Patent Description:
The present invention relates generally to continuous reduction of in vivo degradation of analyte sensor moieties when measuring an analyte in a medium of a living animal using a system including a sensor implanted (partially or fully) or inserted into the living animal. Specifically, the present invention relates to a sensor that utilizes one or more additives, which may be incorporated within an analyte indicator, and/or a material covering at least a portion of the analyte indicator.

A sensor may be implanted (partially or fully) within 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 may include a light source (e.g., a light-emitting diode (LED) or other light emitting element), indicator molecules, and a photodetector (e.g., a photodiode, phototransistor, photoresistor or other photosensitive element). Examples of implantable sensors employing indicator molecules to measure an analyte are described in <CIT> and <CIT>.

A sensor may include an analyte indicator, which may be in the form of indicator molecules embedded in a graft (i.e., layer or matrix). For example, in an implantable fluorescence-based glucose sensor, fluorescent indicator molecules may reversibly bind glucose and, when irradiated with excitation light (e.g., light having a wavelength of approximately <NUM>), emit an amount of light (e.g., light in the range of <NUM> to <NUM>) that depends on whether glucose is bound to the indicator molecule.

If a sensor is implanted in the body of a living animal, the animal's immune system may begin to attack the sensor. For instance, if a sensor is implanted in a human, white blood cells may attack the sensor as a foreign body, and, in the initial immune system onslaught, neutrophils may be the primary white blood cells attacking the sensor. The defense mechanism of neutrophils includes the release of highly caustic substances known as reactive oxygen species. The reactive oxygen species include, for example, hydrogen peroxide and superoxide.

Hydrogen peroxide and other reactive species such as reactive oxygen and nitrogen species may degrade the indicator molecules of an analyte indicator. For instance, in indicator molecules having a boronate group, hydrogen peroxide and other reactive species may degrade the indicator molecules by oxidizing the boronate group, thus disabling the ability of the indicator molecule to bind glucose.

Document <CIT> discloses an implantable sensor according to the preamble of claim <NUM> and a method of fabricating a sensor for measurement of an analyte in a medium within a living animal according to the preamble of claim <NUM>.

There is presently a need in the art for improvements in reducing analyte indicator degradation. There is also a need in the art for continuous analyte sensors having increased longevity.

The present invention overcomes the disadvantages of prior systems by providing, among other advantages, reduced analyte indicator degradation.

One aspect of the present invention provides a sensor according to claim <NUM>.

In some embodiments, the sensor may include at least one additive-containing polymer graft, and the one or more additives may be co-polymerized 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 within the sensor housing.

In some embodiments, the one or more additives may be incorporated with the analyte indicator, e.g., as a co-monomer. In some embodiments, the sensor may include a material, e.g., a membrane, covering at least a portion of the analyte indicator, and the one or more additives are incorporated within the material.

Further variations encompassed within the systems and methods are described in the detailed description of the invention below.

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

<FIG> is a schematic view of a sensor system embodying aspects of the present invention. In some non-limiting embodiments, as shown in <FIG>, the system may include a sensor <NUM> and an external transceiver <NUM>. In some embodiments, the sensor <NUM> may be an implantable sensor configured to be fully or partially implanted in a living animal (e.g., a living human). The sensor <NUM> may be implanted, for example, in a living animal's arm, wrist, leg, abdomen, peritoneum, or other region of the living animal suitable for sensor implantation. For example, in some non-limiting embodiments, the sensor <NUM> may be implanted beneath the skin (i.e., in the subcutaneous or peritoneal tissues). However, this is not required, and, in some alternative embodiments, the sensor <NUM> may be a transcutaneous sensor.

In some embodiments, a transceiver <NUM> may be an electronic device that communicates with the sensor <NUM> to power the sensor <NUM>, provide commands and/or data to the sensor <NUM>, and/or receive data from the sensor <NUM>. In some embodiments, the received data may include one or more sensor measurements. In some embodiments, the sensor measurements may include, for example and without limitation, one or more light measurements from one or more photodetectors of the sensor <NUM> and/or one or more temperature measurements from one or more temperature sensors of the sensor <NUM>. In some embodiments, the transceiver <NUM> may calculate analyte (e.g., glucose) concentrations from the measurement information received from the sensor <NUM>.

In some non-limiting embodiments, the transceiver <NUM> may be a handheld device or an on-body/wearable device. For example, in some embodiments where the transceiver <NUM> is an on-body/wearable device, the transceiver <NUM> may be held in place by a band (e.g., an armband or wristband) and/or adhesive, and the transceiver <NUM> may convey (e.g., periodically, such as every two minutes, and/or upon user initiation) measurement commands (i.e., requests for measurement information) to the sensor <NUM>. In some embodiments where the transceiver <NUM> is a handheld device, positioning (i.e., hovering or swiping/waving/passing) the transceiver <NUM> within range over the sensor implant site (i.e., within proximity of the sensor <NUM>) may cause the transceiver <NUM> to automatically convey a measurement command to the sensor <NUM> and receive a data from the sensor <NUM>.

In some embodiments, as shown in <FIG>, the transceiver <NUM> may include an inductive element <NUM>, such as, for example, a coil. In some embodiments, the transceiver <NUM> may generate an electromagnetic wave or electrodynamic field (e.g., by using a coil) to induce a current in an inductive element <NUM> of the sensor <NUM>. In some non-limiting embodiments, the sensor <NUM> may use the current induced in the inductive element <NUM> to power the sensor <NUM>. However, this is not required, and, in some alternative embodiments, the sensor <NUM> may be powered by an internal power source (e.g., a battery).

In some embodiments, the transceiver <NUM> may convey data (e.g., commands) to the sensor <NUM>. For example, in some non-limiting embodiments, the transceiver <NUM> may convey data by modulating the electromagnetic wave generated by the inductive element <NUM> (e.g., by modulating the current flowing through the inductive element <NUM> of the transceiver <NUM>). In some embodiments, the sensor <NUM> may detect/extract the modulation in the electromagnetic wave generated by the transceiver <NUM>. Moreover, the transceiver <NUM> may receive data (e.g., one or more sensor measurements) from the sensor <NUM>. For example, in some non-limiting embodiments, the transceiver <NUM> may receive data by detecting modulations in the electromagnetic wave generated by the sensor <NUM>, e.g., by detecting modulations in the current flowing through the inductive element <NUM> of the transceiver <NUM>.

In some embodiments, as shown in <FIG>, the sensor <NUM> may include a sensor housing <NUM> (i.e., body, shell, capsule, or encasement), which may be rigid and biocompatible. In exemplary embodiments, sensor housing <NUM> may be formed from a suitable, optically transmissive polymer material, such as, for example, acrylic polymers (e.g., polymethylmethacrylate (PMMA)).

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

In some embodiments, the analyte indicator <NUM> (e.g., polymer graft) of the sensor <NUM> may include indicator molecules <NUM>. The indicator molecules <NUM> may be distributed throughout the entire analyte indicator <NUM> or only throughout one or more portions of the analyte indicator <NUM>. The indicator molecules <NUM> may be fluorescent indicator molecules (e.g., TFM having the chemical name <NUM>-[N-[<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>,-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolano)-<NUM>-(trifluoromethyl)benzyl]-N-[<NUM>-(methacrylamido)propylamino]methyl]-<NUM>-[N-[<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>,-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolano)-<NUM>-(trifluoromethyl)benzyl]-N-[<NUM>-(carboxyethyl)amino]methyl]anthracene sodium salt) or light absorbing, non-fluorescent indicator molecules. In some embodiments, the indicator molecules <NUM> may reversibly bind an analyte (e.g., glucose, oxygen, cardiac markers, low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides). When an indicator molecule <NUM> has bound an analyte, the indicator molecule may become fluorescent, in which case the indicator molecule <NUM> is capable of absorbing (or being excited by) excitation light <NUM> and emitting light <NUM>. In one non-limiting embodiment, the excitation light <NUM> may have a wavelength of approximately <NUM>, and the emission light <NUM> may have a wavelength in the range of <NUM> to <NUM>. When no analyte is bound, the indicator molecule <NUM> may be only weakly fluorescent.

In some embodiments, the sensor <NUM> may include a light source <NUM>, which may be, for example, a light emitting diode (LED) or other light source that emits radiation, including radiation over a range of wavelengths that interact with the indicator molecules <NUM>. In other words, the light source <NUM> may emit the excitation light <NUM> that is absorbed by the indicator molecules in the matrix layer/polymer <NUM>. As noted above, in one non-limiting embodiment, the light source <NUM> may emit excitation light <NUM> at a wavelength of approximately <NUM>.

In some embodiments, the sensor <NUM> may also include one or more photodetectors (e.g., photodiodes, phototransistors, photoresistors or other photosensitive elements). For example, in the embodiment illustrated in <FIG>, sensor <NUM> has a first photodetector <NUM> and a second photodetector <NUM>. However, this is not required, and, in some alternative embodiments, the sensor <NUM> may only include the first photodetector <NUM>. In the case of a fluorescence-based sensor, the one or more photodetectors may be sensitive to fluorescent light emitted by the indicator molecules <NUM> such that a signal is generated by a photodetector (e.g., photodetector <NUM>) in response thereto that is indicative of the level of fluorescence of the indicator molecules and, thus, the amount of analyte of interest (e.g., glucose).

Some part of the excitation light <NUM> emitted by the light source <NUM> may be reflected from the analyte indicator <NUM> back into the sensor <NUM> as reflection light <NUM>, and some part of the absorbed excitation light may be emitted as emitted (fluoresced) light <NUM>. In one non-limiting embodiment, the emitted light <NUM> may have a different wavelength than the wavelength of the excitation light <NUM>. The reflected light <NUM> and emitted (fluoresced) light <NUM> may be absorbed by the one or more photodetectors (e.g., first and second photodetectors <NUM> and <NUM>) within the body of the sensor <NUM>.

Each of the one or more photodetectors may be covered by a filter <NUM> (see <FIG>) that allows only a certain subset of wavelengths of light to pass through. In some embodiments, the one or more filters <NUM> may be thin glass filters. In some embodiments, the one or more filters <NUM> may be thin film (e.g., dichroic) filters deposited on the glass and may pass only a narrow band of wavelengths and otherwise reflect most of the received light. In some embodiments, the filters may be thin film (dichroic) filters deposited directly onto the photo detectors and may pass only a narrow band of wavelengths and otherwise reflect most of the light received thereby. The filters <NUM> may be identical (e.g., both filters <NUM> may allow signals to pass) or different (e.g., one filter <NUM> may be a reference filter and another filter <NUM> may be a signal filter).

In one non-limiting embodiment, the second (reference) photodetector <NUM> may be covered by a reference photodiode filter that passes light at the same wavelength as is emitted from the light source <NUM> (e.g., <NUM>). The first (signal) photodetector <NUM> may detect the amount of fluoresced light <NUM> that is emitted from the molecules <NUM> in the analyte indicator <NUM>. In one non-limiting embodiment, the peak emission of the indicator molecules <NUM> may occur around <NUM>, and the first photodetector <NUM> may be covered by a signal filter that passes light in the range of about <NUM> to <NUM>. In some embodiments, higher glucose levels/concentrations correspond to a greater amount of fluorescence of the molecules <NUM> in the analyte indicator <NUM>, and, therefore, a greater number of photons striking the first photodetector <NUM>.

In some embodiments, as shown in <FIG>, the sensor <NUM> may include a substrate <NUM>. In some embodiments, the substrate <NUM> may be a circuit board (e.g., a printed circuit board (PCB) or 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 <NUM> may be a semiconductor substrate having circuitry fabricated therein. The circuitry may include analog and/or digital circuitry. Also, in some semiconductor substrate embodiments, in addition to the circuitry fabricated in the semiconductor substrate, circuitry may be mounted or otherwise attached to the semiconductor substrate <NUM>. In other words, in some semiconductor substrate embodiments, a portion or all of the circuitry, which may include discrete circuit elements, an integrated circuit (e.g., an application specific integrated circuit (ASIC)) and/or other electronic components, may be fabricated in the semiconductor substrate <NUM> with the remainder of the circuitry is secured to the semiconductor substrate <NUM>, which may provide communication paths between the various secured components.

In some embodiments, the one or more of the sensor housing <NUM>, analyte indicator <NUM>, indicator molecules <NUM>, light source <NUM>, photodetectors <NUM>, <NUM>, temperature transducer <NUM>, substrate <NUM>, and inductive element <NUM> of sensor <NUM> may include some or all of the features described in one or more of <CIT>, <CIT>, and <CIT>. Similarly, the structure and/or function of the sensor <NUM> and/or transceiver <NUM> may be as described in one or more of <CIT>, <CIT>, and <CIT>.

In some embodiments, the sensor <NUM> may include a transceiver interface device, and the transceiver <NUM> may include a sensor interface device. In some embodiments where the sensor <NUM> and transceiver <NUM> include an antenna or antennas (e.g., inductive elements <NUM> and <NUM>), the transceiver interface device may include the inductive element <NUM> of the sensor <NUM>, and the sensor interface device may include the inductive element <NUM> of the transceiver <NUM>. In some of the transcutaneous embodiments where there exists a wired connection between the sensor <NUM> and the transceiver <NUM>, the transceiver interface device and sensor interface device may include the wired connection.

<FIG> and <FIG> illustrate a non-limiting embodiment of a sensor <NUM> embodying aspects of the present invention that may be used in the sensor system illustrated in <FIG>. <FIG> and <FIG> illustrate perspective and exploded views, respectively, of the non-limiting embodiment of the sensor <NUM>.

In some embodiments, as illustrated in <FIG>, the sensor housing <NUM> may include an end cap <NUM>. In some embodiments, the sensor <NUM> may include one or more capacitors <NUM>. The one or more capacitors <NUM> may be, for example, one or more tuning capacitors and/or one or more regulation capacitors. The one or more capacitors <NUM> may be too large for fabrication in the semiconductor substrate <NUM> to be practical. Further, the one or more capacitors <NUM> may be in addition to one or more capacitors fabricated in the semiconductor substrate <NUM>.

In some embodiments, as illustrated in <FIG>, the sensor <NUM> may include a reflector <NUM> (i.e., mirror). Reflector <NUM> may be attached to the semiconductor substrate <NUM> at an end thereof. In a non-limiting embodiment, reflector <NUM> may be attached to the semiconductor substrate <NUM> so that a face portion <NUM> of reflector <NUM> is generally perpendicular to a top side of the semiconductor substrate <NUM> (i.e., the side of semiconductor substrate <NUM> on or in which the light source <NUM> and one or more photodetectors <NUM> are mounted or fabricated) and faces the light source <NUM>. The face <NUM> of the reflector <NUM> may reflect radiation emitted by light source <NUM>. In other words, the reflector <NUM> may block radiation emitted by light source <NUM> from exiting the axial end of the sensor <NUM>.

According to one aspect of the invention, an application for which the sensor <NUM> was developed (although by no means the only application for which it is suitable) is measuring various biological analytes in the living body of an animal (including a human). For example, sensor <NUM> may be used to measure glucose, oxygen, toxins, pharmaceuticals or other drugs, hormones, and other metabolic analytes in, for example, the human body.

In some embodiments, the specific composition of the analyte indicator <NUM> and the indicator molecules <NUM> may vary depending on the particular analyte the sensor is to be used to detect and/or where the sensor is to be used to detect the analyte (e.g., in the in subcutaneous tissues, blood, or peritoneum). In some embodiments, the analyte indicator <NUM> facilitates exposure of the indicator molecules <NUM> to the analyte. In some embodiments, the indicator molecules <NUM> may exhibit a characteristic (e.g., emit an amount of fluorescence light) that is a function of the concentration of the specific analyte to which the indicator molecules <NUM> are exposed.

In some embodiments, the sensor <NUM> 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 on, adjacent to, incorporated in, or dispersed within the analyte indicator or sensor housing as described in <CIT> ). In some embodiments, the one or more therapeutic agents may be incorporated in the analyte indicator <NUM>. In some embodiments, the sensor <NUM> may include a membrane covering at least a portion of the analyte indicator <NUM>, and the 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, beclometasone, fludrocortisone, derivatives thereof, and analogs thereof, a glucocorticoid, an anti-inflammatory drug, e.g., a non-steroidal anti-inflammatory drug including but not limited to acetylsalicylic acid, isobutylphenylpropanoic acid.

<FIG> is a schematic view of a sensor <NUM> embodying aspects of the present invention. In some non-limiting aspects, as shown in <FIG>, the sensor <NUM> may include a drug eluting region <NUM> covering at least a portion of the sensor housing <NUM>. In some non-limiting aspects, as shown in <FIG>, the sensor <NUM> may include an analyte indicator <NUM>, and the analyte indicator <NUM> may include a hydrogel entrapping an additive of the present disclosure. In some non-limiting aspects, as shown in <FIG>, the sensor <NUM> may include sensor electronic components, which may include any of the electronic components described in the present disclosure, including in <FIG> and <FIG> (e.g., the light source <NUM>, the one or more photodetectors <NUM>, the inductive element <NUM>, and/or the one or more capacitors <NUM>), as well as those described in one or more of<CIT>, <CIT>, and <CIT>. In some non-limiting aspects, as shown in <FIG>, the sensor <NUM> may include a metal coating <NUM> covering at least a portion of the sensor housing <NUM>. In some non-limiting aspects, the metal coating <NUM> may include one or more metals selected from Cu, W, Pt, Fe, Mo, Co, oxides, alloys, and complexes thereof. In some non-limiting aspects, the metal coating <NUM> may be coated on the hydrogel entrapping an additive of the present disclosure.

The implantation or insertion of a medical device, such as a bio-sensor, into a user/patient's body can cause the body to exhibit adverse physiological reactions that are detrimental to the functioning of the device. The reactions may range from infections due to implantation surgery to the immunological response of a foreign object implanted in the body. That is, the performance of the implantable bio-sensor can be hindered or permanently damaged in vivo via the immunological response to an infection or the device itself. In particular, the performance of the analyte indicator <NUM> may be deteriorated by the immunological response of the body into which the sensor <NUM> is implanted. For example, as explained above, white blood cells, including neutrophils, may attack an implanted sensor <NUM>. The neutrophils release reactive species including, inter alia, hydrogen peroxide, which may degrade indicator molecules <NUM> (e.g., by oxidizing a boronate group of an indicator molecule <NUM> and disabling the ability of the indicator molecule <NUM> to bind glucose).

In some embodiments, the analyte indicator <NUM> may include one or more additives that interact or react with one or more degradative species without compromising signal integrity or performance of the sensor device. In some embodiments, the one or more additives may be incorporated into the analyte indicator <NUM> that may cover at least a portion of the sensor housing <NUM>. The one or more degradative species may include one or more of hydrogen peroxide, a reactive oxygen species, a reactive nitrogen species, a free radical, enzymes, and a metal ion. In some aspects, the degradative species may include superoxide, hydrogen peroxide, hypochlorite, peroxynitrite, or a combination thereof. In some embodiments, the additive may be copolymerized with the indicator molecule <NUM>. In some embodiments, the one or more additives may be provided in the analyte indicator <NUM> (e.g., polymer graft). In some embodiments, the one or more additives may interact and/or react with degradative species. In some embodiments, the one or more additives may neutralize the degradative species. In some embodiments, the one or more additives may bind to the degradative species. In some embodiments, the one or more additives may sequester the degradative species so as to inhibit, reduce, and/or prevent degradation of the analyte indicator by the degradative species. Accordingly, in some embodiments, the one or more additives reduce degradation of the analyte indicator <NUM>.

According to the invention, the one or more additives are one or more of the following compounds:
<CHM>
wherein in the compound of Formula I, X is a halide, each R3, R4, R5, and R6 is independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxy, aryl, alkoxy, halide, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylamido, aroylamido, heterocyclocarbonylamido, heteroaroylamido, alkanoyl(alkylsubstituted) amido, aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido, and heterocyclocarbonyl(alkyl substituted)amido, and formula I may be optionally substituted with C1-<NUM> alkyl, alkoxy, cyano, halo and/or trifluoromethyl at any position. <CHM>
<CHM>
wherein in the compound of Formula III, X is O, N, S, and each of R and R<NUM> is independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxy, aryl, alkoxy, halide, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylamido, aroylamido, heterocyclocarbonylamido, heteroaroylamido, alkanoyl(alkylsubstituted) amido, aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido, and heterocyclocarbonyl(alkyl substituted)amido, and formula I may be optionally substituted with C1-<NUM> alkyl, alkoxy, cyano, halo and/or trifluoromethyl at any position. In some embodiments, each of R and R1 is independently absent, or a bond or linker for polymerizing the compound of Formula III to a polymer backbone.

In some non-limiting embodiments, a sensor <NUM> for measurement of an analyte (e.g., glucose) in a medium (e.g., interstitial fluid) within a living animal (e.g., a human) contains one or more of the following components: a sensor housing <NUM>; a light source <NUM> within the sensor housing <NUM> configured to emit excitation light <NUM>; an analyte indicator <NUM> covering a portion of the sensor housing <NUM>, one or more indicator molecules <NUM> that are part of the analyte indicator <NUM>, reversibly bind the analyte, are positioned to be irradiated by the excitation light, and are configured to emit light <NUM> indicative of the amount of the analyte in the medium within the living animal; a photodetector <NUM> within the sensor housing <NUM> that is sensitive to light <NUM> emitted by the one or more indicator molecules <NUM> and configured to generate a signal indicative of the amount of the analyte in the medium within the living animal; and one of more compounds of Formulae I-III to interact with degradative species without compromising signal integrity or performance of the sensor <NUM>. In some non-limiting embodiments, the sensor <NUM> may include a drug eluting region <NUM>, e.g., a drug eluting matrix, collar, and/or a layer of catalyst provided on, adjacent to, or incorporated in the analyte indicator <NUM>.

Acoording to the Invention, the one or more compounds of Formulae I-III are provided in the analyte indicator <NUM> (e.g., hydrogel) of the analyte sensor <NUM>. In some non-limiting embodiments, one or more compounds of Formulae I-III may be incorporated into the analyte indicator <NUM> by polymerizing the one or more compounds of Formulae I-III as a co-monomer with indicator monomer and one or more acrylate monomers. In some non-limiting embodiments, one or more compounds of Formulae I-III may be provided as co-monomers of four monomers according to Formula V:.

In some non-limiting embodiments, the analyte indicator <NUM> may contain four monomers: (i) the TFM fluorescent indicator, (ii) hydroxyethylmethacrylate (HEMA), which is a methacrylate, (iii) polyethylene glycol (PEG), and (iv) a compound of Formula I or a compound of Formula III. In some embodiments, the PEG may be polyethylene glycol methacrylate (PEG-methacrylate) or polyethylene glycol diacrylate (PEG-diacrylate or PEGDA), and the one or more compounds of Formulae I-IV may be a compound of Formula I or a compound of Formula III. In some embodiments, the four monomers may be in specific molar ratios. For example, in some non-limiting embodiments in which the analyte indicator <NUM> is opaque, the analyte indicator <NUM> may comprise <NUM> to <NUM> molar percent, HEMA may comprise <NUM> to <NUM> molar percent, PEGDA may comprise <NUM> to <NUM> molar percent, and the compound of Formula I or a compound of Formula III may comprise <NUM> to <NUM> molar percent. With this formulation, the combined (i.e., total) monomers may, in one example, be <NUM>% by volume of the polymerization solution used for the polymerization reaction with the remainder of the polymerization solution being water (i.e., the polymerization solution may be <NUM>% water by volume). For another example, in one non-limiting embodiment, the analyte indicator <NUM> may be made using a polymer solution that is <NUM>% water by volume and <NUM>% monomers by volume.

In some embodiments, the relative molar percent of the compound of Formulae I-III may be within a specific range. In some embodiments, the relative molar percent of the compound of one or more of Formulae I-III ranges between <NUM> and <NUM> molar percent. If the relative molar percent of the compound of one or more of Formulae I-III is greater than this range, the hydrogel is not formed. If the relative molar percent of the compound of one or more of Formulae I-III is lower than this range, the unexpected longevity and functionality-boosting effects described in this disclosure may not obtained.

In some embodiments, the PEGDA may act as a cross-linker and create a sponge-like matrix/hydrogd. In some non-limiting embodiments, the PEG-containing graft/hydrogd may become clear if a sufficient amount of additional PEG is added to the mixture (i.e., if it is fabricated with a higher concentration of PEG), and a clear analyte indicator <NUM> may be made from such a formulation. For example, in one non-limiting embodiment, the polymer graft <NUM> may be made using a polymer solution that is <NUM>-<NUM>% water by volume and <NUM>-<NUM>% monomers by volume, where the TFM fluorescent indicator, HEMA, PEG-methacrylate, and one or more compounds of Formulae I-III may comprise <NUM> to <NUM> %, <NUM> to <NUM> %, <NUM> to <NUM> %, and <NUM> to <NUM>% by weight, of the monomers in the solution. In some embodiments, the polymer graft may be synthesized using conventional free radical polymerization.

In some instances, the amount of the one or more compounds of Formulae I-III incorporated into the analyte indicator is in the range of about <NUM> to about <NUM>.

In some instances, sensors loaded with one or more compounds of Formulae I-III reduce oxidation of analyte indicator molecules by degradative species including superoxide, hydrogen peroxide, hypochlorite, and peroxynitrite. In some instances, loading sensors with low loadings, e.g., less than <NUM> or less than <NUM> of a compound of Formulae I-III is effective to significantly reduce oxidation of analyte indicator molecules by degradative species including superoxide, hydrogen peroxide, hypochlorite, and peroxynitrite. Analyte indicator loaded.

An implanted sensor including an additive-containing analyte indicator may have improved performance over a sensor that does not include an additive-containing analyte indicator. For instance, in some non-limiting embodiments, the additive improves the longevity and functionality of the sensor <NUM>.

An in vivo study was performed in female guinea pigs in which mock sensors with variable amounts (<NUM>- <NUM>) of the tested compounds were entrapped and implanted to assess protection of the indicator signal over time. Manganese porphyrin and N-acetyl-l-cysteine are not part of the invention and were found to have a detrimental effect on indictor signal over time. Implantation was executed subcutaneously in the back of each guinea pig (<NUM> samples per guinea pig) with the Senseonics insertion tool kit according to manufacturer's instructions. These mock sensors were sterilized before implantation. The samples were then explanted after <NUM> days from the Guinea pigs and were washed and disinfected using Enzol enzymatic detergent and glutaraldehyde solution. The explanted samples were then analyzed by fluorimetry to evaluate fluorescence intensity changes and then rank ordered with respect to the % modulation loss to bare indicator hydrogel as controls as shown in <FIG>.

Claim 1:
A sensor (<NUM>) for measurement of an analyte in a medium within a living animal, the sensor comprising:
an analyte indicator (<NUM>); and
one or more compounds that reduce degradation of the analyte indicator, characterized in that, the one or more compounds are selected from one or more of Formulae I-III:
<CHM>
wherein in the compound of Formula I, X is a halide, each R3, R4, R5, and R6 is independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxy, aryl, alkoxy, halide, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylamido, aroylamido, heterocyclocarbonylamido, heteroaroylamido, alkanoyl(alkylsubstituted) amido, aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido, and heterocyclocarbonyl(alkyl substituted)amido, and wherein formula I may be optionally substituted with Cl-<NUM> alkyl, alkoxy, cyano, halo and/or trifluoromethyl at any position;
<CHM>
and
<CHM>
wherein in the compound of Formula III, X is O, N, S, and each of R and R<NUM> is independently selected from H, C1-C20 alkyl, C1-C20 alkoxy, carboxy, aryl, alkoxy, halide, SH, aryloxy, alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylamido, aroylamido, heterocyclocarbonylamido, heteroaroylamido, alkanoyl(alkylsubstituted) amido, aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido, and heterocyclocarbonyl(alkyl substituted)amido, and formula I may be optionally substituted with Cl-<NUM> alkyl, alkoxy, cyano, halo and/or trifluoromethyl at any position, or wherein each of R and R1 is independently absent, or a bond or linker for polymerizing the compound of Formula III to a polymer backbone.