JP2024519422A - Detection and correlation of interferences in analyte monitoring systems - Patents.com - Google Patents

Abstract

Sensors, systems, and methods for detecting and correcting for effects on an analyte indicator of an analyte sensor. The analyte indicator can be configured to exhibit a first detectable characteristic that varies with the analyte concentration and with effects on the analyte indicator (e.g., degradation thereof). The analyte sensor can also include an interferent indicator configured to exhibit a second detectable characteristic (e.g., absorption) that varies with effects on the analyte indicator. The analyte sensor can (i) generate an analyte measurement based on the first detectable characteristic exhibited by the analyte indicator, and (ii) generate an interferent measurement based on the second detectable characteristic exhibited by the interferent indicator. The analyte sensor can be part of a system that also includes a transceiver. The transceiver can use the analyte measurement and the interferent measurement to calculate the analyte level.

Description

Cross-reference to related applications
[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/193,784, filed May 27, 2021, which is incorporated herein by reference in its entirety. In addition, this application is a continuation-in-part of U.S. Patent Application No. 17/092,830, filed November 9, 2020. U.S. Patent Application No. 17/092,830 is a continuation of U.S. Patent Application No. 15/957,604, filed April 19, 2018. U.S. Patent Application No. 15/957,604 claims the benefit of priority to U.S. Provisional Patent Application No. 62/487,289, filed April 19, 2017, which are incorporated herein by reference in their entirety.

[0002] FIELD OF THEINVENTION
[0003] The present invention relates generally to detection and correlation of interferences in analyte monitoring systems. Interferences may include blood in a medium (e.g., interstitial fluid) and/or effects (e.g., oxidation-induced degradation) on an analyte indicator in the analyte monitoring system.

[0004] Background Discussion
[0005] Analyte monitoring systems can 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 extremely beneficial in managing diseases such as diabetes.

[0006] Some analyte monitoring systems include an analyte sensor, which may be implanted (fully or partially) in an animal, and may also include an analyte indicator. Blood in the interstitial fluid in proximity to the analyte indicator and/or effects on 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). Changes in sensitivity parameters may be due, for example, to degradation of the analyte indicator. Degradation may occur due, for example, to oxidation of the analyte indicator induced by reactive oxygen species (ROS) generated by 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. These patents are incorporated herein by reference in their entirety. The rate of in vivo sensitivity loss can be reduced, for example, by using oxidation-resistant indicator molecules, integrating catalytic protection, and/or using membranes that catalyze the degradation 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 can adversely affect analyte sensing accuracy, potentially necessitating recalibration using a reference analyte measurement (e.g., a self-monitored blood glucose measurement), which may be uncomfortable for the user and/or otherwise undesirable.

[0007] The present invention overcomes the shortcomings of conventional systems by providing an analyte monitoring system capable of detecting and correlating one or more interferents. In certain aspects, the one or more interferents may interfere with high accuracy measurements of an analyte (e.g., glucose) in a medium (e.g., interstitial fluid). In certain aspects, the one or more interferents may include blood in the medium. In certain aspects, the one or more interferents may include an effect on an analyte indicator of an analyte sensor. In contrast to prior art systems that can only correct for one or more interferents upon recalibration using a reference analyte measurement, the present analyte monitoring system may provide, among other advantages, the ability to correct for one or more interferents without the need for a reference analyte measurement. In certain aspects, the analyte monitoring system may also include an analyte sensor that measures one or more interferents using an interferent indicator. In certain aspects, the interferent indicator is insensitive to the analyte. In some aspects, the interferent indicator may have one or more properties that vary with the action on the analyte indicator (e.g., degradation due to reactive oxygen species (ROS)). In some aspects, the one or more properties of the interferent indicator may include an absorption that varies in response to the action on the analyte indicator. In some aspects, the one or more properties of the interferent indicator may include an optical property that changes in response to the action on the analyte indicator. In some aspects, the interferent indicator may be used as a reference dye to measure and correct for the action on the analyte indicator. In some aspects, the analyte monitoring system may also correct for one or more interferents using empirical correlations established through laboratory testing.

[0008] In one aspect of the invention, an analyte sensor for measuring an analyte in a medium in a living animal can be provided. The analyte sensor can include an analyte indicator, a degradation indicator, and a sensor element. The analyte indicator can be configured to exhibit a first detectable characteristic that varies with (i) the amount or concentration of the analyte in the medium and (ii) the extent to which the analyte indicator has degraded. The degradation indicator can be configured to exhibit a second detectable characteristic that varies with the extent to which the degradation indicator has degraded. The extent to which the degradation indicator has degraded can also correspond to the extent to which the analyte indicator has degraded. The sensor element can be configured to (i) generate an analyte measurement based on the first detectable characteristic exhibited by the analyte indicator, and (ii) generate a degradation measurement based on the second detectable characteristic exhibited by the degradation indicator.

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

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

[0011] In one aspect, the sensor element can include a first light source and a first photodetector. The first light source can be configured to emit a first excitation light toward the analyte indicator. The first photodetector can be configured to receive the first emission light emitted by the analyte indicator and output an analyte measurement. The analyte measurement can indicate an amount of the first emission light received by the first photodetector. In one aspect, the sensor element can also include a second light source and a second photodetector. The second light source can be configured to emit a second excitation light toward the degradation indicator. The second photodetector can be configured to receive the second emission light emitted by the degradation indicator and output a degradation measurement. The degradation measurement can indicate an amount of the second emission light received by the second photodetector. In one aspect, the first photodetector can be configured to receive the second excitation light reflected from the indicator element and output a first reference signal indicative of an amount of the reflected second excitation light received by the first photodetector. In one aspect, the sensor element can also include a third photodetector. The third photodetector is 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.

[0012] In another aspect of the invention, a method can be provided that includes using an analyte indicator of an analyte sensor to measure an amount or concentration of an analyte in a medium. The method can include using a degradation indicator of the analyte sensor to measure an extent to which the degradation indicator has degraded. The method can include receiving, using a sensor interface device of the transceiver, from the analyte sensor, an analyte measurement indicative of an amount or concentration of the analyte in the medium. The method can include receiving, using a sensor interface device of the transceiver, a degradation measurement indicative of an extent to which the degradation indicator has degraded. The method can include calculating, using a controller of the transceiver, an extent to which the analyte indicator of the analyte sensor has degraded based at least on the received degradation measurement. The method can include adjusting, using a controller of the transceiver, a conversion function based on the calculated extent to which the analyte indicator has degraded. The method can include calculating, using a controller of the transceiver, an analyte level using the adjusted conversion function and the received analyte measurement. The method can include displaying the calculated analyte level.

[0013] In yet another aspect of the invention, an analyte monitoring system can be provided that includes an analyte sensor and a transceiver. The analyte sensor can include an analyte indicator, a degradation indicator, a sensor element, and a transceiver interface device. The analyte indicator can be configured to exhibit a first detectable characteristic that varies with (i) an amount or concentration of an analyte in a medium and (ii) an extent to which the analyte indicator has degraded. The degradation indicator can be configured to exhibit a second detectable characteristic that varies with an extent to which the degradation indicator has degraded. The sensor element can be configured to (i) generate an analyte measurement based on the first detectable characteristic exhibited by the analyte indicator, and further to (ii) generate a degradation measurement based on the second detectable characteristic exhibited by the degradation indicator. The transceiver can include a sensor interface device and a controller. The controller is configured to (i) receive an analyte measurement from the analyte sensor via the analyte sensor's transceiver interface device and sensor interface device, (ii) receive a degradation measurement from the analyte sensor via the analyte sensor's transceiver interface device and sensor interface device, (iii) calculate a degree to which an analyte indicator of the analyte sensor has degraded based on at least the received degradation measurement, (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 measurement.

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

[0015] In yet another aspect of the invention, an analyte monitoring system can be provided that includes an analyte indicator, an interferent indicator, a sensor element, and a controller. The analyte indicator can have a first detectable characteristic that varies in response to at least (i) an amount or concentration of the analyte in the medium, and (ii) an effect on the analyte indicator. The interferent indicator can have an absorption that varies in response to an effect on the analyte indicator. The sensor element can be configured to (i) generate an analyte measurement based on the first detectable characteristic of the analyte indicator, and (ii) generate a reference measurement based on at least the absorption of the interferent indicator. The controller can 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 an analyte level using the adjusted conversion function and the analyte measurement.

[0016] In some embodiments, the action on the analyte indicator may be degradation of the analyte indicator. In some embodiments, the system may further include an indicator element. The indicator element includes an analyte indicator and an interferent indicator, the analyte indicator may include analyte indicator molecules dispersed throughout the indicator element, and the interferent indicator may include interferent indicator molecules dispersed throughout the indicator element.

[0017] In one aspect, the sensor element includes a first light source configured to emit a first excitation light toward the analyte indicator and a signal light detector configured to receive the first emission light emitted by the analyte indicator and output an analyte measurement, where the analyte measurement can indicate an amount of the first emission light received by the signal light detector. In one aspect, the sensor element can further include a second light source configured to emit a second excitation light toward the interferent indicator. In one aspect, the signal light detector can further be configured to receive an amount of the second excitation light and output a reference measurement, where the reference measurement can indicate an amount of the second excitation light received, where the amount of the second excitation light received can indicate an absorption of the interferent indicator. In one aspect, the sensor element can further include a reference light detector, where the reference light detector is configured to receive an amount of the second excitation light and output a reference measurement, where the reference measurement can indicate an amount of the second excitation light received, where the amount of the second excitation light received can indicate an absorption of the interferent indicator.

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

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

[0020] In one aspect, the reference measurement may be a second reference measurement, and the sensor element includes a first light source, a second light source, a first reference light detector, and a signal light detector. In one aspect, the first light source may be configured to emit a first excitation light toward the analyte indicator, the second light source may be configured to emit a second excitation light toward 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 indicative of the amount of the first excitation light received, the signal light detector may be configured to receive a first emission light emitted by the analyte indicator and output an analyte measurement, the analyte measurement may be indicative of the amount of the first emission 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, and the second reference measurement may be indicative of the amount of the second excitation light received.

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

[0022] In certain aspects, the interferent indicator may have a second detectable characteristic that varies as a function of the effect on the analyte indicator, the sensor element may be further configured to generate an interferent measurement based on the second detectable characteristic 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 certain aspects, the processor may also be configured to calculate the effect on the analyte indicator based on at least a ratio of the interferent measurement and the reference measurement.

[0023] In yet another aspect of the invention, a method can be provided that includes using an analyte indicator to generate an analyte measurement indicative of an amount or concentration of an analyte in a medium, the analyte measurement being variable in response to at least an effect on the analyte indicator. The method can include using an interferent indicator to generate a reference measurement indicative of an absorption of the interferent indicator, the absorption being variable in response to an effect on the analyte indicator. The method can include calculating the effect on the analyte indicator based at least on the reference measurement. The method can include adjusting a conversion function based at least on the calculated effect on the analyte indicator. The method can include calculating an analyte level using the adjusted conversion function and the analyte measurement.

[0024] In one embodiment, the effect on the analyte indicator may be degradation of the analyte indicator.

[0025] In one aspect, the step of generating an analyte measurement using an analyte indicator can include emitting a first excitation light toward the analyte indicator and using a signal light detector configured to receive the first emission light emitted by the analyte indicator and output an analyte measurement, where the analyte measurement can indicate an amount of the first emission light received by the signal light detector. In one aspect, the step of generating a reference measurement using an interferent indicator can include emitting a second excitation light toward the interferent indicator. In one aspect, the step of generating a reference measurement using an interferent indicator can further include receiving an amount of the second excitation light using a signal light detector and outputting a reference measurement, where the reference measurement can indicate an amount of the second excitation light received, where the amount of the second excitation light received can indicate an absorption of the interferent indicator. In one aspect, the step of generating a reference measurement using the interferent indicator can further include the step of receiving an amount of the second excitation light using a reference light detector and outputting a reference measurement, where the reference measurement can be indicative of the amount of the second excitation light received, and the amount of the second excitation light received can be indicative of the absorption of the interferent indicator.

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

[0027] In some aspects, the method may further include calculating the amount of blood in the medium. In some aspects, the conversion function may be adjusted based at least on the calculated effect on the analyte indicator and the calculated amount of blood in the medium. In some aspects, the reference measurement may be a second reference measurement, and the step of generating the analyte measurement using the analyte indicator may include emitting a first excitation light toward the analyte indicator, receiving an amount of the first excitation light using a first reference light detector and outputting a first reference measurement indicative of the amount of the first excitation light received, and receiving a first emission light emitted by the analyte indicator using a signal light detector and outputting the analyte measurement. In some aspects, the analyte measurement may be indicative of the amount of the first emission light received. In some aspects, the step of generating the reference measurement using the interferent indicator may include emitting a second excitation light toward the interferent indicator, receiving an amount of the second excitation light using a signal light detector and outputting the second reference measurement. In one aspect, the second reference measurement can be indicative of the amount of second excitation light received, and the amount of blood in the medium can be calculated based on at least the first and second reference measurements.

[0028] In some aspects, the reference measurement may be a second reference measurement, and the step of generating the analyte measurement using the analyte indicator may include the steps of emitting a first excitation light toward the analyte indicator, receiving an amount of the first excitation light using a first reference light detector and outputting a first reference measurement indicative of the amount of the first excitation light received, and receiving a first emission light emitted by the analyte indicator using a signal light detector and outputting the analyte measurement. In some aspects, the analyte measurement may be indicative of the amount of the first emission light received. In some aspects, the step of generating the reference measurement using the interferent indicator may include the steps of emitting a second excitation light toward the interferent indicator, receiving an amount of the second excitation light using a second reference light detector and outputting a second reference measurement. In some aspects, the second reference measurement may be indicative of the amount of the second excitation light received. In some aspects, the amount of blood in the medium may be calculated based on at least the first and second reference measurements.

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

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

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

[0032] In one aspect, the emitted light may be a first emitted light, 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 indicative of the amount of the second emitted light received by the one or more photodetectors, the controller may be further configured to calculate an extent to which the analyte indicator has degraded based at least on the degradation measurement, and the controller may be further configured to adjust the conversion function based on the reference measurement and the calculated extent of degradation of the analyte indicator.

[0033] Further variations of the above system and method are described in the detailed description of the invention below.

[0034] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate various non-limiting aspects of the present invention. In the drawings, like reference numbers indicate identical or functionally similar elements.
FIG. 1 is a schematic diagram illustrating an analyte monitoring system embodying aspects of the present invention. FIG. 1 is a schematic diagram illustrating an analyte sensor embodying aspects of the present invention. FIG. 1 is a schematic diagram illustrating an analyte sensor embodying aspects of the present invention. 1 is a perspective view showing elements of an analyte sensor embodying aspects of the present invention. FIG. 1 is a schematic diagram illustrating a semiconductor substrate layout of an analyte sensor embodying aspects of the present invention. 1 is a chart showing non-limiting examples of sensitivity ratios correlating analyte indicators to interferent indicators, embodying aspects of the present invention. 1 is a cross-sectional perspective view of a transceiver embodying aspects of the present invention; 1 is an exploded perspective view of a transceiver embodying aspects of the present invention; 1 is a schematic diagram illustrating a transceiver embodying aspects of the present invention; 1 is a flow chart illustrating a process for detecting and correlating a change with an analyte indicator that embodies an aspect of the present invention. FIG. 2 is a schematic diagram illustrating a non-limiting example of the construction of an indicator element 106 embodying aspects of the present invention. FIG. 2 is a schematic diagram illustrating a non-limiting example of the construction of an indicator element 106 embodying aspects of the present invention. FIG. 2 is a schematic diagram illustrating a non-limiting example of the construction of an indicator element 106 embodying aspects of the present invention. 1 is a graph showing a correlation plot of indicator interferent and reference dye rates, according to one non-limiting embodiment of the present invention. Fluorometer readouts are shown demonstrating the decrease in fluorescence intensity of the indicator molecule (excitation wavelength 380 nm) in 2 mM glucose and 50 μM hydrogen peroxide with a concomitant increase in fluorescence intensity (excitation wavelength 470 nm) of Compound A in a 1:1 ratio with the indicator molecule, demonstrating the use of Compound A as a copolymerizable reference dye. Fluorometer readouts are shown demonstrating the decrease in fluorescence intensity of the indicator molecule (excitation wavelength 380 nm) in 2 mM glucose and 50 μM hydrogen peroxide with a concomitant increase in fluorescence intensity (excitation wavelength 470 nm) of Compound A in a 1:1 ratio with the indicator molecule, demonstrating the use of Compound A as a copolymerizable reference dye. 1 shows a non-limiting example of an analyte indicator molecule of an analyte indicator before and after degradation by reactive oxygen species (ROS) in accordance with an embodiment of the present invention. 1 shows a non-limiting example of an interferent indicator molecule of an interferent indicator before and after degradation by ROS in accordance with an embodiment of the present invention. 1 shows a white indicator element in the absence of oxidation for an indicator element including an interferent indicator embodying an aspect of the present invention. 1 shows an indicator element including an interferent indicator embodying an aspect of the present invention, the indicator element appearing yellow when oxidized. In accordance with an embodiment of the present invention, a decrease in the intensity or amount of light emitted by an analyte indicator over time is shown. In accordance with an embodiment of the present invention, the indicator element exhibits an increase in absorption over time and a decrease in the intensity or amount of the second excitation light that it reflects over time. 1 is a graph illustrating experimental data from a clinical trial in which the analyte sensor 100 was implanted subcutaneously in a living human body. 1 is a graph showing the extinction coefficients of oxyhemoglobin and deoxyhemoglobin at different wavelengths. 1 is a graph showing the extinction coefficients of oxyhemoglobin, deoxyhemoglobin, methemoglobin, and bilirubin at different wavelengths. 1 is a flow chart illustrating a process for detecting and correlating effects on analyte indicators that embodies aspects of the present invention. 1 shows chemical structures of analyte indicators according to certain embodiments. 1 shows chemical structures of interference indicators according to certain embodiments. 1 illustrates an analyte sensor including multiple sensing areas and multiple indicator elements, according to an embodiment. According to certain embodiments, similar degradation kinetics show that as oxidation increases, the first emission light emitted by the analyte indicator decreases and the second emission light emitted by the interferent indicator increases. 13 shows optical and fluorescent images of an analyte sensor after local oxidation, according to an embodiment. 13 shows optical and fluorescent images of an analyte sensor after local oxidation, according to an embodiment. 13 shows optical and fluorescent images of an analyte sensor after local oxidation, according to an embodiment. 13 shows optical and fluorescent images of an analyte sensor after local oxidation, according to an embodiment. 23 illustrates in vivo measurements from different sensing areas of the analyte sensor shown in FIG. 22, according to an embodiment. 23 illustrates in vivo measurements from different sensing areas of the analyte sensor shown in FIG. 22, according to an embodiment. 23 illustrates in vivo measurements from different sensing areas of the analyte sensor shown in FIG. 22, according to an embodiment. 23 illustrates in vivo measurements from different sensing areas of the analyte sensor shown in FIG. 22, according to an embodiment. According to one embodiment, the individual glucose concentrations calculated individually from the sensing areas of the analyte sensor 100 shown in FIG. According to one embodiment, a combined glucose concentration is shown that is calculated based on a weighted average of the individual glucose concentrations.

[0061] FIG. 1 is a schematic diagram of an example of an analyte monitoring system 50 embodying aspects of the present invention. Analyte monitoring system 50 may be a continuous analyte monitoring system (e.g., a continuous glucose monitoring system). In an aspect, analyte monitoring system 50 may include one or more of analyte sensor 100, transceiver 101, and display device 107. In an aspect, analyte sensor 100 may be a small, 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 human body). However, this is not required, and in an alternative aspect, analyte sensor 100 may be a partially implantable (e.g., transdermal) sensor or a fully external sensor. In an aspect, transceiver 101 may be an externally worn transceiver (e.g., attached by an armband, wristband, waistband, or adhesive patch). In some aspects, the transceiver 101 may remotely power and/or communicate with the sensor 100 to initiate measurements and receive measurements (e.g., via near field communication (NFC)). However, this is not required, and in some alternative aspects, the transceiver 101 may power and/or communicate with the analyte sensor 100 via one or more wired connections. In some non-limiting aspects, the transceiver 101 may be a smartphone (e.g., an NFC-enabled smartphone). In some aspects, the transceiver 101 may communicate information (e.g., one or more analyte measurements) wirelessly (e.g., via a Bluetooth™ communication standard, such as Bluetooth Low Energy) to a hand-held application running on the display device 107 (e.g., a smartphone).

[0062] 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 an embodiment, the analyte sensor 100 can 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 a non-limiting embodiment, the analyte sensor 100 can be an optical sensor (e.g., a fluorometer). In an embodiment, the analyte sensor 100 can be a chemical sensor or a biochemical sensor. In an embodiment, the analyte sensor 100 can be a radio frequency identification (RDIF) device. The analyte sensor 100 can be powered by a radio frequency (RF) signal from a transceiver 101.

[0063] 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 readings) from the analyte sensor 100. The measurement data may include one or more readings from one or more photodetectors of the analyte sensor 100 and/or one or more readings from one or more temperature sensors of the analyte sensor 100. In an aspect, the transceiver 101 may calculate the concentration of the analyte from the measurement data received from the analyte sensor 100. However, it is not required that the transceiver 101 itself perform the analyte concentration calculations, and in an alternative aspect, 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 calculation of the analyte concentration. In another alternative embodiment, the analyte sensor 100 may perform an analyte concentration calculation and communicate the calculated analyte concentration to the transceiver 101.

[0064] In some embodiments (e.g., embodiments in which the analyte sensor 100 is a fully implantable sensing system), the transceiver 101 can implement passive telemetry to communicate with the implantable analyte sensor 100 via an inductive magnetic link for powering and/or data transfer. In some embodiments, the analyte sensor 100 can also include an inductive element 114, which can be, for example, a ferrite based micro-antenna, as shown in FIG. 3. In some embodiments, the inductive element 114 can include a conductor 302 in the form of a coil and a magnetic core 304, as shown in FIG. 3. In some non-limiting embodiments, the core 304 can be, for example, a ferrite core, and is not limited thereto. In some embodiments, the inductive element 114 can be connected to an analyte detection circuit of the analyte sensor 100. For example, in one embodiment, if the analyte sensor 100 is an optical sensor, the inductive element 114 may be connected to a micro-fluorimeter circuitry (e.g., an application specific integrated circuit (ASIC)) and associated optical detection system of the analyte sensor 100. In one embodiment, the analyte sensor 100 may not include a battery, such that the analyte sensor 100 may rely on the transceiver 101 to power the analyte sensor 100 and a data link of the sensor system 105 for communicating analyte-related data from the analyte sensor 100 to the transceiver 101. However, this is not required, and in one alternative embodiment, the analyte sensor 100 may include a battery.

[0065] In one non-limiting embodiment, the analyte sensor 100 may be a small, passive, fully implantable, multi-site sensing system. If the analyte sensor 100 is a fully implantable sensing system without a battery power source, the transceiver 101 may provide energy to operate the analyte sensor 100 through a magnetic field. In one embodiment, the magnetic transceiver-sensing system link may be considered a "weakly coupled transformer" type. The magnetic transceiver-sensing system link may use amplitude modulation (AM) to provide energy and provide a link for data transfer. In one embodiment, data transfer is performed using AM, but in alternative embodiments, other forms of modulation may be used. The magnetic transceiver-sensor link may be less efficient in power transfer and therefore may require relatively high power amplifiers to power the analyte sensor 100 over a longer distance. In one non-limiting aspect, the transceiver 101 and the analyte sensor 100 can also communicate using near-field communications for power transfer (e.g., near-field communications utilizing a frequency of 13.56 MHz, which can achieve high skin penetration and is a medically approved frequency band). However, this is not required, and in other aspects, other frequencies can be used to power and communicate with the analyte sensor 100.

[0066] In certain aspects, as shown in FIG. 7, the transceiver 101 can also include an inductive element 103, such as, for example, a coil. The transceiver 101 can generate an electromagnetic wave or electrodynamic field (e.g., by using the coil 103) to induce a current in the inductive element 114 of the analyte sensor 100, thus powering the analyte sensor 100. The transceiver 101 can also communicate data (e.g., commands) to the analyte sensor 100. For example, in a non-limiting aspect, the transceiver 101 can communicate data by modulating the electromagnetic wave used to power the analyte sensor 100 (e.g., by modulating the current passing through the coil of the transceiver 101). The modulation in the electromagnetic wave generated by the transceiver 101 can be detected/extracted by the analyte sensor 100. Additionally, the transceiver 101 can receive data (e.g., measurement information) from the analyte sensor 100. For example, in a non-limiting aspect, the transceiver 101 can receive data by detecting modulations in the electromagnetic waves generated by the analyte sensor 100, e.g., by detecting modulations in the current passing through the coil 103 of the transceiver 101.

[0067] In one non-limiting embodiment, the analyte sensor 100 may include a sensor housing 102 (i.e., a body, shell, capsule, or container), which may be rigid and biocompatible, as shown in FIG. 2A. In one non-limiting embodiment, the sensor housing 102 may be a silicon tube. However, this is not required, and in other embodiments, different materials and/or shapes may be used for the sensor housing 102. In one embodiment, the analyte sensor 100 may include a transmissive optical cavity. In one non-limiting embodiment, the transmissive optical cavity may be formed of a suitable optically transmissive polymeric material, such as, for example, an acrylic polymer (e.g., polymethylmethacrylate (PMMA)). However, this is not required, and in other embodiments, different materials may be used for the transmissive optical cavity.

[0068] In some embodiments, as shown in FIG. 2A, the analyte sensor 100 can also include an indicator element 106, such as, for example, a polymer graft or hydrogel coated, diffused, bonded, embedded, 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 can also include one or more notches or depressions, and the indicator element 106 can be disposed (partially or entirely) in the notches or depressions. In some embodiments, the indicator element 106 can be porous, allowing an analyte (e.g., glucose) in a medium (e.g., interstitial fluid) to diffuse into the indicator element 106.

[0069] In some embodiments, the indicator element 106 (e.g., a polymer graft or hydrogel) of the sensor 100 can 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 can exhibit one or more detectable properties (e.g., optical properties) that vary depending on (i) the amount or concentration of analyte proximate the indicator element 106 and (ii) an action on the analyte indicator 207 (e.g., a change to the analyte indicator 207). In some embodiments, the change to the analyte indicator 207 can include the degree to which the analyte indicator 207 has degraded. In one non-limiting embodiment, the degradation can be (at least in part) oxidation induced by ROS. In some embodiments, the analyte indicator 207 can also include one or more analyte indicator molecules (e.g., fluorescent analyte indicator molecules), which can be dispersed throughout the indicator element 106. In one non-limiting embodiment, the analyte indicator 207 may be a phenylboron-based analyte indicator. However, a phenylboron-based analyte indicator is not required, and in an alternative embodiment, the analyte sensor 100 may include a different analyte indicator, such as, but not limited to, a glucose oxidase-based indicator, a glucose dehydrogenase-based indicator, and a glucose binding protein-based indicator.

[0070] In certain embodiments, the interferent indicator 209 can exhibit one or more detectable properties (e.g., optical properties) that vary in response to changes to the interferent indicator 209. In certain embodiments, the interferent indicator 209 is not sensitive to the amount of concentration of the analyte proximate the indicator element 106. That is, in certain embodiments, the one or more detectable properties exhibited by the interferent indicator 209 do not vary in response to the amount or concentration of the analyte proximate the indicator element 106. However, this is not required, and in certain alternative embodiments, the one or more detectable properties exhibited by the interferent indicator 209 can vary in response to the amount or concentration of the analyte proximate the indicator element 106.

[0071] In some embodiments, the changes to the interferent indicator 209 can include the degree to which the interferent indicator 209 has degraded. In some embodiments, the degradation can be (at least in part) oxidation induced by ROS. In some embodiments, the interferent indicator 209 can include one or more interferent indicator molecules (e.g., fluorescent interferent indicator molecules) and can be dispersed throughout the indicator element 106. In some non-limiting embodiments, the interferent indicator 209 can be a phenylboron-based interferent indicator. However, a phenylboron-based interferent indicator is not required, and in some alternative embodiments, the analyte sensor 100 can include different interferent indicators, such as, but not limited to, an integrated red-based interferent indicator, a dichlorodihydrofluorescein-based indicator, a dihydrorhodamine-based indicator, and a scopoletin-based interferent indicator.

[0072] In one non-limiting embodiment, the interferent indicator molecule can be a fluorescent probe compound having an excitation wavelength between about 450 nm and about 550 nm, a Stokes shift between about 500 nm and about 650 nm, and a half-life between about 50 days and about 150 days. In one non-limiting embodiment, the interferent indicator molecule can be a compound of formula I:

wherein A", B", C", A', B', C', W', X, Y', and Z' represent -CH, where hydrogen may be optionally and independently replaced with an alkyl group. R1 and R2 are independently selected from one or more vinyl groups, alkyl vinyl groups, acrylamide groups, methacrylamide groups, or other polymerizable groups. Representative non-limiting compounds include the following:

In still other non-limiting embodiments, the interferent indicator molecule can include representative compounds such as:

wherein A, B', C', D', E, F, G, H', I', and J represent -CH, where the hydrogens may be optionally and independently replaced with alkyl groups.

[0073] The compounds can be synthesized using synthetic techniques known in the art, such as those in "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. Pregrant Publication No. US2016/0312033 (Application Serial No. 15/135,788, Yang et al., October 27, 2016). These documents are incorporated herein by reference in their entireties.

[0074] In an alternative embodiment, the molecules of the interferent indicator 209 may be compounds having different chemical formulas with excitation wavelengths between about 450 nm and about 550 nm, Stokes shifts between about 500 nm and about 650 nm, and half-lives between about 50 days and about 150 days.

[0075] In one non-limiting embodiment, the indicator element 106 may include one or more polymer backbones 1002, as shown in Figures 10-12. In one non-limiting embodiment, the polymer backbone 1002 may be a polymer chain. In one embodiment, the indicator element 106 may include one or more analyte indicator molecules A and one or more interferent indicator molecules D, as shown in Figures 10 and 11. In one embodiment, the analyte indicator molecules A and the interferent indicator molecules D may be monomers individually polymerized into the polymer backbone 1002, as shown in Figures 10 and 11. In one non-limiting embodiment, the indicator element 106 may include an equal number of analyte indicator molecules A and interferent indicator molecules D (see Figure 10) or may include a different number of analyte indicator molecules A and interferent indicator molecules D (see Figure 11). In some embodiments, the analyte indicator molecule A may be in a ratio to the interferent indicator molecule D, such as, 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.

[0076] In an alternative embodiment, as shown in FIG. 12, one or more interferent indicator molecules D may be chemically bonded (e.g., by covalent bonds) to the analyte indicator molecule A, which may further be chemically bonded to the polymer backbone 1002. In one non-limiting alternative embodiment, the analyte indicator molecule A and the interferent indicator molecule D may be monomeric, and the analyte indicator molecule A may be polymerized to the polymer backbone 1002. In one other alternative embodiment, one or more analyte indicator molecules A may be chemically bonded to the interferent indicator molecule D, and the interferent indicator molecule D may be chemically bonded to the polymer backbone 1002. In one non-limiting alternative embodiment, the analyte indicator molecule A and the interferent indicator molecule D may be monomeric, and the interferent indicator molecule D may be polymerized to the polymer backbone 1002.

[0077] In an embodiment, the analyte sensor 100 can indirectly measure changes to the analyte indicator 207 using an interferent indicator 209 that is sensitive to degradation by reactive oxygen species (ROS) but not to the analyte. In an embodiment, the interferent indicator 209 can have one or more optical properties that change with the degree of oxidation and can be used as a reference dye to measure and correlate the degree of oxidation of the analyte indicator. In an embodiment, the degree to which the interferent indicator 209 has degraded can correspond to the degree to which the analyte indicator 207 has degraded. For example, in one non-limiting embodiment, the degree to which the interferent indicator 209 has degraded can be proportional to the degree to which the analyte indicator 207 has degraded. In one non-limiting alternative, the degree to which the analyte indicator 207 has degraded can be calculated based on the degree to which the interferent indicator 209 has degraded. In one embodiment, the analyte monitoring system 50 can compensate for changes in the analyte indicator 207 using empirical correlations established through laboratory testing.

[0078] In some embodiments, the analyte sensor 100 may include one or more first light sources 108, as shown in FIG. 2A. The first light source 108 emits a first excitation light 329 over a wavelength range, which interacts with the analyte indicator 207 in the indicator element 106. In one non-limiting embodiment, 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. The light source 227 emits a second excitation light 330 over a wavelength range, which interacts with the interferent indicator 209 in the indicator element 106. In one non-limiting embodiment, the second excitation light 330 may be blue light.

[0079] In some embodiments, as shown in FIG. 2A, the analyte sensor 100 may include 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 include one or more signal photodetectors 224 responsive to a first emission 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 thereto indicates a level of the first emission light 331 of the analyte indicator 207, and thus an amount of the analyte of interest (e.g., glucose). In one non-limiting embodiment, the analyte sensor 100 may include one or more reference photodetectors 226 responsive to a first excitation light 329 that may be reflected from the indicator element 106, such that a signal generated by the photodetector 226 in response thereto indicates a level of the reflected first excitation light 329. In some aspects, the analyte sensor 100 may include one or more interferent light detectors 228 sensitive to the second emission light 332 (e.g., fluorescence) emitted by the interferent indicator 209 of the indicator element 106, such that a signal generated by the interferent light detector 228 in response thereto indicates the level of the second emission light 332 of the interferent indicator 209, i.e., the amount of degradation (e.g., oxidation). In one non-limiting aspect, the one or more signal light detectors 224 may be sensitive to the second excitation light 330, which may be reflected from the indicator element 106. In this manner, the one or more signal light detectors 224 may act as a reference light detector when the one or more light sources 227 are emitting the second excitation light 330.

[0080] However, it is not necessary that the one or more signal photodetectors 224 act as reference photodetectors when the one or more light sources 227 are emitting the second excitation light 330. In an alternative embodiment, as shown in FIG. 2B, the analyte sensor 100 can also include one or more second reference photodetectors 230 that act as reference photodetectors when the one or more light sources 227 are emitting the second excitation light 330. In an embodiment, the one or more second reference photodetectors 230 can 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 indicates the level of the reflected second excitation light 330.

[0081] In some embodiments, the first excitation light 329 may exceed a first wavelength range and the second excitation light 330 may exceed a second wavelength range, most likely different from the first wavelength range. In some non-limiting embodiments, the first and second wavelength ranges do not overlap, but this is not required, and in some alternative embodiments, the first and second wavelength ranges may overlap. In some embodiments, the first emitted light 331 may exceed a third wavelength range and the second emitted light 332 may exceed a fourth wavelength range, most likely different from the third wavelength range. In some non-limiting embodiments, the third and fourth wavelength ranges do not overlap, but this is not required, and in some alternative embodiments, the third and fourth wavelength ranges may overlap. In some embodiments, the first and third wavelength ranges may be different. In some non-limiting embodiments, the first and third wavelength ranges do not overlap, but this is not required, and in some alternative embodiments, the first and third wavelength ranges may overlap. In some embodiments, the second and fourth wavelength ranges may be different. In one non-limiting embodiment, the second and fourth wavelength ranges do not overlap, but this is not required, and in one alternative embodiment, the second and fourth wavelength ranges may overlap. In one embodiment, the second and third wavelength ranges may be different. In one non-limiting embodiment, the second and third wavelength ranges may overlap, but this is not required, and in one alternative embodiment, the second and third wavelength ranges do not overlap.

[0082] In some embodiments, one or more of the photodetectors 224, 226, 228, 230 may be covered with one or more filters to pass only a certain subset of the wavelengths of light and reflect (absorb) the remaining wavelengths. In one non-limiting embodiment, one or more filters may be disposed on one or more of the signal photodetectors 224 to pass only a subset of the wavelengths corresponding to the first emission light 331 and/or the reflected second excitation light 330. In one non-limiting embodiment, one or more filters may be disposed on one or more of the reference photodetectors 226 to pass only a subset of the wavelengths corresponding to the reflected first excitation light 329. In one non-limiting embodiment, one or more filters may be disposed on one or more of the interferent photodetectors 228 to pass only a subset of the wavelengths corresponding to the second emission light 332. In one non-limiting embodiment, when the analyte sensor 100 includes one or more second reference photodetectors 230, one or more filters can be disposed on the one or more second reference photodetectors 230 to pass only a subset of wavelengths that correspond to the reflected second excitation light 330.

[0083] In some embodiments, the interferent indicator 209 can be used as a reference dye to measure and correct for the degree of oxidation of the analyte indicator 207. In some embodiments, the analyte monitoring system 50 can use an empirical correlation established through laboratory testing to correct for changes in the analyte indicator 207. FIG. 5 is a chart showing non-limiting examples of sensitivity ratios correlating the analyte indicator 207 with the interferent indicator 209. In some embodiments, the interferent indicator 209 can be more sensitive to oxidation than the analyte indicator 207, as shown by sensitivity ratio 1 in FIG. 5. However, this is not required, and in some alternative embodiments, the interferent indicator 209 can be less sensitive to oxidation than the analyte indicator 207, as shown by sensitivity ratio 2 in FIG. 5. In some other alternative embodiments, the interferent indicator 209 and the analyte indicator 207 can be equally sensitive to oxidation.

[0084] In one embodiment, as shown in FIG. 4, the substrate 112 may be a circuit board (e.g., a printed circuit board (PCB) or a flexible PCB) on which one or more of the circuit components 111 (e.g., analog and/or digital circuit components) may be mounted or otherwise attached. However, in one alternative embodiment, the substrate 112 may be a semiconductor substrate within which one or more of the circuit components 111 are fabricated. Illustratively, the fabricated circuit components may include analog and/or digital circuits. Also, in an embodiment in which the 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 within the semiconductor substrate. In other words, in one semiconductor substrate embodiment, some or all of the 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, and the remaining circuit components 111 may be fixed to the semiconductor substrate, and communication paths may be provided between the various fixed components.

[0085] In some embodiments, the analyte sensor 100 can include one or more light sources 108, 227, and one or more of the light sources 108, 227 can be mounted on or fabricated within the substrate 112. In some embodiments, the analyte sensor 100 can include one or more photodetectors 224, 226, 228, 230, and one or more of the photodetectors 224, 226, 228, 230 can be mounted on or fabricated within the substrate 112. In some non-limiting embodiments, one or more light sources 108, 227 can be mounted on the substrate 112, one or more photodetectors can be fabricated within the substrate 112, and all or a portion of the circuit components 111 can be fabricated within the substrate 112.

[0086] In certain embodiments, one or more of the indicator element 106, light source(s) 108, 227, photodetectors 224, 226, 228, 230, circuit components 111, and substrate 112 of the analyte sensor 100 may include some or all of the features described in one or more of U.S. patent application Ser. No. 13/761,839, filed Feb. 7, 2013, U.S. patent application Ser. No. 13/937,871, filed Jul. 9, 2013, U.S. patent application Ser. No. 13/650,016, filed Oct. 11, 2012, and U.S. patent application Ser. No. 14/142,017, filed Dec. 27, 2013, the contents of which are incorporated herein by reference in their entireties. Similarly, the structure, function, and/or features of the sensor housing 102, the analyte sensor 100, and/or the transceiver 101 may also be described in one or more of U.S. patent applications Ser. Nos. 13/761,839, 13/937,871, 13/650,016, and 14/142,017. Illustratively, the sensor housing 102 may have one or more hydrophobic, hydrophilic, opaque, and/or immune response blocking membranes or layers on its exterior surface.

[0087] As shown in FIG. 1, in some embodiments, the analyte sensor 100 can be a fully implantable sensor, although this is not required and in some alternative embodiments, the analyte sensor 100 can be a transdermal sensing system with a wired connection to the transceiver 101. For example, in some alternative embodiments, the analyte sensor 100 can be disposed in or on (e.g., at the tip of) a transdermal needle. In these embodiments, instead of wireless communication using inductive elements 103 and 114, the analyte sensor 100 and the transceiver 101 can communicate using one or more wires connecting between the transceiver 101 and the transceiver transdermal needle that contains the analyte sensor 100. As another example, in some alternative embodiments, the analyte sensor 100 can be disposed in a catheter (e.g., for intravenous blood glucose monitoring) and can communicate (wirelessly or using wires) with the transceiver 101.

[0088] In some embodiments, the analyte sensor 100 can include a transceiver interface device. In some embodiments, the transceiver interface device can include an antenna (e.g., inductive element 114) of the analyte sensor 100. In some transcutaneous embodiments where there is a wired connection between the analyte sensor 100 and the transceiver 101, the transceiver interface device can include a wired connection.

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 one non-limiting embodiment, 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 one non-limiting embodiment, 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 vibration of the vibration motor 928. In a non-limiting embodiment, the electronic circuitry of the transceiver may be assembled using standard surface mount device (SMD) reflow and soldering techniques. In one aspect, the electronics and peripheral circuitry can be incorporated into a snap together housing design, where the front housing 206 and the rear housing 220 can be snapped together. In some aspects, the complete assembly process can be performed in one external electronics housing. However, this is not required, and in alternative aspects, the transceiver assembly process can be performed in one or more electronics housings, which can be internal, external, or a combination. In some aspects, the assembled transceivers 101 can be programmed and functionally tested. In some aspects, the assembled transceivers 101 can be packaged in their final shipping containers and ready for sale.

[0090] In an embodiment, the antenna 103 may be contained within the housings 206 and 220 of the transceiver 101, as shown in Figures 6 and 7. In an embodiment, the antenna 103 in the transceiver 101 may be small and/or flat so that the antenna 103 fits within the housings 206 and 220 of the transceiver 101, which are small and lightweight. In an embodiment, the antenna 103 may be robust and resistant to various shocks. In an embodiment, the transceiver 101 may be adapted to be placed on the patient's body, for example, on the abdomen, upper arm, wrist, or thigh. In a non-limiting embodiment, the transceiver 101 may be adapted to be attached to the patient's body by a biocompatible patch. In an embodiment, the antenna 103 may be contained within the housings 206 and 220 of the transceiver 101, but this is not required, and in an alternative embodiment, some or all of the antenna 103 may be located outside the transceiver housing. For example, in one alternative embodiment, the antenna 103 can be wrapped around the user's wrist, arm, leg, or waist, such as the antenna described in U.S. Patent No. 8,073,548, which is incorporated herein by reference in its entirety.

[0091] FIG. 8 is a schematic diagram of an external transceiver 101 according to a non-limiting embodiment. In one embodiment, the transceiver 101 can have a connector 902, such as, for example, a Micro-Universal Serial Bus (USB) connector. The connector 902 can enable 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).

[0092] The transceiver 101 can exchange data to and from an external device via the connector 902 and/or can receive power via the connector 902. The transceiver 101 can include a connector integrated circuit (IC) 904, such as, for example, a USB-IC, that can control the transmission and reception of data via the connector 902. The transceiver 101 can also include a charger IC 906 that can receive power via the connector 902 and charge a battery 908 (e.g., a lithium-polymer battery). In some aspects, the battery 908 can be rechargeable, have a short recharge period, and/or have a small size.

[0093] In some embodiments, the transceiver 101 may also include one or more connectors in addition to (or instead of) the micro-USB connector 904. For example, in one alternative embodiment, the transceiver 101 may also include a spring-based connector (e.g., a pogo pin connector) in addition to (or instead of) the micro-USB connector 904, and the transceiver 101 may use the connection established by the spring-based connector for wired communication to a personal computer (e.g., personal computer 109) or a display device 107 (e.g., a smartphone) and/or to receive power, e.g., to charge the battery 908.

[0094] In an aspect, the transceiver 101 can have a wireless communication IC 910. The wireless communication IC 910 enables wireless communication with an external device, 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 aspect, the wireless communication IC 910 can employ one or more wireless communication standards to wirelessly transmit data. The wireless communication standard employed can 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 one non-limiting aspect, the wireless communication IC 910 can be configured to wirelessly transmit data at frequencies higher than 1 gigahertz (e.g., 2.4 or 5 GHz). In an aspect, the wireless communication IC 910 can include an antenna (e.g., a Bluetooth antenna). In one non-limiting aspect, the antenna of the wireless communication IC 910 can be entirely contained within the housing of the transceiver 101 (e.g., housings 206 and 220). However, this is not required, and in alternative aspects, all or part of the antenna of the wireless communication IC 910 may be external to the transceiver housing.

[0095] In an aspect, the transceiver 101 may also include a display interface device that may enable communication by the transceiver 101 with one or more display devices 107. In an aspect, the display interface device may include an antenna and/or a connector 902 of a wireless communication IC 910. In a non-limiting aspect, the display interface device may additionally include a wireless communication IC 910 and/or a connector IC 904.

[0096] In one embodiment, the transceiver 101 can also include a voltage regulator 912 and/or a booster 914. The battery 908 can provide power (through the booster 914) 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 one non-limiting embodiment, the sensor 100 and the transceiver 101 can 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 one non-limiting embodiment, the antenna can be flexible. However, as noted above, the inductive element 103 of the transceiver 101 can be of any configuration that provides a suitable magnetic field strength when brought within suitable physical proximity to the inductive element 114 of the sensor 100. In one aspect, the transceiver 101 can also include a power amplifier 918 to amplify the signal to be transmitted by the inductive element 103 to the sensor 100.

[0097] In one aspect, the transceiver 101 can include a peripheral interface controller (PIC) controller 920 and a memory 922 (e.g., flash memory). The memory 922 can be non-volatile and/or electronically erasable and/or rewritable. The PIC controller 920 can control the overall operation of the transceiver 101. For example, the PIC controller 920 can control the connector IC 904 or the wireless communication IC 910 to transmit data by wired or wireless communication and/or can control the RFID reader IC 916 to communicate data via the inductive element 103. The PIC controller 920 can also control the processing of data received via the inductive element 103, the connector 902, or the wireless communication IC 910.

[0098] In an embodiment, the transceiver 101 may also include a sensor interface device that may enable the transceiver 101 to communicate with the sensor 100. In an embodiment, the sensor interface device may include an inductive element 103. In a non-limiting embodiment, the sensor interface device may additionally include an RFID reader IC 916 and/or a power amplifier 918. However, in an alternative embodiment, when a wired connection exists between the sensor 100 and the transceiver 101 (e.g., a transcutaneous embodiment), the sensor interface device may also include a wired connection.

[0099] In some aspects, the transceiver 101 can include a display 924 (e.g., a liquid crystal display and/or one or more light emitting diodes) that the PIC controller 920 can control to display data (e.g., analyte concentration values). In some aspects, the transceiver 101 can also include a speaker 926 (e.g., a beeper) and/or a vibration motor 928 that can be activated, for example, when an alarm condition is met (e.g., detection of a hypoglycemic or hyperglycemic condition). The transceiver 101 can also include one or more additional sensors 930, which can include an accelerometer and/or a temperature sensor, that can be used in the processing performed by the PIC controller 920.

[00100] FIG. 9 illustrates a non-limiting embodiment of an analyte monitoring process 950 that may be performed by the analyte monitoring system 50. In one embodiment, the process 950 may detect and correct for effects on the analyte indicator 207.

[00101] In some aspects, the process 950 can include a step 952 in which the analyte monitoring system 50 measures an analyte signal. In some aspects, the step 952 can include the transceiver 101 communicating an analyte measurement command to the analyte sensor 100. In some aspects, the step 952 can include the analyte sensor 100 emitting a first excitation light 329 toward the indicator element 106 using the first light source 108 in response to receiving and decoding the analyte measurement command. The analyte indicator 207 of the indicator element 106 can receive the first excitation light 329 and emit a first emission light 331. The signal light detector 224 can receive the first emission light 331 and generate an analyte measurement signal based on the amount of the first emission light 331 received by the signal light detector 224. In one aspect, 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 generate a reference signal indicative of the amount of reflected first excitation light 329 received by the reference photodetector 226.

[00102] In an aspect, the process 950 can include a step 954 in which the analyte monitoring system 50 measures an interferent signal. In an aspect, the step 954 can include the transceiver 101 communicating an interferent measurement command to the analyte sensor 100. In an aspect, the step 954 can include the analyte sensor 100 emitting a second excitation light 330 toward the indicator element 106 using the second light source 227 in response to receiving and decoding the interferent measurement command. The interferent indicator 209 of the indicator element 106 can receive the second excitation light 330 and emit a second emission light 332. The interferent light detector 228 can receive the second emission light 332 and generate an interferent measurement signal based on the amount of the second emission light 332 received by the interferent light detector 228. In one aspect, step 954 may include the analyte sensor 100 receiving the second excitation light 330 reflected from the indicator element 106 using the signal light detector 224 (and/or the second reference light detector 230) and generating a reference signal indicative of the amount of reflected second excitation light 330 received by the signal light detector 224 (and/or the second reference light detector 230).

[00103] In an alternative embodiment, 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 toward the indicator element 106 using the second light source 227 in response to receiving and decoding the analyte measurement command (instead of in response to receiving and decoding a separate interferent measurement command). In an alternative embodiment, steps 952 and 954 may be performed simultaneously, and the analyte sensor 100 may emit the first and second excitation lights 329, 330 toward the indicator element 106 using the first and second light sources 108, 227 simultaneously. In an alternative embodiment, step 954 may be performed before step 952.

[00104] In an aspect, the process 950 can also include a step 956 in which the analyte monitoring system 50 calculates a change in the analyte indicator 207. In an aspect, the step 956 can include an operation of the transceiver 101 receiving sensor data from the analyte sensor 100. In an aspect, the sensor data can include one or more of an analyte measurement, a first reference measurement, an interferent measurement, a second reference measurement, and a temperature measurement. In an aspect, the analyte measurement can correspond to an amount of the first emission light 331 received by the signal light detector 224, the first reference measurement can correspond to an amount of the reflected first excitation light 329 received by the reference light detector 226, the interferent measurement can correspond to an amount of the second emission light 332 received by the interferent light detector 228, and the second reference measurement can correspond to an amount of the reflected second excitation light 330 received by the signal light detector 224. In an alternative embodiment, 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.

[00105] In one aspect, step 956 can include the transceiver 101 (e.g., the microcontroller 910 of the transceiver 101) determining the degree to which the analyte indicator 207 has degraded based on at least the received interferent measurements. In one non-limiting aspect, step 956 can include the transceiver 101 (i) determining the degree to which the interferent indicator 209 has degraded based on the received interferent measurements, and (ii) determining the degree to which the analyte indicator 207 has degraded based on the determined degree to which the interferent indicator 209 has degraded. In one non-limiting aspect, the transceiver 101 can additionally or alternatively determine the degree to which the analyte indicator 207 has degraded using one or more previous interferent measurements and/or one or more previous determinations of the degree to which the interferent indicator 209 has degraded.

[00106] In certain aspects, the process 950 can include a step 958 in which the analyte monitoring system 50 compensates for the calculated change in the analyte indicator 207 and/or the calculated blood volume in the ISF. In certain non-limiting aspects, the transceiver 101 (e.g., the microcontroller 910 of the transceiver 101) can compensate for the calculated change in 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 certain aspects, adjusting the conversion function can include adjusting one or more parameters of the conversion function. In certain aspects, in step 958, the transceiver 101 can additionally or alternatively adjust the conversion function based on a first reference measurement, which can be indicative of in-vivo hydration of the indicator element 106 and/or wound healing kinetics. In one aspect, in step 958, the transceiver 101 can additionally or alternatively adjust the conversion function based on a second reference measurement, which may be a measurement of the opacity of the indicator element 106 in the wavelength range of the first emitted light 331.

[00107] In some aspects, process 950 can include step 960, in which analyte monitoring system 50 calculates the analyte level (e.g., analyte concentration). In some aspects, transceiver 101 (e.g., microcontroller 910 of transceiver 101) can calculate the analyte level using at least the adjusted conversion function and the analyte measurement in step 960. In some aspects, transceiver 101 can additionally calculate the analyte level using a temperature measurement.

[00108] In some aspects, process 950 can include step 962, in which analyte monitoring system 50 displays the calculated analyte level. In some aspects, in step 962, transceiver 101 can display the analyte level on display 924. In some aspects, in step 962, transceiver 101 can additionally or alternatively communicate the calculated analyte level to display device 107, which can additionally or alternatively communicate the calculated analyte level.

[00109] Example
[00110] Compound A was copolymerized with indicator molecules on the hydrogel. The copolymerization method is described in U.S. Patent Nos. 7,060,503 (Colvin) and 9,778,190 (Huffstetler et al.), both of which are incorporated herein by reference in their entireties.

[00111] Initial characterization and subsequent oxidation studies helped understand the degradation kinetics of both the reference dye (Compound A) and the indicator, as shown in Figures 14A and 14B. Initial fluorometer work was performed at a 1:1 ratio of indicator (TFM):Compound A, demonstrating the use of Compound 1 as a copolymerizable reference dye. The plots in Figures 14A and 14B demonstrate the decrease in fluorescence intensity of the indicator molecule (excitation wavelength 380 nm) and the simultaneous increase in fluorescence intensity of Compound A (excitation wavelength 470 nm) at 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.

[00112] In vivo studies were performed in 18 female guinea pigs using mock sensors with a 1:1 ratio of Compound A in the overlying hydrogel to copolymerized indicator. Mock sensors were implanted in the guinea pigs to evaluate the behavior of Compound A in response to in vivo oxidation and its correlation to the degradation of the indicator molecule. Implantation was performed subcutaneously on the back of each guinea pig with a Senseonics implantation tool kit according to the implantation training file (two specimens per guinea pig). Subjects were divided into three groups according to explant time points: 30, 60, and 90 days. Once the specimens were explanted, they were cleaned and sterilized using ENZOL® enzyme detergent and glutaraldehyde solution. The explant samples were then analyzed by fluorometer to assess the change in fluorescence intensity in Compound A, and the % increase in Compound A intensity was correlated to the % modulation loss in the indicator.

[00113] The in vivo studies were performed as follows: Prior to the oxidation studies, an initial 0-18 modulation was performed to collect initial modulation data. A known concentration of hydrogen peroxide was used to purposefully partially oxidize the sensor. After partial oxidation, a 0-18 modulation was performed again to collect modulation data and record the loss in modulation. This procedure was repeated for 3-5 cycles. Further partial oxidations were now performed on the same sensor, and at each oxidation step, 0-18 modulation data was collected. A correlation plot of the rates of degradation of both the indicator and reference dyes is shown in Figure 13.

[00114] In explant analysis of the samples, the samples showed a strong correlation between in vivo and in vivo oxidation of the samples. This correlation helps to determine 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 to be performed.

[00115] Additional Aspects
[00116] In certain 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 increases. To illustrate, FIG. 15A shows a non-limiting example of an analyte indicator molecule of an analyte indicator 207 before and after degradation caused by reactive oxygen species (ROS). In certain 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 including the analyte indicator molecule shown in FIG. 15A may decrease as degradation of the analyte indicator 207 increases over time.

[00117] In certain 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 the interference indicator 209 becomes increasingly degraded. In certain embodiments, the degree of degradation of the interferent indicator 209 can correspond to the degree of degradation of the analyte indicator 207. Thus, in certain embodiments, the degree of change in the intensity or amount of emitted light emitted by the interferent indicator 209 can correspond to the change in the intensity or amount of emitted light emitted by the analyte indicator 207. To illustrate, FIG. 15B shows a non-limiting example of an interferent indicator molecule of the interferent indicator 209 before and after degradation caused by ROS. In one embodiment, 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 an analyte indicator molecule as shown in FIG. 15B may increase as the degradation of the interferent indicator 209 increases over time. However, this is not required, and in one alternative embodiment, the intensity or amount of emitted light (e.g., second emitted light 332) emitted by the interferent indicator 209 may decrease as the degradation of the interferent indicator 209 increases over time.

[00118] In some embodiments, in addition to (or instead of) the intensity or amount of emitted light (e.g., second emitted light 332) emitted by the interferent indicator 209 changing as the interferent indicator 209 becomes more degraded, the absorption of the interferent indicator 209 may change (e.g., increase or decrease) as the interferent indicator 209 becomes more degraded. 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 absorption of the interferent indicator 209 (e.g., as measured by the amount of second excitation light 330 reflected 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 the interferent indicator 209 becomes more degraded (e.g., oxidized). For example, in one embodiment, the color of the indicator element 106 may change from white in the absence of oxidation, as shown in FIG. 16A, to yellow when oxidized, as shown in FIG. 16B. However, a change from white to yellow is not required, and in an alternative embodiment, degradation may result in a different color change (e.g., white to yellow, white to orange, yellow to red, orange to brown, etc.). In one embodiment, the change in color of the interferent indicator 209 (and thus the color of the indicator element 106 that includes the interferent indicator 209) may change the absorption of the interferent indicator 209 (and thus the absorption of the indicator element 106 that includes the interferent indicator 209).

[00119] In some embodiments, the intensity or amount of emission light 331 emitted by analyte indicator 207 may decrease over time (e.g., as analyte indicator 207 becomes increasingly degraded, such as oxidation), as shown in FIG. 17A. In some embodiments, the absorption of indicator element 106 may increase over time (e.g., as interferent indicator 209 becomes increasingly degraded, such as oxidation), as shown by the yellow line in FIG. 17B. In some embodiments, the intensity or amount of second excitation light 330 reflected by indicator element 106 may decrease over time (e.g., as interferent indicator 209 becomes increasingly degraded, such as oxidation), as shown by the blue line in FIG. 17B. In one embodiment, as shown in Figures 17A and 17B, an increase in absorption of the indicator element 106 and a decrease in the intensity or amount of the second excitation light 330 reflected by the indicator element 106 can correspond to a decrease in the intensity or amount of the emission light 331 emitted by the analyte indicator 207.

[00120] FIG. 18 shows a graph of experimental data from a clinical trial in which the analyte sensor 100 was implanted subcutaneously in a living human body. The glucose signal area in FIG. 18 represents an analyte measurement over time that indicates the amount of first emitted light 331 emitted by the analyte indicator 207 and received by one or more signal light detectors 224. As shown in FIG. 18, the analyte measurement may fluctuate initially (e.g., during a wound healing period after implantation of the analyte sensor 100, when blood volume may increase in the interstitial fluid adjacent the sensor 100). The analyte measurement may then decrease over time due to increasing effects on the analyte indicator 207 (e.g., degradation of the analyte indicator 207).

[00121] The UV reference area of FIG. 18 represents 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 FIG. 18, the first reference measurement can vary initially (e.g., during the wound healing period after implantation of the analyte sensor 100, when blood volume may increase in the interstitial fluid adjacent to the sensor 100).

[00122] The yellow oxidation indicator (YOI) area of FIG. 18 shows interferent measurements indicating the amount of second emitted light 332 emitted by the interferent indicator 209 and received by one or more interferent light detectors 228. In this experiment, the interferent measurements, censored after the 10th day from initiation, were expected to increase over time as the interferent indicator 209 deteriorated more. However, experimental data from the in vivo oxidation study demonstrated that the intensity or amount of light emitted by the interferent indicator 209 increased over time as the interferent indicator 209 deteriorated more. Furthermore, experimental data from the in vivo oxidation study demonstrated that the increase in the intensity or amount of light emitted by the interferent indicator 209 over time corresponded to a decrease in the intensity or amount of light emitted by the analyte indicator 207 over time as the analyte indicator 207 deteriorated more.

[00123] The blue reference area in FIG. 18 represents a second reference measurement 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 in FIG. 2A or one or more second reference photodetectors 230 in FIG. 2B) over time. As shown in FIG. 18, the second reference measurement may fluctuate initially (e.g., during a wound healing period after implantation of the analyte sensor 100, when blood volume may increase in the interstitial fluid adjacent the sensor 100). The second reference measurement may then decrease over time as the absorption of the interferent indicator 209 (and the absorption of the indicator element 106 containing the interferent indicator 209) increases (e.g., due to degradation of the interferent indicator 209, such as oxidation). As shown in FIG. 18, the decrease in the second reference measurement over time corresponds to a decrease in the analyte measurement over time. In other words, the experimental data confirms that the absorbance measurements of the indicator element 106 containing the interferent indicator 209 can be used to calculate the effect of the indicator element 106 on the analyte indicator 207 (e.g., its degradation).

[00124] FIG. 20 illustrates a non-limiting embodiment of a process 2000 that may be performed by the analyte monitoring system 50. In an embodiment, the process 2000 may detect an effect on the analyte indicator 207 and correct for it. In an embodiment, the process 2000 may additionally or alternatively detect blood in a medium (e.g., interstitial fluid) proximate to the analyte indicator 207 and correct for it.

[00125] In some aspects, process 2000 can include step 2002, in which analyte monitoring system 50 performs an analyte measurement. In some aspects, step 2002 can include an operation in which analyte monitoring system 50 (e.g., analyte sensor 100) uses analyte indicator 207 to generate an analyte measurement indicative of an amount or concentration of analyte in the medium. In some aspects, the analyte measurement can vary depending at least on an effect on analyte indicator 207. In some aspects, the effect on analyte indicator 207 can be degradation of analyte indicator 207. In some aspects, degradation can include oxidation-induced degradation, such as, for example, degradation by reactive oxygen species (ROS).

[00126] In some aspects, generating an analyte measurement using the analyte indicator 207 in step 2002 may also include emitting a first excitation light 329 toward the analyte indicator 207 using one or more first light sources 108, and outputting the analyte measurement using a signal light detector 224 configured to receive a first emission light 331 emitted by the analyte indicator 207. In some aspects, the analyte measurement may indicate an amount of the first emission light 331 received by the signal light detector 224.

[00127] In some aspects, step 2002 may include the analyte monitoring system 50 (e.g., the analyte sensor 100) receiving an amount of the first excitation light 329 using one or more first reference light detectors 226 and outputting a first reference measurement indicative of the amount of the first excitation light 329 received. In some aspects, 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 the first analyte indicator 207).

[00128] In one aspect, step 2002 can include the transceiver 101 transmitting an analyte measurement command and the analyte sensor 100 receiving the analyte measurement command. In one aspect, step 2002 can include the analyte sensor 100 emitting a first excitation light 329 toward the indicator element 106 using the first light source 108 in response to receiving and decoding the analyte measurement command. The analyte indicator 207 of the indicator element 106 can receive the first excitation light 329 and emit a first emission light 331. The signal light detector 224 can receive the first emission light 331 and generate an analyte measurement signal based on the amount of the first emission light 331 received by the signal light detector 224. In one aspect, the reference light detector 226 can receive the first excitation light 329 reflected from the indicator element 106 and generate a first reference measurement.

[00129] In certain aspects, process 2000 can include step 2004, in which analyte monitoring system 50 measures the effect on analyte indicator 207. In certain aspects, step 2004 can include analyte monitoring system 50 (e.g., analyte sensor 100) generating a second reference measurement using interferent indicator 209. In certain aspects, the second reference measurement can be indicative of the absorption of interferent indicator 209. In certain aspects, the absorption of interferent indicator 209 can vary depending on the effect on analyte indicator 207 (e.g., its degradation). In certain aspects, the second reference measurement generated in step 2004 can be added to a first reference measurement generated in step 2002, which can be indicative of the amount of first excitation light 329 received by one or more first reference photodetectors 226). However, even in those embodiments in which a first reference measurement is not generated in step 2002, a second reference measurement may be generated in step 2004.

[00130] In some aspects, generating a second reference measurement using the interferent indicator 209 in step 2004 can also include emitting a second excitation light 330 toward the interferent indicator 209 using one or more second light sources 227. In some aspects, generating a second reference measurement using the interferent indicator 209 can include receiving an amount of the second excitation light 330 using one or more light detectors (e.g., one or more signal light detectors 224 as shown in FIG. 2A, or one or more second reference light detectors 230 as shown in FIG. 2B) and outputting a second reference measurement. In some aspects, the second reference measurement can be indicative of an amount of the second excitation light 330 received, which can be indicative of the absorption of the interferent indicator 209.

[00131] In some aspects, step 2004 may include the analyte monitoring system 50 (e.g., the analyte sensor 100) generating an interferent measurement using the interferent indicator 209 (in addition to or instead of generating a second reference measurement). In some aspects, generating the interferent measurement may include emitting a second excitation light 330 toward the interferent indicator 209 using one or more second light sources 227. In some aspects, generating the interferent measurement may include receiving a second emission 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 emission light 332 received by the interferent light detector 228. In some aspects, the second emission light 332 may vary in response to an effect on the analyte indicator 331 (e.g., degradation thereof).

[00132] In an aspect, step 2004 can include the transceiver 101 transmitting an interferent measurement command and the analyte sensor 100 receiving the interferent measurement command. In an aspect, step 2004 can include the analyte sensor 100 measuring an effect on the analyte indicator 207 in response to receiving and decoding the interferent measurement command. In an aspect, measuring the effect on the analyte indicator can include emitting a second excitation light 330 toward the indicator element 106 using the second light source 227. The interferent indicator 209 of the indicator element 106 can receive the second excitation light 330 and emit a second emission light 332. The interferent light detector 228 can receive the second emission light 332 and generate an interferent measurement signal based on the amount of the second emission light 332 received by the interferent light detector 228. The signal light detector 224 (and/or the second reference light detector 230) can receive the second excitation light 330 reflected from the indicator element 106 and generate a second reference signal. In an alternative embodiment, step 2004 may not include the transceiver 101 transmitting the interferent measurement command and the analyte sensor 100 receiving the interferent measurement command, and the analyte sensor 100 can measure an 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).

[00133] 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 also use the first and second light sources 108, 227 to emit the first and second excitation lights 329, 330 simultaneously to the indicator element 106. In some other alternative embodiments, step 2004 may be performed before step 2002.

[00134] In an aspect, process 2000 can include step 2006, in which analyte monitoring system 50 (e.g., transceiver 101) calculates an effect on analyte indicator 207 (e.g., the degree to which analyte indicator 207 has degraded). In an aspect, step 2006 can include an operation of analyte sensor 100 transmitting sensor data and transceiver 101 receiving the sensor data. In an aspect, the sensor data can include one or more of an analyte measurement, a first reference measurement, an interferent measurement, a second reference measurement, and a temperature measurement. In an alternative aspect, step 2002 can include an operation in which the analyte sensor 100 transmits sensor data (e.g., the analyte measurement, the first reference measurement, and/or the temperature measurement) and the transceiver 101 receives the sensor data, and/or step 2004 can include an operation in which the analyte sensor 100 transmits sensor data (e.g., the interferent measurement and/or the second reference measurement) and the transceiver 101 receives the sensor data.

[00135] In some aspects, the analyte monitoring system 50 (e.g., transceiver 101) can calculate an effect on the analyte indicator 207 in step 2006 based on at least one or more measurements (e.g., a second reference measurement indicative of the absorption of the interferent indicator 209 and/or an interferent measurement indicative of the emission of the interferent indicator 209) generated in step 2004. In some aspects, the system 50 can calculate an effect on the analyte indicator 106 based on a change in absorption of the analyte indicator 106. The change in absorption of the analyte indicator 106 can be indicated by the second reference measurement. In some aspects, the system 50 can also calculate an effect on the analyte indicator 207 based on a ratio of the interferent measurement to the second reference measurement. In some aspects, step 2006 can additionally or alternatively include the system 50 calculating an effect on the analyte indicator 207 (e.g., a current effect) using one or more previous interferent measurements and/or a previous calculation of an effect on one or more analyte indicators 207.

[00136] In certain aspects, process 2000 can include step 2008, in which analyte monitoring system 50 (e.g., transceiver 101) calculates the amount of blood in the medium (e.g., interstitial fluid (ISF)). In certain aspects, the amount of blood in the medium can be calculated in step 2008 based on a second reference measurement. The second reference measurement can be indicative of the amount of second excitation light 330 received. In certain aspects, the second reference measurement can be indicative of the absorption of interferent indicator 209. In certain aspects, the amount of blood in the medium can additionally or alternatively be calculated based on a first reference measurement. The first reference measurement can be indicative of the amount of first excitation light 329 received. In certain aspects, the amount of blood in the medium can also be calculated in step 2008 based on at least a ratio of the first and second reference measurements. In certain aspects, the amount of blood in the medium can also be calculated in step 2008 based on the interferent measurement. The interferent measurement value can indicate the amount of second emitted light 332 received.

[00137] Figure 19A is a graph showing the extinction coefficients of oxyhemoglobin ( _HbO2 ) and deoxyhemoglobin (Hb) at different wavelengths. Figure 19B is a graph showing the extinction coefficients of oxyhemoglobin ( _HbO2 ), deoxyhemoglobin (Hb), methemoglobin (MetHb), and bilirubin at different wavelengths. In some aspects, in step 2008, the system 50 can calculate the amount of blood in the 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) together with one or more of the first and second reference measurements.

[00138] In some aspects, process 2000 can include step 2010, in which analyte monitoring system 50 (e.g., transceiver 101) compensates for effects on analyte indicator 207 and/or blood in the medium (e.g., ISF). In some aspects, step 2010 can include an act of analyte monitoring system 50 (e.g., transceiver 101) adjusting a conversion function. In some aspects, the conversion function can be used to calculate an analyte level based on the analyte measurement. In some aspects, step 2010 can adjust the conversion function based on the calculated effects on analyte indicator 207 (e.g., calculated in step 2006). In some aspects, additionally or alternatively, step 2010 can also adjust the conversion function based on the calculated blood in the medium (e.g., calculated in step 2008). In some aspects, adjusting the conversion function can include an act of adjusting one or more parameters of the conversion function.

[00139] In some aspects, process 2000 can include step 2012, in which analyte monitoring system 50 (e.g., transceiver 101) calculates the analyte level (e.g., analyte concentration). In some aspects, step 2012 can include an operation in which analyte monitoring system 50 (e.g., transceiver 101) uses the adjusted conversion function and the analyte measurement. In some aspects, system 50 can additionally calculate the analyte level using a temperature measurement.

[00140] In some embodiments, process 2000 can include step 2014, in which analyte monitoring system 50 displays the calculated analyte level. In some embodiments, to display the calculated analyte level in step 2014, system 50 can display the analyte level on display 924. In some embodiments, to display the calculated analyte level in step 2014, system 50 can additionally or alternatively communicate the calculated analyte level to display device 107, which can additionally or alternatively communicate the calculated analyte level.

[00141] 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 glucose measurement. In some embodiments, the binding affinity of this analyte indicator 207 may be specific for glucose, but may also be subject to oxidative de-boronation by local reactive oxygen species (ROS) (e.g., hydrogen peroxide ( _H2O2 )) present in the interstitial space. In some embodiments, the analyte sensor 100 may characterize the oxidation rate from the local in vivo concentration of ROS based on calibration updates. In some embodiments, the indicator element 106 may utilize an interferent indicator 209 to measure ROS concentration, allowing for reduced calibration frequency.

[00142] In some embodiments, as shown in FIG. 22, the analyte sensor 100 can include a plurality of sensing areas 2202 (e.g., sensing areas 2202a, 2202b, 2202c, and 2202d). In some embodiments, the sensing areas 2202 can each include measurement electronics (e.g., optical measurement electronics). In some embodiments, the measurement electronics in each of the sensing areas 2202 can 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 can include first and second substrates 112, where the sensing areas 2202a and 2202c can be disposed on the first substrate 112 and the sensing areas 2202b and 2202d can be disposed on the second substrate 112. In one embodiment, sensing areas 2202a and 2202c may be the long end distal (LED) and long end central (LEC) sensing areas, respectively, of the analyte sensor 100, and sensing areas 2202b and 2202d may be the short end central (SEC) and short end distal (SED) sensing areas, respectively, of the analyte sensor.

[00143] In some embodiments, as shown in FIG. 22, the analyte sensor 100 can 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 can each include an analyte indicator 207 and an interferent indicator 209. In some embodiments, the analyte sensor 100 can measure 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) using the analyte indicator 207. In some embodiments, the analyte sensor 100 can also measure ROS-induced signal degradation using the interferent indicator 209. In some embodiments, the analyte indicator 207 and the interferent indicator 209 may be copolymerized into a single biocompatible hydrogel in one or more indicator elements 106. 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).

[00144] 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 bound analyte may emit a first emission light 331 (e.g., fluorescence) when illuminated by a first excitation light 329, and the analyte indicator 207 with no bound analyte may not emit light (or may only emit 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 emission 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 alter the absorption of the interferent indicator 209 (e.g., absorption of the second excitation light 330 by the interferent indicator 209). In some embodiments, as shown in FIG. 22, one or more sensing areas 2202 (e.g., sensing areas 2202a and 2202c) may interact with the first indicator element 106a (e.g., emitting first and second excitation lights 329 and 330 toward the first indicator element 106a and measuring first and second emission lights 331 and 332 emitted by the first indicator element 106a), and one or more different sensing areas 2202 (e.g., sensing areas 2202b and 2202d) may interact with the second indicator element 106b.

[00145] In certain aspects, the interferent indicators 209 in one or more indicator elements 106 allow the analyte sensor 100 to be configured to measure in vivo signal degradation and signal changes caused by ROS, thereby reducing the frequency of calibration based on reference analyte measurements (e.g., finger stick blood glucose measurements).

[00146] In an embodiment, the analyte sensor 100 can detect an analyte (e.g., glucose) in each of the multiple sensing areas 2202 (e.g., each of the sensing areas 2202a-2202d). In an embodiment, the multiple sensing areas 2202 can be redundant sensing areas. In an embodiment, in each of the sensing areas 2202, the analyte indicator 207 can be excited by a first excitation light 329 emitted by the light source 108 (e.g., a UV LED), and the interferent indicator 209 can be excited by a second excitation light 330 emitted by the light source 227 (e.g., a blue LED). In an embodiment, the first excitation light 329 and the first emission light 331 emitted by the analyte indicator 207 can 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 can be measured by one or more signal photodetectors 224 (see FIG. 2A) or one or more second reference photodetectors 230 (see FIG. 2B), which can be, for example, one or more blue filter coated photodiodes. In some embodiments, the second emission light 332 emitted by the interferent indicator 209 can be measured by one or more interferent photodetectors 228 (e.g., one or more yellow filter coated photodiodes).

[00147] In some embodiments, as shown in FIG. 22, the analyte sensor 100 can 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 can be dispersed within the one or more drug-eluting polymer matrices 2204. In some embodiments, the one or more therapeutic agents can reduce or stop neutrophil migration into the space in which the analyte sensor 100 is implanted, thereby reducing or stopping hydrogen peroxide production and fibrous encapsulation. Thus, in some embodiments, the one or more therapeutic agents can reduce deterioration of one or more indicator elements 106 (e.g., indicator elements 106a and 106b). In some embodiments, the one or more therapeutic agents can be dispersed within the drug-eluting polymer matrix 2204 can include one or more anti-inflammatory agents, such as, for example, nonsteroidal anti-inflammatory agents (e.g., acetylsalicylic acid (aspirin) and/or isobutylphenylpropionic acid (ibuprofen)). In some aspects, 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, derivatives thereof, and analogs thereof. In some aspects, the one or more therapeutic agents may reduce hydrogen peroxide production by neutrophils and macrophages.

[00148] In vivo oxidation experiments were performed to study the response of analyte indicator 207 and interferent indicator 209 to oxidation. As shown in FIG. 23, as oxidation increases, the first emission light 331 emitted by analyte indicator 207 decreases and the second emission light 332 emitted by interferent indicator 209 increases with similar degradation kinetics. FIGS. 24A-24D show optical and fluorescent images of analyte sensor 100 after localized oxidation. FIGS. 24A and 24B show optical components and brightfield images, respectively, of the sensor underlying analyte sensor 100. FIG. 24C shows fluorescent imaging of analyte indicator 207 where there is a localized decrease in fluorescence due to localized oxidation near the bottom surface of analyte indicator 207, and FIG. 24D shows fluorescent imaging of interferent indicator 209 where there is a corresponding localized increase in fluorescence due to localized oxidation near the bottom surface of interferent indicator 209. That is, the fluorescence imaging shown in Figures 24C and 24D clearly demonstrates that the decrease due to local oxidation of the first emission light 331 emitted by the analyte indicator 207 is spatially correlated with the decrease in the second emission light 332 emitted by the interferent indicator 209.

[00149] In a non-limiting example, a clinical feasibility evaluation was conducted in 10 adults with type 1 diabetes for up to 365 days after informed consent. Accuracy for finger stick blood glucose monitoring was evaluated over a period of home use. Measurements showed that evaluating local oxidation is useful for determining temporary deboronation of the analyte indicator chemistry. Figures 25A-25D show in vivo measurements from sensing areas 2202a, 2202c, 2202b, and 2202d, respectively, of the analyte sensor 100 shown in Figure 22. In some aspects, sensing areas 2202a and 2202c may be the long end distal (LED) and long end central (LEC) sensing areas, respectively, of the analyte sensor 100, and sensing areas 2202b and 2202d may be the short end central (SEC) and short end distal (SED) sensing areas, respectively, of the analyte sensor. As shown in FIGS. 25A-25D, the measurements can include measurements of first and second excitation lights 329 and 330 and first and second emission lights 331 and 332.

[00150] In some embodiments, the analyte sensor 100 shown in FIG. 22 can combine the interferent indicator 209 used to measure oxidation with redundant sensing areas 2202a-2202d to obtain an analyte value using a weighted average. In some embodiments, the analyte monitoring system 50 (e.g., the transceiver 101 of the analyte monitoring system 50) can integrate the oxidation and analyte measurements into an analyte computational model that allows for reduced frequency of calibration (e.g., calibration once a week after day 14). In some embodiments, the analyte monitoring system 50 can selectively utilize information (e.g., measurements) from sensing areas 2202 from a multi-analyte (e.g., glucose and oxidation) multi-site array to calculate a glucose value. In a non-limiting example, FIG. 26A shows individual glucose concentrations calculated from sensing areas 2202a-2202d of the analyte sensor 100 shown in FIG. 22 (e.g., individually based on one or more measurements of the first and second excitation lights 329 and 330 and the first and second emission lights 331 and 332 from sensing area 2202), and FIG. 26B shows an overall glucose concentration calculated based on a weighted average of the individual glucose concentrations. In one aspect, sensing areas 2202a and 2202c may be the long end distal (LED) and long end central (LEC) sensing areas of the analyte sensor 100, respectively, and sensing areas 2202b and 2202d may be the short end central (SEC) and short end distal (SED) sensing areas of the analyte sensor, respectively.

[00151] In a non-limiting example, in a feasibility study with 10 subjects, an analyte monitoring system 50 including the analyte sensor 100 shown in FIG. 22 had an overall MARD of 9.2% at 90 days and 9.3% at 180 days, calibrated once a week and using finger stick blood glucose measurements as the baseline, as shown in the table below.

[00152] In a non-limiting example, these studies demonstrate that the multiple sensing channels of the analyte sensor 100 shown in FIG. 22 allow for accurate measurement of glucose as well as assessment of the oxidation of the indicator element 106. By detecting these multiple analytes (e.g., glucose and oxidation), accuracy can be maintained while significantly reducing calibrations to once a week for up to 365 days. Future studies are planned to evaluate the performance of an analyte monitoring system 50 including the analyte sensor 100 shown in FIG. 22.

[00153] The embodiments of the present application have been described above in detail with reference to the drawings. While the present invention has been described based on these preferred embodiments, it will be apparent to one skilled in the art that certain modifications, variations, and alternative structures of the described embodiments are possible within the spirit and scope of the invention. For example, in embodiments of the present invention, the analyte indicator 207 and the interferent indicator 209 are distributed throughout the same indicator element 106, but this is not required. In an alternative embodiment, the analyte sensor 100 may include a first indicator element that includes the analyte indicator 207 and a second indicator element that includes the interferent indicator 209. In these alternative embodiments, the analyte indicator 207 and the interferent indicator 209 may be spatially separated from one another.

Claims (40)

1. An analyte monitoring system comprising:
an analyte indicator having a first detectable property that varies in response to at least (i) an amount or concentration of an analyte in a medium, and (ii) an action on the analyte indicator;
an interferent indicator having an absorbance that varies depending on its effect on the analyte indicator;
a sensor element configured to: (i) generate an analyte measurement based on a first detectable characteristic of the analyte indicator; and (ii) generate a reference measurement based on absorption of at least the interferent indicator;
A controller,
(i) calculating an effect on the analyte indicator based on at least the reference measurements;
(ii) adjusting a conversion function based on at least the calculated effect on the analyte indicator;
(iii) calculating an analyte level using the adjusted conversion function and the analyte measurement;
A controller configured to:
1. An analyte monitoring system comprising: The analyte monitoring system of claim 1, wherein the effect on the analyte indicator is degradation of the analyte indicator. The analyte monitoring system of claim 1 or 2, further comprising an indicator element including the analyte indicator and the interferent indicator, the analyte indicator including analyte indicator molecules dispersed throughout the indicator element, and the interferent indicator including interferent indicator molecules dispersed throughout the indicator element. 4. The analyte monitoring system of claim 1, wherein the sensor element comprises:
a first light source configured to emit a first excitation light toward the analyte indicator;
a signal light detector configured to receive a first emission light emitted by the analyte indicator and to output the analyte measurement, the analyte measurement indicative of an amount of the first emission light received by the signal light detector;
16. An analyte monitoring system comprising: The analyte monitoring system of claim 4, wherein the sensor element further includes a second light source configured to emit a second excitation light toward the interferent indicator. The analyte monitoring system of claim 5, wherein the signal detector is further configured to receive an amount of the second excitation light and output the reference measurement value, the reference measurement value being indicative of an amount of the second excitation light received, the amount of the second excitation light received being indicative of absorption of the interferent indicator. The analyte monitoring system of claim 5, wherein the sensor element further includes a reference photodetector configured to receive an amount of the second excitation light and output the reference measurement, the reference measurement being indicative of an amount of the second excitation light received, the amount of the second excitation light received being indicative of absorption of the interferent indicator. The analyte monitoring system of any one of claims 5 to 7, wherein the sensor element further includes an interferent light detector configured to receive a second emission light emitted by the interferent indicator and output an interferent measurement value indicative of the amount of the second emission light received by the interferent light detector. The analyte monitoring system of any one of claims 5 to 7, wherein the sensor element further includes an interferent light detector configured to receive a second emission light emitted by the interferent indicator and output an interferent measurement value indicative of the amount of the second emission light received by the interferent light detector. The analyte monitoring system of claim 8, wherein the second emitted light varies in response to an action on the analyte indicator. The analyte monitoring system of claim 8 or 9, wherein the sensor element includes a first reference light detector configured to receive an amount of the first excitation light and output a first reference measurement indicative of the amount of the first excitation light received. The analyte monitoring system of any one of claims 8 to 10, wherein the second emission light emitted by the interferent indicator does not vary with the amount or concentration of the analyte in the medium. The analyte monitoring system of any one of claims 8 to 11, wherein the processor is configured to calculate an effect on the analyte indicator based on at least the reference measurement and the interferent measurement. The analyte monitoring system of any one of claims 8 to 11, wherein the processor is configured to calculate an effect on the analyte indicator based on at least the reference measurement and the interferent measurement. The analyte monitoring system of any one of claims 8 to 12, wherein the processor is configured to calculate an effect on the analyte indicator based on at least a ratio of the interferent measurement to the reference measurement. The analyte monitoring system of any one of claims 8 to 12, wherein the processor is configured to calculate an effect on the analyte indicator based on at least a ratio of the interferent measurement to the reference measurement. The analyte monitoring system of any one of claims 1 to 13, wherein the absorption of the interferent indicator does not vary with the amount or concentration of the analyte in the medium. The analyte monitoring system of any one of claims 1 to 14, wherein the processor is further configured to calculate the amount of blood in the medium. The analyte monitoring system of claim 15, wherein the processor is 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. The analyte monitoring system of claim 15, wherein the processor is 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. 17. The analyte monitoring system of claim 15 or 16, wherein the reference measurement is a second reference measurement and the sensor element comprises:
a first light source configured to emit a first excitation light toward the analyte indicator;
a second light source configured to emit a second excitation light toward the interferent indicator;
a first reference photodetector 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;
a signal light detector configured to: (i) receive a first excitation 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, wherein the analyte measurement value is indicative of an amount of the first emitted light received and the second reference measurement value is indicative of an amount of the second excitation light received;
16. An analyte monitoring system comprising: 17. The analyte monitoring system of claim 15 or 16, wherein the reference measurement is a second reference measurement and the sensor element comprises:
a first light source configured to emit a first excitation light toward the analyte indicator;
a second light source configured to emit a second excitation light toward the interferent indicator;
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;
a signal light detector configured to receive a first emitted light emitted by the analyte indicator and output the analyte measurement, the analyte measurement being indicative of an amount of the first emitted light received; and
a second reference light detector configured to receive an amount of the second excitation light and output the second reference measurement value, the second reference measurement value being indicative of the amount of the second excitation light received;
16. An analyte monitoring system comprising: The analyte monitoring system of claim 17 or 18, wherein the processor is configured to calculate the amount of blood in the medium based on at least the first and second reference measurements. 20. The analyte monitoring system of any one of claims 17 to 19, wherein the processor is configured to calculate the amount of blood in the medium based on at least a ratio of the first and second reference measurements. 21. The analyte monitoring system of any one of claims 15 to 20, wherein the sensor element includes an interferent light detector configured to receive emission light emitted by the interferent indicator and output an interferent measurement value indicative of the amount of the emission light received by the interferent light detector, and the processor configured to calculate the amount of blood in the medium based on at least the interferent measurement value. 22. The analyte monitoring system of claim 1, wherein the interferent indicator has a second detectable characteristic that varies in response to an effect on the analyte indicator, the sensor element is further configured to generate an interferent measurement based on the second detectable characteristic of the analyte indicator, and the processor is configured to calculate the effect on the analyte indicator based on at least the reference measurement and the interferent measurement. 23. The analyte monitoring system of claim 22, wherein the processor is configured to calculate an effect on the analyte indicator based at least on a ratio of the interferent measurement to the reference measurement. 1. A method comprising:
using an analyte indicator to generate an analyte measurement indicative of an amount or concentration of an analyte in a medium, the analyte measurement varying in response to at least an action on the analyte indicator;
using an interferent indicator to generate a reference measurement indicative of the absorbance of said interferent indicator, said absorbance varying as a function of an action on said analyte indicator;
calculating an effect on the analyte indicator based at least on the reference measurements;
adjusting a conversion function based at least on said calculated effect on the analyte indicator;
calculating an analyte level using the adjusted conversion function and the analyte measurement;
A method comprising: The method of claim 24, wherein the effect on the analyte indicator is degradation of the analyte indicator. 26. The method of claim 24 or 25, wherein the step of generating the analyte measurement using the analyte indicator comprises:
emitting a first excitation light toward the analyte indicator;
using a signal light detector configured to receive a first emission light emitted by the analyte indicator and output the analyte measurement, the analyte measurement indicative of an amount of the first emission light received by the signal light detector;
A method comprising: The method of claim 26, wherein the step of generating the reference measurement using the interferent indicator includes the step of emitting a second excitation light toward the interferent indicator. 28. The method of claim 27, wherein the step of generating the reference measurement using the interferent indicator further comprises the step of receiving an amount of the second excitation light using the signal light detector and outputting the reference measurement, the reference measurement being indicative of an amount of the second excitation light received, the amount of the second excitation light being indicative of absorption of the interferent indicator. 28. The method of claim 27, wherein the step of generating the reference measurement using the interferent indicator further includes the step of receiving an amount of the second excitation light using a reference light detector and outputting the reference measurement, the reference measurement being indicative of an amount of the second excitation light received, the amount of the second excitation light being indicative of absorption of the interferent indicator. 30. The method of any one of claims 27 to 29, further comprising using an interferent light detector to receive a second emission light emitted by the interferent indicator and outputting an interferent measurement value indicative of the amount of the second emission light received by the interferent detector. 31. The method of claim 30, wherein the second emitted light varies in response to an action on the analyte indicator. The method of claim 30 or 31, further comprising the step of 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. The method of any one of claims 30 to 32, further comprising calculating an effect on the analyte indicator based on at least the reference measurement and the interferent measurement. The method of any one of claims 30 to 33, further comprising calculating an effect on the analyte indicator based at least on a ratio of the interferent measurement value to the reference measurement value. The method of any one of claims 24 to 34, further comprising the step of calculating the amount of blood in the medium. 36. The method of claim 35, wherein the conversion function is adjusted based on at least the calculated effect on the analyte indicator and the calculated amount of blood in the medium. 37. The method of claim 35 or 36, wherein the reference measurement is a second reference measurement;
generating said analyte measurement using said analyte indicator,
emitting a first excitation light toward the analyte indicator;
receiving an amount of the first excitation light using a first reference light detector and outputting a first reference measurement indicative of the amount of the first excitation light received;
receiving a first emitted light emitted by the analyte indicator using a signal detector and outputting the analyte measurement, the analyte measurement indicative of an amount of the first emitted light received;
Including,
generating the reference measurement using the interferent indicator,
emitting a second excitation light toward the interferent indicator;
receiving an amount of the second excitation light using the signal light detector and outputting the second reference measurement, the second reference measurement indicative of the amount of the second excitation light received;
Including,
calculating an amount of blood in the medium based on at least the first and second reference measurements. 37. The method of claim 35 or 36, wherein the reference measurement is a second reference measurement;
generating said analyte measurement using said analyte indicator,
emitting a first excitation light toward the analyte indicator;
receiving an amount of the first excitation light using a first reference light detector and outputting a first reference measurement indicative of the amount of the first excitation light received;
receiving a first emitted light emitted by the analyte indicator using a signal light detector and outputting the analyte measurement, the analyte measurement indicative of an amount of the first emitted light received;
Including,
generating the reference measurement using the interferent indicator,
emitting a second excitation light toward the interferent indicator;
receiving an amount of the second excitation light using a second reference light detector and outputting the second reference measurement, the second reference measurement being indicative of the amount of the second excitation light received;
Including,
calculating an amount of blood in the medium based on at least the first and second reference measurements. The method of claim 37 or 38, further comprising calculating the amount of blood in the medium based on at least a ratio of the first and second reference measurements. The method of any one of claims 35 to 39, further comprising the steps of receiving the emission light emitted by the interferent indicator using an interferent light detector and outputting an interferent measurement value indicative of the amount of the emission light received by the interferent light detector, and calculating the amount of blood in the medium based on at least the interferent measurement value.