourth sensing area glucose concentration in step 2916 may include adjusting a fourth conversion function using at least the fourth sensing area degradation measurement, and calculating the fourth sensing area glucose concentration using at least the adjusted fourth conversion function and the fourth sensing area glucose measurement.

[0168]

[0193] 29, glucose monitoring process 2900 may include step 2918 of calculating a first weight for a first sensing zone glucose concentration using at least a first sensing zone degradation measurement. In some embodiments, glucose monitoring process 2900 may include step 2920 of calculating a second weight for a second sensing zone glucose concentration using at least a second sensing zone degradation measurement. In some embodiments, glucose monitoring process 2900 may include optional step 2922 of calculating a third weight for a third sensing zone glucose concentration using at least a third sensing zone degradation measurement. In some embodiments, glucose monitoring process 2900 may include optional step 2924 of calculating a fourth weight for a fourth sensing zone glucose concentration using at least a fourth sensing zone degradation measurement.

[0169]

[0194] 29, glucose monitoring process 2900 may include step 2926 of calculating a composite glucose concentration as a weighted average of at least the first sensing area glucose concentration and the second sensing area glucose concentration using at least a first weight and a second weight. In some embodiments, the composite glucose concentration may be calculated as a weighted average of at least the first sensing area glucose concentration, the second sensing area glucose concentration, the third sensing area glucose concentration, and the fourth sensing area glucose concentration using a first weight, a second weight, a third weight, and a fourth weight.

[0170]

[0195] In some embodiments, as shown in FIG. 29, the glucose monitoring process 2900 may include a step 2928 of displaying the calculated composite glucose concentration.

[0171]

[0196] 29, the glucose monitoring process 2900 may include an optional step 2930 of calibrating the calculation of the sensing-zone glucose concentration with a relatively high frequency of SMBG values ​​during an initial period of 365 days. In some embodiments, the initial period may be 14 days. In some alternative embodiments, the initial period may be 7 days. In some embodiments, the relatively high frequency may be one SMBG value per day during the initial period. In some alternative embodiments, the relatively high frequency may be one SMBG value every 12 hours during the initial period.

[0172]

[0197] 29, the glucose monitoring process 2900 may include a step 2932 of calibrating the sensing-zone glucose concentration calculation relatively infrequently for the remainder of the 365-day period. In some embodiments, the relatively infrequent may use (a) one SMBG value every seven days for the 365-day period, or (b) two SMBG values ​​every 14 days for the 365-day period.

[0173]

[0198] In some embodiments, the composite glucose concentrations for multiple time points over 365 days may have (a) an overall mean relative difference (MARD) vs. self-monitoring of blood glucose (SMBG) value of 10.4% or less and a 40 / 40% agreement rate of 98.5% or greater when the sensing zone glucose concentration calculation is calibrated using one SMBG value every 7 days for 365 days, or (b) an overall MARD vs. SMBG value of 10.3% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensing zone glucose concentration calculation is calibrated using two SMBG values ​​every 14 days for 365 days. In some embodiments, the composite glucose concentrations for multiple time points over 365 days may have (a) an overall MARD vs. SMBG value of 10.2% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensing zone glucose concentration calculation is calibrated using one SMBG value every 7 days for 365 days, or (b) an overall MARD vs. SMBG value of 10.1% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensing zone glucose concentration calculation is calibrated using two SMBG values ​​every 14 days for 365 days.

[0174]

[0199] In some embodiments, steps 2902-2928 of process 2900 may be performed for each of a plurality of time points over a 365-day period, although steps 2902-2928 need not necessarily be completed at any one of the plurality of time points before moving on to the next of the plurality of time points. For example, in some embodiments, steps 2902-2908 may be performed at some (or all) of the plurality of time points before steps 2910-2928 are performed at some (or all) of the plurality of time points.

[0175]

[0200] In some embodiments, steps 2902-2908 of process 2900 may be performed by glucose sensor 100. In some embodiments, one or more of steps 2910-2932 of process 2900 may be performed by transceiver 101 (e.g., by controller 920 and / or display 924 of transceiver 101), and / or one or more of steps 2910-2932 of process 2900 may be performed by display device 105 (e.g., by controller and / or display of display device 105). For example, in some embodiments, steps 2910-2926, step 2930, and step 2932 may be performed by transceiver 101, and step 2928 may be performed by display device 105. As another example, in some embodiments, steps 2910-2932 may be performed by display device 105.

[0176]

[0201] All aspects of the present invention have been described above with reference to the drawings. While the present invention has been described based on these preferred aspects, it will be apparent to those skilled in the art that certain modifications, variations, and alternative configurations of the described aspects are possible within the spirit and scope of the invention. For example, in some aspects of the present invention, the analyte indicator 207 and the interferent indicator 209 are distributed in the same indicator element 106, although this is not required. In some alternative aspects, the analyte sensor 100 may include a first indicator element including the analyte indicator 207 and a second indicator element including the interferent indicator 209. In these alternative aspects, the analyte indicator 207 and the interferent indicator 209 may be spatially separated from one another.

Claims

1. 1. A method of glucose monitoring, comprising: For each of multiple time points over a 365 day period: generating a first sensing area glucose measurement and a first sensing area degradation measurement using first measurement electronics in a first sensing area of ​​a glucose sensor, the first measurement electronics using a first analyte indicator of a first indicator element of the glucose sensor to generate the first sensing area glucose measurement and a first interferent indicator of the first indicator element of the glucose sensor to generate the first sensing area degradation measurement, the first sensing area glucose measurement indicating an amount or concentration of glucose in interstitial fluid proximate to the first indicator element, the first sensing area glucose measurement changing in response to degradation of at least the first interferent indicator corresponding to degradation of the first analyte indicator, and the first sensing area degradation measurement indicating degradation of the first interferent indicator; generating a second sensing area glucose measurement and a second sensing area degradation measurement using second measurement electronics in a second sensing area of ​​the glucose sensor, the second measurement electronics using a second analyte indicator of a second indicator element of the glucose sensor to generate the second sensing area glucose measurement and a second interferent indicator of the second indicator element of the glucose sensor to generate the second sensing area degradation measurement, the second sensing area glucose measurement indicating an amount or concentration of glucose in interstitial fluid proximate the second indicator element, the second sensing area glucose measurement changing in response to degradation of at least the second interferent indicator, which corresponds to degradation of the second analyte indicator, and the second sensing area degradation measurement indicating degradation of the second interferent indicator; calculating a first sensing zone glucose concentration using at least the first sensing zone glucose measurements; calculating a second sensing zone glucose concentration using at least the second sensing zone glucose measurements; calculating a first weight for the first sensing area glucose concentration using at least the first sensing area degradation measurement; calculating a second weight for the second sensing area glucose concentration using at least the second sensing area degradation measurement; calculating a composite glucose concentration as a weighted average of at least the first sensing area glucose concentration and the second sensing area glucose concentration using at least the first weight and the second weight; displaying the calculated composite glucose concentration; Including, The method of claim 1, wherein the composite glucose concentrations for the multiple time points over the 365 day period have (a) an overall mean relative difference (MARD) vs. self-monitoring of blood glucose (SMBG) value of 10.4% or less and a 40 / 40% agreement rate of 98.5% or greater when the sensory zone glucose concentration calculation is calibrated using one SMBG value every seven days during the 365 day period, or (b) an overall MARD vs. SMBG value of 10.3% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensory zone glucose concentration calculation is calibrated using two SMBG values ​​every fourteen days during the 365 day period.

2. calculating the first sensing area glucose concentration includes adjusting a first conversion function using at least the first sensing area degradation measurement, and calculating the first sensing area glucose concentration using at least the adjusted first conversion function and the first sensing area glucose measurement; 2. The method of claim 1, wherein calculating the second sensing area glucose concentration comprises: adjusting a second conversion function using at least the second sensing area degradation measurement; and calculating the second sensing area glucose concentration using at least the adjusted second conversion function and the second sensing area glucose measurement.

3. For each of the multiple time points over the 365 day period: generating a third sensing area glucose measurement and a third sensing area degradation measurement using third measurement electronics in a third sensing area of ​​the glucose sensor, the third measurement electronics using a third analyte indicator of a third indicator element of the glucose sensor to generate the third sensing area glucose measurement and a third interferent indicator of the third indicator element of the glucose sensor to generate the third sensing area degradation measurement, the third sensing area glucose measurement indicating an amount or concentration of glucose in interstitial fluid proximate the third indicator element, the third sensing area glucose measurement changing in response to degradation of at least the third interferent indicator, which corresponds to degradation of the third analyte indicator, and the third sensing area degradation measurement indicating degradation of the third interferent indicator; using fourth measurement electronics in a fourth sensing area of ​​the glucose sensor to generate a fourth sensing area glucose measurement and a fourth sensing area degradation measurement, the fourth measurement electronics using a fourth analyte indicator of a fourth indicator element of the glucose sensor to generate the fourth sensing area glucose measurement and a fourth interferent indicator of the fourth indicator element of the glucose sensor to generate the fourth sensing area degradation measurement, the fourth sensing area glucose measurement being indicative of an amount or concentration of glucose in interstitial fluid proximate the fourth indicator element, the fourth sensing area glucose measurement changing in response to degradation of at least the fourth interferent indicator, which corresponds to degradation of the fourth analyte indicator, and the fourth sensing area degradation measurement being indicative of degradation of the fourth interferent indicator; calculating a third sensing zone glucose concentration using at least the third sensing zone glucose measurement; calculating a fourth sensing zone glucose concentration using at least the fourth sensing zone glucose measurement; calculating a third weight for the third sensing area glucose concentration using at least the third sensing area degradation measurement; and calculating a fourth weight for the fourth sensing area glucose concentration using at least the fourth sensing area degradation measurement; 2. The method of claim 1 , wherein the composite glucose concentration is calculated as a weighted average of at least the first sensing area glucose concentration, the second sensing area glucose concentration, the third sensing area glucose concentration, and the fourth sensing area glucose concentration using the first weight, the second weight, the third weight, and the fourth weight.

4. calculating the first sensing area glucose concentration includes adjusting a first conversion function using at least the first sensing area degradation measurement, and calculating the first sensing area glucose concentration using at least the adjusted first conversion function and the first sensing area glucose measurement; calculating the second sensing area glucose concentration includes adjusting a second conversion function using at least the second sensing area degradation measurement, and calculating the second sensing area glucose concentration using at least the adjusted second conversion function and the second sensing area glucose measurement; calculating the third sensing area glucose concentration includes adjusting a third conversion function using at least the third sensing area degradation measurement, and calculating the third sensing area glucose concentration using at least the adjusted third conversion function and the third sensing area glucose measurement; 4. The method of claim 3, wherein calculating the fourth sensing area glucose concentration comprises: adjusting a fourth conversion function using at least the fourth sensing area degradation measurement; and calculating the fourth sensing area glucose concentration using at least the adjusted fourth conversion function and the fourth sensing area glucose measurement.

5. 5. The method of claim 3, wherein the first indicator element and the third indicator element are part of one indicator element, and the second indicator element and the fourth indicator element are part of another indicator element.

6. 6. The method according to claim 3, wherein the first and third measuring electronic circuits are fabricated and / or implemented on a first substrate of the glucose sensor, and the second and fourth measuring electronic circuits are fabricated and / or implemented on a second substrate of the glucose sensor.

7. 7. The method of any one of claims 1-6, wherein the composite glucose concentrations for multiple time points over the 365 day period have (a) an overall MARD to SMBG value of 10.2% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensory zone glucose concentration calculation is calibrated using one SMBG value every seven days during the 365 day period, or (b) an overall MARD to SMBG value of 10.1% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensory zone glucose concentration calculation is calibrated using two SMBG values ​​every 14 days during the 365 day period.

8. 8. The method of any one of claims 1-7, further comprising calibrating the sensing zone glucose concentration calculation using (a) one SMBG value for every seven days of the 365 day period, or (b) two SMBG values ​​for every fourteen days of the 365 day period.

9. The measuring electronic circuits each comprise: a first light source configured to emit a first excitation light; and a signal light detector configured to receive the first emitted light and output a sensing area glucose measurement, the sensing area glucose measurement indicating the amount of the first emitted light received by the signal light detector.

10. The method of claim 9 , wherein each of the measurement electronic circuits further comprises a second light source configured to emit a second excitation light.

11. 11. The method of claim 9 or 10, wherein the measurement electronics each further comprise an interferent photodetector configured to receive second emitted light and output a sensing area degradation measurement, the sensing area glucose measurement indicating the amount of the second emitted light received by the signal photodetector.

12. 11. The method of claim 10, wherein the signal light detector is further configured to receive a quantity of the second excitation light and output a sensing area degradation measurement value, the sensing area degradation measurement value indicating the amount of the received second excitation light.

13. 11. The method of claim 10, wherein each of the measurement electronic circuits further comprises a reference photodetector configured to receive a quantity of the second excitation light and output a sensing area degradation measurement, the sensing area degradation measurement indicating the amount of the received second excitation light.

14. 14. The method of any one of claims 1-13, further comprising calibrating the sensing zone glucose concentration calculation with SMBG values ​​at an increased frequency during the initial 365 day period compared to the remainder of the 365 day period.

15. 15. The method of claim 14, wherein the initial period is 14 days.

16. 16. The method of claim 14 or 15, wherein the increased frequency is one SMBG reading per day during the initial period.

17. 16. The method of claim 14 or 15, wherein the increased frequency is one SMBG reading every 12 hours during the initial period.

18. 1. A glucose monitoring system comprising:

1. A glucose sensor comprising: a first indicator element comprising a first analyte indicator and a first interferent indicator; a second indicator element comprising a second analyte indicator and a second interferent indicator; a first sensing area and a second sensing area; a first measuring electronic circuit in the first sensing area, the first measuring electronic circuit configured to generate a first sensing area glucose measurement and a first sensing area degradation measurement for each of a plurality of time points over a 365 day period, the first measuring electronic circuit configured to use the first analyte indicator to generate the first sensing area glucose measurement and the first interferent indicator to generate the first sensing area degradation measurement, the first sensing area glucose measurement indicating an amount or concentration of glucose in interstitial fluid proximate the first indicator element, the first sensing area glucose measurement changing in response to degradation of at least the first interferent indicator, which corresponds to degradation of the first analyte indicator, and the first sensing area degradation measurement indicating degradation of the first interferent indicator; and a second measuring electronic circuit in the second sensing area, the first measuring electronic circuit configured to generate a second sensing area glucose measurement and a second sensing area degradation measurement for each of a plurality of time points over the 365 day period, the second measuring electronic circuit configured to use the second analyte indicator to generate the second sensing area glucose measurement and the second interferent indicator to generate the second sensing area degradation measurement, the second sensing area glucose measurement indicating an amount or concentration of glucose in interstitial fluid proximate the second indicator element, the second sensing area glucose measurement changing in response to degradation of at least the second interferent indicator, which corresponds to degradation of the second analyte indicator, and the second sensing area degradation measurement indicating degradation of the second interferent indicator. a glucose sensor comprising: A controller that: For each of multiple time points over a 365 day period: calculating a first sensing zone glucose concentration using at least the first sensing zone glucose measurement; calculating a second sensing zone glucose concentration using at least the second sensing zone glucose measurements; calculating a first weight for the first sensing area glucose concentration using at least the first sensing area degradation measurement; calculating a second weight for the second sensing area glucose concentration using at least the second sensing area degradation measurement; Calculating a composite glucose concentration as a weighted average of at least the first sensing area glucose concentration and the second sensing area glucose concentration using at least the first weight and the second weight. With a controller configured as Equipped with the glucose monitoring system is configured to display the calculated composite glucose concentration; The system wherein the composite glucose concentrations for the multiple time points over the 365 day period have (a) an overall mean relative difference (MARD) vs. self-monitoring of blood glucose (SMBG) value of 10.4% or less and a 40 / 40% agreement rate of 98.5% or greater when the sensing zone glucose concentration calculation is calibrated using one SMBG value every seven days during the 365 day period, or (b) an overall MARD vs. SMBG value of 10.3% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensing zone glucose concentration calculation is calibrated using two SMBG values ​​every fourteen days during the 365 day period.

19. the controller is configured to, in calculating the first sensing area glucose concentration, adjust a first conversion function using at least the first sensing area degradation measurement, and calculate the first sensing area glucose concentration using at least the adjusted first conversion function and the first sensing area glucose measurement; 20. The system of claim 18, wherein the controller is configured to adjust a second conversion function using at least the second sensing area degradation measurement in calculating the second sensing area glucose concentration, and to calculate the second sensing area glucose concentration using at least the adjusted second conversion function and the second sensing area glucose measurement.

20. The glucose sensor comprises: a third indicator element including a third analyte indicator and a third interferent indicator; a fourth indicator element including a fourth analyte indicator and a fourth interferent indicator; a third sensing area and a fourth sensing area; third measuring electronics at the third sensing area, the third measuring electronics configured to generate a third sensing area glucose measurement and a third sensing area degradation measurement for each of a plurality of time points over the 365 day period, the third measuring electronics configured to use the third analyte indicator to generate the third sensing area glucose measurement and the third interferent indicator to generate the third sensing area degradation measurement, the third sensing area glucose measurement indicating an amount or concentration of glucose in interstitial fluid proximate the third indicator element, the third sensing area glucose measurement changing in response to degradation of at least the third interferent indicator corresponding to degradation of the third analyte indicator, and the third sensing area degradation measurement indicating degradation of the third interferent indicator; fourth measuring electronics at a fourth sensing area, the fourth measuring electronics configured to generate a fourth sensing area glucose measurement and a fourth sensing area degradation measurement for each of a plurality of time points over the 365 day period, the fourth measuring electronics configured to use the fourth analyte indicator to generate the fourth sensing area glucose measurement and the fourth interferent indicator to generate the fourth sensing area degradation measurement, the fourth sensing area glucose measurement indicating an amount or concentration of glucose in interstitial fluid proximate the fourth indicator element, the fourth sensing area glucose measurement changing in response to degradation of at least the fourth interferent indicator corresponding to degradation of the fourth analyte indicator, and the fourth sensing area degradation measurement indicating degradation of the fourth interferent indicator; Furthermore, The controller, for each of a plurality of time points over the 365 day period: calculating a third sensing zone glucose concentration using at least the third sensing zone glucose measurement; calculating a fourth sensing zone glucose concentration using at least the fourth sensing zone glucose measurement; calculating a third weight for the third sensing area glucose concentration using at least the third sensing area degradation measurement; further configured to calculate a fourth weight for the fourth sensing area glucose concentration using at least the fourth sensing area degradation measurement; 20. The system of claim 18, wherein the composite glucose concentration is calculated as a weighted average of at least the first sensing area glucose concentration, the second sensing area glucose concentration, the third sensing area glucose concentration, and the fourth sensing area glucose concentration using the first weight, the second weight, the third weight, and the fourth weight.

21. the controller is configured to, in calculating the first sensing area glucose concentration, adjust a first conversion function using at least the first sensing area degradation measurement, and calculate the first sensing area glucose concentration using at least the adjusted first conversion function and the first sensing area glucose measurement; the controller is configured to adjust a second conversion function using at least the second sensing area degradation measurement in calculating the second sensing area glucose concentration, and to calculate the second sensing area glucose concentration using at least the adjusted second conversion function and the second sensing area glucose measurement; the controller is configured to adjust a third conversion function using at least the third sensing area degradation measurement in calculating the third sensing area glucose concentration, and to calculate the third sensing area glucose concentration using at least the adjusted third conversion function and the third sensing area glucose measurement; 21. The system of claim 20, wherein the controller is configured to adjust a fourth conversion function using at least the fourth sensing area degradation measurement in calculating the fourth sensing area glucose concentration, and to calculate the fourth sensing area glucose concentration using at least the adjusted fourth conversion function and the fourth sensing area glucose measurement.

22. 22. The system of claim 20 or 21, wherein the first indicator element and the third indicator element are part of one indicator element, and the second indicator element and the fourth indicator element are part of another indicator element.

23. 23. The method of claim 20, wherein the glucose sensor comprises a first substrate and a second substrate, the first measuring electronic circuit and the third measuring electronic circuit being fabricated and / or mounted on the first substrate, and the second measuring electronic circuit and the fourth measuring electronic circuit being fabricated and / or mounted on the second substrate.

24. 24. The method of any one of claims 18-23, wherein the composite glucose concentrations for multiple time points over the 365 day period have (a) an overall MARD to SMBG value of 10.2% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensory zone glucose concentration calculation is calibrated using one SMBG value for every 7 days of the 365 day period, or (b) an overall MARD to SMBG value of 10.1% or less and a 40 / 40% agreement rate of 98.8% or greater when the sensory zone glucose concentration calculation is calibrated using two SMBG values ​​for every 14 days of the 365 day period.

25. 25. The system of any one of claims 18-24, wherein the controller is further configured to calibrate the sensing zone glucose concentration calculation using (a) one SMBG value for every seven days of the 365 day period, or (b) two SMBG values ​​for every fourteen days of the 365 day period.

26. The measuring electronic circuits each comprise: a first light source configured to emit a first excitation light; a signal light detector configured to receive the first emitted light and output a sensing area glucose measurement; 26. The system of claim 18, wherein the sensing area glucose measurement indicates an amount of the first emitted light received by the signal light detector.

27. 27. The system of claim 26, wherein each of the measurement electronic circuits further comprises a second light source configured to emit a second excitation light.

28. 28. The system of claim 26 or 27, wherein each of the measurement electronic circuits further comprises an interferent photodetector configured to receive second emitted light and output a sensing area degradation measurement, the sensing area glucose measurement indicating the amount of the second emitted light received by the signal photodetector.

29. 28. The system of claim 27, wherein the signal light detector is further configured to receive a certain amount of the second excitation light and output a sensing area degradation measurement value, the sensing area degradation measurement value indicating the amount of the received second excitation light.

30. 28. The system of claim 27, wherein each of the measurement electronic circuits further comprises a reference photodetector configured to receive a quantity of second excitation light and output a sensing area degradation measurement, the sensing area degradation measurement indicating the amount of second excitation light received.

31. 31. The system of any one of claims 18-30, wherein the controller is further configured to calibrate the sensing area glucose concentration calculation with SMBG values ​​at an increased frequency during an initial 365 day period compared to a remainder of the 365 day period.

32. 32. The system of claim 31, wherein the initial period is 14 days.

33. 33. The system of claim 31 or 32, wherein the increased frequency is one SMBG reading per day during the initial period.

34. 33. The method of claim 31 or 32, wherein the increased frequency is one SMBG reading every 12 hours during the initial period.

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