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 boronic acid-drug conjugates to reduce degradation.

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>; following documents also refer to implantable analyte sensors: <CIT>: "<NPL>, <CIT>, <CIT>, <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. As used herein, the terms "degradative species" and "biological oxidizers" generally refer to reactive physiological molecules and radicals that degrade the indicator molecules.

Hydrogen peroxide and other degradative 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 may degrade the indicator molecules by oxidizing the boronate group, thus disabling the ability of the indicator molecule to bind glucose. The longevity of certain implantable sensors is achieved in part or in whole using anti-inflammatory drugs such as dexamethasone. In conventional sensors that use anti-inflammatory drugs, there is a constant rate of drug elution for patients with both low- and elevated-levels of oxidative stress. As such, the drug is not effectively utilized, leading to a short than desired sensor lifetime.

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 for measurement of an analyte in a medium within the living animal as defined in independent claim <NUM>.

In some embodiments, the at least one boronic acid-drug conjugate may include a boronic acid-dexamethasone conjugate.

In some embodiments, the sensor may be implantable within a living animal. In some embodiments, the sensor may further include at least one drug eluting polymer matrix covering at least a portion of the sensor housing, and the boronic acid-drug conjugate may be dispersed within the drug eluting polymer matrix. In some embodiments, the drug eluting polymer matrix may have a preformed shape. In some embodiments, the preformed shape may be a ring, a sleeve, a conformal shell, a cylinder, or a monolith. In some embodiments, the drug eluting polymer matrix may be adjacent to the analyte indicator.

In some embodiments, the boronic acid-drug conjugate may be a co-monomer with the analyte indicator. In some embodiments, the boronic acid-drug conjugate may be a co-monomer with the analyte indicator in a hydrogel. In some embodiments, the boronic acid-drug conjugate may be configured to reduce oxidation of the analyte indicator. In some embodiments, the boronic acid-drug conjugate may be configured to interact or react with a degradative species without compromising signal integrity or performance of the sensor device, and the degradative species may be hydrogen peroxide, a reactive oxygen species, a reactive nitrogen species, or a free radical. In some embodiments, the drug of the boronic acid-drug conjugate may be conjugated to the boronic acid moiety via covalent bonds that are stable in the absence of a degradative species. In some embodiments, the drug of the boronic acid-drug conjugate may be conjugated to the boronic acid moiety via covalent bonds that break in the presence of a degradative species and release the drug.

In some embodiments, the drug may be an anti-inflammatory drug. In some embodiments, the anti-inflammatory drug may be a non-steroidal anti-inflammatory drug. In some embodiments, the non-steroidal anti-inflammatory drug may be acetylsalicylic acid. In some embodiments, the non-steroidal anti-inflammatory drug may be isobutylphenylpropanoic acid. In some embodiments, the drug may be a glucocorticoid. In some embodiments, the drug may be dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclometasone, fludrocortisone, a derivative thereof, an analog thereof, or a combination of two or more thereof.

In some embodiments, the analyte indicator may be a graft including indicator molecules. In some embodiments, the sensor may further include a layer of a catalyst capable of converting hydrogen peroxide into water and oxygen on at least a portion of the analyte indicator. In some embodiments, the sensor may further include a membrane covering at least a portion of the analyte indicator. In some embodiments, the membrane may be a porous, opaque diffusion membrane.

In some embodiments, the boronic acid-drug conjugate may be formed by conjugating a boronic acid compound of Formula I to the drug, Formula I may be:
<CHM>
One or more R may be independently selected from hydrogen, hydroxyl, an alkyl group, an alkenyl group, an alkynyl group, a halo group, an aldehyde group, a carboxylate group, an alkoxy group, a carboxyl group, an ester, an amide group, an imide group, a carbonyl group, an amino group, an aryl group, a heteroaryl, a cyclic group, and/or NR<NUM>R<NUM>. R and R<NUM> may be identical or different and each may represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group.

In some embodiments, the boronic acid-drug conjugate may be:
<CHM>
X may be the drug or a linking moiety connecting the boronic acid moiety to the drug, the linking moiety may be a hydroxyl, an alkyl group, an alkenyl group, an alkynyl group, an aldehyde group, a carboxylate group, an alkoxy group, a carboxyl group, an ester, an amide group, an imide group, a carbonyl group, an amino group, an aryl group, a heteroaryl, a cyclic group, and/or NR<NUM>R<NUM>. R and R<NUM> may be identical or different and each may represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group.

In some embodiments, the boronic acid-drug conjugate may be the drug conjugated with one or more of the following compounds either directly or via a linking moiety:
<CHM>
In a conjugate having the linking moiety, the linking moiety may be a hydroxyl, an alkyl group, an alkenyl group, an alkynyl group, an aldehyde group, a carboxylate group, an alkoxy group, a carboxyl group, an ester, an amide group, an imide group, a carbonyl group, an amino group, an aryl group, a heteroaryl, a cyclic group, and/or NR<NUM>R<NUM>. R and R<NUM> may be identical or different and each may represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group.

In some embodiments, the boronic acid-drug conjugate may include the drug conjugated to [<NUM>-(<NUM>-carboxymethyl)phenyl]boronic acid.

Another aspect of the present invention provides a method of fabricating a sensor for measurement of an analyte in a medium within a living animal as defined in independent claim <NUM>.

In some embodiments, the one or more boronic acid-drug conjugates may be co-monomers with the analyte indicator. In some embodiments, the one or more boronic acid-drug conjugates may be co-monomers with the analyte indicator in a hydrogel. In some embodiments, the drug may be an anti-inflammatory drug. In some embodiments, the anti-inflammatory drug may be a non-steroidal anti-inflammatory drug. In some embodiments, the non-steroidal anti-inflammatory drug may be acetylsalicylic acid. In some embodiments, the non-steroidal anti-inflammatory drug may be isobutylphenylpropanoic acid. In some embodiments, the drug may be a glucocorticoid. In some embodiments, the drug may be dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclometasone, fludrocortisone, a derivative thereof, an analog thereof, or a combination of two or more thereof.

In some embodiments, the analyte indicator may be a graft including indicator molecules. In some embodiments, the method may further include applying a layer of a catalyst capable of converting hydrogen peroxide into water and oxygen on at least a portion of the analyte indicator. In some embodiments, the method may further include covering at least a portion of the analyte indicator with a membrane. In some embodiments, the membrane may be a porous, opaque diffusion membrane.

In some embodiments, the boronic acid-drug conjugate may be formed by conjugating a boronic acid compound of Formula I to the drug, Formula I may be:
<CHM>
One or more R substituent may be independently selected from hydrogen, hydroxyl, an alkyl group, an alkenyl group, an alkynyl group, a halo group, an aldehyde group, a carboxylate group, an alkoxy group, a carboxyl group, an ester, an amide group, an imide group, a carbonyl group, an amino group, an aryl group, a heteroaryl, a cyclic group, and/or NR<NUM>R<NUM>. R and R<NUM> may be identical or different and each may represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group.

In some embodiments, the boronic acid-drug conjugate may be:
<CHM>
The X may be the drug or a linking moiety connecting the boronic acid moiety to the drug, the linking moiety may be a hydroxyl, an alkyl group, an alkenyl group, an alkynyl group, an aldehyde group, a carboxylate group, an alkoxy group, a carboxyl group, an ester, an amide group, an imide group, a carbonyl group, an amino group, an aryl group, a heteroaryl, a cyclic group, and/or NR<NUM>R<NUM>. R and R<NUM> may be identical or different and each may represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group.

In some embodiments, the drug of the boronic acid-drug conjugate may be conjugated with one or more of the following compounds either directly or via a linking moiety:
<CHM>
In a conjugate having the linking moiety, the linking moiety may be a hydroxyl, an alkyl group, an alkenyl group, an alkynyl group, an aldehyde group, a carboxylate group, an alkoxy group, a carboxyl group, an ester, an amide group, an imide group, a carbonyl group, an amino group, an aryl group, a heteroaryl, a cyclic group, and/or NR<NUM>R<NUM>. R and R<NUM> may be identical or different and each may represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group.

In some embodiments, the drug of the boronic acid-drug conjugate may be conjugated to [<NUM>-(<NUM>-carboxymethyl)phenyl]boronic acid.

In some embodiments, the drug in the boronic acid-drug conjugate may be dexamethasone.

Yet another aspect, not being part of the present invention, may provide a method for detecting the presence or concentration of an analyte in an in vivo sample. The method may include exposing the in vivo sample to a device having a detectable quality that changes when the device is exposed to an analyte of interest. The device may include a boronic acid-drug conjugate that reacts with a degradative species or biological oxidizers to release drug from the boronic acid-drug conjugate, thereby preventing or reducing degradation or interference of the device from degradative species or biological oxidizers. The device may be the any of the sensors described above. The method may include measuring a change in the detectable quality to thereby detect the presence or concentration of the analyte of interest in the in vivo sample.

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 embodiment, 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 be 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.

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 degradative 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 and/or fluoresce). In some embodiments, degradative species may include one or more of hydrogen peroxide, a reactive oxygen species, a reactive nitrogen species, and a free radical.

In some embodiments, the sensor <NUM> may include one or more boronic acid-drug conjugates that interact or react with one or more degradative species without compromising signal integrity or performance of the sensor device. In some non-limiting embodiments, the one or more boronic acid-drug conjugates may be conjugates of phenylboronic acid compounds with drugs that interact with degradative species without compromising signal integrity or performance of the sensor. In some non-limiting embodiments, the parent drug used to form one or more of the boronic acid-drug conjugates may be dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclometasone, fludrocortisone, derivatives thereof, and analogs thereof, a glucocorticoid, or an anti-inflammatory drug (e.g., a non-steroidal anti-inflammatory drug including but not limited to acetylsalicylic acid, isobutylphenylpropanoic acid).

In some embodiments, the parent drug may be modified with aryl boronic acid moiety which undergoes oxidation by consuming the ROS (acting as a sacrificial boronic acid). Oxidation may rearrange the phenol, which may release the parent drug, lead to the drug action, and lead to a longer sensor life. In some embodiments, a boronic acid-drug conjugate may provide a unique release profile of the parent drug, and the amount of the parent drug released may be proportional to the extent of oxidation. In some embodiments, the boronic acid-drug conjugate may be configured such that an oxidative burst causes release of the drug from the conjugate. Thus, unlike conventional sensors having a constant rate of drug elution, the boronic acid-drug conjugate may release the drug when it is needed and in proportion to the oxidative conditions surrounding the sensor <NUM>. Accordingly, the boronic acid-drug conjugate may advantageously extend the lifetime of implantable sensors.

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) may include a sensor housing <NUM> and an analyte indicator <NUM>. In some embodiments, the analyte indicator may include one or more indicator molecules <NUM>, which may be distributed throughout the analyte indicator <NUM>. In some embodiments, the indicator molecules <NUM> may be configured to reversibly bind the analyte. In some embodiments, the analyte indicator <NUM> may cover at least a portion of the sensor housing <NUM>. In some embodiments, the sensor <NUM> may include a light source <NUM> (e.g., within the sensor housing <NUM>) configured to emit excitation light <NUM>. In some embodiments, the indicator molecules <NUM> may configured to be irradiated by the excitation light <NUM> and emit light <NUM> indicative of the amount of the analyte in the medium within the living animal. In some embodiments, the sensor <NUM> may include a photodetector <NUM> (e.g., 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.

In some embodiments, the sensor <NUM> may include one or more boronic acid-drug conjugates. In some embodiments the one or more boronic acid-drug conjugates may be configured to interact with degradative species. In some embodiments, the one or more boronic acid-drug conjugates may protect indicator molecules <NUM> of the analyte indicator <NUM> by preventing or reducing degradation or interference caused by degradative species or biological oxidizers. In some embodiments, the one or more boronic acid-drug conjugates may protect the indicator molecules <NUM> without compromising signal integrity or performance of the sensor <NUM>.

In some embodiments, the sensor <NUM> may include at least one drug eluting polymer matrix and/or a layer of catalyst that may be provided on, incorporated in, or dispersed within the analyte indicator or sensor housing as described in <CIT>. In some embodiments, one or more boronic acid-drug conjugates 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 boronic acid-drug conjugates may be incorporated within the membrane. In some embodiments, the sensor <NUM> may include a drug-eluting layer covering at least a portion of the analyte indicator <NUM>, wherein the drug-eluting layer includes one or more boronic acid-drug conjugates. In some embodiments, the drug of the boronic acid-drug conjugate may be one or more of dexamethasone, triamcinolone, betamethasone, methylprednisolone, beclometasone, fludrocortisone, derivatives thereof, and analogs thereof, a glucocorticoid, and an anti-inflammatory drug (e.g., a non-steroidal anti-inflammatory drug including but not limited to acetylsalicylic acid, isobutylphenylpropanoic acid).

In some embodiments, the at least one drug eluting layer may include a membrane, mesh, nylon, fabric, polymer material, sponge, or other pore-containing material. In some embodiments, one or more boronic acid-drug conjugates may be incorporated into the analyte indicator <NUM> that may cover at least a portion of the sensor housing <NUM>. In some embodiments, the boronic acid-drug conjugate is a co-monomer with the analyte indicator, for example in a hydrogel.

In some embodiments, one or more boronic acid-drug conjugates may additionally or alternatively be in a drug eluting polymer matrix, which may be as described in <CIT>). In some embodiments, the drug eluting polymer matrix may cover a portion of the sensor housing <NUM>. In some non-limiting embodiments, the drug-eluting polymer matrix may be applied to the sensor housing <NUM> via dip coating. In some non-limiting embodiments, as an alternative to dip coating, the drug-eluting polymer matrix may be applied to the sensor housing <NUM> via spray coating. In some non-limiting embodiments, as an alternative to a dip or spray coated drug-eluting polymer matrix, the drug-eluting polymer matrix may have a pre-formed shape such as, for example, a ring or sleeve. Other pre-formed shapes are possible, such as, for example and without limitation, a shell (e.g., conformal shell), cylinder, or any suitable monolith (e.g. rectangular).

One or more types of boronic acid-drug conjugates may be dispersed within the drug eluting polymer matrix (e.g., an inert polymer matrix). In some embodiments, the one or more the boronic acid-drug conjugates may reduce or stop the migration of neutrophils from entering the insertion site and, thus, reduce or stop the production of hydrogen peroxide and fibrotic encapsulation. In some embodiments, the one or more boronic acid-drug conjugates may be provided in the analyte indicator <NUM> (e.g., polymer graft). In some embodiments, the one or more boronic acid-drug conjugates may interact and/or react with degradative species. In some embodiments, the one or more boronic acid-drug conjugates may neutralize the degradative species. In some embodiments, the one or more boronic acid-drug conjugates may bind to the degradative species. In some embodiments, the one or more boronic acid-drug conjugates 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 boronic acid-drug conjugates reduce deterioration of the analyte indicator <NUM>.

In some non-limiting embodiments, one or more of the boronic acid compounds used in forming the boronic acid-drug conjugates may be a compound of Formula I:
<CHM>.

In some embodiments, one or more R groups attached to the phenyl ring may be independently selected from hydrogen, hydroxyl, an alkyl group, an alkenyl group, an alkynyl group, a halo group, an aldehyde group, a carboxylate group, an alkoxy group, a carboxyl group, an ester, an amide group, an imide group, a carbonyl group, an amino group, an aryl group, a heteroaryl, a cyclic group, and/or NR<NUM>R<NUM>. In some embodiments, R<NUM> and R<NUM> may be identical or different and each may represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group.

In some non-limiting examples, the one or more boronic acid compounds may include the following compound:
<CHM>
wherein X is the parent drug or a linking moiety connected to the parent drug. In some non-limiting embodiments, the linking moiety may be selected from a hydroxyl, an alkyl group, an alkenyl group, an alkynyl group, an aldehyde group, a carboxylate group, an alkoxy group, a carboxyl group, an ester, an amide group, an imide group, a carbonyl group, an amino group, an aryl group, a heteroaryl, a cyclic group, and/or NR<NUM>R<NUM>.

In some non-limiting examples, the parent drug may be conjugated with one or more of the following compounds either directly or via a linking moiety, e.g., as defined above:
<CHM>.

A sensor having one or more boronic acid-drug conjugates may have improved performance over a sensor that does not include a boronic acid-drug conjugate-containing analyte indicator. For instance, in some non-limiting embodiments, the boronic acid-drug conjugate may improve the longevity and functionality of the sensor <NUM>.

Illustrated below is a reaction scheme showing the parent drug ("Target") sequestered when it is conjugated with a boronic acid moiety. The presence of a reactive species in the environment of the sensor, e.g., hydrogen peroxide after an oxidative burst, causes a series of reactions resulting in consumption of the reactive species by the boronic acid moiety, followed by release of the parent drug leading to the drug action which would increase the lifetime of the sensor.

Compound A was synthesized by conjugating dexamethasone with a [<NUM>-(<NUM>-carboxymethyl)phenyl]boronic acid. The stability of the conjugate was tested in phosphate buffered saline (PBS)/H<NUM>O, and no release of the dexamethasone was observed. When compound A was subjected to a known amount of hydrogen peroxide, release of dexamethasone was observed as confirmed by thin layer chromatography (TLC) analysis as shown in <FIG>. Illustrated below is the reaction scheme showing dexamethasone sequestered when it is conjugated with a boronic acid moiety in form of Compound A. Upon addition of hydrogen peroxide, the boronic acid reacts with the hydrogen peroxide and releases the dexamethasone.

A sensor including a sensor housing, a hydrogel on at least a portion of the sensor housing, indicator molecules contained in the hydrogel, and Pt sputtered on at least a portion of the hydrogel has a useful life of about <NUM> days if implanted in a human patient. The sensor is further protected by a boronic acid-drug conjugate covering at least a portion of the surface of the hydrogel and the further protected sensor has a useful life of at least <NUM> days when implanted in a human patient.

Claim 1:
A sensor (<NUM>) for measurement of an analyte in a medium within a living animal, the sensor comprising:
a sensor housing (<NUM>);
an analyte indicator (<NUM>) covering at least a portion of the sensor housing, wherein the analyte indicator includes molecules configured to reversibly bind the analyte; and
a boronic acid-drug conjugate comprising a drug configured to reduce deterioration of the analyte indicator caused by degradative species, conjugated to a boronic acid moiety incorporated in and/or in close proximity to the analyte indicator, wherein the boronic acid-drug conjugate is configured to release the drug in the presence of the degradative species.