Apparatus and method for measuring concentration of target analyte in in vivo biological fluid

Abstract

Provided herein are devices and methods for measuring the concentration of a target analyte in a biological fluid in vivo. In some examples, an apparatus includes an indwelling sensor and sensor electronics. The sensor can include a substrate; the first electrode is arranged on the substrate; an ion carrier disposed on the substrate to selectively transport a target ion to the first electrode or to selectively transport the target ion 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] The present application generally relates to measuring the concentration of an analyte in a biological fluid. The present application also generally relates to measuring an electrophysiological signal. Background Art

[0002] The concentration of ions such as sodium, potassium, magnesium, calcium or ammonium in a host's biological fluids can provide important information about the host's health status. + ) is a biomarker for cardiovascular disease. In another example, potassium ions (K + ) is a biomarker for kidney disease. In fact, in the United States, approximately 14.8 million individuals with diabetes are diagnosed with kidney disease, such as impaired renal function; these patients may benefit from frequent blood potassium measurements to assess renal function and guide treatment, which may include oral medications on the one hand and dialysis on the other. In yet another example, potassium ions (K + ) is a biomarker for both cardiovascular and kidney disease.

[0003] Additionally, approximately 9 million individuals in the United States suffer from both diabetes and arrhythmias. Arrhythmias are primarily caused by improper strengthening of the heart muscle; potassium helps control and moderate the heart muscle's electrical signals. Without treatment, arrhythmias can progress to ventricular fibrillation and sudden cardiac death. Therefore, it would be useful to have a rapid, robust, and convenient way to monitor ion concentrations in a host's biofluids.

[0004] Electrophysiological signals, such as heartbeat, can provide important information about the health status of the host. Therefore, it would be useful to have a fast, robust, and convenient way to monitor one or more of these electrophysiological signals. Summary of the invention

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

[0006] Some examples herein provide a device for continuously measuring the concentration of a target ion in a biological fluid in vivo. The device may include an indwelling analyte sensor, the indwelling analyte sensor including a substrate; a first electrode, the first electrode disposed on the substrate; an ionophore, the ionophore disposed on the substrate and configured to selectively transport the target ion to the first electrode or selectively transport the target ion within the first electrode; and a second electrode, the second electrode disposed on the substrate. The device may include a sensor electronic device, the sensor electronic device being 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 measurement of a 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 that 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.

[0009] In some examples, the first electrode comprises a polymer having an ion carrier therein. In some examples, the first electrode comprises a conductive polymer having an ion carrier therein. In some examples, the first electrode does not substantially contain any plasticizer. In some examples, the first electrode is substantially composed of a conductive polymer and an ion carrier. In some examples, the first electrode is substantially composed of a conductive polymer, an ion carrier, 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 tetrakis[3,5-bis(trifluoromethyl)phenyl]sodium borate (NaTPFB), sodium tetraphenylborate (NaTPB), tetrakis[3,5-bis(trifluoromethyl)phenyl]potassium borate (KTFPB) and tetrakis(4-chlorophenyl)potassium borate (KTClPB). In some examples, the lipophilic salt additive is present in the polymer in an amount of about 0.01 wt % to about 1 wt %.

[0010] In some examples, the conductive polymer is present in an amount of about 90 wt % to about 99.5 wt %. In some examples, the conductive polymer is 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 wt % to about 10 wt %, about 0.2 wt % to about 10 wt %, or about 0.5 wt % to about 10 wt %.

[0011] In some examples, the ion selective membrane (ISM) is a polymer. In one example, the ion selective membrane is fluorosilicone rubber, polydimethylsiloxane polymer, silicone rubber, polyurethane with polysiloxane soft segment, polyurethane with hard segment and soft segment (e.g., polyether or polycarbonate or polydimethylsiloxane soft segment), water-based polyurethane, polyvinyl butyral, polymethyl methacrylate, polyvinyl acrylate, or blends or grafted polymers thereof.

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

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

[0014] In some examples, the biocompatible polymer is present in the ion selective membrane in an amount of about 90% by weight to about 99.5% by weight. In some examples, the biocompatible polymer includes 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 includes a block copolymer. In some examples, the block copolymer includes a hydrophilic block selected from the group consisting of polycarbonate (PC) and polybutadiene (PBD). In some examples, the block copolymer includes a hydrophobic group selected from the group consisting of polydimethylsiloxane (PDMS), diphenylmethane 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% by weight to about 10% by weight.

[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, mixed carbon nanomaterials, graphite, and doped diamond. In some examples, a doped semiconductor, a binary semiconductor, or a 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 is 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, for example, 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 is directly electrically connected to 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 displays 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, mixed 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 is 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 comprises a redox pair. In some examples, the redox pair includes two or more metal centers (e.g., metal cations) having different oxidation states. In some examples, 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 ion-electron conductor. In some examples, the solid contact layer comprises a compound selected from the group consisting 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 In some examples, the solid contact layer inhibits transport of water 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 tri(dodecyl)methylammonium chloride (TDMAC). In some examples, the target ion is ammonium and the ionophore is inactive.

[0019] In one example, the ionophore is covalently coupled to the ISM, for example using a functionalized ISM and / or ionophore and a suitable 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 sensor disclosed herein.

[0020] In some examples, the substrate comprises a material selected from the group consisting of metal, glass, semiconductor, dielectric, transparent conductive oxide, ceramic, and 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, mixed 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 is 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 electrode and the second electrode are disposed directly on the substrate. In some examples, at least a portion of the first electrode and the second electrode are disposed directly on at least a portion of the substrate. In some examples, at least a portion of the first electrode and the second electrode 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 electrode.

[0024] In some examples, the device also includes a biointerface membrane disposed on the ion carrier and the first electrode. In some examples, the device includes a biointerface membrane disposed on the ion carrier and the first electrode and the second electrode, wherein the biointerface membrane is the same. In some examples, the biointerface membrane is configured to inhibit biofouling of the ion carrier or the first electrode. In some examples, the biointerface membrane is configured to inhibit decomposition of the second electrode. In some examples, at least a portion of the biointerface membrane or a separate drug release membrane is configured to release a therapeutic compound into a biological fluid. In some examples, the biointerface membrane includes multiple layers. In some examples, the biointerface membrane is a layer of two or more chemically different or chemically identical biointerface membranes or two or more chemically different biointerface membranes layered 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 a 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 a plurality of layers. In some examples, the second biointerface membrane is a layer of two or more chemically different biointerface membranes or two or more chemically different or chemically identical biointerface membranes layered in an alternating or random configuration or a combination of alternating and random configurations. In some examples, the second biointerface membrane comprises a biocompatible polymer and a salt. In some examples, the second biointerface membrane is substantially composed 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% by weight to about 70% by weight. In some examples, the salt is present in the biointerface membrane in an amount of about 30% by weight to about 60% by weight. 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 2 ), calcium chloride (CaCl 2 ) and ammonium sulfate (NH 4 ) 2 SO 4 ). In some examples, the second biointerface membrane includes multiple layers.

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

[0027] In some examples, the substrate is planar. In some examples, the substrate is a conductive line.

[0028] In some examples, the device includes 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 current regulator.

[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 also include an analog-to-digital converter (ADC) that digitizes a signal corresponding to the measured electromotive force.

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

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

[0036] In some examples, the sensor electronics includes a non-volatile computer readable memory configured to store correlations 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 force to the control signal, (b) select the control signal that most closely matches the signal corresponding to the electromotive force, and (c) generate as 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 the electrophysiological signal to the first electrode. In some examples, a first contribution to the electromotive force from the electrophysiological signal varies 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 is configured to deconvolve the first contribution from the second contribution. In some examples, the sensor electronics includes: a fast Fourier transform (FFT) circuit configured to transform a signal corresponding to the electromotive force from a time domain to a frequency domain; a spectrum 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 transform the high frequency portion into a time domain output corresponding to the electrophysiological signal and transform the low frequency portion into a time domain output corresponding to the concentration of the ions in the physiological fluid. In some examples, the low frequency portion is approximately centered at zero frequency. In some examples, the high frequency portion includes features at a human heartbeat frequency or a harmonic thereof. 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 about 100 Hz to about 1000 kHz. In some examples, the high frequency portion includes features at about 200 Hz to about 400 kHz.

[0038] In some examples, the sensor electronics include: an analog-to-digital converter (ADC) that digitizes the signal corresponding to the electromotive force; a first filter configured to receive the digitized signal from the ADC to remove the second contribution from the digitized signal 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 to remove the first contribution from the digitized signal 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 the second contribution from the 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 from the signal corresponding to the electromotive force, and to 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 stop filter, or a band pass filter. In some examples, the first filter passes frequencies corresponding to a human heartbeat or a heartbeat waveform. In some examples, the second filter includes a low pass filter, a band stop filter, or a band pass filter. In some examples, the second filter passes zero frequency.

[0040] In some examples, a device includes sensor electronics configured to receive electrophysiological signals (eg, cardiac electrical signals).

[0041] Some examples herein provide a device for measuring an electrophysiological signal conducted via an in vivo biological fluid. The device may include an indwelling sensor, the indwelling sensor including: a substrate; a first electrode, the first electrode disposed on the substrate; and a second electrode, the second electrode disposed on the substrate. The device may include sensor electronics, the 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 conducting 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 measurement 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 that 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.

[0044] In some examples, the sensor electronics of the device include: a fast Fourier transform (FFT) circuit configured to transform a signal corresponding to an electromotive force from a time domain to a frequency domain; a spectrum analysis circuit configured to separate the transformed signal into a high-frequency portion corresponding 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 transform the high-frequency portion into a time domain output corresponding to the electrophysiological signal.

[0045] In some examples, the high frequency portion includes features at a human heartbeat frequency or a harmonic thereof. 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 about 100 Hz to about 1000 Hz. In some examples, the high frequency portion includes features at about 200 Hz to about 400 Hz.

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

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

[0048] In some examples, the electrophysiological signals include cardiac electrical signals.

[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 displays 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, mixed 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 is 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 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 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, mixed 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 is 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 pair. In some examples, the redox pair comprises a metal center (cation) having different oxidation states. 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).

[0052] In some examples, the solid contact layer of the device comprises a mixed conductor or a mixed ion-electron conductor. In some examples, the solid contact layer comprises a compound selected from the group consisting 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 .

[0053] In some examples, the solid contact layer of the device inhibits 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 includes 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 examples, the second electrode of the device is disposed directly on the substrate.

[0058] In some examples, the device further comprises 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 the therapeutic compound into the biological fluid. In some examples, the biointerface membrane comprises a plurality of layers that may be arranged in a sequential or 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 biointerface membrane. In some examples, the second biointerface membrane comprises a biocompatible polymer and a salt. In some examples, the biointerface membrane is substantially composed 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% by weight to about 70% by weight. In some examples, the salt is present in the second biointerface membrane in an amount of about 30% by weight to about 60% by weight. In some examples, the biocompatible polymer is selected from the group consisting of the following: a polyurethane segment or a polyurea segment. In some examples, the biocompatible polymer includes: polycarbonate, polydimethylsiloxane (PDMS), diphenylmethane 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 2 ) and calcium chloride (CaCl 2 ). In some examples, the biointerface membrane includes multiple layers.

[0060] In some examples, the substrate of the device is elongated. In some examples, the substrate is a planar or cylindrical elongated shape. In some examples, the substrate of the device is elongated. In some examples, the substrate is a planar or cylindrical elongated shape. 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 the electromotive force at a dynamically configurable frequency.

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

[0064] In some examples, 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, sensor electronics of the device include non-volatile computer-readable memory configured to store the signal.

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

[0070] Some examples herein provide a method for measuring the concentration of a target ion in a biological fluid in vivo. The method may include implanting an indwelling sensor. The sensor may include a substrate; a first electrode disposed on the substrate; an ion carrier disposed on the substrate and configured to selectively transport the target ion to the first electrode or selectively transport the target ion within the first electrode; and a second electrode disposed on the substrate. The method 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 ion carrier transporting the target ion to the first electrode. Obviously, any options described herein related to such an indwelling sensor and operations performed using such a sensor will also be related to this method.

[0071] Some examples herein provide a method for measuring an electrophysiological signal conducted via a biological fluid in vivo. 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 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 the electrophysiological signal to the first electrode. It will be apparent that any options described herein related to such an indwelling sensor and operations performed using such a sensor will also be related to this method.

[0072] Some examples herein provide a device for continuously measuring the concentration of a target analyte in a biological fluid in vivo. The device may include an indwelling sensor, the indwelling sensor including: a substrate; a first electrode, the first electrode disposed on the substrate; an ion carrier, the ion carrier disposed on the substrate and configured to selectively transport the target ion to the first electrode or selectively transport the target ion within the first electrode; an enzyme, the enzyme configured to generate the target ion in response to acting on the target analyte; and a second electrode, the second electrode disposed on the substrate. The sensor electronics are configured to generate a signal corresponding to an electromotive force, the electromotive force being at least partially based on a potential difference generated between the first electrode and the second electrode in response to the ion carrier transporting the target ion to the first electrode. Obviously, any options described herein in relation to other sensors and devices and operations performed using such sensors and devices will also be related to such devices.

[0073] Some examples herein provide a method for continuously measuring the concentration of a target analyte in a biological fluid in vivo. The method may include implanting an indwelling sensor. The indwelling sensor may include a substrate; a first electrode disposed on the substrate; an ion carrier disposed on the substrate and configured to selectively transport a target ion to or within the first electrode; an enzyme configured to generate the target ion in response to acting 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 ion carrier transporting the target ion to the first electrode. Obviously, any options described herein with respect to other sensors and devices and operations performed using such sensors and devices will also be relevant to this method.

[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 analyte sensor, the analyte sensor comprising a substrate, a first electrode disposed on the substrate, an ion selective membrane containing an ion carrier, an ion selective membrane disposed on the substrate and configured to selectively transport at least one target analyte to the first electrode or selectively transport the at least one target analyte within the first electrode, and a second electrode disposed on the substrate. In one aspect, the device also includes a sensor electronic device, the sensor electronic device being 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 ion carrier transporting the at least one target analyte to the first electrode.

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

[0076] On the other hand, alone or in combination with any of the preceding aspects, the first electrode or the 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 aspect, the ionophore is selected from the group consisting of: 4-tert-butylcalix[4]arene tetraacetate tetraethyl ester (sodium ionophore X); calix[4]arene-25,26,27,28-tetrol (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-tri[10-(1-adamantyl)-7,9-dioxo-6,10-diazaundecyl]benzene (magnesium ionophore VI); calcium ionophore I (ETH 1001); calcium ionophore II (ETH129); tri(dodecyl)methylammonium chloride (TDMAC); and inactive antibiotics.

[0078] In another aspect, alone or in combination with any of the preceding aspects, 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 aspect, alone or in combination with any of the preceding aspects, the ion selective membrane is in direct contact with the first electrode.

[0080] In another aspect, either alone or in combination with any of the foregoing aspects, the device further comprises a solid contact layer disposed between the first electrode and the ion selective membrane. In another aspect, either alone or in combination with any of the foregoing 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, either alone or in combination with any of the foregoing aspects, the solid contact layer comprises a redox pair 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, either alone or in combination with any of the foregoing aspects, the solid contact layer comprises a mixed conductor or a mixed ion-electron conductor selected from the group consisting 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 .

[0081] In another aspect, alone or in combination with any of the preceding aspects, 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 preceding 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 preceding 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 preceding aspects, the sensor electronics comprises a constant current. In another aspect, alone or in combination with any of the preceding aspects, the sensor electronics is configured to: (a) measure the electromotive force at a dynamically configurable frequency; (b) maintain the second electrode at a substantially constant potential; or (c) a combination thereof.

[0084] On the other hand, either alone or in combination with any of the preceding 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 the electrophysiological signal to the first electrode, wherein a first contribution to the electromotive force from the electrophysiological signal varies rapidly relative to a second contribution to the electromotive force from a concentration of ions in the physiological fluid, and wherein the sensor electronics are configured to deconvolute the first contribution from the second contribution.

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

[0086] In another aspect, alone or in combination with any of the preceding aspects, 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 the concentration of a target analyte in an in vivo biological fluid is provided, the method comprising an indwelling sensor comprising a substrate, a first electrode disposed on the substrate, an ion carrier disposed on the substrate and configured to selectively transport target ions to the first electrode or selectively transport the target ions within the first electrode, a second electrode disposed on the substrate; and generating a signal corresponding to an electromotive force, the electromotive force being at least partially based on a potential difference generated between the first electrode and the second electrode in response to the ion carrier transporting the target ions to the first electrode.

[0088] In another aspect, the method further includes an enzyme configured to generate the target analyte. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] FIG. 1A to FIG. 1I Example configurations and components of an apparatus for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids are schematically illustrated.

[0090] Figures 2A to 2G Additional example configurations and components of devices for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids are schematically illustrated.

[0091] Figure 3 Example operations and components for measuring the concentration of target ions in in vivo biological fluids and measuring electrophysiological signals in the present apparatus and methods are schematically illustrated.

[0092] Figure 4A An operational flow in an example method for measuring the concentration of a target ion in a biological fluid in vivo is illustrated.

[0093] Figure 4B An operational flow in an example method for measuring electrophysiological signals conducted via a biological fluid in vivo is illustrated.

[0094] FIG. 5A to FIG. 5B Various examples of sensor configurations are schematically illustrated.

[0095] FIG. 6A to FIG. 6G Various additional examples of sensor configurations are schematically illustrated.

[0096] 7A to 7C Example configurations and components of an apparatus for measuring electrophysiological signals and / or concentrations of target analytes in in vivo biological fluids are schematically illustrated.

[0097] Figure 8 An operational flow in an example method for measuring the concentration of a target analyte in a biological fluid in vivo is illustrated.

[0098] FIG. 9A to FIG. 9B is a graph illustrating the measurement sensitivity of an example device to potassium ions.

[0099] FIG. 10A to FIG. 10B is an example of reference in the presence of interfering ions FIG. 9A to FIG. 9B A graph depicting the measurement sensitivity of an example device to potassium ions.

[0100] Fig.11 Reference FIG. 9A to FIG. 9B and FIG. 10A to FIG. 10B A graph depicting the drift of an example device.

[0101] Fig.12 The measured absolute potential (E) of another example device in water (left) and interferent solution (right) is illustrated. 0 ), potential slope (m) and drift.

[0102] FIG. 13A to FIG. 13B An example device configured to detect urea using urease and an ionophore selective for ammonium ions is schematically illustrated.

[0103] FIG. 14A to FIG. 14B An example device using an ionophore selective for ammonium ions is schematically illustrated.

[0104] Fig.15 It is an example FIG. 14A to FIG. 14B A graph of the measurement sensitivity of an example device to ammonium ions.

[0105] Fig.16 Illustrated FIG. 14A to FIG. 14B and Fig.15 The measured absolute potential (E) of the example device for ammonium ions 0 ), potential slope (m) and R2.

[0106] Fig.17 is a diagram depicting an example continuous analyte monitoring system configured to measure target ions and / or other analytes as discussed herein.

[0107] Fig.18A and Fig.18B A graph illustrating the measured sensitivity of an example device.

[0108] Fig.19A and Fig.19B A graph illustrating the measured sensitivity of an example planar sensor device.

[0109] Fig. 20A and Fig. 20B Graph illustrating the measurement sensitivity of an example device in the presence of interfering ions.

[0110] Fig. 20C and Fig.20DGraph illustrating the measurement sensitivity of an example device in the presence of interfering ions.

[0111] Fig.21A , Fig. 21B and Fig. 21C Graphs illustrating measurement sensitivity of example devices with selected solid contact materials.

[0112] Fig.22A , Fig. 22B and Fig. 22C Data for measured sensitivity of an example device having a resistive film is illustrated.

[0113] Fig.23A , Fig. 23B and Fig.23C Graph illustrating the measurement sensitivity of an example device in vivo.

[0114] Fig.24A and Fig. 24B Illustrated is a graph of measured sensitivity of an example device before and after sterilization. DETAILED DESCRIPTION

[0115] Provided herein are devices and methods for measuring electrophysiological signals and / or concentrations of target ions in in vivo biological fluids.

[0116] The ability to continuously measure ion concentrations in real time could lead to improved outcomes for those with acute and chronic illnesses in diverse fields such as nephrology, hepatology, and cardiology. Although bedside and point-of-care instruments for assessing electrolytes in whole blood samples have become commercially available over the past fifty years, these measurements provide only a single snapshot in time, which has limited clinical utility.

[0117] In addition, electrophysiological recordings are widely used in the diagnosis and management of a variety of diseases, such as atrial fibrillation and epilepsy. Previously known electrophysiological measurements utilize electrodes (usually applied to the surface of the skin) to quantify potential fluctuations on various scales from single ion channel proteins to entire organs (such as the heart). In cardiology, it is possible to assess heart rate and rhythm (via ECG / EKG), including its fluctuations, as well as cardiovascular output.

[0118] Provided herein is a body-decorated (in vivo) platform capable of potentiometric readout of electrophysiological signals and / or ion concentrations in biological fluids. For example, the device may include a pair of electrodes configured to be inserted into the dermis or subcutaneous tissue of a host to monitor electrophysiological signals and / or the concentration of selected ions in the host's interstitial fluid by potentiometric titration (the concentration being related to the concentration of the ion in the host's blood).

[0119] In another example, the device may include a single electrode configured to be inserted into the dermis or subcutaneous tissue of the host to monitor electrophysiological signals and / or the concentration of selected ions in the host's interstitial fluid (which is related to the concentration of the ion in the host's blood) by potentiometric titration.

[0120] 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 monitor electrophysiological signals and / or concentrations of selected ions in the host's interstitial fluid by potentiometric titration, and the other electrode configured to be external to the host.

[0121] For example, the interstitial fluid may have an ion concentration that is related to that of whole blood and may be measured on a continuous basis. The continuous basis of measurement is over a period of 3 to 15 days or longer. The measurements discussed herein are performed periodically at intervals of seconds, minutes, hours, or other time periods or combinations of time periods.

[0122] The present devices and methods may allow a host to continuously monitor the concentration of any suitable ion in the blood from anywhere (e.g., at home, at work, while traveling, or in other locations), which may provide improved outcomes for the host. For example, the host may reduce the need to visit a clinic to monitor ion concentrations, be able to receive any needed treatment with reduced time lag, and ultimately may reduce the likelihood of developing severe ion imbalances, such as severe hyperkalemia (≥6.5 mM K in the blood). + , or any other clinically relevant threshold). Additionally or alternatively, the present apparatus and methods may allow a host to continuously monitor his or her cardiac electrical signals, which may provide improved results for the host. For example, the host may reduce the need to go to a clinic or use bulky home-based equipment to periodically monitor cardiac electrical signals, be able to receive any required treatment with reduced time lag, and ultimately reduce the likelihood of suffering from arrhythmias, ventricular fibrillation, or sudden cardiac death. Some examples herein provide apparatus and methods for continuously and simultaneously or interleavedly measuring both ion concentrations and electrophysiological signals using a single body-adorned sensor. However, it should be understood that the present apparatus and methods are used to continuously perform only one of such measurements, e.g., measuring either ion concentrations or electrophysiological signals, but not both.

[0123] In some examples, the devices disclosed herein are used for the treatment of, for example, chronic kidney disease, such as for disease diagnosis, management, and treatment. In addition, the device is used for dialysis to provide treatment guidance and alarms. In some examples, the devices disclosed herein are used for heart failure treatment and management, for managing drugs, such as RAASi drugs, diuretics, insulin therapy, and other uses. In some examples, the devices disclosed herein are additionally or alternatively used to guide other complex conditions caused by ion imbalances of ions that can be measured using the techniques described herein. Other conditions using the devices disclosed herein include diabetic ketoacidosis, hypervolemia / hypovolemia, ascites, asthma, genetic diseases, and asthma. Additionally or alternatively, the devices disclosed herein are used to monitor the patient's condition during hospitalization and during surgery.

[0124] First, some example terms used in this application will be explained. Then, example devices for measuring electrophysiological signals and / or concentrations of target ions in vivo, their components, and methods of making and using such devices will be provided.

[0125] the term

[0126] To facilitate understanding of the disclosed examples, a number of terms are defined below.

[0127] As used herein, the phrases "analyte measuring device," "analyte monitoring device," "analyte sensing device," and / or "multi-analyte sensor device" are broad phrases and will be given their ordinary and customary meanings (and not limited to special or customized meanings) to one of ordinary skill in the art, and refer to (but are not limited to) devices and / or systems responsible for detecting or transducing signals associated with a particular analyte or combination of analytes. For example, these phrases may refer to (but are not limited to) an instrument responsible for detecting a particular analyte or combination of analytes. In one example, the instrument includes a sensor coupled to a circuit disposed within a housing and configured to process signals associated with analyte concentrations into information. In one example, such a device and / or system is capable of providing specific quantitative, semi-quantitative, qualitative, and / or semi-qualitative analytical information using a biorecognition element in combination with a transduction (detection) element.

[0128] As used herein, the terms "biosensor" and / or "sensor" are broad terms and will be given their ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refer to (but not limited to) a portion of an analyte measuring device, an analyte monitoring device, an analyte sensing device, and / or a multi-analyte sensor device that is responsible for detecting or transducing a signal associated with a specific analyte or combination of analytes. In one example, a biosensor or sensor generally includes a body, a working electrode, a reference electrode, and / or a counter electrode that are coupled to the body and form a surface configured to provide a signal during an electrochemical reaction. One or more membranes may be affixed to the body and cover the electrochemical reaction surface. In one example, such a biosensor and / or sensor is capable of providing a specific quantitative, semi-quantitative, qualitative, or semi-qualitative analytical signal using a biorecognition element in combination with a transduction (detection) element.

[0129] As used herein, the phrases "sensing moiety", "sensing membrane" and / or "sensing mechanism" are broad phrases and will be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) a portion of a biosensor and / or sensor that is responsible for detecting or transducing a signal associated with a specific analyte or combination of analytes. In one example, the sensing moiety, sensing membrane and / or sensing mechanism typically includes an electrode that is configured to provide a signal during an electrochemical reaction with one or more membranes covering an electrochemical reaction surface. In one example, such a sensing moiety, sensing membrane and / or sensing mechanism can use a biorecognition element combined with a transduction (detection) element to provide a specific quantitative, semi-quantitative, qualitative, semi-qualitative analytical signal.

[0130] As used herein, the term "about" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and not limited to a special or custom meaning), and refers to (but is not limited to) a certain degree of variability in the value or range, for example, within 10%, within 5%, or within 1% of the value or range limit, and includes the exact value or range. As used herein, the term "substantially" refers to a large portion 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” may mean having no or insignificant amounts of a material such that the amount of material present does not affect the material properties of the composition containing the material, such that the material comprises from about 0% to about 5% by weight of the composition, or from about 0% to about 1% by weight, or about 5% by weight or less, or less than or equal to about 4.5%, 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.

[0131] As used herein, the terms "adhere" and "attach" are broad terms and will be given their ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refer to, but are not limited to, holding, binding or sticking, for example, by adhesion, bonding, grasping, interpenetration or fusion.

[0132] As used herein, the term "analyte" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a substance or chemical component that can be analyzed in a biological fluid (e.g., blood, interstitial fluid, cerebrospinal fluid, lymph, urine, sweat, saliva, etc.). Analytes may include naturally occurring substances, artificial 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, sensing device, and sensing method is glucose. However, other analytes are also contemplated, including but not limited to carboxyprothrombin; acylcarnitines; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profile (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan); androstenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); bilirubin, biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugate 1-β-hydroxy-cholic acid; cortisol; creatine; creatine kinase; creatine kinase MM isoenzyme; creatinine; cyclosporin A; d-penicillamine; desethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylase polymorphism, alcohol dehydrogenase, α1-antitrypsin, cystic fibrosis, Duchenne dystrophy / Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, β-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV- 1. Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol); desbutyl halofantrine; dihydropteridine reductase; diphtheria / tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids / acylglycines; free β-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free triiodothyronine (FT3); fumaryl acetoacetase; galactose / gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione peroxidase; glycerol; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyltransferase; immunoreactive trypsin; beta-hydroxybutyrate; ketone; lactate; lead; lipoprotein ((a), B / A-1, beta); lysozyme; mefloquine; netilmicin; oxygen; phenobarbital; phenytoin; phytanic acid / pristanic acid; potassium, sodium and / or other blood electrolytes; progesterone; prolactin; prolinase; purine nucleoside phosphorylase; quinine;Reverse triiodothyronine (rT3); selenium; serum pancreatic lipase; sisomicin; somatomedin C; specific antibodies (adenovirus, antinuclear antibody, anti-ζ antibody, arbovirus, Aujeszky's disease virus, dengue virus, Guinea worm, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, Leptospira, measles / mumps / rubella, Mycobacterium leprae, Mycoplasma pneumoniae, myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, Poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, Rickettsia (tsutsugamushi), Schistosoma mansoni, Toxoplasma gondii, Treponema pallidum, Trypanosoma cruzi / T. lamblia, vesicular stomata virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyroid stimulating hormone (TSH); thyroxine (T4); thyroxine binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uric acid; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. In some examples, salts, sugars, proteins, fats, vitamins, and hormones naturally present in blood or interstitial fluids may also constitute analytes. Analytes may be naturally present in biological fluids or may be endogenous, such as metabolites, hormones, antigens, antibodies, etc. Alternatively, the analyte may be introduced into the body or be exogenous, such as contrast agents for imaging, radioisotopes, chemical agents, fluorocarbon-based synthetic blood, or drugs or drug compositions, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorinated hydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamine, methamphetamine, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandr ex, Plegine); sedatives (barbiturates, methaqualone, tranquilizers such as diazepam, chlordiazepoxide, meprobamate, sedatives such as chlordiazepoxide, chlordiazepoxide, sedatives such as chlordiazepoxide, sedatives such as sedatives, ...and nicotine. Metabolites of drugs and drug compositions are also contemplated analytes. Analytes produced in vivo such as neurochemicals and other chemicals, for example, ascorbic acid, uric acid, dopamine, norepinephrine, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (FHIAA), and histamine may also be analyzed. ;

[0133] As used herein, the term "ion" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary 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 are 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 + ), chlorine (Cl - ), sulfur (S 2- ), sulfite (SO 3 2- ), sulfate (SO 4 2- ), phosphate (PO 4 3- ) and ammonium (NH 4 + ). Ions are examples of analytes.

[0134] The phrases "biointerface membrane" and "biointerface layer" as used interchangeably herein are broad phrases and will be given their ordinary and customary meanings to one of ordinary skill in the art (and are not limited to special or customary meanings), 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 host tissue and an implantable device. The terms "biointerface" and "bioprotective" are used interchangeably herein.

[0135] As used herein, the phrase "barrier cell layer" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) the part of the foreign body response that forms an adherent monolayer of cells (e.g., macrophages and foreign body giant cells) that substantially blocks the transport of molecules and other substances to the implantable device.

[0136] As used herein, the terms "baseline" and "background" are broad terms and will be given their ordinary and customary meanings to one of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) the amount of signal (e.g., in the form of current and / or voltage) generated by a sensor that is not related to the concentration of the measured analyte.

[0137] As used herein, the term "biostable" 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 a special or customary meaning), and refers to (but is not limited to) materials that are relatively resistant to degradation by processes encountered in the body.

[0138] As used herein, the term "coaxial" should be broadly interpreted to include sensor architectures having elements aligned along a shared axis around a core, which may be configured to have a circular, elliptical, triangular, polygonal, or other cross-section, such elements may include electrodes, insulating layers, or other elements that may be positioned circumferentially around the core layer, such as a core electrode or a core polymer wire.

[0139] As used herein, the term "continuous" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) an uninterrupted or continuous portion, domain, coating or layer of a sensor system as discussed herein.

[0140] As used herein, the term "discontinuous" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) a discontinuous, intermittent or separated portion, layer, coating or domain of a sensor system as discussed herein.

[0141] As used herein, the term "semi-continuous" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) a portion, coating, domain or layer that includes one or more continuous and non-continuous portions, coatings, domains or layers. For example, a coating that is disposed around a sensing area but not about the sensing area is "semi-continuous".

[0142] As used herein, the phrase "continuous analyte sensing" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) a period of time during which monitoring of analyte concentration is performed continuously, continuously, or intermittently (but regularly) (e.g., about every 5 seconds or less to about 10 minutes or more). In other examples, about every 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, or 60 seconds to about 1.25 minutes, 1.50 minutes, 1.75 minutes, 2.00 minutes, 2.25 minutes, 2.50 minutes, 2.75 minutes, 3.00 minutes, 3.25 minutes, 3.50 minutes, 3.75 minutes, 4.00 minutes, 4.25 minutes, 4.50 minutes, 4.75 minutes, 5 minutes, 5.00 minutes, 5.25 minutes, 5.50 minutes, 5.75 minutes, 6.00 minutes, 6.25 minutes, 6.50 minutes, 6.75 minutes, 7.00 minutes, 7.25 minutes, 7.50 minutes, 7.75 minutes, 8.00 minutes, 8.25 minutes, 8.50 minutes, 8.75 minutes, 9.00 minutes, 9.25 minutes, 9.50 minutes or 9.75 minutes once perform monitoring of analyte concentration. In some examples, about every 15 minutes or about every 30 minutes or about every 60 minutes perform monitoring of analyte concentration. Additionally or alternatively, in some examples, about every 1.5 hours, about every 2 hours, about every 4 hours, about every 6 hours or about every 8 hours perform monitoring of analyte concentration.

[0143] As used herein, the term "coupling" is a broad term and will be given its common and customary meaning (and not limited to a special or customized meaning) to a person of ordinary skill in the art, and refers to (but not limited to) two or more system elements or components configured to be attached electronically, mechanically, thermally, operably, chemically, or otherwise. At least one of attachment. Similarly, the phrases "operably connected", "operably linked", and "operably coupled" as used herein may refer to one or more components being connected 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 integrated with each other (i.e., "directly coupled"). In other examples, the components are connected via a remote device. For example, one or more electrodes can be used to detect an analyte in a sample and convert the information into a signal; the signal can then be transmitted to the circuit. In this example, the electrode is "operably linked" to the electronic circuit. As used herein, the phrase "removably coupled" may refer to two or more system elements or components being configured or configured to have been attached electronically, mechanically, thermally, operatively, chemically, or otherwise and being separated 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 being configured or configured to have been attached electronically, mechanically, thermally, operatively, chemically, or otherwise, but cannot be decoupled without damaging at least one of the coupled elements or components.

[0144] As used herein, the term "distal" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a 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 a starting point or attachment point).

[0145] As used herein, the term "domain" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) a region of a membrane system, which can be a layer, a uniform or non-uniform gradient (e.g., an anisotropic region of a membrane), or a portion of a membrane capable of sensing one, two or more analytes. The domains discussed herein can be formed as a single layer, two or more layers, a bilayer pair, or a combination thereof.

[0146] As used herein, the term "drift" is a broad term and will be given its ordinary and customary meaning (and not limited to a special or customized meaning) to those of ordinary skill in the art, and refers to (but not limited to) a progressive increase or decrease in the signal over time that is unrelated to changes in the host system analyte concentration (e.g., host postprandial glucose concentration). Although it is not desired to be bound by any particular theory or any particular analyte, it is believed that the drift associated with glucose measurement is the result of a local reduction in the transport of glucose to the sensor, for example, due to the formation of a foreign body capsule (FBC). It may also be the result of a gradual attenuation of the activity or amount of an enzyme (such as glucose oxidase) within the sensor. It is also believed that an insufficient amount of interstitial fluid surrounding the sensor may result in a reduction in oxygen and / or glucose transported to the sensor. In one example, an increase in local interstitial fluid can slow or reduce drift and thus improve sensor performance. Signal drift may occur due to a changing baseline / background signal measured by the sensor and / or a sensitivity change exhibited by the sensor. Drift may also be a result of sensor electronics or algorithmic models used to compensate for noise or other anomalies that may occur with electrical signals in the picoamp range and nanoamp range, including the microamp range, picoamp range, nanoamp range, and femtoamp range. As described herein, "sensor electronics" may include various combinations of hardware and / or software for detecting, receiving, processing, storing, and / or analyzing signals generated by the devices and systems (including circuits) discussed herein.

[0147] As used interchangeably herein, the phrases "drug release membrane" and "drug release layer" are broad phrases, and each will be given its ordinary and customary meaning (and not limited to a special or customized meaning) to those of ordinary skill in the art, and refer to (but not limited to) a permeable membrane or semipermeable membrane that is permeable to one or more bioactive agents. In one example, the "drug release membrane" and "drug release layer" may include two or more domains, and in some examples may be several microns thick or thicker. In one example, the drug release layer and / or the drug release membrane is substantially the same as the biointerface layer and / or the biointerface membrane. In another example, the drug release layer and / or the drug release membrane is different from the biointerface layer and / or the biointerface membrane. Additional examples of drug releasing layers and membranes can be found in pending U.S. patent application Ser. No. 17 / 697,701, filed on March 17, 2022, entitled “DRUGRELEASING MEMBRANE FOR ANALYTE SENSOR” (which U.S. patent application is incorporated herein by reference in its entirety), and U.S. provisional application Ser. No. 63 / 318,901, filed on March 11, 2022, entitled “DRUGRELEASING MEMBRANE FOR ANALYTE SENSOR” (which U.S. provisional application is incorporated herein by reference in its entirety), and U.S. provisional patent application Ser. No. 63 / 244,644, filed on September 16, 2021, entitled “DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR” (which U.S. provisional patent application is incorporated herein by reference in its entirety).

[0148] As used herein, the term "electrochemical reaction surface" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) the surface of an electrode where an electrochemical reaction occurs. In various examples, the byproduct of the reaction of the analyte being detected includes at least one measurable substance. The at least one measurable substance can react with an electrochemically active surface (such as a working electrode).

[0149] As used herein, the phrase "hard segment" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customary meaning), and refers to (but is not limited to) an element of a copolymer, such as a polyurethane, polycarbonate polyurethane, or polyurethane urea copolymer, which imparts resistance properties, such as resistance to bending or twisting. The phrase "hard segment" can be further characterized as a crystalline, semi-crystalline, or glassy material having a glass transition temperature ("Tg") generally above ambient temperature as determined by dynamic scanning calorimetry. Exemplary hard segment elements for preparing polycarbonate polyurethane or polyurethane urea hard segments include norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), dicyclohexylmethane-4,4′-diisocyanate (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.

[0150] As used herein, the term "host" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a special or customary meaning), and refers to (but is not limited to) a mammal, such as a human.

[0151] As used herein, the terms "indwelling", "embedded", "implanted" or "implantable" are broad terms and will be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) an object including a sensor that is inserted or configured to be inserted in the following manner: subcutaneous insertion (i.e., in the fat layer between the skin and the muscle), intradermal insertion (i.e., penetrating the stratum corneum and positioned in the epidermis or dermis layer of the skin), or percutaneous insertion (i.e., penetrating, entering or passing through the intact skin), which may result in the sensor having an in vivo portion and an extracorporeal portion. The term "indwelling" also encompasses an object configured to be inserted subcutaneously, intradermally or percutaneously, whether or not it has been so inserted.

[0152] As used herein, the phrase "insertable volume" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or custom meaning), and refers to (but is not limited to) the volume in front of and beside 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 perpendicular to the volume in front of and beside the insertion path.

[0153] As used herein, the terms "interferor" and "interfering substance" are broad terms and will be given their ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refer to (but are not limited to) effects and / or substances that interfere with the measurement of an analyte of interest in a sensor to produce a signal that inaccurately represents the analyte measurement, including ions, electroactive substances, endogenous circulating substances, exogenous circulating substances, pharmacological agents, and / or electromagnetic waves (such as from a magnetic resonance imaging (MRI) system or a medical device).

[0154] As used herein, the term "in vivo" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and includes (but is not limited to) parts of devices (e.g., sensors) that are suitable for insertion into and / or presence within a host's living body.

[0155] As used herein, the term "ex vivo" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and includes (but is not limited to) parts of a device (e.g., a sensor) that are adapted to remain and / or exist outside the host's living body.

[0156] As used herein, the term "membrane" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) a structure configured to perform the following functions, including but not limited to: protection of exposed electrode surfaces from biological environments, diffusion resistance (restriction) of analytes, acting as a matrix for catalysts that enable enzymatic reactions, limiting or blocking interfering substances, providing hydrophilicity at electrochemically reactive surfaces of sensor interfaces, acting as an interface between host tissues and implantable devices, regulating host tissue responses via drug (or other substance) release, and combinations thereof. When used herein, the terms "membrane" and "matrix" are intended to be used interchangeably.

[0157] As used herein, the phrase "membrane system" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) a permeable membrane or semi-permeable membrane that may be composed of two or more domains, two or more layers, or two or more layers within a domain and composed of a material that is a few microns thick or thicker, and is at least permeable to the ions whose concentration is to be measured.

[0158] As used herein, the term "micro" is a broad term and will be given its ordinary and customary meaning to persons of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) approximately 10 microns in diameter that is not visible without magnification. -6 The term "micro" is the opposite of the term "large," which refers to large objects that are visible without magnification. Similarly, the term "nano" refers to objects of approximately 10 -9 m small object or scale.

[0159] As used herein, the term "molecular physiological measurement" (MPM) is a broad term used in its ordinary sense and includes, 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, and may include heart rate, heart rate waveform, tissue oxygenation, bioelectrical impedance, electrical response, respiration, core body temperature, and blood pressure, which can be measured and analyzed as discussed herein.

[0160] As used herein, the term "noise" is a broad term and is used in its ordinary sense, including but not limited to signals detected by the sensor or sensor electronics that are unrelated to the analyte concentration and may result in reduced sensor performance. Noise may originate from, for example, physiological sources (such as protein adsorption, foreign body reaction), pharmacological sources (such as drugs), external interference (such as pressure-induced sensor attenuation, triboelectric effects, motion artifacts, electromagnetic waves (such as MRI systems or medical devices)) and / or from sensor electronics (such as Johnson-Nyquist noise, shot noise). One type of noise has been observed during a few hours (e.g., about 2 hours to about 24 hours) after sensor insertion. After the first 24 hours, the noise may disappear or decrease, but in some hosts, the noise may persist for about three to four days. In some cases, predictive modeling, artificial intelligence and / or algorithmic means may be used to reduce noise. In other cases, noise may be reduced by, for example, addressing immune response factors associated with the presence of an implanted sensor using a drug release layer having at least one bioactive agent. For example, the noise of one or more exemplary biosensors disclosed herein may be determined and then compared qualitatively or quantitatively. For example, by obtaining a raw signal time series with a fixed sampling interval (in microvolts (μV)), a smoothed version of the raw signal time series can be obtained, for example, by applying a 3rd order Chebyshev II type low-pass digital filter. Other smoothing algorithms can be used. At each sampling interval, the absolute difference in μV can be calculated to provide a smoothed time series. The smoothed time series can be converted into mM (the unit of "noise") using a glucose sensitivity time series in μV / mM, where the ion sensitivity time series is derived by using a mathematical model between the raw signal and a reference blood ion measurement (e.g., obtained from a blood electrolyte analyzer). Optionally, the time series can be aggregated as needed, for example, by hour or day. Comparison of corresponding time series between different exemplary biosensors having a drug release layer disclosed in the present invention and one or more bioactive agents provides a qualitative or quantitative determination of noise improvement.

[0161] As used herein, the terms "optional" or "optionally" are broad terms, and will be given their ordinary and customary meaning to those skilled in the art (and not limited to a special or customary meaning), and mean (but not limited to) that the subsequently described event or circumstance can occur or not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0162] As used herein, the term "planar" is broadly interpreted to describe a sensor architecture having a substrate comprising a first side and a second side and a plurality of elements arranged on one or more sides of the substrate, which elements may or may not be electrically or otherwise coupled, wherein the elements may include conductive or insulating layers or elements configured to operate as a circuit.

[0163] As used herein, the term "proximal" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customary meaning), and refers to (but is not limited to) the spatial relationship between various elements compared to a specific reference point. For example, some examples of devices include a membrane system having a biointerface layer and a layer containing an ionophore. If an electrode is considered to be a reference point and the ionophore-containing layer is closer to the electrode than the biointerface membrane, then the ionophore-containing layer is closer to the sensor than the biointerface membrane.

[0164] As used herein, the phrases and terms "processor module" and "microprocessor" are each broad phrases and terms and will be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) a computer system, state machine, processor, etc. designed to perform arithmetic or logical operations using logic circuits that respond to and process the basic instructions that drive the computer.

[0165] As used herein, the phrase "sensing membrane" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) a permeable or semipermeable membrane that may include one or more domains, one or more layers, or one or more layers within multiple domains and is composed of a material having a thickness of several microns or more, and which is permeable to reactants and / or co-reactants used to determine the analyte of interest. For example, the sensing membrane may contain an immobilized ion carrier that selectively binds an ion to allow the concentration of the ion to be measured.

[0166] During the general operation of the analyte measurement device, biosensor, sensor, sensing region, sensing portion or sensing mechanism, a biological sample (e.g., blood or interstitial fluid or a component thereof) is contacted directly or after passing through one or more membranes with an ion carrier capable of specifically and reversibly binding to at least one ion. The interaction of the biological sample or a component thereof with the analyte measurement device, biosensor, sensor, sensing region, sensing portion or sensing mechanism results in signal transduction, which allows for qualitative, semi-qualitative, quantitative or semi-quantitative determination of the ions in the biological sample.

[0167] Various examples of sensor architectures are found in pending U.S. application 63 / 321,538, filed on March 17, 2022, entitled “CONTINUOUS ANALYTESENSOR SYSTEMS,” which is incorporated herein by reference in its entirety, and U.S. Patent 8,133,178 to Brauker et al., which is incorporated herein by reference in its entirety, and U.S. Patents 8,828,201, Simpson et al.; 9,131,885, Simpson et al.; 9,237,864, Simpson et al.; and 9,763,608, Simpson et al. (each of which is incorporated herein by reference in its entirety). Examples of methods of forming sensors (sensor electrode layouts and membranes) and sensor systems discussed herein are found in currently pending U.S. Patent Publication No. 2019 / 0307371 to Boock et al., which is incorporated herein by reference in its entirety.

[0168] In one example, the sensing region determines the selectivity between one or more analytes so that only the analytes that must be measured produce (transduce) a detectable signal. The selection is based on any chemical or physical recognition of the analyte by the sensing region, wherein the chemical composition of the analyte is not changed, or wherein the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.

[0169] The sensing region transduces recognition of the analyte into a semi-quantitative or quantitative signal. Thus, "transduction" and their grammatical equivalents as used herein encompass electrochemical techniques and methods. Electrochemical properties include current and / or voltage, capacitance, and potential.

[0170] As used herein, the phrases and terms "small diameter sensor", "small structure sensor" and "microsensor" are broad phrases and terms and will be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) sensing mechanisms that are less than about 2 mm in at least one dimension. In other examples, the sensing mechanism is less than about 1 mm in at least one dimension. In some examples, the sensing mechanism (sensor) is less than about 0.95 mm, 0.9 mm, 0.85 mm, 0.8 mm, 0.75 mm, 0.7 mm, 0.65 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm. In some examples, the largest dimension of the independently measured length, width, diameter, thickness, or circumference of the sensing mechanism does not exceed about 2 mm. In some examples, the sensing mechanism is a coaxial or linear sensor with a diameter of less than about 1 mm, see, for example, U.S. Patent 6,613,379 to Ward et al. and U.S. Patent 7,497,827 to Brister et al., both of which are incorporated herein by reference in their entirety. In some alternative examples, the sensing mechanism includes an electrode deposited on a planar or substantially planar substrate, wherein the thickness of the implantable portion is less than about 1 mm, see, for example, U.S. Patent 6,175,752 to Say et al. and U.S. Patent 5,779,665 to Mastrototaro et al., both of which are incorporated herein by reference in their entirety. Examples of methods for forming sensors (sensor electrode layouts and membranes) and sensor systems for preparing the present sensors are found in U.S. Patent Publication 2019 / 0307371 to Boock et al., which is incorporated herein by reference in its entirety.

[0171] As used herein, the term "sensitivity" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a 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) generated by a predetermined amount (unit) of measured analyte. For example, in one example, the sensor has a sensitivity (or slope) of about 1 picoampere to about 100 picoamperes of current for each 1 mg / dL of glucose analyte. In another example, the sensor has a sensitivity (or slope) of about 10 millivolts to 100 millivolts of potential for each order of magnitude (based on 10 orders of magnitude) change in potassium ions, and in some examples, a sensitivity (or slope) of about 59 millivolts of potential for each order of magnitude (based on 10 orders of magnitude) change in potassium ions, where the current is essentially zero (less than 0.1 picoamperes).

[0172] As used herein, the phrase "soft segment" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) an element of a copolymer, such as a polyurethane, polycarbonate-polyurethane or polyurethaneurea copolymer, which 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 generally no higher than ambient temperature or normal mammalian body temperature).

[0173] As used herein, the terms and phrases "zwitterion" and "zwitterionic compound" are each broad terms and phrases and will be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to special or customary meanings), and refer to, but are not limited to, compounds in which the neutral molecule of the compound has a unit positive charge and a unit negative charge at different positions within the molecule. Such compounds are a class of dipolar compounds and are sometimes also referred to as "inner salts".

[0174] Devices and methods are provided for measuring electrophysiological signals and / or concentrations of target analytes in vivo.

[0175] Now refer to Figure 1A To Figure 1, Figures 2A to 2G , Figure 3 , FIG. 4A to FIG. 4B , FIG. 5A to FIG. 5B , FIG. 6A to FIG. 6G , Figures 7A to 7C and Figure 8 Non-limiting examples of devices and methods for measuring physiological signals and / or concentrations of target analytes in vivo are described.

[0176] FIG. 1A to FIG. 1I An example configuration and components of an apparatus 100 for measuring an electrophysiological signal and / or concentration of a target analyte (such as a target ion 11) in an in vivo biological fluid 10 are schematically illustrated. Figure 1A, the device 100 includes an indwelling sensor 110 and a 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 is referred to as a working electrode (WE), and the second electrode 117 is 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, which is the potential of the first electrode 111 in response to the concentration of a 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 result of the signal. In various examples, the EMF is based at least in part on a potential difference between (i) the first electrode 111 or the second electrode 117 and (ii) another electrode spaced apart from the first electrode or the second electrode.

[0177] Additionally or alternatively, in some examples, the device 100 may include an ion carrier 115 disposed on the substrate 101 and configured to selectively transport the target ion 11 to or within the first electrode 111. In one example, 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 ion carrier 115 transporting the target ion to or through the first electrode 111. In one example, the sensor electronics 120 (and / or an external device that receives the signal via a suitable wired or wireless connection) 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. Additional details on the configuration and use of the sensor electronics 120 are provided further below.

[0178] Optionally, in addition to ion concentration, the first electrode 111 is also used to measure an electrophysiological signal. In other examples, such as when the device 100 is configured to detect an electrophysiological signal rather than an ion concentration, the first electrode 111 need not include an ion carrier, such as ion carrier 115. In other examples, the first electrode 111 may include an inactive ion carrier so that it does not interfere with the measurement of the electrophysiological signal.

[0179] According to such Figure 1AIn the illustrated manner, the biological fluid 10 may include a plurality of ions 11, 12, 13, 14, and 15. In one example, the apparatus 100 is configured to measure the concentration of ion 11, and thus such ions are referred to as "target" ions. In one example, the target ion 11 is any suitable ion, and in a non-limiting example is selected from the group consisting of: sodium (Na + ), potassium (K + ), magnesium (Mg 2+ ), calcium (Ca 2+ ), hydrogen (H + ), Lithium + ), chlorine (Cl - ), sulfite (SO 3 2- ), sulfate (SO 4 2- ), phosphate (PO 4 3- ) and ammonium (NH 4 + In one example, ions 12, 13, 14, and 15 belong to the group consisting of: sodium (Na + ), potassium (K + ), magnesium (Mg 2+ ), calcium (Ca 2+ ), hydrogen (H + ), Lithium + ), chlorine (Cl - ), sulfur (S 2- ), sulfite (SO 3 2- ), sulfate (SO 4 2- ), phosphate (PO 4 3- ) and ammonium (NH 4 + ). In one example, ions 12, 13, 14, and 15 are considered interferents to the measurement of target ion 11 because they are likely to interfere with the sensor's measurement of target ion 11, thereby generating a signal that does not accurately represent the concentration of target ion 11. In one example, ion carrier 115 is selected to selectively transport target ion 11 to or within first electrode 111, and completely, partially, and / or substantially inhibit one or more of ions 12, 13, 14, or 15 from being transported to or within first electrode 111. For example, Figure 1BAs illustrated, the ion carrier 115 can selectively transport or selectively bind a target ion 11 from the biological fluid 10 or from the biological interface membrane 114 (if provided, e.g., as described below) to the first electrode 111 and selectively transport or selectively bind the target ion within the first electrode, while ions 12, 13, 14, and 15 can be substantially retained within the biological fluid 10 or the biological interface membrane 114. Therefore, the contribution to the potential difference between the first electrode 111 and the second electrode 117 in response to the transport of ions to the first electrode 111 or within the first electrode is substantially caused primarily by the target ion 11 rather than by one or more of the ions 12, 13, 14, or 15.

[0180] A variety of ionophores 115 can be used to generate ionophores such as Figure 1A to Figure 1BThe method selectively transports the corresponding ions. In one example, when the target ion 11 is hydrogen (via peroxide), the ion carrier 115 is tri(dodecyl)amine, 4-nonadecylpyridine, N,N-di(octadecyl)methylamine, octadecyl isonicotinate, calix[4]-aza-crown ether. In another example, when the target ion 11 is lithium, the ion carrier 115 is ETH 149. N,N,N′,N′,N″,N″-hexacyclohexyl-4,4′4″-propyltri(3-oxabutyramide) or 6,6-dibenzyl-1,4,8-11-tetraoxacyclotetradecane. In another example, when the target ion 11 is sulfite, the ion carrier 115 is octadecyl 4-formylbenzoate. In another example, when the target ion 11 is sulfate, the ion carrier 115 is 1,3-[bis(3-phenylthioureamethyl)]benzene or zinc phthalocyanine. In another example, when the target ion 11 is phosphate, the ion carrier 115 is 9-decyl-1,4,7-triazacyclododecane-8,10-dione. In another example, when the target ion 11 is sodium, the ion carrier 115 is 4-tert-butylcalix[4]arene-tetrahydrofuran-1,4,7-triazacyclododecane-8,10-dione. In another example, when the target ion 11 is potassium, the ion carrier 115 is potassium ion carrier I (valinemycin), potassium ion carrier II (BB15C5) or potassium ion carrier III (BME44). In another example, when the target ion is magnesium, the ion carrier 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 ion carrier VI). In another example, when the target ion is calcium, the ion carrier 115 is calcium ion carrier I (ETH 1001) or calcium ionophore II (ETH129). In another example, when the target ion is chloride, the ionophore 115 is tri(dodecyl)methylammonium chloride (TDMAC). In another example, when the target ion is ammonium, the ionophore 115 is anabactin.

[0181] exist Figure 1AIn the illustrated non-limiting example, the ion carrier 115 is disposed within the first electrode 111, and in this example, the first electrode is referred to as an ion selective electrode (ISE) because the ion carrier 115 selectively transports the target ion 11. In some examples, the first electrode 111 includes a conductive polymer optionally having the ion carrier 115 therein. Illustratively, the conductive polymer is present in the first electrode 111 in an amount of about 90 wt % to about 99.5 wt %. In one example, the ion carrier 115 is present in the first electrode in an amount of about 0.5 wt % to about 10 wt %. In some examples, the conductive polymer is 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).

[0182] Although conductive polymers (such as those listed above) may be suitably used in the first electrode 111 that does not include the ion carrier 115, other materials may alternatively be used, as described below with reference to Figures 2A to 2G Some non-limiting examples thereof are described. Optionally, the ion carrier 115 is disposed in a membrane, which is disposed on the first electrode 111 (the electrode may not contain the ion carrier 115), for example, as will be referred to below. Figures 2A to 2G Descriptive.

[0183] In one example, the first electrode 111 is configured in a manner that enhances its biocompatibility. For example, the first electrode 111 may not substantially contain any plasticizers, otherwise the plasticizer may leach into the biological fluid 10, which may cause toxicity and / or device performance degradation. As used herein, "substantially" not containing materials such as plasticizers (phthalates, sebacates, nitrophenyl ethers and fluorophenyl nitrophenyl ether plasticizers) is intended to indicate that the first electrode 111 or other aspects discussed herein do not contain a detectable amount of "substantially" non-containing materials. In some examples, the first electrode 111 may be substantially composed of a conductive polymer, optionally with an ion carrier 115. In some examples, the first electrode 111 may be substantially composed of a conductive polymer, an ion carrier 115 and an additive having ion exchange capacity (e.g., an additive that forms a complex with the ion carrier and leads to improved selectivity for the target ion). In one example, the additive contributes to ion selectivity. In another example, the additive may not provide ion selectivity. For example, the additive may contribute to providing a substantially uniform (adjusting and / or weakening) ion concentration in the membrane. Additionally or alternatively, the additive may contribute to 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 increases the selectivity of the ionophore for the target ion compared to the selectivity of the ionophore alone.

[0184] Optionally, the additive may include a lipophilic salt. In a non-limiting example, 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 one example, the additive is present in the first electrode in an amount of about 0.01 wt % to about 1 wt % or other suitable amount.

[0185] Other materials in the sensor 110 are selected. In one example, the substrate 101 comprises a material selected from the group consisting of metals, glass, transparent conductive oxides, semiconductors, dielectrics, ceramics, and polymers (such as biopolymers or synthetic polymers). In some examples, the second electrode 117 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 one example, a binary semiconductor comprises any two elements suitable for a semiconductor. In one example, a ternary semiconductor comprises two or more binary semiconductors. In one example, in the case of using a metal or a metal alloy, the one or more metals 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 an oxidized metal for the second electrode 117 is iridium oxide. In one example, the metal is optionally provided 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 (TiO 2 ), iridium dioxide (IrO 2 ), platinum dioxide (PtO 2 ), zinc oxide (ZnO), copper oxide (CuO), cerium dioxide (CeO 2 ), ruthenium(IV) oxide (RuO 2 ), Tantalum pentoxide (Ta 2 O 5 ), titanium dioxide (TiO 2 ), molybdenum dioxide (MoO 2 ) and manganese dioxide (MnO 2 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).

[0186] In one example, the conductive polymer used for the sensor 110 is 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, the first electrode 111 and the second electrode 117 are optionally formed of the same material as each other, or are formed using different materials from each other. Figure 1A In the illustrated non-limiting example, the first electrode 111 and the second electrode 117 are disposed directly on the substrate 101 , or alternatively disposed on the substrate 101 via one or more intervening layers (not shown).

[0187] In one example, the biocompatibility of sensor 110 is optionally further enhanced by providing a biointerface film on one or more components of sensor 110. Figure 1A In the illustrated non-limiting configuration, the first biointerface membrane (BM1) 114 is disposed on the ion carrier 115 and the first electrode 111. In another example, the first biointerface membrane 114 is disposed on the ion carrier 115 and the first electrode 111, and the second biointerface membrane (BM2) 118 is disposed on the second electrode 117. Alternatively, in Figure 1H In the illustrated non-limiting configuration, a biointerface membrane (BM) 114' is disposed on both the first electrode 111 and the second electrode 117. Although for simplicity of illustration, Figure 1A and Figure 1H The biointerface membrane may be shown to have a rectangular shape, but it is apparent that the membrane may conform to the shape of any underlying layer. In some examples, the biointerface membrane is configured to inhibit biofouling of ion carriers 115, first electrodes 111, and / or second electrodes 117. Non-limiting examples of materials included in the biointerface membrane include hard segments and / or soft segments. Examples of hard segments and soft segments for biointerface membranes 114 / 114′ / 118 or other biointerface membranes as discussed herein include aromatic polyurethane hard segments, aliphatic hard segments, polycarbonate soft segments, or any combination thereof having Si groups. In other examples of biointerface membranes (such as 114 / 114′ / 118 or other biointerface membranes discussed herein), PVP may not be included. In this example that does not include PVP, the biointerface membrane (118, 114, 114′ or other biointerface membranes as discussed herein) may include polyurethane and PDMS. In some examples combined with other examples herein, the biointerface membrane discussed herein may include one or more zwitterionic compounds.

[0188] Additionally or alternatively, the biointerface membrane is configured to release therapeutic compounds into the biological fluid. Therapeutic compounds suitable for release using the biointerface membrane or other membranes discussed herein may include one or more anti-inflammatory agents, anti-infective agents, necrotizing agents, and anesthetics. Typically, anti-inflammatory agents reduce acute and / or chronic inflammation adjacent to the implant so as to reduce the formation of the FBC capsule, thereby reducing or preventing the formation of the barrier cell layer. Suitable anti-inflammatory agents include, but are not limited to, for example, nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetaminophen, 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), interferon, ketoprofen, ketorolac, leflunomide, mefenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naphthalene 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 acetonide, fluticasone propionate, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone acetonide, triamcinolone acetonide, clobetasol propionate, dexamethasone and dexamethasone acetate.

[0189] Typically, immunosuppressants and / or immunomodulators directly interfere with several key mechanisms necessary for the inflammatory response involving different cellular elements. Suitable immunosuppressants and / or immunomodulators include antiproliferative cell cycle inhibitors (e.g., paclitaxel (e.g., sirolimus), cytochalasin D, infliximab), paclitaxel, actinomycin, mitomycin, thospromote VEGF, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopeptin, vincristine, mitomycin, statins, CMYC antisense, sirolimus (and analogs), RestenASE, 2-chloro-deoxyadenosine, PCNA ribozyme, batimastat, prolyl hydroxylase inhibitors, PPARγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catechins, glycating agents, endothelin inhibitors (e.g., ambrisentan, tesosentan, bosentan), statins (e.g., cerivastatin), E. coli heat-labile enterotoxin, NLRP3 inflammasome inhibitors, and advanced coatings.

[0190] Generally, anti-infective agents are substances that can play an anti-infective role by inhibiting the spread of the source of infection or by completely killing the source of infection, which can be used to reduce the immune response without an inflammatory reaction at the implant site. Anti-infective agents include, but are not limited to, anthelmintics (mebendazole); antibiotics, including aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin B, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, miconazole, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), β-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, cefadroxil), oxazolidinone), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; polymyxin E mesylate sodium; polymyxin B sulfate; vancomycin; antivirals, including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sterile crystalline sulfonamides; gatifloxacin; and sulfamethoxazole / trimethoprim.

[0191] Generally, a necrotizing agent is any drug that causes tissue necrosis or cell death. Necrotic agents include cisplatin, BCNU, paclitaxel or paclitaxel derivatives, etc.

[0192] In general, angiogenic agents include substances with direct or indirect angiogenic properties. In some cases, angiogenic agents can additionally affect the formation of barrier cells in vivo. Indirect angiogenesis means that angiogenesis can be mediated through inflammatory pathways or immune stimulation pathways. It is not fully known how agents that induce local angiogenesis indirectly inhibit barrier cell formation; however, it is believed that some barrier-cell effects can be indirectly caused by the action of angiogenic agents.

[0193] Angiogenic agents include mechanisms that promote neovascularization around the membrane and / or reduce or minimize ischemic periods by increasing vascularization near the device-tissue interface. Sphingosine-1-phosphate (S1P) is incorporated into a non-limiting example of a biointerface membrane as a phospholipid with potent angiogenic activity. Monobutyrin is incorporated into another non-limiting example of a biointerface membrane as an effective vasodilator and angiogenic lipid product of adipocytes. In another non-limiting example, an antisense molecule that increases angiogenesis (e.g., thrombospondin 2 antisense) is incorporated into a biointerface membrane.

[0194] Angiogenic agents may include mechanisms that promote inflammation, which are believed to cause accelerated neovascularization in vivo. In one non-limiting example, a xenogeneic carrier (e.g., bovine collagen) that causes an immune response through its exogenous nature stimulates neovascularization and is incorporated into the biointerface membrane of the present disclosure. In another non-limiting example, lipopolysaccharide is incorporated into the biointerface membrane as a potent immunostimulant. In another non-limiting example, a protein known to regulate bone healing in tissues (e.g., bone morphogenetic protein (BMP)) is incorporated into the biointerface membrane.

[0195] Generally, angiogenic agents are substances that can stimulate the formation of new blood vessels, which can accelerate and maintain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include, but are not limited to, 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 growth factor BB (PDEGF-BB), angiopoietin-1, transforming growth factor beta (TGF-β), transforming growth factor alpha (TGF-α), hepatocyte growth factor , tumor necrosis factor-α (TNF-α), placental growth factor (PLGF), angiogenin, interleukin-8 (IL-8), hypoxia-inducible factor-I (HIF-1), angiotensin-converting enzyme (ACE) inhibitor quinaprilat, angiotropin, thrombospondin, peptide KGHK, low oxygen 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.

[0196] Typically, proinflammatory agents are substances that can stimulate an immune response in host tissues, which can accelerate or maintain the formation of mature vascularized tissue beds. For example, proinflammatory agents are typically stimulants or other substances that induce chronic inflammation and chronic particle reactions at the implant site. Although not wishing to be bound by theory, it is believed that the formation of high tissue granulation induces blood vessels to provide sufficient or abundant analyte supply to the device-tissue interface. Proinflammatory agents include, but are not limited to, xenogeneic carriers, lipopolysaccharides, Staphylococcus aureus (S. aureus) peptidoglycans, and proteins.

[0197] Other substances that may be incorporated into one or more films of the present disclosure include various pharmacological agents, excipients, and other substances well known in the art of pharmaceutical formulation.

[0198] Additionally or alternatively, in some examples, the biointerface membrane (e.g., BM1 114, BM2 118, and / or BM1 14') may include a biocompatible polymer and a salt. Figure 1C As illustrated, salt 119 is distributed throughout the biointerface film 118. In a non-limiting example, the biointerface film (e.g., 114, 114', 118) may be substantially composed of a biocompatible polymer and a salt. In one example, the biocompatible polymer is optionally present in the biointerface film in an amount of about 40% by weight to about 70% by weight. In one example, the salt is optionally present in the biointerface film in an amount of about 30% by weight to about 60% by weight. In some examples, the biocompatible polymer is selected from the group consisting of the following: 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 an aromatic or aliphatic diisocyanate for preparing 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 includes one or more of the following: norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), dicyclohexylmethane-4,4′-diisocyanate (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 a combination thereof.

[0199] In one example, the hard segment content is about 5 wt % to about 90 wt % of the segmented block copolymer of the biointerface membrane (e.g., BM1 114, BM2118, and / or BM 114′). In another example, the hard segment is about 15 wt % to about 75 wt %. In yet another example, the hard segment is about 25 wt % to about 55 wt %. Additionally or alternatively, the salt is optionally selected from the group consisting of potassium chloride (KCl), sodium chloride (NaCl), magnesium chloride (MgCl 2 ), calcium chloride (CaCl 2 ) and ammonium sulfate ((NH 4 ) 2 5O 4 ).

[0200] It should be understood that the biointerface membrane (eg, BM1 114, BM2 118, and / or BM 114') may include multiple layers.

[0201] It should also be appreciated that the sensor 110 may have any suitable configuration. Figure 1A In the illustrated non-limiting example, substrate 101 is depicted as a planar or substantially planar sensor. Figure 1D A partial plan view of an example sensor 110 having a planar substrate 101 is shown, with a cross section of the sensor along dashed line 1A-1A corresponding to Figure 1A Illustrated view. In other examples, substrate 101 is substantially coaxially shaped and is referred to as a "wire". Figure 1E A partial plan view of an example sensor 110 having a coaxial substrate 101 is shown, the cross section of the sensor along line 1F-1F corresponding to Figure 1F The illustrated view, and the cross section of the sensor along line 1G-1G corresponds to Figure 1G As noted above, Figure 1H An example in which the biointerface film 114 ′ is disposed on the first electrode 111 and the second electrode 117 is shown. Fig. 1I A similar example is shown, in which a biointerface film 114' is provided on a first electrode 111 and a second electrode 117, and the substrate is linear.

[0202] In addition, the sensor may include any other suitable number and type of layers. Figure 1A and Figure 1B In the manner described, the ion carrier 115 is optionally omitted from the first electrode 111. Additionally or alternatively, the ion carrier 115 is included in another layer disposed on the first electrode 111. For example, Figures 2A to 2G Additional example configurations and components of potentiometric sensors are schematically illustrated. Figure 2A , the device 200 includes an indwelling sensor 210 and a sensor electronics 120. The sensor 210 includes a reference Figure 1A The similarly configured substrate 101, the first electrode (E1′) 211 disposed on the substrate 101, and the first electrode (E1′) 211 disposed on the substrate and connected to the reference electrode 211 are provided. Figure 1AThe similarly configured second electrode (E2) 117. The first electrode 211 is referred to as the working electrode (WE), and the second electrode 117 is referred to as the reference electrode (RE). In one example, the sensor electronics 120 may include a circuit 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 result of the signal. Additionally or alternatively, in some examples, the device 200 may include an ion carrier 115 disposed on the substrate 101 and configured to selectively transport the target ion 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 ion carrier 115 transporting the target ion 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 a signal via a suitable wired or wireless connection). In one example, the sensor electronics 120 is configured to use the signal to generate an output corresponding to a measurement of the concentration of a target ion in the biological fluid. Additional details regarding the configuration and use of the sensor electronics 120 are provided further below.

[0203] Although in reference Figure 1A In the example described, the ion carrier 115 is included in the first electrode 111, but in Figure 2A In the illustrated example, the first electrode 211 does not include the ion carrier 115 (and is therefore referred to as E1′ rather than E1). Instead, the ion carrier 115 is located within an ion selective membrane (ISM) 212 disposed on the first electrode 211. The ion carrier 115 may be similar to the reference Figure 1A to Figure 1B The described manner selectively transports the target ion 11 to the first electrode 211, and such transport can result in a potential difference between the first electrode 211 and the second electrode 117, based on which the sensor electronics 120 can generate an output corresponding to a measurement result of the concentration of the target ion 11 in the biological fluid 10. It should be understood that in examples where the device 200 is used to measure electrophysiological signals rather than ion concentration, the ISM 212 is omitted.

[0204] In one example, the ion selective membrane 212 does not substantially contain any plasticizer in a manner similar to that described with reference to the first electrode 111. In some examples, the ion selective membrane 212 may consist essentially of a biocompatible polymer and an ion carrier 115 configured to selectively bind the target ion. Alternatively, in some examples, the ion selective membrane 212 consists essentially of a biocompatible polymer, an ion carrier 115 configured to selectively bind the target ion 11, and an additive having ion exchange capability (such as a lipophilic salt). Figure 1A to Figure 1B Non-limiting examples of lipophilic salts and non-limiting amounts of additives, biocompatible polymers and ion carriers are provided. Although the first electrode 111 includes a conductive polymer so that an ion carrier 115 can be provided therein while maintaining the conductivity of the electrode, additional types of materials are used in the ion selective membrane 212 because the ion selective membrane 212 does not need to be used as an electrode. For example, the biocompatible polymer of the ion selective membrane 212 may include a hydrophobic polymer. Illustratively, the hydrophobic polymer is selected from the group consisting of the following: silicone, fluorosilicone (FS), polyurethane, polyurethane urea, polyurea. In one example, the biocompatible polymer of ISM 212 (or other ion selective membranes or other membranes discussed herein) may include one or more block copolymers, which are segmented block copolymers. In one example, the hydrophobic polymer is a segmented block copolymer comprising polyurethane and / or polyurea segments and / or polyester segments and one or more of polycarbonate, polydimethylsiloxane (PDMS), diphenylmethane 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), fluoropolymers, polyacrylates, and / or polymethacrylates.

[0205] In one example, instead of one or more hydrophobic copolymers or in addition to one or more hydrophobic copolymers, biocompatible polymers may also include hydrophilic block copolymers. Exemplarily, hydrophilic block copolymers may include one or more hydrophilic blocks selected from the group consisting of the following: polyethylene glycol (PEG) and cellulose polymers. Additionally or alternatively, block copolymers may include one or more hydrophobic blocks selected from the group consisting of the following: polydimethylsiloxane (PDMS), polytetrafluoroethylene, polyethylene-to-tetrafluoroethylene, polyolefins, polyesters, polycarbonates, biostable polytetrafluoroethylene, homopolymers of polyurethane, copolymers, terpolymers, polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethyl methacrylate (PMMA), polyetheretherketone (PEEK), polyurethane, poly (propylene oxide) and their copolymers and blends. In one example, ion selective membrane 212 does not contain PVP or other plasticizers.

[0206] In one example, the biocompatible polymer of the ion selective membrane 212 comprises about 0.1 wt % silicone to about 80 wt % silicone. In one example, the ion selective membrane 212 or other ion selective membranes discussed herein comprise about 5 wt % silicone to about 25 wt % silicone. In another example, the ion selective membrane 212 or other ion selective membranes discussed herein comprise about 35 wt % silicone to about 65 wt % silicone. In another example, the ion selective membrane 212 or other ion selective membranes discussed herein comprise about 30 wt % silicone to about 50 wt % silicone.

[0207] In certain examples, ISM 212 or other ISMs discussed herein may include one or more block copolymers or segmented block copolymers. In one example, the segmented block copolymer may include a hard segment and a soft segment. In this example, the hard segment may include an 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 includes one or more of the following: norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), dicyclohexylmethane-4,4′-diisocyanate (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 a combination thereof. In one example, the hard segment is about 5 wt % to about 90 wt % of the segmented block copolymer of ISM 212. In another example, the hard segment is about 15 wt % to about 75 wt %. In yet another example, the hard segment is about 25 wt % to about 55 wt %. It should be understood that the ion selective membrane 212 and the first electrode 111 are prepared in any suitable manner. Illustratively, the polymer, ion carrier 115 and any additive are dispersed in a suitable organic solvent (e.g., tetrahydrofuran, isopropanol, acetone or methyl ethyl ketone) in appropriate amounts. In one example, the mixture is applied to the substrate 101 (or to the layer thereon) using any suitable technique, such as dipping and drying, spraying, inkjet printing, aerosol jet distribution, slit coating, electrodeposition, electrospraying, electrostatic spinning, chemical vapor deposition, plasma polymerization, physical vapor deposition, spin coating, etc. In one example, the organic solvent is 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 biofilms, are formed using techniques described elsewhere herein or otherwise known in the art.

[0208] Although the first electrode 111 includes a conductive polymer so that the ionophores 115 can be provided therein while maintaining the conductivity of the electrode, additional types of materials are used in the first electrode 211. In one example, when measuring an electrophysiological signal, the first electrode can be configured without an ionophore, or with an inactive ionophore that does not electrically interfere with the electrophysiological signal. Non-limiting example materials for the first electrode 211 of the device 200 are provided above with reference to the second electrode 117, such as metals, metal alloys, transition metal oxides, transparent conductive oxides, carbon materials, doped semiconductors, binary semiconductors, ternary semiconductors, or conductive polymers, such as those described above with reference to Figure 1A described.

[0209] In some examples, the ion selective membrane is in direct contact with the first electrode. In other examples, such as Figure 2A As illustrated, 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 perform the function of enhancing 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 the transport of water from the biological fluid 10 to the first electrode 211 and / or the accumulation of water at the first electrode 211. The solid contact layer 213 may include any suitable material or combination of materials. Non-limiting example materials for the solid contact layer 213 are provided above with reference to the second electrode 117, such as metals, carbon materials (e.g., carbon ink or carbon paste), doped semiconductors, or conductive polymers, such as those described above with reference to Figure 1A Alternatively, the solid contact layer 213 may include a redox pair having a well-controlled oxidized / reduced species concentration ratio for stabilizing the interface potential. In one example, the redox pair may include a metal center with different oxidation states. Illustratively, 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 an alternative example, the solid contact layer 213 may include a mixed conductor or a mixed ion-electron conductor, such as 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 4In one example, the amount of solid contact material present in the solid contact layer is 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, 4 wt%, 4.1 wt%, 4.2 wt%, 4.3 wt%, 4.4 wt%, 4.5 wt%, 4.6 wt%, 4.7 wt%, 4.8 wt%, 4.9 wt%, 5 wt%, 5.1 wt%, 5.2 wt%, 5.3 wt%, 5.4 wt%, 5.5 wt%, 5.6 wt%, 5.7 wt%, 5.8 wt%, 5.9 wt%, 6 wt%, 6.1 wt%, 6.2 wt%, 6.3 wt%, 6.4 wt%, 6.5 wt%, 6.6 wt%, 6.7 wt%, 6.8 wt%, 6.9 wt%, 7 wt%, 7.1 wt%, 7.2 wt%, 7.3 wt%, 7.4 wt%, 7. 5 wt%, 7.6 wt%, 7.7 wt%, 7.8 wt%, 7.9 wt%, 8 wt%, 8.1 wt%, 8.2 wt%, 8.3 wt%, 8.4 wt%, 8.5 wt%, 8.6 wt%, 8.7 wt%, 8.8 wt%, 8.9 wt%, 9 wt%, 9.1 wt%, 9.2 wt%, 9.3 wt%, 9.4 wt%, 9.5 wt%, 9.6 wt%, 9.7 wt%, 9.8 wt%, 9.9 wt%, 10 wt% or more.

[0210] It should also be appreciated that the sensor 210 may have any suitable configuration. Figure 2A In the illustrated non-limiting example, substrate 101 is planar or substantially planar. Figure 2B A partial plan view of an example sensor 210 having a planar substrate 101 is shown, with a cross section of the sensor along dashed line 2A-2A corresponding to Figure 2A Illustrated view. In other examples, substrate 101 is substantially linear, having a coaxial architecture. Figure 2C A partial plan view of an example sensor 110 having a coaxial substrate 101 is shown, the cross section of the sensor along line 2D-2D corresponding to Figure 2DThe illustrated view and the cross section of the sensor along line 2E-2E corresponds to Figure 2E The illustrated view. Figure 2F An example in which the biointerface film 114 ′ is provided on the first electrode 211 and the second electrode 117 is shown. Figure 2G A similar example is shown, where the biointerface film 114' is disposed on the first electrode 211 and the second electrode 117, and the substrate is coaxially shaped.

[0211] Reference below FIG. 5A to FIG. 5B and FIG. 6A to FIG. 6G Other non-limiting configurations of the sensor 110 are described. Figure 5A , a side schematic diagram of an exemplary transdermal analyte sensor 550 is shown. The sensor 550 includes a mounting unit 552 suitable for mounting on the host skin, a small (diameter) structure sensor 534 (as defined herein) suitable for percutaneous insertion through the host skin, and an electrical connector configured to provide safe electrical contact between the sensor and the electronic device preferably contained in the mounting unit 552. Generally speaking, the mounting unit 552 is designed to maintain the integrity of the sensor in the host so as to reduce or eliminate the motion conversion between the mounting unit, the host and / or the sensor. See the co-pending U.S. patent application serial number 11 / 077,715 entitled "TRANSCUTANEOUS ANALYTE SENSOR" filed on March 10, 2005, which is incorporated herein by reference in its entirety. In one example, a drug release membrane 570 is formed onto at least a portion of the sensor 550.

[0212] Figure 5B 5 is a side schematic diagram of a transcutaneous analyte sensor 554 in an alternative example. The transcutaneous analyte sensor 54 includes a mounting unit 552, wherein the sensing mechanism 536 includes a small structure as defined herein and is tethered to the mounting unit 552 via a cable 556 (alternatively, a wireless connection may be utilized). The mounting unit is adapted to be mounted on the skin of a host and is operably connected to the small structure sensor 534 via a tether or the like, which is adapted to be percutaneously inserted through the skin of the host and to measure an analyte therein; see, e.g., U.S. Pat. No. 6,558,330 to Causey III et al., which is incorporated herein by reference in its entirety.

[0213] 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 noted above, in some examples, the potential difference is in response to the ion carrier 115 transporting the target ion 11 to or through the first electrode 111 or to the first electrode 211. In one example, the corresponding contribution to the electromotive force may correspond substantially to the concentration of the target ion 11 in the biological fluid 10 in a logarithmic manner. For example, the EMF generated within the sensor electronics 120 in response to the transport of the target ion 11 is described using a generalized Nernst relation:

[0214]

[0215] Where E is the electromotive force generated within the sensor electronics 120, E 0 represents the apparent potential of the device 100, R is the universal gas constant, T is the operating temperature (in K), and z is the valence or stoichiometry of the electrons participating in the reaction of each target ion 11 (e.g., for K + 、Na + NH 4 + or Cl - is 1; for Ca 2+ or Mg 2+ is 2), F is the Faraday constant, [I o ] is the concentration of the target ion 11 in the biological fluid 10, and [I i ] is the concentration of ions within the first electrode 111 or ISM 212. At room temperature, the Nernst relationship states that for a target monovalent ion 11 (e.g., K + ) per log 10 (concentration change) (tenfold), the change in EMF is 59.13 mV, or for the target divalent ion 11 (such as Mg 2+ ) per log 10 (Concentration change), the EMF change is 29.58mV.

[0216] Because the ion carrier 115 in the first electrode 111 or ISM 212 is highly selective for the target ion 11, for example, Figure 1B In the manner described, it is expected that the other ions 12, 13, 14, and 15 do not substantially affect the value of the electromotive force measured using the sensor electronics 120. Nevertheless, in some examples, the sensor electronics 120 is configured to apply a correction to the above-described Nernst relationship according to the Nicolsky-Shultz-Eisenman equation, which accounts for the interfering ions I b For target ion Ia The impact of k ab is called the selectivity coefficient (in some examples lower values ​​such as 1E-2 are used), and z b is the valence of the interfering ion:

[0217]

[0218] The sensor electronics 120 is configured to provide a high fidelity measurement of the EMF, based on which the concentration [I 0 ]or For example, the sensor electronics 120 is configured to calculate the interfering ion I b The selectivity coefficient k of a given sensor in the presence of ab In one example, a sample with a known concentration of I a and I b of fluid and measure E and E 0 The value of k is determined by ab This relationship helps to quantitatively assess the ratio of the signal generated in the presence of an interfering ion to the signal generated in the presence of an equivalent concentration of the desired ion. For example, a potassium ion sensor with a selectivity coefficient of 0.01 in the presence of sodium would indicate that the sensor is 100 times more sensitive to potassium than to sodium. Similarly, a physiological level of approximately 130 mM sodium would approximately equal a baseline of 1.35 mM added to the potassium signal.

[0219] Alternatively, the sensor electronics 120 may include circuitry such as a non-volatile computer readable memory configured to store correlations between control signals for controlling ion concentrations and electromotive forces corresponding to those control ion concentrations. In one example, the sensor electronics 120 is 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) generate as output a control ion concentration corresponding to the selected control signal. In other examples, sensor baselines and sensitivities are characterized at the factory, and those sensor baselines and sensitivities are implemented in the sensor electronics 120 such that the sensor electronics 120 is used to predict baselines and sensitivities over a period of time in vivo. In one example, the time period predicted by the sensor electronics 120 is from one day to 15 days or more.

[0220] In some examples, the sensor electronics 120 includes a constant potential circuit configured to control a potential and measure a current that varies over time. In other examples, the sensor electronics 120 includes a constant current circuit configured to control a current (e.g., close to a zero value) and measure a potential that varies over time. In some examples, the sensor electronics 120 includes a constant potential circuit and a constant current circuit.

[0221] In some examples, the sensor electronics 120 is configured to sample the potential signal at a sufficiently high sampling rate (e.g., about 1 Hz or greater, or about 10 Hz or greater, or 100 Hz or greater, or about 1 kHz or greater) to be able to measure the concentration of the target ion 11 in the biological fluid 10 and measure the electrophysiological waveform of the host. For example, although the DC component of the potential signal reflects the concentration of the ion of interest, if the AC component of the electrophysiological signal is collected at a sufficiently fast rate (e.g., greater than about 100 Hz, or greater than about 1 kHz), the AC component can measure the electrophysiological waveform, i.e., the waveform associated with the enhancement of the heart. In contrast to wet or dry skin surface electrodes commonly used for electrophysiology, the measurement of electrophysiological signals by indwelling sensors can produce waveforms with excellent fidelity due to the avoidance of the barrier function of the skin stratum corneum. This capability is also used to measure electrophysiological waveforms over extended durations.

[0222] For example, the present ion sensor is expected to be significantly better at quantifying weak electrophysiological signals with high 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 impart between the skin surface electrode and the organ / tissue of interest (e.g., heart, brain, muscle); this impedance is approximately 10s kilo-ohms. On the other hand, an indwelling sensor is able to bypass the stratum corneum and, by virtue of gap sensing, exhibit improved impedance matching characteristics with the organ / tissue of interest, e.g., approximately 10s ohms-100s ohms. The presence of hair, ointments, or medications may also affect the signal fidelity of skin surface electrodes, and these electrodes are known to cause skin irritation, sensitization, and allergic reactions in a significant portion of the population. In addition, the life of skin surface electrodes is quite limited because the gel tends to lose hydration (and chloride ions) over extended durations; these electrodes may also migrate on the skin surface. Despite the use of "wet" type gel electrodes to minimize impedance mismatch, these electrodes still exhibit low impedance values ​​that are difficult to approach for indwelling sensors, not to mention that the gel electrodes produce undesirable gel residues on the skin after removal.

[0223] As recognized by the inventors, the construction and operation of the present solid-state ion-selective sensor share many similar characteristics with electrophysiological sensors. That is, both utilize at least two electrodes / leads to measure potential differences and operate at abnormally low current regimes (typically sub-nanoamperes or sub-picoamperes); both sensing modalities can use measurements of open circuit potential (electromotive force) to infer ion concentration (ion-selective sensor) or organ / tissue activity (electrophysiological sensor). In addition, both the ion-selective electrode and the electrophysiological electrode are connected to an analog front end (such as an instrumentation amplifier, a differential amplifier, a buffer amplifier, a unity gain amplifier, or a voltage follower) that exhibits a relatively high impedance (e.g., greater than about 1 gigahertz, greater than about 10 gigahertz, or greater than about 100 gigahertz). In one example, the front end exhibits low DC offset, low drift, low noise, very high open loop gain (G), and high impedance. OL ) and very high common mode rejection ratio (CMRR). Both technologies measure changes in electrical potential to infer analyte concentration (as in the case of ion selective electrodes) or organ / tissue activity (as in the case of electrophysiology electrodes).

[0224] In the case of ion-selective electrodes, according to the classical Nernst equation provided further above, an electromotive force (e.g., potential difference) is generated across a semipermeable membrane (e.g., a cell membrane, an ion-selective membrane) in a solution whenever there is a concentration gradient of electroactive species (e.g., ions) across the membrane.

[0225] Figure 3 Schematically illustrates example operations and components used in the present apparatus and method for measuring the concentration of target ions in a biological fluid in vivo and measuring electrophysiological signals. Figure 3 As exemplified, such as reference Figure 1A To Figure" or Figures 2A to 2G The indwelling ion selective sensor (which includes a first electrode (e.g., 111 or 211) and a second electrode (e.g., 117)) is used to measure the concentration of the ion of interest while recording the electrophysiological waveform. More specifically, although in actual implementations it is expected that the measurement of the ions in the biological matrix results in a very slow time-varying voltage, thus resulting in a "DC" voltage or offset, in one example, the measurement of the electrophysiological waveform uses relatively fast sampling to obtain the fast time dynamics of the "AC" waveform. In order to achieve simultaneous measurement of two signals, a high impedance amplifier 310 such as described above is used to amplify the potential signal from the sensor. The amplifier 310 may have any suitable configuration, such as an instrument amplifier including an ultra-high input impedance (e.g., greater than about 10 gigahertz or greater than about 100 gigahertz), such as Figure 3As illustrated, or including a unity gain amplifier. In one example, an analog / digital converter (ADC) 330 is used to quantize the analog amplified voltage signal into a digital bit stream. In order to provide a reconstruction of the original waveform with high fidelity, the Nyquist sampling theory is adopted; for the example electrophysiological signal, the ADC samples the amplified potential signal at a sampling rate of at least about 1 Hz, or at least about 10 Hz, or at least about 100 Hz (e.g., about 1 kHz). In some examples, the sampling rate can be dynamically adjusted based on the maximum frequency content of the waveform. Due to fast sampling, the ADC operates in a power-limited manner, either by measuring with duty cycling, operating with medium resolution (e.g., 10 bits or 12 bits), or operating with a low-power architecture (e.g., successive approximation register).

[0226] Optionally, a high-pass, low-pass, band-pass or tunable electrical filter 320 (analog or digital) is used to attenuate out-of-band frequencies to isolate electrophysiological signals or other signals of interest. Optionally, potential recording and electrophysiological recording can be time-interleaved. In half a duty cycle, record potential measurements. In the second half of the duty cycle, record electrophysiological measurements. The duty cycle (cycle) of the measurement can vary from 1 second to 6 hours. In another embodiment, a low-frequency ADC providing improved resolution (e.g., 14, 16 or 24 bits) can be used in parallel with a high-frequency ADC providing reduced resolution (e.g., 10 or 12 bits). For example, using delta-sigma, successive approximation registers, integration or flash ADCs, each of which provides a specified effective number of bits (ENOB), signal-to-noise ratio (SNR), vibration, nonlinearity, accuracy, jitter and quantization error characteristics.

[0227] Based on the foregoing, it should be understood that the first contribution to the electromotive force from the electrophysiological signal changes rapidly relative to the second contribution to the electromotive force from the concentration of ions in the physiological fluid. This difference in time characteristics is used to facilitate deconvolution of the first contribution from the second contribution. For example, the sensor electronic device 120 includes a fast Fourier transform (FFT) circuit configured to transform the signal corresponding to the electromotive force from the time domain to the frequency domain. This can also be done in the digital domain, such as using an arithmetic logic unit (ALU) in a microprocessor without the need for a dedicated FFT hardware implementation. In some examples, the sensor electronic device 120 also includes a spectrum analysis circuit that is 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. For example, because the first contribution (from the electrophysiological signal) changes rapidly relative to the second contribution (from the ion concentration), such contributions will appear at different locations in the frequency domain. For example, the low frequency portion is approximately centered around zero frequency, and the high frequency portion may include features at the human heartbeat frequency or a harmonic (or subharmonic) thereof, and / or features at frequencies corresponding to features of an individual human heartbeat (e.g., about 100 Hz to about 1000 kHz, or about 200 Hz to about 400 Hz). In one example, the spectrum analysis circuit or embedded algorithm is configured to separate contributions in the frequency domain. In one example, the sensor electronics 120 in some examples may include at least one inverse FFT (iFFT) circuit configured to transform the high frequency portion into a time domain output corresponding to an electrophysiological signal and transform the low frequency portion into a time domain output corresponding to the concentration of ions in a 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, isolate the desired signal relative to noise, drift, etc.

[0228] In another example, the components are separated from each other in the time domain. For example, the sensor electronics 120 may include an analog-to-digital converter (ADC) that digitizes a signal corresponding to an electromotive force. In one example, the sensor electronics 120 also includes a first filter configured to receive a digitized signal from the ADC to remove a second contribution from the digitized signal, and to generate an output corresponding to the first contribution when the second contribution is removed. For example, the first filter includes a high-pass filter, a band-stop filter, or a band-pass filter. In some examples, the first filter passes a frequency corresponding to a human heartbeat or a heartbeat waveform. In some examples, the sensor electronics 120 also includes a second filter configured to receive a digitized signal from the ADC to remove a first contribution from the digitized signal, and to generate an output corresponding to the second contribution when the first contribution is removed. For example, the second filter includes a low-pass filter, a band-stop filter, or a band-pass filter. In some examples, the second filter passes zero frequency. Note that if the cardiac (AC) signal is substantially above the DC component (ion signal), it may not be necessary to remove the DC component in order to view and understand the AC component. The DC component will be equivalent to a fixed bias or offset. On the other hand, the DC component is isolated from the AC signal by low-pass filtering the set waveform or averaging the acquired waveform, so that the AC oscillation is smoothed. It will be apparent that, even if only ion concentration or electrophysiological signals are measured, similar processing as provided herein is performed in the frequency domain to isolate the desired signal, for example, relative to noise, drift, etc. In addition, it will be apparent that processing is performed in the analog domain, for example, without using ADC. For example, the sensor electronics 120 includes a first filter, which is configured to remove the second contribution from the signal corresponding to the electromotive force, and generates a first output corresponding to the first contribution when the second contribution is removed; and includes a second filter, which is configured to remove the first contribution from the first output or from the signal corresponding to the electromotive force, and generates a second output corresponding to the second contribution when the first contribution is removed.

[0229] In one example, the output generated by the sensor electronics 120 is used in any suitable manner. In some examples, the sensor electronics 120 includes a non-volatile computer-readable memory configured to store the output or a microprocessor or digital signal processor configured to run a signal processing algorithm. Additionally or alternatively, in some examples, the sensor electronics 120 includes a transmitter configured to wirelessly transmit the output, such as 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 host health and provide appropriate treatment to the host based on the value of the indicator.

[0230] Further details regarding the sensor electronics 120 will now be provided. The example sensor electronics 120 coupled to the indwelling sensor 110 measures the voltage between the first electrode (e.g., 111 or 211) and the second electrode (e.g., 117) using a high input impedance voltmeter or electrometer (otherwise referred to as a measurement system). In some examples, the impedance of the 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 higher. The error contribution of the voltage measurement device (E R ) can be understood by the following equation:

[0231]

[0232] Where R C is the resistance between the first electrode and the second electrode through the conductive medium (e.g., interstitial fluid), and R M is the input impedance of the measurement system. For example, if the impedance of the battery and the voltmeter input impedance are equal, the error is -50%. However, if R M For example, R C By a factor of about 100, the error is reduced to less than about -1%. Measuring the impedance of a potentiometric sensor device is useful for understanding the instrumentation requirements of the measurement system. In addition, it is useful to understand the impedance changes in vivo given the possible contributions of hemorrhage, edema, biofouling, and fibrosis.

[0233] To allow for continuous measurement of voltage over time, analog-to-digital (A / D) conversion is used. The A / D converter digitizes the analog signal into a digital signal (also called "counts") for processing. Therefore, the resulting raw data stream in counts (also called raw sensor data) is directly related to the voltage measured by the high input impedance voltmeter.

[0234] 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, however, a computer system other than a microprocessor may also be used to process data as described herein, for example, an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), or a graphics processing unit (GPU) may be used for some or all of the sensor central processing. In one example, the processor is coupled to a computer readable memory, and the processor is configured to provide semi-permanent storage of data via the computer readable memory, for example, storing data such as a sensor identifier (ID) and programming to process a data stream (e.g., similar to the programming for data smoothing and / or replacement of signal artifacts described in US 8,20,174 granted to Goode et al. (the patent is incorporated herein by reference in its entirety)). The processor may also be used for a cache memory of the system, for example, for temporary storage of 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.

[0235] 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 data sampled at predetermined time intervals (also referred to as sampling rate). In some examples, where the voltmeter is configured to measure the analyte at discrete time intervals, these time intervals determine the sampling rate of the digital filter. In some alternative examples, where the voltmeter is configured to measure the analyte continuously, for example, using a voltage and 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 acquisition time). In these alternative examples, due to the continuity of the voltage measurement, the values ​​obtained by the processor are advantageously averaged within the acquisition time. Therefore, the acquisition time determines the sampling rate of the digital filter. In one example, the processor module is configured with a programmable acquisition time, that is, the predetermined time interval for requesting digital values ​​from the A / D converter can be programmed by the user in the digital circuit of the processor module. In some examples, an acquisition time of about 2 seconds to about 512 seconds is used; however, any acquisition time can be programmed into the processor module. Programmable acquisition time is advantageous in optimizing noise filtering, latency, and processing / battery power.

[0236] Other signal quality considerations for potentiometric sensors are the contributions of inductive or capacitive electromotive force (EMF) or electromagnetic interference (EMI) and radio frequency interference (RFI) that may potentially contaminate voltage signals. For example, mains power line noise (e.g., 50 Hz or 60 Hz and their harmonics) may contribute to periodic voltage disturbances, resulting in inaccurate concentration reports. The voltage amplitudes of these disturbances are expected to be smaller relative to the signal of interest, but they are mainly based on the inductance of the sensor components and systems and the surrounding EM / RF environment. It is worth noting that the lack of coiled or longer lengths of wire can reduce or minimize this effect. Another consideration for low voltage measurements is the contribution of thermoelectric or current EMF, which are mainly driven by different materials in metal or ion contact, respectively. In view of the fact that potentiometric sensors are also or alternatively used to obtain electrophysiological blood signals (such as electrocardiograms (EKG)), the last consideration is biological noise. It is advantageous to obtain this signal, not only to compensate for its contribution to the potential signal, but also as an additional feature of interest in system health monitoring. Further details about electrophysiological signals are provided elsewhere in this article.

[0237] In some examples, the processor module is configured to construct a data packet for transmission to an external source, for example, wired or wireless transmission to a receiver. In some examples, the data packet may include a plurality of bits, which may include a sensor ID code, raw data, filtered data, temperature, and / or error detection or correction. The processor module may be configured to transmit any combination of raw and / or filtered data to an external source using a wired or wireless connection.

[0238] 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 measurement result into a digital value representing the voltage. In one example, the reference electrode of the sensor is biased at or near the expected midpoint of the input voltage range of the A / D converter to maximize the quantifiable dynamic range caused by the change in the EMF generated by the sensor.

[0239] The battery is operably connected to the sensor electronics and provides power to the measuring device, although the applied power is not required to drive the potentiometric sensor itself, e.g., the sensor operates in a current manner (as opposed to an amperometric sensor that operates in an electrolytic manner). In one example, the battery is a lithium manganese dioxide battery; however, any battery of appropriate size and power may be used (e.g., AAA batteries, nickel-cadmium batteries, zinc-carbon batteries, alkaline batteries, lithium batteries, nickel-metal hydride batteries, lithium-ion batteries, zinc-air batteries, zinc-mercury oxide batteries, silver oxide batteries, silver-zinc batteries, and / or fully sealed batteries). In some examples, the battery is rechargeable and / or multiple batteries may be used to power the system. For example, an indwelling sensor may be powered via inductive coupling. In some examples, a quartz crystal is operably connected to the processor and maintains system time for the computer system as a whole, e.g., for programmable acquisition time within a processor module.

[0240] In one example, a temperature probe is provided, where the temperature probe is located on the electronic assembly or on the potentiometric sensor itself, as discussed herein. The temperature probe can be used to measure the ambient temperature near the sensor. This temperature measurement can be used to add temperature compensation to the calculated concentration (activity) value.

[0241] In some examples, the output signal (from the sensor electronics) is sent to a receiver (e.g., a computer or other communication station). In one example, the output signal in some examples may include a raw data stream for providing a usable value of the measured analyte concentration to, for example, a patient or a physician. In some examples, the raw data stream may be algorithmically smoothed or otherwise modified continuously or periodically in a manner such as described in US 8,10,174 to Goode et al. (which is incorporated herein by reference in its entirety) to reduce deviation points that inaccurately represent analyte concentrations, such as due to signal noise or other signal artifacts.

[0242] When the sensor is first implanted into the host tissue, the sensor and receiver are initialized. This may be referred to as a startup mode and includes optionally resetting the sensor data and calibrating the sensor. In selected examples, mating the electronics unit to the mounting unit triggers the startup mode. In other examples, the startup mode is triggered by the receiver. In one example, the sensors disclosed in the present invention are individually calibrated and the sensitivity and E of each sensor are determined. 0 Used to predict in vivo performance and / or reduce data scatter within batches.

[0243] In some examples, the sensor electronics are wirelessly connected to the receiver via unidirectional or bidirectional RF transmission, etc. However, wired connections are also envisioned. The receiver provides many processing and displays of sensor data and can be selectively worn and / or removed when convenient for the host. Therefore, the sensor system can be worn discreetly, and the receiver providing many processing and displays of sensor data can be selectively worn and / or removed when convenient for the host. In particular, the receiver includes programming for retrospectively and / or prospectively starting calibration, converting sensor data, updating calibration, evaluating received reference and sensor data, and evaluating calibration of analyte sensors in a manner such as described in US 7,778,680 (which is incorporated herein by reference in its entirety).

[0244] FIG. 6A to FIG. 6C One aspect of a continuous analyte sensor 600 (eg, an in vivo portion) is illustrated, which includes an elongated conductive body 602 (which is referred to as a substrate). The elongated conductive body 602 includes a core 610 (see Figure 6B ) and a first layer 612 at least partially surrounding the core 610. The first layer 612 includes a working electrode (e.g., located in the window 606) and a film 608 located above the working electrode, which is configured and arranged for multi-axis bending. In some examples, the core 610 and the first layer 612 may have a single material (e.g., platinum). In some examples, the elongated conductor 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 conductor 602 includes multiple layers. In some examples, there are at least two concentric (e.g., annular) layers, such as a core 610 formed of a first material and a first layer 612 formed of a second material. However, in some examples, additional layers may be included. In some examples, the layers are coaxial.

[0245] In one example, the elongated conductor 602 is long and thin, yet flexible and strong. In one example, the smallest dimension of the elongated conductor 602 is less than about 0.1 inches, 0.75 inches, 0.5 inches, 0.25 inches, 0.1 inches, 0.075 inches, 0.01 inches, 0.004 inches, or 0.002 inches. FIG. 6A to FIG. 6C602 is illustrated as having a circular cross-section, but in other examples, the cross-section of the elongated conductor 602 may be oval, rectangular, triangular, polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-shaped, irregular, etc. In one example, a conductive wire electrode is used as the core 610. For such a coated electrode, two additional conductive layers are added (e.g., with an intermediate insulating layer provided for electrical isolation). In one example, the conductive layer may include any suitable material. In some examples, it may be desirable to use a conductive layer that includes conductive particles (i.e., particles of conductive material) in a polymer or other binder.

[0246] In some examples, the material (e.g., stainless steel, titanium, tantalum, platinum, platinum-iridium, iridium, certain polymers, and / or the like) used to form the elongated conductor 602 may be strong and hard, and therefore resistant to breakage. In one example, the ultimate tensile strength of the elongated conductor 602 is about 80 kPsi to about 500 kPsi. In another example, in some examples, the Young's modulus of the elongated conductor 602 is about 660 GPa to about 220 GPa. In yet another example, the yield strength of the elongated conductor 602 is about 60 kPsi to about 2200 MPa. Ultimate tensile strength, Young's modulus, and yield strength are discussed in more detail elsewhere herein. In some examples, the small diameter of the sensor provides (e.g., imparts, enables) flexibility to these materials, and therefore provides flexibility to the entire sensor. Therefore, the sensor can withstand repeated forces applied to it by surrounding tissue. A measure of the ability of the sensor to withstand an implant environment is fatigue life. In some examples, the fatigue life of the sensor is at least 1,000 bending cycles from about 28° to about 110° at a bend radius of about 0.125 inches.

[0247] In addition to providing structural support, elasticity and flexibility, in some examples, the core 610 (or its components) provides electrical conduction from the working electrode to the sensor electronics (not shown) for the electrical signal, which is described elsewhere herein. In some examples, the core 610 includes a conductive material, such as stainless steel, titanium, tantalum, conductive polymers and / or the like. However, in other examples, the core 610 is formed by a non-conductive material (such as a non-conductive polymer). In other examples, the core 610 includes a plurality of material layers. For example, in one example, the core 610 includes an inner core and an outer core (not shown here) arranged concentrically. In another example, the inner core is formed by a first conductive material, and the outer core is formed by a second conductive material. In one example, the first conductive material is stainless steel, titanium, tantalum, conductive polymers, alloys and / or the like, and the second conductive material is selected to provide electrical conduction between the core 610 and the first layer 612 and / or to attach the first layer 612 to the conductive material of the core 610 (for example, if the first layer 612 is formed by a material that cannot be well attached to the core material). In another example, the core 610 is formed of 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 can be a single (or the same) material, such as platinum. Those skilled in the art recognize that other configurations are possible.

[0248] Reference again FIG. 6A to FIG. 6C In some examples, the first layer 612 is formed of a conductive material. The working electrode is an exposed portion of the surface of the first layer 612. Thus, the first layer 612 is formed of a material configured to provide a suitable working electrode, such as, but not limited to, platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, conductive polymers, alloys, and / or the like.

[0249] like FIG. 6B to FIG. 6CAs shown, 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 is used as an insulator and is formed of 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 is configured so that the working electrode is exposed via a window 606. In another example, an elongated conductor 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 by removing a portion of the second layer and (optionally) the third layer (e.g., by removing a portion of the second layer and (optionally) the third layer to form a window 606). Removal of coating material from one or more layers of the elongated conductor 602 (e.g., to expose the working electrode) can be performed manually, by excimer laser, by chemical etching, by laser ablation, by sandblasting, etc.

[0250] In some examples, the sensor also includes a third layer 614 comprising a conductive material. In other examples, the third layer can include a reference electrode, which in some examples is formed from a material applied to the second layer (e.g., an insulator) or other material such as described elsewhere herein. The third layer can be processed using a sticking / dipping / coating step, for example, a dip coating process using die metering, and then the body can be pulled through the die to meter the coating to a precise thickness. In some examples, multiple coating steps are used to build up the coating to a predetermined thickness. This drawing method can be used to form Figure 6B One or more of the electrodes in the depicted device.

[0251] In some examples, the elongated electrical conductor 602 further includes one or more intermediate layers between the core 610 and the first layer 612. In one example, the intermediate layers are insulators, conductors, polymers, and / or adhesives.

[0252] 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 so as to allow for a certain error tolerance (e.g., error tolerance associated with the etching process) that does not result in a defective sensor (e.g., a defect caused by the etching process cutting deeper than intended, thereby inadvertently exposing the working electrode). The ratio varies depending on the type of etching process used, whether laser ablation, sandblasting, 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 about 1:5 to about 1:1, or about 1:3 to about 1:2.

[0253] In some examples, the core 610 comprises a non-conductive polymer and the first layer 612 comprises a conductive material. This sensor configuration can sometimes provide reduced material costs because it replaces typically expensive materials with inexpensive materials. In one example, the core 610 is formed of a non-conductive polymer (such as a nylon or polyester filament, thread, or rope), which can be coated and / or plated with a conductive material such as platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, conductive polymers, and combinations thereof.

[0254] like Figure 6C and Fig.6D As shown, the sensor also includes a membrane 608 covering at least a portion of the working electrode. Membranes are discussed elsewhere herein.

[0255] Figure 6B is a schematic diagram illustrating an elongated conductor 602 (also referred to as an "elongated body") in one example, wherein the elongated conductor 602 is formed of at least two materials and / or layers of conductive materials, as described in more detail elsewhere herein. In some examples, the term "electrode" may be used herein to refer to the elongated conductor 602, which includes an electrode portion for detecting an analyte. In some examples, the elongated conductor 602 provides an electrical connection between a working electrode and sensor electronics (not shown). In certain examples, each electrode (e.g., the elongated conductor 602 on which the working electrode is located) is formed of a thin wire, such as having a diameter of about 0.001 inches or less to about 0.01 inches or more, and is formed of, for example, a plated insulator, a plated wire, or a bulk conductive material. For example, the wire and / or elongated conductor 602 used to form the working electrode has a diameter and / or minimum dimension (e.g., width) of approximately 0.05 mm, 0.08 mm, 0.10 mm, 1.27 mm, 0.15 mm, 0.18 mm, 0.20 mm, 0.23 mm, 0.25 mm, 0.38 mm, 0.51 mm, 0.64 mm, 0.76 mm, 0.89 mm, 1.02 mm, or 1.14 mm (0.002 inches, 0.003 inches, 0.004 inches, 0.005 inches, 0.006 inches, 0.007 inches, 0.008 inches, 0.009 inches, 0.01 inches, 0.015 inches, 0.02 inches, 0.025 inches, 0.03 inches, 0.035 inches, 0.04 inches, or 0.045 inches).

[0256] In some examples, the first electrode includes a wire formed of a conductive material such as platinum, platinum-iridium, palladium, graphite, gold, carbon, a conductive polymer, an alloy, or the like.

[0257] In some examples, the working electrode is formed of a platinum-iridium or iridium wire. In general, 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). While not wishing to be bound by theory, it is believed that platinum-iridium and / or iridium materials can facilitate the manufacture of wires with smaller diameters to further reduce the maximum diameter (size) of the sensor (e.g., the in vivo portion). Advantageously, with respect to sensors implanted intravascularly, a smaller sensor diameter both reduces the risk of clot or thrombosis (or other foreign body reactions) and allows the use of smaller catheters.

[0258] refer to Figure 6B In some examples, the elongated conductor 602 includes at least two concentric layers (e.g., a composite structure). In another example, the elongated conductor 602 includes a core 610 and a first layer 612. The core 610 is formed of one of the at least two materials described above. For example, the core 610 may be formed of a polymer, a metal, an alloy, etc. In some examples, the core 610 is formed of a conductive polymer (such as, but not limited to, polyaniline and polypyrrole). In some examples, a conductive material is added to a non-conductive polymer (e.g., mixed with and / or applied to a non-conductive polymer), thereby making the polymer core conductive. In one example, one or more conductive metals (e.g., carbon, gold, platinum, iridium, etc.) (such as, but not limited to, particles) may be mixed with an uncured polymer, which may be formed into the core 610.

[0259] In other examples, in some examples, core 610 may include an inner core and an outer core. For example, platinum, iridium or gold particles may be ion-implanted onto the surface of the polymer inner core so that the particles form an outer core. For example, polymer filaments may be implanted with gold ions so that the treated filaments are conductive. In some examples, core 610 is formed of a metal such as, but not limited to, at least one of stainless steel, tantalum, titanium and / or their alloys. For example, in one example, core 610 is formed of extruded stainless steel, tantalum, titanium and / or an extruded alloy. In some examples, the material of core 610 is processed to provide the strength and flexibility necessary for multi-axis bending. Processing metal changes its properties, such as, but not limited to, by compressing and / or rearranging the lattice of the metal. For example, tempering can make the metal less brittle and more elastic; hardening can make the metal better retain its shape. Thus, in some examples, the core 610 is formed of a metal that has been processed to provide the necessary combination of strength and flexibility (e.g., from about less than 80 kPsi, 80 kPsi, 90 kPsi, 100 kPsi, 110 kPsi, 120 kPsi, 130 kPsi, 140 kPsi, or 150 kPsi (551 MPa) to about 160 kPsi, 170 kPsi, 180 kPsi, 190 kPsi, 200 kPsi, 210 kPsi, 220 kPsi, or 500 kPsi (3297 MPa) of ultimate tensile strength or more. In one example, the core 610 is formed of a metal that has been annealed, tempered, normalized, hardened, work hardened, fully treated, case hardened, wind hardened, cold worked, and / or the like to make it harder. In one example, the core 610 is formed of fully treated platinum. In another example, the core 610 is formed of work hardened platinum-iridium.

[0260] In some examples, the surface of the elongated conductor 602 and / or the core 610 is treated to remove initiation sites (e.g., irregular locations / points where sensor cracking tends to begin), smooth the surface and / or clean the surface, prepare for the application of the next material, and / or the like. Suitable treatments include, but are not limited to, electropolishing, etching, applying a bonding layer, electrodeposition, and electrostatic deposition.

[0261] In some examples, the elongated conductor 602 (and / or the core 610, and / or the sensor) is linear. However, the linear shape may include one of a variety of cross-sectional shapes, such as, but not limited to, circular, elliptical, rectangular, triangular, cross, star, clover, X, C, irregular or other non-circular configurations, etc. The elongated conductor 602 has a diameter and / or minimum dimension (e.g., width) of approximately 0.05 mm, 0.08 mm, 0.10 mm, 1.27 mm, 0.15 mm, 0.18 mm, 0.20 mm, 0,23 mm, 0.25 mm, 0.38 mm, 0.51 mm, 0.64 mm, 0.76 mm, 0.89 mm, 1.02 mm, or 1.14 mm (0.002 inches, 0.003 inches, 0.004 inches, 0.005 inches, 0.006 inches, 0.007 inches, 0.008 inches, 0.009 inches, 0.01 inches, 0.015 inches, 0.02 inches, 0.025 inches, 0.03 inches, 0.035 inches, 0.04 inches, or 0.045 inches). The elongated conductor 602 may be provided as a spool and / or extended lengths that are subsequently processed and / or singulated into individual sensor lengths.

[0262] In some examples, the elongated electrical conductor 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 current can pass therebetween). The first layer 612 can be formed of 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 some examples, the first layer 612 is relatively thin, such as, but not limited to, a thickness of less than about 50 micro-inches, 50 micro-inches, 55 micro-inches, 60 micro-inches, 65 micro-inches, 70 micro-inches, 75 micro-inches, 80 micro-inches, 85 micro-inches, 90 micro-inches, 95 micro-inches, or 100 micro-inches to about 125 micro-inches, 150 micro-inches, 175 micro-inches, 200 micro-inches, 225 micro-inches, 250 micro-inches, 275 micro-inches, or 300 micro-inches or more. 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 examples, the working electrode is exposed through a window formed in the insulator. In some examples, before applying the membrane material, the surface of the applied first layer 612 is treated, such as to optimize the surface for membrane attachment and use as a working electrode. For example, the surface can be cleaned, smoothed, etched, etc. Advantageously, forming a conductive core 610 with an inexpensive but strong and flexible inner body with a thin layer of a potentially more expensive working electrode material can provide a significant reduction in material costs.

[0263] In some examples, a conductive paste comprising a mixture of a material (e.g., ink) and one or more membrane components is applied to a layer surrounding the core 610, or directly to the core 610. In one example, the conductive paste may include, for example, ion carriers, additives, polymers, and / or enzymes. The use of a conductive paste may reduce or eliminate the need for certain membrane layers (e.g., a separate electrode layer, a separate ion carrier layer, and / or a separate enzyme layer).

[0264] The first layer 612 may 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-to-metal or metal-to-polymer extrusion techniques. Some useful coextrusion techniques are described in U.S. Patents 7,416,802, 7,268,562, 7,153,458, 7,280,879, 5,324,328, and 6,434,430, each of which is incorporated herein by reference in its entirety. 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 spool of 0.005 inch diameter wire having a stainless steel core with a 100 microinch layer of platinum thereon.

[0265] 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 pulling the core 610 out at a speed that provides the appropriate thickness of the first layer 612. However, as will be appreciated by those skilled in the art, any known thin film or thick film method may be used to apply the first layer 612 to the core 610. Some examples of thin film and / or thick film manufacturing techniques can be found 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-A1, U.S. Patent Application Publication No. US-2006-0197891-A1. Publication US-2006-0257996-A1, U.S. Patent Application Publication US-2006-0229512-A1, U.S. Patent Application Publication US-2007-0173709-A1, U.S. Patent Application Publication US-2006-0253012-A1, U.S. Patent Application Publication US-2006-0195029-A1, U.S. Patent Application Publication US-2008-0119703-A1, U.S. Patent Application Publication US-2008-0108942-A1 and U.S. Patent Application Publication US-2008-0200789-A1, the entire contents of each of these U.S. Patent Application Publications are incorporated herein by reference.

[0266] In some examples, the first layer 612 is deposited onto 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 generated and / or achieved. Thus, descriptions of deposition methods and apparatus can be found in U.S. Patents 7,427,338, 7,425,877, 7,427,560, 7,351,321, and 7,384,532, each of which is incorporated herein by reference in its entirety.

[0267] In yet another example, the core 610 is embedded in an insulator and the working electrode body 612 is attached so that the core 610 and the working electrode body are electrically (e.g., functionally, operably) connected, such as described in U.S. Patent 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, such as using an intermediate layer of adhesive, welding and / or conductive material to provide adhesion between the core 610 and the working electrode body material (e.g., at a bonding layer). In some examples, multiple layers are applied on top of the core 610. In some examples, each layer has a limited interface with an adjacent layer, or together forms a physically continuous structure with a chemical composition gradient. In another example, the working electrode body is a C-clip or buckle attached by compressing around and / or around the core 610. In some examples, the working electrode body is attached to the window. In other examples, there is no window, instead, the working electrode body is configured to pierce the insulator and physically contact the core 610 below, so that the working electrode body and the core are operably connected. In some examples, the conductive metal C-clip is attached to the core 610 with an adhesive, weld, and / or bonding layer. In yet another example, an adhesive is attached to the core 610 and then a conductive foil is wrapped around it.

[0268] Various manufacturing techniques can be used to manufacture the elongated conductor 602. In some examples, the first layer 612 is applied to the core 610 in a substantially continuous process. In one example, the manufacture of the elongated conductor 602 involves a reel-to-reel process. In other examples, a sheet-fed technique is used. In some examples, the first layer 612 can be applied to the core 610 by a semi-automatic or fully automatic process. The automation of some or all manufacturing steps generally requires the use of one or more machines, such as robotic devices, which are configured and arranged to perform manufacturing steps. In some examples, one manufacturing step can be automated, such as the production of the elongated conductor 602. 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 these steps, or two or more devices can perform these steps. In some examples, when multiple devices are used, the devices are functionally and / or physically connected, coupled together, interconnected and linked. In one example, the product of one device is directly fed into the next device, and so on. In one example, a reel of previously manufactured core 610 (such as stainless steel, tantalum, or titanium wire) may be fed substantially continuously through an apparatus configured to electroplate core 610 with platinum, gold, carbon, etc., such that a reel of electroplated wire is produced. For example, a manufacturing apparatus and / or system may be configured to automatically co-extrude stainless steel and platinum to produce / produce a reel of linear elongated electrical conductor 602 comprising a stainless steel core and a first layer of platinum (e.g., first layer 612). Examples of continuous manufacturing methods may be found in U.S. Patents 6,103,33, 5,879,828, 5,714,391, 7,429,552, 7,402,349, and 7,387,811, each of which is incorporated herein by reference in its entirety.

[0269] In another example, the first layer 612 includes a working electrode (e.g., a portion exposed by the window 606). For example, if the sensor is configured to detect an analyte other than an ion, the analyte reacts with an enzyme in a membrane covering at least a portion of the working electrode, and the enzyme can generate ions from the analyte, the concentration of which can be measured using an ion carrier and a working electrode in a manner such as described elsewhere herein. Alternatively, for example, if the sensor is configured to detect an ion, the concentration of the ion can be measured using an ion carrier and a working electrode in a manner such as described elsewhere herein.

[0270] As reference Fig. 6A As described and Figure 6CAs shown, the insulator 604 is disposed on (e.g., located at, covering) at least a portion of the elongated conductor 602. In some examples, the sensor is configured and arranged so that the elongated body includes a core 610 and a first layer 612, and a portion of the first layer 612 is exposed via a window 606 in the insulator. In other examples, the sensor is configured and arranged so that the elongated body includes a core embedded in an insulator, and a portion of the core 610 is exposed via a window in the insulator. In one example, an insulating material is applied to the elongated body (e.g., screen printing, inkjet printing, and / or block printing) in a configuration designed to expose a portion of the surface of the first layer 612 (or the surface of the core 610). For example, the insulating material may 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 applying the insulating material. After applying the insulating material, the mask is removed to expose a portion of the elongated body.

[0271] In some examples, the insulating material 604 includes a polymer, such as a non-conductive (e.g., dielectric) polymer. Dipping, spraying, vapor deposition, printing and / or other thin film and / or thick film coating or deposition techniques can be used to deposit the insulating material on the elongated conductor 602 and / or the core 610. In one example, the insulating material is applied as a layer with a thickness of about less than 5 microns, 5 microns, 60 microns or 65 microns to about 20 microns, 25 microns, 30 microns 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, which contain the same or different materials. In some examples, the insulating material includes at least one of polyurethane, polyimide and polyparaxylene. In one example, the insulating material includes polyparaxylene, which can be a favorable polymer coating due to its strength, lubricity and electrical insulation properties. Generally speaking, polyparaxylene is produced by vapor deposition and polymerization of paraxylene (or its substituted derivatives). However, any suitable insulating material may be used, such as, but not limited to, dielectric inks, pastes, or coatings, such as fluorinated polymers, polyethylene terephthalate (PET), polyurethanes, polyimides, other non-conductive polymers, and the like. In some examples, glass or ceramic materials may also be used. Other materials suitable for use include surface-modified coating systems, such as those sold by Advanced Materials Components Express (Bellafonte, Pa) under the trade names AMC18, AMC148, AMC141, and AMC321. However, in some alternative examples, the core 610 is conductive and may not require an insulator coating. In some examples, as described above, the surface of the conductive core (e.g., a portion of the first layer 612) remains exposed during the application of the insulator, or a portion of the applied insulator is removed to expose a portion of the surface of the core 610.

[0272] In some examples where the sensor has an insulated elongated body, a portion of the insulating material is stripped or otherwise removed, such as by hand, excimer laser, chemical etching, laser ablation, sandblasting (e.g., with sodium bicarbonate or other suitable grit), etc., to expose the working electrode. In one example, sandblasting is performed to expose the working electrode, such as by utilizing a grit material that is hard enough to abrade the polymer material but soft enough to minimize or avoid damage to the underlying metal electrode (e.g., platinum electrode). Although a variety of "grit" materials can be used (e.g., sand, talc, walnut shells, ground plastic, sea salt, etc.), in some examples, sodium bicarbonate is an advantageous grit material because it is hard enough to abrade, for example, the polyparaxylene coating without damaging, for example, the underlying platinum conductor. An additional advantage of sodium bicarbonate sandblasting includes its polishing effect on the metal as it strips the polymer layer, thereby eliminating a cleaning step that may otherwise be necessary. In some examples, the opening in the insulator is referred to as a "window" 606, and the surface of the first layer 612 is exposed through the opening.

[0273] In some examples, due to the small size of the sensor, it may be difficult to accurately remove the insulation on one insulated conductive core without affecting and possibly removing the insulation on an adjacent conductive core or on other portions of the sensor. However, in some examples, the insulator is configured such that the accuracy of the laser ablation is significantly improved. In one example, the insulator is configured such that two different types of lasers can be used to ablate separate portions of the insulator. For example, if the insulators of the two elongated bodies are different materials (i.e., one is polyurethane and the other is a fluoropolymer such as or another type of polytetrafluoroethylene), the insulator can be selectively ablated from one of the elongated bodies without removing the insulator from the other elongated body in the same area of ​​the sensor. In some examples, 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 comprising 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 200nm), and the other elongated body can be configured for laser ablation with an infrared laser (e.g., using a wavelength of about 1000nm). In another example, the insulator materials are selected so that the insulator of the first elongated body requires significantly higher laser power to be ablated than the insulator of the second elongated body. For example, the insulator on 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 insulator on each elongated body has a different thickness, so that a single laser is used to remove the insulator on both cores, except that the window in the thinner insulator is formed faster than the window in the thicker insulator. For example, the thickness of the insulator of one elongated body may be about 0.0001 inches to about 0.0003 inches, and the thickness of the insulator of one elongated body may be about 0.0008 inches to about 0.0010 inches. In yet another example, a colorant may be added to the insulator of one of the elongated bodies to change the amount of energy absorbed from the laser. For example, adding a dark colorant or other absorptive material to the first insulator but not to the second insulator may cause the first insulator to absorb more laser energy than the uncolored second insulator. In this way, a small amount of laser energy will ablate one wire but not the other, but a large amount of laser energy will ablate both wires. As understood by those skilled in the art, the settings of the laser can be adjusted to fine-tune the insulator removal process. For example, the laser pulse width and power level can be adjusted to modify and / or modulate the amount of insulator removed, the removal rate, etc. 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 insulating layers require different solvents so that they can be selectively ablated. The same principle can also be used for plasma ablation, where different plasma settings or amounts of energy are required to ablate different materials.

[0274] exist Fig. 6A and 6CIn the illustrated example, a radial window 606 is formed through the insulating material 604 to expose the circumferential surface of the working electrode (e.g., the first layer 612). In other examples, such as described in U.S. Patent 8,828,201, a radial or non-radial window 606 (e.g., for electrical connection to the working electrode body, such as the first layer 612) is formed by removing only a portion of the insulating material 604. In addition, in some examples (not shown), the surface of the reference electrode 614 is exposed. For example, a section of the surface may be masked during deposition of the outer insulating layer, and / or etched after deposition of the outer insulating layer. In some examples, a plurality of microwindows include the surface of the working electrode, wherein the sum of the surface areas of the microwindows is substantially equal to the surface area of ​​the window 606. In some examples, a plurality of microwindows are spaced and / or staggered along the length of the core 610.

[0275] In some examples, the size of the window 606 (or the working electrode body, such as the first layer 612) is set to provide a working electrode with a certain area so that the sensor has suitable sensitivity. In some examples, the diameter of the working electrode is 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 0.1mm (about 0.004 inches) or less to about 2mm (about 0.078 inches) or more, or about 0.5mm (about 0.2 inches) to about 0.75mm (0.3 inches). In such examples, the exposed surface area of ​​the working electrode is about 0.000013in 2 (0.0000839cm 2 ) to about 0.0025in 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).

[0276] 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 changing the cross-section of the electrode itself. In one example, the cross-section of the working electrode can be defined by a cross, star, clover, ribbed, dimple, ridge, irregular, or other non-circular configuration; thus, for any predetermined length of electrode, an increase in specific surface area (compared to the area achieved by a circular cross-section) can be achieved. For example, increasing the surface area of ​​the working electrode can advantageously provide an increased signal in response to the analyte concentration, which in turn can help improve the signal-to-noise ratio. In some examples, applying the insulator to the conductive core can be accomplished by a substantially continuous process, which can be semi-automatic or fully automatic, such as in a manner similar to some of the methods described for forming / manufacturing the conductive core.

[0277] In some examples, the analyte sensor 600 also includes a reference electrode 614. The reference electrode 614 is formed of a material such as described elsewhere herein, which can be used alone as a reference electrode, or can be used as a dual reference and counter electrode. In some examples, the reference electrode 614 is positioned adjacent to at least a portion of the sensor and / or twisted or around at least a portion of the sensor. For example, the reference electrode is spirally twisted and / or wrapped and / or wound around the working electrode in a manner such as described in U.S. Patent 8,828,201. Then, similar to the above, the components of this "wire" are optionally coated or adhered together with an insulating material to provide an insulated attachment.

[0278] refer to FIG. 6B to FIG. 6C In some examples, the reference electrode 614 comprises a material applied to 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 sputtering deposition, as described elsewhere herein. For example, in one example, a coating (or similar formulation) containing a conductor is applied to a reel of an insulating conductive core. In another example, a reel of an insulating elongated body (or core) is cut into individual unit pieces (e.g., "single-piece") and an ink containing a conductor is pad printed thereon. In yet another example, the material is applied in the form of a foil. For example, an adhesive may be applied to an insulating elongated body and then a foil may be wrapped around the insulating elongated body. Alternatively, the sensor may be rolled in conductive particles so that a sufficient amount of the conductor is adhered to and / or embedded in and / or otherwise adhered to the adhesive so that the particles serve as a reference electrode. In some examples, the reference electrode of the sensor comprises a sufficient amount of conductor so that the sensor measures and / or detects an analyte for at least three days.

[0279] In some examples, the sensor is formed of an elongated body (e.g., elongated conductive body 602), such as Figure 6B As shown, the elongated body includes a core 610, a first layer 612 for a working electrode, an insulator 604, and a material layer 614 for a reference electrode. In some examples, such as Figure 6C As shown, the surface of the elongated body (eg, also the surface of the first layer 612) is exposed by forming a window 606 through both the reference electrode material and the insulator. In one example, Figure 6BThe elongated body is provided as an extended length on a spool that is singulated to have a length suitable for a selected sensor configuration (e.g., less than 0.5 inches, 0.5 inches, 1 inch, 1.5 inches, 2 inches, 2.5 inches, 3 inches, 3.5 inches, 4 inches, 4.5 inches, 5 inches, 5.5 inches, 6 inches, 6.5 inches, 7 inches, 7.5 inches, 8 inches, 8.5 inches, 9 inches, 9.5 inches, 10 inches, 10.5 inches, 11 inches, In some embodiments, the first sensor may be configured to have a length of 11.5 inches, 12 inches, 12.5 inches, 13 inches, 13.5 inches, 14 inches, 14.5 inches, 15 inches, 15.5 inches, 16 inches, 16.5 inches, 17 inches, 17.5 inches, 18 inches, 18.5 inches, 19 inches, 19.5 inches, 20 inches, 20.5 inches, 21 inches, 21.5 inches, 22 inches, 22.5 inches, 23 inches, 23.5 inches, or 24 inches or longer). For example, a first sensor configured for percutaneous implantation may have a length of 2.5 inches, while a second sensor configured for percutaneous implantation may have a length of 3 inches. In another example, a first sensor configured for implantation in a peripheral vein of an adult host may have a length of 3 inches, while a second sensor configured for implantation in a central vein of an adult host may have a length of 12 inches. A window is formed on each sensor, such as by scraping and / or etching a radial window through the material of the reference electrode and the insulator, so that the platinum surface is exposed (e.g., the surface of the "working electrode"). In some examples, the roll of the elongated body is singulated and then the windows are formed. In other examples, the windows are formed along the length of the roll of the elongated body and then singulated. In other examples, additional manufacturing steps are performed prior to singulation. The membrane 608 is positioned on the exposed surface (e.g., the working electrode) defined by the edge of the window so that the surface can be used as the working electrode of the sensor to generate a signal associated with the analyte (e.g., ion) (e.g., when the sensor is in contact with a sample from a host). Alternative manufacturing techniques and / or step sequences may be used to produce sensors having Figure 6C The sensor is configured as shown, such as but not limited to masking a portion of the elongated body (or core) prior to applying the insulator and material for the reference electrode.

[0280] Figure 6B is a diagram showing the layers cut away, but during the manufacturing process, the material is usually obtained with all layers terminating at a top end. The step of removing layers 604 and 614 may be performed in order to form a window. Fig.6DThe result of this removal / cutting process is illustrated by side view / cross section. The removal process can be accomplished by the methods already described or other methods known in the art. In one example, the removal step is performed, for example, by laser scraping, and can be performed in a reel-to-reel process on a continuous string. For example, by removing different layers at different lengths, the removed area can be stepped ( Fig.6D ). In such a manufacturing method involving a continuous string, the sensor can be singulated after the removal step. In some examples, if the core is metal, end caps are used, such as by applying an insulating or other isolating material to the tip by dipping, spraying, heat shrink tubing, crimping, etc. If the core is a polymer (e.g., a hydrophobic material), end caps may not be necessary. For example, in Fig.6D In the depicted sensor, an end cap 620 (eg, made of a polymer or insulating material) or other structure is disposed on the core (eg, if the core 610 is not insulated). Fig. 6E can be considered as being built on Figure 6B In the general structure depicted, two or more additional layers are added to create one or more additional electrodes. Methods for selectively removing two or more windows to create two or more electrodes can also be used. For example, by adding another conductive layer 622 and an insulating layer 624 under the reference electrode layer 614, two electrodes (a first working electrode and a second working electrode) can then be formed, thereby creating a two-electrode sensor. For example, the same concept can be applied to create a counter electrode, an electrode for measuring additional analytes or ions, etc. Fig. 6F The example has an additional electrode 622 (with FIG. 6B to FIG. 6D A sensor (compared to FIG. 1 ) in which windows are selectively removed to expose working electrodes 612, 622 between reference electrodes (comprising a plurality of segments) 614, with a small amount of insulator 604, 624 exposed therebetween. Figure 6G Another example is illustrated in which the selective removal of layers is performed stepwise to expose electrodes 612, 622 and insulators 604, 624 along the length of the elongated body.

[0281] Figure 4A Operational flow in an example method 400 for measuring the concentration of a target ion in a biological fluid in vivo is illustrated. Figure 4A The illustrated method 400 may include implanting an indwelling sensor (operation 410). In a preferred embodiment, the indwelling sensor is implanted percutaneously. In other embodiments, the indwelling sensor is implanted subcutaneously or intradermally. FIG. 1A to FIG. 1I or Figures 2A to 2GIn the described manner, the sensor may include a substrate (e.g., 101); a first electrode (e.g., 111 or 211), which is disposed on the substrate; an ion carrier (e.g., 115), which is disposed on the substrate and is configured to selectively transport target ions to the first electrode or selectively transport the target ions within the first electrode; and a second electrode (e.g., 117), which is disposed on the substrate. Non-limiting options for these and other components of the sensor are provided elsewhere herein. Figure 4A The illustrated method 400 may also include generating 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 (operation 420). For example, the sensor electronics 120 may be such as reference Figure 1A To Figure 1L, Figures 2A to 2G , Figure 3 , FIG. 5A to FIG. 5B or FIG. 6A to FIG. 6G Describes the way to generate signals. Figure 4A The illustrated method 400 may also optionally include using the signal to generate an output corresponding to a measurement result of the concentration of the target ion in the biological fluid (operation 430). FIG. 1A to FIG. 1I , Figures 2A to 2G , Figure 3 , FIG. 5A to FIG. 5B and FIG. 6A to FIG. 6G In the manner described, sensor electronics 120 may generate an output, or may transmit a signal to an external device that generates an output.

[0282] Figure 4B Operational flow in an example method 450 for measuring electrophysiological signals conducted via a biological fluid in vivo is illustrated. Figure 4B The illustrated method 450 includes implanting an indwelling sensor (operation 460). FIG. 1A to FIG. 1I or Figures 2A to 2G In the described manner, the sensor may include a substrate (eg, 101); a first electrode (eg, 111 or 211), which is disposed on the substrate; and a second electrode (eg, 117), which is disposed on the substrate. Figure 4B The illustrated method 450 may also include generating 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 biofluid conducting the electrophysiological signal to the first electrode (operation 470). For example, the sensor electronics 120 may be such as referring to FIG. 1A to FIG. 1I , Figures 2A to 2G , Figure 3 , FIG. 5A to FIG. 5B , FIG. 6A to FIG. 6G or 7A to 7C Describes the way to generate signals. Figure 4B The illustrated method 450 may also optionally include using the signal to generate an output corresponding to a measurement result of the electrophysiological signal (operation 480). FIG. 1A to FIG. 1I , Figures 2A to 2G , Figure 3 , FIG. 5A to FIG. 5B , FIG. 6A to FIG. 6G or 7A to 7C In the manner described, sensor electronics 120 may generate an output, or may transmit an output to an external device.

[0283] It should be clear from this disclosure that reference Figure 4A The operation described is optionally combined with Figure 4B The corresponding operation combination, and refer to Figure 4B The operation described is optionally combined with Figure 4A The corresponding operations of the combination. For example, operations 410 and 460 are combined, for example, so that the implanted indwelling sensor includes an ion carrier 115 (for example, within the first electrode 111 or within the ISM 212). In addition, operations 420 and 470 are combined, for example, so that a signal corresponding to an electromotive force is generated, which is based in part on the potential difference generated between the first electrode and the second electrode in response to the ion carrier transporting the target ion 11 to the first electrode, and in part on the potential difference generated in response to the biological fluid conducting the electrophysiological signal to the first electrode. In addition, operations 430 and 480 are combined, for example, so that the signal is used to generate an output corresponding to the measurement result of the target ion in the biological fluid and an output corresponding to the measurement result of the electrophysiological signal.

[0284] It will be apparent that references such as FIG. 1A to FIG. 1I , Figures 2A to 2G , Figure 3 , FIG. 5A to FIG. 5B and FIG. 6A to FIG. 6G The sensors described and such as reference FIG. 4A to FIG. 4B The methods described are suitably applicable to measuring the concentration of any suitable analyte. For example, 7A to 7C Schematically illustrates an example configuration and components of an apparatus for measuring electrophysiological signals and / or concentration of a target analyte in an in vivo biological fluid. Figure 1A As depicted, the device 700 includes an indwelling sensor 710 and sensor electronics 120. Similar to the Figure 1A As depicted, the device 700 includes an indwelling sensor 710 and sensor electronics 120. The indwelling sensor 710 includes Figure 1AThe similarly configured substrate 101, an ion carrier disposed on the substrate and configured to selectively transport the target ion to the first electrode or selectively transport the target ion within the first electrode, an enzyme 715 configured to generate the target ion in response to the target analyte, and an enzyme disposed on the substrate and as described in reference Figure 1A The similarly configured second electrode (E2) 117. In one example, the enzyme 715 is located similar to Figure 1A The material of the first electrode 111 (optionally omitting the ion carrier) or similar Figure 1B The material of the ion selective membrane 212 (optionally omitting the ion carrier).

[0285] exist Fig. 7A In the illustrated non-limiting example, the ion carrier is located in a first electrode (E1) 111 disposed on a substrate, and as shown in reference Figure 1A Alternatively, in Figure 7C In the illustrated non-limiting example, the ionophore is located within an ion selective membrane 212, which is formed by a membrane such as that shown in FIG. Figure 2A The first electrode 211 is configured in the manner described above, and the first electrode 211 is configured in a manner such as reference Figure 2A The first electrode 111 or 211 is referred to as a working electrode (WE), and the second electrode 117 is referred to as a reference electrode (RE).

[0286] 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 and the second electrode in response to the ion carrier transporting the target ion to the first electrode. In one example, the sensor electronics 120 is configured to use the signal to generate an output corresponding to a measurement result of the concentration of the target ion in the biological fluid, and / or is configured to transmit the signal to an external device, which is configured to use the signal to generate an output corresponding to a measurement result 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 the electrophysiological signal to the first electrode 111, and the sensor electronics 120 is configured to use the signal to generate an output corresponding to the measurement result of the electrophysiological signal.

[0287] According to such Fig. 7A In the illustrated manner, biological fluid 10 may include multiple analytes 71, 72, and 73. Device 700 is configured to measure the concentration of analyte 71, and thus such analyte is referred to as a "target" analyte. Figure 7BAs illustrated, the enzyme 715 is located within the enzyme layer 716 and can selectively act on the target analyte 71 from the biological fluid 10 or from the biological interface membrane 114 (if provided, for example, Fig. 7A As illustrated and as referenced Figure 1A , Figure 2A The configuration is similar to that of the reference Figures 1H to 1I The action of the enzyme 715 on the target analyte 71 generates the target ion 11. The ion carrier 115 in the first electrode 111 or in the ion selective membrane 212 can selectively transport or selectively bind the target ion 11 from the enzyme 715 to the first electrode 111 or the first electrode 211 and selectively transport or selectively bind the target ion in the first electrode.

[0288] It should be understood that the target analyte 71 is any suitable analyte, the enzyme 715 is any suitable enzyme that generates suitable ions in response to an action on the analyte, and the ionophore 115 is any suitable ionophore that selectively transports and / or binds ions generated by the enzyme 715 to generate an EMF so that the concentration of the analyte 71 is determined (whether using the sensor electronics 120 or an external device to which the sensor electronics 120 transmits an electrophysiological signal and / or a signal corresponding to the ion concentration). Non-limiting examples of analytes, enzymes, and ionophores used together are listed in Table 1 below.

[0289]

[0290]

[0291] Table 1. Enzymatic potentiometric sensor structure

[0292] Figure 8 An operational flow in an example method for measuring the concentration of a target analyte in a biological fluid in vivo is illustrated. Figure 8 The illustrated method 800 includes implanting an indwelling sensor (operation 810). 7A to 7CIn the manner described, the sensor may include a substrate; a first electrode, the first electrode being disposed on the substrate; an ion carrier, the ion carrier being disposed on the substrate and configured to selectively transport target ions to or within the first electrode; an enzyme, the enzyme being configured to generate the target ions in response to acting on the target analyte; and a second electrode, the second electrode being 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 ion carrier transporting the target ions to the first electrode (operation 820). Method 800 may also optionally include using the signal to generate an output corresponding to a measurement result of the concentration of the analyte in the biological fluid (operation 830). For example, with reference to Figure 1A To Figure 1, Figures 2A to 2G , Figure 3 , FIG. 5A to FIG. 5B and FIG. 6A to FIG. 6G In a similar manner as described, the sensor electronics 120 may generate an output, or may transmit a signal to an external device that generates an output.

[0293] Fig.17 is a diagram depicting an example continuous analyte monitoring system 1700 configured to measure one or more target ions and / or other analytes as discussed herein. According to certain aspects of the present disclosure, the monitoring system 1700 includes an analyte sensor system 1724 operably connected to a host 1720 and a plurality of display devices 1734a-e. It should be noted that the display device 1734e is alternatively or in addition to being a display device, or a drug delivery device that can cooperate with the analyte sensor system 1724 to deliver the 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 communicates directly wirelessly with one or more of the plurality of display devices 1734a-e via wireless communication signals.

[0294] As will be discussed in more detail below, the display devices 1734a-e may also communicate with each other and / or with the analyte sensor system 1724 through each other. 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. Wireless communication signals from, for example, 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. In addition, the wireless communication signals may include data transmitted by one or more of the display devices 1734a-d via a "long-range" uplink signal 1736 (e.g., a cellular signal) to one or more remote servers 1740 or network entities (such as a cloud-based server or database), and receiving long-range downlink signals 1738 transmitted by the remote server 1740.

[0295] Sensor electronics module 1726 includes sensor electronics configured to process sensor information and generate transformed sensor information. In certain embodiments, sensor electronics module 1726 includes an electronics circuit associated with measuring and processing data from continuous analyte sensor 1722, including a forward-looking algorithm associated with processing and calibrating continuous analyte sensor data. Sensor electronics module 1726 can be integrated with continuous analyte sensor 1722 (non-releasably attached) or releasably attached to continuous analyte sensor, thereby realizing physical connection between them. In one example, sensor electronics module 1726 may include hardware, firmware and / or software capable of performing analyte level measurement. For example, sensor electronics module 1726 may include a potentiostat, a power supply for providing power to continuous analyte sensor 1722, other components that can be used for signal processing and data storage, and a telemetry module for transmitting data from itself to one or more display devices 1734a-e. Electronics can be fixed to a printed circuit board (PCB), etc., and can take a variety of forms. For example, the electronic device can 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. Patents 7,310,544 and 6,931,327 and U.S. Patent Publications 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 herein by reference in its entirety for all purposes.

[0296] The display devices 1734a-e are configured to display, alarm, and / or perform drug delivery based on sensor information transmitted by the sensor electronics module 1726 (e.g., in a customized data packet transmitted to the display device based on the corresponding preferences of one or more of the display devices 1734a-e). Each of the display devices 1734a-e may include a display such as a touch screen display for displaying sensor information to a user (most commonly the host 1720 or a caregiver / medical professional) and / or receiving input from the user. In some embodiments, as an alternative or in addition to a touch screen display, the display devices 1734a-e may include other types of user interfaces, such as a voice user interface, for communicating sensor information to a user of the display devices 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 sensor information communicated from the sensor electronics module 1726 (e.g., in a data packet transmitted to the respective display device 1734a-e) without calibration and any additional proactive processing required to display the sensor information in real time.

[0297] exist Fig.17 In some embodiments, one of the plurality of display devices 1734a-e is a custom display device 1734a that is specifically designed to display certain types of displayable sensor information (e.g., numerical values ​​and arrows in some embodiments) 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, a PDA, etc. based on an Android, iOS operating system, or other operating system, wherein the handheld device 1734c may have a relatively large display and is configured to display a graphical representation of continuous sensor data (e.g., including current and historical data). Other display devices may include other handheld devices, such as a tablet computer 1734d, a smart watch 1734b, a drug delivery device 1734e, a blood glucose meter, and / or a desktop or laptop computer.

[0298] As discussed above, because different display devices 1734a-e provide different user interfaces, the contents of the data packets (e.g., the amount, format, and / or type of data to be displayed, alerts, etc.) may be customized (e.g., programmed differently by the manufacturer and / or by the end user) for each specific display device and / or display device type. Thus, in the embodiment of FIG. 1 , one or more of the display devices 1734a-e may be in direct or indirect wireless communication with the sensor electronics module 1726 to enable a variety of different types and / or levels of display and / or functionality associated with the sensor information, as described in greater detail elsewhere herein.

[0299] Continuous Analyte Sensors

[0300] Generally speaking, the continuous analyte sensor 1722 is an implantable analyte sensor that measures the concentration of one or more analytes using at least potentiometric sensing technology. The electrodes comprising the 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 substance measured at the working electrode.

[0301] In some alternative embodiments, additional electrodes may be included within the assembly, such as 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, configured as a baseline subtraction electrode, or configured to measure an additional analyte). U.S. Patent 7,081,195, U.S. Patent Publication 2005 / 0143635, and U.S. Patent Publication 2007 / 0027385 describe some systems and methods for implementing and using additional working electrodes, counter electrodes, and reference electrodes, each of which is incorporated herein by reference in its entirety.

[0302] Working Example

[0303] The following examples are only used to illustrate the present disclosure, rather than to limit the present disclosure. FIG. 9A to FIG. 9B is a graph illustrating the measurement sensitivity of an example device to potassium ions. More specifically, an example sensor was prepared on a coaxial gold wire modified with a PEDOT (PSS) layer acting as a solid contact (SC) and subsequently modified with a fluorosilicone ISM containing potassium ion carrier 2 and KTClPB (1.0 wt % and 0.3 wt %, respectively) as the sensing component. FIG. 9A to FIG. 9B As shown, the sensor exhibits a near-Nernstian (about 58 mV per decade of concentration, n=6) response in aqueous samples containing different concentrations of potassium ions. FIG. 10A to FIG. 10Bis a graph illustrating the measurement sensitivity of devices of substantially the same composition to potassium ions in the presence of interfering ions. More specifically, by measuring the concentration of different interfering ions (140 mM NaCl, 1.2 mM CaCl 2 , 1 mM MgCl 2 ) to evaluate the selectivity of the potassium ion sensor ( FIG. 10A to FIG. 10B ), again demonstrating near-Nernstian sensitivity (about 56 mV per decade of concentration, n=5) and validating the potential use of this sensor in real samples. Fig.11 Reference FIG. 9A to FIG. 9B and FIG. 10A to FIG. 10B More specifically, to demonstrate the potential use of the present ion sensor for continuous monitoring of ions, a potassium ion sensor was immersed in a 10 mM KCl solution and kept drifting for 70 h ( Fig.11 ). The drift of the potential response calculated from four identical sensors immersed in 10 mM KCl solution for 72 h was 2 mV ± 1 mV.

[0304] Fig.12 The absolute potential (E) measured by another example device in water and in a 140 mM NaCl solution is shown. 0 ), potential slope (m), and drift (green and orange, respectively; n=8). More specifically, the sensor of the device consists of a coaxial carbon-coated gold wire modified with a P3OT-doped fluorosilicone ISM (1 wt% potassium ionophore 2; 0.3 wt% KTClPB; 5 mg / mL P3OT) by dip-coating. The sensor exhibits Fig.12 The absolute potential (E 0 ), potential slope (m), and drift characteristics. The sensor showed similar performance in the absence or presence of a model interferent ion (sodium), with minimal sensitivity loss when measuring potassium in the presence of sodium.

[0305] It should be understood that potassium ions are a non-limiting example of ions that can be detected using the present apparatus and methods. FIG. 13A to FIG. 13B An example device configured to detect urea using urease and an ionophore selective for ammonium ions is schematically illustrated. FIG. 13A to FIG. 13B As illustrated, a gold wire (core or substrate) 1301 is partially coated with Ag / AgCl 1330 (reference electrode), leaving a window in which the gold is exposed to be used as a reference electrode. FIG. 6A to FIG. 6GThe first electrode (working electrode) 1311 is formed in the manner described. The working electrode 1311 is formed by removing a portion of one or more covering layers, for example, by an etching process, including but not limited to laser ablation / scraping / etching, sandblasting, or other methods or combinations of methods. In some examples, an insulating material as discussed herein is located between the working electrode 1311 and the reference electrode 1330. In other examples, no insulating material is placed between the working electrode 1311 and the reference electrode 1330. An ammonium selective membrane 1312 is deposited on the first electrode 1311, for example, a reference electrode 1330. Figure 2A The reference electrode 212 includes an ammonium selective ionophore-free ion selective membrane 212. In one example, the reference electrode does not contain any ion selective membrane and ionophore. The urease membrane 1316 (e.g., reference electrode 1316) 7A to 7C The enzyme layer 716) which comprises urease as enzyme 715 is deposited on the ammonium selective membrane.

[0306] FIG. 14A to FIG. 14B An example device using an ionophore selective for ammonium ions is schematically illustrated. More specifically, to characterize the reference FIG. 13A to FIG. 13B The ammonium selective membrane 1312 is used to prepare the device. FIG. 14A to FIG. 14B As illustrated and similar to reference FIG. 13A to FIG. 13B As described, the gold wire (core or substrate) 1301 is partially coated with Ag / AgCl 1330, leaving a window in which the gold is exposed to be used as a reference FIG. 6A to FIG. 6G A first electrode (working electrode) 1311 is formed in the manner described. A solid contact layer (SC) comprising PEDOT:PSS is deposited on the first electrode 1311. An ammonium selective membrane 1312 is deposited on the SC layer 1413, for example, an ion selective membrane 212 as described in reference 2A and comprising an ammonium selective ionophore styrene. In one example, the reference electrode does not contain any ion selective membrane and ionophore. The ammonium selective membrane 1312 is prepared by repeatedly dipping the distal tip of the device into a solution comprising about 1 mg of styrene dissolved in about 660 microliters (μL) of tetrahydrofuran (THF), 33 mg of PVC, and 72.2 μL of a plasticizer dioctyl sebacate (DOS), allowing the tip to dry between dippings in the solution.

[0307] FIG. 14A to FIG. 14B The device response to aqueous ammonium ions was characterized to approximate the FIG. 13A to FIG. 13B The manner in which the device responds to urea, for example, can be characterized as closely simulating the manner in which urease generates ammonium ions in response to the action of urea. Fig.15 It is an example FIG. 14A to FIG. 14BMore 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. Fig.15 As shown, the sensor exhibits near-Nernstian sensitivity (about 57 mV per decade of concentration, n=8) in aqueous samples containing different concentrations of ammonium ions. Fig.16 Illustrated FIG. 14A to FIG. 14B and Fig.15 Example of an absolute potential (E) measured by a device for ammonium ions 0 ), potential slope (m), and R-squared (R2). The R2 value is a coefficient of determination that indicates the strength of the relationship between the linear model and the dependent variable (e.g., the potential response relative to ion concentration), with values ​​close to 1.000 being ideal. The determination of ammonium yielded a linear response range of 0.1 mM to 10 mM with an R2 value of ≥ 0.999. Fig.16 The analytical characteristics summarized in show the performance of the ammonium selective electrode for the detection of ammonium ions in aqueous samples.

[0308] Selectivity coefficient calculation

[0309] Fig.18A and Fig.18B The selectivity of an example continuous potassium ion sensor as discussed herein is illustrated. The selectivity of an ISE can be determined by its selectivity coefficient "K a / b " indicates that this is a numerical measure of how well the ISM can distinguish target ions (a) from interfering ions (b). In some examples as discussed herein, "K a / b ″<1 is expected. The selectivity coefficients discussed herein were calculated for a sensor having a first (working) electrode formed of carbon-coated gold (Au) and a second electrode formed of silver / silver chloride. The ISM formed on the sensor covering the first electrode contained 1 wt % potassium ion carrier 2; 0.3 wt % KTClPB; 6 wt % DEX4041; 5 mg / mL P3OT (poly(3-octylthiophene-2,5-diyl)); and tetrahydrofuran (THF).

[0310] The selectivity coefficient of the sensor was calculated using the fixed interferometry method. Therefore, the sensor was evaluated for the primary ion (range: 10 -6 mM to 50 mM KCl). Potassium activity (a K+ ) is calculated from the intersection of the extrapolated linear part of the EMF response with the -log of the primary ion activity (see figure described below).

[0311] Calculate K Pot K+ / Na+ :

[0312]

[0313] a A , active primary ions

[0314] a B , active interfering ions

[0315] Z, the charge number of the primary ion and the interfering ion (same sign).

[0316] Fig.18A The EMF generated when KCl is introduced into a solution containing 100 mM NaCl is illustrated. Fig.18A The response of the sensor to the addition of KCl in solution is shown. Fig.18B Presented based on Fig.18A The data were calculated and show the EMF generated in response to increasing KCl concentration, given by Fig.18B The slope change indicated by the arrow in indicates that the sensor is able to detect the position of KCl relative to NaCl (the selectivity of KCl relative to NaCl is about -1.29 (activity of potassium)). Fig.18B As shown, in the presence of 100 mM Na+, the continuous potassium ion sensor exhibits sufficient selectivity to measure K+ in the range of 0.1 mM to 50 mM:

[0317] Log K POT K+，Na+ =-1.29 / 2 = -0.64

[0318] K POT K+，Na+ =5.1E- 2 / 100=5.1E -4

[0319] 0.1 mM-50 mM sensor operating range, m(slope)=53 mV / decade of concentration.

[0320] Fig.19ADepicted is 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 comprising 2410 wt % of a polyurethane polymer with a polysiloxane soft segment, 2.2 mg potassium ionophore III: bis[(benzo-15-crown-5)-4-methyl]pimelate (BB15C5), and 0.5 mg KTFPB, with an Ag / AgCl RE 929 located on opposite sides of the planar substrate. The device 920 is configured to be inserted into the dermis or subcutaneous tissue of a host to monitor electrophysiological signals and / or concentrations of selected ions in the host's interstitial fluid by potentiometric titration. A resistive film (not shown) may be used on the WE and / or RE. In one example, the resistive film is used to attenuate the leaching of plasticizers from the ISM. In one example, the resistive film is used to attenuate the leaching of plasticizers from a plasticized polyvinyl chloride (PVC) ISM. A biointerface film (not shown) may be used with or without a releasable anti-inflammatory agent.In one example, a resistive film is used to mitigate leaching (degradation) of silver and / or chloride from the second electrode during use.

[0321] Fig.19B Depicted are the E obtained from three exemplary planar devices 920 0 Experimental data for potassium ion concentration demonstrated acceptable stability and sensitivity for continuous monitoring. Fig.19B Depicted by Fig.19A The planar potassium ion sensor shows the response to potassium and E relative to Ag / AgCl / KCl (potassium decomposition in solution: 0.1mM KCl; potassium peaks are 1mM, 5mM, 10mM KCl) 0 Sensitivity (n=3). Fig.19B The data proves that Fig.19A The sensor device 920 is constructed for repeatable sensitivity and drift resistance.

[0322] Interference test data

[0323] In another example, an exemplary potassium ion sensor was developed, which includes a gold wire / carbon ink WE as a first electrode, which is coated with an ISM containing PVC plasticized with 2-nitrophenyl octyl ether, BME44 ionophore and KTFPB salt; and an Ag / AgCl RE as a second electrode, which is dip-coated with a resistive film (using 25% ethanol, 6% solid polyvinylpyrrolidone- blend) and subjected to an interferent (sodium chloride (NaCl)). Fig. 20A Depicted are data from seven identically prepared sensors and their responses in the presence of 140 mM NaCl interferent followed by a 0.1 mM potassium ion spike at 1 mM, 5 mM, and 10 mM KCl ( Fig. 20B Shows Fig. 20A 20B), followed by a 4-day drift in 10 mM KCl / 140 mM NaCl for potassium sensitivity (n=7), and the corresponding measured sensitivity (m), absolute potential (E) as measured after a 4-day drift of an exemplary potassium ion sensor. 0 ). The data demonstrates the stability and sensitivity of the sensor to pharmacologically relevant concentrations of potassium ions in the presence of pharmacologically relevant concentrations of interferents (e.g., sodium ions). Additional data were 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, and an Ag / AgCl RE as the second electrode. Fig. 20C Depicted are data from three identically prepared sensors and their sensitivity to potassium following a 0.1 mM potassium ion spike at 1 mM, 5 mM, 10 mM KCl in the presence of 140 mM NaCl interferent, and Fig.20D Drift data of the sensor are depicted. The data demonstrates the stability and sensitivity of the sensor to pharmacologically relevant concentrations of potassium ions in the presence of pharmacologically relevant concentrations of interferents (e.g., sodium ions).

[0324] Solid contact data

[0325] In some examples, GO materials were compared with alternative carbon-based solid contact (SC) layer materials. Thus, gold wire electrodes were modified with different commercially available carbon inks (Dupont 7102 and BQ221, hereinafter referred to as "7102" and "BQ221"), one of which was supplemented with MWCNTs (10 μm-20 μm). Sensors constructed with these conductive carbon inks as SCs showed a response to potassium ions in the presence of interfering sodium ions. Samples were prepared using a polyurethane polymer with a polysiloxane soft segment as an ISM with a BME44 ionophore and compared with PVC plasticized with 2-nitrophenyl octyl ether in the case of the same ionophore sensor as a control.

[0326] Therefore, if Fig.21A , Fig.21B and Fig. 21C As depicted, a wire potassium ion sensor is developed that includes an exemplary solid contact (SC) layer disposed between a first electrode and a plasticized ISM 965 and polyurethane-polysiloxane-polycarbonate ion selective membrane, wherein Fig.21A represents an identically prepared sensor with a SC containing BQ221 in a plasticized ISM and a polyurethane-polysiloxane-polycarbonate ion selective membrane, Fig.21Brepresents an identically prepared sensor having a SC comprising 7102 plasticized ISM 965 and a polyurethane-polysiloxane-polycarbonate ion selective membrane, and Fig. 21C Figure 2 shows the same prepared sensor with a SC containing 7102 and a carbon nanotube plasticized ISM and a polyurethane-polysiloxane-polycarbonate ion selective membrane. The data demonstrates the improvement in sensitivity and stability using a SC containing 7102. The conductive ink containing carbon nanotubes has improved performance in m, E and R compared to the other conductive inks tested. 0 No significant improvement was shown in terms of drift.

[0327] Resistor Film Data

[0328] Fig.22A The effect of using a resistive film (RM) disposed on the first electrode and the second electrode on sensitivity and stability is depicted. Thus, in one example, polyvinyl pyrrolidone- A resistive film (RM) of (thermoplastic silicone polycarbonate polyurethane blend) is coated on a 2-nitrophenyl octyl ether plasticized PVC ISM gold wire sensor 940 with a solid contact carbon paste material 7102 and shows 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 reduce the leaching of plasticizers from the ISM, thereby enhancing continuous operation and reducing or eliminating degradation of the second electrode. In one example, the RM material is selected to minimize the migration of low MW materials (e.g., plasticizers), thereby improving sensor life and minimizing plasticizer leaching. In one example, a biocompatible plasticizer for PVC is used, such as polyethylene glycol (PEG).

[0329] Fig. 22B and Fig. 22C The effects of thickness and second electrode composition on the performance of the continuous ion sensor in the presence of physiological amounts of potassium and sodium ions are depicted, respectively. Thus, with a constant second electrode composition (AgCl wt %), a second electrode thickness of at least 0.9 thousandths of an inch (23 microns) provides nearly constant drift data 950 compared to a reference electrode thickness of less than 0.6 thousandths of an inch (15 microns) drift data 951. Fig. 22C Data for second electrodes of different compositions are shown, where data 952 represents 0 wt % AgCl, data 953 represents 15 wt % AgCl, data 954 represents 40 wt % AgCl, and data 955 represents 50 wt % AgCl. Therefore, the data demonstrates the improvement in sensor stability performance using a higher amount of AgCl in the second electrode in the presence of pharmacological amounts of potassium and sodium ions.

[0330] Fig.23A and Fig. 23B Depicted are in vivo animal data representative of an exemplary coaxial potassium ion sensor of the present disclosure utilizing a gold wire first electrode having a graphene oxide solid contact layer coated with a polyurethane-polycarbonate polyol ISM comprising BB15C5 and KTFPB with a polyvinylpyrrolidone Resistive film coating; Ag / AgC1 RE coated with the same resistive film as the second electrode. Fig.23A The data shows the raw signal of the potassium ion sensor 975 in an in vivo environment, and Fig. 23B Depicted Fig.23A An enlarged portion of the diagram shows the correlation between the blood potassium ion concentration (points) measured in vivo using the potassium ion sensor 975 disclosed in the present invention and the in vitro measurement result 977 (blood sample using a benchtop analyzer (radiometer ABL90)).

[0331] Fig.23C Depicted are additional in vivo animal data representative of another exemplary coaxial potassium ion sensor of the present disclosure utilizing a gold wire first electrode having a 7102 carbon ink solid contact layer coated with a 2-nitrophenyl octyl ether plasticized PVC ISM comprising BBE44 and KTFPB with a polyvinyl pyrrolidone- Resistive film coating; Ag / AgCl RE coated with the same resistive film as the second electrode. Fig.23C The data show the correlation between the blood potassium ion concentration measured in vivo using the potassium ion sensor disclosed in the present invention and the in vitro measurement results (blood samples using a benchtop analyzer (radiometer ABL90)).

[0332] disinfect

[0333] In one example, the exemplary potassium ion sensor disclosed herein is sterilized. In one example, the potassium ion sensor disclosed herein is sterilized using high energy radiation. In one example, the potassium ion sensor disclosed herein is sterilized using ethylene oxide (EtO). Fig.24A Depicted are the sensitivity and calibration data of 23 identically prepared sensors prior to EtO sterilization utilizing a gold wire first electrode with a 7102 solid contact layer coated with a polyurethane-polycarbonate-polyol ISM comprising BBE44 and KTFPB with a polyvinylpyrrolidone- a resistive film coating; an Ag / AgCl RE as a second electrode coated with the same resistive film, and Fig. 24B Depicted are sensitivity and calibration data after EtO sterilization of the sensor. Fig.24A and Fig. 24B The data show that the difference between untreated and EtO sterilized sensors is 0 Compared with the control before EtO disinfection, the sensor after EtO disinfection showed positive E 0 Shift and improved distribution. Microscopic characterization showed no significant membrane changes after EtO sterilization. Therefore, EtO sterilization appears to be compatible with the sensor chemistry disclosed in the present invention.

[0334] Unless otherwise indicated, WE is used throughout the disclosure as an abbreviation for working electrode. Unless otherwise indicated, RE is used throughout the disclosure as an abbreviation for reference electrode.

[0335] All references cited herein (including but not limited to published and unpublished applications, patents, and literature citations) are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent that publications and patents or patent applications incorporated by reference conflict with the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such conflicting material.

[0336] 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.

[0337] All numerals used in this specification that represent the amount of ingredients, reaction conditions, etc. should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters described herein are approximate values ​​that can vary depending on the desired properties sought to be obtained. In any application claiming priority to this application, each numerical parameter should be interpreted based on the number of significant digits and ordinary rounding methods, rather than attempting to limit the application of the doctrine of equivalents to the scope of any claim.

[0338] The above description discloses several methods and materials of the present disclosure. The present disclosure is susceptible to modification of methods and materials and changes in manufacturing methods and equipment. Such modifications will become apparent to those skilled in the art by considering the practice of the present disclosure or the disclosure disclosed herein. Therefore, the present disclosure is not intended to be limited to the specific examples disclosed herein, but to cover all modifications and alternatives falling within the true scope and spirit of the present disclosure.

[0339] Although certain examples of the present disclosure have been described with reference to specific combinations of elements, various other combinations may also be provided without departing from the teachings of the present disclosure. Therefore, the present disclosure should not be interpreted as being limited to the specific examples described herein and shown in the accompanying drawings, but may also cover combinations of elements of the various shown examples and aspects thereof.

Claims

1. A device for continuously measuring the concentration of at least one target analyte in a biological fluid in vivo, the device comprising: An indwelling analyte sensor, the indwelling analyte sensor comprising: substrate; a first electrode, the first electrode being disposed on the substrate; an ion selective membrane comprising an ion carrier, the ion selective membrane being disposed on the substrate and configured to selectively transport the at least one target analyte to or within the first electrode; and a second electrode disposed on the substrate; and 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 at least one target analyte to the first electrode.

2. The apparatus according to claim 1, wherein the ion selective membrane is fluorosilicone rubber, polydimethylsiloxane polymer, silicone rubber, polyurethane with polysiloxane soft segments, polyurethane with hard segments and soft segments, water-based polyurethane, polyvinyl butyral, polymethyl methacrylate, polyvinyl acrylate, or blends or grafted polymers thereof.

3. The device according to any of the preceding claims, wherein the first electrode or the second electrode is independently a metal, a metal alloy or a conductive polymer, the conductive polymer being 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).

4. The device according to any of the preceding claims, wherein the ionophore is selected from the group consisting of: 4-tert-butylcalix[4]arenetetraacetic acid tetraethyl ester (sodium ionophore X); calix[4]arene-25,26,27,28-tetrol (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-tri[10-(1-adamantyl)-7,9-dioxo-6,10-diazaundecyl]benzene (magnesium ionophore VI); calcium ionophore I (ETH 1001); calcium ionophore II (ETH129); tri(dodecyl)methylammonium chloride (TDMAC); and inactivin.

5. The apparatus according to any one of the preceding claims, 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. Apparatus according to any preceding claim, wherein the ion selective membrane is in direct contact with the first electrode.

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

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

9. The device of any preceding claim, wherein the solid contact layer comprises a redox pair selected from the group consisting of: Co(II) and Co(III); Ir(II) and Ir(III); and Os(II) and Os(III).

10. The apparatus of any of the preceding claims, wherein the solid contact layer comprises a mixed conductor or a mixed ion-electron conductor selected from the group consisting of strontium titanate (SrTiO3), titanium dioxide (TiO2), (La,Ba,Sr)(Mn,Fe,Co)O 3-d 、La2CuO 4+d , cerium (IV) oxide (CeO2), lithium iron phosphate (LiFePO4) and LiMnPO4.

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

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

14. The apparatus of any preceding claim, wherein the sensor electronics comprises a current regulator.

15. An apparatus according to any of the preceding claims, wherein 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) a combination thereof.

16. An apparatus according to any of the preceding claims, 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 varies rapidly relative to a second contribution to the electromotive force from the concentration of the ions in the physiological fluid, and wherein the sensor electronics are configured to deconvolute the first contribution from the second contribution.

17. The apparatus of any preceding claim, wherein the electrophysiological signal comprises a cardiac electrical signal.

18. The device according to any of the preceding claims, further comprising an enzyme configured to generate the at least one target analyte, wherein the enzyme is selected from oxidases.

19. A method for continuously measuring the concentration of a target analyte in an in vivo biological fluid, the method comprising: A retention sensor, the retention sensor comprising: substrate; a first electrode, the first electrode being disposed on the substrate; an ion carrier disposed on the substrate and configured to selectively transport target ions to the first electrode or selectively transport target ions within the first electrode; a second electrode disposed on the substrate; and A signal is generated 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.

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

21. A device for continuously measuring the concentration of a target ion in a biological fluid in vivo, the device comprising: An indwelling analyte sensor, the indwelling analyte sensor comprising: substrate; a first electrode, the first electrode being disposed on the substrate; an ion carrier disposed on the substrate and configured to selectively transport the target ions to the first electrode or selectively transport the target ions within the first electrode; and a second electrode disposed on the substrate; and A sensor electronics device, the sensor electronics device being configured to: A signal is generated 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.

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

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

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

25. The apparatus of claims 21 to 24, wherein the first electrode comprises substantially no plasticizer.

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

27. The apparatus of claim 24 or claim 25, wherein the first electrode consists essentially of the conductive polymer, the ion carrier and an additive having ion exchange capability.

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

29. The apparatus 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. The apparatus of claim 29, wherein the additive is present in the first electrode in an amount of about 0.01 wt% to about 1 wt%.

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 about 90 wt% to about 99.5 wt%.

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) polystyrene sulfonate (PEDOT:PSS), polyaniline (PANI), poly(pyrrole) (PPy) or poly(3-octylthiophene) (POT).

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

34. Apparatus according to any one of claims 21 to 33, wherein the ionophore is located within an ion selective membrane disposed on the first electrode.

35. The apparatus of claim 34, wherein the ion selective membrane comprises substantially no plasticizer.

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

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

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

39. The apparatus 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 (KTC1PB).

40. The apparatus of any one of claims 37 to 39, wherein the additive is present in the ion selective membrane in an amount of about 0.01 wt% to about 1 wt%.

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% by weight.

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

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

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

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

47. The apparatus 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 wt% to about 10 wt%.

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

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

50. Apparatus according to claim 48 or claim 49, wherein the metal is oxidised or in the form of a metal salt.

51. The apparatus 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. The apparatus 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. The apparatus of claim 48, wherein the conductive polymer is 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).

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

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

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

58. Apparatus according to claim 56 or claim 57, wherein the metal is oxidised or in the form of a metal salt.

59. The apparatus 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. The apparatus 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. The apparatus of claim 56, wherein the conductive polymer is 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).

62. The apparatus of claim 56, wherein the solid contact layer comprises a redox pair.

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

64. The apparatus 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. The apparatus of claim 55, wherein the solid contact layer comprises a mixed conductor or a mixed ion-electron conductor.

66. The apparatus of claim 65, wherein the solid contact layer comprises a compound selected from the group consisting of: strontium titanate (SrTiO3), titanium dioxide (TiO2), (La,Ba,Sr)(Mn,Fe,Co)O 3-d 、La2CuO 4+d , cerium (IV) oxide (CeO2), lithium iron phosphate (LiFePO4) and LiMnPO4.

67. The apparatus 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. The apparatus 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. The apparatus of any one of claims 21 to 68, wherein the target ion is selected from the group consisting of sodium, potassium, hydrogen, lithium, magnesium, calcium, chloride, sulfite, sulfate, phosphate, and ammonium.

70. The apparatus of any one of claims 21 to 69, wherein the target ion is sodium and the ionophore is 4-tert-butylcalix[4]arene-tetraethyltetraacetate (sodium ionophore X) or calix[4]arene-25,26,27,28-tetrol (calix[4]arene).

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

72. The apparatus 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. The apparatus 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 (ETH 129).

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

75. The apparatus of any one of claims 21 to 69, wherein the target ion is ammonium and the ionophore is anibactin.

76. The apparatus of any one of claims 21 to 75, wherein 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.

77. The apparatus 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 conductive polymer.

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

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

80. The apparatus 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. The apparatus 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. The apparatus of claim 77, wherein the conductive polymer is 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).

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

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

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

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

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

88. The apparatus of any one of claims 85 to 87, wherein the biointerface membrane comprises a plurality of layers.

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

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

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

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

93. The apparatus 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% by weight.

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 apparatus of any one of claims 89 to 94, wherein the salt is selected from the group consisting of potassium chloride (KCl), sodium chloride (NaCl), magnesium chloride (MgCl2), calcium chloride (CaCl2), and ammonium sulfate ((NH4)2SO4).

96. The apparatus of any one of claims 89 to 95, wherein the second biointerface membrane comprises a plurality of layers.

97. An apparatus according to any one of claims 21 to 96, wherein the substrate is substantially linear.

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

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

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

101. The apparatus of any one of claims 21 to 100, wherein the sensor electronics comprises a constant current.

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

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

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

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

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

109. The apparatus of any one of claims 21 to 108, wherein the sensor electronics comprises a non-volatile computer readable memory configured to store correlations between control ion concentrations and control signals corresponding to electromotive forces of those control ion concentrations, and 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) generate as the output the controlled ion concentration corresponding to the selected control signal.

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

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

113. The apparatus of claim 112, wherein the sensor electronics comprises: a fast Fourier transform (FFT) circuit configured to transform the signal corresponding to the electromotive force from a time domain to a frequency domain; a spectrum 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 transform the high frequency portion into a time domain output corresponding to the electrophysiological signal and transform the low frequency portion into a time domain output corresponding to the concentration of the ions in the physiological fluid.

114. An apparatus according to claim 113, wherein the low frequency portion is approximately centered about zero frequency.

115. Apparatus according to claim 113 or claim 114, wherein the high frequency portion comprises a feature at the human heartbeat frequency or a harmonic thereof.

116. Apparatus according to any one of claims 113 to 115, wherein the high frequency portion comprises features at frequencies corresponding to features of an individual human heartbeat.

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

118. The apparatus of claim 116, wherein the high frequency portion comprises characteristics at about 200 Hz to about 400 kHz.

119. The apparatus of any one of claims 111 to 118, wherein the sensor electronics comprises: an analog-to-digital converter (ADC) that digitizes the signal corresponding to the electromotive force; a first filter configured to receive the digitized signal from the ADC, to remove the second contribution from the digitized signal, and to generate an output corresponding to the first contribution with the second contribution removed; and A second filter is configured to receive the digitized signal from the ADC, to remove the first contribution from the digitized signal, and to generate an output corresponding to the second contribution with the first contribution removed.

120. The apparatus of any one of claims 111 to 118, wherein the sensor electronics comprises: a first filter configured to remove the second contribution from the 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 is configured to remove the first contribution from the first output or from the signal corresponding to the electromotive force, and to generate a second output corresponding to the second contribution while removing the first contribution.

121. An apparatus according to claim 119 or claim 120, wherein the first filter comprises a high pass filter, a band stop filter or a band pass filter.

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

123. An apparatus according to any one of claims 119 to 122, wherein the second filter comprises a low pass filter, a band stop filter or a band pass filter.

124. An apparatus according to claim 123, wherein the second filter passes zero frequency.

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

126. An apparatus for measuring an electrophysiological signal conducted via a biological fluid in vivo, the apparatus comprising: A retention sensor, the retention sensor comprising: substrate; a first electrode disposed on the substrate; and a second electrode disposed on the substrate; and A sensor electronics device, the sensor electronics device being configured to: A signal is generated 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 biological fluid conducting the electrophysiological signal to the first electrode.

127. The apparatus of claim 126, wherein the sensor electronics are further configured to use the signal to generate an output corresponding to a measurement of the electrophysiological signal.

128. 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 measurement of the concentration of the target ion in the biological fluid.

129. The apparatus of any one of claims 126 to 128, wherein the sensor electronics comprises: a fast Fourier transform (FFT) circuit configured to transform the signal corresponding to the electromotive force from a time domain to a frequency domain; a spectrum analysis circuit configured to separate the transformed 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 is configured to transform the high frequency portion into a time domain output corresponding to the electrophysiological signal.

130. The apparatus of claim 129, wherein the high frequency portion comprises a feature at the human heartbeat frequency or a harmonic thereof.

131. An apparatus according to claim 129 or 130, wherein the high frequency portion includes characteristics at frequencies corresponding to characteristics of an individual human heartbeat.

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

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

134. The apparatus of any one of claims 126 to 133, wherein the sensor electronics comprises: an analog-to-digital converter (ADC) that digitizes the signal corresponding to the electromotive force; and A filter is configured to receive the digitized signal from the ADC, to remove contributions not corresponding to the electrophysiological signal from the digitized signal, and to generate an output corresponding to the electrophysiological signal with the contributions removed.

135. The apparatus of any one of claims 126 to 134, wherein the sensor electronics comprises: A filter is configured to remove a contribution from the signal corresponding to the electromotive force that does not correspond to the electrophysiological signal and to generate an output corresponding to the electrophysiological signal with the contribution removed.

136. The apparatus of claim 135, wherein the filter comprises a high pass filter, a band stop filter, or a band pass filter.

137. An apparatus according to claim 135 or 136, wherein the filter passes frequencies corresponding to a human heartbeat or a heartbeat waveform.

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

139. The apparatus 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 conductive polymer.

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

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

142. The apparatus 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. The apparatus 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. The apparatus 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:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

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

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

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

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

149. The apparatus 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. The apparatus 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. The apparatus 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:PSS), polyaniline (PANI), poly(pyrrole) (PPy), or poly(3-octylthiophene) (POT).

152. The apparatus of claim 145, wherein the solid contact layer comprises a redox pair.

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

154. The apparatus 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. The apparatus of claim 145, wherein the solid contact layer comprises a mixed conductor or a mixed ion-electron conductor.

156. The apparatus of claim 155, wherein the solid contact layer comprises a compound selected from the group consisting of: strontium titanate (SrTiO3), titanium dioxide (TiO2), (La,Ba,Sr)(Mn,Fe,Co)O 3-d 、La2CuO 4+d , cerium (IV) oxide (CeO2), lithium iron phosphate (LiFePO4) and LiMnPO4.

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

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

161. An apparatus according to any one of claims 126 to 160, wherein the second electrode is directly disposed on the substrate.

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

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

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

165. The apparatus of any one of claims 162 to 164, wherein the biointerface membrane comprises a plurality of layers.

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

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

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 film in an amount of about 40% to about 70% by weight.

170. The apparatus of any one of claims 167 to 169, wherein the salt is present in the second biointerface film in an amount of about 30% to about 60% by weight.

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

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

174. The apparatus of any one of claims 167 to 173, wherein the salt is selected from the group consisting of potassium chloride (KCl), sodium chloride (NaCl), magnesium chloride (MgCl2), and calcium chloride (CaCl2).

175. The apparatus of any one of claims 166 to 174, wherein the biointerface membrane comprises a plurality of layers.

176. The apparatus of any one of claims 126 to 175, wherein the substrate is substantially linear.

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

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

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

180. The apparatus of any one of claims 126 to 179, wherein the sensor electronics comprises a current regulator.

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

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

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

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

186. An apparatus according to any one of claims 126 to 185, wherein the sensor electronics include a transmitter configured to transmit the signal wirelessly.

187. A method for measuring the concentration of a target ion in a biological fluid in vivo, the method comprising: Implanting an indwelling sensor, the sensor comprising: substrate; a first electrode, the first electrode being disposed on the substrate; an ion carrier disposed on the substrate and configured to selectively transport the target ions to the first electrode or selectively transport the target ions within the first electrode; and a second electrode disposed on the substrate; and A signal is generated 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.

188. A method for measuring an electrophysiological signal conducted through a biological fluid in vivo, the method comprising: Implanting an indwelling sensor, the sensor comprising: substrate; a first electrode disposed on the substrate; and a second electrode disposed on the substrate; and A signal is generated 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 biological fluid conducting the electrophysiological signal to the first electrode.

189. An apparatus for continuously measuring the concentration of a target analyte in an in vivo biological fluid, the apparatus comprising: A retention sensor, the retention sensor comprising: substrate; a first electrode, the first electrode being disposed on the substrate; an ion carrier disposed on the substrate and configured to selectively transport target ions to the first electrode or selectively transport target ions within the first electrode; an enzyme configured to generate the target ion in response to acting on the target analyte; and a second electrode disposed on the substrate; and A sensor electronics device, the sensor electronics device being configured to: A signal is generated 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.

190. A method for continuously measuring the concentration of a target analyte in an in vivo biological fluid, the method comprising: Implanting an indwelling sensor, the indwelling sensor comprising: substrate; a first electrode, the first electrode being disposed on the substrate; an ion carrier disposed on the substrate and configured to selectively transport target ions to the first electrode or selectively transport target ions within the first electrode; an enzyme configured to generate the target ion in response to acting on the target analyte; and a second electrode disposed on the substrate; and A signal is generated 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.

Images