Reducing in vivo analyte signal degradation using multiple metals

Abstract

A sensor (e.g., an optical sensor) that can be implanted within a living animal (e.g., a human) and used to measure an analyte (e.g., glucose or oxygen) in a medium (e.g., interstitial fluid, blood, or intraperitoneal fluid) within the animal, the sensor including a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and a multi-metal protection system including multiple metals incorporated within and / or proximate to a surface of the analyte indicator that reduces deterioration of the analyte indicator.

Description

[Technical Field]

[0001] Cross-reference to related applications

[0001] This application claims priority to U.S. Patent Application No. 18 / 165,165, filed February 6, 2023, the entire contents of which are incorporated herein by reference.

[0002]

[0002] FIELD OF THE INVENTION

[0003] The present invention relates generally to catalytic protection of materials from in vivo degradation when measuring analytes in a medium of a living animal using a system including a sensor implanted or inserted (partially or completely) in the living animal. Specifically, the present invention relates to sensors that utilize multiple metals that can be collectively or independently incorporated into an analyte indicator, formed on one or more surfaces of an analyte indicator, and / or layered on at least a portion of the surface of an analyte indicator (e.g., one or more metal layers stacked on top of each other). [Background technology]

[0003]

[0004] Background Statement

[0005] The sensor can be implanted (partially or completely) within a living animal (e.g., a human) and used to measure an analyte (e.g., glucose, oxygen, a cardiac marker, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides) in a medium within the living animal (e.g., interstitial fluid (ISF), blood, or peritoneal fluid). The sensor can include a light source (e.g., a light-emitting diode (LED) or other light-emitting element), an indicator molecule, and a photodetector (e.g., a photodiode, phototransistor, photoresistor, or other light-sensitive element). Examples of implantable sensors employing indicator molecules to measure analytes are described in U.S. Pat. Nos. 5,517,313 and 5,512,246, the contents of which are incorporated herein by reference in their entireties.

[0004]

[0006] The sensor may include an analyte indicator, which can take the form of an indicator molecule embedded within a graft (e.g., a layer or matrix). For example, in an implantable fluorescence-based glucose sensor, a fluorescent indicator molecule can reversibly bind to glucose and, upon irradiation with excitation light (e.g., light having a wavelength of approximately 378 nm), emit light (e.g., in the 400 to 500 nm range) whose amount varies depending on whether glucose is bound to the indicator molecule.

[0005]

[0007] When a sensor is implanted in a living animal, the animal's immune system may begin to attack the sensor. For example, when a sensor is implanted in a human, white blood cells may attack the sensor as a foreign body, with neutrophils being the primary white blood cells attacking the sensor in the initial immune system onslaught. Neutrophil defense mechanisms include the release of highly corrosive substances known as reactive oxygen species. Reactive oxygen species include, for example, hydrogen peroxide.

[0006]

[0008] Hydrogen peroxide and other reactive species, such as reactive oxygen and nitrogen species, can degrade the indicator molecules of analyte indicators. For example, in indicator molecules having boronic acid groups, hydrogen peroxide can degrade the indicator molecule by oxidizing the boronic acid group, thereby disabling the indicator molecule's ability to bind glucose. Summary of the Invention [Problem to be solved by the invention]

[0007]

[0009] Currently, there is a need in the art for improvements in protecting analyte indicators from degradation. There is also a need in the art for long-life, continuous analyte sensors.

[0010] Among other advantages, the present invention overcomes the shortcomings of conventional systems by providing for reduced degradation of the analyte indicator. [Means for solving the problem]

[0008]

[0011] In one aspect, the present invention can provide a device having a partially or fully implantable device, the device having an in vivo function, and further having a protective material proximate the surface of the implantable device. The protective material can prevent or reduce degradation or interference of the implantable device due to inflammatory and / or foreign body reactions. Furthermore, the protective material can include a metal, metal complex, or metal oxide that acts as a catalyst to decompose or inactivate in vivo reactive species or biological oxidants. As used herein, the term "metal" includes metal alloys, metal complexes, and metal oxides.

[0009]

[0012] In one aspect, the protective material may cover, be disposed on, be incorporated with, and / or be suspended within the exterior structure of the implantable device.

[0010]

[0013] One aspect of the present invention provides a sensor for measuring an analyte in a medium within a living animal. The sensor can include a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and a protection system. The protection system can include a plurality of metals incorporated into and / or proximate to the surface of the analyte indicator, where the plurality of metals can be configured to reduce deterioration of the analyte indicator. In one aspect, the sensor can also include a protection system having a metal layer including one or more of the plurality of metals. In one aspect, the sensor can also have a metal layer covering at least a portion of the analyte indicator.

[0011]

[0014] In one embodiment, the sensor can have a first metal layer and a second metal layer, where the first metal layer includes a first metal from a plurality of metals and the second metal layer includes a second metal from a plurality of metals, and the first and second metals are different metals. The first metal layer can cover at least a portion of the analyte indicator. The second metal layer can cover at least a portion of the first metal layer. In one embodiment, the second metal layer can have a stronger adhesive strength to the first metal layer than the adhesive strength would be if the second metal layer were directly deposited on the analyte indicator. In one embodiment, the second metal layer can be between at least a portion of the sensor housing and the analyte indicator, and the first metal layer can cover at least a portion of the analyte indicator remote from the sensor housing. In one embodiment, the first metal layer can be between at least a portion of the sensor housing and the analyte indicator, and the second metal layer can cover at least a portion of the analyte indicator remote from the sensor housing.

[0012]

[0015] In one embodiment, the protection system may include metal particles incorporated within the analyte indicator, and the metal particles may include one or more of a plurality of metals. In some embodiments, the metal particles may include a first metal and a second metal, and the first and second metals are different metals. In one embodiment, the metal layer may be a multi-metal layer including a first metal of the plurality of metals and a second metal of the plurality of metals, and the first and second metals are different metals.

[0013]

[0016] In one embodiment, the protective system may include a plurality of metals configured to collectively interact or react with a plurality of decomposition species. In some embodiments, the plurality of metals of the protective system may be configured to collectively interact or react with at least two of hydrogen peroxide, reactive oxygen species, enzymes, metal ions, reactive nitrogen species, and free radicals.

[0014]

[0017] In some embodiments, the plurality of metals of the protective system may be configured to inhibit the oxidative nature of the decomposition species. In some embodiments, the plurality of metals of the protective system may include a first metal selected from Cu, W, Pt, Fe, Mo, and oxides, alloys, and complexes thereof, and a second metal selected from Mo, W, Cu, Fe, and Co, and oxides, alloys, and complexes thereof, where the first metal and the second metal are different from each other.

[0015]

[0018] In some aspects, the sensor can further include a radiation source housed within the sensor body and configured to emit radiation to the indicator element. In some aspects, the sensor can further include a light-sensitive element housed within the sensor body and configured to receive light emitted by the analyte indicator. In some aspects, the sensor can further include a carrier material covering at least a portion of the analyte indicator, wherein the plurality of metals are incorporated into the material.

[0016]

[0019] In certain aspects, the present disclosure includes a method of detecting the presence or concentration of an analyte in a biological sample, the method including exposing the biological sample to a device having a detectable quality, the detectable quality changing upon exposure of the device to the analyte of interest, the device may include a protective material that prevents or reduces degradation or interference of the device from degradative species or biological oxidants, and the device may further include a sensor of the present disclosure, and detecting the presence or concentration of the analyte of interest in the biological sample by measuring the change in the detectable quality.

[0017]

[0020] Another aspect of the invention provides a sensor for measuring an analyte in a medium within a living animal. The sensor can include a sensor housing, an analyte indicator, and a protection system. The analyte indicator can cover at least a portion of the sensor housing. The protection system can include a plurality of metals configured to reduce deterioration of the analyte indicator. The protection system can include first, second, and third metal layers. The first metal layer can cover at least a portion of the analyte indicator and can include a first metal from the plurality of metals. The second metal layer can cover at least a portion of the first metal layer and can include a second metal from the plurality of metals. The third metal layer can cover at least a portion of the second metal layer and can include a third metal from the plurality of metals. The first, second, and third metals can be different.

[0018]

[0021] In some embodiments, the first metal can be platinum. In some embodiments, the second metal can be iridium. In some alternative embodiments, the second metal can be tungsten. In some alternative embodiments, the second metal can be cobalt. In some embodiments, the third metal can be molybdenum.

[0019]

[0022] In some embodiments, a first metal layer can be sputtered onto the analyte indicator. In some embodiments, a second metal layer can be sputtered onto the first metal layer. In some embodiments, a third metal layer can be sputtered onto the second metal layer. In some embodiments, the first metal layer can be a layer of platinum having a thickness of at least 7 nm and at most 13 nm sputtered onto the analyte indicator, the second metal layer can be a layer of iridium having a thickness of at least 3 nm and at most 7 nm sputtered onto the first metal layer, and / or the third metal layer can be a layer of molybdenum having a thickness of at least 17 nm and at most 23 nm sputtered onto the second metal layer.

[0020]

[0023] In some embodiments, the in vivo catalytic activity of the first metal layer and the second metal layer overlying the first metal layer can be greater than the in vivo catalytic activity of the first metal layer alone. In some embodiments, the second metal layer can be less susceptible to catalytic inactivation by thiol-containing molecules than the first metal layer is to catalytic inactivation by thiol-containing molecules.

[0021]

[0024] In some embodiments, a third metal layer covering at least a portion of the second metal layer can have a stronger adhesive strength to the sensor than if the third metal layer were instead directly deposited on the first metal layer or the analyte indicator. In some embodiments, the third metal can have catalytic activity toward degradation species that the first and second metals do not. In some embodiments, the third metal can have catalytic activity toward hypochlorous acid, and the first and second metals may not be active toward hypochlorous acid. In some embodiments, the first, second, and third metals can have catalytic activity toward hydrogen peroxide. In some embodiments, the third metal can have catalytic activity toward multiple reactive oxygen species. In some embodiments, the first metal layer can be free of the second and third metals, the second metal layer can be free of the first and third metals, and the third metal layer can be free of the first and second metals.

[0022]

[0025] In some embodiments, the protection system may include metal particles incorporated within the analyte indicator, the metal particles including one or more of the plurality of metals, and in some embodiments, the first metal layer may be a multi-metal layer including two or more of the plurality of metals.

[0023]

[0026] In some embodiments, the plurality of metals can be configured to collectively interact or react with a plurality of decomposition species, hi some embodiments, the plurality of metals of the protection system can be configured to collectively interact or react with at least two of hydrogen peroxide, reactive oxygen species, enzymes, metal ions, reactive nitrogen species, and free radicals.

[0024]

[0027] In some aspects, the sensor may further include a radiation source and a light-sensitive element, wherein the radiation source may be contained within the sensor housing and the radiation source may be configured to emit radiation to the analyte indicator. The light-sensitive element may be contained within the sensor housing and the light-sensitive element may be configured to receive light emitted by the analyte indicator.

[0025]

[0028] Yet another aspect of the present invention may provide a method of manufacturing. The method may include covering at least a portion of an analyte indicator of the sensor with a first metal layer including a first metal of a plurality of metals of the protection system. The analyte indicator may cover at least a portion of a sensor housing of the sensor. The method may include covering at least a portion of the first metal layer with a second metal layer including a second metal of the plurality of metals. The method may include covering at least a portion of the second metal layer with a third metal layer including a third metal of the plurality of metals. The plurality of metals may be configured to reduce deterioration of the analyte indicator, and the first, second, and third metals may be different.

[0026]

[0029] In some embodiments, covering at least a portion of the analyte indicator with a first metal layer can include sputtering a layer of the first metal over at least a portion of the analyte indicator. In some embodiments, the sputtered layer of the first metal can have a thickness of at least 7 nm and at most 13 nm. In some embodiments, the first metal can be platinum.

[0027]

[0030] In some embodiments, covering at least a portion of the first metal layer with a second metal layer can include sputtering a layer of the second metal onto at least a portion of the first metal layer. In some embodiments, the sputtered layer of the second metal can have a thickness of 3 nm or more and 7 nm or less. In some embodiments, the second metal can be iridium. In some alternative embodiments, the second metal can be tungsten. In some alternative embodiments, the second metal can be cobalt.

[0028]

[0031] In some embodiments, covering at least a portion of the second metal layer with a third metal layer can include sputtering a layer of the third metal over at least a portion of the second metal layer. In some embodiments, the sputtered third metal layer can have a thickness of at least 17 nm and at most 23 nm. In some embodiments, the third metal can be molybdenum.

[0029]

[0032] Further variations encompassed within the above systems and methods are also described in the detailed description below. [Brief explanation of the drawings]

[0030]

[0033] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate various non-limiting aspects of the present invention, in which like reference numbers indicate identical or functionally similar elements. [Figure 1]

[0034] 1 is a schematic diagram illustrating a sensor system embodying aspects of the present invention. [Figure 2]

[0035] 1 shows a perspective view of a sensor embodying aspects of the present invention; [Figure 3]

[0036] 1 shows an exploded view of a sensor embodying aspects of the present invention. [Figure 4A]

[0037] 1 is a schematic diagram illustrating an analyte indicator and protective layer embodying aspects of the present invention. [Figure 4B] 1 is a schematic diagram illustrating an analyte indicator and protective layer embodying aspects of the present invention. [Figure 5A]

[0038] 1 is a schematic diagram illustrating an analyte indicator and protective layer embodying aspects of the present invention. [Figure 5B] 1 is a schematic diagram illustrating an analyte indicator and protective layer embodying aspects of the present invention. [Figure 6A]

[0039] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 6B] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 7A]

[0040] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 7B] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 8A]

[0041] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 8B] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 9A]

[0042] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 9B] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 10A]

[0043] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 10B] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 11A]

[0044] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 11B] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 12]

[0045] 1 is a schematic diagram illustrating an analyte indicator and protective material embodying aspects of the present invention. [Figure 13]

[0046] 1 is a schematic diagram illustrating an analyte indicator and protective layer embodying aspects of the present invention. [Figure 14A]

[0047] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 14B] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 15]

[0048] 1 is a schematic diagram illustrating an analyte indicator, a protective layer, and a protective material embodying aspects of the present invention. [Figure 16A]

[0049] 1 is a schematic diagram illustrating an analyte indicator embodying an embodiment of the present invention and a support material having first and second metals incorporated therein. [Figure 16B]

[0050] 1 is a schematic diagram illustrating an analyte indicator, a first metal layer, and a support material having first and second metals incorporated therein, embodying an embodiment of the present invention. [Figure 16C]

[0051] 1 is a schematic diagram illustrating an analyte indicator embodying an embodiment of the present invention, a first support material having a metal incorporated therein, and a second support material having a different metal incorporated therein. [Figure 17]

[0052] 1 is a schematic diagram illustrating an analyte indicator and protective layer embodying aspects of the present invention. [Figure 18]

[0053] 1 is a flow chart illustrating a process according to an embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0031]

[0054] In one aspect, the invention includes a sensor device, which can be for implantation or insertion within a living animal and for measuring an analyte in a medium within the living animal, and can include a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and at least one multi-metallic material that reduces deterioration of the analyte indicator.

[0032]

[0055] In certain embodiments, the sensor device may also include at least one multi-metallic material that covers at least a portion of an analyte indicator disposed on the sensor housing.

[0033]

[0056] In certain embodiments, the sensor device can include a sensor housing having an analyte indicator covering at least a portion of a surface of the sensor housing, a first single or multi-metal material or layer covering at least a portion of the analyte indicator, and a second single or multi-metal material or layer covering at least a portion of the first single or multi-metal layer.

[0034]

[0057] In certain embodiments, the sensor device can also include a sensor housing having an analyte indicator covering at least a portion of a surface of the sensor housing, a first single or multi-metallic material or layer disposed between at least a portion of the sensor housing and the analyte indicator, and a second single or multi-metallic material or layer distal to the sensor housing and covering at least a portion of the analyte indicator.

[0035]

[0058] In certain embodiments, a sensor device can include a sensor housing having an analyte indicator covering at least a portion of a surface of the sensor housing, at least one metal incorporated within the analyte indicator, and at least one single or multiple metal material or layer distal to the sensor housing and covering at least a portion of the analyte indicator.

[0036]

[0059] In another aspect, the present invention relates to a method for using an implantable device in an in vivo application. The method includes at least the step of providing an implantable device having an in vivo function. The implantable device has a protective material applied thereon, the protective material applied by this method preventing or reducing degradation or interference of the implantable device due to inflammatory and / or foreign body reactions. The protective material applied by this method includes a plurality of metals (including metal complexes and metal oxides) that catalytically degrade or inactivate a plurality of different biodegradative species or biological oxidizers. As used herein, the terms "degenerative species" and "biological oxidizer" collectively refer to reactive physiological molecules or radicals that degrade indicator molecules. The method further includes the step of partially or completely implanting the implantable device within a patient's body.

[0037]

[0060] In another aspect, the present invention relates to a method for detecting the presence or concentration of an analyte in a biological sample, the method comprising at least exposing the biological sample to a device having a detectable quality that changes upon exposure of the device to the analyte of interest, the device comprising, in part, a protective material that prevents or reduces degradation or interference of the device by degradative species or biological oxidants, and the method further comprising determining the presence or concentration of the analyte of interest in the biological sample by measuring any change in the detectable quality.

[0038]

[0061] In another aspect, the present invention is an implantable glucose sensor for determining the presence or concentration of glucose in an animal. The sensor device can include a sensor body having an outer surface surrounding the sensor body, a radiation source within the sensor body that emits radiation into the sensor body, and an indicator element that is affected by the presence or concentration of glucose in the animal. The indicator element having an indicator molecule is positioned proximate to at least a portion of the outer surface of the sensor body. The sensor can further include a photosensitive element disposed within the sensor body and positioned to receive radiation within the sensor body. The photosensitive element is configured to emit a signal in response to radiation received from the indicator element, the signal indicating the presence or concentration of glucose in the animal. The sensor can also include a protective material that protects the indicator molecule from degradative species and biological oxidants.

[0039]

[0062] FIG. 1 is a schematic diagram of a sensor system embodying embodiments of the present invention. In one embodiment, as shown in FIG. 1, the system can include a sensor 100 and an external transceiver 101. In one embodiment, the sensor 100 can be an implantable sensor configured to be fully or partially implanted within a living animal (e.g., a living human). The sensor 100 can be implanted, for example, in the arm, wrist, leg, abdomen, peritoneum, or other area of ​​the living animal suitable for implanting a sensor. For example, in one embodiment, the sensor 100 can be implanted just below the skin (i.e., subcutaneously or within the peritoneal tissue). However, this is not required, and in an alternative embodiment, the sensor 100 can be a transcutaneous sensor.

[0040]

[0063] In certain 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 certain embodiments, the received data may include one or more sensor measurements. In certain embodiments, the sensor measurements may include, for example and without limitation, one or more light measurements from one or more light detectors of sensor 100 and / or one or more temperature measurements from one or more temperature sensors of sensor 100. In certain embodiments, transceiver 101 may also calculate the concentration of an analyte (e.g., glucose) from the measurement information received from sensor 100.

[0041]

[0064] In some embodiments, the transceiver 101 may be a handheld device or an on-body / wearable device. For example, in some embodiments, if the transceiver 101 is an on-body / wearable device, a band (e.g., an armband or wristband) and / or adhesive may hold the transceiver 101 in place, and the transceiver 101 may transmit measurement commands (i.e., requests for measurement information) to the sensor 100 (periodically, e.g., every two minutes, and / or upon user activation). In some embodiments, if the transceiver 101 is a handheld device, positioning the transceiver 101 (i.e., hovering or swiping / waving / passing) within range of the sensor implantation site (i.e., in proximity to the sensor 100) may cause the transceiver 101 to automatically transmit measurement commands to the sensor 100 and also receive data from the sensor 100.

[0042]

[0065] 1, the transceiver 101 may also include an inductive element 103, such as, for example, a coil. In some embodiments, the transceiver 101 may generate an electromagnetic wave or field (e.g., by using a coil) to induce a current in the inductive element 114 of the sensor 100. In some embodiments, the sensor 100 may also use the current induced in the inductive element 114 to power the sensor 100. However, this is not required, and in some alternative embodiments, the sensor 100 may be powered by an internal power source (e.g., a battery).

[0043]

[0066] In an aspect, the transceiver 101 can communicate data (e.g., commands) to the sensor 100. For example, in an aspect, the transceiver 101 can communicate data by modulating the electromagnetic waves generated by the inductive element 103 (e.g., by modulating the current passing through the inductive element 103 of the transceiver 101). In an aspect, the sensor 100 can detect / extract the modulation in the electromagnetic waves generated by the transceiver 101. Additionally, the transceiver 101 can receive data (e.g., one or more sensor measurements) from the sensor 100. For example, in an aspect, the transceiver 101 can receive data by detecting modulation in the electromagnetic waves generated by the sensor 100, e.g., by detecting modulation in the current passing through the inductive element 103 of the transceiver 101.

[0044]

[0067] 1, the sensor 100 can also include a sensor housing 102 (i.e., a body, shell, capsule, or container). The sensor housing 102 can be rigid and biocompatible. In an exemplary embodiment, the sensor housing 102 can be formed from a suitable optically transmissive polymeric material, such as, for example, an acrylic polymer (e.g., polymethyl methacrylate (PMMA)).

[0045]

[0068] In one embodiment, the sensor 100 can include an analyte indicator 106, as shown in FIG. 1 . In one embodiment, the analyte indicator 106 can be a polymer graft coated, diffused, adhered, or embedded onto at least a portion of the exterior surface of the sensor housing 102. The analyte indicator 106 (e.g., a polymer graft) can cover the entire surface of the sensor housing 102 or only one or more portions of the surface of the housing 102. Instead of coating the analyte indicator 106 on the exterior surface of the sensor housing 102, the analyte indicator 106 can be disposed on the exterior surface of the sensor housing 102 in other ways, such as by deposition or adhesion. In one embodiment, the analyte indicator 106 can be a fluorescent glucose-indicating polymer. In one embodiment, the polymer is biocompatible and stable, and is designed to be implanted on the surface of the sensor housing 102 and support direct measurement of glucose in interstitial fluid (ISF), blood, or intraperitoneal fluid after implantation of the sensor 100. In some embodiments, the analyte indicator 106 may be a hydrogel.

[0046]

[0069] In some embodiments, the analyte indicator 106 (e.g., polymer graft) of the sensor 100 can also include indicator molecules 104. The indicator molecules 104 can be dispersed throughout the analyte indicator 106 or can be dispersed only in one or more portions of the analyte indicator 106. The indicator molecules 104 can be fluorescent indicator molecules (e.g., TFM, which has the chemical name 9-[N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-3-(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene sodium salt) or light-absorbing, non-fluorescent indicator molecules. In some embodiments, indicator molecule 104 may reversibly bind to an analyte (e.g., glucose, oxygen, a cardiac marker, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides). When indicator molecule 104 binds to an analyte, the indicator molecule becomes fluorescent, where indicator molecule 104 can absorb (or be excited by) excitation light 329 and emit light 331. In one embodiment, excitation light 329 may have a wavelength of approximately 378 nm, and emission light 331 may have a wavelength in the range of 400 to 500 nm. When no analyte is bound, indicator molecule 104 may fluoresce weakly.

[0047]

[0070] In certain embodiments, the sensor 100 can include a light source 108. The light source 108 can be, for example, a light emitting diode (LED) or other light source that emits radiation, including radiation that falls within the wavelength range that interacts with the indicator molecules 104. In other words, the light source 108 can emit excitation light 329 that is absorbed by the indicator molecules in the matrix layer / polymer 104. As noted above, in one embodiment, the light source 108 can emit excitation light 329 at a wavelength of approximately 378 nm.

[0048]

[0071] In certain embodiments, sensor 100 can also include one or more photodetectors (e.g., photodiodes, phototransistors, photoresistors, or other light-sensitive elements). For example, in the embodiment shown in FIG. 1, sensor 100 has first photodetector 224 and second photodetector 226. However, this is not required, and in certain alternative embodiments, sensor 100 may include only the first photodetector. In the case of a fluorescence-based sensor, the one or more photodetectors may be sensitive to fluorescence emitted by indicator molecule 104, such that a signal generated in response by the photodetector (e.g., photodetector 224) indicates the level of fluorescence of the indicator molecule, which in turn indicates the amount of analyte of interest (e.g., glucose).

[0049]

[0072] A portion of the excitation light 329 emitted by the light source 108 may be reflected by the analyte indicator 106 and returned to the sensor 100 as reflected light 333, and a portion of the absorbed excitation light may be emitted as emitted (fluorescent) light 331. In one 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 may be absorbed by one or more photodetectors (e.g., first and second photodetectors 224 and 226) within the body of the sensor 100.

[0050]

[0073] Each of the one or more photodetectors may be covered by a filter 112 (see FIG. 3) that passes only a specific subset of wavelengths of light. 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, which may pass only a narrow wavelength band and otherwise reflect most of the light received by the filter. In some embodiments, the filters may be thin film (dichroic) filters deposited directly on the photodetectors, which may pass only a narrow wavelength band and otherwise reflect most of the light received by the filter. The filters 112 may be the same (e.g., both filters 112 may pass the signal) or different (e.g., one filter 112 may be a reference filter and the other filter 112 may be a signal filter).

[0051]

[0074] In one embodiment, the second (reference) photodetector 226 may be covered with a reference photodiode filter that passes light of the same wavelength (e.g., 378 nm) as emitted by the light source 108. The first (signal) photodetector 224 can detect the amount of fluorescent light 331 emitted from the molecules 104 in the analyte indicator 106. In one embodiment, the peak emission point of the indicator molecules 104 may occur around 435 nm, and the first photodetector 224 may be covered with a signal filter that passes light that falls in the range of approximately 400 nm to 500 nm. In some embodiments, an increase in glucose level / concentration corresponds to an increase in the amount of fluorescence of the molecules 104 in the analyte indicator 106, and therefore, an increase in the number of photons impinging on the first photodetector 224.

[0052]

[0075] In certain embodiments, as shown in FIG. 1 , the sensor 100 may also include a substrate 116. In certain embodiments, the 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 attached. However, in certain alternative embodiments, the substrate 116 may be a semiconductor substrate having circuitry fabricated therein. The circuitry may include analog and / or digital circuitry. Also, in certain semiconductor substrate embodiments, circuitry may be mounted or otherwise attached on the semiconductor substrate 116 in addition to the circuitry fabricated therein. In other words, in certain semiconductor substrate embodiments, some or all of the circuitry, which may include discrete circuit elements, integrated circuits (e.g., application specific integrated circuits (ASICs)), and / or other electronic components, may be fabricated within the semiconductor substrate 116, with the remainder of the circuitry being fixed to the semiconductor substrate 116 to provide communication paths between the various fixed components.

[0053]

[0076] In certain 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 inductive element 114 of sensor 100 may include some or all of the features described in one or more of U.S. patent application Ser. No. 13 / 761,839, filed Feb. 7, 2013, U.S. patent application Ser. No. 13 / 937,871, filed July 9, 2013, and U.S. patent application Ser. No. 13 / 650,016, filed Oct. 11, 2012, all of which are incorporated herein by reference in their entireties. Similarly, the structure and / or function of sensor 100 and / or transceiver 101 may be as described in one or more of U.S. patent application Ser. Nos. 13 / 761,839, 13 / 937,871, and 13 / 650,016, the entire contents of which are incorporated herein by reference.

[0054]

[0077] In some embodiments, sensor 100 can include a transceiver interface device, and transceiver 101 can also include a sensor interface device. In some embodiments, if sensor 100 and transceiver 101 include one or more antennas (e.g., inductive elements 103 and 114), the transceiver interface device can include inductive element 114 of sensor 100, and the sensor interface device can include inductive element 103 of transceiver 101. In transcutaneous embodiments, if a wired connection exists between sensor 100 and transceiver 101, the transceiver interface device and sensor interface device can include the wired connection.

[0055]

[0078] Figures 2 and 3 illustrate an embodiment of a sensor 100 embodying an embodiment of the present invention that can be used in the sensor system shown in Figure 1. Figures 2 and 3 illustrate a perspective view and an exploded view, respectively, of an embodiment of sensor 100.

[0056]

[0079] 3, the sensor housing 102 can include end caps 113. In some embodiments, the sensor 100 can include one or more capacitors 118. The one or more capacitors 118 can be, for example, one or more tuning capacitors and / or one or more regulation capacitors. The one or more capacitors 118 can be impractical and too large to be fabricated within the semiconductor substrate 116. Additionally, the one or more capacitors 118 can be in addition to one or more capacitors fabricated within the semiconductor substrate 116.

[0057]

[0080] 3 , the sensor 100 can include a reflector 119 (e.g., a mirror). The reflector 119 can be attached to one end of the semiconductor substrate 116. In one embodiment, the reflector 119 can be attached to the semiconductor substrate 116 so that a surface portion 121 of the reflector 119 is generally perpendicular to the top surface of the semiconductor substrate 116 (i.e., the side of the semiconductor substrate 116 on which the light source 108 and one or more photodetectors 110 are mounted or fabricated) and faces the light source 108. The surface 121 of the reflector 119 can reflect radiation emitted by the light source 108. In other words, the reflector 119 can block radiation emitted by the light source 108 from exiting the axial end of the sensor 100.

[0058]

[0081] In accordance with one aspect of the present invention, sensor 100 has been developed for (but is by no means limited to) the measurement of various biological analytes in living animals (including humans). For example, sensor 100 can be used to measure glucose, oxygen, toxins, pharmaceutical or other drugs, hormones, and other metabolic analytes in, for example, the human body.

[0059]

[0082] In certain embodiments, the specific compositions of the analyte indicator 106 and the indicator molecule 104 can vary depending on the particular analyte to be detected using the sensor and / or the location where the sensor is to be used to detect the analyte (e.g., subcutaneous tissue, blood, or intraperitoneal). In certain embodiments, the analyte indicator 106 facilitates exposure of the indicator molecule 104 to the analyte. In certain embodiments, the indicator molecule 104 can exhibit a characteristic (e.g., the amount of fluorescence it emits) that is a function of the concentration of the particular analyte to which the indicator molecule 104 is exposed.

[0060]

[0083] In certain embodiments, the sensor 100 can include at least one drug-eluting polymer matrix, and / or a layer of catalyst, and / or one or more therapeutic agents, which can be provided on, incorporated within, or dispersed within the analyte indicator or sensor housing, as described in U.S. Pat. No. 9,931,068 (Huffstetler et al.), which is incorporated herein by reference in its entirety. In certain embodiments, the one or more therapeutic agents can be incorporated within the analyte indicator 106. In certain embodiments, the sensor 100 can include a membrane that covers at least a portion of the analyte indicator 106, and the one or more therapeutic agents can be incorporated within the membrane. In certain embodiments, the one or more therapeutic agents include nonsteroidal anti-inflammatory drugs, including but not limited to dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclomethasone, fludrocortisone, derivatives thereof, and analogs thereof, glucocorticoids, anti-inflammatory drugs, e.g., acetylsalicylic acid, isobutylphenylpropanoic acid.

[0061]

[0084] The implantation or insertion of a medical device, such as a biosensor, into a user's / patient's body can cause physiological side effects in the body that are detrimental to the device's function. These side effects can range from infection due to the implantation procedure to an immune response to a foreign object implanted in the body. That is, the performance of an implantable biosensor can be inhibited or irreparably damaged in vivo by infection or an immune response to the device itself. Specifically, the performance of the analyte indicator 106 can be deteriorated by an immune response in the body in which the sensor 100 is implanted. For example, as discussed above, white blood cells, including neutrophils, can attack the implanted sensor 100. Release of neutrophils, particularly hydrogen peroxide, can degrade the indicator molecule 104 (e.g., by oxidizing the boronic acid group of the indicator molecule 104 and disabling the indicator molecule's 104 ability to bind glucose and / or fluoresce).

[0062]

[0085] In certain embodiments, the analyte indicator 106 can be protected by multiple metals (including metal alloys, metal complexes, or metal oxides) that interact or react with one or more decomposition species without degrading the signal integrity or performance of the sensor device. In certain embodiments, one or more metals can be incorporated into the analyte indicator 106, which may cover at least a portion of the sensor housing 102. In certain embodiments, one or more metal layers can additionally or alternatively be deposited on the analyte indicator 106. In certain embodiments, the decomposition species can include one or more of hydrogen peroxide, enzymes, metal ions, reactive oxygen species, reactive nitrogen species, and free radicals.

[0063]

[0086] In certain embodiments, one or more metals can be incorporated into the analyte indicator 106, which may cover at least a portion of the sensor housing 102. In certain embodiments, the one or more metals can additionally or alternatively cover at least a portion of a surface of the analyte indicator 106 that is distal from the portion of the sensor housing 102. In certain embodiments, the one or more metals can additionally or alternatively cover at least a portion of a surface of the analyte indicator 106 that is proximal to the sensor housing 102. In certain embodiments, the layer covering at least a portion of the analyte indicator 106 can include at least two different metal species, and the surface of each of the at least two different metal species can be exposed to degradation species or biological oxidants.

[0064]

[0087] Although a platinum layer has been clinically demonstrated to improve the in vivo shelf-life of Senseonics implanted CGM sensors (Colvin AE, Jiang H. 2012, Platinum Catalyst Enhances Biostability and Functional Lifetime of Implantable Glucose Sensors, J Biomed Mater Res Part A 2013 May; 101(5):1274-82), increasing the surface area of ​​the platinum layer (and therefore the amount of catalyst) does not further improve the in vivo shelf-life, and even in the presence of a platinum layer with an extended surface area, the indicator moiety may oxidize. In certain embodiments, the present invention provides greater protection against various degradative species, extending the shelf-life of partially or fully implantable devices.

[0065]

[0088] In some embodiments, the sensor 100 can include a multi-metal protection system including multiple protective metals. In some embodiments, the multiple metals can interact and / or react with decomposition species. In some embodiments, the multiple metals can neutralize decomposition species. In some embodiments, the multiple metals can bind to decomposition species. In some embodiments, the multiple metals can sequester decomposition species to inhibit, reduce, and / or prevent degradation of the indicator molecule 104 of the analyte indicator 106 caused by the decomposition species. Thus, in some embodiments, the multiple metals can reduce degradation of the analyte indicator 106. In some embodiments, the multiple metals can also include one or more phenylboronic acid compounds. The phenylboronic acid compounds interact with the decomposition species without degrading the signal integrity or performance of the sensor.

[0066]

[0089] In one embodiment, a sensor 100 for measuring an analyte (e.g., glucose) in a medium (e.g., interstitial fluid) within a living animal (e.g., a human) can include a sensor housing 102 and an analyte indicator 106. In one embodiment, the analyte indicator can include one or more indicator molecules 104, which can be dispersed throughout the analyte indicator 106. In one embodiment, the analyte indicator 104 can be configured to reversibly bind to the analyte. In one embodiment, the analyte indicator 106 can cover at least a portion of the sensor housing 102. In one embodiment, the sensor 100 can also include a light source 108 (e.g., within the sensor housing 102) configured to emit excitation light 329. In one embodiment, the indicator molecule 104 can be configured to emit light 331 upon illumination with the excitation light 329, the light 331 indicating the amount of analyte in the medium within the living animal. In certain embodiments, the sensor 100 may also include a photodetector 224 (e.g., within the sensor housing 102) configured to respond to light 331 emitted by one or more indicator molecules 104 and generate a signal indicative of the amount of analyte in the medium within the living animal.

[0067]

[0090] In some embodiments, the sensor 100 may also include a multi-metal protection system that includes multiple protective metals. In some embodiments, the multiple metals may interact with multiple degradative species. In some embodiments, the multi-metal protection system may protect the indicator molecule 104 of the analyte indicator 106 by preventing or reducing degradation or interference caused by degradative species or biological oxidants. In some embodiments, the multi-metal protection system may protect the indicator molecule 104 without compromising the signal integrity or performance of the sensor 100. In some embodiments, the sensor 100 may include a drug-eluting substrate and / or catalyst layer disposed on or incorporated within the analyte indicator 106.

[0068]

[0091] In some embodiments, the multi-metal protection system may include a first metal layer 800 and a second metal layer 801, as shown in Figures 4A-5B. In some embodiments, the sensor 100 may include a sensor housing 102 and an analyte indicator 106 covering at least a portion of the sensor housing 102. In some embodiments, the first metal layer 800 may cover at least a portion of the analyte indicator 106, and the second metal layer 801 may cover at least a portion of the first metal layer 800, as shown in Figure 4A. In an alternative embodiment, the second metal layer 801 may cover at least a portion of the analyte indicator 106, and the first metal layer 800 may cover at least a portion of the second metal layer 801, as shown in Figure 4B.

[0069]

[0092] 5A and 5B, a first metal layer 800 may be deposited on a first surface of the analyte indicator 106, and a second metal layer may be deposited on a second surface of the analyte indicator 106, where the second surface may be a surface of the analyte indicator 106 different from the first surface. For example, in one embodiment, as shown in FIG. 5A, the first metal layer 800 may cover at least a portion of the first surface of the analyte indicator 106, and the second metal layer 801 may cover at least a portion of the second surface of the analyte indicator 106, where the second surface may be a side of the analyte indicator 106 opposite the first surface. In one embodiment, the second metal layer 801 may be disposed between the sensor housing 102 and the analyte indicator 106. 5B, in some embodiments, a second metal layer 801 may cover at least a portion of a first surface of the analyte indicator 106, and a first metal layer 800 may cover at least a portion of a second surface of the analyte indicator 106. In some embodiments, the first metal layer 800 may be disposed between the sensor housing 102 and the analyte indicator 106.

[0070]

[0093] In some embodiments, first metal layer 800 may include a first metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals (e.g., alloys such as Pt / Rh and Pt / Lr). In some embodiments, first metal layer 800 may include a first metal and one or more additional metals selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals. In some embodiments, second metal layer 801 may include a second metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals. In some embodiments, second metal layer 801 may include a second metal and one or more additional metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals. In some embodiments, the first metal and the second metal may be different metals. In one embodiment, the first metal can be platinum and the second metal can be molybdenum. In one embodiment, the first metal can be copper and the second metal can be molybdenum. In an alternative embodiment, the first metal can be platinum and the second metal can be tungsten. In another alternative embodiment, the first metal can be tungsten and the second metal can be molybdenum. In another alternative embodiment, the first metal layer 800 includes platinum and the second metal layer 801 includes tungsten.

[0071]

[0094] 6A-11B, the multi-metal protection system may include (i) one or more metal layers on or adjacent to the analyte indicator 106, and (ii) metal particles of one or more metals incorporated within the analyte indicator 106. In some embodiments, as shown in FIGS. 6A and 11A, the multi-metal protection system may include a first metal layer 800 and first metal particles 802. In some embodiments, the first metal layer 800 may cover a portion of the analyte indicator 106, and the first metal particles 802 may be incorporated within the analyte indicator 106. In some embodiments, the first metal layer 800 may include at least a first metal (e.g., a metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals), and the first metal particles 802 may include at least a second metal (e.g., a metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals), and the first and second metals may be different metals. In an alternative embodiment, as shown in FIGS. 6B and 11B , a multi-metal protection system may include a second metal layer 801 and second metal particles 803. In some embodiments, the second metal layer 801 may cover at least a portion of the analyte indicator 106, and the second metal particles 803 may be incorporated within the analyte indicator 106. In some embodiments, the second metal layer 801 may include at least a second metal, and the second metal particles 803 may include at least a first metal, and the first and second metals may be different metals.

[0072]

[0095] 11A and 11B, a multi-metal protection system may include one of first and second metal layers 800 and 801 and both first and second metal particles 802 and 803. For example, in one embodiment, as shown in FIG. 11A, a multi-metal protection system may include first metal layer 800, first metal particles 802, and second metal particles 803. In one embodiment, first metal layer 800 and second metal particles 803 may each include at least a first metal (e.g., a metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals). In some embodiments, first metal layer 800 and second metal particles 803 may comprise at least the same first metal, although this is not required, and in some alternative embodiments, first metal layer 800 and second metal particles 803 may comprise different metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals. In some embodiments, first metal particles 802 may comprise at least a second metal (e.g., a metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals), and the second metal may be different from one or more of the first metals selected for first metal layer 800 and second metal particles 803.

[0073]

[0096] 11B, the multi-metal protection system may include a second metal layer 801, first metal particles 802, and second metal particles 803. In some embodiments, the second metal layer 801 and the first metal particles 802 may each include at least a second metal (e.g., a metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals). In some embodiments, the second metal layer 801 and the first metal particles 802 may include at least the same second metal, but this is not required. In some alternative embodiments, the second metal layer 801 and the first metal particles 802 may include different metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals. In some embodiments, second metal particles 803 may include at least a first metal (e.g., a metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals), and the first metal may be different from one or more second metals selected for second metal layer 801 and first metal particles 802.

[0074]

[0097] 7A-10B, the multi-metal protection system may include a first metal layer 800, a second metal layer 801, and metal particles of one or more metals incorporated into the analyte indicator 106. In some embodiments, as shown in FIGS. 7A, 7B, 10A, and 10B, one of the first and second metal layers 800 and 801 may cover at least a portion of the analyte indicator 106, and the other of the first and second metal layers 800 and 801 may cover at least a portion of one of the first and second metal layers 800 and 801 (see the previous discussion of FIGS. 4A and 4B). 8A-9B, one of the first and second metal layers 800 and 801 may be deposited on a first surface of the analyte indicator 106, and the other of the first and second metal layers 800 and 801 may be deposited on a second surface of the analyte indicator 106, which may be a surface of the analyte indicator 106 different from the first surface (see the above discussion of FIGS. 5A and 5B). In some embodiments, as shown in FIGS. 7A-10B, the multi-metal protection system may include one or more of first and second metal particles 802 and 803 in addition to the first and second metal layers 800 and 801.

[0075]

[0098] In some embodiments, as shown in Figures 9A-10B, the multi-metal protection system can include both first and second metal particles 802 and 803 in addition to first and second metal layers 800 and 801 (see the previous discussion of Figures 11A-11B). In some embodiments, first metal layer 800 and second metal particles 803 can each include at least a first metal (e.g., a metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals). In some embodiments, first metal layer 800 and second metal particles 803 can include at least the same first metal, but this is not required; in some alternative embodiments, first metal layer 800 and second metal particles 803 can include different metals selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals. In some embodiments, second metal layer 801 and first metal particles 802 may each include at least a second metal (e.g., a metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals). In some embodiments, second metal layer 801 and first metal particles 802 may include at least the same second metal, but this is not required; in some alternative embodiments, second metal layer 801 and first metal particles 802 may include different metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals. In some embodiments, one or more (e.g., all) of the metals in first metal layer 800, second metal layer 801, first metal particles 802, and second metal particles 803 may be different.

[0076]

[0099] In an alternative embodiment, the multi-metal protection system need not include a metal layer on the surface of the analyte indicator, as shown in Figure 12. For example, as shown in Figure 12, in some embodiments, the multi-metal protection system may include first metal particles 802 and second metal particles 803, which may be incorporated into the analyte indicator 106. In some embodiments, the first metal particles 802 may include at least a second metal (e.g., a metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals), the second metal particles 803 may include at least a first metal (e.g., a metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals), and the first and second metals may be different metals.

[0077]

[0100] As noted above, in some embodiments, the sensor 100 may also include a sensor housing 102, an analyte indicator 106 covering at least a portion of the sensor housing 102, and a multi-metal protection system. In some embodiments, the multi-metal protection system may include a multi-metal layer 810 covering at least a portion of the analyte indicator 106, as shown in FIGS. 13-15. In some embodiments, the multi-metal layer 810 may include at least a first metal 806 and a second metal 807, as shown in FIGS. 13-15. In some embodiments, the first metal 806 may be selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals. In some embodiments, the second metal 807 may be selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals. In some embodiments, the first metal 806 and the second metal 807 may be different metals.

[0078]

[0101] 14A-15, a multi-metal protection system can include a multi-metal layer 810 and one or more of first and second metal particles 802 and 803. In some embodiments, the first metal 806 and the second metal particles 803 can include at least the same metal, but this is not required. In some alternative embodiments, the first metal 806 and the second metal particles 803 can include different metals selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of these metals. In some embodiments, the second metal 807 and the first metal particles 802 can include at least the same metal, but this is not required. In some alternative embodiments, the second metal 807 and the first metal particles 802 can include at least the same metal, but this is not required. In some alternative embodiments, the second metal 807 and the first metal particles 802 can include different metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of these metals. In some embodiments, one or more (e.g., all) of the metals of the first metal layer 800, the second metal layer 801, the first metal particles 802, and the second metal particles 803 may be different. In some embodiments, as shown in FIGS. 16A-16C, a sensor device may include one or more support materials 810 and 811. In some embodiments, the one or more support materials may independently be a membrane, mesh, nylon, fiber, matrix, sponge, or other pore-containing material that covers at least a portion of the analyte indicator 106. In some embodiments, as shown in FIG. 16A, the first and second metal particles 802 and 803 may be incorporated within the support material 810 that covers the analyte indicator 106. In some embodiments, as shown in FIG. 16B, the first and second metal particles 802 and 803 may be incorporated within the support material 810 that covers the first metal reservoir 800 that covers the analyte indicator 106. An additional metal layer may also be provided between the support material 810 and the first metal layer 800 (not shown). In one embodiment, as shown in Figure 16C, metal particles may be incorporated within the first support material 811 and different metal particles 803 may be incorporated within the second support material 812, where the first support material 811 covers the analyte indicator 106. An additional metal layer (not shown) may also be provided between the first support material 811 and the indicator 106 and / or between the first support material 811 and the second support material 812.

[0079]

[0103] In certain embodiments, a fully or partially implantable sensor 100 that includes a multi-metal protection system can have improved performance over a sensor that does not include a multi-metal protection system. Illustratively, in certain embodiments, a multi-metal protection system can extend the useful life and improve the functionality of sensor 100.

[0080]

[0104] In some embodiments, a multi-metal protection system can improve protection against decomposition species. Assays were performed using a series of 1 cm x 1 cm metal foils, and the results are reported in Tables 1 and 2. In one assay, the protective activity listed in Table 1 was found against hydrogen peroxide.

[0081] [Table 1]

[0082]

[0105] Contrary to expectations, Au, Pd, Ni, Ta, and Mg showed no detectable activity towards hydrogen peroxide.

[0106] In one assay, the protective activity listed in Table 2 was found against hypochlorite.

[0083] [Table 2]

[0084]

[0107] These results demonstrate, for example and without limitation, that platinum can be used to degrade hydrogen peroxide but is not useful for degrading hypochlorite. These results also demonstrate, for example and without limitation, that copper is more active than molybdenum toward hydrogen peroxide but less active than molybdenum toward hypochlorite. Contrary to expectations, Au, Pd, Ni, Ta, Mg, Pt, Pt / Rh, and Pt / Ir showed no detectable activity toward hypochlorite.

[0085]

[0108] In some embodiments, multiple metals in a multi-metal protection system (e.g., one or more metal layers on the analyte indicator 106 and / or one or more metal particles incorporated within the analyte indicator 106) can improve protection against degradative species because one of the metals can degrade one type of degradative species (e.g., hydrogen peroxide) and another of the metals can degrade another type of degradative species (e.g., hypochlorite).

[0086]

[0109] In certain embodiments, multiple metals in a multi-metal protection system (e.g., one or more metal layers on the analyte indicator 106 and / or one or more metal particles incorporated within the analyte indicator 106) can additionally or alternatively improve protection against degradative species because one metal layer (e.g., first metal layer 800) can act to promote adhesion of another metal layer (e.g., second metal layer 801). For example, molybdenum can adhere more strongly to platinum than to the analyte indicator 106, which may be, for example and without limitation, a hydrogel that is more indicative of glucose than molybdenum. 4A, 7A, and 10A, the multi-metal protection system can include a first metal layer 800 disposed on at least a portion of the analyte indicator 106 and a second metal layer 801 disposed on at least a portion of the first metal layer 800, where the first and second metal layers 800 and 801 can include first and second metals (e.g., platinum and molybdenum), respectively. In certain embodiments, the first metal (e.g., platinum) of the first metal layer 800 can promote adhesion of the second metal of the second metal layer 801. That is, the second metal layer 801 can have a stronger adhesive strength to the first metal layer 800 than the second metal layer 801 would have to the analyte indicator 106 if the second metal layer 801 were directly disposed on the analyte indicator 106. Thus, the multiple metals of the multi-metal protection system allow the system to include metals that cannot be used if only one metal is used. In one embodiment, the multi-metal protection system may include a Pt layer covered by a Mo layer, which allows for increased adhesion to the hydrogel and improved catalysis of both hydrogen peroxide and hypochlorite.

[0087]

[0110] As noted above, in certain embodiments, the sensor 100 can include a sensor housing 102, an analyte indicator 106 covering at least a portion of the sensor housing 102, and a protection system. In certain embodiments, the protection system can include a plurality of metals configured to reduce deterioration of the analyte indicator 106. In certain embodiments, as shown in FIG. 17 , the protection system can also include a first metal layer 800, a second metal layer 801, and a third metal layer 823. In certain embodiments, the first metal layer 800 can cover at least a portion of the analyte indicator 106 and can include a first metal of the plurality of metals. In certain embodiments, the second metal layer 801 can cover at least a portion of the first metal layer 800 and can include a second metal of the plurality of metals. In certain embodiments, the third metal layer 823 can cover at least a portion of the second metal layer 801 and can include a third metal of the plurality of metals. In some embodiments, the first metal layer 800 may not include the second and third metals, the second metal layer 801 may not include the first and third metals, and / or the third metal layer 823 may not include the first and second metals.

[0088]

[0111] In some embodiments, the first, second, and third metals of the first, second, and third metal layers 800, 801, and 823, respectively, may be different. In some embodiments, the first metal may be, for example and without limitation, platinum. In some embodiments, the second metal may be, for example and without limitation, iridium. In some alternative embodiments, the second metal may be tungsten or cobalt. In some embodiments, the third metal may be, for example and without limitation, molybdenum.

[0089]

[0112] In some embodiments, the first metal layer 800 can be sputtered onto the analyte indicator 106. In some embodiments, the second metal layer 801 can be sputtered onto the first metal layer 800. In some embodiments, the third metal layer 823 can be sputtered onto the second metal layer 801. In some embodiments, the first metal layer 800 can be a layer of platinum having a thickness of 5 nm to 20 nm, or preferably 7 nm to 13 nm, sputtered onto the analyte indicator 106 (e.g., 10 nm thick). In some embodiments, the second metal layer 801 can be a layer of iridium having a thickness of 1 nm to 15 nm, or preferably 3 nm to 8 nm, sputtered onto the first metal layer 800 (e.g., 5 nm, 6 nm, or 7 nm thick). In an alternative embodiment, the second metal layer 801 can be a 10 nm thick layer of iridium. In one embodiment, the third metal layer 823 may be a layer of molybdenum having a thickness of 10 nm or more and 30 nm or less, or preferably 17 nm or more and 23 nm or less, sputtered onto the second metal layer 801 (20 nm thick).

[0090]

[0113] In certain embodiments, the first metal layer 801 (e.g., platinum) and the second metal layer 801 (e.g., iridium) covering the first metal layer 800 can have greater in vivo catalytic activity than the first metal layer 800 alone. In certain embodiments, catalytic activity may refer to an increase in the rate of a chemical reaction caused by the presence of a catalyst. In certain embodiments, the second metal layer 801 (e.g., iridium) can be more resistant to catalytic deactivation, including but not limited to, by thiols or sulfur-containing molecules, than the first metal layer 800 (e.g., platinum), which is more susceptible to catalytic deactivation, including but not limited to, by thiols or sulfur-containing molecules. This catalytic deactivation is common in the human body. In certain embodiments, the first and second metal layers 800 and 801 may capture a greater amount of the surface of the analyte indicator 106 (e.g., a hydrogel) than the first metal layer 800 alone.

[0091]

[0114] In some embodiments, the third metal (e.g., molybdenum) can have catalytic activity for decomposition species that the first and second metals (e.g., platinum and indium) are not. In some embodiments, the third metal (e.g., molybdenum) can have catalytic activity for hypochlorous acid, and the first and second metals (e.g., platinum and iridium) may not have activity for hypochlorous acid. In some embodiments, the first, second, and third metals can have catalytic activity for hydrogen peroxide. In some embodiments, the third metal can also have catalytic activity for multiple reactive oxygen species.

[0092]

[0115] In certain embodiments, the first metal layer 800 (e.g., platinum) can have stronger adhesion to the analyte indicator 106 than the second metal layer 801 (e.g., indium) would have if the second metal layer 801 were directly deposited on the analyte indicator 106. Thus, in certain embodiments, the first metal layer 800 can promote adhesion of the second metal layer 801 to the sensor 100.

[0093]

[0116] In certain embodiments, the first metal layer 800 (e.g., platinum) can have a stronger adhesion to the analyte indicator 106 than the third metal layer 823 (e.g., molybdenum) does when the third metal layer 823 is deposited directly on the analyte indicator 106. In certain embodiments, the second metal layer 801 (e.g., iridium) can have a stronger adhesion to the first metal layer 800 (e.g., platinum) than the third metal layer 823 (e.g., molybdenum) does when the third metal layer 823 is deposited directly on the first metal layer 800. Thus, in certain embodiments, the second metal layer 801 can promote adhesion of the third metal layer 823 to the sensor 100. In certain embodiments, the third metal layer 823 (e.g., molybdenum) covering at least a portion of the second metal layer 801 can have stronger adhesion to the sensor 100 than the third metal layer 823 would have if the third metal layer 823 were instead deposited directly on the first metal layer 801 or the analyte indicator 106. In this manner, the first and second metal layers 800 and 801 can enable sufficient adhesion of the third metal layer 823 to the sensor 100 (e.g., for in vivo applications).

[0094]

[0117] The degree to which the first, second, and third metal layers 800, 801, and 823 adhere to each other and to the analyte indicator 106 can be assessed, for example, by experimental testing. In some embodiments, the experimental testing may include sputtering samples of the first, second, and third metals (e.g., Pt, Ir, and Mo) of the first, second, and third metal layers 800, 801, and 823 at multiple thicknesses onto the other metals and onto the analyte indicator 106. In some embodiments, the experimental testing may include visually inspecting the sputtered metal samples to visually identify cracks or flakes. In some embodiments, the experimental testing may additionally or alternatively include subjecting the sputtered metal samples to harsh conditions (e.g., a series of hydration and drying processes) before extracting and quantifying the amount of residual metal. Other experimental tests used to measure adhesion may be used as well.

[0095]

[0118] 17, a protection system including first, second, and third metal layers 800, 801, and 823 may additionally include one or more metal layers overlying third metal layer 823 (e.g., a fourth metal layer overlying at least a portion of third metal layer 823 and including a fourth metal from the plurality of metals, and a fifth metal layer overlying at least a portion of the fourth metal layer and including a fifth metal from the plurality of metals, or no fifth metal layer). For example, in one embodiment, the first, second, third, and fourth layers may be platinum, indium, platinum, and molybdenum, respectively. 17, the protection system including first, second, and third metal layers 800, 801, and 823 may additionally include particles of a first metal (e.g., platinum), particles of a second metal (e.g., indium), particles of a third metal (e.g., molybdenum), and / or particles of one or more other metals (e.g., Cu, W, Fe, and / or Co) incorporated within the analyte indicator 106. In some embodiments, one or more of the first, second, and third metal layers 800, 801, and 823 may be a multi-metal layer including more than one metal.

[0096]

[0119] 18 illustrates a process 1800 for fabricating a sensor according to certain embodiments. In certain embodiments, as shown in FIG. 18, process 1800 can include step 1802 of coating at least a portion of sensor housing 102 of sensor 100 with analyte indicator 106. In certain embodiments, analyte indicator 106 can be a hydrogel, and step 1802 can also include growing the hydrogel on at least a portion of sensor housing 102.

[0097]

[0120] 18 , process 1800 may also include step 1804 of covering at least a portion of analyte indicator 106 of sensor 100 with a first metal layer 800 including a first metal of multiple metals of the protection system. In some embodiments, covering at least a portion of analyte indicator 106 with first metal layer 800 in step 1804 may also include sputtering a layer of the first metal onto at least a portion of analyte indicator 106. In some embodiments, the sputtered layer of the first metal may have a thickness of 7 nm or more and 13 nm or less (e.g., 10 nm). In some embodiments, the first metal may be platinum.

[0098]

[0121] 18, process 1800 can include step 1806 of covering at least a portion of first metal layer 800 with a second metal layer 801 including a second metal of a plurality of metals. In some embodiments, covering at least a portion of first metal layer 800 with second metal layer 801 in step 1806 can also include sputtering a layer of the second metal onto at least a portion of first metal layer 800. In some embodiments, the sputtered layer of second metal 801 can have a thickness of 3 nm or more and 7 nm or less (e.g., 5 nm). In some embodiments, the second metal can be iridium.

[0099]

[0122] 18 , process 1800 can include step 1808 of covering at least a portion of second metal layer 801 with a third metal layer 823 including a third metal from a plurality of metals. The plurality of metals can be configured to reduce deterioration of the analyte indicator, and the first, second, and third metals can be different. In some embodiments, covering at least a portion of second metal layer 801 with third metal layer 823 in step 1808 can also include sputtering a layer of the third metal onto at least a portion of second metal layer 801. In some embodiments, the sputtered third metal layer can have a thickness of 17 nm or more and 23 nm or less. In some embodiments, the third metal can be molybdenum. example

[0123] One non-limiting example sensor ("Sensor Example 1") includes a sensor housing, a hydrogel on at least a portion of the sensor housing, an indicator molecule contained within the hydrogel, and Pt sputtered onto at least a portion of the hydrogel, and has a useful life of 90 days when implanted in a human patient.

[0100]

[0124] One non-limiting example sensor ("Sensor Example 2") is the same as Sensor Example 1, but is further protected by a layer of Mo on the Pt, and has a useful life of at least 180 days when implanted in a human patient.

[0101]

[0125] One non-limiting example sensor ("Sensor Example 3") is the same as Sensor Example 1, but is further protected by sputtered Cu in combination with Pt on a hydrogel, and has a useful life of at least 180 days when implanted in a human patient.

[0102]

[0126] One non-limiting example sensor ("Sensor Example 4") is the same as Sensor Example 1, but further protected by sputtered Cu in combination with Pt on a hydrogel, with a Mo layer on the co-sputtered Pt / Cu, and has a useful life of at least 270 days when implanted in a human patient.

[0103]

[0127] One non-limiting example sensor ("Sensor Example 5") is the same as Sensor Example 1, but is further protected by Cu incorporated within the hydrogel, and has a useful life of at least 180 days when implanted in a human patient.

[0104]

[0128] One non-limiting example sensor ("Sensor Example 6") is the same as Sensor Example 1, but is further protected by Cu incorporated within the hydrogel and a Mo layer on the Pt, and has a useful life of at least 270 days when implanted in a human patient.

[0105]

[0129] One non-limiting example sensor ("Sensor Example 7") is the same as Sensor Example 1, but is further protected by Pt and Cu incorporated within a hydrogel and a W layer on the Pt, and has a useful life of at least 270 days when implanted in a human patient.

[0106]

[0130] One non-limiting example sensor ("Sensor Example 8") is the same as Sensor Example 1, but is further protected by Pt, Cu, and Mo incorporated within a hydrogel and a W layer on the Pt, and has a useful life of at least 300 days when implanted in a human patient.

[0107]

[0131] One non-limiting example sensor ("Sensor Example 9") is the same as Sensor Example 1, but is further protected by Pt, Cu, and W incorporated within a hydrogel and a Mo layer on the Pt, and has a useful life of at least 300 days when implanted in a human patient.

[0108]

[0132] One non-limiting example sensor ("Sensor Example 10") is the same as Sensor Example 1, but is further protected with Ir sputtered onto at least a portion of the Pt and Mo sputtered onto at least a portion of the Ir, and has a useful life of 365 days when implanted in a human patient.

[0109]

[0133] The embodiments of the present invention have been thoroughly described above with reference to the drawing figures. While 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 of the described embodiments are possible within the spirit and scope of the present invention. For example, in some embodiments, the analyte sensor 100 may be an optical sensor, although this is not required, and in one or more alternative embodiments, the analyte sensor may be a different type of analyte sensor, such as, for example, an electrochemical sensor, a diffusion sensor, or a pressure sensor. Also, in some embodiments, the analyte sensor 100 may be an implantable sensor, although this is not required, and in some alternative embodiments, the analyte sensor may be a transcutaneous sensor having a wired connection to an external transceiver. For example, in some alternative embodiments, the analyte sensor 100 may be disposed within or on (e.g., at the tip of) a transcutaneous needle. In these embodiments, instead of wireless communication using an antenna (e.g., inductive element 114), the analyte sensor can communicate with an external transceiver using one or more wires connected between the external transceiver and the transceiver transcutaneous needle containing the analyte sensor. As another example, in an alternative embodiment, the analyte sensor can be placed within a catheter (e.g., for intravenous blood glucose monitoring) and can communicate (wirelessly or using wires) with an external transceiver. [Explanation of symbols]

[0110] 100 sensors 101 External Transceiver 102 Sensor housing 103 Inducible Elements 104 Indicator molecule 106 Analyte Indicators 108 Light source 112 filters 113 End Cap 114 Inducible Elements 116 PCB 118 Capacitor 119 Reflector 224, 226 Photodetectors 329 Excitation Light 331 Emitted light 670 Temperature Converter 800 1st metal layer 801 2nd metal layer 802 First metal particles 803 Second metal particles 806 First metal 807 Second metal 810 Multiple metal layers 811 First carrier material 812 Second carrier material

Claims

1. 1. A sensor for measuring an analyte in a medium within a living animal, comprising: A sensor housing; an analyte indicator covering at least a portion of the sensor housing; a protection system including a plurality of metals configured to reduce deterioration of the analyte indicator; Equipped with a sensor wherein the protection system includes first, second, and third metal layers, the first metal layer covering at least a portion of the analyte indicator and including a first metal from the plurality of metals, the second metal layer covering at least a portion of the first metal layer and including a second metal from the plurality of metals, and the third metal layer covering at least a portion of the second metal layer and including a third metal from the plurality of metals, and the first, second, and third metals are different.

2. 2. The sensor of claim 1, wherein the first metal is platinum.

3. 3. The sensor of claim 1, wherein the second metal is iridium.

4. 3. The sensor of claim 1, wherein the second metal is tungsten.

5. 3. The sensor of claim 1, wherein the second metal is cobalt.

6. The sensor of any one of claims 1 to 5, wherein the third metal is molybdenum.

7. The sensor of any one of claims 1 to 6, wherein the first metal layer is sputtered onto the analyte indicator.

8. The sensor of any one of claims 1 to 7, wherein the second metal layer is sputtered onto the first metal layer.

9. The sensor of any one of claims 1 to 8, wherein the third metal layer is sputtered onto the second metal layer.

10. 10. The sensor of claim 1, wherein the first metal layer is a layer of platinum having a thickness of 7 nm or more and 13 nm or less and sputtered onto the analyte indicator; the second metal layer is a layer of iridium having a thickness of 3 nm or more and 7 nm or less and sputtered onto the first metal layer; and / or the third metal layer is a layer of molybdenum having a thickness of 17 nm or more and 23 nm or less and sputtered onto the second metal layer.

11. A sensor according to any one of claims 1 to 10, wherein the in vivo catalytic activity of the first metal layer and the second metal layer covering the first metal layer is greater than the in vivo catalytic activity of the first metal layer alone.

12. 12. The sensor according to claim 1, wherein the second metal layer is less susceptible to catalytic deactivation by thiol-containing molecules than the first metal layer is to catalytic deactivation by thiol-containing molecules.

13. A sensor as described in any one of claims 1 to 12, wherein the third metal layer covering at least a portion of the second metal layer has a stronger adhesive strength to the sensor than the third metal layer would have if the third metal layer were instead directly deposited on the first metal layer or the analyte indicator.

14. The sensor of any one of claims 1 to 13, wherein the third metal is catalytically active towards decomposition species for which the first and second metals are not active.

15. 15. The sensor according to claim 1, wherein the third metal has catalytic activity with respect to hypochlorous acid, and the first and second metals have no activity with respect to hypochlorous acid.

16. The sensor of any one of claims 1 to 15, wherein the first, second, and third metals have catalytic activity towards hydrogen peroxide.

17. 17. The sensor according to claim 1, wherein the third metal has catalytic activity towards a plurality of reactive oxygen species.

18. 18. The sensor of claim 1, wherein the first metal layer does not contain the second and third metals, the second metal layer does not contain the first and third metals, and the third metal layer does not contain the first and second metals.

19. 19. The sensor of any one of claims 1 to 18, wherein the protection system comprises metal particles incorporated within the analyte indicator, the metal particles comprising one or more of the plurality of metals.

20. 20. The sensor of claim 1, wherein the first metal layer is a multi-metal layer comprising two or more of the plurality of metals.

21. The sensor of any preceding claim, wherein the plurality of metals are configured to collectively interact or react with a plurality of decomposition species.

22. 22. The sensor of any one of claims 1 to 21, wherein the plurality of metals of the protection system are configured to collectively interact or react with at least two of hydrogen peroxide, reactive oxygen species, enzymes, metal ions, reactive nitrogen species, and free radicals.

23. The sensor according to any one of claims 1 to 22, further comprising: a radiation source contained within the sensor housing and configured to emit radiation to the analyte indicator; a photosensitive element contained within the sensor housing and configured to receive light emitted by the analyte indicator; A sensor comprising:

24. A manufacturing method comprising: covering at least a portion of an analyte indicator of a sensor with a first metal layer comprising a first metal of a plurality of metals of a protection system, the analyte indicator covering at least a portion of a sensor housing of the sensor; covering at least a portion of the first metal layer with a second metal layer comprising a second metal of the plurality of metals; covering at least a portion of the second metal layer with a third metal layer including a third metal of the plurality of metals, the plurality of metals being configured to reduce deterioration of the analyte indicator, and the first, second, and third metals being different; A method comprising:

25. 25. The method of claim 24, wherein covering at least a portion of the analyte indicator with the first metal layer comprises sputtering a layer of the first metal onto at least a portion of the analyte indicator.

26. 26. The method of claim 25, wherein the layer of sputtered first metal has a thickness of not less than 7 nm and not more than 13 nm.

27. The method of any one of claims 24 to 26, wherein the first metal is platinum.

28. 28. The method of claim 24, wherein covering at least a portion of the first metal layer with the second metal layer comprises sputtering a layer of the second metal onto at least a portion of the first metal layer.

29. 29. The method of claim 28, wherein the layer of sputtered second metal has a thickness of at least 3 nm and at most 7 nm.

30. The method of any one of claims 24 to 29, wherein the second metal is indium.

31. The method of any one of claims 24 to 29, wherein the second metal is tungsten.

32. The method of any one of claims 24 to 29, wherein the second metal is cobalt.

33. 33. The method of any one of claims 24 to 32, wherein covering at least a portion of the second metal layer with the third metal layer comprises sputtering a layer of the third metal onto at least a portion of the second metal layer.

34. 34. The method of claim 33, wherein the layer of sputtered third metal has a thickness of not less than 17 nm and not more than 23 nm.

35. The method of any one of claims 24 to 34, wherein the third metal is molybdenum.

36. 1. A method for detecting the presence or concentration of an analyte in a biological sample, comprising: exposing the biological sample to a device having a detectable quality that changes upon exposure of the device to an analyte of interest, the device comprising a protective material that prevents or reduces degradation or interference of the device from degradative species or biological oxidants, the device being the device of claim 1; detecting the presence or concentration of an analyte of interest in the biological sample by measuring the change in the detectable quality; A method comprising:

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