Mediation of analyte signal degradation in vivo

Abstract

A sensor (e.g., an optical sensor) is implantable in a living animal (e.g., a human) and can be 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 can include a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and one or more compounds containing a boronate ester or boronic acid group that reduce degradation of the analyte indicator.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 809,238, filed on February 22, 2019, which is incorporated herein by reference in its entirety. background Technical Field

[0004] The present invention generally relates to a sustained reduction in in vivo degradation of an analyte sensor portion when measuring an analyte in a medium of a living animal using a system comprising a sensor (partially or completely) implanted or inserted into the living animal. Specifically, the present invention relates to sensors utilizing one or more additives that can be incorporated into an analyte indicator and / or a material covering at least a portion of the analyte indicator. Background Art

[0006] The sensor can be implanted (partially or completely) in a living animal (e.g., a human) and used to measure an analyte (e.g., glucose, oxygen, cardiac markers, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides) in a medium (e.g., interstitial fluid (ISF), blood, or intraperitoneal fluid) within the living animal. 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, a phototransistor, a photoresistor, or other photosensitive element). Examples of implantable sensors that utilize indicator molecules to measure analytes are described in U.S. Pat. Nos. 5,517,313 and 5,512,246, which are incorporated herein by reference in their entirety.

[0007] The sensor can include an analyte indicator, which can be in the form of an indicator molecule embedded within the implant (i.e., layer or matrix). For example, in a fluorescence-based implantable glucose sensor, the fluorescent indicator molecule can reversibly bind to glucose and, when illuminated by excitation light (e.g., light having a wavelength of approximately 378 nm), emit an amount of light (e.g., light in the range of 400 nm to 500 nm) depending on whether glucose is bound to the indicator molecule.

[0008] If the sensor is implanted in a living animal, the animal's immune system may begin to attack the sensor. For example, if the sensor is implanted in a human, white blood cells may perceive the sensor as a foreign object and attack it. In this initial immune system attack, neutrophils may be the primary white blood cells attacking the sensor. Neutrophil defense mechanisms include the release of highly corrosive substances called reactive oxygen species. These reactive oxygen species include, for example, hydrogen peroxide.

[0009] Hydrogen peroxide and other reactive species, such as reactive oxygen species and reactive nitrogen species, may degrade the indicator molecules of the analyte indicator. For example, in an indicator molecule having a boronate group, hydrogen peroxide may degrade the indicator molecule by oxidizing the boronate group, thereby rendering the indicator molecule unable to bind to glucose.

[0010] There is a need in the art for improvements in reducing degradation of analyte indicators. There is also a need in the art for continuous analyte sensors with extended lifespans. Summary of the Invention

[0011] The present invention overcomes the shortcomings of existing systems by providing, among other advantages, reduced analyte indicator degradation.

[0012] One aspect of the present invention provides a sensor that can be implanted or inserted into a living animal and measures an analyte in a medium within the living animal. The sensor may include a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and one or more additives that reduce deterioration of the analyte indicator.

[0013] In some embodiments, the sensor can include at least one additive-containing polymer graft, and one or more additives can be copolymerized with or dispersed within the additive-containing polymer graft. In some embodiments, the additive-containing polymer graft can cover at least a portion of the sensor housing. In some embodiments, the additive-containing polymer graft can be within the sensor housing.

[0014] In some embodiments, one or more additives can be incorporated into the analyte indicator, for example as a comonomer.In some embodiments, a sensor can include a material, such as a film, covering at least a portion of the analyte indicator, and one or more additives can be incorporated into the material.

[0015] Further variations encompassed within the systems and methods are described below in the detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate several non-limiting embodiments of the present invention.In the drawings, like reference numbers indicate identical or functionally similar elements.

[0017] Figure 1 is a schematic diagram illustrating a sensor system embodying aspects of the present invention.

[0018] Figure 2 A perspective view of a sensor embodying aspects of the present invention is shown.

[0019] Figure 3 Shown is an exploded view of a sensor embodying aspects of the present invention.

[0020] Detailed description of preferred embodiments

[0021] Figure 1 is a schematic diagram of a sensor system implementing aspects of the present invention. In some non-limiting embodiments, Figure 1 As shown, the system may include a sensor 100 and an external transceiver 101. In some embodiments, the sensor 100 may be an implantable sensor configured to be fully or partially implanted in a living animal (e.g., a living human). The sensor 100 may be implanted, for example, in the arm, wrist, leg, abdomen, peritoneum, or other area of ​​the living animal suitable for sensor implantation. For example, in some non-limiting embodiments, the sensor 100 may be implanted under the skin (i.e., in subcutaneous or peritoneal tissue). However, this is not required, and in some alternative embodiments, the sensor 100 may be a transcutaneous sensor.

[0022] In some embodiments, the transceiver 101 can be an electronic device that communicates with the sensor 100 to power the sensor 100, provide commands and / or data to the sensor 100, and / or receive data from the sensor 100. In some embodiments, the received data can include one or more sensor measurements. In some embodiments, the sensor measurements can include, for example, but not limited to, one or more light measurements from one or more photodetectors of the sensor 100 and / or one or more temperature measurements from one or more temperature sensors of the sensor 100. In some embodiments, the transceiver 101 can calculate an analyte (e.g., glucose) concentration based on the measurement information received from the sensor 100.

[0023] In some non-limiting embodiments, the transceiver 101 can be a handheld device or an on-body / wearable device. For example, in some embodiments where the transceiver 101 is an on-body / wearable device, the transceiver 101 can be held in place by a band (e.g., an armband or wristband) and / or an adhesive, and the transceiver 101 can transmit (e.g., periodically, such as every two minutes, and / or upon user initiation) measurement commands (i.e., requests for measurement information) to the sensor 100. In some embodiments where the transceiver 101 is a handheld device, positioning the transceiver 101 (i.e., hovering or sweeping / waving / passing) within range above the sensor implant site (i.e., in the vicinity of the sensor 100) can cause the transceiver 101 to automatically transmit measurement commands to the sensor 100 and receive data from the sensor 100.

[0024] In some embodiments, as Figure 1 As shown, the transceiver 101 may include an inductive element 103, such as a coil. In some embodiments, the transceiver 101 may generate electromagnetic waves or an electrodynamic field (e.g., by using a coil) to induce a current in the inductive element 114 of the sensor 100. In some non-limiting embodiments, the sensor 100 may 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).

[0025] In some embodiments, the transceiver 101 can transmit data (e.g., commands) to the sensor 100. For example, in some non-limiting embodiments, the transceiver 101 can transmit data by modulating the electromagnetic waves generated by the inductive element 103 (e.g., by modulating the current flowing through the inductive element 103 of the transceiver 101). In some embodiments, the sensor 100 can detect / extract the modulation in the electromagnetic waves generated by the transceiver 101. In addition, the transceiver 101 can receive data (e.g., one or more sensor measurements) from the sensor 100. For example, in some non-limiting embodiments, the transceiver 101 can receive data by detecting the modulation in the electromagnetic waves generated by the sensor 100 (e.g., by detecting the modulation in the current flowing through the inductive element 103 of the transceiver 101).

[0026] In some embodiments, as Figure 1 As shown, the sensor 100 can include a sensor housing 102 (i.e., a body, housing, capsule, or encasement), which can be rigid and biocompatible. In an exemplary embodiment, the sensor housing 102 can be formed from a suitable optically transparent polymer material, such as an acrylic polymer (e.g., polymethyl methacrylate (PMMA)).

[0027] In some embodiments, as Figure 1As shown, the 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 the sensor housing 102. The analyte indicator 106 (e.g., a polymer graft) may cover the entire surface of the sensor housing 102 or only one or more portions of the surface of the housing 102. As an alternative to coating the analyte indicator 106 on the outer surface of the sensor housing 102, the analyte indicator 106 may be disposed on the outer surface of the sensor housing 102 in other ways, such as by deposition or adhesion. In some embodiments, the analyte indicator 106 may be a fluorescent glucose indicator polymer. In a non-limiting embodiment, the polymer is biocompatible and stable, is transplanted onto the surface of the sensor housing 102, and is designed to allow 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.

[0028] In some embodiments, the analyte indicator 106 (e.g., a polymer implant) of the sensor 100 can include an indicator molecule 104. The indicator molecule 104 can be distributed throughout the analyte indicator 106 or only in one or more portions of the analyte indicator 106. The indicator molecule 104 can have a boronate group. The indicator molecule 104 can be a fluorescent indicator molecule (e.g., a TFM having 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 a light-absorbing, non-fluorescent indicator molecule. In some embodiments, the indicator molecule 104 can reversibly bind to an analyte (e.g., glucose, oxygen, a cardiac marker, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides). When the indicator molecule 104 is bound to the analyte, the indicator molecule may fluoresce, in which case the indicator molecule 104 can absorb (or be excited by) excitation light 329 and emit light 331. In one non-limiting embodiment, the excitation light 329 can have a wavelength of approximately 378 nm, and the emitted light 331 can have a wavelength in the range of 400 nm to 500 nm. When no analyte is bound, the indicator molecule 104 may only be weakly fluorescent.

[0029] In some embodiments, the sensor 100 can include a light source 108, which can be, for example, a light emitting diode (LED) or other light source that emits radiation, including radiation within a 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 described above, in one non-limiting embodiment, the light source 108 can emit excitation light 329 having a wavelength of approximately 378 nm.

[0030] In some embodiments, the sensor 100 may also include one or more photodetectors (e.g., photodiodes, phototransistors, photoresistors, or other light-sensitive elements). Figure 1 In the illustrated embodiment, the sensor 100 has a first photodetector 224 and a second photodetector 226. However, this is not required, and in some alternative embodiments, the sensor 100 may include only the first photodetector 224. In the case of a fluorescence-based sensor, one or more photodetectors may be sensitive to the fluorescence emitted by the indicator molecules 104, such that a signal is generated in response thereto by the photodetector (e.g., photodetector 224) that is indicative of the level of fluorescence of the indicator molecules and, therefore, the amount of the target analyte (e.g., glucose).

[0031] A portion of the excitation light 329 emitted by the light source 108 can be reflected from the analyte indicator 106 back into the sensor 100 as reflected light 333, and a portion of the absorbed excitation light can be emitted as emitted (fluorescent) light 331. In one non-limiting embodiment, the emitted light 331 can have a wavelength that is different from the wavelength of the excitation light 329. The reflected light 333 and the emitted (fluorescent) light 331 can be absorbed by one or more photodetectors within the body of the sensor 100 (e.g., the first and second photodetectors 224 and 226).

[0032] Each of the one or more photodetectors may be filtered by a filter 112 (see Figure 3) covered by a filter that allows only a specific subset of wavelengths of light to pass through. In some embodiments, one or more filters 112 can be thin glass filters. In some embodiments, one or more filters 112 can be thin film (e.g., dichroic) filters deposited on glass and can pass only a narrow band of wavelengths while otherwise reflecting most of the received light. In some embodiments, the filters can be thin film (dichroic) filters deposited directly on the photodetector and can pass only a narrow band of wavelengths while otherwise reflecting most of the light received thereby. The filters 112 can be the same (e.g., both filters 112 can allow a signal to pass through) or different (e.g., one filter 112 can be a reference filter and the other filter 112 can be a signal filter).

[0033] In one non-limiting embodiment, the second (reference) photodetector 226 can be covered by a reference photodiode filter that allows light of the same wavelength as that emitted from the light source 108 (e.g., 378 nm) to pass. The first (signal) photodetector 224 can detect the amount of fluorescence 331 emitted from the molecules 104 in the analyte indicator 106. In one non-limiting embodiment, the peak emission of the indicator molecules 104 can occur at approximately 435 nm, and the first photodetector 224 can be covered by a signal filter that passes light in the range of approximately 400 nm to 500 nm. In some embodiments, a higher glucose content / concentration corresponds to a greater amount of fluorescence of the molecules 104 in the analyte indicator 106, and therefore corresponds to a greater number of photons striking the first photodetector 224.

[0034] In some embodiments, as Figure 1 As shown, the sensor 100 may include a substrate 116. In some 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 some alternative embodiments, the substrate 116 may be a semiconductor substrate having circuits fabricated therein. The circuits may include analog and / or digital circuits. Furthermore, in some semiconductor substrate embodiments, in addition to the circuits fabricated in the semiconductor substrate, circuits may also be mounted or otherwise attached to the semiconductor substrate 116. In other words, in some semiconductor substrate embodiments, part or all of the circuits, which may include discrete circuit elements, integrated circuits (e.g., application specific integrated circuits (ASICs)), and / or other electronic components, may be fabricated in the semiconductor substrate 116, with the remainder of the circuits being fixed to the semiconductor substrate 116, thereby providing communication paths between multiple fixed components.

[0035] 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 inductive element 114 of sensor 100 can include some or all of the features described in one or more of U.S. Application Nos. 13 / 761,839, filed February 7, 2013, 13 / 937,871, filed July 9, 2013, and 13 / 650,016, filed October 11, 2012, all of which are incorporated herein by reference in their entirety. Similarly, the structure and / or functionality of sensor 100 and / or transceiver 101 can be as described in one or more of U.S. Patent Application Nos. 13 / 761,839, 13 / 937,871, and 13 / 650,016.

[0036] 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., inductive elements 103 and 114), the transceiver interface device may include inductive element 114 of sensor 100, and the sensor interface device may include inductive element 103 of transceiver 101. In some percutaneous 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.

[0037] Figure 2 and Figure 3 A non-limiting embodiment of a sensor 100 embodying aspects of the present invention is shown, which may be used in Figure 1 The sensor system shown. Figure 2 and 3 A perspective view and an exploded view, respectively, of a non-limiting embodiment of the sensor 100 are shown.

[0038] In some embodiments, as Figure 3 As shown, sensor housing 102 can include end caps 113. In some embodiments, sensor 100 can include one or more capacitors 118. One or more capacitors 118 can be, for example, one or more tuning capacitors and / or one or more regulating capacitors. One or more capacitors 118 can be too large to be practical to fabricate in semiconductor substrate 116. Furthermore, one or more capacitors 118 can be in addition to one or more capacitors fabricated in semiconductor substrate 116.

[0039] In some embodiments, as Figure 3 As shown, the sensor 100 can include a reflector 119 (i.e., a mirror). The reflector 119 can be attached to the semiconductor substrate 116 at its end. In one non-limiting embodiment, the reflector 119 can be attached to the semiconductor substrate 116 such that a surface portion 121 of the reflector 119 is generally perpendicular to the top side of the semiconductor substrate 116 (i.e., the side of the semiconductor substrate 116 having the light source 108 and one or more photodetectors 110 mounted or fabricated thereon or therein) 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 prevent radiation emitted by the light source 108 from escaping the axial end of the sensor 100.

[0040] According to one aspect of the present invention, an application for which the sensor 100 is developed (although by no means the only application for which the sensor is suitable) is the measurement of various biological analytes in living animals (including humans). For example, the sensor 100 can be used to measure glucose, oxygen, toxins, pharmaceuticals or other drugs, hormones, and other metabolic analytes in humans.

[0041] In some embodiments, the specific composition of analyte indicator 106 and indicator molecule 104 can vary depending on the specific analyte that the sensor will be used to detect and / or the location where the sensor will be used to detect the analyte (e.g., in subcutaneous tissue, blood, or peritoneum). In some embodiments, analyte indicator 106 facilitates exposure of indicator molecule 104 to the analyte. In some embodiments, indicator molecule 104 can exhibit a property (e.g., emit a certain amount of fluorescence) that is a function of the concentration of the specific analyte to which indicator molecule 104 is exposed.

[0042] In some embodiments, the sensor 100 may include at least one drug eluting polymer matrix and / or a layer of catalyst and / or one or more therapeutic agents, which may be provided on, incorporated into, or distributed 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 some embodiments, the one or more therapeutic agents may be incorporated into the analyte indicator 106. In some embodiments, the sensor 100 may include a membrane covering at least a portion of the 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, anti-inflammatory drugs (e.g., nonsteroidal anti-inflammatory drugs, including but not limited to acetylsalicylic acid, isobutylphenylpropionic acid).

[0043] Implanting or inserting a medical device, such as a biosensor, into the body of a user / patient can cause the body to exhibit adverse physiological reactions that can adversely affect the operation of the device. Reactions vary and can range from infection caused by 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 hampered or permanently damaged in the body through an immune response to the infection or the device itself. Specifically, the performance of the analyte indicator 106 can be degraded by an immune response in the body in which the sensor 100 is implanted. For example, as described above, white blood cells, including neutrophils, can attack the implanted sensor 100. Neutrophils, among other things, release hydrogen peroxide, which can degrade the indicator molecule 104 (e.g., by oxidizing the boronate groups of the indicator molecule 104 and rendering the indicator molecule 104 incapable of binding glucose).

[0044] In some embodiments, the analyte indicator 106 may include one or more additives that interact or react with one or more degradation substances without compromising the signal integrity or performance of the sensor device. In some embodiments, the additive may be incorporated into the analyte indicator 106, which may cover at least a portion of the sensor housing 102. Degradation substances may include one or more of hydrogen peroxide, reactive oxygen species, reactive nitrogen species, free radicals, enzymes, and metal ions. In some embodiments, the additive may be copolymerized with the indicator molecule 104. In some embodiments, one or more additives may be provided in the analyte indicator 106 (e.g., a polymer implant). In some embodiments, one or more additives may interact and / or react with degradation substances. In some embodiments, one or more additives may neutralize degradation substances. In some embodiments, one or more additives may be combined with degradation substances. In some embodiments, one or more additives may chelate degradation substances to inhibit, reduce, and / or prevent degradation of the analyte indicator caused by degradation substances. Accordingly, in some embodiments, one or more additives reduce the degradation of the analyte indicator 106.

[0045] In some non-limiting embodiments, the one or more additives can be compounds containing boronate ester and boronic acid groups that interact with the degradation species without compromising the signal integrity or performance of the sensor.

[0046] In some non-limiting embodiments, a sensor 100 for measuring an analyte (e.g., glucose) in a medium (e.g., interstitial fluid) in a living animal (e.g., a human) includes one or more of the following components: a sensor housing 102; a light source 108 within the sensor housing 102 configured to emit excitation light 329; an analyte indicator 106 covering a portion of the sensor housing 102; one or more indicator molecules 104 that are part of the analyte indicator 106, reversibly bind to the analyte, are positioned to be illuminated by the excitation light, and are configured to emit light 331 indicative of the amount of analyte in the culture medium in the living animal; a photodetector 224 within the sensor housing 102 that is sensitive to light 331 emitted by the one or more indicator molecules 104 and is configured to generate a signal indicative of the amount of analyte in the medium in the living animal; and one or more compounds having boronate and boronic acid groups that interact with degradative substances without impairing the signal integrity or performance of the sensor 100. In some non-limiting embodiments, the sensor 100 can include a drug eluting matrix and / or catalyst layer disposed on or incorporated into the analyte indicator 106 .

[0047] In some non-limiting embodiments, the one or more compounds comprising a boronate ester or boronic acid group can be a boronic acid compound of Formula I:

[0048] RB(OH)2 [Formula I]. In some embodiments, R is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NRR2. In some embodiments, R1 and R2 can be the same or different and each can represent a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate.

[0049] In some non-limiting examples, the one or more boronic acid group-containing compounds may include one or more of the following phenylboronic acid-containing compounds:

[0050] Wherein one or more R can be independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NRR.In some embodiments, R and R can be the same or different and each can represent a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate.In some non-limiting examples, the one or more compounds containing boronic acid groups can include one or more of the following compounds:

[0051]

[0052] In some non-limiting embodiments, the one or more compounds comprising a boronate ester or boronic acid group can be a boronate ester compound of Formula II: wherein R is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl.

[0053] In some non-limiting embodiments, one or more compounds containing a boronate or boronic acid group can be provided in an analyte indicator 106 (e.g., a polymer implant) of an analyte sensor 100. In some non-limiting embodiments, the one or more compounds containing a boronate or boronic acid group can be incorporated into the analyte indicator 106 by polymerizing the one or more compounds containing a boronate or boronic acid group as comonomers with an indicator monomer and one or more acrylate monomers. In some non-limiting embodiments, the one or more compounds containing a boronate or boronic acid group can be provided as comonomers with four monomers according to Formula III:

[0054] ABCD [Formula III], wherein A is an indicator monomer, B is a methacrylate monomer, C is a polyethylene glycol monomer, and D is a boronate or boronic acid group-containing compound monomer, wherein A is 0.001 to 10 wt % of the total polymer, B is 1 to 99 wt % of the total polymer, C is 1 to 99 wt % of the total polymer, and D is 0.001 to 99 wt % of the total polymer. In some aspects, A is 0.01 to 10 wt % of the total polymer, B is 1 to 99 wt % of the total polymer, C is 1 to 99 wt % of the total polymer, and D is 0.01 to 99 wt % of the total polymer.

[0055] In some non-limiting embodiments, the analyte indicator 106 can include four monomers: (i) a TFM fluorescent indicator, (ii) hydroxyethyl methacrylate (HEMA), which is a methacrylate, (iii) polyethylene glycol (PEG), and (iv) a boronate or boronic acid group of formula I. In some embodiments, PEG can be polyethylene glycol methacrylate (PEG-methacrylate) or polyethylene glycol diacrylate (PEG-diacrylate or PEGDA), and the monomer containing a boronate or boronic acid group of formula I can be a group containing 4-vinylboronic acid. In some embodiments, these four monomers can have a specific molar ratio. For example, in some non-limiting embodiments in which the analyte indicator 106 is opaque, the analyte indicator 106 can account for 0.001 to 10 mole percent, HEMA can account for 10 to 90 mole percent, PEGDA can account for 10 to 90 mole percent, and the group containing 4-vinylboronic acid can account for 0.001 to 90 mole percent. Using this formulation, in one example, the combined (i.e., total) monomers can be 30% by volume of the polymerization solution used in the polymerization reaction, with the remainder of the polymerization solution being water (i.e., the polymerization solution can be 70% by volume water). For another example, in one non-limiting embodiment, the analyte indicator 106 can be made using a polymer solution that is 50% by volume water and 50% by volume monomers.

[0056] In some embodiments, the relative molar percentage of the compound containing a borate ester or boronic acid group may be within a specific range. In some embodiments, the relative molar percentage of the compound containing a borate ester or boronic acid group is in the range of 0.1 to 100 molar percent. If the relative molar percentage of the compound containing a borate ester or boronic acid group is greater than this range, no hydrogel is formed. If the relative molar percentage of the compound containing a borate ester or boronic acid group is less than this range, the unexpectedly long life and enhanced functionality described in the present disclosure may not be achieved.

[0057] In some embodiments, PEGDA can be used as a cross-linking agent and produce a spongy 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 may become clear, and a clarified polymer graft 106 can be made from such a formulation. For example, in one non-limiting embodiment, a polymer solution can be used to prepare the polymer graft 106, the polymer solution being 50-60% by volume of water and 40-50% by volume of monomers, wherein the TFM fluorescent indicator, HEMA, PEG-methacrylate, and a compound comprising a boronate or boronic acid group 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 monomers in the solution. In some embodiments, the polymer graft can be synthesized using conventional free radical polymerization.

[0058] Implanted sensors including an analyte indicator containing an additive can have improved performance compared to sensors that do not include an analyte indicator containing an additive. For example, in some non-limiting embodiments, the additive can improve the lifespan and function of the sensor 100. Table 1 shows experimental results comparing analyte signal modulation (S) in a sensor without an additive in a polymer implant (control) and a non-limiting embodiment of a sensor 100 with an additive in a polymer implant (sample ID = H) after 15 days in an animal model (guinea pig).

[0059] Table 1:

[0060]

[0061]

[0062] Modulation (%) = (increase in fluorescence signal in the presence of a given glucose concentration) / (fluorescence signal in the absence of glucose) × 100

[0063] Table 1 shows that after 15 days in vivo, the % modulation of the control sample (no additive) decreased from 87% to 57%, meaning that only 66% of its original modulation was retained after 15 days of implantation. In contrast, the % modulation of sample H (containing additive) decreased from 104% to 98%, meaning that a high 94% of its original modulation was retained. Therefore, the non-limiting experimental results of 15 days of analyte indicator modulation in an animal model indicate that the polymer implant containing additives significantly increased the lifespan and functionality of the sensor.

[0064] The embodiments of the present invention have been fully described above with reference to the accompanying drawings. Although the present invention has been described based on these preferred embodiments, it will be apparent to those skilled in the art that specific modifications, variations, and alternative configurations may be made to the embodiments described within the spirit and scope of the present invention. For example, although in some embodiments, the analyte sensor 100 may be an optical sensor, this is not essential, 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. In addition, although in some embodiments, the analyte sensor 100 may be an implantable sensor, this is not essential, and in some alternative embodiments, the analyte sensor may be a transcutaneous sensor with a wired connection to an external transceiver. For example, in some alternative embodiments, the analyte sensor 100 may be located in or on a transcutaneous needle (e.g., at its tip). In these embodiments, as an alternative to 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 an external transceiver and a transceiver transcutaneous needle comprising the analyte sensor. As another example, in some alternative embodiments, an analyte sensor may be located in a catheter (eg, for intravenous glucose monitoring) and may communicate (wirelessly or wired) with an external transceiver.

Claims

1. A sensor for measuring an analyte in a medium within a living animal, the sensor comprising: Sensor housing; an analyte indicator covering at least a portion of the sensor housing, wherein the analyte indicator comprises an indicator molecule comprising a boronate group; and A) It is characterized in that the sensor also includes: One or more compounds selected from the following: Compounds of formula I: RB(OH)2[Formula I], wherein R in formula I is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, heteroaryl, polycyclic group and / or NR1R2, wherein R1 and R2 may be the same or different and each may represent a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate; Compounds of formula II: wherein R in formula II is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl; or a combination thereof; or B) is characterized in that the analyte indicator comprises a polymer comprising comonomers of four monomers according to formula III: ABCD[Formula III], Wherein A is an indicator molecule monomer, B is a methacrylate monomer, C is a polyethylene glycol monomer, and D is one or more compounds selected from the following: Compounds of formula I: RB(OH)2[Formula I], wherein R in formula I is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, or Phenylboronic acid compounds wherein one or more R in the phenylboronic acid compound is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryl or methacrylate, or Boric acid ester compound of formula II: wherein R in formula II is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl, or Its combination, 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. wherein one or more of the compound of formula I, the phenylboronic acid compound, and the compound of formula II interacts or reacts with a degradation substance to neutralize the degradation substance, bind to the degradation substance, and / or chelate the degradation substance, thereby inhibiting, reducing, or preventing degradation of the indicator molecule of the analyte indicator caused by the reaction of the indicator molecule with the degradation substance, wherein the degradation substance is hydrogen peroxide, reactive oxygen species, reactive nitrogen species, enzymes, free radicals, or metal ions.

2. The sensor according to claim 1, wherein the sensor is implantable in the living animal.

3. The sensor according to claim 1, wherein the one or more compounds further comprises a phenylboronic acid compound wherein one or more R in the phenylboronic acid compound is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryl or methacrylate.

4. The sensor of claim 1, wherein the one or more compounds are co-monomers with the analyte indicator in a hydrogel.

5. The sensor of claim 1, wherein the one or more compounds are embedded in a hydrogel that covers at least a portion of the sensor housing.

6. The sensor of claim 1, wherein the one or more compounds reduce chemical degradation and / or oxidation of the analyte indicator. The sensor of claim 6 , wherein the one or more compounds reduce the degradation rate of the analyte indicator.

8. The sensor of claim 6, wherein the one or more compounds chelate the degradation species to reduce and / or prevent degradation of the analyte indicator caused by the degradation species.

9. The sensor according to any one of claims 1 to 8, wherein the sensor comprises one or more compounds of formula I: RB(OH)2[Formula I], Wherein R in formula I is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate.

10. The sensor according to any one of claims 1 to 8, wherein the sensor comprises one or more phenylboronic acid compounds wherein one or more R in the phenylboronic acid compound is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryl or methacrylate.

11. The sensor according to any one of claims 1 to 8, wherein the sensor comprises one or more compounds of formula II: wherein R in formula II is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl.

12. The sensor of claim 1, wherein the one or more compounds are selected from 2-acrylamidophenylboronic acid, 3-(acrylamido)phenylboronic acid, a 4-vinylboronic acid containing group, and (3-methacrylamidophenyl)boronic acid.

13. The sensor of claim 1, wherein the analyte indicator comprises a polymer comprising comonomers of four monomers according to Formula III: ABCD [Formula III], Wherein A is a monomer of the indicator molecule, B is a methacrylate monomer, C is a polyethylene glycol monomer, and D is one or more compounds selected from the following: Compounds of formula I: RB(OH)2[Formula I], wherein R in formula I is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, or Phenylboronic acid compounds wherein one or more R in the phenylboronic acid compound is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryl or methacrylate, or Boric acid ester compound of formula II: wherein R in formula II is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl, or Its combination, wherein A is 0.01 to 10 wt % of the total polymer, B is 1 to 99 wt % of the total polymer, C is 1 to 99 wt % of the total polymer, and D is 0.01 to 99 wt % of the total polymer.

14. The sensor of claim 13, wherein the one or more compounds are provided in a molar ratio of 0.1 to 100 relative to a monomer of the analyte indicator.

15. The sensor of claim 1, wherein the sensor comprises at least one drug eluting polymer matrix covering a portion of the sensor housing.

16. A method of making a sensor for measuring an analyte in a medium within a living animal, the method comprising: applying an analyte indicator to a sensor housing of the sensor such that the applied analyte indicator covers at least a portion of the sensor housing, wherein the analyte indicator comprises an indicator molecule comprising a boronate group; and A) It is characterized in that the method further comprises: One or more compounds selected from the following are incorporated into the analyte indicator: Compounds of formula I: RB(OH)2[Formula I], wherein R in formula I is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, heteroaryl, polycyclic group and / or NR1R2, wherein R1 and R2 may be the same or different and each may represent a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate; Compounds of formula II: wherein R in formula II is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl; or a combination thereof; or B) It is characterized in that the method further comprises: The analyte indicator is incorporated into a polymer comprising comonomers of four monomers according to Formula III: ABCD[Formula III], Wherein A is a monomer of the indicator molecule, B is a methacrylate monomer, C is a polyethylene glycol monomer, and D is one or more compounds selected from the following: Compounds of formula I: RB(OH)2[Formula I], wherein R in formula I is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, or Phenylboronic acid compounds wherein one or more R in the phenylboronic acid compound is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryl or methacrylate, or Boric acid ester compound of formula II: wherein R in formula II is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl, or Its combination, 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. wherein one or more of the compound of formula I, the phenylboronic acid compound, and the compound of formula II interacts or reacts with a degradation substance to neutralize the degradation substance, bind to the degradation substance, and / or chelate the degradation substance, thereby inhibiting, reducing, or preventing degradation of the indicator molecule of the analyte indicator caused by the reaction of the indicator molecule with the degradation substance, wherein the degradation substance is hydrogen peroxide, reactive oxygen species, reactive nitrogen species, enzymes, free radicals, or metal ions.

17. The method of claim 16, wherein the one or more compounds are co-monomers with the analyte indicator.

18. The method of claim 16, wherein the one or more compounds are co-monomers with the analyte indicator in the hydrogel.

19. The method of claim 16, wherein the one or more compounds are embedded in a hydrogel that covers at least a portion of the sensor housing.

20. The method of claim 16, wherein the one or more compounds reduce chemical degradation and / or oxidation of the analyte indicator.

21. The method of claim 16, wherein the one or more compounds reduce the degradation rate of the analyte indicator.

22. The method of claim 17, wherein the one or more compounds are associated with the degradation species.

23. The method of claim 18, wherein the one or more compounds chelate the degradation species to reduce and / or prevent degradation of the analyte indicator by the degradation species.

24. The method of any one of claims 16 to 23, wherein the method further comprises incorporating one or more compounds of formula I into the analyte indicator: RB(OH)2[Formula I], Wherein R in formula I is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate.

25. The method of any one of claims 16 to 23, wherein the method further comprises incorporating one or more phenylboronic acid compounds into the analyte indicator wherein one or more R in the phenylboronic acid compound is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryl or methacrylate.

26. The method of any one of claims 16 to 23, wherein the method further comprises incorporating one or more compounds of Formula II into the analyte indicator: wherein R in formula II is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl.

27. The method of claim 16, wherein the one or more compounds are selected from 2-acrylamidophenylboronic acid, 3-(acrylamido)phenylboronic acid, 4-vinylboronic acid containing groups, and (3-methacrylamidophenyl)boronic acid.

28. The method of claim 16, wherein the method comprises incorporating the analyte indicator into a polymer comprising comonomers of four monomers according to Formula III: ABCD [Formula III], wherein A is a monomer of an analyte indicator, B is a methacrylate monomer, C is a polyethylene glycol monomer, and D is one or more compounds selected from the group consisting of: Compounds of formula I: RB(OH)2[Formula I], wherein R in formula I is selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, or Phenylboronic acid compounds wherein one or more R in the phenylboronic acid compound is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxyl, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryl or methacrylate, or Boric acid ester compound of formula II: wherein R in formula II is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group and / or NR1R2, wherein R1 and R2 are the same or different and each represents a hydrogen atom, hydroxy, alkyl, alkoxy, amino, aryl, heteroaryl, cyclic group, polycyclic group, carboxylic acid, vinyl, acrylate, acryloyl or methacrylate, and wherein X and Y = alkyl, or Its combination, wherein A is from 0.01 to 10 wt % of the total polymer, B is from 1 to 99 wt % of the total polymer, C is from 1 to 99 wt % of the total polymer, and D is from 0.01 to 99 wt % of the total polymer.

29. The method of claim 28, wherein the one or more compounds are provided in a molar ratio of 0.1 to 100 relative to the monomer of the indicator molecule.

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