Detection and correction of analyte indicator changes

Abstract

Sensors, systems, and methods for detecting and correcting changes in an analyte indicator of an analyte sensor. The analyte indicator can be configured to exhibit a first detectable property that varies as a function of analyte concentration and the extent of degradation of the analyte indicator. The analyte sensor can also include a degradation indicator configured to exhibit a second detectable property that varies as a function of the extent of degradation of the degradation indicator. A sensor element can (i) generate an analyte measure based on the first detectable property exhibited by the analyte indicator and (ii) generate a degradation measure based on the second detectable property exhibited by the degradation indicator. The analyte sensor can be part of a system that also includes a transceiver. The transceiver can calculate an analyte level using the analyte and degradation measures.

Description

[0001] This application is a divisional application of a patent application filed on April 19, 2018, with application number 201880038614.5 and invention name “Detection and Correction of Changes in Analyte Indicators”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 487,289, filed April 19, 2017, which is incorporated herein by reference in its entirety. Background of the Invention

[0004] Field of the Invention

[0005] The present invention generally relates to the detection and correction of changes in analyte indicators. Specifically, the present invention may relate to the detection and correction of oxidation-induced degradation of analyte indicators in analyte monitoring systems.

[0006] Background Discussion

[0007] 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 very useful in the management of diseases such as diabetes.

[0008] Some analyte monitoring systems include analyte sensors that can be (completely or partially) implanted in animals and can include analyte indicators. Due to changes in sensitivity parameters (e.g., calibration constants), analyte sensors may lose sensitivity when implanted in animals. Changes in sensitivity parameters may be due to, for example, degradation of analyte indicators. For example, degradation may be caused by oxidation of analyte indicators induced by reactive oxygen species (ROS) produced by cells. See, for example, U.S. Patent No. 8,143,068, U.S. Patent No. 9,427,181, and U.S. Patent Application Publication No. 2012 / 0238842, each of which is incorporated herein by reference as a whole. It is possible to reduce the sensitivity loss rate in vivo by, for example, using antioxidant indicator molecules, integrating catalytic protection, and / or using enzymes that catalyze reactive oxygen species (ROS) degradation. However, reducing the sensitivity loss rate in vivo does not completely prevent sensitivity loss. Sensitivity parameters gradually changing over time may have a negative impact on analyte sensing accuracy, and may require recalibration (e.g., self-monitoring blood glucose measurement) using a reference analyte measurement, which may be uncomfortable and / or undesirable for the user. SUMMARY OF THE INVENTION

[0009] The present invention overcomes the shortcomings of existing systems by providing an analyte monitoring system that can detect changes in analyte indicators and correct the changes detected. In contrast to prior art systems that can only correct analyte indicator changes when recalibrating using a reference analyte measurement, among other advantages, an analyte monitoring system can provide the ability to correct analyte indicator changes without the need for reference analyte measurement. In some embodiments, an analyte monitoring system can include an analyte sensor that indirectly measures an analyte indicator using a degradation indicator, the degradation indicator being sensitive to reactive oxygen species (ROS) degradation but insensitive to analyte. In some embodiments, the degradation indicator can have optical properties that vary with the degree of oxidation and can be used as a reference dye for measuring and correcting the degree of oxidation of an analyte indicator. In some embodiments, an analyte monitoring system can utilize the empirical relationship established by laboratory testing to correct the change in an analyte indicator.

[0010] An aspect of the present invention can provide an analyte sensor for measuring the analyte in a medium in an animal. The analyte sensor may include an analyte indicator, a degradation indicator, and a sensor element. The analyte indicator may be configured to display a first detectable property, which varies according to the amount or concentration of the analyte in (i) the medium, and (ii) the degree of degradation of the analyte indicator. The degradation indicator may be configured to display a second detectable property, which varies according to the degree of degradation of the degradation indicator. The degree of degradation of the degradation indicator may correspond to the degree of degradation of the analyte indicator. The sensor element may be configured to produce an analyte measurement based on the first detectable property displayed by the analyte indicator, and (ii) produce a degradation measurement based on the second detectable property displayed by the degradation indicator.

[0011] In some embodiments, the degree of degradation of the degradation indicator can be proportional to the degree of degradation of the analyte indicator. In some embodiments, the degradation of the analyte indicator can include oxidation induced by reactive oxygen species (ROS), and the degradation of the degradation indicator includes ROS-induced oxidation. In some embodiments, the analyte indicator can be an analyte indicator based on phenylboronic acid. In some embodiments, the degradation indicator can be a degradation indicator based on phenylboronic acid.

[0012] In some embodiments, the analyte sensor can further include an indicator element comprising the analyte indicator and the degradation indicator. In some embodiments, the analyte indicator can include analyte indicator molecules distributed throughout the indicator element, and the degradation indicator can include degradation indicator molecules distributed throughout the indicator element. In some embodiments, the second detectable property does not vary based on the amount or concentration of the analyte in the medium.

[0013] In some embodiments, the sensor element may include a first light source and a first photodetector. The first light source may be configured to emit a first excitation light toward an analyte indicator. The first photodetector may be configured to receive the first emission light emitted by the analyte indicator and output an analyte measurement. The analyte measurement may indicate the amount of the first emission light received by the first photodetector. In some embodiments, the sensor element may include a second light source and a second photodetector. The second light source may be configured to emit a second excitation light toward a degradation indicator. The second photodetector may be configured to receive the second emission light emitted by the degradation indicator and output a degradation measurement. The degradation measurement may indicate the amount of the second emission light received by the second photodetector. In some embodiments, the first photodetector may be configured to receive the second excitation light reflected from the indicator element and output a first reference signal indicating the amount of the reflected second excitation light received by the first photodetector. In some embodiments, the sensor element may include a third photodetector configured to receive the first excitation light reflected from the indicator element and output a second reference signal indicating the amount of the reflected first excitation light received by the third photodetector.

[0014] Another aspect of the present invention may provide a method comprising measuring the amount or concentration of an analyte in a medium using an analyte indicator of an analyte sensor. The method may include measuring the extent of degradation of the degradation indicator using a degradation indicator of the analyte sensor. The method may include receiving an analyte measurement from the analyte sensor using a sensor interface device of a transceiver, the measurement indicating the amount or concentration of the analyte in the medium. The method may include receiving a degradation measurement from the analyte sensor using the sensor interface device of the transceiver, the measurement indicating the extent of degradation of the degradation indicator. The method may include calculating, using a controller of the transceiver, the extent of degradation of the analyte indicator of the analyte sensor based at least on the received degradation measurement. The method may include adjusting, using the controller of the transceiver, a transfer function based on the calculated extent of degradation of the analyte indicator. The method may include calculating, using the controller of the transceiver, an analyte level using the adjusted transfer function and the received analyte measurement. The method may include displaying the calculated analyte level.

[0015] Another aspect of the present invention can provide an analyte monitoring system comprising an analyte sensor and a transceiver. The analyte sensor may include an analyte indicator, a degradation indicator, a sensor element, and a transceiver interface device. The analyte indicator may be configured to display a first detectable property, which varies according to the amount or concentration of the analyte in (i) the medium and (ii) the degree of degradation of the analyte indicator. The degradation indicator may be configured to display a second detectable property, which varies according to the degree of degradation of the degradation indicator. The sensor element may be configured to (i) produce an analyte measurement based on the first detectable property displayed by the analyte indicator and (ii) produce a degradation measurement based on the second detectable property displayed by the degradation indicator. The transceiver may include a sensor interface device and a controller. The controller can be configured to: (i) receive an analyte measurement from the analyte sensor via the transceiver interface device and the sensor interface device of the analyte sensor; (ii) receive a degradation measurement from the analyte sensor via the transceiver interface device and the sensor interface device of the analyte sensor; (iii) calculate an extent of degradation of an analyte indicator of the analyte sensor based at least on the received degradation measurement; (iv) adjust a transfer function based on the calculated extent of degradation of the analyte indicator; and (v) calculate an analyte level using the adjusted transfer function and the received analyte measurement.

[0016] In some embodiments, the analyte sensor can further include an indicator element, and the indicator element can include the analyte indicator and a degradation indicator.In some embodiments, the second detectable property does not vary based on the amount or concentration of the analyte in the medium.

[0017] Further variations encompassed within the systems and methods are described below in the detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate various non-limiting embodiments of the present invention. In the drawings, like reference numbers indicate identical or functionally similar elements.

[0019] Figure 1 is a schematic diagram illustrating an analyte monitoring system embodying aspects of the present invention.

[0020] Figure 2 is a schematic diagram illustrating an analyte sensor embodying aspects of the present invention.

[0021] Figure 3 is a perspective view illustrating components of an analyte sensor embodying aspects of the present invention.

[0022] Figure 4 is a schematic diagram illustrating a semiconductor substrate layout of an analyte sensor embodying aspects of the present invention.

[0023] Figure 5 is a graph illustrating non-limiting examples of sensitivity ratios relating analyte indicators to degradation indicators embodying aspects of the present invention.

[0024] Figure 6 is a cross-sectional perspective view of a transceiver embodying aspects of the present invention.

[0025] Figure 7 is an exploded perspective view of a transceiver embodying aspects of the present invention.

[0026] Figure 8 is a schematic diagram illustrating a transceiver embodying aspects of the present invention.

[0027] Figure 9 is a flow chart illustrating a process for detecting and correcting for changes in an analyte indicator embodying aspects of the present invention.

[0028] Figure 10-12 The illustrations are schematic diagrams of non-limiting examples of structures of indicator elements 106 embodying aspects of the present invention.

[0029] Figure 13 is a graph illustrating a correlation plot of degradation rates of an indicator and a reference dye according to one non-limiting embodiment of the present invention.

[0030] Figure 14A and 14B Fluorometer readings are shown, with a 1:1 ratio of indicator molecule:Compound A, demonstrating a decrease in the fluorescence intensity of the indicator molecule (excitation wavelength 380 nm) and a simultaneous increase in the fluorescence intensity of Compound A (excitation wavelength 470 nm) in the presence of 2 mM glucose and 50 uM hydrogen peroxide, confirming the use of Compound A as a copolymerizable reference dye. Detailed Description of the Invention

[0031] Figure 1is a schematic diagram of an exemplary analyte monitoring system 50 embodying aspects of the present application. The analyte monitoring system 50 can be a continuous analyte monitoring system (e.g., a continuous glucose monitoring system). In some embodiments, the analyte monitoring system 50 can include one or more of an analyte sensor 100, a transceiver 101, and a display device 107. In some embodiments, the analyte sensor 100 can be a small, fully subcutaneous implanted sensor that measures an amount or concentration of an analyte (e.g., glucose) in a medium (e.g., interstitial fluid) of a living subject (e.g., a living human). However, this is not required, and in some alternative embodiments, the analyte sensor 100 can be a partially implanted (e.g., transcutaneous) sensor or a fully external sensor. In some embodiments, the transceiver 101 can be an externally worn transceiver (e.g., attached by an armband, wristband, waistband, or patch). In some embodiments, the transceiver 101 can be remotely powered and / or communicate with the sensor 100 to initiate and receive measurements (e.g., through near field communication (NFC)). However, this is not required, and in some alternative embodiments, the transceiver 101 can be powered and / or communicate with the analyte sensor 100 through one or more wired connections. In some non-limiting embodiments, the transceiver 101 can be a smart phone (e.g., a NFC-enabled smart phone). In some embodiments, the transceiver 101 can wirelessly transmit information (e.g., one or more analyte measurements) to a handheld application running on a display device 107 (e.g., a smart phone), for example, through a Bluetooth™ communication standard, such as, but not limited to, Bluetooth Low Energy.

[0032] Figure 2 is a schematic diagram of an analyte sensor 100 embodying aspects of the present application, and Figure 3 is a perspective view illustrating elements of an analyte sensor 100 embodying aspects of the present application. In some embodiments, the analyte sensor 100 can detect the presence, amount, and / or concentration of an analyte (e.g., glucose, oxygen, a cardiac marker, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides). In some non-limiting embodiments, the analyte sensor 100 can be an optical sensor (e.g., a fluorimeter). In some embodiments, the analyte sensor 100 can be a chemical or biochemical sensor. In some embodiments, the analyte sensor 100 can be a radio frequency identification (RFID) device. The analyte sensor 100 can be powered by a radio frequency (RF) signal from an external transceiver 101.

[0033] The analyte sensor 100 can communicate with an external transceiver 101. The transceiver 101 can 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 some embodiments, the transceiver 101 can calculate the analyte concentration from the measurement data received from the analyte sensor 100. However, the transceiver 101 itself is not required to perform the analyte concentration calculation, and in some alternative embodiments, the transceiver 101 can instead transmit / forward the measurement data received from the analyte sensor 100 to another device for calculating the analyte concentration. In other alternative embodiments, the analyte sensor 100 can perform the analyte concentration calculation.

[0034] 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 connection for power and / or data transmission. Figure 3 As shown, the analyte sensor 100 may include a sensing element 114, which may be, for example, a ferrite-based micro-antenna. Figure 3 As shown, the sensing element 114 can include a conductor 302 in the form of a coil and a magnetic core 304. In some non-limiting embodiments, the core 304 can be, for example, but not limited to, a ferrite core. In some embodiments, the sensing element 114 can be connected to the analyte detection circuit of the analyte sensor 100. For example, in some embodiments, where the analyte sensor 100 is an optical sensor, the sensing element 114 can be connected to a microfluorometer circuit (e.g., an application specific integrated circuit (ASIC)) and an associated optical detection system of the analyte sensor 100. In some embodiments, the analyte sensor 100 can not include a battery, and as a result, the analyte sensor 100 can rely on the transceiver 101 to provide power to the analyte sensor 100 of the sensor system 105 and to provide a data connection to transmit analyte-related data from the analyte sensor 100 to the transceiver 101.

[0035] In some non-limiting embodiments, the analyte sensor 100 can be a small, passive, fully implantable multi-site sensing system. For the analyte sensor 100 (which is a fully implantable sensing system without a battery power source), the transceiver 101 can provide energy to operate the analyte sensor 100 through a magnetic field. In some embodiments, the magnetic transceiver-sensing system connection can be considered a "weakly coupled transformer" type. The magnetic transceiver-sensing system connection can utilize amplitude modulation (AM) to provide energy and data transmission connection. Although in some embodiments, AM is utilized for data transmission, in alternative embodiments, other types of modulation can be used. The magnetic transceiver-sensor connection may have low energy transmission efficiency, and therefore, a relatively high-power amplifier may be required to provide energy for the analyte sensor 100 over a long distance. In some non-limiting embodiments, the transceiver 101 and the analyte sensor 100 can utilize near-field communication (e.g., at a frequency of 13.56 MHz, which can achieve a high permeability through the skin and is a medically approved frequency band) to communicate for energy transmission. However, this is not required, and in other embodiments, different frequencies may be used to power and communicate with the analyte sensor 100 .

[0036] In some embodiments, as Figure 7 As shown, the transceiver 101 may include an inductive element 103, such as a coil. The transceiver 101 may generate electromagnetic waves or an electric field (e.g., by utilizing the coil 103) to induce a current in the inductive element 114 of the analyte sensor 100, which powers the analyte sensor 100. The transceiver 101 may also transmit data (e.g., instructions) to the analyte sensor 100. For example, in a non-limiting embodiment, the transceiver 101 may transmit data by modulating the electromagnetic waves used to power the analyte sensor 100 (e.g., by modulating the current flowing through the coil of the transceiver 101). The modulation of the electromagnetic waves generated by the transceiver 101 may be detected / extracted by the analyte sensor 100. In addition, the transceiver 101 may receive data (e.g., measurement information) from the analyte sensor 100. For example, in a non-limiting embodiment, the transceiver 101 may receive data by detecting modulation of electromagnetic waves generated by the analyte sensor 100 , eg, by detecting modulation of current flowing through the coil 103 of the transceiver 101 .

[0037] In some non-limiting embodiments, Figure 2As described in , the analyte sensor 100 may include a sensor housing 102 (i.e., a body, shell, capsule, or packaging) that may be rigid and biocompatible. In one non-limiting embodiment, the sensor housing 102 may be a silicone tube. However, this is not required, and in other embodiments, different materials and / or shapes may be used for the sensor housing 102. In some embodiments, the analyte sensor 100 may include a transmission light cavity. In some non-limiting embodiments, the transmission light cavity may be formed from a suitable optically transmissive polymer material, such as an acrylic polymer (e.g., polymethyl methacrylate (PMMA)). However, this is not required, and in other embodiments, different materials may be used for the transmission light cavity.

[0038] In some embodiments, as Figure 2 As shown, the analyte sensor 100 can include an indicator element 106, for example, a polymer graft or hydrogel coated, spread, adhered, embedded, or grown on or in at least a portion of the outer surface of the sensor housing 102. In some non-limiting embodiments, the sensor housing 102 can include one or more cutouts or grooves, and the indicator element 106 can be (partially or completely) located in the cutouts or grooves. In some embodiments, the indicator element 106 can be porous and can allow an analyte (e.g., glucose) in a medium (e.g., interstitial fluid) to diffuse into the indicator element 106.

[0039] In some embodiments, the indicator element 106 (e.g., a polymer implant or hydrogel) of the sensor 100 can include one or more of an analyte indicator 207 and a degradation indicator 209. In some embodiments, the analyte indicator 207 can display one or more detectable properties (e.g., optical properties) that change according to (i) the amount or concentration of the analyte approaching the indicator element 106 and (ii) the change in the analyte indicator 207. In some embodiments, the change in the analyte indicator 207 can include the extent of degradation of the analyte indicator 207. In some non-limiting embodiments, the degradation can be (at least in part) ROS-induced oxidation. In some embodiments, the analyte indicator 207 can include one or more analyte indicator molecules (e.g., fluorescent analyte indicator molecules) that can be distributed throughout the indicator element 106. In some non-limiting embodiments, the analyte indicator 207 can be an analyte indicator based on phenylboronic acid. However, a phenylboronic acid-based analyte indicator is not required, and in some alternative embodiments, 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.

[0040] In some embodiments, degradation indicator 209 can exhibit one or more detectable properties (e.g., optical properties) that change based on changes in degradation indicator 209. In some embodiments, degradation indicator 209 is insensitive to the amount or concentration of analyte in proximity to indicator element 106. That is, in some embodiments, one or more detectable properties exhibited by degradation indicator 209 do not change based on the amount or concentration of analyte in proximity to indicator element 106. However, this is not required, and in some alternative embodiments, one or more detectable properties exhibited by degradation indicator 209 can change based on the amount or concentration of analyte in proximity to indicator element 106.

[0041] In some embodiments, the change in degradation indicator 209 can include the degree of degradation of degradation indicator 209. In some embodiments, degradation can be (at least in part) ROS-induced oxidation. In some embodiments, degradation indicator 209 can include one or more degradation indicator molecules (e.g., fluorescent degradation indicator molecules) that can be distributed throughout indicator element 106. In some non-limiting embodiments, degradation indicator 209 can be a degradation indicator based on phenylboronic acid. However, degradation indicators based on phenylboronic acid are not required, and in some alternative embodiments, analyte sensor 100 can include different degradation indicators, such as, but not limited to, amplex red-based degradation indicators, dichlorodihydrofluorescein-based indicators, dihydrorhodamine-based indicators, and scopolamine-based indicators.

[0042] In some non-limiting embodiments, the degradation indicator molecule can be a fluorescent probe compound having an excitation wavelength of about 450 nm to about 550 nm, a Stokes shift of about 500 nm to about 650 nm, and a half-life of about 50 days to about 150 days. In some non-limiting embodiments, the degradation indicator molecule can be a compound of Formula I:

[0043]

[0044] wherein A, B, C, A', B', C', W, X, Y and Z represent -CH, wherein hydrogen may be optionally and independently substituted with an alkyl group,

[0045] R1 and R2 are independently selected from one or more vinyl groups, alkyl vinyl groups, acrylamide groups, methacrylamide groups or other polymerizable groups.

[0046] Exemplary and non-limiting compounds include the following:

[0047]

[0048] The compounds can be synthesized using synthetic techniques known in the art, such as “Preparation and use of MitoPY1 for imaging hydrogen peroxide in mitochondria of live cells,” Dickinson, et al. Nat Protoc. 2013 June; 8(6): 1249-1259 and U.S. Laid-Open Publication No. US2016 / 0312033 (App. Ser. No. 15 / 135,788, Yang et al., October 27, 2016), the disclosures of which are incorporated herein in their entireties.

[0049] In some alternative embodiments, the molecules that degrade the indicator 209 can be compounds having a different formula having an excitation wavelength of about 450 nm to about 550 nm, a Stokes shift of about 500 nm to about 650 nm, and a half-life of about 50 days to about 150 days.

[0050] In some non-limiting embodiments, as shown in Figure 10-12 , the indicator element 106 can include one or more polymer backbones 1002. In some non-limiting embodiments, the polymer backbone 1002 can be a polymer chain. In some embodiments, as shown in Figure 10 and 11 , the indicator element 106 can include one or more analyte indicator molecules A and one or more degradation indicator molecules D. In some embodiments, as shown in Figure 10 and 11 , the analyte indicator molecules A and the degradation indicator molecules D can be monomers that are individually polymerized to the polymer backbone 1002. In some non-limiting embodiments, the indicator element 106 can include an equal number of analyte indicator molecules A and degradation indicator molecules D (see Figure 10 ) or a different number of analyte indicator molecules A and degradation indicator molecules D (see Figure 11 ). In some embodiments, the ratio of analyte indicator molecules A to degradation indicator molecules D can be, for example, but not limited to, 1:1 as shown in Figure 10 , 2:1 as shown in Figure 11 , 1:2, 3:1, 5:1, 10:1, etc.

[0051] In some alternative embodiments, as shown in Figure 12As shown, one or more degradation indicator molecules D can be chemically bonded to analyte indicator molecule A (e.g., via a covalent bond), and analyte indicator molecule A can be chemically bonded to polymer backbone 1002. In a non-limiting alternative embodiment, analyte indicator molecule A and degradation indicator molecule D can be monomers, and analyte indicator molecule A can be polymerized to polymer backbone 1002. In some other alternative embodiments, one or more analyte indicator molecules A can be chemically bonded to degradation indicator molecule D, and degradation indicator molecule D can be chemically bonded to polymer backbone 1002. In a non-limiting alternative embodiment, analyte indicator molecule A and degradation indicator molecule D can be monomers, and degradation indicator molecule D can be polymerized to polymer backbone 1002.

[0052] In some embodiments, the analyte sensor 100 can indirectly measure the change of the analyte indicator 207 using a degradation indicator 209, which may be sensitive to degradation by reactive oxygen species (ROS), but not to the analyte. In some embodiments, the degradation indicator 207 may have one or more optical properties that vary with the degree of oxidation and can be used as a reference dye to measure and correct the degree of oxidation of the analyte indicator. In some embodiments, the degree of degradation of the degradation indicator 209 can be proportional to the degree of degradation of the analyte indicator 207. For example, in some non-limiting embodiments, the degree of degradation of the degradation indicator 209 can be proportional to the degree of degradation of the analyte indicator 207. In some non-limiting embodiments, the degree of degradation of the analyte indicator 207 can be calculated based on the degree of degradation of the degradation indicator 209. In some embodiments, the analyte monitoring system 50 can correct the change of the analyte indicator 207 using an empirical relationship established through laboratory testing.

[0053] In some embodiments, as Figure 2 As shown, the analyte sensor 100 can include one or more first light sources 108 that emit a first excitation light 329 within a wavelength range that interacts with the analyte indicator 207 in the indicator element 106. In some non-limiting embodiments, the first excitation light 329 can be ultraviolet (UV) light. In some embodiments, the analyte sensor 100 can include one or more light sources 227 that emit a second excitation light 330 within a wavelength range that interacts with the degradation indicator 209 in the indicator element 106. In some non-limiting embodiments, the second excitation light 330 can be blue light.

[0054] In some embodiments, as Figure 2As shown, the analyte sensor 100 may also 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 that are sensitive to first emitted light 331 (e.g., fluorescence) emitted by the analyte indicator 207 of the indicator element 106, such that the signal generated by the photodetector 224 in response to the first emitted light 331 indicates the level of the first emitted light 331 of the analyte indicator 207, thereby indicating the amount of the analyte of interest (e.g., glucose). In some non-limiting embodiments, the analyte sensor 100 may include one or more reference photodetectors 226 that may be sensitive to first excitation light 329 that may be reflected from the indicator element 106. In some embodiments, the analyte sensor 100 can include one or more degradation photodetectors 228 that are sensitive to second emission light 332 (e.g., fluorescence) emitted by the degradation indicator 209 of the indicator element 106, such that the signal generated by the photodetector 228 in response to the second emission light 332 indicates the level of the second emission light 332 of the degradation indicator 209, thereby indicating the amount of degradation (e.g., oxidation). In some non-limiting embodiments, the one or more signal photodetectors 224 can be sensitive to the second excitation light 330 that may be reflected from the indicator element 106. In this way, when the one or more light sources 227 emit the second excitation light 330, the one or more signal photodetectors 224 can act as a reference photodetector.

[0055] In some embodiments, first excitation light 329 may be in a first wavelength range, and second excitation light 330 may be in a second wavelength range, which may be 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, first emission light 331 may be in a third wavelength range, and second emission light 332 may be in a fourth wavelength range, which may be 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 some non-limiting embodiments, the second and fourth wavelength ranges do not overlap, but this is not required, and in some alternative embodiments, the second and fourth wavelength ranges may overlap. In some non-limiting embodiments, the second and third wavelength ranges may overlap.

[0056] In some embodiments, one or more of the photodetectors 224, 226, 228 can be covered by one or more filters that allow only a specific subset of wavelengths of light to pass through and reflect (or absorb) the remaining wavelengths. In some non-limiting embodiments, the one or more filters on the one or more signal photodetectors 224 can allow only a subset of wavelengths corresponding to the first emission light 331 and / or the reflected second excitation light 330. In some non-limiting embodiments, the one or more filters on the one or more reference photodetectors 226 can allow only a subset of wavelengths corresponding to the reflected first excitation light 329. In some non-limiting embodiments, the one or more filters on the one or more degradation photodetectors 228 can allow only a subset of wavelengths corresponding to the second emission light 332.

[0057] In some embodiments, degradation indicator 209 can be used as a reference dye to measure and correct for the degree of oxidation of analyte indicator 207. In some embodiments, analyte monitoring system 50 can correct for changes in analyte indicator 207 using empirical relationships established through laboratory testing. Figure 5 is a graph illustrating a non-limiting example of a sensitivity ratio for associating analyte indicator 207 with degradation indicator 209. In some embodiments, as Figure 5As shown in sensitivity ratio 1, the degradation indicator 209 can be more sensitive to oxidation than the analyte indicator 207. However, this is not required, and in some alternative embodiments, as shown in sensitivity ratio 2, the degradation indicator 207 can be less sensitive to oxidation than the analyte indicator 207. In some other alternative embodiments, the degradation indicator 209 and the analyte indicator 207 can be equally sensitive to oxidation. Figure 5 As shown in sensitivity ratio 1, the degradation indicator 209 can be more sensitive to oxidation than the analyte indicator 207. However, this is not required, and in some alternative embodiments, as shown in sensitivity ratio 2, the degradation indicator 207 can be less sensitive to oxidation than the analyte indicator 207. In some other alternative embodiments, the degradation indicator 209 and the analyte indicator 207 can be equally sensitive to oxidation.

[0058] In some embodiments, the substrate 112 can be a circuit board (e.g., a printed circuit board (PCB) or a flexible PCB) on which one or more circuit components 111 (e.g., analog and / or digital circuit components) can be mounted or attached. However, in some alternative embodiments, the substrate 112 can be a semiconductor substrate in which one or more circuit components 111 are fabricated. For example, the fabricated circuit components can include analog and / or digital circuitry. Also, in some embodiments in which the substrate 112 is a semiconductor substrate, circuit components can be mounted or attached to the semiconductor substrate in addition to the circuit components fabricated in the semiconductor substrate. In other words, in some semiconductor substrate embodiments, some or all of the circuit components 111 (which can include discrete circuit elements, integrated circuits (e.g., application specific integrated circuits (ASICs)), and / or other electronic components (e.g., non-volatile memory)) can be fabricated in the semiconductor substrate, and the remaining circuit components 111 are affixed to the semiconductor substrate, which can provide communication paths between the various affixed components.

[0059] 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, and one or more of the photodetectors 224, 226, 228 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 some of the circuit components 111 can be fabricated within the substrate 112.

[0060] In some embodiments, one or more of the indicator element 106, light source 108, 227, photodetectors 224, 226, 228, circuit assembly 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. application serial number 13 / 761,839 filed on February 7, 2013, U.S. application serial number 13 / 937,871 filed on July 9, 2013, U.S. application serial number 13 / 650,016 filed on October 11, 2012, and U.S. application serial number 14 / 142,017 filed on December 27, 2013 (all of which are incorporated herein by reference in their entirety). Similarly, the structure, function, and / or features of the sensor housing 102, analyte sensor 100, and / or transceiver 101 can be as described in one or more of U.S. Application Serial Nos. 13 / 761,839, 13 / 937,871, 13 / 650,016, and 14 / 142,017. For example, the sensor housing 102 can have one or more hydrophobic, hydrophilic, opaque, and / or immune response blocking films or layers on its exterior.

[0061] Although in some embodiments, such as Figure 1 As described in , the analyte sensor 100 can be a fully implantable sensor, but this is not required, and, in some alternative embodiments, the analyte sensor 100 can be a transcutaneous sensing system with a wired connection to the transceiver 101. For example, in some alternative embodiments, the analyte sensor 100 can be located within or on a transcutaneous needle (e.g., at its tip). In these embodiments, instead of wireless communication using sensing elements 103 and 114, the analyte sensor 100 and the transceiver 101 can communicate using one or more wires connected between the transceiver 101 and the transceiver transcutaneous needle including the analyte sensor 100. For another example, in some alternative embodiments, the analyte sensor 100 can be located in a catheter (e.g., for venous blood glucose monitoring) and can communicate with the transceiver 101 (wirelessly or using a wire).

[0062] 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., sensing element 114) of the analyte sensor 100. In some transcutaneous embodiments, where a wired connection exists between the analyte sensor 100 and the transceiver 101, the transceiver interface device can include a wired connection.

[0063] Figure 6 and 7 are cross-sectional and exploded views, respectively, of a non-limiting embodiment of a transceiver 101 that may be included in Figure 1In the illustrated analyte monitoring system 50. Figure 7 As described in

[0015] , in some non-limiting embodiments, 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 tag 222, and / or a vibration motor 928. In some non-limiting embodiments, vibration motor 928 may be attached to either front housing 206 or rear housing 220 so that battery 212 does not dampen vibrations of vibration motor 928. In non-limiting embodiments, transceiver electronics may be assembled using standard surface mount device (SMD) reflow and soldering techniques. In one embodiment, electronics and peripherals may be placed into a snap-on housing design, where front housing 206 and rear housing 220 snap together. In some embodiments, the entire assembly process may be performed in a single external electronics house. However, this is not required, and in alternative embodiments, the transceiver assembly process may be performed in one or more electronics houses, which may be internal, external, or a combination thereof. In some embodiments, the assembled transceivers 101 can be programmed and functionally tested. In some embodiments, the assembled transceivers 101 can be packaged in their final shipping containers and ready for sale.

[0064] In some embodiments, as Figure 6 and 7 As illustrated, the antenna 103 can be contained within the housing 206 and 220 of the transceiver 101. In some embodiments, the antenna 103 in the transceiver 101 can be small and / or flat, so that the antenna 103 is installed within the housing 206 and 220 of the small and lightweight transceiver 101. In some embodiments, the antenna 103 can be robust and able to withstand various impacts. In some embodiments, the transceiver 101 can be suitable for placement on, for example, the abdominal area, upper arm, wrist, or thigh of the patient's body. In some non-limiting embodiments, the transceiver 101 can be suitable for attachment to the patient's body via a biocompatible patch. Although, in some embodiments, the antenna 103 can be contained within the housing 206 and 220 of the transceiver 101, this is not required, and in some alternative embodiments, part or all of the antenna 103 can be located outside the transceiver housing. For example, in some alternative embodiments, antenna 103 may be wrapped around a user's wrist, arm, leg, or waist, such as the antenna described in US Pat. No. 8,073,548, which is incorporated herein by reference in its entirety.

[0065] Figure 8is a schematic diagram of an external transceiver 101 according to a non-limiting embodiment. In some embodiments, the transceiver 101 can have a connector 902, such as 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).

[0066] The transceiver 101 can exchange data with an external device through the connector 902 and / or receive power through the connector 902. The transceiver 101 may include a connector integrated circuit (IC) 904, such as a USB-IC, which can control the transmission and reception of data through the connector 902. The transceiver 101 may also include a charger IC 906, which can receive power through the connector 902 and charge a battery 908 (e.g., a lithium-polymer battery). In some embodiments, the battery 908 may be rechargeable, may have a short charging time, and / or may have a small size.

[0067] In some embodiments, transceiver 101 can include one or more connectors in addition to (or in lieu of) Micro-USB connector 904. For example, in an alternative embodiment, transceiver 101 can include a spring-based connector (e.g., a Pogo pin connector) in addition to (or in lieu of) Micro-USB connector 904, and transceiver 101 can use the connection established through the spring-based connector for wired communication with a personal computer (e.g., personal computer 109) or display device 107 (e.g., a smartphone) and / or for receiving power, which can be used, for example, to charge battery 908.

[0068] In some embodiments, the transceiver 101 may have a wireless communication IC 910 that enables wireless communication with external devices, such as one or more personal computers (e.g., personal computer 109) or one or more display devices 107 (e.g., smartphones). In some non-limiting embodiments, the wireless communication IC 910 may employ one or more wireless communication standards to wirelessly transmit data. The wireless communication standard employed may be any suitable wireless communication standard, such as the ANT standard, the Bluetooth standard, or the Bluetooth Low Energy (BLE) standard (e.g., BLE 4.0). In some non-limiting embodiments, the wireless communication IC 910 may be configured to wirelessly transmit data at a frequency greater than one gigahertz (e.g., 2.4 or 5 GHz). In some embodiments, the wireless communication IC 910 may include an antenna (e.g., a Bluetooth antenna). In some non-limiting embodiments, the antenna of the wireless communication IC 910 may be completely contained within the housing of the transceiver 101 (e.g., housings 206 and 220). However, this is not required, and in alternative embodiments, all or a portion of the antenna of the wireless IC 910 may be external to the transceiver housing.

[0069] In some embodiments, the transceiver 101 can include a display interface device that enables the transceiver 101 to communicate with one or more display devices 107. In some embodiments, the display interface device can include an antenna and / or connector 902 of the wireless communication IC 910. In some non-limiting embodiments, the display interface device can additionally include the wireless communication IC 910 and / or connector 904.

[0070] In some embodiments, the transceiver 101 may include a voltage regulator 912 and / or a voltage booster 914. The battery 908 may power a radio frequency identification (RFID) reader IC 916 (via the voltage booster 914), which uses the inductive element 103 to transmit information (e.g., instructions) to the sensor 101 and receive information (e.g., measurement information) from the sensor 100. In some non-limiting embodiments, the sensor 100 and the transceiver 101 may communicate using near-field communication (NFC) (e.g., at a frequency of 13.56 MHz). In the illustrated embodiment, the inductive element 103 is a flat antenna. In some non-limiting embodiments, the antenna may be flexible. However, as described above, the inductive element 103 of the transceiver 101 may be in any configuration that allows for achieving sufficient field strength when in sufficient physical proximity to the inductive element 114 of the sensor 100. In some embodiments, the transceiver 101 may include a power amplifier 918 to amplify the signal transmitted to the sensor 100 via the inductive element 103.

[0071] In some embodiments, the transceiver 101 may include a peripheral interface controller (PIC) controller 920 and a memory 922 (e.g., flash memory), which may be non-volatile and / or capable of being electronically erased and / or rewritten. The PIC controller 920 may control the overall operation of the transceiver 101. For example, the PIC controller 920 may control the connector IC 904 or the wireless communication IC 910 to transmit data via wired or wireless communication and / or control the RFID reader IC 916 to transmit data via the inductive element 103. The PIC controller 920 may also control the processing of data received via the inductive element 103, the connector 902, or the wireless communication IC 910.

[0072] In some embodiments, the transceiver 101 can include a sensor interface device that can enable communication with the sensor 100 via the transceiver 101. In some embodiments, the sensor interface device can include the sensing element 103. In some non-limiting embodiments, the sensor interface device can additionally include an RFID reader IC 916 and / or a power amplifier 918. However, in some alternative embodiments, where a wired connection exists between the sensor 100 and the transceiver 101 (e.g., transcutaneous embodiments), the sensor interface device can include a wired connection.

[0073] In some embodiments, 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 embodiments, the transceiver 101 can include a speaker 926 (e.g., a buzzer) and / or a vibration motor 928 that can be activated, for example, when an alarm condition is met (e.g., a hypoglycemic or hyperglycemic condition is detected). The transceiver 101 can also include one or more additional sensors 930, which can include an accelerometer and / or a temperature sensor, which can be used for processing by the PIC controller 920.

[0074] Figure 9A non-limiting embodiment of an analyte monitoring process 950 that can be performed by the analyte monitoring system 50 is described. In some embodiments, the process 950 can detect and correct changes in the analyte indicator 207. In some embodiments, the process 950 can include step 952, in which the analyte monitoring system 50 measures the analyte signal. In some embodiments, step 952 can include the transceiver 101 transmitting the analyte measurement instruction to the analyte sensor 100. In some embodiments, step 952 can include the analyte sensor 100 (in response to receiving and decoding the analyte measurement instruction) using the first light source 108 to emit first excitation light 329 to the indicator element 106. The analyte indicator 207 of the indicator element 106 can receive the first excitation light 329 and emit first emission light 331. The signal photodetector 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 photodetector 224. In some embodiments, step 952 can include analyte sensor 100 receiving first excitation light 329 reflected from indicator element 106 using reference photodetector 226 and generating a reference signal indicative of an amount of reflected first excitation light 329 received by reference photodetector 226 .

[0075] In some embodiments, process 950 may include step 954, in which the analyte monitoring system 50 measures the degradation signal. In some embodiments, step 954 may include the transceiver 101 transmitting the degradation measurement instruction to the analyte sensor 100. In some embodiments, step 954 may include the analyte sensor 100 (in response to receiving and decoding the degradation measurement instruction) emitting second excitation light 330 to the indicator element 106 using the second light source 227. The degradation indicator 209 of the indicator element 106 may receive the second excitation light 330 and emit second emission light 332. The degradation photodetector 228 may receive the second emission light 332 and generate an analyte measurement signal based on the amount of the second emission light 332 received by the degradation photodetector 228. In some embodiments, step 954 may include the analyte sensor 100 receiving the second excitation light 330 reflected from the indicator element 106 using the signal photodetector 224 and generating a reference signal indicating the amount of the reflected second excitation light 330 received by the signal photodetector 224.

[0076] In some alternative embodiments, step 954 may not include transmitting the degradation measurement instruction to the analyte sensor 100, and the analyte sensor 100 may (in response to receiving and decoding the analyte measurement instruction (instead of responding to receiving and decoding the degradation measurement instruction)) use the second light source 227 to emit the second excitation light 330 to the indicator element 106. In some alternative embodiments, steps 952 and 954 may be performed simultaneously, and the analyte sensor 100 may use the first and second light sources 108, 227 to simultaneously emit the first and second excitation lights 329, 330 to the indicator element 106. In some alternative embodiments, step 954 may be performed before step 952.

[0077] In some embodiments, process 950 may include step 956, in which the analyte monitoring system 50 calculates a change in the analyte indicator 207. In some embodiments, step 956 may include the transceiver 101 receiving sensor data from the analyte sensor 100. In some embodiments, the sensor data may include one or more of an analyte measurement, a first reference measurement, a degradation measurement, a second reference measurement, and a temperature measurement. In some embodiments, the analyte measurement may correspond to the amount of first emitted light 331 received by the signal photodetector 224, the first reference measurement may correspond to the amount of reflected first excitation light 329 received by the reference photodetector 226, the degradation measurement may correspond to the amount of second emitted light 332 received by the degradation photodetector 228, and the second reference measurement may correspond to the amount of reflected second excitation light 330 received by the signal photodetector 224. In some alternative embodiments, one or more of the analyte measurement and the first reference measurement may be received during step 952, and one or more of the degradation measurement and the second reference measurement may be received during step 954.

[0078] In some embodiments, step 956 may include transceiver 101 (e.g., microcontroller 910 of transceiver 101) determining, based at least on the received degradation measurement, the extent of degradation of analyte indicator 207. In some non-limiting embodiments, step 956 may include transceiver 101 (i) determining, based on the received degradation measurement, the extent of degradation of degradation indicator 209 and (ii) determining, based on the determined extent of degradation of degradation indicator 209, the extent of degradation of analyte indicator 207. In some non-limiting embodiments, transceiver 101 may additionally or alternatively use one or more previous degradation measurements and / or one or more previous determinations of the extent of degradation of degradation indicator 209 to determine the extent of degradation of analyte indicator 207.

[0079] In some embodiments, process 950 can include step 958, in which analyte monitoring system 50 revises the calculated change in analyte indicator 207. In some non-limiting embodiments, transceiver 101 (e.g., microcontroller 910 of transceiver 101) can revise the calculated change in analyte indicator 207 by adjusting a conversion function used to calculate the analyte level based on the analyte measure. In some embodiments, adjusting the conversion function can include adjusting one or more parameters of the conversion function. In some embodiments, in step 958, transceiver 101 can additionally or optionally adjust the conversion function based on a first reference measure, which can be indicative of in vivo hydration of indicator element 106 and / or wound healing kinetics. In some embodiments, in step 958, transceiver 101 can additionally or optionally adjust the conversion function based on a second reference measure, which can be a measure of opacity of indicator element 106 in the wavelength range of first emitted light 331.

[0080] In some embodiments, process 950 can include step 960, in which analyte monitoring system 50 calculates an analyte level (e.g., an analyte concentration). In some embodiments, in step 960, transceiver 101 (e.g., microcontroller 910 of transceiver 101) can calculate the analyte level using at least the adjusted conversion function and the analyte measure. In some embodiments, transceiver 101 can additionally use a temperature measure to calculate the analyte level.

[0081] In some embodiments, process 950 can include step 962, in which analyte monitoring system 50 displays the calculated analyte level. In some embodiments, in step 962, transceiver 101 can display the analyte level on display 924. In some embodiments, in step 962, transceiver 101 can additionally or optionally transmit the calculated analyte level to display device 107, and display device 107 can additionally or optionally transmit the calculated analyte level. Embodiments

[0082] Compound A is co-polymerized onto the hydrogel with the indicator molecule. Methods of co-polymerization are described in U.S. Patent Nos. 7,060,503 (Colvin) and 9,778,190 (Huffstetler et al.), which are incorporated herein in their entireties.

[0083]

[0084] As Figure 14A and 14BInitial characterization and subsequent oxidation testing helped understand the degradation kinetics of the reference dye (Compound A) and the indicator as shown. Initial fluorometric work was performed with a 1:1 ratio of indicator (TFM):Compound A, confirming the use of Compound A as a copolymerizable reference dye. Figure 14A and Figure 14B The graph in Figure 2 demonstrates that the fluorescence intensity of the indicator molecule (excitation wavelength 380 nm) decreases under 2 mM glucose and 50 μM hydrogen peroxide, while the fluorescence intensity of Compound A (excitation wavelength 470 nm) increases. The chemical name of TFM is 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.

[0085] In vivo studies were conducted in 18 female guinea pigs using a simulated sensor (having a 1:1 ratio of copolymerized indicator: Compound A in a hydrogel) implanted in the guinea pigs to evaluate the performance of Compound A in response to in vivo oxidation and its relationship to indicator molecule degradation. Implantation was performed subcutaneously on the back of each guinea pig using the Senseonics implant kit according to the implant training document (2 samples per guinea pig). The subjects were divided into 3 groups for explant time points: 30, 60, and 90 days. Once the samples were removed, the Senseonics implant kit was used to implant the samples. They are cleaned and sterilized with an enzymatic detergent and glutaraldehyde solution. The removed samples are then analyzed by fluorometry to assess the change in fluorescence intensity of Compound A and to correlate the % increase in Compound A intensity with the % modulation loss of the indicator.

[0086] In vitro studies were performed as follows: an initial 0–18 modulation was performed prior to oxidation testing to collect initial modulation data. A known concentration of hydrogen peroxide was used to intentionally partially oxidize the sensor. Following partial oxidation, a 0–18 modulation was performed again to collect modulation data and record the loss of modulation. This process was repeated for 3–5 cycles, where the same sensor underwent further partial oxidation and 0–18 modulation data was collected at each oxidation step. Correlations of indicator and reference dye degradation rates are shown in Figure 2. Figure 13 Shown in.

[0087] In the sample removal analysis, a strong correlation was shown between samples oxidized in vitro and in vivo. This correlation can be used to determine the amount of modulation remaining in the signal path by analyzing the amount of indicator dye oxidation, thereby reducing the number of calibrations performed.

[0088] The embodiments of the present invention have been fully described above with reference to the accompanying drawings. Although the present invention has been described based on these preferred embodiments, it will be apparent to those skilled in the art that certain modifications, variations and alternative constructions may be made to the embodiments within the spirit and scope of the present invention. For example, although in embodiments of the present invention analyte indicator 207 and degradation indicator 209 are distributed in identical indicator element 106, this is not essential. In some alternative embodiments, analyte sensor 100 may include a first indicator element (which includes analyte indicator 207) and a second indicator element (which includes degradation indicator 209). In these alternative embodiments, analyte indicator 207 and degradation indicator 209 may be spatially separated from each other.

Claims

1. An analyte sensor for measuring an analyte in a medium within a living animal, the analyte sensor comprising: sensor housing, an analyte indicator having a first detectable property that varies as a function of (i) the amount or concentration of analyte in the medium and (ii) the extent of degradation of the analyte indicator; a degradation indicator having a second detectable property that varies according to an extent of degradation of the degradation indicator, wherein the extent of degradation of the degradation indicator corresponds to an extent of degradation of the analyte indicator; as well as a sensor element configured to (i) generate a measure of analyte based on the first detectable property, and (ii) generate a measure of degradation based on the second detectable property; The degradation indicator is a compound of formula I: wherein A", B", C", A', B', C', W', X, Y' and Z' represent -CH, wherein the hydrogens of -CH may be optionally and independently substituted with alkyl groups; wherein -NR1R2 comprises one or more vinyl groups, alkyl vinyl groups, acrylamide groups, methacrylamide groups or other polymerizable groups.

2. The analyte sensor of claim 1, wherein -NR1R2 is selected from 3. The analyte sensor of claim 1, wherein the extent to which the degradation indicator degrades is proportional to the extent to which the analyte indicator degrades.

4. The analyte sensor of claim 1, wherein the degradation of the analyte indicator comprises reactive oxygen species (ROS)-induced oxidation, and the degradation of the degradation indicator comprises ROS-induced oxidation. The analyte sensor of claim 1 , wherein the analyte indicator is a phenylboronic acid-based analyte indicator. The analyte sensor of claim 1 , wherein the degradation indicator is a phenylboronic acid-based degradation indicator.

7. The analyte sensor of claim 1, further comprising an indicator element comprising the analyte indicator and the degradation indicator.

8. The analyte sensor of claim 7, wherein the analyte indicator comprises analyte indicator molecules distributed throughout the indicator element, and the degradation indicator comprises degradation indicator molecules distributed throughout the indicator element.

9. The analyte sensor of claim 1, wherein the ratio of analyte indicator molecules to degradation indicator molecules is 1:1, 2:1, 1:2, 3:1, 5:1, or 10:

1.

10. The analyte sensor of claim 9, wherein the analyte indicator molecule (A) and the degradation indicator molecule are monomers that are separately polymerized to a polymer backbone.

11. The analyte sensor of claim 9, wherein one or more degradation indicator molecules are chemically bonded to an analyte indicator molecule and the analyte indicator molecule is chemically bonded to a polymer backbone, or one or more analyte indicator molecules are chemically bonded to a degradation indicator molecule and the degradation indicator molecule is chemically bonded to a polymer backbone.

12. The analyte sensor of claim 1, wherein the degradation indicator is a fluorescent probe compound having an excitation wavelength of 450 nm to 550 nm, a Stokes shift of 500 nm to 650 nm, and a half-life of 50 days to 150 days.

13. The analyte sensor of claim 1, wherein the sensor element comprises: a first light source configured to emit a first excitation light toward the analyte indicator; and A first photodetector is configured to receive first emission light emitted by the analyte indicator and output an analyte measurement, wherein the analyte measurement is indicative of an amount of the first emission light received by the first photodetector.

14. The analyte sensor of claim 13, wherein the sensor element comprises: a second light source configured to emit second excitation light toward the degradation indicator; and A second photodetector is configured to receive second emission light emitted by the degradation indicator and output a degradation metric, wherein the degradation metric is indicative of an amount of the second emission light received by the second photodetector.

15. The analyte sensor of claim 13, wherein the first photodetector is 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.

16. The analyte sensor of claim 14, wherein the sensor element comprises a third photodetector configured to receive the first excitation light reflected from the indicator element and output a second reference signal indicative of an amount of the reflected first excitation light received by the third photodetector.

17. The analyte sensor of claim 1, wherein the second detectable property does not vary based on the amount or concentration of analyte in the medium.

18. A method for measuring an analyte in a medium, comprising: measuring the amount or concentration of an analyte in a medium using an analyte indicator of an analyte sensor comprising a sensor housing; measuring the extent of degradation of the degradation indicator using the degradation indicator of the analyte sensor; receiving an analyte measurement from the analyte sensor using a sensor interface device of a transceiver, indicating an amount or concentration of analyte in the medium; receiving, using a sensor interface device of the transceiver, a degradation measure from the analyte sensor indicating an extent of degradation of the degradation indicator; calculating, using a controller of the transceiver, an extent of degradation of an analyte indicator of the analyte sensor based at least on the received degradation measure; adjusting, with a controller of the transceiver, the transfer function based on the calculated extent of degradation of the analyte indicator; calculating, with a controller of the transceiver, an analyte level using the adjusted transfer function and the received analyte measurement; as well as displays calculated analyte levels; The degradation indicator is a compound of formula I: wherein A", B", C", A', B', C', W', X, Y' and Z' represent -CH, wherein the hydrogens of -CH may be optionally and independently substituted with alkyl groups; wherein -NR1R2 comprises one or more vinyl groups, alkyl vinyl groups, acrylamide groups, methacrylamide groups or other polymerizable groups.

19. The method of claim 18, wherein -NR1R2 is selected from 20. An analyte monitoring system comprising: An analyte sensor comprising: sensor housing, an analyte indicator having a first detectable property that varies as a function of (i) the amount or concentration of analyte in the medium and (ii) the extent of degradation of the analyte indicator; a degradation indicator having a second detectable property that varies according to the extent to which the degradation indicator is degraded; a sensor element configured to (i) generate a measure of analyte based on the first detectable property and (ii) generate a measure of degradation based on the second detectable property; as well as transceiver interface device; as well as A transceiver comprising: a sensor interface device; and The controller is configured as follows: (i) receiving the analyte measurement from the analyte sensor via the transceiver interface device of the analyte sensor and the sensor interface device; (ii) receiving the degradation measure from the analyte sensor via the transceiver interface device of the analyte sensor and the sensor interface device; (iii) calculating an extent of degradation of an analyte indicator of the analyte sensor based at least on the received degradation measure; (iv) adjusting the transfer function based on the calculated extent of analyte indicator degradation; (v) calculating an analyte level using the adjusted transfer function and the received analyte measurement; The degradation indicator is a compound of formula I: wherein A", B", C", A', B', C', W', X, Y' and Z' represent -CH, wherein the hydrogens of -CH may be optionally and independently substituted with alkyl groups; wherein -NR1R2 comprises one or more vinyl groups, alkyl vinyl groups, acrylamide groups, methacrylamide groups or other polymerizable groups.

21. The analyte monitoring system of claim 20, wherein -NR1R2 is selected from 22. The analyte monitoring system of claim 20, wherein the analyte sensor further comprises an indicator element comprising the analyte indicator and the degradation indicator.

23. The analyte monitoring system of claim 20, wherein the second detectable property does not vary based on the amount or concentration of analyte in the medium.

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