Apparatus and method for identifying degrading substances

Abstract

This invention relates to a sensor (e.g., an optical sensor) that can be implanted in a living animal (e.g., a human) and used to determine analytes (e.g., glucose or oxygen) in intracellular media (e.g., interstitial fluid, blood, or peritoneal fluid). The sensor may include a sensor substrate, electrodes or a housing, an analyte indicator covering at least a portion of the sensor, and one or more probes for identifying degradation substances in the sensor environment.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 934,599, filed November 13, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] In general, this invention relates to the detection, identification, capture, separation, isolation, neutralization, inactivation, and / or inhibition of degrading substances that interact with the analyte sensor portion when measuring analytes in a live animal medium using a system comprising (partially or wholly) implanted or inserted into a sensor within a live animal. Specifically, this invention relates to a sensor utilizing one or more probes that may be incorporated into an analyte indicator and / or a material covering at least a portion of the analyte indicator to detect, identify, capture, separate, isolate, neutralize, inactivate, and / or inhibit degrading substances that interact with the analyte sensor portion. Background Technology

[0004] Sensors can be implanted (partially or wholly) into a living animal (e.g., a human) to measure analytes (e.g., glucose, oxygen, cardiac markers, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides) in media within the animal's body (e.g., interstitial fluid (ISF), blood, or peritoneal fluid). Sensors may include a light source (e.g., a light-emitting diode (LED) or other light-emitting element), indicator molecules, and a photodetector (e.g., a photodiode, phototransistor, photoresistor, or other photosensitive element). Examples of implantable sensors using indicator molecules to measure analytes are described in U.S. Patents 5,517,313 and 5,512,246, the entire contents of which are incorporated herein by reference.

[0005] The sensor may include an analyte indicator, which may be in the form of indicator molecules embedded in a graft (i.e., a layer or matrix). For example, in an implantable fluorescence-based glucose sensor, the fluorescent indicator molecule can reversibly bind to glucose and emit a certain amount of light (e.g., light in the 400 to 500 nm range) when irradiated with excitation light (e.g., light with a wavelength of approximately 378 nm), depending on whether glucose binds to the indicator molecule.

[0006] If a sensor is implanted in a living animal, the animal's immune system may begin to attack it. For example, if the sensor is implanted in a human, white blood cells may attack it as if it were a foreign object, and neutrophils may be the primary white blood cells attacking the sensor in the initial immune system attack. Neutrophil defense mechanisms include releasing highly caustic substances called reactive oxygen species (ROS). For instance, in indicator molecules with borate ester groups, degradative substances can degrade the indicator molecule by oxidizing the borate ester groups, thereby disabling the indicator molecule's ability to bind glucose.

[0007] Known reactive oxygen species include, for example, hydrogen peroxide and superoxide. While it has been hypothesized that hydrogen peroxide and other reactive substances such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) may degrade indicator molecules of analyte indicators, no experimental evidence has been identified of degradative substances that react with the indicator. Furthermore, prior to this invention, there were no apparatus or methods for detecting and identifying degradative substances that react with indicator molecules in implantable medical devices or sensors. Most generated ROS / RNS have short lifetimes and may or may not affect the degradation profile depending on factors such as location, proximity, diffusion, and environmental properties.

[0008] Currently, there is a need in the art for a method to detect, identify, capture, separate, isolate, neutralize, inactivate, and / or inhibit degrading substances that interact with the analyte sensor portion when using a system comprising (partially or entirely) implanted or inserted into a live animal to measure analytes in a live animal medium. Furthermore, there is a need in the art for continuous analyte sensors with extended lifespans. Summary of the Invention

[0009] The present invention provides a method for detecting, identifying, capturing, separating, isolating, neutralizing, inactivating and / or inhibiting degrading substances that interact with the analyte sensor portion when using a system comprising (partially or entirely) implanted or inserted into a live animal to determine an analyte in a live animal medium.

[0010] One aspect of the present invention provides a sensor for implantation or insertion into a living animal to measure analytes in a medium within the animal's body. The sensor may include an analyte indicator and one or more selectively degradable substance probes, which can be used to understand their reactivity to corresponding degradable substances generated around the device. In some embodiments, the sensor may include multiple selectively degradable substance probes, each with different characteristic absorption and emission properties to detect different degradable substances. In some embodiments, the analyte indicator and one or more degradable substance probes are disposed on a substrate. The substrate may be an electrode or a sensor surface. In some embodiments, the sensor may include a sensor housing, and the analyte indicator may cover at least a portion of the sensor housing.

[0011] In some embodiments, the sensor may include at least one polymer graft containing a probe, and the one or more degradable substance probes may be copolymerized, entrapped, or dispersed in the polymer graft containing the probe. In some embodiments, the polymer graft containing the probe may cover at least a portion of the sensor housing. In some embodiments, the polymer graft containing the probe may be within the sensor housing.

[0012] In some embodiments, the one or more degradation substance probes may be combined with an analyte indicator, for example, as a comonomer. In some embodiments, the sensor may include a material, such as a membrane, covering at least a portion of the analyte indicator, and the one or more degradation substance probes may be incorporated into that material.

[0013] In some embodiments, this disclosure provides a sensor for determining an analyte in a medium in a living animal, the sensor comprising: an analyte indicator; and one or more degradation substance probes, wherein the degradation substance probes have selective absorption and / or emission characteristics for a specific degradation substance.

[0014] In some embodiments, this disclosure provides a method for manufacturing a sensor for determining an analyte in a medium within a living animal, the method comprising: applying an analyte indicator to the sensor such that the applied analyte indicator covers at least a portion of the sensor, wherein the analyte indicator comprises one or more degradation substance probes, wherein the degradation substance probes have selective absorption and / or emission characteristics for a specific degradation substance.

[0015] In some embodiments, this disclosure provides a method for detecting and identifying changes in degrading substances in the in vivo environment of an implanted medical device, comprising: a) implanting a sensor of this disclosure into an animal; b) explanting the sensor at predetermined time points; c) characterizing changes in the absorption / emission properties of the one or more degrading substance probes compared to the absorption / emission properties of the one or more degrading substance probes prior to implantation; and d) quantifying the reactivity of the one or more degrading substance probes with the one or more degrading substances.

[0016] In some embodiments, this disclosure provides a method for screening compounds for inclusion in an implantable sensor, comprising: applying an analyte indicator to the sensor such that the applied analyte indicator covers at least a portion of the sensor, wherein the analyte indicator comprises one or more degradation substance probes having selective absorption and / or emission characteristics for a specific degradation substance; applying a test compound to the sensor to form a test sensor; implanting the test sensor into an animal; explanting the sensor at predetermined time points; characterizing changes in the absorption / emission properties of the one or more degradation substance probes compared to their absorption / emission properties prior to implantation; comparing the characterized changes in the absorption / emission properties of the one or more degradation substance probes with the characterized absorption / emission properties of the one or more degradation substance probes in a control sensor, wherein the control sensor does not include the test compound; and detecting whether the presence of the test compound increases or decreases the degradation substance in the in vivo environment of the implantable sensor.

[0017] In some embodiments, this disclosure provides a method for screening compounds for inclusion in an implantable sensor, comprising: applying an analyte indicator to the sensor such that the applied analyte indicator covers at least a portion of the sensor, wherein the analyte indicator comprises one or more degradation substance probes, wherein the degradation substance probes have selective absorption and / or emission characteristics for a specific degradation substance; applying a test compound to the sensor to form a test sensor; performing an in vitro test under simulated physiological conditions for a specified period of time; characterizing changes in the absorption / emission properties of the one or more degradation substance probes compared to the absorption / emission properties of the one or more degradation substance probes prior to the in vitro test; and comparing the characterized changes in the absorption / emission properties of the one or more degradation substance probes with the characterized absorption / emission properties of the one or more degradation substance probes in a control sensor, wherein the control sensor does not include the test compound; and detecting whether the presence of the test compound increases or decreases the degradation substance.

[0018] In some embodiments, this disclosure provides a method for identifying and / or quantifying degradable substances in a medical device environment, comprising: applying an analyte indicator to a sensor such that the applied analyte indicator covers at least a portion of the sensor, wherein the analyte indicator comprises one or more degradable substance probes, wherein the degradable substance probes have selective absorption and / or emission characteristics for a specific degradable substance; exposing the sensor to an environment containing the degradable substance; characterizing changes in the absorption / emission properties of the one or more degradable substance probes compared to the absorption / emission properties of the one or more degradable substance probes prior to the exposure step; and quantifying the reactivity of the one or more degradable substance probes with one or more degradable substances.

[0019] Other variations included in the systems and methods are described in the following detailed description of the invention. Attached Figure Description

[0020] Various non-limiting embodiments of the invention are illustrated in the accompanying drawings, which are incorporated herein by reference and form a part of the application. In the drawings, the same reference numerals denote the same or functionally similar elements.

[0021] Figure 1 This is a schematic diagram illustrating a sensor system that embodies various aspects of the present invention.

[0022] Figure 2 A perspective view of a sensor embodying various aspects of the present invention is shown.

[0023] Figure 3 An exploded view of the sensor embodying various aspects of the present invention is shown.

[0024] Figure 4 This is a schematic diagram illustrating a sensor that embodies various aspects of the present invention.

[0025] Figure 5 An exemplary reaction scheme for a compound of formula VIII (“APF”) is shown.

[0026] Figure 6 The steps of a method for screening compounds for inclusion in implantable sensors according to some embodiments of the present disclosure are shown.

[0027] Figure 7 The steps of a method for screening compounds for inclusion in implantable sensors according to some embodiments of the present disclosure are shown.

[0028] Figure 8 The steps of a method for identifying and / or quantifying degradable substances in a medical device environment according to some embodiments of this disclosure are shown. Detailed Implementation

[0029] Figure 1 This is a schematic diagram illustrating various aspects of the sensor system of the present invention. In some non-limiting embodiments, such as Figure 1 As shown, the system may include sensor 100 and external transceiver 101. In some embodiments, sensor 100 may be an implantable sensor configured to be fully or partially implanted in a living animal (e.g., a living human). For example, sensor 100 may be implanted in the arm, wrist, leg, abdomen, peritoneum, or other suitable areas for sensor implantation in a living animal. For example, in some non-limiting embodiments, sensor 100 may be implanted under the skin (i.e., in subcutaneous or peritoneal tissue). However, this is not necessary, and in some alternative embodiments, sensor 100 may be a percutaneous sensor.

[0030] In some embodiments, transceiver 101 may be an electronic device that communicates with sensor 100 to power sensor 100, provide commands and / or data to sensor 100, and / or receive data from sensor 100. In some embodiments, the received data may include one or more sensor measurements. In some embodiments, sensor measurements may include, for example, one or more light measurements from one or more photodetectors of sensor 100, and / or one or more temperature measurements from one or more temperature sensors of sensor 100. In some embodiments, transceiver 101 may calculate the concentration of an analyte (e.g., glucose) based on the measurement information received from sensor 100.

[0031] In some non-limiting embodiments, transceiver 101 may be a handheld device or an on-body / wearable device. For example, in some embodiments where transceiver 101 is an on-body / wearable device, transceiver 101 may be held in place by a strap (e.g., an armband or wristband) and / or adhesive, and transceiver 101 may transmit (e.g., periodically, such as every two minutes, and / or upon user activation) measurement commands (i.e., requests for measurement information) to sensor 100. In some embodiments where transceiver 101 is a handheld device, placing (i.e., hovering or sliding / waving / passing) transceiver 101 within a certain range above the sensor implantation site (i.e., in the vicinity of sensor 100) may cause transceiver 101 to automatically transmit measurement commands to and receive data from sensor 100.

[0032] like Figure 1As shown, in some embodiments, transceiver 101 may include an inductor 103, such as a coil. In some embodiments, transceiver 101 may generate electromagnetic waves or an electric field (e.g., by using a coil) to induce a current in the inductor 114 of sensor 100. In some non-limiting embodiments, sensor 100 may be powered using the current induced in the inductor 114. However, this is not necessary, and in some alternative embodiments, sensor 100 may be powered by an internal power source (e.g., a battery).

[0033] In some embodiments, transceiver 101 can transmit data (e.g., commands) to sensor 100. For example, in some non-limiting embodiments, transceiver 101 can transmit data by modulating electromagnetic waves generated by inductor 103 (e.g., by modulating the current flowing through inductor 103 of transceiver 101). In some embodiments, sensor 100 can detect / extract modulation in the electromagnetic waves generated by transceiver 101. Furthermore, transceiver 101 can receive data from sensor 100 (e.g., measurement results from one or more sensors). For example, in some non-limiting embodiments, transceiver 101 can receive data by detecting modulation in the electromagnetic waves generated by sensor 100 (e.g., by detecting modulation in the current flowing through inductor 103 of transceiver 101).

[0034] like Figure 1 As shown, in some embodiments, sensor 100 may include sensor housing 102 (i.e., body, shell, capsule, or sleeve), which may be rigid and biocompatible. In an exemplary embodiment, sensor housing 102 may be formed of a suitable light-transmitting polymer material such as an acrylic polymer (e.g., polymethyl methacrylate (PMMA)).

[0035] like Figure 1As shown, in some embodiments, sensor 100 may include an analyte indicator 106. In some non-limiting embodiments, the analyte indicator 106 may be a polymer graft coated, diffused, adhered, or embedded on at least a portion of the outer surface of sensor housing 102. The analyte indicator 106 (e.g., a polymer graft) may cover the entire surface of sensor housing 102 or only one or more portions of the surface of housing 102. As an alternative to coating the analyte indicator 106 on the outer surface of sensor housing 102, the analyte indicator 106 may be arranged on the outer surface of sensor housing 102 in other ways, such as by deposition or adhesion. In some embodiments, the analyte indicator 106 may be a fluorescent glucose indicating polymer. In one non-limiting embodiment, the polymer is biocompatible and stable, grafted onto the surface of sensor housing 102, and designed to allow direct measurement of glucose in interstitial fluid (ISF), blood, or intraperitoneal fluid after implantation of sensor 100. In some embodiments, the analyte indicator 106 may comprise a hydrogel.

[0036] In some embodiments, the analyte indicator 106 of the sensor 100 (e.g., a polymer graft) may comprise indicator molecule 104. Indicator molecule 104 may be distributed throughout the analyte indicator 106 or only in one or more portions of the analyte indicator 106. Indicator molecule 104 may be a fluorescent indicator molecule (e.g., TFM, chemically named 9-[N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane)-3-(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene sodium salt) or a light-absorbing non-fluorescent indicator molecule. In some embodiments, indicator molecule 104 can reversibly bind to an analyte (e.g., glucose, oxygen, cardiac markers, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides). When indicator molecule 104 binds to an analyte, it may become fluorescent, in which case indicator molecule 104 is able to absorb (or be excited by) excitation light 329 and emit light 331. In a non-limiting embodiment, excitation light 329 may have a wavelength of about 378 nm, and emitted light 331 may have a wavelength in the range of 400 nm to 500 nm. When not bound to an analyte, indicator molecule 104 may only fluoresce weakly.

[0037] In some embodiments, sensor 100 may include a light source 108, which may be, for example, a light-emitting diode (LED) or other light source emitting radiation, including radiation in the wavelength range that interacts with indicator molecules 104. In other words, light source 108 may emit excitation light 329, which is absorbed by indicator molecules in the matrix layer / polymer 104. As described above, in a non-limiting embodiment, light source 108 may emit excitation light 329 with a wavelength of approximately 378 nm.

[0038] In some embodiments, sensor 100 may further include one or more photodetectors (e.g., photodiodes, phototransistors, photoresistors, or other photosensitive elements). For example, in Figure 1 In the illustrated embodiment, sensor 100 has a first photodetector 224 and a second photodetector 226. However, this is not necessary, and in some alternative embodiments, sensor 100 may include only the first photodetector 224. In the case of a fluorescence-based sensor, the one or more photodetectors may be sensitive to the fluorescence emitted by the indicator molecule 104, such that a signal is generated by the photodetector (e.g., photodetector 224) in response to this signal, the signal indicating the fluorescence level of the indicator molecule, and thus indicating the amount of the target analyte (e.g., glucose).

[0039] A portion of the excitation light 329 emitted by the light source 108 can be reflected back into the sensor 100 from the analyte indicator 106 as reflected light 333, and a portion of the absorbed excitation light can be emitted as emitted (fluorescent) light 331. In a non-limiting embodiment, the emitted light 331 may have a wavelength different from that of the excitation light 329. The reflected light 333 and the emitted (fluorescent) light 331 can be absorbed by one or more photodetectors (e.g., first and second photodetectors 224 and 226) within the sensor 100 body.

[0040] Each of the one or more photodetectors can be covered by filter 112 (see [link]). Figure 3The filter allows only a subset of wavelengths of light to pass through. In some embodiments, the one or more filters 112 may be thin glass filters. In some embodiments, the one or more filters 112 may be thin film (e.g., dichroic) filters deposited on glass, and may allow only a narrow band of light to pass through while otherwise reflecting most of the received light. In some embodiments, the filter may be a thin film (dichroic) filter deposited directly on the photodetector, and may allow only a narrow band of light to pass through while otherwise reflecting most of the light received. The filters 112 may be the same (e.g., both filters 112 may allow signals to pass through) or different (e.g., one filter 112 may be a reference filter and the other filter 112 may be a signal filter).

[0041] In one non-limiting embodiment, the second (reference) photodetector 226 may be covered by a reference photodiode filter that allows light with the same wavelength (e.g., 378 nm) emitted from the light source 108 to pass through. The first (signal) photodetector 224 can detect the amount of fluorescence 331 emitted from the molecule 104 in the analyte indicator 106. In one non-limiting embodiment, the peak emission of the indicator molecule 104 may occur at about 435 nm, and the first photodetector 224 may be covered by a signal filter that allows light in the range of about 400 nm to 500 nm to pass through. In some embodiments, a higher glucose content / concentration corresponds to a greater fluorescence amount of the molecule 104 in the analyte indicator 106, and therefore corresponds to a greater number of photons striking the first photodetector 224.

[0042] In some implementation schemes, such as Figure 1As shown, sensor 100 may include a substrate 116. In some embodiments, substrate 116 may be a circuit board (e.g., a printed circuit board (PCB) or a flexible PCB) on which circuit components (e.g., analog and / or digital circuit components) may be mounted or otherwise connected. However, in some alternative embodiments, substrate 116 may be a semiconductor substrate having circuitry fabricated therein. The circuitry may include analog and / or digital circuitry. Furthermore, in some semiconductor substrate embodiments, in addition to the circuitry fabricated in the semiconductor substrate, the circuitry may also be mounted to or otherwise connected to the semiconductor substrate 116. In other words, in some semiconductor substrate embodiments, some or all of the circuitry, which may include discrete circuitry elements, integrated circuits (e.g., application-specific integrated circuits, ASICs), and / or other electronic components, may be fabricated in the semiconductor substrate 116, and the remainder of the circuitry may be fixed to the semiconductor substrate 116, which can provide communication paths between various fixed components.

[0043] In some embodiments, one or more of the sensor housing 102, analyte indicator 106, indicator molecule 104, light source 108, photodetectors 224, 226, temperature transducer 670, substrate 116, and inductor 114 of sensor 100 may include some or all of the features described in one or more of U.S. Application Serial No. 13 / 761,839, filed February 7, 2013; U.S. Application Serial No. 13 / 937,871, filed July 9, 2013; and U.S. Application Serial No. 13 / 650,016, filed October 11, 2012, all of which are incorporated herein by reference in their entirety. Similarly, the structure and / or function of sensor 100 and / or transceiver 101 may be as described in one or more of U.S. Application Serial Nos. 13 / 761,839, 13 / 937,871, and 13 / 650,016.

[0044] In some embodiments, sensor 100 may include a transceiver interface device, and transceiver 101 may include a sensor interface device. In some embodiments where sensor 100 and transceiver 101 include one or more antennas (e.g., inductors 103 and 114), the transceiver interface device may include inductor 114 of sensor 100, and the sensor interface device may include inductor 103 of transceiver 101. In some transdermal embodiments where there is a wired connection between sensor 100 and transceiver 101, the transceiver interface device and the sensor interface device may include a wired connection.

[0045] Figure 2 and 3 Non-limiting embodiments of a sensor 100 embodying various aspects of the present invention are shown, the sensor 100 being used in... Figure 1 The sensor system shown. Figure 2 and 3 Perspective view and exploded view of a non-limiting embodiment of sensor 100 are shown respectively.

[0046] In some implementation schemes, such as Figure 3 As shown, the sensor housing 102 may include an end cap 113. In some embodiments, the sensor 100 may include one or more capacitors 118. The one or more capacitors 118 may, for example, be one or more tuning capacitors and / or one or more regulating capacitors. The one or more capacitors 118 may be too large and impractical for fabrication in the semiconductor substrate 116. Furthermore, the one or more capacitors 118 may be a supplement to one or more capacitors fabricated in the semiconductor substrate 116.

[0047] In some implementation schemes, such as Figure 3 As shown, sensor 100 may include a reflector 119 (i.e., a mirror). Reflector 119 may be attached to an end of semiconductor substrate 116. In a non-limiting embodiment, reflector 119 may be attached to semiconductor substrate 116 such that the surface portion 121 of reflector 119 is substantially perpendicular to the top side of semiconductor substrate 116 (i.e., the side of semiconductor substrate 116 having a light source 108 and one or more photodetectors 110 mounted or manufactured thereon or within it) and faces the light source 108. Surface 121 of reflector 119 may reflect radiation emitted by light source 108. In other words, reflector 119 may block radiation emitted by light source 108 from leaving the axial end of sensor 100.

[0048] According to one aspect of the invention, the developed sensor 100 is used (although by no means the only application for which the sensor is suitable) to determine various bioanalytes in living animals (including humans). For example, the sensor 100 can be used to determine, for example, glucose, oxygen, toxins, pharmaceuticals or other drugs, hormones and other metabolic analytes in the human body.

[0049] In some embodiments, the specific composition of the analyte indicator 106 and indicator molecule 104 may vary depending on the specific analyte the sensor will use to detect and / or the location where the sensor will use to detect the analyte (e.g., in subcutaneous tissue, blood, or peritoneum). In some embodiments, the analyte indicator 106 promotes the exposure of indicator molecule 104 to the analyte. In some embodiments, indicator molecule 104 may exhibit properties that are a function of the concentration of the specific analyte to which it is exposed (e.g., emitting a certain amount of fluorescence).

[0050] In some embodiments, sensor 100 may include at least one drug-eluting polymer matrix and / or catalyst layer and / or one or more therapeutic agents, which may be provided on, adjacent to, incorporated into, or distributed within an analyte indicator or sensor housing, as described in U.S. Patent No. 9,931,068 (Huffstetler et al.), which is incorporated herein by reference in its entirety. In some embodiments, the one or more therapeutic agents may be incorporated into analyte indicator 106. In some embodiments, sensor 100 may include a membrane covering at least a portion of analyte indicator 106, and the one or more therapeutic agents may be incorporated into the membrane. In some embodiments, the one or more therapeutic agents include dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclomethasone, fludrocortisone, derivatives thereof and analogs thereof, glucocorticoids, and anti-inflammatory drugs (e.g., nonsteroidal anti-inflammatory drugs, including but not limited to acetylsalicylic acid and isobutylphenylpropionic acid).

[0051] Figure 4 This is a schematic diagram of a sensor 100 illustrating various aspects of the present invention. In some non-limiting aspects, such as... Figure 4 As shown, sensor 100 may include a drug elution region 401 covering at least a portion of sensor housing 102. In some non-limiting aspects, such as Figure 4 As shown, sensor 100 may include analyte indicator 106, and analyte indicator 106 may comprise a hydrogel copolymerized with one or more degradation substance probes of the present disclosure, carrying one or more degradation substance probes of the present disclosure, or embedding one or more degradation substance probes of the present disclosure. In some non-limiting aspects, such as Figure 4 As shown, sensor 100 may include sensor electronics, which may include any electronic components described in this disclosure, including... Figure 1 and Figure 3(e.g., light source 108, the one or more photodetectors 110, inductor 114, and / or the one or more capacitors 118), and those described in one or more of U.S. Application Serial No. 13 / 761,839, filed February 7, 2013; U.S. Application Serial No. 13 / 937,871, filed July 9, 2013; and U.S. Application Serial No. 13 / 650,016, filed October 11, 2012, which are incorporated herein by reference in their entirety. In some non-limiting respects, such as Figure 4 As shown, sensor 100 may include a metal coating 403 covering at least a portion of sensor housing 102. In some non-limiting aspects, the metal coating 403 may include one or more metals selected from Cu, W, Pt, Fe, Mo, Co, their oxides, alloys, and complexes. In some non-limiting aspects, the metal coating 403 may be applied to a hydrogel copolymerized with, carrying, or embedding one or more degradation substance probes of the present disclosure.

[0052] Implanting or inserting medical devices, such as biosensors, into a user / patient's body can lead to adverse physiological responses that negatively impact the device's function. These responses can range from infections resulting from the implantation procedure to immune responses to foreign bodies implanted in the body. In other words, the performance of an implantable biosensor may be impaired or permanently damaged in the body through an immune response to infection or the device itself. Specifically, the performance of the analyte indicator 106 may be degraded due to an immune response in the body where the sensor 100 has been implanted. For example, as explained above, white blood cells, including neutrophils, may attack the implanted sensor 100. Neutrophils release degrading substances, including hydrogen peroxide, which can degrade indicator molecule 104 (e.g., by oxidizing the borate ester groups of indicator molecule 104 and disabling its ability to bind glucose). Prior to this invention, there were no methods for identifying degrading substances that react with implanted indicator molecules. Most of the resulting degrading substances are short-lived and have not yet been identified.

[0053] In some embodiments, the analyte indicator 106 may include one or more degradation substance probes that interact or react with one or more degradation substances and have different characteristic absorption and emission properties, which can be used to understand their reactivity to corresponding degradation substances generated around the sensor. In some embodiments, the one or more degradation substance probes may be incorporated into the analyte indicator 106, which may cover at least a portion of the sensor housing 102. Degradation substances to be detected by the one or more degradation substance probes may include, but are not limited to, one or more of peroxide compounds, reactive oxygen species, reactive nitrogen species, free radicals, enzymes, and metal ions. In some aspects, degradation substances may include superoxide, hydrogen peroxide, hypochlorite, peroxynitrite, or combinations thereof.

[0054] In some embodiments, the one or more degradation substance probes may be dispersed in, embedded within, or copolymerized with indicator molecules 104. In some embodiments, the one or more degradation substance probes may be provided in an analyte indicator 106 (e.g., a polymer graft or hydrogel). In some embodiments, the one or more degradation substance probes may interact with and / or react with degradation substances, and exhibit different characteristic absorption and emission properties due to such interactions and / or reactions. In some embodiments, the one or more degradation substance probes are selective for specific degradation substances. In some embodiments, the absorption and emission properties of the degradation substance probes are detectable and quantifiable. In some embodiments, the detected absorption and emission properties of the degradation substance probes indicate the identity of one or more degradation substances. In some embodiments, the detected absorption and emission properties of the degradation substance probes indicate the amount of one or more degradation substances.

[0055] In some embodiments, the one or more degradation substance probes can isolate, neutralize, and / or inhibit the activity of degradation substances. In some embodiments, the one or more degradation substance probes can bind to degradation substances. In some embodiments, the one or more degradation substance probes can isolate degradation substances to inhibit, reduce, and / or prevent the analyte indicator from being degraded by the degradation substances. Therefore, in some embodiments, the one or more degradation substance probes reduce the degradation of analyte indicator 106.

[0056] In some non-limiting embodiments, the one or more degradation substance probes may be one or more fluorescent probes. In one non-limiting embodiment, the one or more degradation substance probes may utilize a borate ester deprotection mechanism to provide high selectivity and optical dynamic range for the detection of a specific degradation substance. For example, in some embodiments, a degradation substance probe that has high selectivity for the detection of hydrogen peroxide compared to superoxide, nitric oxide, tert-butyl hydroperoxide, hypochlorite, singlet oxygen, ozone, and / or hydroxyl radicals may be used. In some embodiments, the one or more degradation substance probes are water-soluble systems that selectively respond to a specific degradation substance in vivo relative to other degradation substances. In some embodiments, the one or more degradation substance probes have low reactivity with thiols present in high concentrations within cells and do not require external activating enzymes.

[0057] In some non-limiting embodiments, the one or more degradation substance probes may be one or more of the following compounds:

[0058] (Formula I);

[0059] (Formula II);

[0060] (Formula III);

[0061] (Form IV),

[0062] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R6 is independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxyl, aryl, heteroaryl, polycyclic, alkoxy, halogen, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylamide, arylamide, heterocyclic carbonylamide, heteroarylamide, alkanoyl (alkyl-substituted)amide, aryl (alkyl-substituted)amide, heteroaryl (alkyl-substituted)amide and heterocyclic carbonyl (alkyl-substituted)amide, and formulas I-VIII may optionally be substituted at any position with C1-5 alkyl, alkoxy, cyano, halogen and / or trifluoromethyl;

[0063] (Formula V);

[0064] (Formula VI);

[0065] (Equation VII); or

[0066] (Formula VIII).

[0067] This disclosure relates to the use of compounds that capture reactive oxygen species or otherwise react with reactive oxygen species. In some aspects, compounds of formulas I-VIII are used according to this disclosure. Each reference cited in Table 1 and each detection reagent listed in Table 1 and disclosed in the cited references is incorporated herein by reference in its entirety. One object of this disclosure is to use probes that selectively react with specific degrading substances compared to other degrading substances, in order to identify specific degrading substances that come into contact with a given sensor 100 when it is implanted in a subject.

[0068] Table 1

[0069] In some non-limiting embodiments, a sensor 100 for determining an analyte (e.g., glucose) in a medium (e.g., interstitial fluid) within a living animal (e.g., a human) includes one or more of the following components: a sensor housing 102; a light source 108 configured within the sensor housing 102 to emit excitation light 329; an analyte indicator 106 covering a portion of the sensor housing 102; one or more indicator molecules 104, which are part of the analyte indicator 106, reversibly bind to the analyte, are positioned to be irradiated by the excitation light, and are configured to emit light 331 indicating the amount of the analyte in the medium within the living animal; a photodetector 224 within the sensor housing 102, the photodetector being sensitive to the light 331 emitted by the one or more indicator molecules 104, and configured to generate a signal indicating the amount of the analyte in the medium within the living animal; and one or more compounds of formulas I-VIII that selectively interact or react with a degradation substance. In some non-limiting embodiments, sensor 100 may include one or more degradation substance probes, such as compounds of formula I-VIII, positioned to be irradiated with excitation light and configured to emit light indicating the amount of degradation substance in a medium within a living animal. In some non-limiting embodiments, compounds of formula I-VIII are irradiated with excitation light after the sensor has been interpreted for in vitro analysis. In such non-limiting embodiments, an excitation light source external to the sensor may be used to excite compounds of formula I-VIII. In some non-limiting embodiments, sensor 100 may include a drug elution region 401, such as a drug elution matrix, a collar, and / or a catalyst layer provided on, adjacent to, or incorporated into the analyte indicator 106.

[0070] In some non-limiting embodiments, as illustrated in Table 1, each of the one or more degradation substance probes may be selective for one or more degradation substances relative to the other degradation substances. For example, in some embodiments, compounds of formulas I and V may be peroxynitrite selective. In some embodiments, compounds of formulas II and VI may be superoxide selective. In some embodiments, compounds of formulas III and VII may be hydrogen peroxide selective. In some embodiments, compounds of formulas IV and VIII may be hypochlorite and peroxynitrite selective. Exemplary reaction schemes and reactivity quantifications for compound VIII (“APF”) are shown in... Figure 5 Neutralize in Table 2 below.

[0071] Table 2

[0072] In some embodiments, each of the one or more degradation substance probes may undergo a specific change in its emission characteristics upon reaction with the degradation substance, allowing for the detection, identification, and quantification of the degradation substance in the environment of sensor 100. For example, in some embodiments, compounds of formulas I-VIII may be substantially non-fluorescent in the absence of the degradation substance and become strongly fluorescent upon reaction with the degradation substance. The emission characteristics of each probe demonstrate selectivity for a specific degradation substance, thereby allowing for the identification of degradation substances in the vicinity of sensor 100.

[0073] As a non-limiting example, the following reaction illustrates a non-limiting implementation method useful according to this disclosure:

[0074]

[0075] In some non-limiting embodiments, one or more compounds of formulas I-VIII may be provided in the analyte indicator 106 (e.g., hydrogel) of the analyte sensor 100. In some non-limiting embodiments, one or more compounds of formulas I-VIII may be incorporated into the analyte indicator 106 by polymerizing one or more compounds of formulas I-VIII as comonomers with an indicator monomer and one or more acrylate monomers. In some non-limiting embodiments, one or more compounds of formulas I-VIII may be provided as comonomers of four monomers according to formula IX:

[0076] ABCD [Formula IX],

[0077] Wherein A is an indicator monomer, B is a methacrylate monomer, C is a polyethylene glycol monomer, and D is one or more compounds selected from monomers of formulas I-VIII, wherein A comprises 0.001 to 10% by weight of the total polymer, B comprises 1 to 99% by weight of the total polymer, C comprises 1 to 99% by weight of the total polymer, and D comprises 0.001 to 99% by weight of the total polymer. In some aspects, A comprises 0.01 to 10% by weight of the total polymer, B comprises 1 to 99% by weight of the total polymer, C comprises 1 to 99% by weight of the total polymer, and D comprises 0.01 to 99% by weight of the total polymer.

[0078] In some non-limiting embodiments, the analyte indicator 106 may comprise four monomers: (i) a TFM fluorescent indicator, (ii) hydroxyethyl methacrylate (HEMA), which is a methacrylate, (iii) polyethylene glycol (PEG), and (iv) compounds of formulas I-VIII. In some embodiments, PEG may be polyethylene glycol methacrylate (PEG-methacrylate) or polyethylene glycol diacrylate (PEG-diacrylate or PEGDA), and one or more compounds of formulas I-VIII may be two or more compounds of formulas I-VIII. In some embodiments, the four monomers may have a specific molar ratio. For example, in some non-limiting embodiments where the analyte indicator 106 is opaque, the analyte indicator 106 may comprise 0.001 to 10 molar percentages, HEMA may comprise 10 to 90 molar percentages, PEGDA may comprise 10 to 90 molar percentages, and the compound of formula I or the compound of formula III may comprise 0.001 to 90 molar percentages. In one example of such a formulation, the combined (i.e., all) monomers may comprise 30% by volume of the polymerization solution used for the polymerization reaction, while the remainder of the polymerization solution is water (i.e., the polymerization solution may contain 70% by volume water). In another example, in a non-limiting embodiment, analyte indicator 106 can be prepared using a polymer solution of 50% by volume water and 50% by volume monomers.

[0079] In some embodiments, the relative molar percentages of the compounds of formulas I-VIII can be within a specific range. In some embodiments, the relative molar percentages of one or more compounds of formulas I-VIII are from 0.1 to 100 molar percentages. If the relative molar percentages of one or more compounds of formulas I-VIII are greater than this range, a hydrogel will not form. If the relative molar percentages of one or more compounds of formulas I-VIII are less than this range, the unexpected long lifespan and enhanced functionality described in this disclosure may not be achieved.

[0080] In some embodiments, PEGDA can act as a crosslinking agent and produce a sponge-like matrix / hydrogel. In some non-limiting embodiments, if a sufficient amount of additional PEG is added to the mixture (i.e., if it is made with a higher concentration of PEG), the PEG-containing graft / hydrogel can become clear, and the clear analyte indicator 106 can be made from such a formulation. For example, in one non-limiting embodiment, the polymer graft 106 can be made using a polymer solution of 50-60% by volume water and 40-50% by volume monomer, wherein the TFM fluorescent indicator, HEMA, PEG-methacrylate, and one or more compounds of formulas I-VIII can account for 0.01 to 10% by weight, 1 to 99% by weight, 1 to 99% by weight, and 0.01 to 99% by weight of the monomer in the solution. In some embodiments, the polymer graft can be synthesized using conventional free radical polymerization.

[0081] In some cases, the amount of one or more compounds of formulas I-VIII incorporated into analyte indicator 106 is about 0.1 mg to 5 mg, about 0.2 mg to 4 mg, about 0.5 mg to 3 mg, about 1 mg to 2.5 mg, about 1.5 mg to 2 mg, or about 2 mg to 2.4 mg, including all iterations of weight within these specified ranges.

[0082] In some cases, sensors loaded with one or more compounds of formulas I-VIII reduce the oxidation of analyte indicator molecules by degradation substances, including superoxide, hydrogen peroxide, hypochlorite, and peroxynitrite.

[0083] In some embodiments, sensor 100 may additionally include a series of dyes that can be embedded or copolymerized onto a hydrogel and implanted into an animal model. Sensor 100 implanted in an animal model can be explanted at specified time intervals and its absorption / emission properties can be characterized to confirm and quantify reactivity with the degradation substance. In some embodiments, changes in signal intensity can be compared to quantify relative amounts where different degradation substances are generated and detected by different probes. In some embodiments, a mixture of dyes can be used. In some embodiments, changes in the relative signal of the dye mixture upon reaction with the degradation substance can allow for determination of the relative ratio of degradation substances produced. For example, the relative ratio of one or two (or more) specific degradation substances to all other degradation substances can be determined by using a dye mixture, each dye being specific to the specific degradation substance.

[0084] Some embodiments of this disclosure may include methods for identifying the relative amount and / or identity of degradation substances generated in the body upon implantation of sensor 100. Some embodiments may include implanting a sensor according to this disclosure and detecting changes in the absorption and / or emission characteristics of one or more degradation substance probes forming part of implanted sensor 100.

[0085] Some embodiments of this disclosure may include methods for screening compounds to determine which compounds can be used to inhibit or neutralize the activity of a specific degrading substance. Some embodiments of this disclosure may include methods for screening compounds to determine which compounds lead to an increase in the production of degrading substances. Some embodiments of this disclosure may include methods for screening compounds to determine which compounds lead to a decrease in the production of degrading substances. Some embodiments of this disclosure may include methods for detecting and quantifying performance measurement results of an implantable sensor after modification of the implantable sensor. In some embodiments, the method may include modifying sensor 100 to incorporate one or more other materials believed to improve its performance or lifespan, implanting the modified sensor in an animal, and using the degrading substance probes and / or dyes of this disclosure to detect changes in the absorption and / or emission characteristics of one or more degrading substance probes or dyes forming part of the modified implantable sensor. In some embodiments, the method may include modifying sensor 100 to replace one or more materials with one or more new materials believed to improve its performance or lifespan, implanting the modified sensor in an animal, and using the degrading substance probes and / or dyes of this disclosure to detect changes in the absorption and / or emission characteristics of one or more degrading substance probes or dyes forming part of the modified implantable sensor.

[0086] In some embodiments, the method may include modifying sensor 100 to incorporate one or more other materials believed to improve its performance or lifetime, subjecting the modified sensor to in vitro performance testing, and using the degradable substance probes and / or dyes of this disclosure to detect changes in the absorption and / or emission characteristics of one or more degradable substance probes or dyes forming part of the modified implantable sensor. In some embodiments, the method may include modifying sensor 100 to replace one or more materials with one or more novel materials believed to improve its performance or lifetime, subjecting the modified sensor to in vitro performance testing, and using the degradable substance probes and / or dyes of this disclosure to detect changes in the absorption and / or emission characteristics of one or more degradable substance probes or dyes forming part of the modified implantable sensor.

[0087] Figure 6This is a flowchart illustrating a method 600 for screening compounds for inclusion in an implantable sensor 100 embodying various aspects of the present invention. In some embodiments, method 600 may include step 602 of applying an analyte indicator 106 to the sensor 100 such that the applied analyte indicator 106 covers at least a portion of the sensor 100. In some embodiments, the analyte indicator 106 may comprise one or more degradable substance probes. In some embodiments, the degradable substance probes may have selective absorption and / or emission characteristics for a particular degradable substance. In some embodiments, method 600 may include step 604 of applying a test compound to the sensor to form a test sensor. In some embodiments, method 600 may include step 606 of performing an in vitro test under simulated physiological conditions for a specified period of time. In some embodiments, method 600 may include step 608 of characterizing changes in the absorption / emission performance of the one or more degradable substance probes compared to their absorption / emission performance prior to the in vitro test. In some embodiments, method 600 may include step 610 of comparing changes in the characterized absorption / emission properties of the one or more degradation substance probes with the characterized absorption / emission properties of the one or more degradation substance probes in a control sensor. In some embodiments, the control sensor does not include the test compound. In some embodiments, method 600 may include step 612 of detecting whether the presence of the test compound increases or decreases the degradation substance.

[0088] Figure 7This is a flowchart illustrating a method 700 for screening compounds for inclusion in an implantable sensor 100 embodying various aspects of the present invention. In some embodiments, method 700 may include step 702 of applying an analyte indicator 106 to the sensor 100 such that the applied analyte indicator 106 covers at least a portion of the sensor 100. In some embodiments, the analyte indicator 106 may comprise one or more degradable substance probes. In some embodiments, the degradable substance probes may have selective absorption and / or emission characteristics for a particular degradable substance. In some embodiments, method 700 may include step 704 of applying a test compound to the sensor to form a test sensor. In some embodiments, method 700 may include step 706 of implanting the test sensor into an animal. In some embodiments, method 700 may include step 708 of explanting the sensor at a predetermined time point. In some embodiments, method 700 may include step 710 of characterizing changes in the absorption / emission performance of the one or more degradable substance probes compared to their absorption / emission performance prior to implantation. In some embodiments, method 700 may include step 712 of comparing changes in the characterized absorption / emission properties of the one or more degradation substance probes with the characterized absorption / emission properties of the one or more degradation substance probes in a control sensor. In some embodiments, the control sensor does not include the test compound. In some embodiments, method 700 may include step 714 of detecting whether the presence of the test compound increases or decreases degradation substances in the in vivo environment of the implantable sensor.

[0089] Figure 8 This is a flowchart illustrating a method 800 for identifying and / or quantifying degradable substances in a medical device environment, embodying several aspects of the present invention. In some embodiments, method 800 may include step 802 of applying an analyte indicator 106 to a sensor 100 such that the applied analyte indicator 106 covers at least a portion of the sensor 100. In some embodiments, the analyte indicator 106 may comprise one or more degradable substance probes. In some embodiments, the degradable substance probes may have selective absorption and / or emission characteristics for a particular degradable substance. In some embodiments, method 800 may include step 804 of exposing the sensor to an environment containing degradable substances. In some embodiments, method 800 may include step 806 of characterizing changes in the absorption / emission performance of the one or more degradable substance probes compared to their absorption / emission performance prior to the exposure step. In some embodiments, method 800 may include step 808 of quantifying the reactivity of the one or more degradable substance probes with one or more degradable substances.

[0090] Embodiments of the invention have been fully described above with reference to the accompanying drawings. Although the 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 can be made to the embodiments within the spirit and scope of the invention. For example, while in some embodiments the analyte sensor 100 may be an optical sensor, this is not required, and in one or more alternative embodiments, the analyte sensor may be a different type of analyte sensor, such as an electrochemical sensor, a diffusion sensor, or a pressure sensor. Furthermore, while in some embodiments the analyte sensor 100 may be an implantable sensor, this is not required, and in some alternative embodiments, the analyte sensor may be a percutaneous sensor with a wired connection to an external transceiver. For example, in some alternative embodiments, the analyte sensor 100 may be located within or on a percutaneous needle (e.g., at its tip). In these embodiments, instead of wireless communication using an antenna (e.g., inductive element 114), the analyte sensor may communicate with an external transceiver using one or more wires connected between the external transceiver and the transceiver percutaneous needle including the analyte sensor. In another instance, in some alternative implementations, the analyte sensor may be located in a catheter (e.g., for intravenous blood glucose monitoring) and may communicate with an external transceiver (wireless or wired).

Claims

1. A sensor for measuring an analyte in a medium in a living animal, the sensor comprising: an analyte indicator; and one or more degradation species probes having absorption and / or emission characteristics selective for a particular degradation species, wherein the one or more degradation species probes comprise: (a) a degradation species probe of Formula I: (Formula I); (b) a degradation species probe of Formula II: (Formula II); (c) a degradation species probe of Formula IV: (Formula IV); (d) a degradation species probe of Formula I and a degradation species probe of Formula II; (e) a degradation species probe of Formula II and a degradation species probe of Formula IV; (f) a degradation species probe of Formula I and a degradation species probe of Formula IV; or (g) a degradation species probe of Formula I, a degradation species probe of Formula II, and a degradation species probe of Formula IV; wherein each R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxyl, aryl, heteroaryl, polycyclic group, alkoxy, halogen, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylcarbamido, aroylcarbamido, heterocyclic carbonylcarbamido, heteroaroylcarbamido, alkanoyl (alkyl substituted) carbamido, aroyl (alkyl substituted) carbamido, heteroaroyl (alkyl substituted) carbamido, and heterocyclic carbonyl (alkyl substituted) carbamido.

2. The sensor of claim 1, further comprising a sensor housing, wherein the analyte indicator covers at least a portion of the sensor housing.

3. The sensor of claim 1, further comprising a sensor substrate or a sensor electrode, wherein the analyte indicator covers at least a portion of the sensor substrate or the sensor electrode.

4. The sensor of claim 1, wherein the sensor is implantable in a living animal.

5. The sensor of claim 1, wherein the one or more degradation species probes are co-monomers with the analyte indicator.

6. The sensor of claim 1, wherein the one or more degradation species probes are co-monomers with the analyte indicator in a hydrogel.

7. The sensor of claim 2, wherein the one or more degradation species probes are embedded in a hydrogel covering at least a portion of the sensor housing.

8. The sensor of claim 1, wherein the one or more degradation species probes bind to the degradation species.

9. The sensor of claim 1, wherein the one or more degradation species probes reduce chemical degradation and / or oxidation of the analyte indicator.

10. The sensor of claim 1, wherein the one or more degradation species probes sequester the degradation species so as to reduce and / or prevent degradation of the analyte indicator by the degradation species.

11. The sensor of claim 1, wherein the analyte indicator comprises a polymer comprising co-monomers of four monomers according to Formula IX: A-B-C-D [Formula IX], wherein A is an analyte indicator monomer, B is a methacrylate ester monomer, C is a polyethylene glycol monomer, and D is one or more degradation species probes, wherein A is 0.01 to 10 weight percent of the total polymer, B is 1 to 99 weight percent of the total polymer, C is 1 to 99 weight percent of the total polymer, and D is 0.01 to 99 weight percent of the total polymer.

12. The sensor of claim 1, wherein the one or more degradation species probes are provided in a molar ratio of 0.1 to 100 relative to analyte indicator monomers.

13. The sensor of claim 1, wherein the sensor comprises a mixture of two or more of the degradation species probes.

14. A method of making a sensor for determining an analyte in a medium in a living animal, the method comprising: applying an analyte indicator to a sensor such that the applied analyte indicator covers at least a portion of the sensor, wherein the analyte indicator comprises one or more degradation species probes, wherein the degradation species probes have absorption and / or emission characteristics that are selective for a particular degradation species, wherein the one or more degradation species probes comprises: (a) a degradation species probe of Formula I: (Formula I); (b) a degradation species probe of Formula II: (Formula II); (c) a degradation species probe of Formula IV: (Formula IV); (d) a degradation species probe of Formula I and a degradation species probe of Formula II; (e) a degradation species probe of Formula II and a degradation species probe of Formula IV; (f) a degradation species probe of Formula I and a degradation species probe of Formula IV; or (g) a degradation species probe of Formula I, a degradation species probe of Formula II, and a degradation species probe of Formula IV; wherein each R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxyl, aryl, heteroaryl, polycyclic group, alkoxy, halogen, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylcarbamido, aroylcarbamido, heterocyclic carbonylcarbamido, heteroaroylcarbamido, alkanoyl (alkyl substituted) carbamido, aroyl (alkyl substituted) carbamido, heteroaroyl (alkyl substituted) carbamido, and heterocyclic carbonyl (alkyl substituted) carbamido.

15. The method of claim 14, wherein the one or more degradation species probes are co-monomers with the analyte indicator.

16. The method of claim 14, wherein the one or more degradation species probes are co-monomers with the analyte indicator in a hydrogel.

17. The method of claim 14, further comprising a sensor housing, wherein the one or more degradation species probes are embedded in a hydrogel that covers at least a portion of the sensor housing.

18. The method of claim 14, wherein the one or more degradation species probes reduce chemical degradation and / or oxidation of the analyte indicator.

19. The method of claim 14, wherein the one or more degradation species probes interact or react with a degradation species, wherein the degradation species is hydrogen peroxide, a reactive oxygen species, a reactive nitrogen species, an enzyme, a free radical, or a metal ion.

20. The method of claim 14, wherein the one or more degradation species probes bind to the degradation species.

21. The method of claim 14, wherein the one or more degradation species probes sequester the degradation species so as to reduce and / or prevent degradation of the analyte indicator by the degradation species.

22. The method of claim 14, wherein the analyte indicator comprises a polymer comprising co-monomers of four monomers according to Formula IX: A-B-C-D [Formula IX], wherein A is an analyte indicator monomer, B is a methacrylate ester monomer, C is a polyethylene glycol monomer, and D is one or more degradation species probes, wherein A is 0.01 to 10 weight percent of the total polymer, B is 1 to 99 weight percent of the total polymer, C is 1 to 99 weight percent of the total polymer, and D is 0.01 to 99 weight percent of the total polymer.

23. The method of any one of claims 14-22, wherein the one or more degradation species probes are provided in a molar ratio of 0.1 to 100 relative to analyte indicator monomers.

24. The method of any one of claims 14-22, wherein the sensor comprises a mixture of two or more of the degradation species probes.

25. Use of a sensor according to any one of claims 1-13 in a method of detecting and identifying changes in degradation species in an environment.

26. A method of screening a compound for inclusion in an implantable sensor, comprising: applying an analyte indicator to a sensor such that the applied analyte indicator covers at least a portion of the sensor, wherein the analyte indicator comprises one or more degradation species probes having absorption and / or emission characteristics selective for a particular degradation species, wherein the one or more degradation species probes comprise: (a) a degradation species probe of Formula I: (Formula I); (b) a degradation species probe of Formula II: (Formula II); (c) a degradation species probe of Formula IV: (Formula IV); (d) a degradation species probe of Formula I and a degradation species probe of Formula II; (e) a degradation species probe of Formula II and a degradation species probe of Formula IV; (f) a degradation species probe of Formula I and a degradation species probe of Formula IV; or (g) a degradation species probe of Formula I, a degradation species probe of Formula II, and a degradation species probe of Formula IV; wherein each R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxyl, aryl, heteroaryl, polycyclic group, alkoxy, halogen, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylcarbamido, aroylcarbamido, heterocyclic carbonylcarbamido, heteroaroylcarbamido, alkanoyl (alkyl substituted) carbamido, aroyl (alkyl substituted) carbamido, heteroaroyl (alkyl substituted) carbamido, and heterocyclic carbonyl (alkyl substituted) carbamido; applying a test compound to the sensor to form a test sensor; conducting an in vitro test under simulated physiological conditions for a defined period of time; characterizing a change in absorption / emission properties of the one or more degradation species probes as compared to the absorption / emission properties of the one or more degradation species probes prior to conducting the in vitro test; and comparing the characterized change in absorption / emission properties of the one or more degradation species probes to the characterized absorption / emission properties of the one or more degradation species probes in a control sensor, wherein the control sensor does not include the test compound; and detecting whether the presence of the test compound increases or decreases a degradation species.

27. A method of identifying and / or quantifying a degradation species in a medical device environment, comprising: applying an analyte indicator to a sensor such that the applied analyte indicator covers at least a portion of the sensor, wherein the analyte indicator comprises one or more degradation species probes having absorption and / or emission characteristics selective for a particular degradation species, wherein the one or more degradation species probes comprise: (a) a degradation species probe of Formula I: (Formula I); (b) a degradation species probe of Formula II: (Formula II); (c) a degradation species probe of Formula IV: (Formula IV); (d) a degradation species probe of Formula I and a degradation species probe of Formula II; (e) a degradation species probe of Formula II and a degradation species probe of Formula IV; (f) a degradation species probe of Formula I and a degradation species probe of Formula IV; or (g) a degradation species probe of Formula I, a degradation species probe of Formula II, and a degradation species probe of Formula IV; wherein each R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxyl, aryl, heteroaryl, polycyclic group, alkoxy, halogen, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylcarbamido, aroylcarbamido, heterocyclic carbonylcarbamido, heteroaroylcarbamido, alkanoyl (alkyl substituted) carbamido, aroyl (alkyl substituted) carbamido, heteroaroyl (alkyl substituted) carbamido, and heterocyclic carbonyl (alkyl substituted) carbamido; exposing the sensor to an environment containing a degradation substance; characterizing a change in the absorption / emission properties of the one or more degradation substance probes compared to the absorption / emission properties of the one or more degradation substance probes prior to the exposing step; and quantifying the reactivity of the one or more degradation substance probes with one or more degradation substances.

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