Device and method for determining the concentration of a target analyte in an in vivo biological fluid

Abstract

Provided herein are devices and methods for continuously measuring the concentration of a target analyte in an in vivo biological fluid. In some examples, the device includes an indwelling sensor and sensor electronics. The sensor may include a substrate, a first electrode disposed on the substrate, an ionophore disposed on the substrate and configured to selectively transport a target ion to or within the first electrode, and a second electrode disposed on the substrate. The sensor electronics are configured to generate a signal corresponding to an electromotive force based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode.

Description

[Technical Field]

[0001] This application relates generally to measuring analyte concentrations in biological fluids. This application also relates generally to measuring electrophysiological signals. [Background technology]

[0002] The concentration of ions (e.g., sodium, potassium, magnesium, calcium, or ammonium) in a host's biological fluids can provide important information about the health status of the host. Illustratively, potassium ions (K + ) is a biomarker for cardiovascular disease. + ) is a biomarker for kidney disease. Indeed, in the United States, approximately 14.8 million diabetic patients have been diagnosed with kidney disease, e.g., renal dysfunction. These patients can benefit from frequent blood potassium measurements to assess kidney function and guide treatment, which may include oral medications at one end of the spectrum and dialysis at the other. In yet another example, potassium ions (K + ) is a biomarker for both cardiovascular and renal disease.

[0003] Furthermore, approximately 9 million people in the United States have both diabetes and cardiac arrhythmias. Cardiac arrhythmias are primarily caused by inappropriate strengthening of the heart muscle. Potassium helps control and moderate the electrical signals of the heart muscle. Untreated cardiac arrhythmias can progress to ventricular fibrillation and sudden cardiac death. Therefore, it would be useful to have a rapid, robust, and convenient method for monitoring the concentrations of ions in the host's biological fluids.

[0004] Electrophysiological signals, such as heart rate, can provide important information about the health of a host. It would therefore be useful to have a rapid, robust, and convenient method for monitoring one or more such electrophysiological signals. Summary of the Invention

[0005] Provided herein are devices and methods for measuring electrophysiological signals and / or target analyte concentrations in in vivo biological fluids.

[0006] Some examples herein provide a device for continuously measuring the concentration of a target ion in an in vivo biological fluid. The device can include an in-dwelling analyte sensor, the in-dwelling analyte sensor including a substrate, a first electrode disposed on the substrate, an ionophore disposed on the substrate and configured to selectively transport a target ion to or within the first electrode, and a second electrode disposed on the substrate. The device can include sensor electronics configured to generate a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode.

[0007] In some examples, the sensor electronics are further configured to use the signal to generate an output corresponding to a measure of the concentration of the target ion in the biological fluid.

[0008] In some examples, the sensor electronics are further configured to transmit the signal to an external device configured to use the signal to generate an output corresponding to a measure of the concentration of the target ion in the biological fluid.

[0009] In some examples, the first electrode comprises a polymer having an ionophore therein. In some examples, the first electrode comprises a conductive polymer having an ionophore therein. In some examples, the first electrode is substantially free of plasticizers. In some examples, the first electrode consists essentially of a conductive polymer and an ionophore. In some examples, the first electrode consists essentially of a conductive polymer, an ionophore, and an additive having ion exchange capacity. In some examples, the additive comprises a lipophilic salt. In some examples, the lipophilic salt is selected from the group consisting of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTPFB), sodium tetraphenylborate (NaTPB), potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (KTFPB), and potassium tetrakis(4-chlorophenyl)borate (KTClPB). In some examples, the lipophilic salt additive is present in the polymer in an amount of about 0.01 to about 1 weight percent.

[0010] In some examples, the conductive polymer is present in an amount of about 90 to about 99.5 weight percent. In some examples, the conductive polymer can be selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT). In some examples, the ionophore is present in the conductive polymer in an amount of about 0.01 to about 10 weight percent, about 0.2 to about 10 weight percent, or about 0.5 to about 10 weight percent.

[0011] In some examples, the ion-selective membrane (ISM) is a polymer. In one example, the ion-selective membrane is a fluorosilicone rubber, a polydimethylsiloxane polymer, a silicone rubber, a polyurethane with a polysiloxane soft segment, a polyurethane with a hard segment and a soft segment, such as a polyester or polycarbonate or a polydimethylsiloxane soft segment, a water-based polyurethane, polyvinyl butyral, polymethyl methacrylate, polyvinyl acrylate, or a blend or graft polymer thereof.

[0012] In some examples, the ionophore is within an ion-selective membrane disposed on the first electrode. In some examples, the ion-selective membrane substantially excludes any phthalate, sebacate, nitrophenyl ether, and fluorophenyl nitrophenyl ether plasticizers. In some examples, the ion-selective membrane is substantially free of plasticizers. In some examples, the ion-selective membrane consists essentially of a biocompatible polymer and an ionophore configured to selectively bind to a target ion.

[0013] In some examples, the ion-selective membrane consists essentially of a biocompatible polymer, an ionophore configured to selectively bind a target ion, and an additive having ion-exchange capabilities, e.g., the ability to exchange ions. In some examples, the additive comprises a lipophilic salt. In some examples, the lipophilic salt is selected from the group consisting of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTPFB), sodium tetraphenylborate (NaTPB), potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (KTFPB), and potassium tetrakis(4-chlorophenyl)borate (KTClPB). In some examples, the additive is present in the ion-selective membrane in an amount of about 0.01 to about 1 weight percent.

[0014] In some examples, the biocompatible polymer is present in the ion-selective membrane in an amount of about 90 to about 99.5 weight percent. In some examples, the biocompatible polymer comprises a hydrophobic polymer. In some examples, the hydrophobic polymer is selected from the group consisting of silicone, fluorosilicone (FS), polyurethane, fluoropolymer, poly(vinyl chloride) (PVC), polyacrylate, and polymethacrylate. In some examples, the biocompatible polymer comprises a block copolymer. In some examples, the block copolymer comprises a hydrophilic block selected from the group consisting of polycarbonate (PC) and polybutadiene (PBD). In some examples, the block copolymer comprises a hydrophobic group selected from the group consisting of polydimethylsiloxane (PDMS), methylene diphenyl diisocyanate (MDI), polysulfone (PSF), and methyl methacrylate (MMA). In some examples, the ionophore is present in the ion-selective membrane in an amount of about 0.5 to about 10 weight percent.

[0015] In some examples, the first electrode comprises a metal, a metal alloy, a transition metal oxide, a transparent conductive oxide, a carbon material, a doped semiconductor, a binary semiconductor, a ternary semiconductor, or a conductive polymer. In some examples, the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium. In some examples, the metal is oxidized or in the form of a metal salt. In some examples, the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond. In some examples, the doped semiconductor, binary semiconductor, or ternary semiconductor is selected from the group consisting of p-doped or n-doped silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide. In some examples, the conductive polymer may be selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

[0016] In some examples, the ion selective membrane is in direct contact with at least a portion of the first electrode. In some examples, the ion selective membrane is in direct contact with at least a majority of the surface area of ​​the first electrode.

[0017] In some examples, the ion-selective membrane is in indirect contact with at least a portion of the first electrode, e.g., a solid contact layer is disposed between the first electrode and the ion-selective membrane. In some examples, at least a portion of the solid contact layer is electrically coupled to the first electrode and / or in direct electrical communication with the first electrode. In some examples, the solid contact layer comprises a metal, a carbon material, a doped semiconductor, or a conductive polymer. In some examples, the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium. In some examples, the metal is oxidized or in the form of a metal salt. In some examples, the metal exhibits a nanostructured surface. In some examples, the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond. In some examples, the doped semiconductor is selected from the group consisting of p-doped or n-doped silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide. In some examples, the conductive polymer can be selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT). In some examples, the solid contact layer includes a redox couple. In some examples, the redox couple includes two or more metal centers (e.g., metal cations) having different oxidation states. In some examples, both of the two or more metal centers are transition metals. In some examples, the metal center is selected from the group consisting of Co(II) and Co(III), Ir(II) and Ir(III), and Os(II) and Os(III). In some examples, the solid contact layer comprises a mixed conductor or a mixed ionic-electronic conductor.In some examples, the solid contact layer is strontium titanate (SrTiO3), titanium dioxide (TiO2), (La,Ba,Sr)(Mn,Fe,Co)O. 3-d ,La2CuO 4+d The solid contact layer comprises a compound selected from the group consisting of cerium(IV) oxide (CeO), lithium iron phosphate (LiFePO,), and LiMnPO. In some examples, the solid contact layer inhibits water transport from the biological fluid to the first electrode. In some examples, the solid contact layer is configured to enhance electrical stability of the first electrode.

[0018] In some examples, the target ion is selected from the group consisting of sodium, potassium, hydrogen, lithium, magnesium, calcium, chloride, sulfite, sulfate, phosphate, and ammonium. In some examples, the target ion is sodium, and the ionophore is 4-tert-butylcalix[4]arene-tetraacetic acid tetraethyl ester (sodium ionophore X) or calix[4]arene-25,26,27,28-tetraol (calix[4]arene). In some examples, the target ion is potassium, and the ionophore is potassium ionophore I (valinomycin), potassium ionophore II: bis[(benzo-15-crown-5)-4'-ylmethyl]pimelate (BB15C5); potassium ionophore III: or 2-dodecyl-2-methyl-1,3-propanediylbis[N-[5'-nitro(benzo-15-crown-5)-4'-yl]carbamate] (BME44). In some examples, the target ion is magnesium and the ionophore is 4,5-bis(benzoylthio)-1,3-dithiole-2-thione (Bz2dmit) or 1,3,5-tris[10-(1-adamantyl)-7,9-dioxo-6,10-diazaundecyl]benzene (magnesium ionophore VI). In some examples, the target ion is calcium and the ionophore is calcium ionophore I (ETH 1001) or calcium ionophore II (ETH129). In some examples, the target ion is chloride and the ionophore is tridodecylmethylammonium chloride (TDMAC). In some examples, the target ion is ammonium and the ionophore is nonactin.

[0019] In one example, the ionophore is covalently attached to the ISM using, for example, a functionalized ISM and / or ionophore and an appropriate coupling chemistry, such as a carbodiimide or polycarbodiimide coupling / crosslinking agent. Other coupling / crosslinking agents can be used to couple the ionophore to the ISM or another membrane of the sensors of the present disclosure.

[0020] In some examples, the substrate comprises a material selected from the group consisting of a metal, a glass, a semiconductor, a dielectric, a transparent conductive oxide, a ceramic, and a polymer. In some examples, the substrate is rigid, semi-rigid, or flexible.

[0021] In some examples, the second electrode comprises a metal, a metal alloy, a transition metal oxide, a transparent conductive oxide, a carbon material, a doped semiconductor, a binary semiconductor, a ternary semiconductor, or a conductive polymer. In some examples, the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium. In some examples, the metal is oxidized or in the form of a metal salt. In some examples, the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond. In some examples, the doped semiconductor is selected from the group consisting of p-doped or n-doped silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide. In some examples, the conductive polymer may be selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

[0022] In some examples, the first electrode is disposed directly on the substrate.

[0023] In some examples, the first and second electrodes are disposed directly on the substrate. In some examples, at least a portion of the first and second electrodes are disposed directly on at least a portion of the substrate. In some examples, at least a portion of the first and second electrodes are indirectly coupled to at least a portion of the substrate, for example, using an adhesive or other material that bonds a portion of the substrate to at least a portion of the electrodes.

[0024] In some examples, the device further includes a biointerface membrane disposed on the ionophore and the first electrode. In some examples, the device includes a biointerface membrane disposed on the ionophore and the first electrode and the second electrode, where the biointerface membranes are the same. In some examples, the biointerface membrane is configured to inhibit biofouling of the ionophore or the first electrode. In some examples, the biointerface membrane is configured to inhibit disintegration of the second electrode. In some examples, at least a portion of the biointerface membrane, or a separate drug-releasing membrane, is configured to release a therapeutic compound into the biological fluid. In some examples, the biointerface membrane includes multiple layers. In some examples, the biointerface membrane is two or more chemically different or chemically identical biointerface membranes, or two or more chemically different biointerface membrane layers stacked in an alternating or random configuration, or a combination of alternating and random configurations.

[0025] In some examples, the device includes a second biointerface membrane disposed on the second electrode. In some examples, the second biointerface membrane is the same as or chemically different from the biointerface membrane. In some examples, the second biointerface membrane includes multiple layers. In some examples, the second biointerface membrane is two or more chemically different biointerface membranes, or two or more chemically different or chemically identical biointerface membrane layers stacked in an alternating or random configuration, or a combination of alternating and random configurations. In some examples, the second biointerface membrane includes a biocompatible polymer and a salt. In some examples, the second biointerface membrane consists essentially of a biocompatible polymer and a salt. In some examples, the biocompatible polymer is present in the second biointerface membrane in an amount of about 40 to about 70 weight percent. In some examples, the salt is present in the biointerface membrane in an amount of about 30 to about 60 weight percent. In some examples, the biocompatible polymer is selected from the group consisting of polyvinyl butyral (PVB), polyurethane, and silicone. In some examples, the salt is selected from the group consisting of potassium chloride (KCl), sodium chloride (NaCl), magnesium chloride (MgCl), calcium chloride (CaCl), and ammonium sulfate (NH)SO. In some examples, the second biointerface membrane comprises multiple layers.

[0026] In some examples, the substrate is substantially elongated. In some examples, the substrate has an elongated shape that is planar or cylindrical.

[0027] In some examples, the substrate is a plane. In some examples, the substrate is a wire.

[0028] In some examples, the device comprises sensor electronics configured to continuously measure the electromotive force.

[0029] In some examples, the sensor electronics are configured to measure the electromotive force at a dynamically configurable frequency.

[0030] In some examples, the sensor electronics include a galvanostat.

[0031] In some examples, the sensor electronics include a high input impedance analog front end coupled to the first electrode and the second electrode. In some examples, the high impedance analog front end includes at least one of an instrumentation amplifier, a differential amplifier, a voltage follower, a unity gain amplifier, an isolation amplifier, or a buffer. In some examples, the high impedance analog front end has an input impedance greater than about 100 gigaohms.

[0032] In some examples, the sensor electronics are configured to maintain the second electrode at a substantially constant potential.

[0033] In some examples, the sensor electronics further includes an analog-to-digital converter (ADC) that digitizes a signal corresponding to the measured electromotive force.

[0034] In some examples, the sensor electronics includes a non-volatile computer-readable memory configured to store the signal.

[0035] In some examples, the sensor electronics include a transmitter configured to wirelessly transmit the signal.

[0036] In some examples, the sensor electronics includes a non-volatile computer-readable memory configured to store a correlation between control ion concentrations and control signals corresponding to the electromotive forces of those control ion concentrations. The sensor electronics is configured to (a) compare the signal corresponding to the electromotive forces with the control signals, (b) select the control signal that most closely matches the signal corresponding to the electromotive forces, and (c) generate as an output the control ion concentration corresponding to the selected control signal.

[0037] In some examples, the electromotive force is further based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid conducting an electrophysiological signal to the first electrode. In some examples, a first contribution to the electromotive force from the electrophysiological signal changes rapidly relative to a second contribution to the electromotive force from the concentration of ions in the physiological fluid. In some examples, the sensor electronics are configured to analyze the first contribution from the second contribution. In some examples, the sensor electronics include a fast Fourier transform (FFT) circuit that converts a signal corresponding to the electromotive force from a time domain to a frequency domain, a spectral analysis circuit configured to separate the converted signal into a high-frequency portion corresponding to the first contribution and a low-frequency portion corresponding to the second contribution, and at least one inverse FFT (iFFT) circuit configured to convert the high-frequency portion to a time-domain output corresponding to the electrophysiological signal and the low-frequency portion to a time-domain output corresponding to the concentration of ions in the physiological fluid. In some examples, the low-frequency portion is centered approximately at a zero frequency. In some examples, the high-frequency portion includes a frequency characteristic of a human heartbeat or any harmonic thereof. In some examples, the high frequency portion includes features at frequencies corresponding to characteristics of an individual human heartbeat. In some examples, the high frequency portion includes features between about 100 Hz and about 1000 kHz. In some examples, the high frequency portion includes features between about 200 Hz and about 400 kHz.

[0038] In some examples, the sensor electronics includes an analog-to-digital converter (ADC) that digitizes a signal corresponding to the electromotive force; a first filter configured to receive the digitized signal from the ADC, remove the second contribution therefrom, and generate an output corresponding to the first contribution with the second contribution removed; and a second filter configured to receive the digitized signal from the ADC, remove the first contribution therefrom, and generate an output corresponding to the second contribution with the first contribution removed.

[0039] In some examples, the sensor electronics include a first filter configured to remove a second contribution from the signal corresponding to the electromotive force and generate a first output corresponding to the first contribution with the second contribution removed, and a second filter configured to remove the first contribution from the first output or the signal corresponding to the electromotive force and generate a second output corresponding to the second contribution with the first contribution removed. In some examples, the first filter includes a high-pass filter, a band-block filter, or a band-pass filter. In some examples, the first filter passes frequencies corresponding to human heartbeats or heartbeat waveforms. In some examples, the second filter includes a low-pass filter, a band-block filter, or a band-pass filter. In some examples, the second filter passes zero frequencies.

[0040] In some examples, the device includes sensor electronics configured to receive electrophysiological signals, for example cardiac electrical signals.

[0041] Some examples herein provide a device for measuring electrophysiological signals conducted through an in vivo biological fluid. The device can include an indwelling sensor, the indwelling sensor including a substrate, a first electrode disposed on the substrate, and a second electrode disposed on the substrate. The device can include sensor electronics configured to generate a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid transporting the electrophysiological signal to the first electrode.

[0042] In some examples, the sensor electronics of the device are further configured to use the signal to generate an output corresponding to a measure of the electrophysiological signal.

[0043] In some examples, the sensor electronics of the device are further configured to transmit the signal to an external device configured to use the signal to generate an output corresponding to a measure of the concentration of the target ion in the biological fluid.

[0044] In some examples, the sensor electronics of the device include a fast Fourier transform (FFT) circuit that converts the signal corresponding to the electromotive force from the time domain to the frequency domain, a spectral analysis circuit configured to separate the converted signal into a high-frequency portion that corresponds to the electrophysiological signal and a low-frequency portion that does not correspond to the electrophysiological signal, and at least one inverse FFT (iFFT) circuit configured to convert the high-frequency portion into a time-domain output that corresponds to the electrophysiological signal.

[0045] In some examples, the high frequency portion includes features at frequencies corresponding to features of an individual human heartbeat. In some examples, the high frequency portion includes features at frequencies between about 100 Hz and about 1000 Hz. In some examples, the high frequency portion includes features at frequencies between about 200 Hz and about 400 Hz.

[0046] In some examples, the sensor electronics of the device include an analog-to-digital converter (ADC) that digitizes a signal corresponding to the electromotive force, and a filter configured to receive the digitized signal from the ADC, remove therefrom contributions that do not correspond to the electrophysiological signal, and generate an output corresponding to the electrophysiological signal with the contributions removed.

[0047] In some examples, the sensor electronics of the device include a filter configured to remove contributions that do not correspond to the electrophysiological signal from the signal corresponding to the electromotive force and to generate an output corresponding to the removed electrophysiological signal. In some examples, the filter includes a high-pass filter, a band-block filter, or a band-pass filter. In some examples, the filter passes frequencies corresponding to a human heartbeat or heartbeat waveform.

[0048] In some examples, the electrophysiological signal includes a cardiac electrical signal.

[0049] In some examples, the first electrode or the second electrode of the device comprises a metal, a metal alloy, a transition metal oxide, a transparent conductive oxide, a carbon material, a doped semiconductor, a binary semiconductor, a ternary semiconductor, or a conductive polymer. In some examples, the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium. In some examples, the metal is oxidized or in the form of a metal salt. In some examples, the metal exhibits a nanostructured surface. In some examples, the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond. In some examples, the doped semiconductor is selected from the group consisting of p-doped or n-doped silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide. In some examples, the conductive polymer may be selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

[0050] In some examples, the device includes a solid contact layer disposed on the first electrode. In some examples, the solid contact layer includes a metal, a carbon material, a doped semiconductor, or a conductive polymer. In some examples, the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium. In some examples, the metal is oxidized or in the form of a metal salt. In some examples, the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond. In some examples, the doped semiconductor is selected from the group consisting of p-doped or n-doped silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide. In some examples, the conductive polymer may be selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

[0051] In some examples, the solid contact layer of the device comprises a redox couple. In some examples, the redox couple comprises metal centers (cations) having different oxidation states. In some examples, the metal centers are selected from the group consisting of Co(II) and Co(III), Ir(II) and Ir(III), and Os(II) and Os(III).

[0052] In some examples, the solid contact layer of the device comprises a mixed conductor or a mixed ionic-electronic conductor. In some examples, the solid contact layer comprises strontium titanate (SrTiO), titanium dioxide (TiO), (La,Ba,Sr)(Mn,Fe,Co)O, 3-d ,La2CuO 4+d, cerium (IV) oxide (CeO2), lithium iron phosphate (LiFePO4), and LiMnPO4.

[0053] In some instances, the solid contact layer of the device inhibits the transport of water from the biological fluid to the first electrode.

[0054] In some examples, the solid contact layer of the device is configured to enhance the electrical stability of the first electrode.

[0055] In some examples, the substrate of the device comprises a material selected from the group consisting of metal, glass, semiconductor, transparent conductive oxide, dielectric, ceramic, and polymer.

[0056] In some examples, the first electrode of the device is disposed directly on the substrate.

[0057] In some instances, the second electrode of the device is disposed directly on the substrate.

[0058] In some examples, the device further includes a biointerface membrane disposed on the first electrode. In some examples, the biointerface membrane is configured to inhibit biofouling of the first electrode. In some examples, the biointerface membrane is configured to release a therapeutic compound into the biological fluid. In some examples, the biointerface membrane includes multiple layers that can be arranged in a sequential pattern, a random pattern, or a combination thereof.

[0059] In some examples, the device includes a second biointerface membrane disposed on the second electrode. In some examples, the second biointerface membrane is the same as or chemically different from the first biointerface membrane. In some examples, the second biointerface membrane includes a biocompatible polymer and a salt. In some examples, the biointerface membrane consists essentially of the biocompatible polymer and the salt. In some examples, the biocompatible polymer is present in the second biointerface membrane in an amount of about 40 to about 70 weight percent. In some examples, the salt is present in the second biointerface membrane in an amount of about 30 to about 60 weight percent. In some examples, the biocompatible polymer is selected from the group consisting of polyurethane segments or polyurea segments. In some examples, the biocompatible polymer includes polycarbonate, polydimethylsiloxane (PDMS), methylene diphenyl diisocyanate (MDI), polysulfone (PSF), methyl methacrylate (MMA), poly(ε-caprolactone) (PCL), or 1,4-butanediol (BD). In some examples, the biocompatible polymer does not include polyvinylpyrrolidone (PVP). In some examples, the salt is selected from the group consisting of potassium chloride (KCl), sodium chloride (NaCl), magnesium chloride (MgCl), and calcium chloride (CaCl). In some examples, the biointerface membrane comprises multiple layers.

[0060] In some examples, the substrate of the device is elongated. In some examples, the substrate has an elongated shape that is planar or cylindrical. In some examples, the substrate of the device is elongated. In some examples, the substrate has an elongated shape that is planar or cylindrical. In some examples, the substrate of the device is planar. In some examples, the substrate is a wire.

[0061] In some examples, the sensor electronics of the device are configured to continuously measure the electromotive force.

[0062] In some examples, the sensor electronics of the device are configured to measure electromotive force at a dynamically configurable frequency.

[0063] In some examples, the sensor electronics of the device include a galvanostat.

[0064] In some examples, the sensor electronics of the device include a high impedance analog front end coupled to the first electrode and the second electrode.

[0065] In some examples, the sensor electronics of the device include at least one of an instrumentation amplifier, a differential amplifier, a voltage follower, a unity gain amplifier, an isolation amplifier, or a buffer.

[0066] In some examples, the sensor electronics of the device have an input impedance greater than about 100 gigaohms.

[0067] In some examples, the sensor electronics of the device are configured to maintain the second electrode at a substantially constant potential.

[0068] In some examples, the sensor electronics of the device include a non-volatile computer-readable memory configured to store the signal.

[0069] In some examples, the sensor electronics of the device include a transmitter configured to transmit the signal wirelessly.

[0070] Some examples herein provide methods for measuring the concentration of a target ion in an in vivo biological fluid. The method may include implanting an indwelling sensor. The sensor may include a substrate, a first electrode disposed on the substrate, an ionophore disposed on the substrate and configured to selectively transport the target ion to or within the first electrode, and a second electrode disposed on the substrate. The method may further include generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode. It should be apparent that any options described herein as relating to such an indwelling sensor, and operations performed using such a sensor, also relate to such methods.

[0071] Some examples herein provide methods for measuring electrophysiological signals conducted through an in vivo biological fluid. The method may include implanting an indwelling sensor. The sensor may include a substrate, a first electrode disposed on the substrate, and a second electrode disposed on the substrate. The method may include generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid transporting the electrophysiological signal to the first electrode. It should be apparent that any options described herein as relating to such indwelling sensors, and operations performed using such sensors, also relate to such methods.

[0072] Some examples herein provide devices for continuously measuring the concentration of a target analyte in an in vivo biological fluid. The device can include an indwelling sensor, which includes a substrate, a first electrode disposed on the substrate, an ionophore disposed on the substrate and configured to selectively transport a target ion to or within the first electrode, an enzyme configured to produce the target ion in response to an action on the target analyte, and a second electrode disposed on the substrate. The sensor electronics are configured to generate a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode. It should be apparent that any options described herein as relating to such other sensors and devices, and operations performed using such sensors and devices, also relate to such devices.

[0073] Some examples herein provide methods for continuously measuring the concentration of a target analyte in an in vivo biological fluid. The method may include implanting an indwelling sensor. The indwelling sensor may include a substrate, a first electrode disposed on the substrate, an ionophore disposed on the substrate and configured to selectively transport a target ion to or within the first electrode, an enzyme configured to produce the target ion in response to an action on the target analyte, and a second electrode disposed on the substrate. The method may include generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode. It should be apparent that any options described herein as relating to such other sensors and devices, as well as operations performed using such sensors and devices, also relate to such methods.

[0074] In one example, a device for continuously measuring the concentration of at least one target analyte in an in vivo biological fluid is provided, the device comprising an in-dwelling analyte sensor comprising a substrate, a first electrode disposed on the substrate, an ion-selective membrane comprising an ionophore disposed on the substrate and configured to selectively transport at least one target analyte to or within the first electrode, and a second electrode disposed on the substrate. In one aspect, the device further comprises sensor electronics configured to generate a signal corresponding to an electromotive force, the electromotive force based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the at least one target analyte to the first electrode.

[0075] In another aspect, alone or in combination with any of the previous aspects, the ion-selective membrane is a fluorosilicone rubber, a polydimethylsiloxane polymer, a silicone rubber, a polyurethane with a polysiloxane soft segment, a polyurethane with hard and soft segments, a water-based polyurethane, polyvinyl butyral, polymethyl methacrylate, polyvinyl acrylate, or a blend or graft polymer thereof.

[0076] In another aspect, alone or in combination with any of the previous aspects, the first or second electrode is independently a metal, a metal alloy, or a conductive polymer selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

[0077] In another embodiment, alone or in combination with any of the previous embodiments, the ionophore is 4-tert-butylcalix[4]arene-tetraacetic acid tetraethyl ester (sodium ionophore X); calix[4]arene-25,26,27,28-tetraol (calix[4]arene); potassium ionophore I (valinomycin); potassium ionophore II: bis[(benzo-15-crown-5)-4'-ylmethyl]pimelate (BB15C5 ); potassium ionophore III: 2-dodecyl-2-methyl-1,3-propanediylbis[N-[5'-nitro(benzo-15-crown-5)-4'-yl]carbamate] (BME44); 4,5-bis(benzoylthio)-1,3-dithiole-2-thione (Bz2dmit); 1,3,5-tris[10-(1-adamantyl)-7,9-dioxo-6,10-diazaundecyl]benzene (magnesium ionophore VI); calcium ionophore I (ETH 1001); calcium ionophore II (ETH129); selected from the group consisting of tridodecylmethylammonium chloride (TDMAC) and nonactin.

[0078] In another embodiment, alone or in combination with any of the previous embodiments, the ion-selective membrane further comprises a lipophilic salt selected from the group consisting of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTPFB), sodium tetraphenylborate (NaTPB), potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (KTFPB), and potassium tetrakis(4-chlorophenyl)borate (KTClPB).

[0079] In another embodiment, alone or in combination with any of the previous embodiments, the ion selective membrane is in direct contact with the first electrode.

[0080] In another aspect, alone or in combination with any of the previous aspects, the device further comprises a solid contact layer disposed between the first electrode and the ion-selective membrane. In another aspect, alone or in combination with any of the previous aspects, the solid contact layer comprises a metal, a carbon material, a carbon ink, a carbon paste, a doped semiconductor, or a conductive polymer. In another aspect, alone or in combination with any of the previous aspects, the solid contact layer is selected from the group consisting of Co(II) and Co(III), Ir(II) and Ir(III), and Os(II) and Os(III). In another aspect, alone or in combination with any of the previous aspects, the solid contact layer is selected from the group consisting of strontium titanate (SrTiO), titanium dioxide (TiO), (La,Ba,Sr)(Mn,Fe,Co)O 3-d ,La2CuO 4+d , cerium (IV) oxide (CeO2), lithium iron phosphate (LiFePO4), and LiMnPO4, or a mixed conductor or mixed ionic-electronic conductor.

[0081] In another aspect, alone or in combination with any of the previous aspects, the at least one target analyte is selected from the group consisting of sodium ions, potassium ions, hydrogen ions, lithium ions, magnesium ions, calcium ions, chloride ions, sulfite ions, sulfate ions, phosphate ions, ammonium ions, uric acid, urea, ketones, and glucose.

[0082] In another aspect, alone or in combination with any of the previous aspects, the device further comprises a biointerface membrane disposed on the ionophore and the first electrode, wherein the biocompatible polymer is selected from the group consisting of polyvinyl butyral (PVB), polyurethane, and silicone. In another aspect, alone or in combination with any of the previous aspects, the biointerface membrane is configured to release a therapeutic compound into a biological fluid.

[0083] In another aspect, alone or in combination with any of the previous aspects, the sensor electronics include a galvanostat. In another aspect, alone or in combination with any of the previous aspects, the sensor electronics are configured to (a) measure the electromotive force at a dynamically configurable frequency, (b) maintain the second electrode at a substantially constant potential, or (c) any combination thereof.

[0084] In another aspect, alone or in combination with any of the previous aspects, the electromotive force is further based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid conducting an electrophysiological signal to the first electrode, wherein a first contribution to the electromotive force from the electrophysiological signal changes rapidly relative to a second contribution to the electromotive force from a concentration of ions in the physiological fluid, and the sensor electronics are configured to parse the first contribution from the second contribution.

[0085] In another aspect, alone or in combination with any of the previous aspects, the electrophysiological signal comprises a cardiac electrical signal.

[0086] In another embodiment, alone or in combination with any of the previous embodiments, the device further comprises an enzyme configured to generate at least one target analyte, wherein the enzyme is selected from an oxidase.

[0087] In one example, a method for continuously measuring a concentration of a target analyte in an in vivo biological fluid is provided, the method including: embedding an indwelling sensor comprising a substrate, a first electrode disposed on the substrate, an ionophore disposed on the substrate and configured to selectively transport a target ion to or within the first electrode, and a second electrode disposed on the substrate; generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode.

[0088] In another aspect, the method further includes an enzyme configured to generate the target analyte. [Brief explanation of the drawings]

[0089] [Figure 1A] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 1B] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 1C] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 1D] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 1E] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 1F] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 1G] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 1H] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 1I] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or concentrations of target ions in an in vivo biological fluid. [Figure 2A]10A-10C are schematic diagrams illustrating additional exemplary configurations and components of a device for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids. [Figure 2B] 10A-10C are schematic diagrams illustrating additional exemplary configurations and components of a device for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids. [Figure 2C] 10A-10C are schematic diagrams illustrating additional exemplary configurations and components of a device for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids. [Figure 2D] 10A-10C are schematic diagrams illustrating additional exemplary configurations and components of a device for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids. [Figure 2E] 10A-10C are schematic diagrams illustrating additional exemplary configurations and components of a device for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids. [Figure 2F] 10A-10C are schematic diagrams illustrating additional exemplary configurations and components of a device for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids. [Figure 2G] 10A-10C are schematic diagrams illustrating additional exemplary configurations and components of a device for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids. [Figure 3] FIG. 10 is a schematic diagram illustrating exemplary operations and components for use in the present device and method for both measuring the concentration of target ions and measuring electrophysiological signals in biological fluids in vivo. [Figure 4A] FIG. 1 illustrates a flow of operations in an exemplary method for measuring the concentration of a target ion in an in vivo biological fluid. [Figure 4B] 1 illustrates a flow of operations in an exemplary method for measuring electrophysiological signals conducted through in vivo biological fluids. [Figure 5A] 1A-1C are diagrams illustrating various examples of sensor configurations. [Figure 5B]1A-1C are diagrams illustrating various examples of sensor configurations. [Figure 6A] 10A-10C are diagrams illustrating various additional examples of sensor configurations. [Figure 6B] 10A-10C are diagrams illustrating various additional examples of sensor configurations. [Figure 6C] 10A-10C are diagrams illustrating various additional examples of sensor configurations. [Figure 6D] 10A-10C are diagrams illustrating various additional examples of sensor configurations. [Figure 6E] 10A-10C are diagrams illustrating various additional examples of sensor configurations. [Figure 6F] 10A-10C are diagrams illustrating various additional examples of sensor configurations. [Figure 6G] 10A-10C are diagrams illustrating various additional examples of sensor configurations. [Figure 7A] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or target analyte concentrations in in vivo biological fluids. [Figure 7B] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or target analyte concentrations in in vivo biological fluids. [Figure 7C] FIG. 1 is a schematic diagram illustrating an exemplary configuration and components of a device for measuring electrophysiological signals and / or target analyte concentrations in in vivo biological fluids. [Figure 8] FIG. 1 illustrates a flow of operations in an exemplary method for determining the concentration of a target analyte in an in vivo biological fluid. [Figure 9A] 1 is a plot showing the measured sensitivity of an exemplary device to potassium ions. [Figure 9B] 1 is a plot showing the measured sensitivity of an exemplary device to potassium ions. [Figure 10A] 9A-9B are plots showing the measured sensitivity of the exemplary device described with reference to FIGS. 9A-9B to potassium ions in the presence of interfering ions. [Figure 10B]9A-9B are plots showing the measured sensitivity of the exemplary device described with reference to FIGS. 9A-9B to potassium ions in the presence of interfering ions. [Figure 11] 10A-10B are plots illustrating drift for an exemplary device described with reference to FIGS. [Figure 12] 1 shows plots of the measured absolute potential (E), potential gradient (m), and drift of another exemplary device in water (left) and interferent solution (right). [Figure 13A] FIG. 1 is a schematic diagram of an exemplary device configured to detect urea using a urease enzyme and an ionophore selective for ammonium ions. [Figure 13B] FIG. 1 is a schematic diagram of an exemplary device configured to detect urea using a urease enzyme and an ionophore selective for ammonium ions. [Figure 14A] FIG. 1 shows a schematic of an exemplary device using an ionophore that is selective for ammonium ions. [Figure 14B] FIG. 1 shows a schematic of an exemplary device using an ionophore that is selective for ammonium ions. [Figure 15] 14A-14B are plots showing the measured sensitivity of the exemplary device of FIGS. 14A-14B to ammonium ions. [Figure 16] 14A-14B and 15 show plots of the measured absolute potential (E0), potential gradient (m), and R2 for the exemplary device of FIGS. 14A-14B and 15 for ammonium ions. [Figure 17] FIG. 1 depicts an exemplary continuous analyte monitoring system configured to measure target ions and / or other analytes as discussed herein. [Figure 18A] FIG. 1 shows a plot of the measured sensitivity of an exemplary device. [Figure 18B] FIG. 1 shows a plot of the measured sensitivity of an exemplary device. [Figure 19A]FIG. 10 shows a plot of the measured sensitivity of an exemplary planar sensor device. [Figure 19B] FIG. 10 shows a plot of the measured sensitivity of an exemplary planar sensor device. [Figure 20A] FIG. 10 shows a plot of the measured sensitivity of an exemplary device in the presence of interfering ions. [Figure 20B] FIG. 10 shows a plot of the measured sensitivity of an exemplary device in the presence of interfering ions. [Figure 20C] FIG. 10 shows a plot of the measured sensitivity of an exemplary device in the presence of interfering ions. [Figure 20D] FIG. 10 shows a plot of the measured sensitivity of an exemplary device in the presence of interfering ions. [Figure 21] 1A, 1B, and 1C show plots of measured sensitivity of exemplary devices with selected solid contact materials. [Figure 22-1] FIG. 1A shows measured sensitivity data for an exemplary device having a resistive film. [Figure 22-2] 1A and 1B show measured sensitivity data for an exemplary device having a resistive film. [Figure 23-1] 1A and 1B show plots of the measured sensitivity of an exemplary device in vivo. [Figure 23-2] C shows a plot of the measured sensitivity of an exemplary device in vivo. [Figure 24] 1A and 1B show plots of the measured sensitivity of an exemplary device before and after sterilization. DETAILED DESCRIPTION OF THE INVENTION

[0090] Provided herein are devices and methods for continuously measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids.

[0091] The ability to continuously measure ion concentrations in real time can facilitate improved outcomes for patients with acute and chronic diseases in different fields such as nephrology, hepatology, and cardiology. Although bedside and point-of-care devices for the assessment of electrolytes in whole blood samples have been commercially available for the past 50 years, these measurements provide only a single snapshot in time, which has limited clinical utility.

[0092] Furthermore, electrophysiological recordings are widely used in the diagnosis and management of many diseases, such as atrial fibrillation and epilepsy. Previously known electrophysiological measurements utilize electrodes (often applied to the surface of the skin) to quantify variations in electrical potentials at a wide variety of scales, from single ion channel proteins to entire organs such as the heart. In cardiology, it allows for the assessment of heart rate and rhythm (via ECG / EKG), including their variability, as well as cardiovascular output.

[0093] Provided herein are body-mounted (in vivo) platforms that enable potentiometric readout of electrophysiological signals and / or concentrations of ions in biological fluids. For example, the devices may include a pair of electrodes configured to be inserted into the dermis or subcutaneous tissue of a host to potentiometrically monitor electrophysiological signals and / or concentrations of selected ions in the host's interstitial fluid, which concentrations correlate to the concentrations of those ions in the host's blood.

[0094] In another example, the device may include a single electrode configured to be inserted into the dermis or subcutaneous tissue of a host to potentiometrically monitor electrophysiological signals and / or the concentration of a selected ion in the host's interstitial fluid, which concentration correlates to the concentration of that ion in the host's blood.

[0095] In yet another example, the device may include two electrodes, one electrode configured to be inserted into the dermis or subcutaneous tissue of the host to potentiometrically monitor electrophysiological signals and / or concentrations of selected ions in the interstitial fluid of the host, and the other electrode configured to be external to the host.

[0096] For example, interstitial fluid can have ion concentrations that correlate to those of whole blood and can be measured continuously. A continuous basis of measurement can span a period of 3 to 15 days or more. Measurements discussed herein are taken periodically at intervals of seconds, minutes, hours, or other time periods, or combinations of time periods.

[0097] The present devices and methods may enable a host to continuously monitor the concentration of any suitable ion in the blood from any location (e.g., at home, at work, while traveling, or elsewhere), which may provide improved outcomes for the host. For example, the host may be less likely to need to visit a clinic for ion concentration monitoring, may receive any necessary treatment with a reduced time lag, and may ultimately be more likely to develop severe ion imbalances, such as severe hyperkalemia (blood > 6.5 mM K). +, or any other clinically relevant threshold), may be reduced. Additionally, or alternatively, the present devices and methods may enable the host to continuously monitor his or her cardiac electrical signals, which may provide improved outcomes for the host. For example, the host may be able to reduce the need to visit a clinic or use cumbersome home-based equipment for periodic monitoring of the cardiac electrical signals, receive any necessary treatment with a reduced time lag, and ultimately reduce the likelihood of suffering from cardiac arrhythmia, ventricular fibrillation, or sudden cardiac death. Some examples herein provide devices and methods for continuous and simultaneous or alternating measurement of both ion concentrations and electrophysiological signals using a single body-mounted sensor. However, it will be understood that the present devices and methods may be used to continuously perform only one of such measurements, e.g., measure either ion concentrations or electrophysiological signals, but not both.

[0098] In some examples, the devices of the present disclosure are used in the treatment of chronic kidney disease, for example, in the diagnosis, management, and treatment of the disease. Additionally, the devices are used in dialysis to provide treatment guidance and alerts. In some examples, the devices of the present disclosure are used in heart failure treatment and management, for the administration of medications such as RAASi drugs, diuretics, insulin therapy, and other uses. In some examples, the devices of the present disclosure are additionally or alternatively used to diagnose other problems resulting from ionic imbalances of ions that can be measured using the techniques described herein. Other conditions for which the devices of the present disclosure are used include diabetic ketoacidosis, hypervolemia / hypovolemia, ascites, asthma, genetic disorders, and asthma. Additionally or alternatively, the devices of the present disclosure are used during hospitalization and surgery to monitor the patient's condition.

[0099] We first explain some exemplary terms used herein, then provide exemplary devices for measuring electrophysiological signals and / or concentrations of target ions in vivo, their components, and methods for making and using such devices.

[0100] term To facilitate understanding of the disclosed embodiments, several terms are defined below.

[0101] As used herein, the phrases “analyte measuring device,” “analyte monitoring device,” “analyte sensing device,” and / or “multi-analyte sensor device” are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, apparatus and / or systems responsible for detecting specific analytes or combinations of analytes or transducing signals associated therewith. For example, but not limited to, these terms may refer to instruments responsible for detecting specific analytes or combinations of analytes. In one example, the instrument includes a sensor coupled to a circuit arranged within a housing and configured to process signals associated with analyte concentrations into information. In one example, such devices and / or systems are capable of providing specific quantitative, semi-quantitative, qualitative, and / or semi-qualitative analytical information using a biological recognition element combined with a transduction (detection) element.

[0102] As used herein, the terms "biosensor" and / or "sensor" are broad terms and are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, a portion of an analyte measuring device, analyte monitoring device, analyte sensing device, and / or multi-analyte sensing device responsible for detecting a specific analyte or combination of analytes or transducing a signal associated therewith. In one example, a biosensor or sensor generally comprises a body and working, reference, and / or counter electrodes coupled to the body and forming a surface configured to provide a signal during an electrochemical reaction. One or more membranes may be affixed to the body and cover the electrochemically reactive surface. In one example, such biosensors and / or sensors are capable of providing a specific quantitative, semi-quantitative, qualitative, or semi-qualitative analytical signal using a biological recognition element combined with a transduction (detection) element.

[0103] As used herein, the phrases "sensing moiety," "sensing membrane," and "sensing mechanism" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), and refer, without limitation, to a portion of a biosensor and / or sensor responsible for detecting a particular analyte or combination of analytes or transducing a signal associated therewith. In one example, a sensing moiety, sensing membrane, and / or sensing mechanism generally comprises electrodes configured to provide a signal during an electrochemical reaction with one or more membranes covering an electrochemically reactive surface. In one example, such a sensing moiety, sensing membrane, and / or sensing mechanism can provide specific quantitative, semi-quantitative, qualitative, or semi-qualitative analytical information using a biological recognition element combined with a transduction (detection) element.

[0104] As used herein, the term "about" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to allowing for a degree of variability in values ​​or ranges, for example, within 10%, within 5%, or within 1% of the stated limits of a stated value or range, including, but not limited to, the exactly stated value or range. As used herein, the term "substantially" refers to a majority or majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the phrase "substantially free" can mean having no or an insignificant amount of material present such that the amount of material present does not affect the material properties of the composition including the material, such as about 0% to about 5% by weight of the composition being the material, or about 0% to about 1%, or about 5% by weight or less, or about 4.5% by weight or less, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001% by weight or less, or about 0% by weight.

[0105] As used herein, the terms "stick" and "adhere" are broad terms and are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, holding, joining, or fastening, for example, by adhering, bonding, grasping, interpenetrating, or fusing.

[0106] As used herein, the term "analyte" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, a substance or chemical constituent in a biological fluid (e.g., blood, interstitial fluid, cerebrospinal fluid, lymphatic fluid, urine, sweat, saliva, etc.) that can be analyzed. Analytes can include naturally occurring substances, man-made substances, metabolites, electrolytes, ions, gases, hormones, proteins, enzymes, neurotransmitters, infectious agents, and / or reaction products. In some examples, the analyte measured by the sensing region, devices, and methods is glucose. However, other analytes are contemplated as well, including acarboxyprothrombin; acylcarnitines; adenine phosphoribosyltransferase; adenosine deaminase; albumin; α-fetoprotein; amino acid profile (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); bilirubin, biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-β-hydroxycholic acid; cortisol; Creatine; Creatine kinase; Creatine kinase MM isoenzyme; Creatinine; Cyclosporine A; d-Penicillamine; Desethylchloroquine; Dehydroepiandrosterone sulfate; DNA (acetylation polymorphisms, alcohol dehydrogenase, alpha-1-antitrypsin, cystic fibrosis, Duchenne / Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, Hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber's hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol); Desbutylhalofantrine; Dihydropteridine reductase;Diphtheria / tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids / acylglycines; free β-human chorionic gonadotropin; free erythrocyte porphyrins; free thyroxine (FT4); free triiodothyronine (FT3); fumarylacetoacetase; galactose / gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione peroxidase; glycerol; glycocholate; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-α-hydroxyprogesterone hypoxanthine phosphoribosyltransferase; immunoreactive trypsin; beta-hydroxybutyrate; ketones; lactate; lead; lipoproteins ((a), B / A-1, β); lysozyme; mefloquine; netilmicin; oxygen; phenobarbitone; phenytoin; phytanic acid / pristanic acid; potassium, sodium, and / or other blood electrolytes; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse triiodothyronine tri-iodothyronine, rT3); selenium; serum pancreatic lipase; sisomicin; somatomedin C; specific antibodies (adenovirus, antinuclear antibody, anti-zeta antibody, arbovirus, pseudorabies virus, dengue virus, guinea worm, Echinococcus granulosus, Entamoeba histolytica, enterovirus, giardiasis, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, Leishmania Ptospira, measles / mumps / rubella, Mycobacterium leprae, Mycoplasma pneumoniae, myoglobin, Onchocerca volvulus, parainfluenza virus, malaria parasites, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (tsutsugamushi disease), Schistosoma mansoni, Toxoplasma gondii, Treponema pallidum, Trypanosoma cruzi / rangeli, vesicular stomatitis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone;Analytes may be naturally occurring in biological fluids or endogenous, e.g., metabolites, hormones, antigens, antibodies, etc. ... Alternatively, the analyte can be introduced into the body or can be exogenous, such as a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamine, methamphetamine, Ritalin, Silurt, Preludine, Didrex, Prestate, Boranil, Sandre antidepressants (barbiturates, tranquilizers such as methaqualone, Valium, Librium, Miltaunt, Serax, Equuanil, and Tranxine); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, and psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tasionex, fentanyl, Darvon, Talwin, and Lomotil); synthetic narcotics (fentanyl, meperidine, amphetamine, methamphetamine, and phencyclidine analogs, e.g., ecstasy); anabolic steroids;Analytes of interest include, but are not limited to, nicotine and nicotine. Metabolites of drugs and pharmaceutical compositions are also contemplated. Analytes such as neurochemicals and other chemicals produced in the body, such as ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (FHIAA), and histamine, can also be analyzed.

[0107] As used herein, the term "ion" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, an atom or molecule that has a net electrical charge due to the loss or gain of one or more electrons. Ions in biological fluids may be referred to as "electrolytes." Non-limiting examples of ions in biological fluids include sodium (Na + ), potassium (K + ), magnesium (Mg 2+ ), calcium (Ca 2+ ), hydrogen (H + ), lithium (Li + ), chloride (Cl - ), sulfide (S 2- ), sulfite (SO3 2- ), sulfate (SO4 2- ), phosphate (PO4 3- ), and ammonium (NH4 + ) An ion is an example of an analyte.

[0108] As used interchangeably herein, the phrases "biointerface membrane" and "biointerface layer" are broad terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, a permeable membrane (which may include multiple domains) or layer that acts as a bioprotective interface between the host tissue and the implantable device. The terms "biointerface" and "bioprotective" are used interchangeably herein.

[0109] As used herein, the phrase "barrier cell layer" is a broad phrase that is to be given its ordinary and customary meaning to those skilled in the art (and is not to be limited to any special or customized meaning), and refers, without limitation, to the portion of the foreign body response that forms a cohesive monolayer of cells (e.g., macrophages and foreign body giant cells) that substantially blocks the transport of molecules and other substances into the implantable device.

[0110] As used herein, the terms "baseline" and "background" are broad terms that are to be given their ordinary and customary meaning to those of skill in the art (and are not to be limited to any special or customized meaning), and refer to, but are not limited to, the amount of signal (e.g., in the form of current and / or voltage) produced by a sensor that is independent of the concentration of the analyte being measured.

[0111] As used herein, the term "biostable" is a broad term that is to be given its ordinary and customary meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, materials that are relatively resistant to degradation by processes encountered in vivo.

[0112] As used herein, the term "coaxial" should be interpreted broadly to include sensor architectures having elements aligned along a shared axis around a core that may be configured to have a circular, elliptical, triangular, polygonal, or other cross-section, and such elements may include electrodes, insulating layers, or other elements that may be positioned circumferentially around a core layer, such as a core electrode or core polymer wire.

[0113] As used herein, the term "continuous" is a broad term and is to be given its ordinary and customary meaning to those of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, an uninterrupted or unbroken portion, domain, coating, or layer of the sensor system discussed herein.

[0114] As used herein, the term "discontinuous" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, disconnected, interrupted, or separated portions, layers, coatings, or domains of the systems discussed herein.

[0115] As used herein, the term "semi-continuous" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, a portion, coating, domain, or layer that includes one or more continuous and discontinuous portions, coatings, domains, or layers. For example, a coating that is disposed around but not over a sensing area is "semi-continuous."

[0116] As used herein, the phrase "continuous analyte sensing" is a broad phrase that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, continuous, continuous, and / or intermittent (but periodic) monitoring of analyte concentration over a period of time, such as, for example, every about 5 seconds or less to about 10 minutes or more. In further embodiments, monitoring of the analyte concentration is performed every about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds to about 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, 4.00, 4.25, 4.50, 4.75, 5.00, 5.25, 5.50, 5.75, 6.00, 6.25, 6.50, 6.75, 7.00, 7.25, 7.50, 7.75, 8.00, 8.25, 8.50, 8.75, 9.00, 9.25, 9.50, or 9.75 minutes. In some examples, the analyte concentration is monitored about every 15 minutes, or about every 30 minutes, or about every 60 minutes. Additionally or alternatively, in some examples, the analyte concentration is monitored about every 1.5 hours, about every 2 hours, about every 4 hours, about every 6 hours, or about every 8 hours.

[0117] As used herein, the term "coupled" is a broad term and is to be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, two or more system elements or components that are configured to be electrically, mechanically, thermally, operatively, chemically, or otherwise attached to at least one other. Similarly, as used herein, the phrases "operably connected," "operably linked," and "operably coupled" can refer to one or more components that are coupled to another component in a manner that facilitates the transmission of at least one signal between the components. In some examples, the components are part of the same structure and / or are integrated with one another (i.e., "directly coupled"). In other examples, the components are connected via remote means. For example, one or more electrodes can be used to detect analytes in a sample and convert that information into a signal, which can then be transmitted to an electronic circuit. In this example, the electrodes are "operably coupled" to the electronic circuit. As used herein, the phrase "removably coupled" may refer to two or more system elements or components that are configured or configured to be electrically, mechanically, thermally, operatively, chemically, or otherwise attached and detached without damaging any of the coupled elements or components. As used herein, the phrase "permanently coupled" may refer to two or more system elements or components that are configured or attached electrically, mechanically, thermally, operatively, chemically, or otherwise attached, but cannot be separated without damaging at least one of the coupled elements or components.

[0118] As used herein, the term "distal" is a broad term and is to be given its ordinary and customary meaning to those skilled in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, an area that is relatively far away from a reference point such as an origin or attachment point.

[0119] As used herein, the term "domain" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, a region of a membrane system that may be a layer, a uniform or non-uniform gradient (e.g., an anisotropic region of a membrane), or a portion of a membrane that is capable of sensing one, two, or more analytes. Domains discussed herein can be formed as a single layer, as two or more layers, as a pair of bilayers, or as combinations thereof.

[0120] As used herein, the term "drift" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning), referring to, but not limited to, a gradual increase or decrease in signal over time that is unrelated to changes in host systemic analyte concentrations, such as the host's postprandial glucose concentration. While not wishing to be bound by any particular theory or any particular analyte, drift associated with glucose measurements is believed to be the result of a local decrease in glucose transport to the sensor, for example, due to the formation of a foreign body capsule (FBC). It may also be the result of a gradual decrease in the activity or amount of enzymes, such as glucose oxidase, within the sensor. It is also believed that an insufficient amount of interstitial fluid surrounding the sensor can reduce oxygen and / or glucose transport to the sensor. In one example, an increase in local interstitial fluid can slow or reduce drift, thus improving sensor performance. Signal drift can occur due to changes in the baseline / background signal measured by the sensor and / or changes in the sensitivity exhibited by the sensor. Drift may also be the result of sensor electronics or algorithmic models used to compensate for noise or other anomalies that may occur with electrical signals in the picoampere and nanoampere ranges, including the microampere, picoampere, nanoampere, and femtoampere ranges. As discussed herein, "sensor electronics" may include various combinations of hardware and / or software, including circuitry, employed to detect, receive, process, store, and / or analyze the signal(s) generated by the devices and systems discussed herein.

[0121] As used interchangeably herein, the phrases "drug-release membrane" and "drug-release layer" are each broad phrases that are given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, a permeable or semi-permeable membrane that is permeable to one or more bioactive agents. In one example, a "drug-release membrane" and a "drug-release layer" can include two or more domains and can be several microns or thicker. In one example, the drug-release layer and / or drug-release membrane is substantially the same as the biointerface layer and / or biointerface membrane. In another example, the drug-release layer and / or drug-release membrane is separate from the biointerface layer and / or biointerface membrane. Further examples of drug release layers and membranes can be found in pending U.S. patent application Ser. No. 17 / 697,701, entitled "DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR," filed March 17, 2022, which is incorporated by reference in its entirety, and U.S. provisional application Ser. No. 63 / 318,901, entitled "DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR," filed March 11, 2022, which is incorporated by reference in its entirety, and U.S. provisional application Ser. No. 63 / 244,644, entitled "DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR," filed September 16, 2021, which is incorporated by reference in its entirety.

[0122] As used herein, the term "electrochemically reactive surface" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the surface of an electrode on which an electrochemical reaction occurs. In various examples, the by-product of the reaction of the analyte being detected includes at least one measurable species. The at least one measurable species is capable of reacting with an electrochemically active surface, such as a working electrode.

[0123] As used herein, the phrase "hard segment" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, an element of a copolymer, such as a polyurethane, polycarbonate polyurethane, or polyurethane urea copolymer, that imparts resistance properties, such as resistance to bending or twisting. The term "hard segment" can be further characterized as a crystalline, semi-crystalline, or glassy material that has a glass transition temperature, typically determined by dynamic scanning calorimetry ("Tg"), above ambient temperature. Exemplary hard segment elements used to prepare polycarbonate polyurethane or polyurethane urea hard segments include norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocyanate, and cyclohexane-4,4'-diisocyanate. isocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0124] As used herein, the term "host" is a broad term and is given its ordinary and customary meaning to those of skill in the art (and is not limited to any special or customized meaning), and refers to mammals, such as, but not limited to, humans.

[0125] As used herein, the terms "indwelling," "indwelling," "implanted," or "implantable" are broad terms that are to be given their ordinary and customary meaning to those of ordinary skill in the art (and are not to be limited to any special or customized meaning) and refer to an object (e.g., a sensor) that is inserted or configured to be inserted subcutaneously (i.e., within the fatty layer between the skin and muscle), intradermally (i.e., penetrating the stratum corneum and located within the epidermal or dermal layer of the skin), or transcutaneously (i.e., penetrating, entering, or passing through intact skin), which may result in a sensor having an in vivo portion and an ex vivo portion. The term "indwelling" also encompasses an object configured to be inserted subcutaneously, intradermally, or percutaneously, whether or not it is itself inserted.

[0126] As used herein, the phrase "insertable volume" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the volume anterior and lateral to the insertion path of the insertable portion of the analyte sensor, as described herein, and the incision made in the skin for inserting the insertable portion of the analyte sensor. The insertable volume also includes up to 5 mm radially or perpendicularly to the volume anterior and lateral to the insertion path.

[0127] As used herein, the terms "interfering substance" and "interfering species" are broad terms and are to be given their ordinary and customary meaning to those of skill in the art (and are not limited to any special or customized meaning), and refer to effects and / or species, including, but not limited to, ions, electroactive substances, endogenous circulating species, exogenous circulating species, pharmacological agents, and / or electromagnetic waves (such as from a magnetic resonance imaging (MRI) system or medical device), that interfere with the measurement of an analyte of interest at a sensor, producing a signal that does not accurately represent the analyte measurement.

[0128] As used herein, the term "in vivo" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), encompassing, but not limited to, portions of a device (e.g., a sensor) adapted for insertion into and / or presence within the body of a host.

[0129] As used herein, the term "ex vivo" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), encompassing, but not limited to, a portion of a device (e.g., a sensor) that is adapted to reside and / or exist outside the host organism.

[0130] As used herein, the term "membrane" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to a structure configured to perform functions including, but not limited to, protecting exposed electrode surfaces from the biological environment, resisting (limiting) the diffusion of analytes, acting as a matrix for catalysts to enable enzymatic reactions, limiting or screening interfering species, providing hydrophilicity at electrochemically reactive surfaces of a sensor interface, acting as an interface between host tissue and an implantable device, modulating host tissue response through drug (or other substance) release, and combinations thereof. As used herein, the terms "membrane" and "matrix" are meant to be interchangeable.

[0131] As used herein, the phrase "membrane system" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, a permeable or semi-permeable membrane that may be composed of two or more domains, layers, or layers within domains, that is composed of materials several microns or more in thickness, and that is at least permeable to the ions whose concentrations are to be measured.

[0132] As used herein, the term "micro" is a broad term and is to be given its ordinary and customary meaning to those skilled in the art (and is not to be limited to any special or customized meaning), and refers to a size of approximately 10 microns that is not visible without magnification. -6 "Micro" refers to objects or scales that are small, but not limited to, those on the order of 10 microns. The term "micro" is in contrast to the term "macro," which refers to objects that are large enough to be seen without magnification. Similarly, the term "nano" refers to objects that are approximately 10 -9 Refers to a small object or scale of m.

[0133] As used herein, the term "molecular physiological measure" (MPM) is a broad term used in its ordinary sense to include, but is not limited to, signals that can be monitored in vivo or ex vivo, or via a combination of both, using the systems and methods discussed herein, including heart rate, heart rate waveform(s), tissue oxygenation, bioelectrical impedance, galvanic response, respiration, core body temperature, and blood pressure, which can be measured and analyzed as discussed herein.

[0134] As used herein, the term "noise" is a broad term and is used in its ordinary sense to include, but is not limited to, signals detected by the sensor or sensor electronics that are unrelated to analyte concentration and may result in reduced sensor performance. Noise can arise, for example, from physiological sources (protein adsorption, foreign body response, etc.), pharmacological sources (drugs, etc.), external perturbations (e.g., pressure-induced sensor damping, triboelectric effects, motion artifacts, electromagnetic waves (e.g., MRI systems or medical devices)), and / or sensor electronics (e.g., Johnson-Nyquist noise, shot noise). Some types of noise are observed within several hours (e.g., about 2 to about 24 hours) after sensor insertion. After the first 24 hours, noise may disappear or decrease, but in some hosts, noise may persist for about 3 to 4 days. In some cases, noise can be reduced using predictive modeling, artificial intelligence, and / or algorithmic means. In other cases, noise can be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as by using a drug-releasing layer with at least one bioactive agent. For example, the noise of one or more exemplary biosensors as disclosed herein can be determined and then compared qualitatively or quantitatively. By way of example, by acquiring a raw signal time series at a fixed sampling interval (in microvolts (μV)), a smoothed version of the raw signal time series can be obtained, for example, by applying a third-order low-pass digital Chebyshev Type II filter. Other smoothing algorithms can also be used. At each sampling interval, the absolute difference in μV can be calculated to provide a smoothed time series. This smoothed time series can be converted to units of mM (units of "noise") using the glucose sensitivity time series in μV / mM, which is derived by using a mathematical model between the raw signal and reference blood ion measurements (e.g., obtained from a blood mineral analyzer). Optionally, the time series can be aggregated, for example, by hour or day, as desired.Comparison of corresponding time series between different exemplary biosensors having a drug-releasing layer and one or more bioactive agents of the present disclosure provides a qualitative or quantitative determination of noise improvement.

[0135] As used herein, the terms "optional" or "optionally" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), meaning, without limitation, that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when it does not occur.

[0136] As used herein, the term "planar" should be interpreted broadly to describe a sensor architecture having a substrate including a first side and a second side and a plurality of elements disposed on one or more sides of the substrate, which may or may not be electrically or otherwise coupled, and which may include conductive or insulating layers or elements configured to operate as a circuit.

[0137] As used herein, the term "proximal" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning), referring to, but not limited to, the spatial relationship between various elements compared to a particular reference point. For example, some example devices include membrane systems having a biointerface membrane or layer that includes an ionophore. If the electrode is considered to be the reference point and the ionophore-containing layer is positioned closer to the electrode than the biointerface membrane, then the ionophore-containing layer is more proximal to the sensor than the biointerface membrane.

[0138] As used herein, the phrases and terms "processor module" and "microprocessor" are each broad phrases and terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning) and refer to, but are not limited to, a computer system, state machine, processor, or the like, designed to perform arithmetic or logical operations using logic circuitry that responds to and processes the basic instructions that drive a computer.

[0139] As used herein, the phrase "sensing membrane" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers, without limitation, to a permeable or semi-permeable membrane that may include one or more domains, layers, or layers within domains, is composed of a material having a thickness of several microns or more, and is permeable to reactants and / or co-reactants used in determining an analyte of interest. As an example, a sensing membrane may include immobilized ionophores that selectively bind ions to allow the concentration of those ions to be measured.

[0140] During typical operation of an analyte measuring device, biosensor, sensor, sensing region, sensing moiety, or sensing mechanism, a biological sample, e.g., blood or interstitial fluid, or a component thereof, contacts, either directly or after passing through one or more membranes, an ionophore capable of specifically and reversibly binding at least one ion. The interaction of the biological sample or its component with the analyte measuring device, biosensor, sensor, sensing region, sensing moiety, or sensing mechanism results in a transduction of a signal that allows for a qualitative, semi-qualitative, quantitative, or semi-qualitative determination of the ion in the biological sample.

[0141] Various examples of sensor architectures can be found in pending U.S. Application No. 63 / 321,538, entitled "CONTINUOUS ANALYTE SENSOR SYSTEMS," filed March 17, 2022, which is incorporated herein by reference in its entirety, as well as U.S. Patent No. 8,133,178 to Brauker et al., and U.S. Patent No. 8,828,201 to Simpson et al., U.S. Patent No. 9,131,885 to Simpson et al., U.S. Patent No. 9,237,864 to Simpson et al., and U.S. Patent No. 9,763,608 to Simpson et al., which are incorporated herein by reference in their entireties. Examples of methods of forming the sensors (sensor electrode layouts and membranes) and sensor systems discussed herein can be found in currently pending U.S. Patent Application Publication No. 2019 / 0307371 to Boock et al., which is incorporated herein by reference in its entirety.

[0142] In one example, the sensing region determines selectivity between one or more analytes such that only the analyte that must be measured results in (transduces) a detectable signal. This selection can be based on any chemical or physical recognition of the analyte by the sensing region, where the chemical composition of the analyte does not change, or where the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.

[0143] The sensing region converts the recognition of the analyte into a semi-quantitative or quantitative signal. Thus, as used herein, "transducing" or "transduction" and their grammatical equivalents encompass electrochemical techniques and methods. Electrochemical properties include current and / or voltage, capacitance, and potential.

[0144] As used herein, the phrases and terms “small diameter sensor,” “miniature structured sensor,” and “microsensor” are broad phrases and terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning) and refer to, but are not limited to, a sensing mechanism having at least one dimension less than about 2 mm. In further embodiments, the sensing mechanism has at least one dimension less than about 1 mm. In some examples, the sensing mechanism (sensor) is less than about 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm. In some examples, the largest independently measured dimension of length, width, diameter, thickness, or circumference of the sensing mechanism does not exceed about 2 mm. In some examples, the sensing mechanism is a needle-type sensor having a diameter less than about 1 mm. See, for example, U.S. Patent No. 6,613,379 to Ward et al. and U.S. Patent No. 7,497,827 to Brister et al., both of which are incorporated by reference in their entireties. In some alternative embodiments, the sensing mechanism includes electrodes deposited on a planar or substantially planar substrate, and the thickness of the embedded portion is less than about 1 mm. See, for example, U.S. Patent No. 6,175,752 to Say et al. and U.S. Patent No. 5,779,665 to Mastrototaro et al., both of which are incorporated by reference in their entireties. Examples of methods of forming sensors (sensor electrode layout and films) and sensor systems used to prepare the present sensors are found in U.S. Patent Application Publication No. 2019 / 0307371 to Boock et al., which is incorporated by reference in its entirety.

[0145] As used herein, the term "sensitivity" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the amount of signal (e.g., in the form of current and / or voltage) produced by a given amount (unit) of analyte measured. For example, in one example, the sensor has a current sensitivity (or slope) of about 1 to about 100 picoamps per 1 mg / dL of glucose analyte. In another example, the sensor has a potential sensitivity (or slope) of about 10 to 100 millivolts per order of magnitude (base 10 digit) change in potassium ion, and in some examples, a potential sensitivity (or slope) of about 59 millivolts per order of magnitude (base 10 digit) change in potassium ion at essentially zero current (less than 0.1 picoamps).

[0146] As used herein, the phrase "soft segment" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, an element of a copolymer, such as a polyurethane, polycarbonate-polyurethane, or polyurethane-urea copolymer, that imparts flexibility to the chain. The phrase "soft segment" can be further characterized as an amorphous material having a low Tg, e.g., a Tg that is typically no higher than ambient temperature or normal mammalian body temperature.

[0147] As used herein, the terms "zwitterion" and "zwitterionic compound" are broad terms and phrases, respectively, that are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning), and refer to, but are not limited to, compounds in which a neutral molecule of the compound has a unit positive charge and a unit negative charge at different locations within the molecule. Such compounds are a type of zwitterionic compound and are sometimes referred to as "inner salts."

[0148] Devices and methods are provided for measuring electrophysiological signals and / or target analyte concentrations in vivo.

[0149] Non-limiting examples of devices and methods for measuring physiological signals and / or target analyte concentrations in vivo will now be described with reference to Figures 1A-1I, 2A-2G, 3, 4A-4B, 5A-5B, 6A-6G, 7A-7C, and 8.

[0150] 1A-1I are schematic diagrams illustrating exemplary configurations and components of a device 100 for measuring in vivo electrophysiological signals and / or concentrations of target analytes, such as target ions 11, in a biological fluid 10. Referring initially to FIG. 1A, the device 100 includes an indwelling sensor 110 and sensor electronics 120. The sensor 110 includes a substrate 101, a first electrode (E1) 111 disposed on the substrate, and a second electrode (E2) 117 disposed on the substrate. The first electrode 111 may be referred to as a working electrode (WE), while the second electrode 117 may be referred to as a reference electrode (RE). In one example, the sensor electronics 120 is configured to generate a signal corresponding to an electromotive force (EMF). In some examples, the EMF is based, at least in part, on a potential difference generated between the first electrode 111 and the second electrode 117 in response to the biological fluid 10 conducting an electrophysiological signal to the first electrode 111. In some examples, the EMF is based at least in part on a potential difference generated between the first electrode 111 and the second electrode 117, the potential difference being a function of the potential of the first electrode 111 in response to the concentration of the target analyte present in the biological fluid 10. In one example, the sensor electronics 120 is configured to use the signal to generate an output corresponding to a measurement of the signal. In various examples, the EMF is based at least in part on a potential difference between (i) either the first electrode 111 or the second electrode 117 and (ii) another electrode spaced apart from the first electrode or the second electrode.

[0151] Additionally or alternatively, in some examples, device 100 may include an ionophore 115 disposed on substrate 101 and configured to selectively transport target ions 11 to or within first electrode 111. In one example, the EMF is based at least in part on a potential difference generated between first electrode 111 and second electrode 117 in response to ionophore 115 transporting target ions to or through first electrode 111. In one example, sensor electronics 120 (and / or an external device receiving the signal via a suitable wired or wireless connection) is configured to use the signal to generate an output corresponding to a measure of the concentration of the target ions in the biological fluid. Further details regarding the configuration and use of sensor electronics 120 are provided further below.

[0152] Optionally, first electrode 111 is used to measure electrophysiological signals in addition to ion concentrations. In other examples, such as when device 100 is configured to detect electrophysiological signals but not ion concentrations, first electrode 111 need not include an ionophore, such as ionophore 115. In other examples, first electrode 111 may include an ionophore that is inert so as not to interfere with the measurement of electrophysiological signals.

[0153] 1A, biological fluid 10 may include multiple ions 11, 12, 13, 14, and 15. In one example, device 100 is configured to measure the concentration of ion 11, and thus, such ion is referred to as the "target" ion. In one example, target ion 11 may be any suitable ion, and in a non-limiting example, is sodium (Na + ), potassium (K + ), magnesium (Mg 2+ ), calcium (Ca 2+ ), hydrogen (H + ), lithium (Li + ), chloride (Cl - ), sulfite (SO3 2- ), sulfate (SO4 2- ), phosphate (PO4 3-), and ammonium (NH4 + In one example, ions 12, 13, 14, and 15 are selected from the group consisting of sodium (Na + ), potassium (K + ), magnesium (Mg 2+ ), calcium (Ca 2+ ), hydrogen (H + ), lithium (Li + ), chloride (Cl - ), sulfide (S 2- ), sulfite (SO3 2- ), sulfate (SO4 2- ), phosphate (PO4 3- ), and ammonium (NH4 + ions 12, 13, 14, and 15. In one example, ions 12, 13, 14, and 15 are considered interferents in the measurement of target ion 11 because they have the potential to interfere with the measurement of target ion 11 by the sensor, producing a signal that does not accurately represent the concentration of target ion 11. In one example, ionophore 115 is selected to selectively transport target ion 11 to or within first electrode 111 and completely, partially, and / or substantially inhibit the transport of one or more of ions 12, 13, 14, or 15 to or within first electrode 111. For example, as shown in FIG. 1B , ionophore 115 may selectively transport or selectively bind target ion 11 from biological fluid 10 or biointerface membrane 114 (e.g., if provided, as discussed below) to and within first electrode 111, while ions 12, 13, 14, and 15 may substantially remain within biological fluid 10 or biointerface membrane 114. Thus, the contribution to the potential difference between the first electrode 111 and the second electrode 117 in response to the transport of ions to or within the first electrode 111 is caused primarily by the target ion 11, rather than substantially by one or more of ions 12, 13, 14, or 15.

[0154] A wide variety of ionophores 115 can be used to selectively transport corresponding ions in the manner described with reference to FIGS. 1A-1B. In one example, when the target ion 11 is hydrogen (via peroxide), the ionophore 115 is tridodecylamine, 4-nonadecylpyridine, N,N-dioctadecylmethylamine, octadecyl isonicotinate, or calix[4]aza-crown. In another example, when the target ion 11 is lithium, the ionophore 115 is ETH149, N,N,N',N',N'',N''-hexacyclohexyl-4,4',4''-propylidinetris(3-oxabutylamide), or 6,6-dibenzyl-1,4,8-11-tetraoxacyclotetradecane. In another example, when the target ion 11 is sulfite, the ionophore 115 is octadecyl 4-formylbenzoate. In another example, when the target ion 11 is sulfate, the ionophore 115 is 1,3-[bis(3-phenylthioureidomethyl)]benzene or zinc phthalocyanine. In another example, when the target ion 11 is phosphate, the ionophore 115 is 9-decyl-1,4,7-triazacyclodecane-8,10-dione. In another example, when the target ion 11 is sodium, the ionophore 115 is 4-tert-butylcalix[4]arene-tetraacetic acid tetraethyl ester (sodium ionophore X) or calix[4]arene-25,26,27,28-tetraol (calix[4]arene). In another example, when the target ion 11 is potassium, the ionophore 115 is potassium ionophore I (valinomycin), potassium ionophore II (BB15C5), or potassium ionophore III (BME44). In another example, when the target ion is magnesium, the ionophore 115 is 4,5-bis(benzoylthio)-1,3-dithiole-2-thione (Bz2dmit) or 1,3,5-tris[10-(1-adamantyl)-7,9-dioxo-6,10-diazaundecyl]benzene (magnesium ionophore VI).In another example, when the target ion is calcium, ionophore 115 is calcium ionophore I (ETH 1001) or calcium ionophore II (ETH 129). In another example, when the target ion is chloride, ionophore 115 is tridodecylmethylammonium chloride (TDMAC). In yet another example, when the target ion is ammonium, ionophore 115 is nonactin.

[0155] 1A, an ionophore 115 can be provided in the first electrode 111; in such an example, the first electrode can be referred to as an ion-selective electrode (ISE) because the ionophore 115 selectively transports target ions 11. In some examples, the first electrode 111 can include a conductive polymer optionally having the ionophore 115 therein. Illustratively, the conductive polymer can be present in the first electrode 111 in an amount of about 90 to about 99.5 weight percent. In one example, the ionophore 115 is present in the first electrode in an amount of about 0.5 to about 10 weight percent. In some examples, the conductive polymer is a conductive polymer selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

[0156] While conductive polymers (such as those listed above) may be suitably used in the first electrode 111 that excludes the ionophore 115, other materials may alternatively be used, some non-limiting examples of which are described below with reference to Figures 2A-2G. Optionally, the ionophore 115 may be provided in a membrane disposed on the first electrode 111 (which electrode may exclude the ionophore 115), for example, as described below with reference to Figures 2A-2G.

[0157] In one example, the first electrode 111 is configured to enhance its biocompatibility. For example, the first electrode 111 may be substantially free of any plasticizers that could otherwise leach into the biological fluid 10, potentially causing toxicity and / or degradation of device performance. As used herein, the "substantially" free of materials such as plasticizers (e.g., phthalate, sebacate, nitrophenyl ester, and fluorophenylnitrophenyl ester plasticizers) is intended to mean that the first electrode 111 or other embodiments discussed herein contain "substantially" no detectable amount of the excluded material. In some examples, the first electrode 111 may consist essentially of a conductive polymer, optionally in addition to the ionophore 115. In some examples, the first electrode 111 may consist essentially of a conductive polymer, the ionophore 115, and an additive with ion exchange capability, such as an additive that complexes with the ionophore and provides improved selectivity for target ions. In one example, the additive contributes to ion selectivity. In another example, the additive may not provide ion selectivity. For example, the additive may help provide a substantially uniform (regulated and / or dilute) concentration of ions in the membrane. Additionally or alternatively, the additive may help compensate for any changes in ion concentration in the biological fluid to cause ion exchange within the membrane, which may induce a non-selective potential difference. Additionally or alternatively, the ionophore and ion exchanger may form a complex that improves the selectivity of the ionophore for the target ion compared to the selectivity of the ionophore alone.

[0158] Optionally, the additive can include a lipophilic salt. In a non-limiting example, the lipophilic salt can be selected from the group consisting of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTPFB), sodium tetraphenylborate (NaTPB), potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (KTFPB), and potassium tetrakis(4-chlorophenyl)borate (KTClPB). In one example, the additive can be present in the first electrode in an amount of about 0.01 to about 1 weight percent, or other suitable amount.

[0159] Other materials in the sensor 110 are selected. In one example, the substrate 101 may include a material selected from the group consisting of metal, glass, transparent conductive oxide, semiconductor, dielectric, ceramic, and polymer (such as a biopolymer or synthetic polymer). In some examples, the second electrode 117 includes a metal, a metal alloy, a transition metal oxide, a transparent conductive oxide, a carbon material, a doped semiconductor, a binary semiconductor, a ternary semiconductor, or a conductive polymer. In one example, a binary semiconductor includes any two elements suitable for use in a semiconductor. In one example, a ternary semiconductor includes two or more binary semiconductors. In one example, in embodiments where a metal or metal alloy is used, the metal used may be selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium. In one example, the metal is optionally oxidized or optionally in the form of a metal salt. A non-limiting example of a metal oxide used in the second electrode 117 is iridium oxide. In one example, the metal is optionally arranged in the form of a nanostructured surface. In one example, the carbon material is selected from the group consisting of carbon paste, graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond. In one example, the doped semiconductor is selected from the group consisting of silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide. In one example, the transition metal oxide is selected from the group consisting of titanium dioxide (TiO2), iridium dioxide (IrO2), platinum dioxide (PtO2), zinc oxide (ZnO), copper oxide (CuO), cerium dioxide (CeO2), ruthenium(IV) oxide (RuO2), tantalum pentoxide (Ta2O5), titanium dioxide (TiO2), molybdenum dioxide (MoO2), and manganese dioxide (MnO2). In one example, the metal alloy is selected from the group consisting of platinum-iridium (Pt-Ir), platinum-silver (Pt-Ag), platinum-gold (Pt-Au), gold-iridium (Au-Ir), gold-copper (Au-Cu), gold-silver (Au-Ag), and cobalt-iron (Co-Fe).

[0160] In one example, the conductive polymer used in sensor 110 is a conductive polymer selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT). That is, first electrode 111 and second electrode 117 are optionally formed from the same material as each other or from different materials. In the non-limiting example illustrated in FIG. 1A, first electrode 111 and second electrode 117 are disposed directly on substrate 101, or alternatively, disposed on substrate 101 via one or more intervening layers (not illustrated).

[0161] In one example, the biocompatibility of the sensor 110 is optionally further enhanced by providing a biointerface membrane on one or more components of the sensor 110. For example, in the non-limiting configuration illustrated in FIG. 1A, a first biointerface membrane (BM1) 114 is disposed on the ionophore 115 and the first electrode 111. In another example, the first biointerface membrane 114 is disposed on the ionophore 115 and the first electrode 111, and a second biointerface membrane (BM2) 118 is disposed on the second electrode 117. Alternatively, in the non-limiting configuration shown in FIG. 1H, a biointerface membrane (BM) 114′ is disposed on both the first electrode 111 and the second electrode 117. While FIGS. 1A and 1H may suggest that the biointerface membrane(s) have a rectangular shape for ease of illustration, it should be apparent that the membrane(s) may conform to the shape of any underlying layer. In some examples, the biointerface membrane(s) are configured to inhibit biofouling of the ionophore 115, the first electrode 111, and / or the second electrode 117. Non-limiting examples of materials that may be included in the biointerface membrane(s) include hard segments and / or soft segments. Examples of hard and soft segments used for biointerface membranes 114 / 114' / 118 or other biointerface membranes discussed herein include aromatic polyurethane hard segments with Si groups, aliphatic hard segments, polycarbonate soft segments, or any combination thereof. In other examples of biointerface membrane(s) such as 114 / 114' / 118 or other biointerface membranes discussed herein, PVP may not be included. In this example where PVP is not included, the biointerface membrane (118, 114, 114', or other biointerface membranes discussed herein) may include polyurethane and PDMS. In some examples, which may be combined with other examples herein, the biointerface membranes discussed herein may include one or more zwitterionic compounds.

[0162] Additionally or alternatively, the biointerface membrane(s) are configured to release a therapeutic compound into the biological fluid. Therapeutic compounds suitable for release using the biointerface membrane(s) or other membranes discussed herein may include one or more of an anti-inflammatory agent, an anti-infective agent, a necrotic agent, and an anesthetic agent. Generally, the anti-inflammatory agent reduces acute and / or chronic inflammation adjacent to the implant to reduce FBC capsule formation and reduce or prevent barrier cell layer formation. Suitable anti-inflammatory agents include, for example, nonsteroidal anti-inflammatory drugs such as acetomethophen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 muteins, anti-IL-6 iNOS inhibitors (e.g., L-NAME or L-NMDA), interferons, ketoprofen, ketorolac, leflunomide, melenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin. Drugs, NSAIDs), and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, dexamethasone, and dexamethasone acetate.

[0163] Generally, immunosuppressants and / or immunomodulators directly interfere with several key mechanisms required for the involvement of different cellular elements in the inflammatory response. Suitable immunosuppressants and / or immunomodulators include antiproliferative agents, cell cycle inhibitors (e.g., paclitaxel (e.g., sirolimus), cytochalasin D, infiximab), taxol, actinomycin, mitomycin, thospromote VEGF, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopeptin, vincristine, mitomycin, statins, C These include MYC antisense, sirolimus (and analogs), restenase, 2-chlorodeoxyadenosine, PCNA ribozyme, batimustat, prolyl hydroxylase inhibitors, PPARγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catchin, glycation agents, endothelin inhibitors (e.g., ambrisentan, tesosentan, bosentan), statins (e.g., cerivastatin), E. coli scalding enterotoxin, NLRP3 inflammasome inhibitors, and advanced coatings.

[0164] Generally, anti-infective agents are substances that can act against infection by inhibiting the spread of the infectious agent or by killing the infectious agent altogether, which can act to reduce the immune response without an inflammatory reaction at the implant site. Anti-infectives include anthelmintics (mebendazole), antibiotics containing aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolide antibiotics (azithromycin, clarithromycin, erythromycin), penicillin antibiotics (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, thicacillin). antiviral medications including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolone antibiotics (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum; gatifloxacin; and sulfamethoxazole / trimethoprim.

[0165] Generally, a necrotic agent is any drug that causes tissue necrosis or cell death. Necrotic agents include cisplatin, BCNU, taxol, or taxol derivatives.

[0166] Generally, angiogenic agents include substances with direct or indirect angiogenic properties. In some cases, angiogenic agents may additionally affect the formation of barrier cells in vivo. Indirect angiogenesis means that angiogenesis may be mediated through inflammatory or immune-stimulating pathways. It is not fully known how agents that induce local angiogenesis indirectly inhibit barrier cell formation; however, it is thought that some barrier cell effects may result indirectly from the effects of angiogenic agents.

[0167] The angiogenic agent promotes neovascularization around the membrane and / or increases angiogenesis near the device-tissue interface, thereby reducing or minimizing the ischemic period. Sphingosine-1-phosphate (S1P), a phospholipid with potent angiogenic activity, is incorporated into the biointerface membrane in one non-limiting example. Monobutyrin, a potent vasodilator and angiogenic lipid product of adipocytes, is incorporated into the biointerface membrane in another non-limiting example. In another non-limiting example, an antisense molecule (e.g., thrombospondin-2 antisense) that increases angiogenesis is incorporated into the biointerface membrane.

[0168] Angiogenic agents may include mechanisms that promote inflammation, which is thought to accelerate neovascularization in vivo. In one non-limiting example, a heterologous carrier, such as bovine collagen, elicits an immune response and stimulates neovascularization due to its foreign nature and is incorporated into the biointerface membrane of the present disclosure. In another non-limiting example, lipopolysaccharide, a potent immunostimulant, is incorporated into the biointerface membrane. In another non-limiting example, a protein, such as a bone morphogenetic protein (BMP), known to regulate bone healing in tissues, is incorporated into the biointerface membrane.

[0169] Generally, angiogenic agents are substances that can stimulate neovascularization, which can accelerate and sustain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include copper ions, iron ions, tridodecylmethylammonium chloride, basic fibroblast growth factor (bFGF), (also known as heparin-binding growth factor II and fibroblast growth factor II), acidic fibroblast growth factor (aFGF), (also known as heparin-binding growth factor-I and fibroblast growth factor-I), vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor BB (PDEGF-BB), angiopoietin-1, transforming growth factor beta (TGF-beta), transforming growth factor alpha (TGF-alpha), hepatocyte growth factor, tumor necrosis factor-alpha (TNF-alpha), placental growth factor (PGF-alpha), and erythrocyte growth factor (YGF). These include, but are not limited to, thrombolytic enzyme inhibitors (PLGF), angiogenin, interleukin-8 (IL-8), hypoxia inducible factor-I (HIF-1), angiotensin-converting enzyme (ACE) inhibitor quinaprilat, angiotropin, thrombospondin, peptide KGHK, hypoxic tension, lactate, insulin, copper sulfate, estradiol, prostaglandins, Cox inhibitors, endothelial cell binding agents (e.g., decorin or vimentin), glenipin, hydrogen peroxide, nicotine, and growth hormone.

[0170] Generally, pro-inflammatory agents are substances capable of stimulating an immune response in host tissue, which can accelerate or sustain the formation of a mature vascularized tissue bed. For example, pro-inflammatory agents are generally irritants or other substances that induce chronic inflammation and a chronic granular response at the implantation site. Without wishing to be bound by theory, it is believed that the formation of advanced tissue granulation induces blood vessels, which provide an adequate or abundant supply of analytes to the device-tissue interface. Pro-inflammatory agents include, but are not limited to, heterologous carriers, lipopolysaccharides, Staphylococcus aureus peptidoglycan, and proteins.

[0171] Other substances that can be incorporated into one or more membranes of the present disclosure include various drugs, excipients, and other substances well known in the art of pharmaceutical formulation.

[0172] Additionally or alternatively, in some examples, the biointerface membrane(s) (e.g., BM1 114, BM2 118, and / or BM 114′) may include a biocompatible polymer and a salt. For example, as shown in FIG. 1C, salt 119 is distributed throughout biointerface membrane 118. In one non-limiting example, the biointerface membrane(s) (e.g., 114, 114′, 118) may consist essentially of a biocompatible polymer and a salt. In one example, the biocompatible polymer is optionally present in the biointerface membrane(s) in an amount of about 40 to about 70 weight percent. In one example, the salt is optionally present in the biointerface membrane(s) in an amount of about 30 to about 60 weight percent. In some examples, the biocompatible polymer is selected from the group consisting of polyvinyl butyral (PVB) or polyurethane. In certain examples, the biocompatible polymer may be a segmented block copolymer. In one example, the segmented block copolymer may include a hard segment and a soft segment. In this example, the hard segment may include the aromatic or aliphatic diisocyanate used to prepare the hard segment of the segmented block copolymer.In one example, the aliphatic or aromatic diisocyanate used to provide the hard segment of the polymer is norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (4,4'-diphenylmethane diisocyanate), or the like. diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyldiisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0173] In one example, the hard segment content is from about 5% to about 90% by weight of the segmented block copolymer of the biointerface membrane (e.g., BM1 114, BM2 118, and / or BM 114'). In another example, the hard segment can be from about 15% to about 75% by weight. In yet another example, the hard segment can be from about 25% to about 55% by weight. Additionally or alternatively, the salt is optionally selected from the group consisting of potassium chloride (KCl), sodium chloride (NaCl), magnesium chloride (MgCl), calcium chloride (CaCl), and ammonium sulfate ((NH)SO).

[0174] It will be appreciated that the biointerface membrane(s) (eg, BM1 114, BM2 118, and / or BM 114') may include multiple layers.

[0175] It will be further understood that the sensor 110 can have any suitable configuration. In the non-limiting example shown in FIG. 1A, the substrate 101 can be planar or substantially planar. FIG. 1D shows a partial planar view of an exemplary sensor 110 having a planar substrate 101, with a cross-section of the sensor taken along dotted line 1A-1A corresponding to the view shown in FIG. 1A. In other examples, the substrate 101 is substantially coaxially shaped and referred to as a "wire." FIG. 1E shows a partial planar view of an exemplary sensor 110 having a coaxial substrate 101, with a cross-section of the sensor taken along line 1F-1F corresponding to the view shown in FIG. 1F, and a cross-section of the sensor taken along line 1G-1G corresponding to the view shown in FIG. 1G. As mentioned above, FIG. 1H shows an example in which a biointerface membrane 114' is disposed over the first electrode 111 and the second electrode 117. FIG. 1I shows a similar example in which a biointerface membrane 114' is disposed over the first electrode 111 and the second electrode 117, and the substrate is wire-shaped.

[0176] Additionally, the sensor may include any other suitable number and type of layers. For example, the ionophore 115 is optionally omitted from the first electrode 111 in the manner described above with reference to FIGS. 1A and 1B. Additionally or alternatively, the ionophore 115 is included in a separate layer disposed on the first electrode 111. For example, FIGS. 2A-2G schematically illustrate additional exemplary configurations and components of a potentiometric sensor. Referring now to FIG. 2A, device 200 includes an indwelling sensor 210 and sensor electronics 120. Sensor 210 includes a substrate 101 configured similarly as described with reference to FIG. 1A, a first electrode (E1′) 211 disposed on substrate 101, and a second electrode (E2) 117 disposed on the substrate and configured similarly as described with reference to FIG. 1A. First electrode 211 may be referred to as the working electrode (WE), while second electrode 117 may be referred to as the reference electrode (RE). In one example, the sensor electronics 120 may include circuitry configured to generate a signal corresponding to an electromotive force (EMF). In some examples, the EMF is based at least in part on a potential difference generated between the first electrode 211 and the second electrode 117 in response to the biological fluid 10 conducting the signal to the first electrode 111, and the sensor electronics 120 is configured to use the signal to generate an output corresponding to a measurement of the signal. Additionally or alternatively, in some examples, the device 200 may include an ionophore 115 disposed on the substrate 101 and configured to selectively transport target ions 11 to the first electrode 211. In one example, the EMF is based at least in part on a potential difference generated between the first electrode 211 and the second electrode 117 in response to the ionophore 115 transporting the target ions 11 to the first electrode 211. In one example, the sensor electronics 120 (or an external device to which the sensor electronics 120 is configured to transmit the signal via a suitable wired or wireless connection) may transmit the signal. In one example, the sensor electronics 120 is configured to use the signal to generate an output corresponding to a measure of the concentration of the target ion in the biological fluid. Further details regarding the construction and use of the sensor electronics 120 are provided further below.

[0177] While in the embodiment described with reference to FIG. 1A , the ionophore 115 is contained within the first electrode 111, in the embodiment illustrated in FIG. 2A , the first electrode 211 does not include the ionophore 115 (and thus may be referred to as E1′ rather than E1). Instead, the ionophore 115 may be within an ion-selective membrane (ISM) 212 disposed on the first electrode 211. The ionophore 115 may selectively transport target ions 11 to the first electrode 211 in a manner similar to that described with reference to FIGS. 1A-1B , and such transport may create a potential difference between the first electrode 211 and the second electrode 117, based on which the sensor electronics 120 may generate an output corresponding to a measure of the concentration of the target ions 11 in the biological fluid 10. It will be understood that in embodiments in which the device 200 is used to measure electrophysiological signals and not ion concentrations, the ISM 212 is omitted.

[0178] In a manner similar to that described with reference to the first electrode 111, the ion-selective membrane 212, in one example, substantially excludes plasticizers. In some examples, the ion-selective membrane 212 can consist essentially of a biocompatible polymer and an ionophore 115 configured to selectively bind to a target ion. Alternatively, in some examples, the ion-selective membrane 212 consists essentially of a biocompatible polymer, an ionophore 115 configured to selectively bind to a target ion 11, and an additive having ion exchange capacity, a lipophilic salt, or the like. Non-limiting examples of lipophilic salts, as well as non-limiting amounts of additives, biocompatible polymers, and ionophores, are provided above with reference to FIGS. 1A-1B. While the first electrode 111 includes a conductive polymer so that the ionophore 115 can be provided therein while maintaining the electrode's electrical conductivity, additional types of materials can be used in the ion-selective membrane 212, as the ion-selective membrane 212 need not be used as an electrode. For example, the biocompatible polymer of ion-selective membrane 212 can include a hydrophobic polymer. Illustratively, the hydrophobic polymer can be selected from the group consisting of silicone, fluorosilicone (FS), polyurethane, polyurethaneurea, and polyurea. In one example, the biocompatible polymer of ISM 212 (or other ion-selective membranes or other membranes discussed herein) can include one or more block copolymers that are segmented block copolymers. In one example, the hydrophobic polymer can be a segmented block copolymer including polyurethane and / or polyurea segments and / or polyester segments and one or more of polycarbonate, polydimethylsiloxane (PDMS), methylene diphenyl diisocyanate (MDI), polysulfone (PSF), methyl methacrylate (MMA), poly(ε-caprolactone) (PCL), and 1,4-butanediol (BD). In other examples, the hydrophobic polymer may alternatively or additionally include poly(vinyl chloride) (PVC), a fluoropolymer, a polyacrylate, and / or a polymethacrylate.

[0179] In one example, the biocompatible polymer may include a hydrophilic block copolymer instead of or in addition to one or more hydrophobic copolymers. Illustratively, the hydrophilic block copolymer may include one or more hydrophilic blocks selected from the group consisting of polyethylene glycol (PEG) and a cellulosic polymer. Additionally or alternatively, the block copolymer may include one or more hydrophobic blocks selected from the group consisting of polydimethylsiloxane (PDMS), polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, polyurethane homopolymers, copolymers, and terpolymers, polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethyl methacrylate (PMMA), polyether ether ketone (PEEK), polyurethane, poly(propylene oxide), and copolymers and blends thereof. In one example, the ion-selective membrane 212 does not contain PVP or other plasticizers.

[0180] In one example, the biocompatible polymer of ion-selective membrane 212 comprises between about 0.1% and about 80% silicone by weight. In one example, ion-selective membrane 212, or other ion-selective membranes discussed herein, comprises between about 5% and about 25% silicone by weight. In yet another example, ion-selective membrane 212, or other ion-selective membranes discussed herein, comprises between about 35% and about 65% silicone by weight. In yet another example, ion-selective membrane 212, or other ion-selective membranes discussed herein, comprises between about 30% and about 50% silicone by weight.

[0181] In certain embodiments, ISM 212 or other ISMs discussed herein can include one or more block copolymers or segmented block copolymers. In one example, the segmented block copolymer can include a hard segment and a soft segment. In this example, the hard segment can include the aromatic or aliphatic diisocyanate used to prepare the hard segment of the segmented block copolymer. In one example, the aliphatic or aromatic diisocyanate used to provide the hard segment of the polymer is norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (4,4'-diphenylmethane diisocyanate), or the like. diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyldiisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.In one example, the hard segment is about 5% to about 90% by weight of the segmented block copolymer of ISM 212. In another example, the hard segment can be about 15% to about 75% by weight. In yet another example, the hard segment can be about 25% to about 55% by weight. It is understood that the ion-selective membrane 212 and first electrode 111 can be prepared in any suitable manner. Illustratively, the polymer, ionophore 115, and any additives can be dispersed in appropriate amounts in a suitable organic solvent (e.g., tetrahydrofuran, isopropyl alcohol, acetone, or methyl ethyl ketone). In one example, the mixture is coated onto the substrate 101 (or onto a layer thereon) using any suitable technique, such as dipping and drying, spray coating, inkjet printing, aerosol jet dispensing, slot coating, electrodeposition, electrospraying, electrospinning, chemical vapor deposition, plasma polymerization, physical vapor deposition, spin coating, or the like. In one example, the organic solvent may be removed to form a solid material corresponding to the ion selective membrane 212 or the first electrode 111. Other layers in device 100 or device 200, such as electrodes, solid contact layers, and / or biological membranes, may be formed using techniques described elsewhere herein or otherwise known in the art.

[0182] Although the first electrode 111 comprises a conductive polymer so that the ionophore 115 can be provided therein while maintaining the electrode's electrical conductivity, additional types of materials are used in the first electrode 211. In one example, the first electrode can be configured without an ionophore when measuring electrophysiological signals, or with an inert ionophore that does not electrically interfere with the electrophysiological signals. Non-limiting exemplary materials for use in the first electrode 211 of the device 200 are provided above with reference to the second electrode 117, and are, for example, metals, metal alloys, transition metal oxides, transparent conductive oxides, carbon materials, doped semiconductors, binary semiconductors, ternary semiconductors, or conductive polymers, as described above with respect to FIG. 1A.

[0183] In some embodiments, the ion-selective membrane is in direct contact with the first electrode. In other embodiments, such as illustrated in FIG. 2A , the sensor 210 may further include a solid contact layer 213 disposed between the first electrode 211 and the ion-selective membrane 212. The solid contact layer 213 may function to enhance the reproducibility and stability of the EMF by converting the signal into a measurable potential signal. Additionally or alternatively, the solid contact layer 213 may inhibit water transport from the biological fluid 10 to the first electrode 211 and / or water accumulation at the first electrode 211. The solid contact layer 213 may include any suitable material or combination of materials. Non-limiting exemplary materials for use in the solid contact layer 213 are provided above with reference to the second electrode 117, such as a metal, a carbon material (e.g., carbon ink or carbon paste), a doped semiconductor, or a conductive polymer, as described above with respect to FIG. 1A . Alternatively, the solid contact layer 213 may include a redox couple having a well-controlled concentration ratio of oxidizing / reducing species used to stabilize the interfacial potential. In one example, the redox couple may include metal centers having different oxidation states. Illustratively, the metal centers are selected from the group consisting of Co(II) and Co(III), Ir(II) and Ir(III), and Os(II) and Os(III). In an alternative embodiment, the solid contact layer 213 may include strontium titanate (SrTiO), titanium dioxide (TiO), (La,Ba,Sr)(Mn,Fe,Co)O, or the like. 3-d ,La2CuO 4+d, cerium (IV) oxide (CeO2), lithium iron phosphate (LiFePO4), and LiMnPO4, or mixed ionic-electronic conductors. In one example, the amount of solid contact material present in the solid contact layer is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 5.25, 5.26, 5.27, 5.28, 5.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5.41, 5.42, 5.43, 5. 8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10 weight percent or more.

[0184] It will be further understood that the sensor 210 can have any suitable configuration. In the non-limiting example shown in FIG. 2A, the substrate 101 is planar or substantially planar. FIG. 2B shows a partial planar view of an exemplary sensor 210 having a planar substrate 101, with a cross-section of the sensor taken along dotted line 2A-2A corresponding to the view shown in FIG. 2A. In other examples, the substrate 101 is substantially wire-shaped and has a coaxial architecture. FIG. 2C shows a partial planar view of an exemplary sensor 110 having a coaxial substrate 101, with a cross-section of the sensor taken along line 2D-2D corresponding to the view shown in FIG. 2D, and a cross-section of the sensor taken along line 2E-2E corresponding to the view shown in FIG. 2E. FIG. 2F shows an example in which a biointerface membrane 114′ is disposed over the first electrode 211 and the second electrode 117. FIG. 2G shows a similar example in which a biointerface membrane 114′ is disposed over the first electrode 211 and the second electrode 117, and the substrate is axially shaped.

[0185] Further non-limiting configurations of the sensor 110 are described below with reference to Figures 5A-5B and 6A-6G. Referring to Figure 5A, a schematic side view of an exemplary transcutaneous analyte sensor 550 is shown. The sensor 550 includes a mounting unit 552 adapted for mounting on the skin of a host, a small (diameter) structure sensor 534 (as defined herein) adapted for transcutaneous insertion through the skin of the host, and electrical connections configured to provide secure electrical contact between the sensor and electronics preferably housed within the mounting unit 552. Generally, the mounting unit 552 is designed to maintain the integrity of the sensor in the host so as to reduce or eliminate translational motion between the mounting unit, host, and / or sensor. See co-pending U.S. patent application Ser. No. 11 / 077,715, filed Mar. 10, 2005, entitled "TRANSCUTANEOUS ANALYTE SENSOR," which is incorporated herein by reference in its entirety. In one example, the drug-releasing membrane 570 is formed over at least a portion of the sensor 550 .

[0186] 5B is a side schematic view of a transcutaneous analyte sensor 554 in an alternative embodiment. The transcutaneous analyte sensor 54 includes a mounting unit 552, with a sensing mechanism 536 comprising a miniaturized structure as defined herein, tethered to the mounting unit 552 via a cable 556 (alternatively, a wireless connection can be utilized). The mounting unit is adapted for mounting to the skin of a host and operably connected, such as via a tether, to a miniaturized structured sensor 534 adapted for transcutaneous insertion through the host's skin and measurement of an analyte therein; see, for example, U.S. Patent No. 6,558,330 to Causey III et al., which is incorporated herein by reference in its entirety.

[0187] The sensor electronics 120 is configured to measure an electromotive force based on a potential difference generated between a first electrode (e.g., 111 or 211) and a second electrode (e.g., 117). As described above, in some examples, the potential difference is responsive to the ionophore 115 transporting target ions 11 to or through the first electrode 111 or first electrode 211. In one example, the corresponding contribution to the electromotive force may scale substantially logarithmically with the concentration of the target ions 11 in the biological fluid 10. For example, the EMF generated within the sensor electronics 120 in response to the transport of the target ions 11 may be described using a generalized Nernst relationship:

[0188]

number

[0189] Because the ionophore 115 in the first electrode 111 or ISM 212 is highly selective for the target ion 11, for example, in a manner as described with reference to FIG. 1B, other ions 12, 13, 14, and 15 are expected to have substantially no effect on the value of the electromotive force measured using the sensor electronics 120. Nevertheless, in some examples, the sensor electronics 120 may be configured to detect k ab is called the selectivity coefficient (lower values, e.g., 1E-2, are used in some examples), and z b is the valence of the interfering ion, and the target ion I a Interfering ions I b The method is configured to apply a correction to the above Nernst relation according to the Nikolsky-Schultz-Eisenmann equation, which accounts for the effect given by:

[0190]

number

[0191] The sensor electronics 120 is configured to provide a high fidelity measurement of the EMF, based on which the concentration [I] or

[0192]

number

[0193] Alternatively, sensor electronics 120 may include circuitry, such as a non-volatile computer-readable memory, configured to store a correlation between control ion concentrations and control signals corresponding to the electromotive forces of those control ion concentrations. In one example, sensor electronics 120 is configured to (a) compare a signal corresponding to the electromotive forces with the control signals, (b) select the control signal that most closely matches the signal corresponding to the electromotive forces, and (c) generate as an output the control ion concentration corresponding to the selected control signal. In yet another example, the sensor baseline and sensitivity are characterized at the factory and implemented within sensor electronics 120 so that sensor electronics 120 can use them to predict the baseline and sensitivity over a period of time in vivo. In one example, the period for which predictions are made by sensor electronics 120 is from 1 to 15 days or more.

[0194] In some examples, the sensor electronics 120 includes a constant voltage circuit configured to control the potential and measure the current as a function of time. In other examples, the sensor electronics 120 includes a galvanostat circuit configured to control the current (e.g., at a near-zero value) and measure the potential as a function of time. In some examples, the sensor electronics 120 includes a constant voltage circuit and a galvanostat circuit.

[0195] In some examples, the sensor electronics 120 is configured to sample the potential difference signal at a sufficiently high sampling rate (e.g., about 1 Hz or more, or about 10 Hz or more, or 100 Hz or more, or about 1 kHz or more) to enable both measuring the concentration of target ions 11 in the biological fluid 10 and measuring the host's electrophysiological waveforms. For example, the DC component of the potential difference signal reflects the concentration of the target ions, while the AC component of the electrophysiological signal, if acquired fast enough (e.g., greater than about 100 Hz or greater than about 1 kHz), can measure electrophysiological waveforms, i.e., waveforms associated with cardiac potentiation. In contrast to wet or dry skin surface electrodes typically used for electrophysiology, measuring electrophysiological signals with indwelling sensors can produce waveforms with superior fidelity due to avoidance of the barrier function of the skin's stratum corneum. This capability is also used to measure electrophysiological waveforms over extended durations.

[0196] For example, the ion sensors of the present invention are expected to be significantly more suitable for quantifying weak electrophysiological signals with higher fidelity (e.g., signal-to-noise ratio) than skin-surface electrodes. This is primarily due to the high impedance that the stratum corneum is known to present between skin-surface electrodes and target organs / tissues (e.g., heart, brain, muscle). This impedance is on the order of tens of kiloohms. Indwelling sensors, on the other hand, can bypass the stratum corneum and, by sensing interstitially, exhibit improved impedance matching characteristics with target organs / tissues, e.g., on the order of tens to hundreds of ohms. The presence of hair, ointments, or medications can also affect the signal fidelity of skin-surface electrodes, and these electrodes are known to cause skin irritation, sensitization, and allergic reactions in a notable portion of the population. Furthermore, the lifespan of skin-surface electrodes is significantly limited because gels tend to lose hydration (and chloride ions) over time. These electrodes can also move across the skin surface. "Wet" type gel electrodes are used to minimize impedance mismatch, but gel electrodes have difficulty approaching the low impedance values ​​characteristic of indwelling sensors, not to mention leaving an undesirable gel residue on the skin after removal.

[0197] As recognized by the inventors, the construction and operation of the solid-state ion-selective sensors of the present invention share many similar characteristics with electrophysiological sensors. That is, both utilize at least two electrodes / leads to measure potential differences and operate in exceptionally low current regimes (often sub-nanoampere or sub-picoampere). Both sensing modalities may use measurements of open-circuit potential (electromotive force) to infer ion concentration (ion-selective sensors) or organ / tissue activity (electrophysiological sensors). Furthermore, both ion-selective and electrophysiological electrodes are interfaced with an analog front-end that exhibits a relatively high impedance (e.g., greater than about 1 gigaohm, greater than about 10 gigaohms, or greater than about 100 gigaohms), such as an instrumentation amplifier, differential amplifier, buffer amplifier, unity gain amplifier, or voltage follower. In one example, this front-end exhibits low DC offset, low drift, low noise, and very high open-loop gain (G OL ), and very high common-mode rejection ratio (CMRR). Both techniques measure potential changes to infer analyte concentration, as in the case of ion-selective electrodes, or to measure organ / tissue activity, as in the case of electrophysiological electrodes.

[0198] In the case of ion-selective electrodes, according to the classical Nernst equation provided further above, whenever there is a concentration gradient of an electroactive species (e.g., ion) across a semipermeable membrane (e.g., cell membrane, ion-selective membrane) in a solution, an electromotive force (e.g., potential difference) is generated across said membrane.

[0199] Figure 3 is a schematic diagram illustrating exemplary operations and components for use in the present device and method for both measuring the concentration of a target ion in an in vivo biological fluid and measuring an electrophysiological signal. As shown in Figure 3, an indwelling ion-selective sensor, such as those described with reference to Figures 1A-1I or 2A-2G, including a first electrode (e.g., 111 or 211) and a second electrode (e.g., 117), is used to measure the concentration of the target ion while simultaneously recording an electrophysiological waveform. More specifically, while measuring ions in a biological matrix is ​​expected to result in a very slowly time-varying voltage under practical implementations, thus resulting in a "DC" voltage or offset, measuring the electrophysiological waveform, in one example, uses relatively rapid sampling to capture the fast time dynamics of an "AC" waveform. To achieve simultaneous measurement of both signals, a high-impedance amplifier 310, as described above, is used to amplify the potential difference signal from the sensor. The amplifier 310 may have any suitable configuration, including, for example, an instrumentation amplifier with an ultra-high input impedance (e.g., greater than about 10 gigaohms or greater than about 100 gigaohms), as shown in FIG. 3, or may include a unity-gain amplifier. In one example, an analog-to-digital converter (ADC) 330 is used to quantize the analog amplified voltage signal into a digital bit stream. To reconstruct the original waveform with high fidelity, the Nyquist sampling theory is used. For example, in the case of electrophysiological signals, the ADC samples the amplified voltage signal at a sampling rate of at least about 1 Hz, or at least about 10 Hz, or at least about 100 Hz, such as about 1 kHz. In some examples, this sampling rate may be dynamically adjusted based on the maximum frequency component of the waveform. Such ADCs are operated in a power-constrained manner due to high-speed sampling, by duty cycle measurement, by operating at a moderate resolution (e.g., 10 or 12 bits), or by employing a low-power architecture (e.g., successive approximation register).

[0200] Optionally, a high-pass, low-pass, band-pass, or tunable electrical filter 320 (either analog or digital) is used to attenuate out-of-band frequencies to isolate the electrophysiological signal(s) or other signals of interest. Optionally, the potentiometric and electrophysiological recordings can be time-interleaved. During one half of the duty cycle, potentiometric measurements are recorded. During the second half of the duty cycle, electrophysiological measurements are recorded. The duty cycle (period) of this measurement can vary from 1 second to 6 hours. In another embodiment, a low-frequency ADC providing improved resolution (e.g., 14-bit, 16-bit, or 24-bit) can be employed in parallel with a high-frequency ADC providing descaled resolution (e.g., 10-bit or 12-bit). By way of example, delta-sigma, successive approximation register, integrating, or flash ADCs can be used, each providing a specified effective number of bits (ENOB), signal-to-noise ratio (SNR), jitter, nonlinearity, precision, dither, and quantization error characteristics.

[0201] From the foregoing, it will be appreciated that the first contribution to the electromotive force from the electrophysiological signal varies rapidly relative to the second contribution to the electromotive force from the concentration of ions in the physiological fluid. Such a difference in time characteristics is used to facilitate deconvolving the first contribution from the second contribution. For example, the sensor electronics 120 includes a fast Fourier transform (FFT) circuit configured to convert the signal corresponding to the electromotive force from the time domain to the frequency domain. This can also be performed in the digital domain, for example, using an arithmetic logic unit (ALU) within a microprocessor, without a dedicated FFT hardware implementation. In some examples, the sensor electronics 120 also includes a spectral analysis circuit configured to separate the converted signal into a high-frequency portion corresponding to the first contribution and a low-frequency portion corresponding to the second contribution. For example, because the first contribution (from the electrophysiological signal) varies rapidly relative to the second contribution (from the ion concentration), such contributions occur at different locations in the frequency domain. For example, the low-frequency portion may be centered approximately at zero frequency, and the high-frequency portion may include features at frequencies corresponding to the human heart rate or any harmonics (or subharmonics) thereof, and / or characteristics of individual human heart rates, e.g., between about 100 Hz and about 1000 kHz, or between about 200 Hz and about 400 Hz. In one example, a spectral analysis circuit or embedded algorithm is configured to separate contributions in the frequency domain. In one example, the sensor electronics 120 may, in some examples, include at least one inverse FFT (iFFT) circuit configured to convert the high-frequency portion to a time-domain output corresponding to an electrophysiological signal and to convert the low-frequency portion to a time-domain output corresponding to the concentration of ions in the physiological fluid. It will be apparent that even if only ion concentrations or electrophysiological signals are measured, similar processing is performed in the frequency domain to, for example, separate the desired signal from noise, drift, etc.

[0202] In another example, the components are separated from one another in the time domain. For example, sensor electronics 120 may include an analog-to-digital converter (ADC) that digitizes a signal corresponding to the electromotive force. In one example, sensor electronics 120 may also include a first filter configured to receive the digitized signal from the ADC, remove the second contribution therefrom, and generate an output corresponding to the first contribution with the second contribution removed. For example, the first filter includes a high-pass filter, a band-block filter, or a band-pass filter. In some examples, the first filter passes frequencies corresponding to a human heartbeat or heartbeat waveform. In some examples, sensor electronics 120 also includes a second filter configured to receive the digitized signal from the ADC, remove the first contribution therefrom, and generate an output corresponding to the second contribution with the first contribution removed. For example, the second filter includes a low-pass filter, a band-block filter, or a band-pass filter. In some examples, the second filter passes zero frequencies. Note that if the cardiac (AC) signal essentially rides on a DC component (ion signal), it may not be necessary to remove the DC component to see and understand the AC signal. The DC component is equivalent to a fixed bias or offset. Alternatively, the DC component can be separated from the AC signal by low-pass filtering the aggregate waveform or by performing averaging of the acquired waveform, thereby smoothing the AC oscillations. Even when only ion concentration or electrophysiological signals are measured, it will be apparent that processing similar to that provided herein can be performed in the frequency domain to separate the desired signal from, for example, noise, drift, etc. Furthermore, it will be apparent that processing can be performed in the analog domain, e.g., without the use of an ADC. For example, the sensor electronics 120 can include a first filter configured to remove a second contribution from the signal corresponding to the electromotive force and generate a first output corresponding to the first contribution with the second contribution removed, and a second filter configured to remove the first contribution from the signal corresponding to the electromotive force and generate a second output corresponding to the second contribution with the first contribution removed.

[0203] In one example, the output generated by sensor electronics 120 is used in any suitable manner. In some examples, sensor electronics 120 includes a non-volatile computer-readable memory configured to store the output, or a microprocessor or digital signal processor configured to execute a signal processing algorithm. Additionally or alternatively, in some examples, sensor electronics 120 includes a transmitter configured to wirelessly transmit the output, e.g., a near field communication (NFC), Bluetooth, WiFi, or cellular transmitter. The output is used in any suitable manner, for example, to continuously monitor one or more indicators of the host's health and provide appropriate therapy to the host based on the value of the indicator(s).

[0204] Further details regarding the sensor electronics 120 will now be provided. In the exemplary sensor electronics 120 coupled to an indwelling sensor 110, voltage is measured between a first electrode (e.g., 111 or 211) and a second electrode (e.g., 117) using a high input impedance voltmeter or electrometer, otherwise referred to as a measurement system. In some instances, the impedance of a potentiometric sensor system is relatively high (e.g., greater than about 1 GΩ), which means that the input impedance of the measurement system must be significantly high. The error contribution (E R ) can be understood by the following formula:

[0205]

number

[0206] Assuming that voltage is measured continuously as a function of time, analog-to-digital (A / D) conversion is used. The A / D converter digitizes the analog signal into a digital signal, also referred to as "counts," for processing. The resulting raw data stream in counts, also referred to as raw sensor data, is thus directly related to the voltage measured by a high-input impedance voltmeter.

[0207] The processor module includes a central control unit that controls the processing of the sensor electronics. In some examples, the processor module includes a microprocessor, although computer systems other than microprocessors can be used to process data as described herein; for example, an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA), or a graphical processing unit (GPU) can be used for some or all of the sensor's central processing. In one example, the processor is coupled to computer-readable memory, through which the processor is configured to provide semi-permanent storage of data, such as sensor identifiers (IDs), and programming for processing data streams (e.g., programming for data smoothing and / or signal artifact replacement similar to that described in U.S. Patent No. 8,20174 to Goode et al., which is incorporated herein by reference in its entirety). The processor can additionally be used for system cache memory, e.g., to temporarily store recent sensor data. In some examples, the processor module is coupled to one or more computer-readable memory storage components, such as ROM, RAM, dynamic RAM, static RAM, non-static RAM, EEPROM, rewritable ROM, flash memory, etc.

[0208] In some examples, the processor module includes a digital filter, e.g., an IIR or FIR filter, configured to smooth the raw data stream from the A / D converter. In some examples, the digital filter is programmed to filter the sampled data at predetermined time intervals (also referred to as the sample rate). In some examples, the voltmeter is configured to measure the analyte at discrete time intervals, and these time intervals determine the sample rate of the digital filter. In some alternative embodiments, where the voltmeter is configured to measure the analyte continuously, e.g., using a current-to-frequency converter as described above, the processor module can be programmed to request digital values ​​from the A / D converter at predetermined time intervals, also referred to as the acquisition time. In these alternative embodiments, values ​​acquired by the processor are advantageously averaged over the acquisition time due to the continuity of the current measurements. Thus, the acquisition time determines the sample rate of the digital filter. In one example, the processor module is configured with a programmable acquisition time, i.e., the predetermined time interval for requesting digital values ​​from the A / D converter is user-programmable within the digital circuitry of the processor module. Acquisition times of about 2 seconds to about 512 seconds are used in some examples. However, any acquisition time can be programmed into the processor module. A programmable acquisition time is advantageous for optimizing noise filtering, time lag, and processing / battery power.

[0209] An additional signal quality consideration for potentiometric sensors is the contribution of inductive or capacitive electromotive force (EMF) or electromagnetic interference (EMI) and radio frequency interference (RFI), which can potentially contaminate the voltage signal. For example, mains power line noise (e.g., 50 or 60 Hz and its harmonics) can contribute periodic voltage perturbations, leading to inaccurate concentration reports. The voltage amplitude of these interferences is small relative to the signal of interest, but is expected to be primarily due to the inductance of the sensor components and system, as well as the surrounding EM / RF environment. Notably, the absence of coiled or long wires can reduce or minimize this effect. Another consideration for low-voltage measurements is the contribution of thermoelectric or galvanic EMF, which are primarily driven by dissimilar materials in metallic or ionic contact, respectively. A final consideration is biological noise, given that potentiometric sensors may also or alternatively be used to acquire electrophysiological signals, such as electrocardiograms (EKGs). It is advantageous to acquire this signal not only to compensate for its contribution to the voltage difference signal, but also as an additional signature of the subject in whole-body health monitoring. Further details regarding electrophysiological signals are provided elsewhere herein.

[0210] In some examples, the processor module is configured to construct a data packet for transmission to an external source, such as wired or wireless transmission to a receiver. In some examples, the data packet may include a plurality of bits that may include a sensor ID code, raw data, filtered data, and / or error detection or correction. The processor module can be configured to transmit any combination of raw data and / or filtered data using a wired or wireless connection to the external source.

[0211] In some examples, the analog portion of the A / D converter is configured to continuously measure the voltage difference between the first electrode (e.g., 111 or 211) and the second electrode (e.g., 117) and convert the voltage measurements into digital values ​​representing the voltage. In one example, the sensor's reference electrode is biased at or near the expected midpoint of the A / D converter's input voltage range to maximize the quantifiable dynamic range resulting from variations in the EMF generated by the sensor.

[0212] A battery is operably connected to the sensor electronics and provides power for the measurement device, although the applied power need not be used to drive the potentiometric sensor itself; for example, the sensor operates galvanically (as opposed to an amperometric sensor, which operates electrolytically). In one example, the battery is a lithium manganese dioxide battery; however, any suitable size and power battery can be used (e.g., AAA, nickel-cadmium, zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion, zinc-air, zinc-mercury oxide, silver-oxygen, silver-zinc, and / or sealed). In some embodiments, the battery is rechargeable and / or multiple batteries can be used to power the system. The indwelling sensor can be powered, for example, via inductive coupling. In some embodiments, the quartz crystal is operably connected to the processor and maintains system time for the entire computer system, for example, during a programmable acquisition time within the processor module.

[0213] In one example, a temperature probe is provided, which may be located on the electronics assembly or on the potentiometric sensor itself, as described herein. The temperature probe may be used to measure the ambient temperature near the sensor. This temperature measurement may be used to add temperature compensation to the calculated concentration (activity) value.

[0214] In some examples, the output signal (from the sensor electronics) is transmitted to a receiver (e.g., a computer or other communications station). In one example, the output signal may include a raw data stream that, in some examples, is used to provide a useful value of the measured analyte concentration to a patient or physician, for example. In some examples, the raw data stream may be algorithmically smoothed or otherwise modified, continuously or periodically, to reduce outlying points that do not accurately represent the analyte concentration due to signal noise or other signal artifacts, for example, in a manner such as described in U.S. Pat. No. 8,101,174 to Goode et al., which is incorporated herein by reference in its entirety.

[0215] When the sensor is first implanted in host tissue, the sensor and receiver are initialized. This can be referred to as a start-up mode, which optionally includes resetting sensor data and calibrating the sensor. In selected embodiments, mating the electronics unit to the mounting unit triggers the start-up mode. In other embodiments, the start-up mode is triggered by the receiver. In one example, sensors of the present disclosure are individually calibrated, and the sensitivity and E of each individual sensor are used to predict in vivo performance and / or reduce data variance within a lot.

[0216] In some embodiments, the sensor electronics are wirelessly connected to the receiver, such as via one-way or two-way RF transmission. However, wired connections are also contemplated. The receiver provides much of the processing and display of the sensor data and can be selectively worn and / or removed at the host's convenience. Thus, the sensor system can be unobtrusively worn, and the receiver, which provides much of the processing and display of the sensor data, can be selectively worn and / or removed at the host's convenience. In particular, the receiver includes programming for retroactively and / or prospectively initiating calibration, converting sensor data, updating calibration, evaluating received reference and sensor data, and evaluating the calibration of the analyte sensor, in a manner such as described in U.S. Pat. No. 7,778,680, the entirety of which is incorporated herein by reference.

[0217] 6A-6C illustrate one embodiment (e.g., in vivo portion) of a continuous analyte sensor 600 including an elongated conductive body 602 (referred to as a substrate). The elongated conductive body 602 includes a core 610 (see FIG. 6B) and a first layer 612 at least partially surrounding the core 610. The first layer 612 includes a working electrode (e.g., located within a window 606) and a membrane 608 located over the working electrode, the membrane 608 being configured and arranged for multi-axis bending. In some examples, the core 610 and the first layer 612 can be a single material (e.g., platinum). In some examples, the elongated conductive body 602 is a composite of at least two materials, such as a composite of two conductive materials or a composite of at least one conductive material and at least one non-conductive material. In some examples, the elongated conductive body 602 includes multiple layers. In certain examples, there are at least two concentric (e.g., annular) layers, such as a core 610 formed from a first material and a first layer 612 formed from a second material. However, in some examples, additional layers can be included. In some examples, the layers are coaxial.

[0218] In one example, the elongated conductive body 602 is long and thin, yet flexible and strong. In one example, the smallest dimension of the elongated conductive body 602 is less than about 0.1 inches, less than about 0.75 inches, less than about 0.5 inches, less than about 0.25 inches, less than about 0.1 inches, less than about 0.075 inches, less than about 0.01 inches, less than about 0.004 inches, or less than about 0.002 inches. While the elongated conductive body 602 is illustrated in FIGS. 6A-6C as having a circular cross-section, in other embodiments, the cross-section of the elongated conductive body 602 can be oval, rectangular, triangular, polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-shaped, irregular, etc. In one embodiment, a conductive wire electrode is used as the core 610. To such a coated electrode, two additional conductive layers are added (e.g., with an intervening insulating layer providing electrical isolation). In one example, the conductive layer can include any suitable material. In certain embodiments, it may be desirable to use a conductive layer that includes conductive particles (i.e., particles of a conductive material) in a polymer or other binder.

[0219] In certain examples, the materials used to form the elongated conductive body 602 (e.g., stainless steel, titanium, tantalum, platinum, platinum-iridium, iridium, certain polymers, and / or the like) can be strong and rigid, and therefore resistant to breakage. In one example, the ultimate tensile strength of the elongated conductive body 602 is between about 80 kPsi and about 500 kPsi. In another example, the Young's modulus of the elongated conductive body 602 is between about 660 GPa and about 220 GPa. In yet another example, the yield strength of the elongated conductive body 602 is between about 60 kPsi and about 2200 MPa. Ultimate tensile strength, Young's modulus, and yield strength are described in more detail elsewhere herein. In some embodiments, the small diameter of the sensor provides flexibility (e.g., imparts flexibility, enables flexibility) to these materials, and thus to the entire sensor. Thus, the sensor can withstand repeated forces exerted by the surrounding tissue. One measure of a sensor's ability to withstand an embedded environment is its fatigue life. In some examples, the sensor's fatigue life is at least 1,000 cycles of flexion from about 28° to about 110° at a bend radius of about 0.125 inches.

[0220] In addition to providing structural support, resilience, and flexibility, in some examples, the core 610 (or components thereof) provides electrical conduction for electrical signals from the working electrode to the sensor electronics (not shown), as described elsewhere herein. In some examples, the core 610 may include a conductive material such as stainless steel, titanium, tantalum, a conductive polymer, and / or the like. However, in other examples, the core 610 is formed from a non-conductive material, such as a non-conductive polymer. In still other examples, the core 610 includes multiple layers of material. For example, in one example, the core 610 includes a concentrically arranged inner core and an outer core (not shown here). In a further example, the inner core is formed from a first conductive material and the outer core is formed from a second conductive material. In one example, the first conductive material is stainless steel, titanium, tantalum, a conductive polymer, an alloy, and / or the like, and the second conductive material is a conductive material selected to provide electrical conduction between the core 610 and the first layer 612 and / or to attach the first layer 612 to the core 610 (e.g., if the first layer 612 is formed from a material that does not adhere well to the core material). In another example, the core 610 is formed from a non-conductive material (e.g., a non-conductive metal and / or a non-conductive polymer), and the first layer 612 is a conductive material such as stainless steel, titanium, tantalum, a conductive polymer, and / or the like. The core 610 and the first layer 612 may be a single (or the same) material, e.g., platinum. Those skilled in the art will appreciate that additional configurations are possible.

[0221] 6A-6C, in some examples, the first layer 612 is formed from a conductive material. The working electrode is the exposed portion of the surface of the first layer 612. Thus, the first layer 612 is formed from a material configured to provide a suitable working electrode, such as, but not limited to, platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, an alloy, and / or the like.

[0222] As shown in FIGS. 6B-6C , the second layer 604 surrounds at least a portion of the first layer 612, thereby defining the boundary of the working electrode. In some examples, the second layer 604 serves as an insulator and is formed from an insulating material such as polyimide, polyurethane, parylene, or any other known insulating material. For example, in one example, the second layer is disposed on the first layer 612 and configured such that the working electrode is exposed through a window 606. In another example, an elongated conductive body 602 including a core 610, a first layer 612, and a second layer is provided, and the working electrode is exposed (i.e., formed) by removing a portion of the second layer, thereby forming a window 606 through which the working electrode (e.g., the exposed surface of the first layer 612) is exposed. In some examples, the working electrode is exposed (e.g., formed) by removing a portion of the second layer and (optionally) a third layer. Removal of coating material from one or more layers of elongated conductive body 602 (eg, to expose the working electrode) may be performed by hand, excimer laser, chemical etching, laser ablation, grit blasting, or the like.

[0223] In some examples, the sensor further includes a third layer 614 comprising a conductive material. In further embodiments, the third layer may include a reference electrode, which in some examples is formed from a material applied onto the second layer (e.g., an insulator) or other material as described elsewhere herein. The third layer can be processed using a paste / dip / coating step, for example, using a die-metered dip coating process, and then the body can be drawn through a die to meter the coating to a precise thickness. In some examples, multiple coating steps are used to build the coating to a predetermined thickness. Such drawing methods can be utilized to form one or more of the electrodes in the device depicted in FIG. 6B.

[0224] In some examples, the elongated conductive body 602 further includes one or more intermediate layers positioned between the core 610 and the first layer 612. In one example, the intermediate layer is an insulator, a conductor, a polymer, and / or an adhesive.

[0225] It is contemplated that the ratio between the thickness of the electrode layer and the thickness of the insulator (e.g., polyurethane or polyimide) layer can be controlled to allow for a certain margin of error (e.g., the margin of error associated with the etching process) that will not result in a defective sensor (e.g., due to defects resulting from the etching process cutting deeper than intended, thereby unintentionally exposing the working electrode). This ratio will vary depending on the type of etching process used, whether laser ablation, grit blasting, chemical etching, or some other etching method. In one non-limiting example, the ratio of the thickness of the electrode layer to the thickness of the insulator layer can be from about 1:5 to about 1:1, or from about 1:3 to about 1:2.

[0226] In a particular example, the core 610 comprises a non-conductive polymer and the first layer 612 comprises a conductive material. Such a sensor configuration may reduce material costs in that typically expensive materials are replaced with less expensive materials. In one example, the core 610 is formed from a non-conductive polymer, such as a nylon or polyester filament, string, or cord, which may be coated and / or plated with a conductive material, such as platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, conductive polymers, and alloys or combinations thereof.

[0227] 6C and 6D, the sensor also includes a membrane 608 covering at least a portion of the working electrode. Membranes are discussed elsewhere herein.

[0228] FIG. 6B is a schematic diagram illustrating an example elongated conductive body 602 (also referred to as an "elongated body") formed from at least two layers of materials and / or conductive materials, as described in more detail elsewhere herein. In some examples, the term "electrode" may be used herein to refer to the elongated conductive body 602 including the portion of the electrode that detects an analyte. In some examples, the elongated conductive body 602 provides an electrical connection between a working electrode and the sensor electronics (not shown). In particular examples, each electrode (e.g., the elongated conductive body 602 on which the working electrode is located) is formed from a thin wire, e.g., having a diameter of about 0.001 inches or less to about 0.01 inches or more, and may be formed from, for example, plated insulator, plated wire, or bulk conductive material. For example, the wire and / or elongated conductive body 602 used to form the working electrode may include a diameter and / or smallest dimension (e.g., width) of about 0.05, 0.08, 0.10, 1.27, 0.15, 0.18, 0.20, 0.23, 0.25, 0.38, 0.51, 0.64, 0.76, 0.89, 1.02, or 1.14 mm (0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, or 0.045 inches).

[0229] In some examples, the first electrode comprises a wire formed from a conductive material such as platinum, platinum-iridium, palladium, graphite, gold, carbon, a conductive polymer, an alloy, or the like.

[0230] In some examples, the working electrode is formed from platinum-iridium or iridium wire. Platinum-iridium and iridium materials are generally stronger (e.g., more resilient and less likely to fail due to stress or strain fracture or fatigue). Without wishing to be bound by theory, it is believed that platinum-iridium and / or iridium materials facilitate the fabrication of wires with smaller diameters, further reducing the maximum diameter (size) of the sensor (e.g., the in vivo portion). Advantageously, for sensors implanted within blood vessels, a smaller sensor diameter reduces the risk of clot or thrombus formation (or other foreign body response) and allows for the use of smaller catheters.

[0231] Referring to FIG. 6B , in some examples, the elongated conductive body 602 includes at least two concentric layers (e.g., a composite structure). In a further example, the elongated conductive body 602 includes a core 610 and a first layer 612. The core 610 is formed from one of at least two materials described above. For example, the core 610 can be formed from a polymer, a metal, an alloy, or the like. In some examples, the core 610 is formed from a conductive polymer such as, but not limited to, polyaniline and polypyrrole. In some examples, a conductive material is added (e.g., mixed and / or coated) to a non-conductive polymer, thereby making the polymer core conductive. In one example, one or more conductive metals, such as, but not limited to, particles (e.g., carbon, gold, platinum, iridium, etc.), can be mixed with an uncured polymer, which can be formed into the core 610.

[0232] In other examples, the core 610 may include an inner core and an outer core in some instances. For example, platinum, iridium, or gold particles may be ion-implanted onto the surface of the polymer inner core, with the particles forming the outer core. For example, gold may be ion-implanted into a polymer filament fiber so that the treated filament fiber is conductive. In some instances, the core 610 is formed from a metal, such as, but not limited to, at least one of stainless steel, tantalum, titanium, and / or alloys thereof. For example, in one example, the core 610 is formed from extruded stainless steel, tantalum, titanium, and / or extruded alloys. In some instances, the material of the core 610 is treated to provide the strength and flexibility required for multi-axial bending. Treating a metal changes its properties, such as, but not limited to, by compressing and / or rearranging the metal's crystal lattice. For example, tempering can make the metal less brittle and more elastic. Hardening can make the metal better retain its shape. Thus, in certain examples, core 610 is formed from a metal that has been processed to provide the requisite combination of strength and flexibility (e.g., an ultimate tensile strength of less than about 80, 80, 90, 100, 110, 120, 130, 140, or 150 KPsi (551 MPa) to about 160, 170, 180, 190, 200, 210, 220, or 500 KPsi (3297 MPa)) or more. In one example, core 610 is formed from a metal that has been annealed, tempered, normalized, hardened, work-hardened, fully worked, case-hardened, drawn air-hardened, cold-worked, and / or the like to make it more rigid. In one example, core 610 is formed from fully worked platinum. In another example, core 610 is formed from work-hardened platinum-iridium.

[0233] In some examples, the surface of the elongated conductive body 602 and / or core 610 is treated to remove initiation sites (e.g., locations / points of irregularities where sensor failure tends to begin), to smooth and / or clean the surface, to prepare it for the application of the next material, and / or the like. Suitable treatments include, but are not limited to, electropolishing, etching, application of a tie layer, electrodeposition, and electrostatic deposition.

[0234] In some examples, the elongated conductive body 602 (and / or the core 610, and / or the sensor) is wire-shaped, however, the wire-shape may include one of a variety of cross-sectional shapes, such as, but not limited to, circular, oval, rectangular, triangular, cross, star, cloverleaf, X-shaped, C-shaped, irregular, or other non-circular configurations. The elongated conductive body 602 includes a diameter and / or minimum dimension (e.g., width) of approximately 0.05, 0.08, 0.10, 1.27, 0.15, 0.18, 0.20, 0.23, 0.25, 0.38, 0.51, 0.64, 0.76, 0.89, 1.02, or 1.14 mm (0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, or 0.045 inches). The elongated conductive body 602 can be provided as a reel and / or extended length, which is then processed and / or singulated into individual sensor lengths.

[0235] In some examples, the elongated conductive body 602 includes a first layer 612 applied to the core 610. In some examples, the first layer 612 is applied to the core 610 so that they are electrically connected (e.g., in electrical contact so that an electric current can pass therebetween). The first layer 612 can be formed from a variety of conductive materials, such as, but not limited to, at least one of platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, conductive polymers, and alloys. In certain examples, the first layer 612 is relatively thin, for example, but not limited to, less than about 50, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 microinches to about 125, 150, 175, 200, 225, 250, 275, or 300 microinches or more in thickness. As described in more detail elsewhere herein, at least a portion of the surface of the first layer 612 provides a working electrode. For example, as described herein, in some instances, the working electrode is exposed through a window formed in the insulator. In some instances, the surface of the applied first layer 612 is treated prior to application of the membrane material to optimize the surface, for example, for membrane attachment and for function as a working electrode. For example, the surface can be cleaned, smoothed, etched, etc. Advantageously, using a thin layer of a potentially more expensive working electrode material to form the inexpensive, yet strong and flexible, inner body conductive core 610 can provide a substantial reduction in material costs.

[0236] In some examples, a conductive paste comprising a mixture of material (e.g., ink) and one or more membrane components is applied to a layer surrounding core 610 or directly to core 610. In one example, the conductive paste may include, for example, ionophores, additives, polymers, and / or enzymes. The use of a conductive paste may reduce or eliminate the need for certain membrane layers (e.g., separate electrode layers, separate ionophore layers, and / or separate enzyme layers).

[0237] The first layer 612 can be applied to the core 610 using a variety of manufacturing methods. In one example, the first layer 612 is coextruded with the core 610 using known techniques, such as, but not limited to, metal-on-metal or polymer-on-metal extrusion techniques. Some useful coextrusion techniques are described in U.S. Patent Nos. 7,416,802, 7,268,562, 7,153,458, 7,280,879, 5,324,328, and 6,434,430, the entire contents of each of which are incorporated herein by reference. In one example, a stainless steel inner body (not shown here) is coextruded with the platinum first layer 612, such as, but not limited to, through a die, to form a thin reel of 0.005-inch diameter wire having a stainless steel core with a 100-microinch layer of platinum thereon.

[0238] In some examples, the first layer 612 is applied to the core 610 (which in some examples is pre-treated as described above) using a thin film or thick film technique (e.g., spraying, electrodeposition, vapor deposition, dipping, spin coating, sputtering, evaporation, printing, etc.). For example, in one example, the first layer 612 is applied by dipping the core 610 into a solution of the first layer 612 material and withdrawing the core 610 at a rate that provides an appropriate first layer 612 thickness. However, as will be appreciated by one of ordinary skill in the art, any known thin film or thick film method can be used to apply the first layer 612 to the core 610. Some examples of thin film and / or thick film manufacturing techniques are disclosed in U.S. Patent Application Publication No. US-2005-0181012-A1, U.S. Patent Application Publication No. US-2006-0036143-A1, U.S. Patent Application Publication No. US-2007-0163880-A1, U.S. Patent Application Publication No. US-2006-0270923-A1, U.S. Patent Application Publication No. US-2007-0027370-A1, U.S. Patent Application Publication No. US-2006-0015020-A1, U.S. Patent Application Publication No. US-2006-0189856-A1, U.S. Patent Application Publication No. US-2007-0197890 ...270923-A1, U.S. Patent Application Publication No. US-2007-0027370-A1, U.S. Patent Application Publication No. US No. US-2006-0257996-A1, US Patent Application Publication No. US-2006-0229512-A1, US Patent Application Publication No. US-2007-0173709-A1, US Patent Application Publication No. US-2006-0253012-A1, US Patent Application Publication No. US-2006-0195029-A1, US Patent Application Publication No. US-2008-0119703-A1, US Patent Application Publication No. US-2008-0108942-A1, and US Patent Application Publication No. US-2008-0200789-A1, the entire contents of each of which are incorporated herein by reference.

[0239] In some examples, the first layer 612 is deposited on the core 610. In one example, the first layer 612 is plated (e.g., electroplated) onto the core 610. In one example, a thin layer of platinum is plated onto the tantalum core by immersing the inner body in a platinum-containing solution and applying an electric current to the inner body for a period of time such that a desired thickness of the platinum first layer 612 is produced and / or achieved. Accordingly, descriptions of deposition methods and devices can be found in U.S. Patent Nos. 7,427,338; 7,425,877; 7,427,560; 7,351,321; and 7,384,532, the entire contents of each of which are incorporated herein by reference.

[0240] In yet another example, the core 610 is embedded in an insulator and the working electrode body 612 is attached such that the core 610 and working electrode body are electrically (e.g., functionally, operatively) connected, as described in U.S. Pat. No. 8,828,201, the entire contents of which are incorporated herein by reference. In one example, the working electrode body is formed as a foil attached to the core 610 using adhesive, welding, and / or an intermediate layer of conductive material, etc., to provide adhesion between the core 610 and the working electrode body material (e.g., at a tie layer). In some examples, multiple layers are applied on top of the core 610. In some examples, each layer has a finite interface with adjacent layers or, together, forms a physically continuous structure with a chemical composition gradient. In another example, the working electrode body is a C-clip or snap ring that is compression-mounted around and / or around the core 610. In some examples, the working electrode body is mounted over a window. In other examples, there is no window; instead, the working electrode body is configured to penetrate the insulator and physically contact the underlying core 610, thereby operatively connecting the working electrode body and the core. In some examples, a conductive metal C-clip is attached to the core 610 by adhesive, welding, and / or a bonding layer. In yet another example, an adhesive is attached to the core 610, and then a conductive foil is wrapped around it.

[0241] The elongated conductive body 602 can be manufactured using a variety of manufacturing techniques. In some examples, the first layer 612 is applied to the core 610 in a substantially continuous process. In one example, manufacturing the elongated conductive body 602 includes a reel-to-reel process. In other examples, sheet-fed techniques are used. In some examples, applying the first layer 612 to the core 610 can be by either a semi-automated process or a fully automated process. Automation of some or all manufacturing steps generally requires the use of one or more machines, such as robotic devices, configured and arranged to perform the manufacturing step(s). In some examples, a single manufacturing step, such as manufacturing the elongated conductive body 602, can be automated. However, in other examples, two or more manufacturing steps can be automated. For example, a device can be configured to perform two or more of the steps, or two or more devices can perform a step. In some examples, when multiple devices are used, the devices are functionally and / or physically connected, coupled, interconnected, or linked to each other. In one example, the product of one device is fed directly to the next device, and so on. In one example, a reel of previously manufactured core 610, such as stainless steel, tantalum, or titanium wire, can be substantially continuously fed through a device configured to electroplate core 610 with platinum, gold, carbon, etc., to produce a reel of plated wire. For example, the manufacturing device and / or system can be configured to automatically co-extrude stainless steel and platinum to produce / manufacture a reel of wire-like elongated conductive body 602 including a stainless steel core and a first layer of platinum (e.g., first layer 612). Examples of continuous manufacturing processes can be found in U.S. Patent Nos. 6,103,33, 5,879,828, 5,714,391, 7,429,552, 7,402,349, and 7,387,811, the entire contents of each of which are incorporated herein by reference.

[0242] In a further example, first layer 612 includes a working electrode (e.g., the portion exposed through window 606). For example, if the sensor is configured to detect an analyte other than an ion, the analyte can react enzymatically with an enzyme in a membrane covering at least a portion of the working electrode, where the enzyme can produce ions from the analyte, the concentration of which can be measured using an ionophore and the working electrode in a manner as described elsewhere herein. Alternatively, for example, if the sensor is configured to detect ions, the concentration of the ions can be measured using an ionophore and the working electrode in a manner as described elsewhere herein.

[0243] As described with reference to FIG. 6A and shown in FIG. 6C , the insulator 604 is disposed on (e.g., disposed over, covers) at least a portion of the elongated conductive body 602. In some examples, the sensor is configured and arranged such that the elongated body includes a core 610 and a first layer 612, with a portion of the first layer 612 exposed through a window 606 in the insulator. In other examples, the sensor is configured and arranged such that the elongated body includes a core embedded in the insulator, with a portion of the core 610 exposed through a window in the insulator. In one example, the insulating material is applied to the elongated body (e.g., by screen printing, inkjet printing, and / or block printing) in a configuration designed to leave a portion of the surface of the first layer 612 (or the surface of the core 610) exposed. For example, the insulating material can be printed in a pattern that does not cover a portion of the elongated body. In another example, a portion of the elongated body is masked before application of the insulating material. Removing the mask after application of the insulating material exposes a portion of the elongated body.

[0244] In some examples, the insulating material 604 comprises a polymer, such as a non-conductive (e.g., dielectric) polymer. Dip coating, spray coating, vapor deposition, printing, and / or other thin and / or thick film coating or deposition techniques can be used to deposit the insulating material on the elongated conductive body 602 and / or core 610. In one example, the insulating material is applied as a layer having a thickness of less than about 5, 5, 60, or 65 microns to about 20, 25, 30, or 35 microns or more. In some examples, the insulator is applied as a single layer of material. In other examples, the insulator is applied as two or more layers comprising either the same or different materials. In some examples, the insulating material comprises at least one of polyurethane, polyimide, and parylene. In one example, the insulating material comprises parylene, which can be an advantageous polymer coating due to its strength, lubricity, and electrical insulation properties. Generally, parylene is produced by vapor deposition and polymerization of paraxylylene (or its substituted derivatives). However, any suitable insulating material can be used, such as, but not limited to, a dielectric ink, paste, or paint, for example, fluorinated polymers, polyethylene terephthalate (PET), polyurethane, polyimide, other non-conductive polymers, etc. In some examples, glass or ceramic materials can also be used. Other materials suitable for use include surface energy modification coating systems, such as those commercially available under the trade names AMC18, AMC148, AMC141, and AMC321 by Advanced Materials Components Express, Bellafonte, Pennsylvania. However, in some alternative embodiments, the core 610 may be conductive and not require a coating of insulator. In some examples, the surface of the conductive core (e.g., a portion of the first layer 612) is left exposed during application of the insulator, as described above, or a portion of the applied insulator is removed to expose a portion of the surface of the core 610.

[0245] In some examples where the sensor has an insulated elongated body, a portion of the insulating material is peeled or otherwise removed, e.g., by hand, excimer laser operation, chemical etching, laser ablation, grit blasting (e.g., with sodium bicarbonate or other suitable grit), etc., to expose the working electrode. In one example, grit blasting has been implemented to expose the working electrode, utilizing a grit material that is hard enough to ablate, for example, the polymer material, but soft enough to minimize or avoid damage to the underlying metal electrode (e.g., platinum electrode). While various "grit" materials (e.g., sand, talc, walnut shells, crushed plastic, sea salt, etc.) can be used, in some examples, sodium bicarbonate is an advantageous grit material because it is hard enough to ablate, for example, a parylene coating without damaging, for example, the underlying platinum conductor. One additional advantage of sodium bicarbonate blasting includes its abrasive action on the metal as it peels off the polymer layer, thereby eliminating a cleaning step that might otherwise be required. In some examples, the opening in the insulator through which the surface of the first layer 612 is exposed is referred to as a “window” 606 .

[0246] Due to the small size of the sensor in some instances, it can be difficult to precisely remove the insulation on one insulated conductive core without affecting, and possibly removing, the insulation on adjacent conductive cores or on other portions of the sensor. However, in some instances, the insulation is configured to substantially improve the precision of laser ablation. In one example, the insulation is configured to allow two different types of lasers to be used to ablate separate portions of the insulation. For example, if the insulation on two elongated bodies is of different materials (i.e., one is polyurethane and the other is a fluoropolymer such as TEFLON® or another type of polytetrafluoroethylene), it is possible to selectively ablate the insulation from one elongated body while not removing it from the other elongated body in the same region of the sensor. In some instances, the two insulating materials require different laser parameters for optimal ablation, such that a first laser setting can be used to ablate the first material but not the second material, and a second laser setting can be used to ablate the second material but not the first material. In another example, for a sensor including two elongated bodies, the insulator covering one elongated body can be configured for laser ablation with an ultraviolet laser (e.g., using a wavelength of about 200 nm), while the other elongated body can be configured for laser ablation with an infrared laser (e.g., using a wavelength of about 1000 nm). In another example, the insulator material is selected so that the insulator of the first elongated body requires substantially higher laser power for ablation than the insulator of the second elongated body. For example, the insulators covering the two elongated bodies can be identical, except that the insulator of the first elongated body is thicker than the insulator of the second elongated body. In another example, the insulators on each of the elongated bodies have different thicknesses such that a single laser is used to ablate the insulator on both cores, except that a window in the thinner insulator forms more quickly than a window in the thicker insulator.For example, the insulation of one elongate body may be about 0.0001 inches to about 0.0003 inches thick, while the insulation of the other elongate body may be about 0.0008 inches to about 0.0010 inches thick. In yet another example, a colorant can be added to the insulation of one of the elongate bodies to modify the amount of energy absorbed from the laser. For example, by adding a dark colorant or other absorbing material to one insulation but not the second insulation, the first insulation can absorb much more laser energy than the uncolored second insulation. In this way, a small amount of laser energy will ablate one wire but not the other, while a large amount of laser energy will ablate both. As will be appreciated by those skilled in the art, the laser setup can be adjusted to fine-tune the insulation removal process. For example, the laser pulse width and power level can be adjusted to modify and / or modulate the amount of insulation removed, the removal rate, and / or the like. This principle can be used for assemblies (e.g., sensors) of three or more elongated bodies (e.g., cores, wires). The same principle applies to chemical ablation, where different solvents are required for different insulating layers so that they can be selectively ablated. The same principle can also be used with plasma ablation, where different plasma settings or energy amounts are required to ablate different materials.

[0247] In the examples shown in FIGS. 6A and 6C , a radial window 606 is formed through the insulating material 604, exposing the circumferential surface of the working electrode (e.g., first layer 612). In other examples, such as those described in U.S. Pat. No. 8,828,201, a radial or non-radial window 606 (e.g., for electrical connection to the working electrode body, e.g., first layer 612) is formed by removing only a portion of the insulating material 604. Additionally, in some examples (not shown), the surface of the reference electrode 614 is exposed. For example, sections of the surface can be masked during deposition of the outer insulating layer and / or etched after deposition of the outer insulating layer. In some examples, multiple micro-windows comprise the surface of the working electrode, and the sum of the surface areas of the micro-windows is substantially equal to the surface area of ​​the window 606. In certain examples, the multiple micro-windows are spaced and / or staggered along the length of the core 610.

[0248] In some examples, the window 606 (or working electrode body, e.g., first layer 612) is sized to provide a working electrode with an area such that the sensor has suitable sensitivity. In some examples, the working electrode has a diameter of about 0.001 inches or less to about 0.01 inches or more, or about 0.002 inches to about 0.008 inches, or about 0.004 inches to about 0.005 inches. The length of the window can be about 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078 inches) or more, or about 0.5 mm (about 0.2 inches) to about 0.75 mm (0.3 inches). In such examples, the exposed surface area of ​​the working electrode is about 0.000013 inches. 2 (0.0000839cm 2 ) ~ approx. 0.0025 in 2 (0.016129cm 2 ) (assuming a diameter of about 0.001 inches to about 0.01 inches and a length of about 0.004 inches to about 0.078 inches).

[0249] In some examples, the exposed surface area of ​​the working electrode (and / or other electrodes) (e.g., the conductive core / core 610) can be increased by modifying the cross-section of the electrode itself. In one example, the cross-section of the working electrode can be defined by a cross, star, cloverleaf, rib, dimple, ridge, irregular, or other non-circular configuration, thus achieving a certain increased surface area (compared to the area achieved by a circular cross-section) for any given length of the electrode. Increasing the surface area of ​​the working electrode can be advantageous for providing an increased signal in response to analyte concentration, which in turn can help improve the signal-to-noise ratio, for example. In some examples, the application of the insulator to the conductive core can be achieved by a substantially continuous process, which can be semi-automated or fully automated, such as in a manner similar to some of the methods described with respect to the formation / manufacturing of the conductive core.

[0250] In some examples, the analyte sensor 600 further includes a reference electrode 614. Preferably, the reference electrode 614, which can function as a reference electrode alone or as a dual reference and counter electrode, is formed using materials such as those described elsewhere herein. In some examples, the reference electrode 614 is juxtaposed with and / or twisted around at least a portion of the sensor. For example, the reference electrode is helically twisted and / or wrapped and / or wound around the working electrode in a manner such as described in U.S. Pat. No. 8,828,201. This assembly of "wires" is then optionally coated with an insulating material similar to those described above or glued together to provide an insulating attachment.

[0251] 6B-6C, in some examples, the reference electrode 614 includes a material applied onto at least a portion of the insulating material 604. In some examples, the material is applied using thin-film and / or thick-film techniques, such as, but not limited to, dipping, spraying, printing, electrodeposition, vapor deposition, spin coating, and sputter deposition, as described elsewhere herein. For example, a conductor-containing paint (or similar formulation) is applied to a reel of insulated conductive core in one example. In another example, a reel of insulated elongate body (or core) is cut (e.g., "singulated") into single-unit pieces, and a conductor-containing ink is pad-printed thereon. In yet other examples, the material is applied as a foil. For example, an adhesive can be applied to the insulated elongate body, and then the foil can be wrapped around it. Alternatively, the sensor can be wrapped within conductive particles, whereby a sufficient amount of the conductor is attached to, and / or embedded in, and / or otherwise adhered to the adhesive for the particles to function as the reference electrode. In some examples, the reference electrode of the sensor comprises a sufficient amount of electrical conductor for the sensor to measure and / or detect the analyte for at least 3 days.

[0252] In some examples, the sensor is formed from an elongated body (e.g., an elongated conductive body 602) as shown in Figure 6B, which includes a core 610, a first layer 612 for use in the working electrode, an insulator 604, and a layer 614 of material for use in the reference electrode. In some examples, as shown in Figure 6C, a surface of the elongated body (e.g., also a surface of the first layer 612) is exposed by the formation of a window 606 through both the material of the reference electrode and the insulator. In one example, the elongate body of FIG. 6B is provided as an extended length on a reel that is singulated into multiple pieces having a length appropriate for a selected sensor configuration (e.g., lengths of less than 0.5 inches, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, or 24 inches or more). For example, a first sensor configured for transcutaneous implantation may use a 2.5 inch length, while a second sensor configured for transcutaneous implantation may use a 3 inch length. In another example, a first sensor configured for implantation in a peripheral vein of an adult host may use a 3 inch length, while a second sensor configured for implantation in a central vein of an adult host may use a 12 inch length. A window is formed on each sensor, such as by milling and / or etching a radial window through the reference electrode material and insulator, such that a platinum surface (e.g., a surface of the "working electrode") is exposed. In some embodiments, a reel of elongate bodies is singulated, and then the window is formed. In other embodiments, a window is formed along the length of a reel of elongate bodies, and then singulated. In further embodiments, additional manufacturing steps are performed prior to singulation. The membrane 608 is disposed on an exposed surface (e.g., working electrode) defined by the edge of the window, such that the surface can function as the working electrode of the sensor (e.g., when the sensor is in contact with a host sample) and generate a signal associated with an analyte, e.g., an ion.Alternative manufacturing techniques and / or sequences of steps can be used to produce a sensor having the configuration shown in FIG. 6C, including, but not limited to, masking a portion of the elongated body (or core) prior to application of insulators and materials for use in the reference electrode.

[0253] While Figure 6B illustrates layers that have been cut away, the resulting material typically has all layers terminating in a tip during the manufacturing process. Removing layers 604 and 614 can be performed to form window(s). Figure 6D illustrates the results of this removal / cutting process in a side / cross-sectional view. The removal process can be accomplished by methods already described or other methods known in the art. In one example, the removal step is performed, for example, by laser skiving, which can be performed on a continuous strand in a reel-to-reel process. The removed area can be stepped, for example, by removing different lengths of different layers (Figure 6D). In such manufacturing methods involving a continuous strand, the sensor can be singulated after the removal step. In some examples, if the core is metal, end caps are employed by applying insulating or other isolating material over the tip, for example, by dipping, spraying, shrink tubing, crimp wrapping, etc. If the core is polymeric (e.g., a hydrophobic material), end caps may not be necessary. For example, in the sensor depicted in FIG. 6D , an end cap 620 (e.g., of a polymer or insulating material) or other structure is provided over the core (e.g., if the core 610 is not insulating). FIG. 6E can be considered to build on the general structure depicted in FIG. 6B in that two or more additional layers are added to create one or more additional electrodes. Also, a method of selectively removing two or more windows to form two or more electrodes can be used. For example, by adding another conductive layer 622 and an insulating layer 624 below the reference electrode layer 614, two electrodes (first and second working electrodes) can be formed, resulting in a dual-electrode sensor. The same concept can be applied to create, for example, a counter electrode, an electrode for measuring additional analytes or ions, etc. FIG. 6F (compared to FIGS. 6B-6D ) illustrates a sensor with an additional electrode 622, in which a window has been selectively removed to expose the working electrodes 612, 622 between the reference electrode (including multiple segments) 614 and a small amount of insulator 604, 624 between them.FIG. 6G illustrates another example in which selective removal of various layers is performed in stages to expose electrodes 612, 622 and insulators 604, 624 along the length of the elongate body.

[0254] FIG. 4A illustrates a flow of operations in an exemplary method 400 for measuring the concentration of a target ion in a biological fluid in vivo. The method 400 illustrated in FIG. 4A may include implanting an indwelling sensor (operation 410). In a preferred embodiment, the indwelling sensor is implanted transcutaneously. In other embodiments, the indwelling sensor is implanted subcutaneously or intradermally. As described with reference to FIGS. 1A-1I or 2A-2G, the sensor may include a substrate (e.g., 101), a first electrode (e.g., 111 or 211) disposed on the substrate, an ionophore (e.g., 115) disposed on the substrate and configured to selectively transport a target ion to or within the first electrode, and a second electrode (e.g., 117) disposed on the substrate. Non-limiting options for these and other components of the sensor are provided elsewhere herein. The method 400 shown in FIG. 4A may also include generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode (Operation 420). For example, the sensor electronics 120 may generate the signal in a manner as described with reference to FIGS. 1A-1L, 2A-2G, 3, 5A-5B, or 6A-6G. The method 400 shown in FIG. 4A may also optionally include using the signal to generate an output corresponding to a measure of the concentration of the target ion in the biological fluid (Operation 430). For example, the sensor electronics 120 may generate the output or transmit the signal to an external device that generates the output in a manner as described with reference to FIGS. 1A-1I, 2A-2G, 3, 5A-5B, and 6A-6G.

[0255] FIG. 4B illustrates a flow of operations in an exemplary method 450 for measuring electrophysiological signals conducted through a biological fluid in vivo. The method 450 illustrated in FIG. 4B includes implanting an indwelling sensor (operation 460). As described with reference to FIGS. 1A-1I or 2A-2G, the sensor may include a substrate (e.g., 101), a first electrode (e.g., 111 or 211) disposed on the substrate, and a second electrode (e.g., 117) disposed on the substrate. The method 450 illustrated in FIG. 4B may also include the sensor electronics generating a signal corresponding to an electromotive force (operation 470), the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid transporting the electrophysiological signal to the first electrode. For example, sensor electronics 120 may generate the signal in a manner as described with reference to Figures 1A-1I, 2A-2G, 3, 5A-5B, 6A-6G, or 7A-7C. Method 450 shown in Figure 4B may also optionally include using the signal to generate an output corresponding to a measure of the electrophysiological signal (operation 480). For example, sensor electronics 120 may generate the output or transmit the output to an external device in a manner as described with reference to Figures 1A-1I, 2A-2G, 3, 5A-5B, 6A-6G, or 7A-7C.

[0256] It will be apparent from this disclosure that the operations described with reference to FIG. 4A may optionally be combined with respective operations from FIG. 4B, and vice versa. For example, operations 410 and 460 may be combined, for example, such that the implanted indwelling sensor includes an ionophore 115 (e.g., in the first electrode 111 or in the ISM 212). Additionally, operations 420 and 470 may be combined, for example, such that a signal is generated corresponding to an electromotive force based in part on a potential difference generated between the first and second electrodes in response to the ionophore transporting target ions 11 to the first electrode, and in part on a potential difference generated in response to the biological fluid conducting an electrophysiological signal to the first electrode. Additionally, operations 430 and 480 may be combined, for example, such that the signal is used to generate an output corresponding to a measurement of the target ions in the biological fluid and an output corresponding to a measurement of the electrophysiological signal.

[0257] It will be apparent that sensors such as those described with reference to Figures 1A-1I, 2A-2G, 3, 5A-5B, and 6A-6G, and methods such as those described with reference to Figures 4A-4B, are suitably adapted for use in measuring the concentration of any suitable analyte. For example, Figures 7A-7C are schematic diagrams illustrating exemplary configurations and components of a device for measuring electrophysiological signals and / or target analyte concentrations in biological fluids in vivo. Device 700 includes an indwelling sensor 710 and sensor electronics 120, similar to that described with reference to Figure 1A. Device 700 includes an indwelling sensor 710 and sensor electronics 120, similar to that described with reference to Figure 1A. The indwelling sensor 710 includes a substrate 101 configured similarly to that described with reference to Figure 1A, an ionophore disposed on the substrate and configured to selectively transport target ions to or into the first electrode, an enzyme 715 configured to produce target ions in response to an action on a target analyte, and a second electrode (E2) 117 disposed on the substrate and configured similarly to that described with reference to Figure 1A. In one example, the enzyme 715 is disposed in a material similar to that of the first electrode 111 of Figure 1A (optionally omitting the ionophore) or a material similar to that of the ion-selective membrane 212 of Figure 1B (optionally omitting the ionophore).

[0258] In the non-limiting example shown in Figure 7A, the ionophore is disposed within a first electrode (E1) 111 disposed on a substrate and configured similarly as described with reference to Figure 1A. Alternatively, in the non-limiting example shown in Figure 7C, the ionophore is disposed within an ion-selective membrane 212, which may be configured in the manner described with reference to Figure 2A, and the first electrode 211 is configured in the manner described with reference to Figure 2A. The first electrode 111 or 211 may be referred to as the working electrode (WE), while the second electrode 117 may be referred to as the reference electrode (RE).

[0259] In one example, sensor electronics 120 is configured to generate a signal corresponding to an electromotive force (EMF). In some examples, the EMF is based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode. In one example, sensor electronics 120 is configured to use the signal to generate an output corresponding to a measurement of the concentration of the target ion in the biological fluid and / or is further configured to transmit the signal to an external device configured to use the signal to generate an output corresponding to a measurement of the concentration of the target ion in the biological fluid. Optionally, in some examples, the EMF is based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid 10 conducting an electrophysiological signal to the first electrode 111, and sensor electronics 120 is configured to use the signal to generate an output corresponding to a measurement of the electrophysiological signal.

[0260] In the manner illustrated in FIG. 7A, biological fluid 10 may include multiple analytes 71, 72, and 73. Device 700 may be configured to measure the concentration of analyte 71, and therefore, such analyte may be referred to as a "target" analyte. As shown in FIG. 7B, enzyme 715 may be disposed within enzyme layer 716 and may selectively act on target analytes 71 from biological fluid 10 or from biointerface membrane 114 (e.g., when provided as illustrated in FIG. 7A and configured similarly to those described with reference to FIGS. 1A and 2A, and optionally configured similarly to biointerface membrane 114' as described with reference to FIGS. 1H-1I). Action of enzyme 715 on target analytes 71 produces target ions 11. The ionophore 115 in the first electrode 111 or in the ion selective membrane 212 may selectively transport or selectively bind the target ion 11 from the enzyme 715 to or within the first electrode 111 or first electrode 211 .

[0261] It is understood that target analyte 71 is any suitable analyte, enzyme 715 is any suitable enzyme that produces a suitable ion in response to acting on the analyte, and ionophore 115 is any suitable ionophore that selectively transports and / or binds the ion produced by enzyme 715 so as to produce an EMF such that the concentration of analyte 71 can be determined (whether using sensor electronics 120 or an external device that transmits an electrophysiological signal and / or a signal corresponding to ion concentration). Non-limiting examples of analytes, enzymes, and ionophores that can be used together are listed in Table 1 below.

[0262] [Table 1]

[0263] FIG. 8 illustrates a flow of operations in an exemplary method for measuring the concentration of a target analyte in a biological fluid in vivo. Method 800 shown in FIG. 8 includes implanting an indwelling sensor (OPERATION 810). As described with reference to FIGS. 7A-7C , the sensor may include a substrate, a first electrode disposed on the substrate, an ionophore disposed on the substrate and configured to selectively transport a target ion to or within the first electrode, an enzyme configured to produce the target ion in response to an action on the target analyte, and a second electrode disposed on the substrate. Method 800 may also include generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode (OPERATION 820). Method 800 may also optionally include using the signal to generate an output corresponding to a measure of the concentration of the analyte in the biological fluid (OPERATION 830). For example, the sensor electronics 120 may generate an output or transmit a signal to an external device that generates an output in a manner similar to that described with reference to Figures 1A-1I, 2A-2G, 3, 5A-5B, and 6A-6G.

[0264] 17 is a diagram depicting an exemplary continuous analyte monitoring system 1700 configured to measure one or more target ions and / or other analytes as discussed herein. The monitoring system 1700 includes an analyte sensor system 1724 operably connected to a host 1720 and a plurality of display devices 1734a-e in accordance with certain aspects of the present disclosure. Note that the display device 1734e may alternatively, or in addition to, be a drug delivery device capable of acting in cooperation with the analyte sensor system 1724 to deliver a drug to the host 1720. In one example, the analyte sensor system 1724 may include a sensor electronics module 1726 and a continuous analyte sensor 1722 associated with the sensor electronics module 1726. In one example, the sensor electronics module 1726 may wirelessly communicate directly with one or more of the plurality of display devices 1734a-e via wireless communication signals.

[0265] As discussed in more detail below, the display devices 1734a-e may also communicate between and / or through each other to the analyte sensor system 1724. For ease of reference, wireless communication signals from the analyte sensor system 1724 to the display devices 1734a-e may be referred to as “uplink” signals 1728. For example, wireless communication signals from the display devices 1734a-e to the analyte sensor system 1724 may be referred to as “downlink” signals 1730. Wireless communication signals between two or more of the display devices 1734a-e are referred to as “crosslink” signals 1732. Additionally, wireless communication signals may include data transmitted by one or more of the display devices 1734a-d to one or more remote servers 1740 or network entities, such as cloud-based servers or databases, via “long-range” uplink signals 1736 (e.g., cellular signals), and may receive long-range downlink signals 1738 transmitted by the remote servers 1740.

[0266] The sensor electronics module 1726 includes sensor electronics configured to process sensor information and generate converted sensor data information. In certain embodiments, the sensor electronics module 1726 includes electronic circuitry associated with measuring and processing data from the continuous analyte sensor 1722, including predictive algorithms associated with processing and calibrating the continuous analyte sensor data. The sensor electronics module 1726 can be integral with (permanently attached to) or removably attached to the continuous analyte sensor 1722, achieving a physical connection therebetween. In one example, the sensor electronics module 1726 can include hardware, firmware, and / or software that enable analyte level measurement. For example, the sensor electronics module 1726 can include a potentiostat, a power supply for providing power to the continuous analyte sensor 1722, other components useful for signal processing and data storage, and a telemetry module for transmitting data therefrom to one or more display devices 1734a-e. The electronics can be mounted on a printed circuit board (PCB) or the like and can take a variety of forms. For example, the electronics may take the form of an integrated circuit (IC), such as an application specific integrated circuit (ASIC), a microcontroller, and / or a processor. Examples of systems and methods for processing sensor analyte data are described in more detail herein and in U.S. Pat. Nos. 7,310,544 and 6,931,327, as well as U.S. Patent Application Publication Nos. 2005 / 0043598, 2007 / 0032706, 2007 / 0016381, 2008 / 0033254, 2005 / 0203360, 2005 / 0154271, 2005 / 0192557, 2006 / 0222566, 2007 / 0203966, and 2007 / 0208245, each of which is incorporated by reference in its entirety for all purposes.

[0267] The display devices 1734a-e are configured to display, alert, and / or justify medication delivery based on sensor information transmitted by the sensor electronics module 1726 (e.g., in customized data packages transmitted to one or more of the display devices 1734a-e based on their respective preferences). Each of the display devices 1734a-e may include a display, such as a touchscreen display, for displaying the sensor information to a user (in most cases, the host 1720 or a caregiver / healthcare professional) and / or receiving input from the user. In some embodiments, the display devices 1734a-e may include other types of user interfaces, such as a voice user interface, instead of or in addition to a touchscreen display for communicating the sensor information to a user of the display device 1734a-e and / or receiving user input. In some embodiments, one, some, or all of the display devices 1734a-e are configured to display or otherwise communicate the sensor information as it is communicated from the sensor electronics module 1726 (e.g., in data packages transmitted to the respective display devices 1734a-e) without any additional anticipated processing required for calibration and real-time display of the sensor information.

[0268] 17 embodiment, one of the plurality of display devices 1734a-e may be a custom display device 1734a specially designed to display a particular type of displayable sensor information (e.g., in some embodiments, numerical values ​​and arrows) associated with the analyte value received from the sensor electronics module 1726. In some embodiments, one of the plurality of display devices 1734a-e is a handheld device 1734c, such as a mobile phone based on an Android, iOS, or other operating system, a palmtop computer, or the like, which has a relatively large display and may be configured to display a graphical representation of continuous sensor data (e.g., including current and historical data). Other display devices may include a tablet 1734d, a smartwatch 1734b, a drug delivery device 1734e, a blood glucose meter, and / or other handheld devices such as a desktop or laptop computer.

[0269] As described above, because different display devices 1734a-e provide different user interfaces, the content of the data package (e.g., amount, format, and / or type of data displayed, alarms, etc.) can be customized (e.g., programmed differently by the manufacturer and / or end user) for each particular display device and / or type of display device. Thus, in the embodiment of Figure 1, one or more of the display devices 1734a-e can be in direct or indirect wireless communication with the sensor electronics module 1726 to enable multiple different types and / or levels of display and / or functionality associated with the sensor information, as described in more detail elsewhere herein.

[0270] Continuous analyte sensors Generally, continuous analyte sensor 1722 is an implantable analyte sensor that utilizes at least potentiometric sensing technology to measure one or more analyte concentrations. Electrodes comprising continuous analyte sensor 1722 may include a working electrode, a counter electrode, and / or a reference electrode. In one embodiment, a counter electrode is provided to balance the current generated by the species being measured at the working electrode.

[0271] In some alternative embodiments, additional electrodes may be included in the assembly, for example, a three-electrode system (working electrode, reference electrode, and counter electrode) and an additional working electrode (e.g., an electrode that can be used to generate oxygen, an electrode configured as a baseline subtraction electrode, or an electrode configured to measure an additional analyte). U.S. Pat. No. 7,081,195, U.S. Patent Application Publication No. 2005 / 0143635, and U.S. Patent Application Publication No. 2007 / 0027385, each of which is incorporated herein by reference in its entirety, describe some systems and methods for implementing and using additional working, counter, and / or reference electrodes.

[0272] Example of operation The following examples are intended to be purely illustrative and not limiting of the present disclosure. Figures 9A-9B are plots showing the measured sensitivity of an exemplary device to potassium ions. More specifically, the example sensor was prepared on a coaxial gold wire modified with a PEDOT(PSS) layer, which served as the solid contact (SC), followed by a fluorosilicone ISM containing potassium ionophore 2 and KTClPB (1.0 wt % and 0.3 wt %, respectively) as the sensing components. The sensor exhibited near-Nernstian (approximately 58 mV per 10 of concentration, n=6) responses in aqueous samples containing different concentrations of potassium ions, as shown in Figures 9A-9B. Figures 10A-10B are plots showing the measured sensitivity of a substantially identical composition device to potassium ions in the presence of interfering ions. More specifically, the selectivity of the potassium ion sensor was evaluated by measuring the change in potassium activity in samples containing different interfering ions (140 mM NaCl, 1.2 mM CaCl, 1 mM MgCl) (Figures 10A-10B), again demonstrating near-Nernstian sensitivity (approximately 56 mV per 10 of concentration, n = 5), validating the potential use of such sensors in real samples. Figure 11 is a plot showing the drift of the exemplary device described with reference to Figures 9A-9B and 10A-10B. More specifically, to demonstrate the potential use of the present ion sensor for continuous ion monitoring, a potassium ion sensor was immersed in a 10 mM KCl solution and allowed to drift for 70 hours (Figure 11). The calculated drift in the potentiometric response from four identical sensors immersed in a 10 mM KCl solution for 72 hours was 2 ± 1 mV.

[0273] Figure 12 illustrates plots of the measured absolute potential (E), potential gradient (m), and drift of another exemplary device in both water and 140 mM NaCl solution (green and orange, respectively; n = 8). More specifically, the device's sensors included coaxial carbon-coated gold wires modified by a dip-coating technique with a P3OT-doped fluorosilicone ISM (1 wt% potassium ionophore 2; 0.3 wt% KTClPB; 5 mg / mL P3OT). These sensors exhibited the absolute potential E, potential gradient (m), and drift characteristics shown in Figure 12. The sensors exhibited similar performance in the absence of a model interfering ion (sodium), indicating minimal loss of sensitivity when measuring potassium in the presence of sodium.

[0274] It will be understood that potassium ions are a non-limiting example of ions detected using the present devices and methods. For example, FIGS. 13A-13B are schematic diagrams illustrating an exemplary device configured to detect urea using a urease enzyme and an ionophore selective for ammonium ions. As shown in FIGS. 13A-13B, a gold wire (core or substrate) 1301 is partially coated with Ag / AgCl 1330 (reference electrode), leaving a window through which the gold is exposed to form a first electrode (working electrode) 1311 in the manner described with reference to FIGS. 6A-6G. The working electrode 1311 is formed by removing a portion of one or more top layers, for example, by an etching process, including, but not limited to, laser ablation / skiving / etching, grit blasting, or other method or combination of methods. In some examples, an insulating material as discussed herein is disposed between the working electrode 1311 and the reference electrode 1330. In other examples, an insulating material is not disposed between the working electrode 1311 and the reference electrode 1330. An ammonium-selective membrane 1312, such as that described with reference to Figure 2A, containing the ammonium-selective ionophore nonactin, is deposited on the first electrode 1311. In one example, the reference electrode is devoid of any ion-selective membrane and ionophore. An urease membrane 1316, such as that described with reference to Figures 7A-7C, containing urease as the enzyme 715, is deposited on the ammonium-selective membrane.

[0275] 14A-14B are schematic diagrams illustrating an exemplary device using an ionophore selective for ammonium ions. More specifically, a device was prepared for the purpose of characterizing the ammonium-selective membrane 1312 described with reference to FIGS. 13A-13B. As shown in FIGS. 14A-14B and similarly as described with reference to FIGS. 13A-13B, a gold wire (core or substrate) 1301 was partially coated with Ag / AgCl 1330 to leave windows within which the gold was exposed, forming a first electrode (working electrode) 1311 in the manner described with reference to FIGS. 6A-6G. A solid contact layer (SC) containing PEDOT:PSS was deposited on the first electrode 1311. An ammonium-selective membrane 1312, such as the ion-selective membrane 212 described with reference to 2A and containing the ammonium-selective ionophore nonactin, was deposited on the SC layer 1413. In one example, the reference electrode lacks any ion-selective membrane and ionophore. The ammonium-selective membrane 1312 was prepared by repeatedly dipping the distal tip of the device into a solution containing approximately 1 mg of nonactin dissolved in approximately 660 microliters (μL) of tetrahydrofuran (THF), 33 mg of PVC, and 72.2 μL of the plasticizer dioctyl sebacate (DOS), allowing the tip to dry between dippings in the solution.

[0276] The response of the device of Figures 14A-14B to aqueous ammonium ions was characterized as a way to closely simulate the response of the device of Figures 13A-13B to urea, e.g., to closely simulate the production of ammonium ions by urease in response to the action of urea. Figure 15 is a plot showing the measured sensitivity of the exemplary device of Figures 14A-14B to ammonium ions. More specifically, the device was first conditioned in about 0.1 M ammonium chloride for about 2 hours and then immersed in aqueous ammonium chloride solutions having concentrations of about 0.1 mM, 1 mM, and 10 mM, respectively. The sensor exhibited near-Nernstian sensitivity (about 57 mV per 10 of concentration, n=8) in aqueous samples containing different concentrations of ammonium ions, as shown in Figure 15. Figure 16 shows plots of the measured absolute potential (E), potential gradient (m), and R-squared (R) of the exemplary device of Figures 14A-14B and 15 to ammonium ions. The R value is a coefficient of determination that indicates the strength of the relationship between a linear model and a dependent variable (e.g., potential response to ion concentration), and values ​​close to 1.000 are desirable. Determination of ammonium yielded a linear response range of 0.1 to 10 mM with an R value ≥ 0.999. The analytical characteristics summarized in Figure 16 demonstrate the performance of the ammonium-selective electrode for the detection of ammonium ions in aqueous samples.

[0277] Calculation of selectivity coefficient 18A and 18B show the selectivity of an exemplary continuous potassium ion sensor described herein. The selectivity of an ISE is measured by its selectivity coefficient, K a / b ", which is a numerical measure of how well the ISM can discriminate target ions (a) from interfering ions (b). In some examples described herein, "K a / b"<1 is desirable. The selectivity coefficients discussed herein were calculated for a sensor having a first (working) electrode formed from carbon-coated gold (Au) and a second electrode formed from silver / silver chloride. The ISM formed on the sensor overlying the first electrode included 1 wt. % potassium ionophore 2; 0.3 wt. % KTClPB; 6 wt. % DEX4041; 5 mg / mL P3OT (poly(3-octylthiophene-2,5-diyl)); and tetrahydrofuran (THF).

[0278] The selectivity coefficient of the sensor was calculated using fixed interference method. Therefore, the selectivity of the primary ions (range: 10 -6 The sensor response to potassium (~50 mM KCl) was evaluated in a solution with a fixed background of interfering ions (100 mM NaCl). K+ ) was calculated from the intersection of the extrapolated linear part of the EMF response to −log of the activity of the primary ion (see plot described below).

[0279] K pot K+ / Na+ Calculate:

[0280]

number

[0281] Figure 18A shows the EMF generated when KCl was introduced into a solution containing 100 mM NaCl. Figure 18A shows the sensor's response to the addition of KCl to the solution. Figure 18B presents data calculated based on Figure 18A, showing the EMF generated in response to increasing concentrations of KCl. The slope change indicated by the arrow in Figure 18B indicates when the sensor can detect KCl over NaCl (the selectivity of KCl over NaCl is approximately -1.29 (activity of potassium)). As shown in Figure 18B, the continuous potassium ion sensor demonstrated sufficient selectivity to measure K in the range of 0.1 to 50 mM in the presence of 100 mM Na: Log K POT K+,Na+ =-1.29 / 2=-0.64 K POT K+,Na+ =5.1E -2 / 100=5.1E -4 Sensor operation in the range of 0.1–50 mM, m(slope) = 53 mV / 10 concentration.

[0282] FIG. 19A shows a planar configuration of an exemplary potassium ion sensor device 920 of the present disclosure, consisting of a platinum WE 922 modified with a solid contact layer 924 and a sensing membrane 927 containing a polyurethane polymer with 24 10 wt % polysiloxane soft segments, 2.2 mg of potassium ionophore III: bis[(benzo-15-crown-5)-4-methyl] pimelate (BB15C5), and 0.5 mg of KTFPB, with an Ag / AgCl RE 929 located on the opposite side of the planar substrate. The device 920 is configured to be inserted into the dermis or subcutaneous tissue of a host to potentiometrically monitor electrophysiological signals and / or concentrations of selected ions in the host's interstitial fluid. A resistive membrane (not shown) can be used over the WE and / or RE. In one example, the resistive membrane is used to attenuate leaching of plasticizers from the ISM. In one example, a resistive membrane is used to attenuate leaching of plasticizers from a plasticized polyvinyl chloride (PVC) ISM. A biointerface membrane (not shown) can be used with or without a releasable anti-inflammatory agent. In one example, a resistive membrane is used to attenuate leaching (degradation) of silver and / or chloride from the second electrode during use.

[0283] Figure 19B shows experimental data of E vs. potassium ion concentration obtained from three exemplary planar devices 920, demonstrating acceptable stability and sensitivity for continuous monitoring. Accordingly, Figure 19B illustrates the sensitivity to potassium and E exhibited by the planar potassium ion sensor of Figure 19A for Ag / AgCl / KCl (n=3) (potassium break in solution: 0.1 mM KCl; potassium spikes were 1, 5, and 10 mM KCl, respectively). The data in Figure 19B demonstrate the repeatable sensitivity and resistance to drift of the sensor device 920 structure of Figure 19A.

[0284] Interferent Test Data In another example, an exemplary potassium ion sensor was developed that included a gold wire / carbon ink WE as the first electrode coated with an ISM containing 2-nitrophenyl octyl ether plasticized PVC, BME44 ionophore, and KTFPB salt, and an Ag / AgCl RE as the second electrode dip-coated with a resistive film (polyvinylpyrrolidone-CARBOSIL® blend using 25% ethanol, 6% solids) and exposed to an interferent (sodium chloride (NaCl)). Figure 20A shows data from seven identically prepared sensors and their sensitivity to potassium in the presence of 140 mM NaCl interferent after 0.1 mM potassium ion spikes in 1, 5, and 10 mM KCl (Figure 20B shows an enlarged portion of Figure 20A), followed by 4 days of drift in 10 mM KCl / 140 mM NaCl (n=7), and the corresponding measured sensitivity (m) and absolute potential (E) measured after 4 days of drift for an exemplary potassium ion sensor. This data demonstrates the stability and sensitivity of the sensor to pharmacologically relevant concentrations of potassium ion in the presence of pharmacologically relevant concentrations of interferents (e.g., sodium ions). Further data was obtained using a gold wire first electrode, a carbon ink solid contact layer, and a fluorocarbon-based ISM material FS730 (DuPont) containing BME44 ionophore and KTFPB salt, with an Ag / AgCl RE as the second electrode. Figure 20C shows data from three identically prepared sensors and their sensitivity to potassium in the presence of 140 mM NaCl interferent after spiking 0.1 mM potassium ion at 1, 5, and 10 mM KCl, and Figure 20D shows sensor drift data. The data demonstrate the stability and sensitivity of the sensor to pharmacologically relevant concentrations of potassium ion in the presence of pharmacologically relevant concentrations of interferents (e.g., sodium ion).

[0285] Solid contact layer data In some examples, GO materials were compared with alternative carbon-based solid contact (SC) layer materials. Therefore, gold wire electrodes were modified with different commercially available carbon inks (Dupont 7102 and BQ221, hereafter referred to as "7102" and "BQ221"), one of which was supplemented with MWCNTs (10-20 µm). Sensors constructed using these conductive carbon inks as SCs demonstrated a response to potassium ions in the presence of interfering sodium ions. Samples were prepared using a polyurethane polymer with polysiloxane soft segments as the ISM with the BME44 ionophore and compared with 2-nitrophenyl octyl ether-plasticized PVC with the same ionophore as a control.

[0286] Thus, a wire potassium ion sensor was developed that included an exemplary solid contact (SC) layer disposed between a first electrode and a plasticized ISM 965 and polyurethane-polysiloxane-polycarbonate ion-selective membrane, as shown in Figures 21A, 21B, and 21C. Figure 21A depicts a similarly prepared sensor with an SC containing BQ221 in a plasticized ISM and polyurethane-polysiloxane-polycarbonate ion-selective membrane; Figure 21B depicts a similarly prepared sensor with an SC containing 7102 plasticized ISM 965 and a polyurethane-polysiloxane-polycarbonate ion-selective membrane; and Figure 21C depicts a similarly prepared sensor with an SC containing 7102 and a carbon nanotube-plasticized ISM and a polyurethane-polysiloxane-polycarbonate ion-selective membrane. The data demonstrate improved sensitivity and stability using an SC containing 7102. The carbon nanotube-containing conductive ink did not show significant improvements in m, E0, or drift compared to the other conductive inks tested.

[0287] Resistive Film Data FIG. 22A shows the effect of using resistive films (RM) disposed on the first and second electrodes on sensitivity and stability. Thus, in one example, a resistive film (RM) of polyvinylpyrrolidone-CARBOSIL® (thermoplastic silicone polycarbonate polyurethane blend) was coated on a 2-nitrophenyl octyl ether plasticized PVC ISM gold wire sensor 940 with a solid-contact carbon paste material 7102 and showed significantly improved drift compared to a plasticized PVC control sensor 942 without the RM. In one example, the resistive film is selected to minimize and / or attenuate plasticizer leaching from the ISM, thus improving continuous operation and reducing or eliminating degradation of the second electrode. In one example, the RM material is selected to minimize migration of low MW materials (e.g., plasticizers) to improve sensor lifetime and minimize plasticizer leaching. In one example, a biocompatible plasticizer for PVC, such as polyethylene glycol (PEG), is used.

[0288] 22B and 22C depict the effect of thickness and second electrode composition, respectively, on continuous ion sensor performance in the presence of physiological amounts of potassium and sodium ions. Thus, for a constant second electrode composition (AgCl wt %), a second electrode thickness of at least 0.9 thousandths of an inch (23 microns) provided near-constant drift data 950 compared to drift data 951 for a reference electrode thickness of less than 0.6 thousandths of an inch (15 microns). FIG. 22C shows data for second electrodes of various compositions, where data 952 represents 0 AgCl wt %, data 953 represents 15 AgCl wt %, data 954 represents 40 AgCl wt %, and data 955 represents 50 AgCl wt %. Thus, this data demonstrates improved sensor stability performance with higher amounts of AgCl in the second electrode in the presence of pharmacological amounts of potassium and sodium ions.

[0289] 23A and 23B show in vivo animal data for an exemplary coaxial potassium ion sensor representative of the present disclosure, utilizing a gold wire first electrode with a graphene oxide solid contact layer coated with a polyurethane-polycarbonate-polyol ISM containing BB15C5 and KTFPB with a polyvinylpyrrolidone-CARBOSIL® resistive film coating, and an Ag / AgCl RE as the second electrode, also coated with the same resistive film. The data in FIG. 23A shows the raw signal of the potassium ion sensor 975 in an in vivo environment, while FIG. 23B shows an expanded section of FIG. 23A illustrating the correlation between blood potassium ion concentrations (dots) measured in vivo using the potassium ion sensor 975 of the present disclosure and in vitro (blood sample measurements using a bench analyzer (Radiometer ABL90)) measurements 977.

[0290] Figure 23C shows in vivo animal data for an exemplary coaxial potassium ion sensor representative of the present disclosure, utilizing a gold wire first electrode with a 7102 carbon ink solid contact layer coated with a 2-nitrophenyl octyl ether plasticized PVC ISM containing BBE44 and KTFPB with a polyvinylpyrrolidone-CARBOSIL® resistive film coating, and an Ag / AgCl RE as the second electrode, also coated with the same resistive film. The data in Figure 23C demonstrate a correlation between blood potassium ion concentrations measured in vivo with the potassium ion sensor of the present disclosure and in vitro (blood sample measurements using a bench analyzer (Radiometer ABL90)) measurements.

[0291] sterile In one example, an exemplary potassium ion sensor of the present disclosure is sterilized. In one example, a potassium ion sensor of the present disclosure is sterilized with high-energy radiation. In one example, a potassium ion sensor of the present disclosure is sterilized with ethylene oxide (EtO). FIG. 24A shows sensitivity and calibration data before EtO sterilization for 23 identically prepared sensors utilizing a gold wire first electrode with a 7102 solid contact layer coated with a polyurethane-polycarbonate-polyol ISM containing BBE44 and KTFPB with a polyvinylpyrrolidone-CARBOSIL® resistive film coating, and an Ag / AgCl RE as the second electrode coated with the same resistive film, and FIG. 24B shows sensitivity and calibration data after EtO sterilization of the sensors. The data in FIGS. 24A and 24B show a significant difference in E between untreated and EtO-sterilized sensors (n=23 each). The post-EtO sensors showed a positive E offset and improved distribution compared to the pre-EtO sterilization control. Microscopic characterization showed no significant membrane changes after EtO sterilization, and therefore EtO sterilization appears to be compatible with the sensor chemistry disclosed herein.

[0292] Unless otherwise indicated, WE is used throughout this disclosure as an abbreviation for working electrode. Unless otherwise indicated, RE is used throughout this disclosure as an abbreviation for reference electrode.

[0293] All references cited herein, including, but not limited to, published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and made a part of this specification. To the extent that the publications and patents or patent applications incorporated by reference conflict with the present disclosure contained herein, the present specification is intended to supersede and / or supersede any such conflicting material.

[0294] As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0295] All numbers expressing quantities of ingredients, reaction conditions, and so forth used herein should be understood to be modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to this application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0296] The above description discloses various methods and materials of the present disclosure. The present disclosure is susceptible to modifications in the methods and materials, and to changes in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from consideration of the present disclosure or practice of the present disclosure disclosed herein. Accordingly, the present disclosure is not intended to be limited to the particular embodiments disclosed herein, but rather is intended to cover all modifications and alternatives falling within the true scope and spirit of the present disclosure.

[0297] Although particular embodiments of the present disclosure have been illustrated with reference to particular combinations of elements, various other combinations may be provided without departing from the teachings of the present disclosure. Thus, the present disclosure should not be construed as being limited to the particular exemplary embodiments described herein and illustrated in the figures, but may also encompass combinations of elements of the various illustrated embodiments and aspects thereof.

Claims

1. 1. A device for continuously measuring the concentration of at least one target analyte in an in vivo biological fluid, comprising:

1. An indwelling analyte sensor comprising: A substrate; a first electrode disposed on the substrate; an ion-selective membrane comprising an ionophore, the ion-selective membrane being disposed on the substrate and configured to selectively transport the at least one target analyte to or into the first electrode; a second electrode disposed on the substrate; a sensor electronics configured to generate a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the at least one target analyte to the first electrode;

2. 10. The device of claim 1, wherein the ion-selective membrane is a fluorosilicone rubber, a polydimethylsiloxane polymer, a silicone rubber, a polyurethane with a polysiloxane soft segment, a polyurethane with hard and soft segments, a water-based polyurethane, polyvinyl butyral, polymethyl methacrylate, polyvinyl acrylate, or a blend or graft polymer thereof.

3. 3. The device of claim 1 or 2, wherein the first electrode or the second electrode is independently a metal, a metal alloy, or a conducting polymer selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene)polystyrenesulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

4. The ionophore is 4-tert-butylcalix[4]arene-tetraacetic acid tetraethyl ester (sodium ionophore X) calix[4]arene-25,26,27,28-tetraol (calix[4]arene); potassium ionophore I (valinomycin); potassium ionophore II: bis[(benzo-15-crown-5)-4'-ylmethyl]pimelate (BB15C5); potassium ionophore III:

4. The device of claim 1, wherein the ionophore is selected from the group consisting of 2-dodecyl-2-methyl-1,3-propanediylbis[N-[5'-nitro(benzo-15-crown-5)-4'-yl]carbamate] (BME44); 4,5-bis(benzoylthio)-1,3-dithiole-2-thione (Bz2dmit); 1,3,5-tris[10-(1-adamantyl)-7,9-dioxo-6,10-diazaundecyl]benzene (magnesium ionophore VI); calcium ionophore I (ETH 1001); calcium ionophore II (ETH129); tridodecylmethylammonium chloride (TDMAC) and nonactin.

5. 5. The device of any one of claims 1 to 4, wherein the ion-selective membrane further comprises a lipophilic salt selected from the group consisting of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTPFB), sodium tetraphenylborate (NaTPB), potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (KTFPB), and potassium tetrakis(4-chlorophenyl)borate (KTClPB).

6. 6. The device of claim 1, wherein the ion-selective membrane is in direct contact with the first electrode.

7. 7. The device of claim 1, further comprising a solid contact layer disposed between the first electrode and the ion-selective membrane.

8. The device of claim 1 , wherein the solid contact layer comprises a metal, a carbon material, a carbon ink, a carbon paste, a doped semiconductor, or a conductive polymer.

9. 9. The device of claim 1, wherein the solid contact layer comprises a redox couple selected from the group consisting of Co(II) and Co(III), Ir(II) and Ir(III), and Os(II) and Os(III).

10. The solid contact layer is made of strontium titanate (SrTiO ３ ), titanium dioxide (TiO ２ ), (La, Ba, Sr) (Mn, Fe, Co) O ３－ｄ , La ２ CuO ４＋ｄ , cerium (IV) oxide (CeO ２ ), lithium iron phosphate (LiFePO ４ ), and LiMnPO ４ 10. The device of claim 1, comprising a mixed conductor or mixed ionic-electronic conductor selected from the group consisting of:

11. 11. The device of any one of claims 1 to 10, wherein the at least one target analyte is selected from the group consisting of sodium ions, potassium ions, hydrogen ions, lithium ions, magnesium ions, calcium ions, chloride ions, sulfite ions, sulfate ions, phosphate ions, ammonium ions, uric acid, urea, ketones, and glucose.

12. 12. The device of claim 1, further comprising a biointerface membrane disposed on the ionophore and the first electrode, wherein the biocompatible polymer is selected from the group consisting of polyvinyl butyral (PVB), polyurethane, and silicone.

13. The device of claim 1 , wherein the biointerface membrane is configured to release a therapeutic compound into the biological fluid.

14. The device of claim 1 , wherein the sensor electronics include a galvanostat.

15. 15. The device of claim 1, wherein the sensor electronics are configured to: (a) measure the electromotive force using a dynamically configurable frequency; (b) maintain the second electrode at a substantially constant potential; or (c) a combination thereof.

16. 16. The device of claim 1, wherein the electromotive force is further based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid conducting an electrophysiological signal to the first electrode, wherein a first contribution to the electromotive force from the electrophysiological signal changes rapidly relative to a second contribution to the electromotive force from a concentration of the ion in the physiological fluid, and wherein the sensor electronics are configured to parse the first contribution from the second contribution.

17. The device of claim 1 , wherein the electrophysiological signal comprises a cardiac electrical signal.

18. 18. The device of claim 1, further comprising an enzyme configured to generate the at least one target analyte, the enzyme being selected from an oxidase.

19. 1. A method for continuously measuring the concentration of a target analyte in a biological fluid in vivo, said method comprising: An indwelling sensor, A substrate; a first electrode disposed on the substrate; an ionophore disposed on the substrate and configured to selectively transport target ions to or within the first electrode; an indwelling sensor comprising: a second electrode disposed on the substrate; generating a signal corresponding to an electromotive force, the electromotive force being generated at least in part based on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode.

20. 20. The method of claim 19, further comprising an enzyme configured to generate the target analyte.

21. 1. A device for continuously measuring target ions in an in vivo biological fluid, comprising:

1. An indwelling analyte sensor comprising: A substrate; a first electrode disposed on the substrate; an ionophore disposed on the substrate and configured to selectively transport target ions to or within the first electrode; a second electrode disposed on the substrate; A sensor electronic device, and sensor electronics configured to generate a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode.

22. 22. The device of claim 21, wherein the sensor electronics is further configured to use the signal to generate an output corresponding to a measure of the concentration of the target ion in the biological fluid.

23. 23. The device of any one of claims 21 to 22, wherein the sensor electronics are further configured to transmit the signal to an external device configured to use the signal to generate an output corresponding to a measure of the concentration of the target ion in the biological fluid.

24. 24. The device of any one of claims 21 to 23, wherein the first electrode comprises a conductive polymer having the ionophore therein.

25. 25. The device of any one of claims 21 to 24, wherein the first electrode is substantially free of plasticizers.

26. 26. The device of claim 24 or 25, wherein the first electrode consists essentially of the conductive polymer and the ionophore.

27. 26. The device of claim 24 or 25, wherein the first electrode consists essentially of the conductive polymer, the ionophore, and an additive having ion exchange capacity.

28. 28. The device of claim 27, wherein the additive comprises a lipophilic salt.

29. 29. The device of claim 28, wherein the lipophilic salt is selected from the group consisting of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTPFB), sodium tetraphenylborate (NaTPB), potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (KTFPB), and potassium tetrakis(4-chlorophenyl)borate (KTClPB).

30. 30. The device of claim 29, wherein the additive is present in the first electrode in an amount of about 0.01 to about 1 weight percent.

31. 31. The device of any one of claims 21 to 30, wherein the conductive polymer is present in the first electrode in an amount of from about 90 to about 99.5 weight percent.

32. 32. The device of any one of claims 21 to 31, wherein the conductive polymer is selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene)polystyrenesulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

33. 33. The device of any one of claims 21 to 32, wherein the ionophore is present in the first electrode in an amount of about 0.5 to about 10 weight percent.

34. 34. The device of any one of claims 21 to 33, wherein the ionophore is in an ion-selective membrane disposed on the first electrode.

35. 35. The device of claim 34, wherein the ion-selective membrane is substantially free of plasticizers.

36. 36. The device of claim 34 or 35, wherein the ion-selective membrane consists essentially of a biocompatible polymer and an ionophore configured to selectively bind the target ion.

37. 36. The device of claim 34 or 35, wherein the ion-selective membrane consists essentially of a biocompatible polymer, an ionophore configured to selectively bind to the target ion, and an additive having ion exchange capacity.

38. 38. The device of claim 37, wherein the additive comprises a lipophilic salt.

39. 39. The device of claim 38, wherein the lipophilic salt is selected from the group consisting of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTPFB), sodium tetraphenylborate (NaTPB), potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (KTFPB), and potassium tetrakis(4-chlorophenyl)borate (KTClPB).

40. 40. The device of any one of claims 37 to 39, wherein the additive is present in the ion-selective membrane in an amount of from about 0.01 to about 1 weight percent.

41. 41. The device of any one of claims 34 to 40, wherein the biocompatible polymer is present in the ion-selective membrane in an amount of about 90 to about 99.5 weight percent.

42. 42. The device of any one of claims 21 to 41, wherein the biocompatible polymer comprises a hydrophobic polymer.

43. 43. The device of claim 42, wherein the hydrophobic polymer is selected from the group consisting of silicone, fluorosilicone (FS), polyurethane, fluoropolymer, poly(vinyl chloride) (PVC), polyacrylate, and polymethacrylate.

44. 44. The device of any one of claims 21 to 43, wherein the biocompatible polymer comprises a block copolymer.

45. 45. The device of claim 44, wherein the block copolymer comprises a hydrophilic block selected from the group consisting of polycarbonate (PC) and polybutadiene (PBD).

46. 46. ​​The device of claim 44 or 45, wherein the block copolymer comprises a hydrophobic group selected from the group consisting of polydimethylsiloxane (PDMS), methylene diphenyl diisocyanate (MDI), polysulfone (PSF), and methyl methacrylate (MMA).

47. 47. The device of any one of claims 21 to 46, wherein the ionophore is present in the ion-selective membrane in an amount of about 0.5 to about 10 weight percent.

48. 48. The device of any one of claims 21 to 47, wherein the first electrode comprises a metal, a metal alloy, a transition metal oxide, a transparent conductive oxide, a carbon material, a doped semiconductor, a binary semiconductor, a ternary semiconductor, or a conducting polymer.

49. 49. The device of claim 48, wherein the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium.

50. 50. The device of claim 48 or 49, wherein the metal is oxidized or in the form of a metal salt.

51. 49. The device of claim 48, wherein the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond.

52. 49. The device of claim 48, wherein the doped semiconductor is selected from the group consisting of silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide.

53. 49. The device of claim 48, wherein the conductive polymer is selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene)polystyrenesulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

54. 54. The device of any one of claims 21 to 53, wherein the ion-selective membrane is in direct contact with the first electrode.

55. 54. The device of any one of claims 21 to 53, further comprising a solid contact layer disposed between the first electrode and the ion-selective membrane.

56. 56. The device of claim 55, wherein the solid contact layer comprises a metal, a carbon material, a doped semiconductor, or a conducting polymer.

57. 57. The device of claim 56, wherein the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium.

58. 58. The device of claim 56 or 57, wherein the metal is oxidized or in the form of a metal salt.

59. 57. The device of claim 56, wherein the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond.

60. 57. The device of claim 56, wherein the doped semiconductor is selected from the group consisting of silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide.

61. 57. The device of claim 56, wherein the conductive polymer is selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene)polystyrenesulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

62. 57. The device of claim 56, wherein the solid contact layer comprises a redox couple.

63. 63. The device of claim 62, wherein the redox pair comprises metal centers having different oxidation states.

64. 64. The device of claim 63, wherein the metal center is selected from the group consisting of Co(II) and Co(III), Ir(II) and Ir(III), and Os(II) and Os(III).

65. 56. The device of claim 55, wherein the solid contact layer comprises a mixed conductor or a mixed ionic-electronic conductor.

66. The solid contact layer is made of strontium titanate (SrTiO ３ ), titanium dioxide (TiO ２ ), (La, Ba, Sr) (Mn, Fe, Co) O ３－ｄ , La ２ CuO ４＋ｄ , cerium (IV) oxide (CeO ２ ), lithium iron phosphate (LiFePO ４ ), and LiMnPO ４ 66. The device of claim 65, comprising a compound selected from the group consisting of:

67. 67. The device of any one of claims 55 to 66, wherein the solid contact layer inhibits transport of water from the biological fluid to the first electrode.

68. 68. The device of any one of claims 55 to 67, wherein the solid contact layer is configured to enhance the electrical stability of the first electrode.

69. 69. The device of any one of claims 21 to 68, wherein the target ions are selected from the group consisting of sodium, potassium, hydrogen, lithium, magnesium, calcium, chloride, sulfite, sulfate, phosphate, and ammonium.

70. 70. The device of any one of claims 21 to 69, wherein the target ion is sodium and the ionophore is 4-tert-butylcalix[4]arene-tetraacetic acid tetraethyl ester (sodium ionophore X) or calix[4]arene-25,26,27,28-tetraol (calix[4]arene).

71. 70. The device of any one of claims 21 to 69, wherein the target ion is potassium and the ionophore is potassium ionophore I (valinomycin), potassium ionophore II (BB15C5), or potassium ionophore III (BME44).

72. 70. The device of any one of claims 21 to 69, wherein the target ion is magnesium and the ionophore is 4,5-bis(benzoylthio)-1,3-dithiole-2-thione (Bz2dmit) or 1,3,5-tris[10-(1-adamantyl)-7,9-dioxo-6,10-diazaundecyl]benzene (magnesium ionophore VI).

73. 70. The device of any one of claims 21 to 69, wherein the target ion is calcium and the ionophore is calcium ionophore I (ETH 1001) or calcium ionophore II (ETH129).

74. 70. The device of any one of claims 21 to 69, wherein the target ion is chloride and the ionophore is tridodecylmethylammonium chloride (TDMAC).

75. 70. The device of any one of claims 21 to 69, wherein the target ion is ammonium and the ionophore is nonactin.

76. 76. The device of any one of claims 21 to 75, wherein the substrate comprises a material selected from the group consisting of metals, glasses, semiconductors, dielectrics, transparent conductive oxides, ceramics, and polymers.

77. 77. The device of any one of claims 21 to 76, wherein the second electrode comprises a metal, a metal alloy, a transition metal oxide, a transparent conductive oxide, a carbon material, a doped semiconductor, a binary semiconductor, a ternary semiconductor, or a conducting polymer.

78. 78. The device of claim 77, wherein the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium.

79. 78. The device of claim 77, wherein the metal is oxidized or in the form of a metal salt.

80. 78. The device of claim 77, wherein the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond.

81. 78. The device of claim 77, wherein the doped semiconductor is selected from the group consisting of silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide.

82. 78. The device of claim 77, wherein the conductive polymer is selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene)polystyrenesulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

83. 83. The device of any one of claims 21 to 82, wherein the first electrode is disposed directly on the substrate.

84. 83. The device of any one of claims 21 to 82, wherein the second electrode is disposed directly on the substrate.

85. 85. The device of any one of claims 21 to 84, further comprising a biointerface membrane disposed on the ionophore and the first electrode.

86. 86. The device of claim 85, wherein the biointerface membrane is configured to inhibit biofouling of the ionophore or the first electrode.

87. 87. The device of claim 85 or 86, wherein the biointerface membrane is configured to release a therapeutic compound into the biological fluid.

88. 88. The device of any one of claims 85 to 87, wherein the biointerface membrane comprises multiple layers.

89. 89. The device of any one of claims 21 to 88, further comprising a second biointerface membrane disposed on the second electrode.

90. 90. The device of claim 89, wherein the second biointerface membrane comprises a biocompatible polymer and a salt.

91. 90. The device of claim 89, wherein the second biointerface membrane consists essentially of a biocompatible polymer and a salt.

92. 92. The device of any one of claims 89 to 91, wherein the biocompatible polymer is present in the second biointerface membrane in an amount of about 40 to about 70 weight percent.

93. 93. The device of any one of claims 89 to 92, wherein the salt is present in the biointerface membrane in an amount of about 30 to about 60 weight percent.

94. 94. The device of any one of claims 89 to 93, wherein the biocompatible polymer is selected from the group consisting of polyvinyl butyral (PVB), polyurethane, and silicone.

95. The salt may be potassium chloride (KCl), sodium chloride (NaCl), magnesium chloride (MgCl ２ ), calcium chloride (CaCl ２ ), and ammonium sulfate ((NH ４ ) ２ SO ４ 95. The device of any one of claims 89 to 94, wherein the device is selected from the group consisting of:

96. 96. The device of any one of claims 89 to 95, wherein the second biointerface membrane comprises multiple layers.

97. 97. The device of any one of claims 21 to 96, wherein the substrate is substantially wire-shaped.

98. 98. The device of any one of claims 21 to 97, wherein the substrate is planar.

99. 99. The device of any one of claims 21 to 98, wherein the sensor electronics are configured to continuously measure the electromotive force.

100. 99. The device of any one of claims 21 to 98, wherein the sensor electronics are configured to measure the electromotive force at a dynamically configurable frequency.

101. 101. The device of any one of claims 21 to 100, wherein the sensor electronics include a galvanostat.

102. 102. The device of any one of claims 21 to 101, wherein the sensor electronics comprises a high input impedance analog front end coupled to the first electrode and the second electrode.

103. 103. The device of claim 102, wherein the high impedance analog front end comprises at least one of an instrumentation amplifier, a differential amplifier, a voltage follower, a unity gain amplifier, an isolation amplifier, or a buffer.

104. 104. A device as claimed in claim 102 or claim 103, wherein the high impedance analog front end has an input impedance greater than about 100 gigaohms.

105. 105. The device of any one of claims 21 to 104, wherein the sensor electronics are configured to maintain the second electrode at a substantially constant potential.

106. 106. The device of any one of claims 21 to 105, wherein the sensor electronics further comprises an analog-to-digital converter (ADC) that digitizes the signal corresponding to the measured electromotive force.

107. 107. The device of any one of claims 21 to 106, wherein the sensor electronics comprises non-volatile computer readable memory configured to store the signal.

108. 108. The device of any one of claims 21 to 107, wherein the sensor electronics comprises a transmitter configured to transmit the signal wirelessly.

109. the sensor electronics comprising a non-volatile computer readable memory configured to store a correlation between control ion concentrations and control signals corresponding to the electromotive forces of those control ion concentrations; 109. The device of any one of claims 21 to 108, wherein the sensor electronics are configured to: (a) compare the signal corresponding to the electromotive force with the control signal; (b) select the control signal that most closely matches the signal corresponding to the electromotive force; and (c) produce as the output the control ion concentration that corresponds to the selected control signal.

110. 110. The device of any one of claims 21 to 109, wherein the electromotive force is further based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid conducting an electrophysiological signal to the first electrode.

111. 111. The device of claim 110, wherein a first contribution to the electromotive force from the electrophysiological signal changes rapidly relative to a second contribution to the electromotive force from the concentration of the ions in the physiological fluid.

112. 112. The device of claim 111, wherein the sensor electronics are configured to parse the first contribution from the second contribution.

113. the sensor electronics a Fast Fourier Transform (FFT) circuit for converting a signal corresponding to the electromotive force from a time domain to a frequency domain; a spectral analysis circuit configured to separate the transformed signal into a high frequency portion corresponding to the first contribution and a low frequency portion corresponding to the second contribution; and at least one inverse FFT (iFFT) circuit configured to convert the high frequency portion into a time domain output corresponding to the electrophysiological signal and to convert the low frequency portion into a time domain output corresponding to the concentration of the ions in the physiological fluid.

114. 114. The device of claim 113, wherein the low frequency portion is centered approximately at zero frequency.

115. 115. A device as claimed in claim 113 or claim 114, wherein the high frequency portion comprises characteristics at the frequency of a human heartbeat or any harmonic thereof.

116. 116. A device as claimed in any one of claims 113 to 115, wherein the high frequency portion includes features at frequencies corresponding to features of an individual human heartbeat.

117. 117. The device of claim 116, wherein the high frequency portion includes features at about 100 Hz to about 1000 kHz.

118. 117. The device of claim 116, wherein the high frequency portion includes features at about 200 Hz to about 400 kHz.

119. the sensor electronics an analog-to-digital converter (ADC) for digitizing the signal corresponding to the electromotive force; a first filter configured to receive the digitized signal from the ADC, remove the second contribution therefrom, and generate an output corresponding to the first contribution with the second contribution removed; a second filter configured to receive the digitized signal from the ADC, remove the first contribution therefrom, and generate an output corresponding to the second contribution from which the first contribution has been removed.

120. the sensor electronics a first filter configured to remove the second contribution from a signal corresponding to the electromotive force and to generate a first output corresponding to the first contribution with the second contribution removed; and a second filter configured to remove the first contribution from the first output or a signal corresponding to the electromotive force and to generate a second output corresponding to the second contribution from which the first contribution has been removed.

121. 121. A device according to claim 119 or claim 120, wherein the first filter comprises a high-pass filter, a band-block filter, or a band-pass filter.

122. 122. The device of claim 121, wherein the first filter passes frequencies corresponding to a human heartbeat or heartbeat waveform.

123. 123. The device of any one of claims 119 to 122, wherein the second filter comprises a low-pass filter, a band-block filter, or a band-pass filter.

124. 124. The device of claim 123, wherein the second filter passes zero frequencies.

125. 125. The device of any one of claims 110 to 124, wherein the electrophysiological signal comprises a cardiac electrical signal.

126. 1. A device for measuring electrophysiological signals conducted through in vivo biological fluids, comprising: An indwelling sensor, A substrate; a first electrode disposed on the substrate; a second electrode disposed on the substrate; A sensor electronic device, and sensor electronics configured to generate a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid transporting the electrophysiological signal to the first electrode.

127. 127. The device of claim 126, wherein the sensor electronics is further configured to use the signal to generate an output corresponding to a measure of the electrophysiological signal.

128. 127. The device of claim 126, wherein the sensor electronics are further configured to transmit the signal to an external device configured to use the signal to generate an output corresponding to a measure of the concentration of the target ion in the biological fluid.

129. the sensor electronics a Fast Fourier Transform (FFT) circuit for converting a signal corresponding to the electromotive force from a time domain to a frequency domain; a spectral analysis circuit configured to separate the converted signal into a high frequency portion corresponding to the electrophysiological signal and a low frequency portion not corresponding to the electrophysiological signal; and at least one inverse FFT (iFFT) circuit configured to convert the high frequency portion into a time domain output corresponding to the electrophysiological signal.

130. 130. The device of claim 129, wherein the high frequency portion comprises a frequency characteristic of a human heartbeat or any harmonic thereof.

131. 131. A device as described in claim 129 or 130, wherein the high frequency portion includes features at frequencies corresponding to features of an individual human heartbeat.

132. 132. The device of any one of claims 129 to 131, wherein the high frequency portion comprises features at about 100 Hz to about 1000 Hz.

133. 132. The device of any one of claims 129 to 131, wherein the high frequency portion includes features at about 200 Hz to about 400 Hz.

134. the sensor electronics an analog-to-digital converter (ADC) for digitizing the signal corresponding to the electromotive force; 134. The device of any one of claims 126 to 133, comprising: a filter configured to receive the digitized signal from the ADC, remove contributions therefrom that do not correspond to the electrophysiological signal, and generate an output that corresponds to the electrophysiological signal with the contributions removed.

135. the sensor electronics 135. A device according to any one of claims 126 to 134, comprising a filter configured to remove contributions that do not correspond to the electrophysiological signal from the signal corresponding to the electromotive force and to generate an output corresponding to the electrophysiological signal with the contributions removed.

136. 136. The device of claim 135, wherein the filter comprises a high-pass filter, a band-block filter, or a band-pass filter.

137. 137. A device as described in claim 135 or 136, wherein the filter passes frequencies corresponding to a human heartbeat or heartbeat waveform.

138. 138. The device of any one of claims 126 to 137, wherein the electrophysiological signal comprises a cardiac electrical signal.

139. 139. The device of any one of claims 126 to 138, wherein the first electrode or the second electrode comprises a metal, a metal alloy, a transition metal oxide, a transparent conductive oxide, a carbon material, a doped semiconductor, a binary semiconductor, a ternary semiconductor, or a conducting polymer.

140. 140. The device of claim 139, wherein the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium.

141. 141. The device of claim 139 or 140, wherein the metal is oxidized or in the form of a metal salt.

142. 140. The device of claim 139, wherein the carbon material is selected from the group consisting of carbon paste, graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond.

143. 140. The device of claim 139, wherein the doped semiconductor is selected from the group consisting of silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide.

144. 140. The device of claim 139, wherein the conductive polymer is selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:139PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

145. 145. The device of any one of claims 126 to 144, further comprising a solid contact layer disposed on the first electrode.

146. 146. The device of claim 145, wherein the solid contact layer comprises a metal, a carbon material, a doped semiconductor, or a conductive polymer.

147. 147. The device of claim 146, wherein the metal is selected from the group consisting of gold, platinum, silver, iridium, rhodium, ruthenium, nickel, chromium, and titanium.

148. 148. The device of claim 146 or 147, wherein the metal is oxidized or in the form of a metal salt.

149. 147. The device of claim 146, wherein the carbon material is selected from the group consisting of carbon paste, graphene oxide, reduced graphene oxide, carbon nanotubes, C60, porous carbon nanomaterials, mesoporous carbon, glassy carbon, hybrid carbon nanomaterials, graphite, and doped diamond.

150. 147. The device of claim 146, wherein the doped semiconductor is selected from the group consisting of silicon, germanium, silicon-germanium, zinc oxide, gallium arsenide, indium phosphide, gallium nitride, cadmium telluride, indium gallium arsenide, and aluminum arsenide.

151. 147. The device of claim 146, wherein the conductive polymer is selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:146PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

152. 146. The device of claim 145, wherein the solid contact layer comprises a redox couple.

153. 153. The device of claim 152, wherein the redox pair comprises metal centers having different oxidation states.

154. 154. The device of claim 153, wherein the metal center is selected from the group consisting of Co(II) and Co(III), Ir(II) and Ir(III), and Os(II) and Os(III).

155. 146. The device of claim 145, wherein the solid contact layer comprises a mixed conductor or a mixed ionic-electronic conductor.

156. The solid contact layer is made of strontium titanate (SrTiO ３ ), titanium dioxide (TiO ２ ), (La, Ba, Sr) (Mn, Fe, Co) O ３－ｄ , La ２ CuO ４＋ｄ , cerium (IV) oxide (CeO ２ ), lithium iron phosphate (LiFePO ４ ), and LiMnPO ４ 156. The device of claim 155, comprising a compound selected from the group consisting of:

157. 157. The device of any one of claims 145 to 156, wherein the solid contact layer inhibits transport of water from the biological fluid to the first electrode.

158. 158. The device of any one of claims 145 to 157, wherein the solid contact layer is configured to enhance the electrical stability of the first electrode.

159. 159. The device of any one of claims 126 to 158, wherein the substrate comprises a material selected from the group consisting of metal, glass, semiconductor, transparent conductive oxide, dielectric, ceramic, and polymer.

160. 160. The device of any one of claims 126 to 159, wherein the first electrode is disposed directly on the substrate.

161. 161. The device of any one of claims 126 to 160, wherein the second electrode is disposed directly on the substrate.

162. 162. The device of any one of claims 126 to 161, further comprising a biointerface membrane disposed on the first electrode.

163. 163. The device of claim 162, wherein the biointerface membrane is configured to inhibit biofouling of the first electrode.

164. 164. The device of claim 162 or 163, wherein the biointerface membrane is configured to release a therapeutic compound into the biological fluid.

165. 165. The device of any one of claims 162 to 164, wherein the biointerface membrane comprises multiple layers.

166. 166. The device of any one of claims 126 to 165, further comprising a second biointerface membrane disposed on the second electrode.

167. 167. The device of claim 166, wherein the second biointerface membrane comprises a biocompatible polymer and a salt.

168. 168. The device of claim 166 or 167, wherein the biointerface membrane consists essentially of a biocompatible polymer and a salt.

169. The device of claim 167 or 168, wherein the biocompatible polymer is present in the second biointerface membrane in an amount of about 40 to about 70 weight percent.

170. 170. The device of any one of claims 167 to 169, wherein the salt is present in the second biointerface membrane in an amount of about 30 to about 60 weight percent.

171. 171. The device of any one of claims 167 to 170, wherein the biocompatible polymer is selected from the group consisting of polyurethane segments or polyurea segments.

172. 172. The device of any one of claims 167 to 171, wherein the biocompatible polymer comprises polycarbonate, polydimethylsiloxane (PDMS), methylene diphenyl diisocyanate (MDI), polysulfone (PSF), methyl methacrylate (MMA), poly(ε-caprolactone) (PCL), or 1,4-butanediol (BD).

173. 173. The device of any one of claims 167 to 172, wherein the biocompatible polymer does not include polyvinylpyrrolidone (PVP).

174. The salt may be potassium chloride (KCl), sodium chloride (NaCl), magnesium chloride (MgCl ２ ), and calcium chloride (CaCl ２ 174. The device of any one of claims 167 to 173, wherein the device is selected from the group consisting of:

175. 175. The device of any one of claims 166 to 174, wherein the biointerface membrane comprises multiple layers.

176. 176. A device according to any one of claims 126 to 175, wherein the substrate is substantially wire-shaped.

177. 176. The device of any one of claims 126 to 175, wherein the substrate is planar.

178. 178. The device of any one of claims 126 to 177, wherein the sensor electronics are configured to continuously measure the electromotive force.

179. 178. The device of any one of claims 126 to 177, wherein the sensor electronics are configured to measure the electromotive force at a dynamically configurable frequency.

180. 180. The device of any one of claims 126 to 179, wherein the sensor electronics include a galvanostat.

181. 181. The device of any one of claims 126 to 180, wherein the sensor electronics comprises a high impedance analog front end coupled to the first electrode and the second electrode.

182. 182. The device of any one of claims 126 to 181, wherein the sensor electronics comprise at least one of an instrumentation amplifier, a differential amplifier, a voltage follower, a unity gain amplifier, an isolation amplifier, or a buffer.

183. 183. The device of any one of claims 126 to 182, wherein the sensor electronics have an input impedance greater than about 100 gigaohms.

184. 184. The device of any one of claims 126 to 183, wherein the sensor electronics are configured to maintain the second electrode at a substantially constant potential.

185. 185. The device of any one of claims 126 to 184, wherein the sensor electronics comprises non-volatile computer readable memory configured to store the signal.

186. 186. The device of any one of claims 126 to 185, wherein the sensor electronics comprises a transmitter configured to transmit the signal wirelessly.

187. 1. A method for measuring the concentration of a target ion in an in vivo biological fluid, comprising: Implanting an indwelling sensor, said sensor comprising: A substrate; a first electrode disposed on the substrate; an ionophore disposed on the substrate and configured to selectively transport target ions to or within the first electrode; a second electrode disposed on the substrate; generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode.

188. 1. A method for measuring electrophysiological signals conducted through an in vivo biological fluid, comprising: Implanting an indwelling sensor, said sensor comprising: A substrate; a first electrode disposed on the substrate; a second electrode disposed on the substrate; generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the biological fluid transporting the electrophysiological signal to the first electrode.

189. 1. A device for continuously measuring at least a target analyte in an in vivo biological fluid, comprising: An indwelling sensor, A substrate; a first electrode disposed on the substrate; an ionophore disposed on the substrate and configured to selectively transport target ions to or within the first electrode; an enzyme configured to generate the target ion in response to action on the target analyte; a second electrode disposed on the substrate; A sensor electronic device, and sensor electronics configured to generate a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode.

190. 1. A method for continuously measuring the concentration of a target analyte in an in vivo biological fluid, comprising: A substrate; a first electrode disposed on the substrate; an ionophore disposed on the substrate and configured to selectively transport target ions to or within the first electrode; an enzyme configured to generate the target ion in response to action on the target analyte; a second electrode disposed on the substrate; The method includes: the sensor electronics generating a signal corresponding to an electromotive force, the electromotive force being based at least in part on a potential difference generated between the first electrode and the second electrode in response to the ionophore transporting the target ion to the first electrode.

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