Mediation of In Vivo Analyte Signal Degradation

Abstract

A sensor (e.g., an optical sensor) that can be implanted in 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 may include a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and one or more compounds that include a boronate or boronic acid moiety that reduces degradation of the analyte indicator.

Description

Technical Field

[0001] Cross - reference to Related Applications

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 237,396, filed Aug. 26, 2021, which is incorporated herein by reference in its entirety.

[0002]

[0002] Field of the Invention

[0003] The present invention generally relates to continuously reducing in - vivo degradation of an analyte sensor portion when measuring an analyte in a medium of a living animal using a system that includes a sensor (partially or fully) implanted or inserted into the living animal. Specifically, the present invention relates to sensors that utilize one or more additives that may be incorporated within an analyte indicator, and / or a material that covers at least a portion of the analyte indicator.

Background Art

[0003]

[0004] Consideration of the Background

[0005] Sensors can be (partially or fully) implanted within a living animal (e.g., a human) to measure an analyte (e.g., glucose, oxygen, cardiac markers, low - density lipoprotein (LDL), high - density lipoprotein (HDL), or triglycerides) in a medium within the living animal (e.g., interstitial fluid (ISF), blood, or intraperitoneal fluid). The sensor may include a light source (e.g., a light - emitting diode (LED) or other light - emitting element), an indicator molecule, and a light detector (e.g., a photodiode, a phototransistor, a photore resistor, 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.

[0004]

[0006] The sensor may include an analyte indicator that can be in the form of an indicator molecule embedded in a graft (i.e., a layer or matrix). For example, in an implantable fluorescent glucose sensor, the fluorescent indicator molecule binds reversibly to glucose and, when irradiated with excitation light (e.g., light having a wavelength of about 378 nm), may emit an amount of light (e.g., light in the range of 400 - 500 nm) depending on whether glucose is bound to the indicator molecule.

[0005]

[0007] When the sensor is implanted into a living animal, the animal's immune system may begin to attack the sensor. For example, when the sensor is implanted into a human, white blood cells may attack the sensor as a foreign object, and in the initial immune system onslaught, neutrophils may be the main white blood cells attacking the sensor. The defense mechanism of neutrophils includes 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 may decompose the indicator molecules of the analyte indicator. For example, in an indicator molecule having a boronate group, hydrogen peroxide may oxidize the boronate group to decompose the indicator molecule, thus potentially impairing the ability of the indicator molecule to bind to glucose.

[0007]

[0009] Currently, in the art, there is a need for improvement in reducing the decomposition of analyte indicators. Also, in the art, there is a need for a continuous analyte sensor with an extended lifespan.

Summary of the Invention

[0008]

[0010] Among several advantages, the present invention overcomes the drawbacks of prior systems by providing a reduction in the decomposition of analyte indicators.

[0009]

[0011] One aspect of the present invention provides a sensor that is implanted or inserted within a living animal for measuring 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 the degradation of the analyte indicator.

[0010]

[0012] In some embodiments, the sensor may include at least one additive-containing polymer graft, and the one or more additives may be copolymerized with or dispersed within the additive-containing polymer graft. In some embodiments, the additive-containing polymer graft may cover at least a portion of the sensor housing. In some embodiments, the additive-containing polymer graft may be present within the sensor housing.

[0011]

[0013] In some embodiments, the one or more additives may be incorporated, for example, as a comonomer with the analyte indicator. In some embodiments, the sensor may include a material, such as a membrane, covering at least a portion of the analyte indicator, and the one or more additives are incorporated within the material.

[0012]

[0014] Another aspect of the present invention provides a sensor for measuring an analyte in a medium within a 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 compounds containing a boronate or boronic acid moiety that reduce the degradation of the analyte indicator. The one or more compounds containing a boronic acid moiety have the formula I:

[0013]

Chemical formula

[0014] (wherein R = methylene or an alkyl group, aryl group, heteroaryl group, cyclic group, polycyclic group, polyalkylene glycol group, polyethylene glycol (PEG) group, linear or substituted polyalkylene glycol or PEG group, or a combination thereof) of the compound, or the boronic acid is of formula II:

[0015]

Chemical formula

[0016] a compound of formula I substituted with a boronate group of formula (wherein X and Y = alkyl).

[0017]

[0015] In some embodiments, the sensor may be implantable within a living animal. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may be comonomers with an analyte indicator. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may be comonomers with an analyte indicator in a hydrogel. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may be encapsulated in a hydrogel that covers at least a portion of the sensor housing.

[0018]

[0016] In some embodiments, one or more compounds containing a boronate or boronic acid moiety may reduce chemical decomposition and / or oxidation of the analyte indicator. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may reduce the decomposition rate of the analyte indicator. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may bind to degradation species. In some embodiments, one or more compounds containing a boronic acid-containing moiety may sequester degradation species so as to reduce and / or prevent degradation of the analyte indicator by the degradation species.

[0019]

[0017] In some embodiments, the compound containing a boronate or boronic acid moiety is

[0020] [Chemical formula]

[0021] may be selected from.

[0022]

[0018] In some embodiments, the analyte indicator covering at least a part of the sensor housing may include a polymer containing comonomers of four monomers according to formula II: AxByCzDw [formula II], where A may be an analyte indicator monomer, B may be a methacrylate monomer, C may be a polyethylene glycol monomer, D may be a compound or monomer containing a boronate or boronic acid moiety, A may be 0.01-10 wt% of the total polymer, B may be 1-99 wt%, C may be 1-99 wt%, and D may be 0.01-99 wt%. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may be provided at a molar ratio of 0.1-100 relative to the analyte indicator monomer.

[0023]

[0019] In some embodiments, the sensor may include at least one drug eluting polymer matrix covering a part of the sensor housing.

[0024]

[0020] Yet another aspect of the present invention provides a method for fabricating a sensor for measuring an analyte in a medium within a living animal. The method may include applying an analyte indicator to the sensor housing of the sensor such that the applied analyte indicator covers at least a part of the sensor housing, and the analyte indicator may include one or more compounds containing a boronate or boronic acid moiety that reduces the degradation of the analyte indicator. One or more compounds containing a boronic acid moiety have the formula I:

[0025] [Chemical formula]

[0026] (wherein R = methylene or an alkyl group, aryl group, heteroaryl group, cyclic group, polycyclic group, polyalkylene glycol group, polyethylene glycol (PEG) group, linear or substituted polyalkylene glycol or PEG group, or a combination thereof) of the compound, or the boronic acid is of formula II:

[0027]

Chemical formula

[0028] It may be selected from compounds of formula I substituted with a boronate group of (wherein X and Y = alkyl).

[0029]

[0021] In some embodiments, one or more compounds containing a boronate or boronic acid moiety may be comonomers with an analyte indicator. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may be comonomers with an analyte indicator in a hydrogel. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may be encapsulated in a hydrogel that covers at least a portion of the sensor housing.

[0030]

[0022] In some embodiments, one or more compounds containing a boronate or boronic acid moiety may reduce chemical degradation and / or oxidation of the analyte indicator. In some embodiments, one or more compounds containing a boronate or boronic acid moiety may reduce the degradation rate of the analyte indicator.

[0031]

[0023] In some embodiments, one or more compounds comprising a boronate or boronic acid moiety can interact or react with the analyte species without compromising the signal integrity or performance of the sensor device, and the analyte species can be hydrogen peroxide, reactive oxygen species, reactive nitrogen species, enzymes, free radicals, or metal ions. In some embodiments, one or more compounds comprising a boronate or boronic acid moiety can bind to the analyte species. In some embodiments, one or more compounds comprising a boronate or boronic acid moiety can sequester the analyte species so as to reduce and / or prevent the degradation of the analyte indicator by the analyte species.

[0032]

[0024] In some embodiments, the compound boronate or boronic acid moiety is

[0033]

Chemical formula

[0034] may be selected from.

[0035]

[0025] In some embodiments, the analyte indicator covering at least a portion of the sensor housing may comprise a polymer comprising a comonomer of four monomers according to formula III: ABCD [formula III], where A may be an analyte indicator monomer, B may be a methacrylate monomer, C may be a polyethylene glycol monomer, D may be a compound or monomer comprising a boronate or boronic acid moiety, A may be 0.01 to 10% by weight of the total polymer, B may be 1 to 99% by weight, C may be 1 to 99% by weight, and D may be 0.01 to 99% by weight.

[0036]

[0026] In some embodiments, one or more compounds comprising a boronate or boronic acid moiety may be provided in a molar ratio of 0.1 to 100 relative to the analyte indicator monomer.

[0037]

[0027] Further variations included in the system and method are described in the following detailed description of the invention.

[0038]

[0028] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various non-limiting embodiments of the invention. In the drawings, like reference numerals indicate the same or functionally similar elements.

Brief Description of the Drawings

[0039]

Figure 1

[0029] It is a schematic diagram showing a sensor system embodying an aspect of the present invention.

Figure 2

[0030] It is a diagram showing a perspective view of a sensor embodying an aspect of the present invention.

Figure 3

[0031] It is a diagram showing an exploded view of a sensor embodying an aspect of the present invention.

Modes for Carrying Out the Invention

[0040]

[0032] FIG. 1 is a schematic diagram of a sensor system embodying an aspect of the present invention. In some non-limiting embodiments, as shown in FIG. 1, the system can include a sensor 100 and an external transceiver 101. In some embodiments, the sensor 100 can 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 regions of a living animal suitable for sensor implantation. For example, in some non-limiting embodiments, the sensor 100 may be implanted under the skin (i.e., subcutaneously or within peritoneal tissue). However, this is not essential, and in some alternative embodiments, the sensor 100 may be a transcutaneous sensor.

[0041]

[0033] In some embodiments, the transceiver 101 may be an electronic device that supplies power to the sensor 100, provides commands and / or data to the sensor 100, and / or communicates with the sensor 100 to receive data from the sensor 100. In some embodiments, the received data may include one or more sensor measurements. In some embodiments, the sensor measurements may include, for example, but not limited to, one or more optical 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 may be able to calculate the analyte (e.g., glucose) concentration from the measurement information received from the sensor 100.

[0042]

[0034] In some non-limiting embodiments, the transceiver 101 may 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 may be held in place by a band (e.g., an armband or a wristband) and / or an adhesive, and the transceiver 101 may be able to transmit a measurement command (i.e., a request for measurement information) to the sensor 100 (e.g., periodically, such as every two minutes, and / or when activated by the user). In some embodiments where the transceiver 101 is a handheld device, by positioning (i.e., hovering or waving / shaking / passing) the transceiver 101 within the range over the sensor embedding site (i.e., within the proximity of the sensor 100), the transceiver 101 can automatically transmit a measurement command to the sensor 100 and receive data from the sensor 100.

[0043]

[0035] In some embodiments, as shown in FIG. 1, the transceiver 101 may include an inductive element 103, such as a coil. In some embodiments, the transceiver 101 may generate an electromagnetic wave or an electrodynamic field (e.g., using a coil) to induce a current in the inductive element 114 of the sensor 100. In some non-limiting embodiments, the sensor 100 can use the current induced in the inductive element 114 to power the sensor 100. However, this is not essential, and in some alternative embodiments, the sensor 100 may be powered by an internal power source (e.g., a battery).

[0044]

[0036] In some embodiments, the transceiver 101 may transmit data (e.g., commands) to the sensor 100. For example, in some non-limiting embodiments, the transceiver 101 may transmit data by modulating the electromagnetic wave 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 may detect / extract the modulation in the electromagnetic wave generated by the transceiver 101. Further, the transceiver 101 may receive data (e.g., one or more sensor measurements) from the sensor 100. For example, in some non-limiting embodiments, the transceiver 101 may receive data by detecting the modulation in the electromagnetic wave generated by the sensor 100, e.g., by detecting the modulation in the current flowing through the inductive element 103 of the transceiver 101.

[0045]

[0037] In some embodiments, as shown in FIG. 1, the sensor 100 may include a sensor housing 102 (i.e., a body, shell, capsule, or container) that can be rigid and biocompatible. In an exemplary embodiment, the sensor housing 102 may be formed from a suitable optically transmissive polymer material, such as an acrylic polymer (e.g., polymethyl methacrylate (PMMA)).

[0046]

[0038] In some embodiments, as shown in FIG. 1, 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., 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. Instead of coating the outer surface of the sensor housing 102 with the analyte indicator 106, the analyte indicator 106 may be disposed on the outer surface of the sensor housing 102 by other methods such as deposition or adhesion. In some embodiments, the analyte indicator 106 may be a fluorescent glucose indicator polymer. In one non-limiting embodiment, the polymer is biocompatible and stable, grafted to the surface of the sensor housing 102, and designed to directly measure 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.

[0047]

[0039] In some embodiments, the analyte indicator 106 (e.g., polymer graft) of the sensor 100 may include indicator molecules 104. The indicator molecules 104 may be distributed throughout the analyte indicator 106 or only across one or more portions of the analyte indicator 106. The indicator molecules 104 may have a boronate group. The indicator molecules 104 may be fluorescent indicator molecules (e.g., chemical name 9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamide)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene sodium salt), or light-absorbing non-fluorescent indicator molecules. In some embodiments, the indicator molecules 104 may reversibly bind to an analyte (e.g., glucose, oxygen, cardiac markers, low density lipoprotein (LDL), high density lipoprotein (HDL), or triglycerides). When the indicator molecule 104 binds to the analyte, the indicator molecule may become fluorescent, in which case the indicator molecule 104 can absorb (or be excited by) the excitation light 329 and emit light 331. In one non-limiting embodiment, the excitation light 329 may have a wavelength of about 378 nm, and the emitted light 331 may have a wavelength in the range of 400-500 nm. When no analyte is bound, the indicator molecule 104 may simply be weakly fluorescent.

[0048]

[0040] In some embodiments, the sensor 100 can include a light source 108, such as, for example, a light emitting diode (LED), or another light source that emits radiation, including radiation over a wavelength range that interacts with the indicator molecules 104. In other words, the light source 108 can emit the excitation light 329 that is absorbed by the indicator molecules 104 in the matrix layer / polymer. As described above, in one non-limiting embodiment, the light source 108 may emit the excitation light 329 at a wavelength of about 378 nm.

[0049]

[0041] In some embodiments, sensor 100 may also include one or more photodetectors (e.g., a photodiode, a phototransistor, a photore resistor, or other photosensitive element). For example, in the embodiment shown in FIG. 1, sensor 100 has a first photodetector 224 and a second photodetector 226. However, this is not essential, and in some alternative embodiments, 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 light emitted by the indicator molecule 104, whereby a signal indicating the level of fluorescence of the indicator molecule and thus the amount of the target analyte (e.g., glucose) is generated by a photodetector (e.g., photodetector 224) responsive thereto.

[0050]

[0042] A portion of the excitation light 329 emitted by the light source 108 may be reflected from the analyte indicator 106 and return to the sensor 100 as reflected light 333, and a portion of the absorbed excitation light may be emitted as emitted (fluorescence) light 331. In one non-limiting embodiment, the emitted light 331 may have a wavelength different from that of the excitation light 329. The reflected light 333 and the emitted (fluorescence) light 331 may be absorbed by one or more photodetectors (e.g., the first and second photodetectors 224 and 226) within the body of the sensor 100.

[0051]

[0043] Each of the one or more photodetectors may be covered by a filter 112 (see FIG. 3) that passes only light of a specific subset of wavelengths. 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 reflect most of the received light otherwise. In some embodiments, the filter may be a thin film (dichroic) filter deposited directly on the photodetector, which may pass only a narrow wavelength band and reflect most of the light received thereby otherwise. The filters 112 may be the same (e.g., both filters 112 may pass signals) or different (e.g., one filter 112 may be a reference filter and the other filter 112 may be a signal filter).

[0052]

[0044] In one non-limiting embodiment, the second (reference) photodetector 226 may be covered by a reference photodiode filter that passes light of the same wavelength (e.g., 378 nm) as emitted from the light source 108. The first (signal) photodetector 224 may be able to detect the amount of fluorescence light 331 emitted from the molecules 104 in the analyte indicator 106. In one non-limiting embodiment, the peak emission of the indicator molecule 104 may occur at about 435 nm, and the first photodetector 224 may be covered by a signal filter that passes light in the range of about 400 nm to 500 nm. In some embodiments, higher glucose levels / concentrations correspond to a greater amount of fluorescence of the molecules 104 in the analyte indicator 106 and thus a greater number of photons impinging on the first photodetector 224.

[0053]

[0045] In some embodiments, as shown in FIG. 1, sensor 100 may include a substrate 116. In some embodiments, substrate 116 may be a circuit board (e.g., a printed circuit board (PCB) or a flexible PCB) on which circuit components (e.g., analog and / or digital circuit components) can be mounted or otherwise attached. However, in some alternative embodiments, substrate 116 may be a semiconductor substrate having circuits fabricated thereon. The circuits may include analog and / or digital circuits. Also, in some semiconductor substrate embodiments, in addition to the circuits fabricated on the semiconductor substrate, circuits can be mounted or otherwise attached to semiconductor substrate 116. In other words, in some semiconductor substrate embodiments, some or all of a circuit that may include discrete circuit elements, integrated circuits (e.g., application specific integrated circuits (ASICs)), and / or other electronic components may be fabricated on semiconductor substrate 116, and the remainder of the circuit may be fixed to semiconductor substrate 116, thereby providing communication paths between the various components so fixed.

[0054]

[0046] In some embodiments, one or more of sensor housing 102, analyte indicator 106, indicator molecule 104, light source 108, photodetectors 224, 226, temperature transducer 670, substrate 116, and induction element 114 of sensor 100 can include some or all of the features described in one or more of U.S. Application No. 13 / 761,839, filed Feb. 7, 2013, U.S. Application No. 13 / 937,871, filed Jul. 9, 2013, and U.S. Application No. 13 / 650,016, filed Oct. 11, 2012, all of which are hereby incorporated by reference in their entirety. Similarly, the structure and / or function of sensor 100 and / or transceiver 101 may be as described in one or more of U.S. Application No. 13 / 761,839, No. 13 / 937,871, and No. 13 / 650,016.

[0055]

[0047] 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 the wired connection.

[0056]

[0048] Figures 2 and 3 show non - limiting embodiments of sensor 100 embodying aspects of the present invention that can be used in the sensor system shown in Figure 1. Figures 2 and 3 show a perspective view and an exploded view, respectively, of non - limiting embodiments of sensor 100.

[0057]

[0049] In some embodiments, as shown in Figure 3, sensor housing 102 may include end cap 113. In some embodiments, sensor 100 may include one or more capacitors 118. The one or more capacitors 118 may be, for example, one or more tuning capacitors and / or one or more trimming capacitors. The one or more capacitors 118 may be too large to be practical for fabrication on semiconductor substrate 116. Further, the one or more capacitors 118 may be added to one or more capacitors fabricated on semiconductor substrate 116.

[0058]

[0050] In some embodiments, as shown in FIG. 3, sensor 100 may include a reflector 119 (i.e., a mirror). Reflector 119 may be attached to semiconductor substrate 116 at its end. In a non-limiting embodiment, reflector 119 may be attached to semiconductor substrate 116 such that the face 121 of reflector 119 is generally perpendicular to the upper side of semiconductor substrate 116 (i.e., the side of semiconductor substrate 116 on or in which light sources 108 and one or more photodetectors 110 are mounted or fabricated), and faces light source 108. The face 121 of reflector 119 can reflect the radiation emitted by light source 108. In other words, reflector 119 can block the radiation emitted by light source 108 from exiting the axial end of sensor 100.

[0059]

[0051] According to one aspect of the present invention, the use for which sensor 100 has been developed is (but by no means the only use for which it is suitable) the measurement of various biological analytes in the living body of animals (including humans). For example, sensor 100 can be used to measure, for example, glucose, oxygen, toxins, pharmaceuticals or other drugs, hormones, and other metabolic analytes in the human body.

[0060]

[0052] In some embodiments, the specific composition of analyte indicator 106 and indicator molecule 104 can vary depending on the specific analyte to be detected by the sensor and / or the location (e.g., subcutaneous tissue, blood, or intraperitoneal) in which the sensor is used to detect the analyte. In some embodiments, analyte indicator 106 facilitates the exposure of indicator molecule 104 to the analyte. In some embodiments, indicator molecule 104 can exhibit a property that is a function of the concentration of the specific analyte to which indicator molecule 104 is exposed (e.g., emits a certain amount of fluorescent light).

[0061]

[0053] In some embodiments, sensor 100 may include at least one drug-eluting polymer matrix and / or a layer of catalyst and / or one or more therapeutic agents that may be provided in, incorporated into, or dispersed within an analyte indicator or the sensor housing, as described in U.S. Patent No. 9,931,068 (Huffstetler et al.), which is hereby incorporated by reference in its entirety. In some embodiments, one or more therapeutic agents may be incorporated into analyte indicator 106. In some embodiments, sensor 100 may include a membrane that covers at least a portion of analyte indicator 106, and one or more therapeutic agents may be incorporated within the membrane. In some embodiments, the one or more therapeutic agents include dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclomethasone, fludrocortisone, their derivatives, and their analogs, glucocorticoids, anti-inflammatory agents, such as non-steroidal anti-inflammatory agents including, but not limited to, acetylsalicylic acid, isobutylphenylpropanoic acid.

[0062]

[0054] When implanting or inserting a medical device such as a biosensor into a user / patient's body, the body may exhibit adverse physiological reactions that are harmful to the device's function. The reactions can vary from infection due to the implantation surgery to an immunological response to the foreign object implanted in the body. That is, the performance of an implantable biosensor can be impeded or permanently damaged in vivo by an infectious disease or an immunological response to the device itself. In particular, the performance of analyte indicator 106 can be deteriorated by the immunological response of the body in which sensor 100 is implanted. For example, as described above, white blood cells including neutrophils may attack the implanted sensor 100. Neutrophils, in particular, release hydrogen peroxide, and hydrogen peroxide may decompose indicator molecule 104 (e.g., by oxidizing the boronate group of indicator molecule 104 and impairing the ability of indicator molecule 104 to bind to glucose).

[0063]

[0055] In some embodiments, the analyte indicator 106 may include one or more additives that interact or react with one or more degradation species without impairing the integrity or performance of the sensor device's signal. In some embodiments, the additive may be incorporated into the analyte indicator 106 that can cover at least a portion of the sensor housing 102. The degradation species 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, the one or more additives may be provided in the analyte indicator 106 (e.g., polymer graft). In some embodiments, the one or more additives may interact and / or react with the degradation species. In some embodiments, the one or more additives may neutralize the degradation species. In some embodiments, the one or more additives may bind to the degradation species. In some embodiments, the one or more additives may sequester the degradation species so as to inhibit, reduce, and / or prevent the degradation of the analyte indicator by the degradation species. Thus, in some embodiments, the one or more additives reduce the degradation of the analyte indicator 106.

[0064]

[0056] In some non-limiting embodiments, the one or more additives may be boronate and boronic acid-containing partial compounds that interact with the degradation species without impairing the integrity or performance of the sensor's signal.

[0065]

[0057] In some non-limiting embodiments, 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) 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 irradiated by the excitation light, and are configured to emit light 331 indicative of the amount of analyte in the medium within the living animal; a photodetector 224 within the sensor housing 102 that is sensitive to the 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 within the living animal; and one or more compounds having boronate and boronic acid-containing moieties that interact with degradation species without compromising the integrity or performance of the signals of the sensor 100. In some non-limiting embodiments, the sensor 100 may include a drug elution matrix and / or a layer of catalyst provided to or incorporated into the analyte indicator 106.

[0066]

[0058] In some non-limiting embodiments, one or more of the compounds containing a boronate or boronic acid-containing moiety have the formula I:

[0067]

Chem.

[0068] (wherein R = methylene or an alkyl group, aryl group, heteroaryl group, cyclic group, polycyclic group, polyalkylene glycol group, polyethylene glycol (PEG) group, linear or substituted polyalkylene glycol or PEG group, or a combination thereof), which may be a boronic acid compound. The inventors have found that the R group of formula I results in unexpectedly excellent incorporation of the compound into the hydrogel, improved activation, and improved sensor lifetime.

[0069] In some embodiments, the boronic acid moiety of Formula I may be substituted with a boronate group of Formula II:

[0070] [Chemical formula]

[0071] (wherein X and Y = alkyl).

[0072] In some non-limiting examples, one or more boronate or boronic acid-containing compounds may be the following compounds:

[0073] [Chemical formula]

[0074] may include one or more of.

[0075]

[0059] In some non-limiting embodiments, one or more compounds containing a boronate or boronic acid moiety may be provided in the analyte indicator 106 (e.g., polymer graft) of the analyte sensor 100. In some non-limiting embodiments, one or more compounds containing a boronate or boronic acid moiety can be incorporated into the analyte indicator 106 by polymerizing one or more compounds containing a boronate or boronic acid moiety as a comonomer with an indicator monomer and one or more acrylate monomers. In some non-limiting embodiments, one or more compounds containing a boronate or boronic acid moiety have the formula III: It may be provided as a comonomer of four monomers according to [Formula III] ABCD, where A is an indicator monomer, B is a methacrylate monomer, C is a polyethylene glycol monomer, D is a boronate or boronic acid-containing partial compound monomer, A is 0.001 to 10% by weight of the total polymer, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.001 to 99% by weight. In some embodiments, A is 0.01 to 10% by weight of the total polymer, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.01 to 99% by weight.

[0076]

[0060] In some non-limiting embodiments, the analyte indicator 106 may 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-containing moiety of Formula I. In some embodiments, the PEG may be polyethylene glycol methacrylate (PEG-methacrylate) or polyethylene glycol diacrylate (PEG-diacrylate or PEGDA), and the boronate or boronic acid-containing moiety monomer of Formula I may be a 4-vinyl boronic acid-containing moiety. In some embodiments, the four monomers may be in a specific molar ratio. For example, in some non-limiting embodiments where the analyte indicator 106 is opaque, the analyte indicator 106 may constitute 0.001 to 10 mole percent, HEMA may constitute 10 to 90 mole percent, PEGDA may constitute 10 to 90 mole percent, and the 4-vinyl boronic acid-containing moiety may constitute 0.001 to 90 mole percent. In this formulation, the combined (i.e., total) monomers may be, in one example, 30 volume percent of the polymerization solution used in the polymerization reaction, and the remainder of the polymerization solution is water (i.e., the polymerization solution may be 70 volume percent water). As another example, in one non-limiting embodiment, the analyte indicator 106 may be prepared using a polymer solution that is 50 volume percent water and 50 volume percent monomers.

[0077]

[0061] In some embodiments, the relative molar percentage of the compound containing a boronate or boronic acid moiety may be within a specific range. In some embodiments, the relative molar percentage of the compound containing a boronate or boronic acid moiety ranges from 0.1 to 100 mole percent. If the relative molar percentage of the compound containing a boronate or boronic acid moiety is greater than this range, a hydrogel is not formed. If the relative molar percentage of the compound containing a boronate or boronic acid moiety is lower than this range, the unexpected lifespan and function improvement effects described in the present disclosure may not be obtained.

[0078] In some embodiments, PEGDA may act as a crosslinking agent to produce a sponge-like matrix / hydrogel. In some non-limiting embodiments, the PEG-containing graft / hydrogel may become transparent when a sufficient amount of additional PEG is added to the mixture (i.e., when fabricated using a higher concentration of PEG), and a transparent polymer graft 106 may be made from such formulations. For example, in one non-limiting embodiment, the polymer graft 106 may be made using a polymer solution that is 50 - 60% by volume water and 40 - 50% by volume monomer, where the TFM fluorescent indicator, HEMA, PEG-methacrylate, and the compound containing a boronate or boronic acid moiety may constitute 0.01 - 10 wt%, 1 - 99 wt%, 1 - 99 wt%, and 0.01 - 99 wt% of the monomers in the solution. In some embodiments, the polymer graft may be synthesized using conventional free radical polymerization.

[0079]

[0062] An embedded sensor containing an additive-containing analyte indicator may have improved performance compared to a sensor that does not contain an additive-containing analyte indicator. For example, in some non-limiting embodiments, the additive can improve the lifespan and function of the sensor 100.

[0080]

[0063] The embodiments of the present invention have been fully described above with reference to the 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 constructions can be made to the described embodiments within the spirit and scope of the present invention. For example, in some embodiments, the analyte sensor 100 may be an optical sensor, but this is not essential. 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. Also, in some embodiments, the analyte sensor 100 may be an implantable sensor, but this is not essential. 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 located within or on a transcutaneous needle (e.g., at its tip). In these embodiments, instead of using wireless communication with an antenna (e.g., inductive element 114), the analyte sensor may communicate with the external transceiver using one or more wires connected between the external transceiver and the transcutaneous needle of the transceiver including the analyte sensor. As another example, in some alternative embodiments, the analyte sensor may be located within a catheter (e.g., for intravascular glucose monitoring) and may communicate with the external transceiver (using wireless or wires). The present invention includes the following aspects. [1] A sensor for measuring an analyte in a medium within a living animal, the sensor comprising: a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and one or more compounds comprising a boronate or boronic acid moiety that reduces the degradation of the analyte indicator, wherein the one or more compounds comprising the boronic acid-containing moiety have the formula I:

Chemical formula

Chemical formula

[10] The compound comprising a boronate or boronic acid moiety is

Chem.

[11] The analyte indicator covering at least a portion of the sensor housing comprises a polymer comprising a comonomer of four monomers according to formula II: A x B y C z D w [Formula II] A is an analyte indicator monomer, B is a methacrylate monomer, C is a polyethylene glycol monomer, D is a compound or monomer containing a boronate or boronic acid moiety, A is 0.01 to 10% by weight of the total polymer, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.01 to 99% by weight, the sensor according to any one of items 1 to 10.

[12] The sensor according to 11, wherein one or more compounds containing a boronate or boronic acid moiety are provided at a molar ratio of 0.1 to 100 with respect to the analyte indicator monomer.

[13] The sensor according to any one of items 1 to 12, comprising at least one drug-eluting polymer matrix covering a part of the sensor housing.

[14] A method of fabricating a sensor for measuring an analyte in a medium within a living animal, the method comprising applying an analyte indicator to the sensor housing of the sensor such that the applied analyte indicator covers at least a part of the sensor housing, the analyte indicator comprising one or more compounds containing a boronate or boronic acid moiety that reduces the degradation of the analyte indicator, and the one or more compounds containing a boronic acid moiety are of formula I:

Chem.

Chem.

[15] The method according to 14, wherein one or more compounds containing a boronate or boronic acid moiety are comonomers with the analyte indicator.

[16] The method according to 14 or 15, wherein one or more compounds containing a boronate or boronic acid moiety are comonomers with the analyte indicator in a hydrogel.

[17] The method according to any one of items 14 to 16, wherein one or more compounds containing a boronate or boronic acid moiety are encapsulated in a hydrogel covering at least a part of the sensor housing.

[18] The method according to any one of items 14 to 17, wherein one or more compounds containing a boronate or boronic acid moiety reduce the chemical degradation and / or oxidation of the analyte indicator.

[19] The method according to any one of claims 14 to 18, wherein one or more compounds comprising a boronate or boronic acid moiety reduce the degradation rate of the analyte indicator.

[20] The method according to any one of claims 14 to 19, wherein one or more compounds comprising a boronate or boronic acid moiety interact or react with the degradation species without impairing the integrity or performance of the signal of the sensor device, and the degradation species are hydrogen peroxide, reactive oxygen species, reactive nitrogen species, enzymes, free radicals or metal ions.

[21] The method according to claim 19, wherein one or more compounds comprising a boronate or boronic acid moiety bind to the degradation species.

[22] The method according to claim 20 or 21, wherein one or more compounds comprising a boronate or boronic acid moiety reduce the degradation of the analyte indicator by the degradation species and / or block the degradation species to prevent such degradation.

[23] The compound boronate or boronic acid moiety is

Chem.

[24] The analyte indicator covering at least a part of the sensor housing comprises a polymer comprising a comonomer of four monomers according to formula III: ABCD [formula III], wherein A is an analyte indicator monomer, B is a methacrylate monomer, C is a polyethylene glycol monomer, D is a compound or monomer comprising a boronate or boronic acid moiety, A is 0.01 to 10% by weight of the total polymer, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.01 to 99% by weight, the method according to any one of claims 14 to 23.

[25] The method according to claim 24, wherein one or more compounds comprising a boronate or boronic acid moiety are provided at a molar ratio of 0.1 to 100 relative to the analyte indicator monomer.

Claims

1. A sensor for measuring an analyte in a medium within a living animal, the sensor comprising: a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and one or more compounds comprising a boronate or boronic acid moiety that reduces degradation of the analyte indicator, wherein the one or more compounds comprising a boronic acid-containing moiety has the formula I: 【Chemical 1】 (wherein R = methylene or an alkyl group, aryl group, heteroaryl group, cyclic group, polycyclic group, polyalkylene glycol group, polyethylene glycol (PEG) group, linear or substituted polyalkylene glycol or PEG group, or a combination thereof), or the boronic acid is a compound of formula I substituted with a boronate group of formula II: 【Chemical Formula 2】 (wherein X and Y = alkyl), the sensor.

2. The sensor according to claim 1, which is implantable within a living animal.

3. The sensor according to claim 1, wherein the one or more compounds comprising a boronate or boronic acid moiety is a comonomer with the analyte indicator.

4. The sensor according to claim 1, wherein the one or more compounds comprising a boronate or boronic acid moiety is a comonomer with the analyte indicator in a hydrogel.

5. The sensor according to claim 1, wherein the one or more compounds comprising a boronate or boronic acid moiety is encapsulated in a hydrogel that covers at least a portion of the sensor housing.

6. The compound comprising a boronate or boronic acid moiety is [Chemical Formula 3] selected from, the sensor according to any one of claims 1 to 5.

7. An analyte indicator that covers at least a portion of the sensor housing is a polymer that includes comonomers of four monomers according to Formula II: A ｘ B ｙ C ｚ D ｗ [wherein the polymer] includes comonomers of four monomers according to [Formula II], A is an analyte indicator monomer, B is a methacrylate monomer, C is a polyethylene glycol monomer, D is a compound or monomer comprising a boronate or boronic acid moiety, A is 0.01 to 10% by weight of the total polymer, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.01 to 99% by weight, the sensor according to any one of claims 1 to 5.

8. The sensor according to claim 7, wherein the one or more compounds comprising a boronate or boronic acid moiety are provided in a molar ratio of 0.1 to 100 relative to the analyte indicator monomer.

9. The sensor according to claim 1, comprising at least one drug eluting polymer matrix covering a portion of the sensor housing.

10. A method of fabricating 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, the analyte indicator comprising one or more compounds comprising a boronate or boronic acid moiety that reduces degradation of the analyte indicator, the one or more compounds comprising a boronic acid-containing moiety being of formula I: 【Chemical 4】 wherein R = methylene or an alkyl group, aryl group, heteroaryl group, cyclic group, polycyclic group, polyalkylene glycol group, polyethylene glycol (PEG) group, linear or substituted polyalkylene glycol or PEG group, or a combination thereof), or the boronic acid is a compound of formula I substituted with a boronate group of formula II: 【Chemical Formula 5】 wherein X and Y = alkyl). **Claim 11** The method of claim 10, wherein the one or more compounds comprising a boronate or boronic acid moiety are comonomers with the analyte indicator. **Claim 12** The method of claim 10, wherein the one or more compounds comprising a boronate or boronic acid moiety are comonomers with the analyte indicator in a hydrogel. **Claim 13** The method of claim 10, wherein the one or more compounds comprising a boronate or boronic acid moiety are encapsulated in a hydrogel that covers at least a portion of the sensor housing. **Claim 14** The method of claim 10, wherein the one or more compounds comprising a boronate or boronic acid moiety interact or react with degradation species without impairing the integrity or performance of the signal of the sensor device, the degradation species being hydrogen peroxide, reactive oxygen species, reactive nitrogen species, enzymes, free radicals or metal ions. **Claim 15** The compound boronate or boronic acid moiety is 【Chemical Formula 6】 selected from, the method according to any one of claims 10 to 14. **Claim 16** The analyte indicator covering at least a portion of the sensor housing comprises a polymer comprising a comonomer of four monomers according to formula III: ABCD [formula III], The method according to any one of claims 10 to 14, wherein A is an analyte indicator monomer, B is a methacrylate monomer, C is a polyethylene glycol monomer, D is a compound or monomer containing a boronate or boronic acid moiety, A is 0.01 to 10% by weight of the total polymer, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.01 to 99% by weight.

17. The method according to claim 16, wherein one or more compounds containing a boronate or boronic acid moiety are provided in a molar ratio of 0.1 to 100 relative to the analyte indicator monomer.

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