Patent Description:
The present invention relates generally to catalytic protection of materials from in vivo degradation 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 multiple metals, which may be collectively or independently incorporated within an analyte indicator, formed on one or more surfaces of an analyte indicator, and/or stacked on at least a portion of a surface of the analyte indicator (e.g., one metal layer on top of another metal layer).

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>, and patent publications <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.

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 may degrade the indicator molecules by oxidizing the boronate group, thus disabling the ability of the indicator molecule to bind glucose.

There is presently a need in the art for improvements in protecting analyte indicator from 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.

In one aspect, the present disclosure may provide a device having a partially or fully implantable device which has in vivo functionality, as well as a protective material in close proximity to the surface of the implantable device. The protective material may prevent or reduce degradation or interference of the implantable device due to inflammation reactions and/or foreign body response. Further, the protective material can include metals, metal complexes, or metal oxides which catalytically decompose or inactivate in vivo reactive species or biological oxidizers. As used herein, the term "metal" includes metal alloys, metal complexes, and metal oxides.

In one aspect, the protective material may be covering, provided on, incorporated with and/or suspended within the external structure of the implantable device.

One aspect of the present invention provides a sensor for measurement of 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 a protective system including multiple metals incorporated in and/or in close proximity to a surface of the analyte indicator, and the multiple metals may be configured to reduce deterioration of the analyte indicator. In one aspect, the sensor may include a protective system having a metal layer including one or more of the multiple metals. In one aspect, the sensor may have metal layer covering at least a portion of the analyte indicator.

In one aspect, the sensor may have a first metal layer and a second metal layer, the first metal layer including a first metal of the multiple metals, the second metal layer may include a second metal of the multiple metals, and the first and second metals are different metals. The first metal layer may cover at least a portion of the analyte indicator. The second metal layer may cover at least a portion of the first metal layer. In one aspect, the second metal layer may be capable of adhering to the first metal layer better than the second metal layer is capable of adhering to the analyte indicator. In one aspect, the second metal layer may be between at least a portion of the sensor housing and the analyte indicator, and the first metal layer may cover at least a portion of the analyte indicator that is distal to the sensor housing. In one aspect, the first metal layer may be between at least a portion of the sensor housing and the analyte indicator, and the second metal layer may cover at least a portion of the analyte indicator that is distal to the sensor housing.

In one aspect, the protective system may include metal particles incorporated within the analyte indicator, and the metal particles may include one or more of the multiple metals. In some aspects, the metal particles may include a first metal and a second metal, and the first and second metals are different metals. In one aspect, the metal layer may be a multi-metal layer that includes a first metal of the multiple metals and a second metal of the multiple metals, and the first and second metals are different metals.

In one aspect, the protective system may include multiple metals that are configured to collectively interact or react with multiple degradative species. In some aspects, the multiple metals of the protective system may be configured to collectively interact or react with at least two of hydrogen peroxide, a reactive oxygen species, enzymes, metal ions, a reactive nitrogen species, and a free radical.

In some aspects, the multiple metals of the protective system may be configured to inhibit oxidative properties of the degradative species. In some aspects, the multiple metals of the protective system may include a first metal selected from Cu, W, Pt, Fe, Mo, oxides, alloys, and complexes thereof and a second metal selected from Mo, W, Cu, Fe, and Co, oxides, alloys, and complexes thereof, and the first metal and the second metal are different from each other.

In some aspects, the sensor may further include a radiation source contained in said sensor body and configured to emit radiation to the indicator element. In some aspects, the sensor may further include a photosensitive element contained in the sensor body and configured to receive light emitted by the analyte indicator. In some aspects, the sensor may further include a carrier material covering at least a portion of the analyte indicator, wherein multiple metals are incorporated within the material.

In some aspects, the present disclosure includes a method for detecting the presence or concentration of an analyte in an in vivo sample including the steps of exposing the in vivo sample to a device having a detectable quality that changes when the device is exposed to an analyte of interest, wherein the device may include protective material that prevents or reduces degradation or interference of the device from degradative species or biological oxidizers, and wherein the device may include a sensor of the present disclosure; and measuring a change in the detectable quality to thereby detect the presence or concentration of an 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.

In some embodiments, the present disclosure includes a sensor device that may be for implantation or insertion within a living animal and measurement of an analyte in a medium within the living animal. The sensor device may include a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and at least one multi-metal material that reduces deterioration of the analyte indicator.

In some embodiments, the sensor device may include at least one multi-metal material covering at least a portion of an analyte indicator that is provided on a sensor housing.

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

In some embodiments, the sensor device may include a sensor housing having an analyte indicator covering at least a portion of a surface of the sensor housing, a first single- or multi-metal material or layer provided between at least a portion of the sensor housing and the analyte indicator, and a second single- or multi-metal material or layer covering at least a portion of the analyte indicator that is distal to the sensor housing.

In some embodiments, the sensor device may include a sensor housing having an analyte indicator covering at least a portion of a surface of the sensor housing, at least one metal incorporated within the analyte indicator and at least one single- or multi-metal material or layer covering at least a portion of an analyte indicator distal to the sensor housing.

In another aspect, the present disclosure relates to a method for using an implantable device in in vivo applications. The method includes at least providing an implantable device which has an in vivo functionality. The implantable device has a protective material applied onto the device, wherein the protective material applied by the method prevents or reduces degradation or interference of the implantable device due to inflammation reactions and/or foreign body response. The protective material applied by the method includes multiple metals (including metal complexes and metal oxides) which catalytically decompose or inactivate multiple different in vivo degradative species or biological oxidizers. As used herein, the terms "degradative species" and "biological oxidizers" generally refer to reactive physiological molecules and radicals that degrade the indicator molecules. The method further includes partially or fully implanting the implantable device in a subject body.

In another aspect, the present disclosure relates to a method for detecting the presence or concentration of an analyte in an in vivo sample. The method includes at least 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 includes in part protective material, wherein the protective material prevents or reduces degradation or interference of the device from degradative species or biological oxidizers. The method further includes measuring any change in the detectable quality to thereby determine the presence or concentration of an analyte of interest in the in vivo sample.

In another aspect, the present disclosure is an implantable glucose sensor for determining the presence or concentration of glucose in an animal. The sensor device can include a sensor body having an outer surface surrounding the sensor body, a radiation source in said sensor body which emits radiation within said sensor body, an indicator element that is affected by the presence or concentration of glucose in said animal, where the indicator element having indicator molecules is positioned in close proximity to at least a portion of the outer surface of the sensor body. Further, the sensor can include a photosensitive element located in the sensor body, positioned to receive radiation within the sensor body, where the photosensitive element is configured to emit a signal responsive to radiation received from an indicator element and which is indicative of the presence or concentration of glucose in an animal. Moreover, the sensor includes a protective material that protects the indicator molecules from degradative species or biological oxidizers.

<FIG> is a schematic view of a sensor system embodying aspects of the present disclosure. 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 disclosure 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, 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.

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, 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, the analyte indicator <NUM> may be protected by multiple metals (including metal alloys, metal complexes, or metal oxides) that interact or react with one or more degradative species without compromising signal integrity or performance of the sensor device. In some embodiments, one or more metals may be incorporated into the analyte indicator <NUM> that may cover at least a portion of the sensor housing <NUM>. In some embodiments, one or more metal layers may be additionally or alternatively applied to the analyte indicator <NUM>. In some embodiments, the degradative species may include one or more of hydrogen peroxide, enzymes, metal ions, a reactive oxygen species, a reactive nitrogen species, and a free radical.

In some embodiments, one or more metals may be incorporated into the analyte indicator <NUM> that may cover at least a portion of the sensor housing <NUM>. In some embodiments, one or more metals may additionally or alternatively cover at least a portion of the surface of the analyte indicator <NUM> that is distal to a portion of the sensor housing <NUM>. In some embodiments, one or more metals may additionally or alternatively cover at least a portion of the surface of the analyte indicator <NUM> that is proximal to the sensor housing <NUM>. In some embodiments, a layer covering at least a portion of the analyte indicator <NUM> may include at least two different metal species, and surfaces of each of the at least two different metal species may be exposed to degradative species or biological oxidizers.

While a platinum layer has been clinically demonstrated to improve in vivo longevity of the Senseonics implanted CGM sensors (<NPL>), increasing the surface area (and therefore amount of catalyst) of the platinum layer may not further improve in vivo longevity, and the indicator moiety may be oxidized even in the presence of a platinum layer having an increased surface area. In some embodiments, the present disclosure provides broader protection against various degradative species and increases longevity of partially or fully implantable devices.

In some embodiments, the sensor <NUM> may include a multiple metal protective system that includes multiple protective metals. In some embodiments, the multiple metals may interact and/or react with degradative species. In some embodiments, the multiple metals may neutralize degradative species. In some embodiments, the multiple metals may bind to degradative species. In some embodiments, the multiple metals may sequester degradative species so as to inhibit, reduce, and/or prevent degradation of the indicator molecules <NUM> of the analyte indicator <NUM> caused by the degradative species. Accordingly, in some embodiments, the multiple metalsmay reduce deterioration of the analyte indicator <NUM>. In some non-limiting embodiments, the multiple metals may include one or more phenylboronic acid compounds that interact with degradative species without compromising signal integrity or performance of the sensor.

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 a multiple metal protective system that includes multiple protective metals. In some embodiments, the multiple metals may interact with multiple degradative species. In some embodiments, the multiple metal protective system 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 multiple metal protective system may protect the indicator molecules <NUM> without compromising signal integrity or performance of the sensor <NUM>. In some non-limiting embodiments, the sensor <NUM> may include a drug eluting matrix and/or a layer of catalyst provided on or incorporated in the analyte indicator <NUM>.

In some non-limiting embodiments, as shown in <FIG>, the multiple metal protective system may include a first metal layer <NUM> and a second metal layer <NUM>. In some non-limiting embodiments, a sensor <NUM> may include a sensor housing <NUM>, and an analyte indicator <NUM> covering at least a portion of the sensor housing <NUM>. In some embodiments, as shown in <FIG>, the first metal layer <NUM> may cover at least a portion of the analyte indicator <NUM>, and the second metal layer <NUM> may cover at least a portion of the first metal layer <NUM>. In some non-limiting alternative embodiments, as shown in <FIG>, the second metal layer <NUM> may cover at least a portion of the analyte indicator <NUM>, and the first metal layer <NUM> may cover at least a portion of the second metal layer <NUM>.

In some non-limiting embodiments, as illustrated in <FIG>, the first metal layer <NUM> may be applied to a first surface of an analyte indicator <NUM>, the second metal layer <NUM> may be applied to a second surface of the analyte indicator <NUM>, and the second surface may be a different surface of the analyte indicator <NUM> than the first surface. For example, in some non-limiting embodiments, as shown in <FIG>, the first metal layer <NUM> may cover at least a portion of a first surface of the analyte indicator <NUM>, the second metal layer <NUM> may cover at least a portion of a second surface of the analyte indicator <NUM>, and the second surface may be on a side of the analyte indicator <NUM> opposite to the first surface. In some embodiments, the second metal layer <NUM> may be provided between the sensor housing <NUM> and the analyte indicator <NUM>. For another example, in some non-limiting embodiments, as shown in <FIG>, the second metal layer <NUM> may cover at least a portion of the first surface of the analyte indicator <NUM>, and the first metal layer <NUM> may cover at least a portion of the second surface of the analyte indicator <NUM>. In some embodiments, the first metal layer <NUM> may be provided between the sensor housing <NUM> and the analyte indicator <NUM>.

The first metal layer <NUM> includes a first metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals (e.g., alloys such as Pt/Rh and Pt/Lr). In some non-limiting embodiments, the first metal layer <NUM> may include the first metal and one or more additional metals selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals. The second metal layer <NUM> includes a second metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals. In some non-limiting embodiments, the second metal layer <NUM> may include the second metal and one or more additional metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals. In some embodiments, the first metal and the second metal may be different metals. In some non-limiting embodiments, the first metal may be platinum, and the second metal may be molybdenum. In some non-limiting embodiments, the first metal may be copper, and the second metal may be molybdenum. In some non-limiting alternative embodiments, the first metal may be platinum, and the second metal may be tungsten. In some other non-limiting alternative embodiments, the first metal may be tungsten, and the second metal may be molybdenum. In some other non-limiting alternative embodiments, the first metal layer <NUM> includes platinum and the second metal layer <NUM> includes tungsten.

In some non-limiting embodiments, as shown in <FIG>, the multiple metal protective system may include (i) one or more metal layers on or in proximity to the analyte indicator <NUM> and (ii) metal particles of one or more metals incorporated into the analyte indicator <NUM>. In some non-limiting embodiments, as shown in <FIG> and <FIG>, the multiple metal protective system may include the first metal layer <NUM> and first metal particles <NUM>. In some embodiments, the first metal layer <NUM> may cover a portion of the analyte indicator <NUM>, and the first metal particles <NUM> may be incorporated in the analyte indicator <NUM>. In some embodiments, the first metal layer <NUM> may include at least the first metal (e.g., the metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals), the first metal particles <NUM> may include at least the second metal (e.g., the metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals), and the first and second metals may be different metals. In some non-limiting alternative embodiments, as shown in <FIG> and <FIG>, the multiple metal protective system may include the second metal layer <NUM> and second metal particles <NUM>. In some embodiments, the second metal layer <NUM> may cover at least a portion of the analyte indicator <NUM>, and the second metal particles <NUM> may be incorporated in the analyte indicator <NUM>. In some embodiments, the second metal layer <NUM> may include at least the second metal, the second metal particles <NUM> may include at least the first metal, and the first and second metals may be different metals.

In some non-limiting embodiments, as shown in <FIG>, the multiple metal protective system may include one of the first and second metal layers <NUM> and <NUM> and both of the first and second metal particles <NUM> and <NUM>. For example, in some non-limiting embodiments, as shown in <FIG>, the multiple metal protective system may include the first metal layer <NUM>, the first metal particles <NUM>, and the second metal particles <NUM>. In some non-limiting embodiments, the first metal layer <NUM> and the second metal particles <NUM> may each include at least a first metal (e.g., a metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals). In some non-limiting embodiments, the first metal layer <NUM> and the second metal particles <NUM> may include at least the same first metal, but this is not required, and, in some non-limiting alternative embodiments, the first metal layer <NUM> and the second metal particles <NUM> may include different metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals. In some non-limiting embodiments, the first metal particles <NUM> may include at least the second metal (e.g., the metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals), and the second metal may be different than the one or more first metals selected for the first metal layer <NUM> and the second metal particles <NUM>.

For another example, in some non-limiting embodiments, as shown in <FIG>, the multiple metal protective system may include the second metal layer <NUM>, the first metal particles <NUM>, and the second metal particles <NUM>. In some non-limiting embodiments, the second metal layer <NUM> and the first metal particles <NUM> may each include at least a second metal (e.g., a metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals). In some non-limiting embodiments, the second metal layer <NUM> and the first metal particles <NUM> may include at least the same second metal, but this is not required, and, in some non-limiting alternative embodiments, the second metal layer <NUM> and the first metal particles <NUM> may include different metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals. In some non-limiting embodiments, the second metal particles <NUM> may include at least the first metal (e.g., the metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals), and the first metal may be different than the one or more second metals selected for the second metal layer <NUM> and the first metal particles <NUM>.

In some non-limiting embodiments, as shown in <FIG>, the multiple metal protective system may include a first metal layer <NUM>, a second metal layer <NUM>, and metal particles of one or more metals incorporated into the analyte indicator <NUM>. In some embodiments, as shown in <FIG>, <FIG>, one of the first and second metal layers <NUM> and <NUM> may cover at least a portion of the analyte indicator <NUM>, and the other of the first and second metal layers <NUM> and <NUM> may cover at least a portion of the one of the first and second metal layers <NUM> and <NUM> (see description of <FIG> above). In some alternative embodiments, as shown in <FIG>, one of the first and second metal layers <NUM> and <NUM> may be applied to a first surface of an analyte indicator <NUM>, the other of the first and second metal layer <NUM> and <NUM> may be applied to a second surface of the analyte indicator <NUM>, and the second surface may be a different surface of the analyte indicator <NUM> than the first surface (see description of <FIG> above). In some embodiments, as shown in <FIG>, the multiple metal protective system may include one or more of the first and second metal particles <NUM> and <NUM> in addition to the first and second metal layers <NUM> and <NUM>.

In some non-limiting embodiments, as shown in <FIG>, the multiple metal protective system may include both of the first and second metal particles <NUM> and <NUM> in addition to the first and second metal layers <NUM> and <NUM> (see description of <FIG> above). In some non-limiting embodiments, the first metal layer <NUM> and the second metal particles <NUM> may each include at least a first metal (e.g., a metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals). In some non-limiting embodiments, the first metal layer <NUM> and the second metal particles <NUM> may include at least the same first metal, but this is not required, and, in some non-limiting alternative embodiments, the first metal layer <NUM> and the second metal particles <NUM> may include different metals selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals. In some non-limiting embodiments, the second metal layer <NUM> and the first metal particles <NUM> may each include at least a second metal (e.g., a metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals). In some non-limiting embodiments, the second metal layer <NUM> and the first metal particles <NUM> may include at least the same second metal, but this is not required, and, in some non-limiting alternative embodiments, the second metal layer <NUM> and the first metal particles <NUM> may include different metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals. In some non-limiting embodiments, one or more (e.g., all) of the metals of the first metal layer <NUM>, second metal layer <NUM>, first metal particles <NUM>, and second metal particles <NUM> may be different.

In some non-limiting alternative embodiments, as shown in <FIG>, the multiple metal protective system need not include a metal layer on a surface of the analyte indicator. For example, as shown in <FIG>, in some embodiments, the multiple metal protective system may include the first metal particles <NUM> and second metal particles <NUM>, which may be incorporated in the analyte indicator <NUM>. In some embodiments, the first metal particles <NUM> may include at least the second metal (e.g., the metal selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals), the second metal particles <NUM> may include at least a first metal (e.g., a metal selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals), and the first and second metals may be different metals.

As noted above, in some embodiments, a sensor <NUM> may include a sensor housing <NUM>, an analyte indicator <NUM> that covers at least a portion of the sensor housing <NUM>, and a multiple metal protective system. In some non-limiting embodiments, as shown in <FIG>, the multiple metal protective system may include a multi-metal layer <NUM> covers at least a portion of the analyte indicator <NUM>. In some embodiments, as shown in <FIG>, the multi-metal layer <NUM> may include at least a first metal <NUM> and a second metal <NUM>. In some embodiments, the first metal <NUM> may be selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals. In some embodiments, the second metal <NUM> may be selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals. In some embodiments, the first metal <NUM> and the second metal <NUM> may be different metals.

In some embodiments, as shown in <FIG>, the multiple metal protective system may include the multi-metal layer <NUM> and one or more of the first and second metal particles <NUM> and <NUM>. In some non-limiting embodiments, the first metal <NUM> and the second metal particles <NUM> may include at least the same metal, but this is not required, and, in some non-limiting alternative embodiments, the first metal <NUM> and the second metal particles <NUM> may include different metals selected from Cu, W, Pt, Fe, Mo, Co, and oxides, alloys, and complexes of those metals. In some non-limiting embodiments, the second metal <NUM> and the first metal particles <NUM> may include at least the same metal, but this is not required, and, in some non-limiting alternative embodiments, the second metal <NUM> and the first metal particles <NUM> may include different metals selected from Mo, W, Cu, Fe, Co, and oxides, alloys, and complexes of those metals. In some non-limiting embodiments, one or more (e.g., all) of the metals of the first metal layer <NUM>, second metal layer <NUM>, first metal particles <NUM>, and second metal particles <NUM> may be different.

In some embodiments, as shown in <FIG>, the sensor device may include one or more carrier materials <NUM> and <NUM>. In some embodiments, the one or more carrier materials may be independently a membrane, mesh, nylon, fabric, matrix, sponge, or other pore-containing material covering at least a portion of the analyte indicator <NUM>. In some embodiments, first and second metal particles <NUM> and <NUM> may be incorporated within the carrier material <NUM> covering the analyte indicator <NUM> as shown in <FIG>. In some embodiments, first and second metal particles <NUM> and <NUM> may be incorporated within the carrier material <NUM> covering a first metal layer <NUM> that covers the analyte indicator <NUM> as shown in <FIG>. Additional metal layers may also be provided between the carrier material <NUM> and the first metal layer <NUM> (not shown). In some embodiments, metal particles <NUM> may be incorporated into a first carrier material <NUM> and different metal particles <NUM> may be incorporated into a second carrier material <NUM>, wherein the first carrier material <NUM> covers the analyte indicator <NUM> as shown in <FIG>. Additional metal layers may also be provided between the first carrier material <NUM> and the indicator <NUM> and/or between the first carrier material <NUM> and the second carrier material <NUM> (not shown).

In some embodiments, a fully or partially implantable sensor <NUM> including a multiple metal protective system may have improved performance over a sensor that does not include a multiple metal protective system. For instance, in some non-limiting embodiments, the multiple metal protective system may improve the longevity and functionality of the sensor <NUM>.

In some embodiments, a multiple metal protective system may improve protection against degradative species. Assays with a series of <NUM> x <NUM> metal foils were conducted and the results are reported in Tables <NUM> and <NUM>. In an assay, protective activities listed in Table <NUM> were found against hydrogen peroxide.

Unexpectedly, Au, Pd, Ni, Ta, Mg had no detectable activity against hydrogen peroxide.

In an assay, protective activities listed in Table <NUM> were found against hypochlorite.

The results demonstrate that, for example and without limitation, platinum can be used to degrade hydrogen peroxide but is not useful to degrade hypochlorite. The results also demonstrate that, for example and without limitation, copper was found to be more reactive than molybdenum against hydrogen peroxide but less reactive than molybdenum against hypochlorite. Unexpectedly, Au, Pd, Ni, Ta, Mg, Pt, Pt/Rh, Pt/Ir had no detectable activity against hypochlorite.

In some embodiments, the multiple metals (e.g., in one or more metal layers on the analyte indicator <NUM> and/or one or more metal particles incorporated in the analyte indicator <NUM>) in the multiple metal protective system may improve protection against degradative species because one of the metals may degrade one type of degradative species (e.g., hydrogen peroxide) and another one of the metals may degrade another type of degradative species (e.g., hypochlorite).

In some embodiments, the multiple metals (e.g., in one or more metal layers on the analyte indicator <NUM> and/or one or more metal particles incorporated in the analyte indicator <NUM>) in the multiple metal protective system may additionally or alternatively improve protection against degradative species because one metal layer (e.g., the first metal layer <NUM>) may act to promote adhesion of another metal layer (e.g., the second metal layer <NUM>). For example, molybdenum may adhere better to platinum than to an analyte indicator <NUM>, which may be, for example and without limitation, a glucose indicating hydrogel than molybdenum. For instance, in the embodiments shown in <FIG>, <FIG>, and <FIG>, the multiple metal protective system may include a first metal layer <NUM> applied to at least a portion of the analyte indicator <NUM> and a second metal layer <NUM> applied to at least a portion of the first metal layer <NUM>, and the first and second metal layers <NUM> and <NUM> may include first and second metals (e.g., platinum and molybdenum), respectively. In some embodiments, the first metal (e.g., platinum) of the first metal layer <NUM> may promote adhesion of the second metal of the second metal layer <NUM>. The second metal layer <NUM> adheres better to the first metal layer <NUM> than the second metal layer <NUM> would adhere to the analyte indicator <NUM> if applied directly to the analyte indicator <NUM>. Accordingly, the multiple metals of the multiple metal protective system may allow the system to include a metal that could not be used if only one metal were used. In some non-limiting embodiments, the multiple metal protective system may include a Pt layer covered by a Mo layer, which may enable improved adhesion to the hydrogel and improve catalysis against both hydrogen peroxide and hypochlorite.

A non-limiting example of a sensor ("Example Sensor <NUM>") includes 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, and has a useful life of <NUM> days implanted in a human patient.

A non-limiting example of a sensor ("Example Sensor <NUM>") that is the same as Example Sensor <NUM> but is further protected by a Mo layer provided over the Pt has a useful life of at least <NUM> days when it is implanted in a human patient.

A non-limiting example of a sensor ("Example Sensor <NUM>") that is the same as Example Sensor <NUM> but is further protected by Cu sputtered in combination with the Pt on the hydrogel has a useful life of at least <NUM> days when it is implanted in a human patient.

A non-limiting example of a sensor ("Example Sensor <NUM>") that is the same as Example Sensor <NUM> but is further protected by Cu that is sputtered in combination with the Pt on the hydrogel and has a Mo layer over the co-sputtered Pt/Cu has a useful life of at least <NUM> days when it is implanted in a human patient.

A non-limiting example of a sensor ("Example Sensor <NUM>") that is the same as Example Sensor <NUM> but is further protected by Cu that is incorporated in the hydrogel has a useful life of at least <NUM> days when it is implanted in a human patient.

A non-limiting example of a sensor ("Example Sensor <NUM>") that is the same as Example Sensor <NUM> but is further protected by Cu incorporated in the hydrogel and a Mo layer provided over the Pt has a useful life of at least <NUM> days when it is implanted in a human patient.

A non-limiting example of a sensor ("Example Sensor <NUM>") that is the same as Example Sensor <NUM> but is further protected by Pt and Cu incorporated in the hydrogel and a W layer over the Pt has a useful life of at least <NUM> days when it is implanted in a human patient.

A non-limiting example of a sensor ("Example Sensor <NUM>") that is the same as Example Sensor <NUM> but is further protected by Pt, Cu, and Mo incorporated in the hydrogel and a W layer over the Pt has a useful life of at least <NUM> days when it is implanted in a human patient.

A non-limiting example of a sensor ("Example Sensor <NUM>") that is the same as Example Sensor <NUM> but is further protected by Pt, Cu, and W incorporated in the hydrogel and a Mo layer over the Pt has a useful life of at least <NUM> days when it is 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; and
a protective system including multiple metals incorporated in and/or in close proximity to a surface of the analyte indicator, the multiple metals are configured to reduce deterioration of the analyte indicator, the protective system includes a first metal layer (<NUM>), the first metal layer covers at least a portion of the analyte indicator and includes a first metal of the multiple metals, and the first metal is selected from Cu, W, Pt, Fe, Mo, oxides, alloys, and complexes thereof;
characterized in that the protective system includes a second metal layer (<NUM>), the second metal layer covers at least a portion of the first metal layer and includes a second metal of the multiple metals, the first and second metals are different, the second metal is selected from Mo, W, Cu, Fe, and Co, oxides, alloys, and complexes thereof, and the second metal layer has greater adhesion to the first metal layer than the second metal layer would have if applied directly to the analyte indicator.