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WO2025075851A1 - Dispositifs et procédés pour détecter et compenser l'encrassement dans des systèmes de détection électrochimique - Google Patents

Dispositifs et procédés pour détecter et compenser l'encrassement dans des systèmes de détection électrochimique Download PDF

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Publication number
WO2025075851A1
WO2025075851A1 PCT/US2024/048484 US2024048484W WO2025075851A1 WO 2025075851 A1 WO2025075851 A1 WO 2025075851A1 US 2024048484 W US2024048484 W US 2024048484W WO 2025075851 A1 WO2025075851 A1 WO 2025075851A1
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Prior art keywords
membrane
active surface
electrochemically active
surface area
sensor system
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English (en)
Inventor
Hifza NAJIB
Wenjie LAN
Ellese ROBERTS
Forrest GOODWIN
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Dexcom Inc
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Dexcom Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0031—Implanted circuitry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means using enzyme electrodes, e.g. with immobilised oxidase
    • A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors

Definitions

  • This disclosure is directed to devices and methods of detecting fouling and compensating and/or de-fouling of electrodes in continuous transcutaneous analyte monitoring devices.
  • Electrochemical activation involves applying electrical pulses to remove adsorbed material off the surface in real time.
  • Electrochemical activation involves the use of single anodic and/or cathodic potentials or a train of pulses to periodically clean the electrode surface. Depending on the particular conditions of the electrochemical activation, adsorbed material may be removed or the surface chemistry can be altered to reduce the adsorption of fouling agents.
  • N-acetyl cysteine is an antioxidant drug or supplement used by healthcare providers to treat acetaminophen (TYLENOL®) poisoning. It works by binding the poisonous forms of acetaminophen that are formed in the liver. When administered to a patient utilizing a continuous transcutaneous analyte sensor, the presence of NAC can cause interference. While not be held to any theory, N-acetyl cysteine may bind to an electroactive surface and/or foul the electroactive surface, for example, when the electroactive surface comprises gold and other substances that have affinity for thiols.
  • a continuous monitoring sensor system comprising a sensor area comprising a working electrode, the working electrode having an at least partially implanted electrochemically active surface area, at least one membrane adjacent the electrochemically active surface area; and a controller configured to provide a swept potential range to the at least partially implanted electrochemically active surface area.
  • the electrochemically active surface area comprises metal. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises gold, platinum, palladium, indium, iridium, or binary or tertiary alloys thereof. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises metal and carbon. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises carbon.
  • the electrochemically active surface area comprises covalently coupled mediator.
  • the at least one membrane comprises covalently coupled mediator.
  • the at least one membrane is a resistance membrane. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.
  • the swept potential range is between about -2.0 volts to about 2.0 volts verses a reference electrode. In one aspect, alone or in combination with any one of the previous aspects, the swept potential range is between about -1.0 volts to about 1.0 volts verses a reference electrode. In one aspect, alone or in combination with any one of the previous aspects, the swept potential range is between about -0.5 volts to about 1.0 volts verses a reference electrode. In one aspect, alone or in combination with any one of the previous aspects, the swept potential range applied continuously, semi-continuously, intermittently, or randomly.
  • the controller is configured to provide a plurality of swept potential ranges to the implanted electrochemically active surface area.
  • the swept potential range includes at least a first potential value, a second potential value, a third potential value, a fourth potential value, and a fifth potential value.
  • the first potential value and the fifth potential value are equal or different.
  • the controller is configured to measure a current response to the swept potential range. In one aspect, alone or in combination with any one of the previous aspects, the controller is configured to measure plurality of current values corresponding a plurality of potential values.
  • the controller is configured to measure a current response to the swept potential range. In one aspect, alone or in combination with any one of the previous aspects, the controller is configured to measure plurality of current values corresponding a plurality of potential values.
  • the controller is configured to provide a bias voltage to the implanted electrochemically active surface area.
  • the bias voltage is at least non-zero to about 1.5 volts, at least 0.1 volts to about 1.0 volts, at least 0.2 volts to about 0.8 volts, at least 0.3 volts to about 0.7 volts, or at least 0.4 volts to about 0.6 volts.
  • a continuous monitoring sensor system comprising a sensor area comprising a working electrode, the working electrode having an electrochemically active surface area at least partially implanted, a controller configured to provide a sinusoidal potential range across the electrochemically active surface area, and an impedance detector.
  • the electrochemically active surface area comprises metal. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof. [0019] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises metal and carbon. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises carbon.
  • the electrochemically active surface area comprises covalently coupled mediator.
  • the electrochemically active surface area is in contact with at least one membrane.
  • the at least one membrane comprises covalently coupled mediator.
  • the at least one membrane is an interference membrane.
  • the at least one membrane is biosensing membrane.
  • the at least one membrane is a resistance membrane.
  • the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.
  • the sinusoidal potential range is modulated in a frequency range.
  • the frequency range is between about 1 MHz (megahertz) to about 1 MHz.
  • the frequency range is between about 10 MHz to about 100 kHz (kilohertz).
  • the frequency range is between about 10 MHz to about 30 kHz.
  • the frequency range is between about 100 MHz to about 10 kHz.
  • the sinusoidal potential range is applied continuously, semi-continuously, intermittently, or randomly.
  • the electrochemically active surface area comprises metal. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises metal and carbon. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises carbon. [0026] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof.
  • the electrochemically active surface area comprises covalently coupled mediator.
  • the electrochemically active surface area is in contact with at least one membrane.
  • the at least one membrane comprises covalently coupled mediator.
  • the at least one membrane is an interference membrane.
  • the at least one membrane is biosensing membrane.
  • the at least one membrane is a resistance membrane.
  • the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.
  • the foulant is endogenous. In one aspect, alone or in combination with any one of the previous aspects, the foulant is exogenous.
  • the foulant comprises a thiol group. In one aspect, alone or in combination with any one of the previous aspects, the foulant comprises a cystine group. In one aspect, alone or in combination with any one of the previous aspects, the foulant is N-acetylcysteine.
  • the swept potential range applied continuously, semi-continuously, intermittently, or randomly.
  • a method of detecting biofouling of an implanted biosensor system comprising (a) perturbing an implanted electrochemical biosensor system having an electrochemically active surface area with at least one sinusoidal signal over a frequency range; (b) monitoring at least one property of the at least one sinusoidal signal during step (a); and (c) detecting a change of the at least one property of the electrochemically active surface area; and (d) correlating the change of the at least on property with biofouling.
  • the method further comprises determining a baseline measurement corresponding to the at least one property.
  • (c) detecting a change of the at least one property of the electrochemically active surface area includes comparing the at least one property to the baseline measurement.
  • the method further comprises applying a swept potential to the electrochemically active surface of an implanted electrochemical biosensor after detecting the change.
  • the method further comprises determining a baseline measurement corresponding to the at least one property.
  • the method further comprises applying a swept potential to the electrochemically active surface of an implanted electrochemical biosensor after detecting the change.
  • the electrochemically active surface area comprises metal. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises metal and carbon. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises carbon. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof.
  • the electrochemically active surface area comprises covalently coupled mediator.
  • the electrochemically active surface area is in contact with at least one membrane.
  • the at least one membrane comprises covalently coupled mediator.
  • the at least one property is electrical resistance. In one aspect, alone or in combination with any one of the previous aspects, the at least one property is an impedance modulus value. In one aspect, alone or in combination with any one of the previous aspects, the at least one property is a phase angle value.
  • the foulant is endogenous. In one aspect, alone or in combination with any one of the previous aspects, the foulant is exogenous. [0044] In one aspect, alone or in combination with any one of the previous aspects, the foulant comprises a thiol group. In one aspect, alone or in combination with any one of the previous aspects, the foulant comprises a cystine group. In one aspect, alone or in combination with any one of the previous aspects, the foulant is N-acetylcysteine.
  • the at least one sinusoidal signal is applied continuously, semi-continuously, intermittently, or randomly.
  • a method of continually detecting fouling and electrochemically removing fouling of an implantable sensing electrode comprising (a) perturbing an electrochemical biosensor system having an at least partially implanted electrochemically active surface area with at least one sinusoidal signal over a frequency range; (b) monitoring at least one property of the at least one sinusoidal signal during step (a); and (c) detecting a change of the at least one property of the electrochemically active surface area; (d) correlating the change of the at least on property with a presence or an absence of fouling; (e) applying a swept potential across the electrochemically active surface of the electrochemical active surface area and electrochemically removing at least one foulant from the electrochemically active surface; and (f) repeating step (d) until the change is below a threshold value.
  • the electrochemically active surface area comprises metal and carbon. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises carbon. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof. In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises covalently coupled mediator.
  • the electrochemically active surface area is in contact with at least one membrane.
  • the at least one membrane comprises coupled mediator.
  • the at least one membrane is an interference membrane. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane is biosensing membrane. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane is a resistance membrane. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.
  • the sinusoidal potential range is modulated in a frequency range.
  • the frequency range is between about 1 MHz to about 10 MHz. In one aspect, alone or in combination with any one of the previous aspects, the frequency range is between about 10 MHz to about 100 kHz. In one aspect, alone or in combination with any one of the previous aspects, the frequency range is between about 10 MHz to about 30 kHz. In one aspect, alone or in combination with any one of the previous aspects, the frequency range is between about 100 MHz to about 10 kHz.
  • the at least one property is electrical resistance. In one aspect, alone or in combination with any one of the previous aspects, the at least one property is an impedance modulus value. In one aspect, alone or in combination with any one of the previous aspects, the at least one property is a phase angle value.
  • the foulant is endogenous. In one aspect, alone or in combination with any one of the previous aspects, the foulant is exogenous.
  • the foulant comprises a thiol group. In one aspect, alone or in combination with any one of the previous aspects, the foulant comprises a cystine group. In one aspect, alone or in combination with any one of the previous aspects, the foulant is N-acetylcysteine.
  • the at least one sinusoidal potential range is applied continuously, semi-continuously, intermittently, or randomly.
  • the swept potential range is applied continuously, semi-continuously, intermittently, or randomly.
  • FIG. 1 is a schematic flow diagram illustrating main steps for performing an exemplary method in accordance with the broadest aspect of the present disclosure.
  • FIG. 2 is a schematic flow diagram illustrating main steps for performing an exemplary method in accordance with the broadest aspect of the present disclosure.
  • FIG. 3 is a schematic flow diagram illustrating main steps for performing an exemplary method in accordance with the broadest aspect of the present disclosure.
  • FIG. 4 is a side-view schematic illustrating an in vivo portion of an analyte sensor, in one example, in accordance with the broadest aspect of the present disclosure.
  • FIG. 5 is a perspective-view schematic illustrating an in vivo portion of an analyte sensor, in one example, in accordance with the broadest aspect of the present disclosure.
  • FIG. 6 is a side-view schematic illustrating an in vivo portion of an analyte sensor, in another example, in accordance with the broadest aspect of the present disclosure.
  • FIGS. 7A-7C are cross-sectional views through the sensor of FIG. 4 on line 9-9, illustrating various examples of an exemplary membrane system.
  • FIG. 8 is a perspective-view schematic illustrating an in vivo portion of a singleworking-electrode analyte sensor
  • FIG. 9 illustrates an exemplary sensor construct for testing in accordance with the broadest aspect of the present disclosure.
  • FIG. 10 illustrates plots that record pulse voltammetry conducted intermittently between 2.5 and 40 hours post sensor activation.
  • FIG. 11 illustrates Cyclic Voltammetry (CV) on an electrode in Ferrocyanide solution before and after exposure to foulant.
  • FIG. 12 illustrates an Electrochemical Impedance Spectroscopy (EIS) measurements on an electrode before and after exposure to foulant.
  • EIS Electrochemical Impedance Spectroscopy
  • FIG. 13 is a diagram illustrating certain embodiments of an example continuous transcutaneous analyte sensor system communicating with at least one display device in accordance with various technologies described in the present disclosure.
  • Devices and methods are herein disclosed and described to provide continuous analyte sensing.
  • Devices and methods are herein disclosed and described to provide continuous analyte sensing while detecting fouling of an electroactive surface of the device.
  • Devices and methods are herein disclosed and described to provide continuous analyte sensing while detecting fouling of an electroactive surface of the device and to reduce or eliminate the fouling of the electroactive surface of the device.
  • analyte measuring device As used herein are broad terms and phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to the area of an analyte-monitoring device responsible for the detection of, or transduction of a signal associated with, a particular analyte or combination of analytes. For example, those terms may refer without limitation to the region of a monitoring device responsible for the detection of a particular analyte.
  • sensing region generally comprises a non-conductive body, a working electrode (anode), a reference electrode (optional), and/or a counter electrode (cathode) passing through and secured within the body forming electrochemically reactive surfaces on the body and an electronic connective means at another location on the body, and a multi-domain membrane affixed to the body and covering the electrochemically reactive surface.
  • such devices are capable of providing specific quantitative, semi-quantitative, qualitative, semi qualitative analytical information using a biological recognition element combined with a transducing (detecting) element.
  • the term "about” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not be limited to a special or customized meaning), and refers without limitation to allowing for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.
  • the term “substantially” as used herein refers to a majority of, or mostly, as in 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%.
  • substantially free of can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that about 0 wt.% to about 5 wt.% of the composition is the material, or about 0 wt.% to about 1 wt.%, or about 5 wt.% or less, or less than or equal to about 4.5 wt.%, 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 wt.% or less, or about 0 wt.%.
  • adhere and "attach” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not be limited to a special or customized meaning), and refer without limitation to hold, bind, or stick, for example, by gluing, bonding, grasping, interpenetrating, or fusing.
  • analyte as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a substance or chemical constituent in a biological fluid (e.g., blood, interstitial fluid, cerebral spinal fluid, lymph fluid, urine, sweat, saliva, etc.) that can be analyzed.
  • a biological fluid e.g., blood, interstitial fluid, cerebral spinal fluid, lymph fluid, urine, sweat, saliva, etc.
  • Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products.
  • the analyte measured by the sensing regions, devices, and methods is glucose.
  • acarboxyprothrombin acylcarnitine
  • adenine phosphoribosyl transferase adenosine deaminase
  • albumin alpha-fetoprotein
  • amino acid profiles arginine (Krebs cycle), histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, tryptophan); andrenostenedione
  • antipyrine arabinitol enantiomers
  • arginase benzoylecgonine (cocaine); bilirubin, biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-
  • Salts, sugar, protein, fat, vitamins, and hormones naturally occurring in blood or interstitial fluids can also constitute analytes in certain examples.
  • the analyte can be naturally present in the biological fluid, or endogenous, for example, a metabolic product, a hormone, an antigen, an antibody, and the like.
  • Analytes such as neurochemicals and other chemicals generated within the body can also be analyzed, such as, for example, ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5- hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (FHIAA), and histamine.
  • bioactive agent as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to any substance that has an effect on or elicits a response from living tissue.
  • biointerface membrane and “biointerface layer” as used interchangeably herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a permeable membrane (which can include multiple domains) or layer that functions as a bioprotective interface between host tissue and an implantable device.
  • biointerface and “bioprotective” are used interchangeably herein.
  • continuous is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an uninterrupted or unbroken portion, domain, coating, or layer.
  • continuous analyte sensing is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the period in which monitoring of analyte concentration is continuously, continually, and/or intermittently (but regularly) performed, for example, from about every 5 seconds or less to about 10 minutes or more. In further examples, monitoring of analyte concentration is performed from about every 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 second to about
  • Coupled is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to two or more system elements or components that are configured to be at least one of electrically, mechanically, thermally, operably, chemically or otherwise attached.
  • the phrases "operably connected”, “operably linked”, and “operably coupled” as used herein may refer to one or more components linked to another component(s) in a manner that facilitates transmission of at least one signal between the components. In some examples, components are part of the same structure and/or integral with one another (i.e. "directly coupled”).
  • components are connected via remote means.
  • one or more electrodes can be used to detect an analyte in a sample and convert that information into a signal; the signal can then be transmitted to an electronic circuit.
  • the electrode is "operably linked" to the electronic circuit.
  • removably coupled as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached and detached without damaging any of the coupled elements or components.
  • permanently coupled may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached but cannot be uncoupled without damaging at least one of the coupled elements or components.
  • discontinuous as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to disconnected, interrupted, or separated portions, layers, coatings, or domains.
  • distal is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region spaced relatively far from a point of reference, such as an origin or a point of attachment.
  • domain is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region of the membrane system that can be a layer, a uniform or non-uniform gradient (for example, an anisotropic region of a membrane), or a portion of a membrane that is capable of sensing one, two, or more analytes.
  • the domains discussed herein can be formed as a single layer, as two or more layers, as pairs of bi-layers, or as combinations thereof.
  • drug releasing membrane and “drug releasing layer” as used interchangeably herein are each a broad phrase, and each are to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi- permeable membrane which is permeable to one or more bioactive agents.
  • the "drug releasing membrane” and “drug releasing layer” can be comprised of two or more domains and is typically of a few microns thickness or more.
  • the drug releasing layer and/or drug releasing membrane are substantially the same as the biointerface layer and/or biointerface membrane.
  • the drug releasing layer and/or drug releasing membrane are distinct from the biointerface layer and/or biointerface membrane.
  • electrochemically reactive surface and “electrochemically active surface” as used herein interchangeably and are broad phrases, and are to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the surface of an electrode where an electrochemical reaction takes place.
  • Electrodes with electrochemically active surfaces include platinum and its binary and tertiary alloys, palladium and its binary and tertiary alloys, gold and its binary and tertiary alloys, silver and its binary and tertiary alloys, iridium or indium and its binary and tertiary alloys, indium tin oxide, bismuth molybdate (BizMoOe), tin sulfide metal oxide (SnS?), boron doped diamond, platinum coated boron doped diamond, conductive graphite and inks therefrom, gold, platinum, pallidum or iridium coated silicon wafers, doped polyaniline, doped poly(3,4- ethylenedioxythio-phene) polystyrene sulfonate (PEDOT:PSS), doped polypyrrole (Ppy), amorphous carbon, carbon nanotubes, graphene metallic nanoparticles.
  • PEDOT:PSS doped polypyrrole
  • hydrogen peroxide produced by an enzyme-catalyzed reaction of an analyte being detected reacts can create a measurable electronic current.
  • glucose oxidase produces hydrogen peroxide (H2O2) as a byproduct.
  • H2O2 reacts with the surface of the working electrode to produce two protons (2H + ), two electrons (2e“) and one molecule of oxygen (O2), which produces the electronic current being detected.
  • electron transfer is provided using a mediator or "wired enzyme" during reduction-oxidation (redox) of the transducing element and the analyte.
  • foulant and “biofoulant” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to substances that bind, couple, or associate with an electroactive surface of an in vivo electrode and reduce the effective surface area of the electroactive surface resulting in signal drift and/or noise.
  • the terms “implanted” or “implantable” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to objects (e.g., sensors) that are inserted subcutaneously (i.e. in the layer of fat between the skin and the muscle) or transcutaneously (i.e. penetrating, entering, passing through intact skin, or passing through the top layer of skin (stratum corneum)), which may result in a sensor that has an in vivo portion and an ex vivo portion.
  • the terms “implanted” or “implantable” as used herein encompasses indwelling sensors.
  • indwell or "indwelling,” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to reside within a host's body.
  • Some medical devices can indwell within a host's body for various lengths of time, depending upon the purpose of the medical device, such as but not limited to minutes, a few hours, days, weeks, to months, years, or even the host's entire lifetime. In some examples, indwelling medical devices can be removed, for example, without surgical intervention.
  • interferents and “interfering species” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to effects and/or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement.
  • interfering species are compounds with an oxidation potential that overlaps with the analyte to be measured or one or more mediators.
  • in vivo is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of the portion of a device (for example, a sensor) adapted for insertion into and/or existence within a living body of a host.
  • a device for example, a sensor
  • ex vivo is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of a portion of a device (for example, a sensor) adapted to remain and/or exist outside of a living body of a host.
  • membrane as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a structure configured to perform functions including, but not limited to, protection of the exposed electrode surface from the biological environment, diffusion resistance (limitation) of the analyte, service as a matrix for a catalyst for enabling an enzymatic reaction, limitation or blocking of interfering species, provision of hydrophilicity at the electrochemically reactive surfaces of the sensor interface, service as an interface between host tissue and the implantable device, modulation of host tissue response via drug (or other substance) release, and combinations thereof.
  • the terms “membrane” and “matrix” are meant to be interchangeable.
  • membrane system as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can be comprised of two or more domains, layers, or layers within a domain, and is typically constructed of materials of a few microns thickness or more, which is permeable to oxygen and is optionally permeable to, e.g., glucose or another analyte.
  • the membrane system comprises an immobilized glucose oxidase enzyme, which enables a reaction to occur between glucose and oxygen whereby a concentration of glucose can be measured.
  • noise is a broad term and is used in its ordinary sense, including, without limitation, a signal detected by the sensor or sensor electronics that is unrelated to analyte concentration and can result in reduced sensor performance.
  • One type of noise has been observed during the few hours (e.g., about 2 to about 24 hours) after sensor insertion. After the first 24 hours, the noise may disappear or diminish, but in some hosts, the noise may last for about three to four days.
  • noise can be reduced using predictive modeling, artificial intelligence, and/or algorithmic means.
  • noise can be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as using a drug releasing layer with at least one bioactive agent.
  • noise of one or more exemplary biosensors as presently disclosed can be determined and then compared qualitatively or quantitatively.
  • a smoothed version of the raw signal timeseries can be obtained, e.g., by applying a 3rd order lowpass digital Chebyshev Type II filter. Others smoothing algorithms can be used.
  • an absolute difference, in units of pA can be calculated to provide a smoothed timeseries.
  • This smoothed timeseries can be converted into units of mg/dL, (the unit of "noise"), using a glucose sensitivity timeseries, in units of pA/mg/dL, where the glucose sensitivity timeseries is derived by using a mathematical model between the raw signal and reference blood glucose measurements (e.g., obtained from Blood Glucose Meter).
  • the timeseries can be aggregated as desired, e.g., by hour or day. Comparison of corresponding timeseries between different exemplary biosensors with the presently disclosed drug releasing layer and one or more bioactive agents provides for qualitative or quantitative determination of noise improvement.
  • potentiostat is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an electrical system that applies a potential between the working and reference electrodes of a two- or three-electrode cell at a preset value and measures the current flow through the working electrode.
  • the potentiostat forces whatever current is necessary to flow between the working and counter electrodes to keep the desired potential, as long as the needed cell voltage and current do not exceed the compliance limits of the potentiostat.
  • proximal is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference.
  • some examples of a device include a membrane system having a biointerface layer and an enzyme layer. If the sensor is deemed to be the point of reference and the enzyme layer is positioned nearer to the sensor than the biointerface layer, then the enzyme layer is more proximal to the sensor than the biointerface layer.
  • processor module and "microprocessor” as used herein are each a broad phrase and term, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a computer system, state machine, processor, or the like designed to perform arithmetic or logic operations using logic circuitry that responds to and processes the basic instructions that drive a computer.
  • si-continuous is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a portion, coating, domain, or layer that includes one or more continuous and noncontinuous portions, coatings, domains, or layers.
  • a coating disposed around a sensing region but not about the sensing region is "semi-continuous.”
  • the interaction of the biological sample or component thereof with the analyte measuring device, biosensor, sensor, sensing region, sensing portion, or sensing mechanism results in transduction of a signal that permits a qualitative, semi-qualitative, quantitative, or semi-qualitative determination of the analyte level, for example, glucose, in the biological sample.
  • the sensing region or sensing portion can comprise at least a portion of a conductive substrate or at least a portion of a conductive surface, for example, a wire or conductive trace or a substantially planar substrate including substantially planar trace(s), and a membrane.
  • the sensing region or sensing portion can comprise a non-conductive body, a working electrode, a reference electrode, and a counter electrode (optional), forming an electrochemically reactive surface at one location on the body and an electronic connection at another location on the body, and a sensing membrane affixed to the body and covering the electrochemically reactive surface.
  • Mutations of the PBP can contribute to or alter one or more of the binding constants, extended stability of the protein, including thermal stability, to bind the protein to a special encapsulation matrix, membrane or polymer, or to attach a detectable reporter group or "label" to indicate a change in the binding region.
  • changes in the binding region include, but are not limited to, hydrophobic/hydrophilic environmental changes, three-dimensional conformational changes, changes in the orientation of amino acid side chains in the binding region of proteins, and redox states of the binding region.
  • Such changes to the binding region provide for transduction of a detectable signal corresponding to the one or more analytes present in the biological fluid.
  • the sensing region determines the selectivity among one or more analytes, so that only the analyte which has to be measured leads to (transduces) a detectable signal.
  • the selection may be based on any chemical or physical recognition of the analyte by the sensing region, where the chemical composition of the analyte is unchanged, or in which the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.
  • the sensing region transduces the recognition of analytes into a semi- quantitative or quantitative signal.
  • transducing or “transduction” and their grammatical equivalents as are used herein encompasses optical, electrochemical, acoustical/mechanical, or colorimetrical technologies and methods.
  • Electrochemical properties include current and/or voltage, capacitance, and potential.
  • Optical properties include absorbance, fluorescence/phosphorescence, wavelength shift, phase modulation, bio/chemiluminescence, reflectance, light scattering, and refractive index.
  • sensitivity is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an amount of signal (e.g., in the form of electrical current and/or voltage) produced by a predetermined amount (unit) of the measured analyte.
  • a sensor has a sensitivity (or slope) of from about 1 to about 100 picoAmps of current for every 1 mg/dL of glucose analyte.
  • solid portions as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to portions of a membrane's material having a mechanical structure that demarcates cavities, voids, or other non-solid portions.
  • Electrochemical sensing technology utilizes electrodes to apply potential to a system to facilitate a desired chemical reaction.
  • surface area is diminished on an electrode, for example, by fouling, the performance of the electrochemical system can be affected.
  • the desired analyte cannot reach the electrode surface for electron transfer and/or surface area of the system can be diminished by fouling.
  • fouling occurs when a fouling agent forms an impermeable membrane or coating around or within at least a portion of the surface of an electrode.
  • fouling occurs when a fouling agent forms an impermeable membrane or coating around or within at least a portion of the surface of an electrode that is indwelling in a subject.
  • electrochemical activation is used in an electrochemical analyte detection device where at least a portion of the electroactive surface of the electrode is presented to human blood, plasma, or tissue.
  • the present device and method utilizing electrochemical activation obviates a need for significant design changes to an existing device, which otherwise can take several years of development in a regulated environment such as the medical device industry.
  • FIGs. 1-3 a general summary of the methods of the present disclosure are provided. Thus, as depicted in FIG.
  • step 100 a method comprising step 100, measuring one or more parameters and processing the one or more parameters, step 101, applying a select potential across and electrochemically active surface of an implanted or indwelling electrochemical biosensor, at least a portion of the electrochemically active surface being covered by at least one foulant, and step 102, electrochemically removing at least one foulant from the surface.
  • FIG. 2 depicts a method comprising step 201, perturbing an implanted or indwelling electrochemical biosensor system having a electrochemically active surface area with at least one signal over a frequency range.
  • the frequency is sinusoidal.
  • Step 202 comprises monitoring at least one property of the at least one sinusoidal signal during step 201
  • step 203 comprises detecting a change of the at least one property of the electrochemically active surface area
  • step 204 comprises correlating the change of the least one property with biofouling.
  • FIG. 3 depicts a method comprising step 301 perturbing an electrochemical biosensor system having an at least partially implanted or indwelling electrochemically active surface area with at least one signal over a frequency range.
  • the at least one signal is perturbed with a sinusoidal signal.
  • Step 302 comprises monitoring at least one property of the at least one signal during step 301.
  • Step 303 comprises detecting a change of the at least one property of the electrochemically active surface area and step 304 comprises correlating the change of the at least one property with the presence or absence of fouling.
  • Step 305 comprises applying swept potential across the electrochemically active surface of the electrochemically active surface area and electrochemically removing at least one foulant from the electrochemically active surface.
  • Step 306 comprises repeating step 305 until the change is brought below a threshold value.
  • the methods depicted in FIGS. 1-3 can be performed independently and/or in combination.
  • a combination of direct current (DC) and alternating current (AC) are applied or measured in the methods and devices disclosed herein.
  • DC is used for analyte detection whereas AC is used for de-fouling/cleaning of an electrode surface.
  • DC is used for analyte detection and clea nsing/anti-fou ling, whereas AC is used for detection only.
  • Electrochemical Impedance Spectroscopy uses both AC and DC current, whereas a small AC current (e.g., 20-200 mV peak to peak) is applied to the system while at a DC bias voltage (e.g., 10-1000 mV), while measuring phases shift due to the applied AC voltage.
  • a DC bias voltage e.g. 10-1000 mV
  • cyclic voltammetry is employed where DC current is applied in a predetermined sequence.
  • the sensor system comprises hardware and software to conduct amperometric analysis, potentiometric analysis and a combination of amperometric analysis and potentiometric analysis.
  • the devices and method disclosed herein are applicable to continuous transcutaneous analyte monitoring systems as well as continuous multianalyte monitoring systems.
  • Electrodes are subject to fouling during use. Some electrodes can be modified to reduce fouling.
  • the devices and methods disclosed herein are applicable to any electrode that is fouled by a species with a redox chemistry that occurs in a potential range that is otherwise benign to redox chemistry of membranes, enzymes, cofactors and/or releasing drugs used in continuous analyte sensing devices.
  • electrodes suitable for use in the devices and methods disclosed herein include, for example, platinum and its binary and tertiary alloys, palladium and its binary and tertiary alloys, gold and its binary and tertiary alloys, silver and its binary and tertiary alloys, iridium or indium and its binary and tertiary alloys, indium tin oxide, bismuth molybdate (Bi2Mo06), tin sulfide metal oxide (SnS2), boron doped diamond, platinum coated boron doped diamond, conductive graphite and inks therefrom, gold, platinum, pallidum or iridium coated silicon wafers, doped polyaniline, doped poly(3,4-ethylenedioxythio-phene) polystyrene sulfonate (PEDOT:PSS), doped polypyrrole (Ppy), amorphous carbon, carbon nanotubes, graphene metallic nanoparticles.
  • FIGS. 4-6 illustrate exemplary examples of a single working electrode continuous transcutaneous analyte sensor 800.
  • sensor 800 comprises an elongated conductive body 802, which includes a core 810 and a first layer 812 at least partially surrounding the core.
  • the first layer includes a working electrode (e.g., located in window 806) and a membrane 808 located over the working electrode configured and arranged for multi-axis bending.
  • the core and first layer can be of a single material (e.g., platinum).
  • the elongated conductive body 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.
  • the elongated conductive body comprises a plurality of layers.
  • additional layers can be included in some examples.
  • the layers are coaxial.
  • the elongated conductive body may be long and thin, yet flexible and strong.
  • the smallest dimension of the elongated conductive body is less than about 0.1 inches, 0.075 inches, 0.05 inches, 0.025 inches, 0.01 inches, 0.004 inches, or 0.002 inches.
  • the elongated conductive body is illustrated in FIGS. 4-6 as having a circular or substantially circular cross-section, in other examples the cross-section of the elongated conductive body can be ovoid, rectangular, triangular, polyhedral, star-shaped, C- shaped, T-shaped, X-shaped, Y-Shaped, irregular, or the like.
  • a conductive wire electrode is employed as a core.
  • the core 810 (or a component thereof) provides electrical conduction for an electrical signal from the working electrode to sensor electronics (not shown), which are described elsewhere herein.
  • the core 810 comprises a conductive material, such as titanium, stainless steel, tantalum, a conductive polymer, and/or the like.
  • the core is formed from a non-conductive material, such as a non-conductive polymer.
  • the core comprises a plurality of layers of materials.
  • the core includes an inner core and an outer core.
  • the inner core is formed of a first conductive material and the outer core is formed of a second conductive material.
  • the first conductive material is stainless steel, titanium, tantalum, a conductive polymer, an alloy, and/or the like
  • the second conductive material is conductive material selected to provide electrical conduction between the core and the first layer, and/or to attach the first layer to the core (e.g., if the first layer is formed of a material that does not attach well to the core material).
  • the core is formed of a non-conductive material (e.g., a non-conductive metal and/or a non-conductive polymer) and the first layer is a conductive material, such as titanium, stainless steel, tantalum, a conductive polymer, and/or the like.
  • the core and the first layer can be of a single (or same) material, e.g., platinum.
  • a single (or same) material e.g., platinum.
  • the first layer 812 is formed of a conductive material.
  • the working electrode is an exposed portion of the surface of the first layer.
  • the first layer is formed of a material configured to provide a suitable electroactive surface for the working electrode, a material such as but not limited to platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, an alloy and/or the like.
  • a second layer 804 surrounds a least a portion of the first layer 812, thereby defining the boundaries of the working electrode.
  • the second layer 804 serves as an insulator and is formed of an insulating material, such as polyimide, polyurethane, parylene, or any other known insulating materials, for example, fluorinated polymers, polyethyleneterephthalate, polyurethane, polyimide, other nonconducting polymers, or the like. Glass or ceramic materials can also be employed.
  • Suitable for use include surface energy modified coating systems such as are marketed under the trade names AMC18, AMC148, AMC141, and AMC321 by Advanced Materials Components Express of Bellafonte, Pa.
  • the working electrode may not require a coating of insulator.
  • Removal of coating materials from one or more layers of elongated conductive body can be performed by hand, excimer lasing, chemical etching, laser ablation, grit-blasting, or the like.
  • the senor further comprises a third layer 814 comprising a conductive material.
  • the third layer may comprise a reference electrode, which may be formed of a silver-containing material that is applied onto the second layer (e.g., an insulator).
  • the silver-containing material may include any of a variety of materials and be in various forms, such as, Ag/AgCl-polymer pastes, paints, polymer- based conducting mixture, and/or inks that are commercially available, for example.
  • the third layer can be processed using a pasting/dipping/coating step, for example, using a diemetered dip coating process.
  • an Ag/AgCI polymer paste is applied to an elongated body by dip-coating the body (e.g., using a meniscus coating technique) and then drawing the body through a die to meter the coating to a precise thickness.
  • multiple coating steps are used to build up the coating to a predetermined thickness.
  • the silver grain in the Ag/AgCI solution or paste can have an average particle size corresponding to a maximum particle dimension that is less than about 100 microns, or less than about 50 microns, or less than about 30 microns, or less than about 20 microns, or less than about 10 microns, or less than about 5 microns.
  • the silver chloride grain in the Ag/AgCI solution or paste can have an average particle size corresponding to a maximum particle dimension that is less than about 100 microns, or less than about 80 microns, or less than about 60 microns, or less than about 50 microns, or less than about 20 microns, or less than about 10 microns.
  • the silver grain and the silver chloride grain may be incorporated at a ratio of the silver chloride grain:silver grain of from about 0.01:1 to 2:1 by weight, or from about 0.1:1 to 1:1.
  • the silver grains and the silver chloride grains are then mixed with a carrier (e.g., a polyurethane) to form a solution or paste.
  • a carrier e.g., a polyurethane
  • the Ag/AgCI component form from about 10% to about 65% by weight of the total Ag/AgCI solution or paste, or from about 20% to about 50%, or from about 23% to about 37%.
  • the Ag/AgCI solution or paste has a viscosity (under ambient conditions) that is from about 1 to about 500 centipoise, or from about 10 to about 300 centipoise, of from about 50 to about 150 centipoise.
  • the above-exemplified sensor has an overall diameter of not more than about 0.020 inches (about 0.51 mm), more preferably not more than about 0.018 inches (about 0.46 mm), and most preferably not more than about 0.016 inches (0.41 mm).
  • the working electrode has a diameter of from about 0.001 inches or less to about 0.010 inches or more, preferably from about 0.002 inches to about 0.008 inches, and more preferably from about 0.004 inches to about 0.005 inches.
  • the length of the window can be from about 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078 inches) or more, and preferably from about 0.5 mm (about 0.02 inches) to about 0.75 mm (0.03 inches).
  • the exposed surface area of the working electrode is preferably from about 0.000013 in2 (0.0000839 cm2) or less to about 0.0025 in2(0.016129 cm2) or more (assuming a diameter of from about 0.001 inches to about 0.010 inches and a length of from about 0.004 inches to about 0.078 inches).
  • the exposed surface area of the working electrode is selected to produce an analyte signal with a current in the femtoampere range, picoampere range, the nanoampere range, the or the microampere range such as is described in more detail elsewhere herein.
  • a current in the picoampere range or less can be dependent upon a variety of factors, for example the electronic circuitry design (e.g., sample rate, current draw, A/D converter bit resolution, etc.), the membrane system (e.g., permeability of the analyte through the membrane system), and the exposed surface area of the working electrode.
  • the exposed electroactive working electrode surface area can be selected to have a value greater than or less than the above-described ranges taking into consideration alterations in the membrane system and/or electronic circuitry.
  • the exposed surface area of the working (and/or other) electrode can be increased by altering the cross-section of the electrode itself.
  • the cross-section of the working electrode can be defined by a cross, star, cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circular configuration; thus, for any predetermined length of electrode, a specific increased surface area can be achieved (as compared to the area achieved by a circular cross-section).
  • Increasing the surface area of the working electrode can be advantageous in providing an increased signal responsive to the analyte concentration, which in turn can be helpful in improving the signal-to-noise ratio, for example.
  • the elongated conductive body further comprises one or more intermediate layers located between the core and the first layer.
  • the intermediate layer is an insulator, a conductor, a polymer, and/or an adhesive.
  • the core comprises a non-conductive polymer and the first layer comprises a conductive material.
  • a sensor configuration can sometimes provide reduced material costs, in that it replaces a typically expensive material with an inexpensive material.
  • the core is formed of a non-conductive polymer, such as, a nylon or polyester filament, string or cord, which can be coated and/or plated with a conductive material, such as platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, and allows or combinations thereof.
  • the senor also includes a membrane 808 covering at least a portion of the working electrode.
  • Membranes are discussed in detail in greater detail elsewhere herein, for example, with reference to FIGS. 7A-7C.
  • Exemplary sensor configurations may be applied to any planar or non-planar surface, for example.
  • the sensor system has additional electrodes arranged as one or more concentric substantially ring-shaped electrodes, or rows or arrays of electrodes on a planar or substantially planar substrate.
  • FIG. 7A is a cross-sectional view through a sensor, illustrating one example of the membrane system 908.
  • the membrane system includes an interference domain 942, an enzyme domain 944, and a diffusion resistance domain 946 located around the working electrode 938, all of which are described in more detail elsewhere herein.
  • the membrane system may include a bioprotective domain 948, also referred to as a cell-impermeable domain or biointerface domain, comprising a surface-modified base polymer as described in more detail elsewhere herein.
  • a unitary diffusion resistance domain and bioprotective domain may be included in the membrane system (e.g., wherein the functionality of both domains is incorporated into one domain, i.e., the bioprotective domain).
  • the sensor is configured for implantation from about 1 to 30 days).
  • the membrane system 908 can be modified for use in other devices, for example, by including only one or more of the domains, or additional domains.
  • the membrane system may include an electrode domain 936.
  • the electrode domain 936 is provided to ensure that an electrochemical reaction occurs between the electroactive surfaces of the working electrode and the reference electrode, and thus the electrode domain may be situated more proximal to the electroactive surfaces than the interference and/or enzyme domain.
  • the electrode domain may include a coating that maintains a layer of water at the electrochemically reactive surfaces of the sensor. In other words, the electrode domain may be present to provide an environment between the surfaces of the working electrode and the reference electrode, which facilitates an electrochemical reaction between the electrodes.
  • a sensing membrane comprising one or more domains of polymeric membranes may be formed from materials such as polytetrafluoroethylene, silicone, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, polyethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers.
  • materials such as polytetrafluoroethylene, silicone, polyethylene-co
  • the sensing membrane generally provides one or more of the following functions: 1) protection of the exposed electrode surface from the biological environment, 2) diffusion resistance (limitation) of the analyte, 3) a catalyst for enabling an enzymatic reaction, 4) limitation or blocking of interfering species, and 5) hydrophilicity at the electrochemically reactive surfaces of the sensor interface, such as described in the above-referenced co-pending U.S. patent applications.
  • one or more domains of the membranes are formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, polyethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers.
  • the electrode domain includes a flexible, water-swellable, hydrogel film having a "dry film” thickness of from about 0.05 micron or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns.
  • “Dry film” thickness refers to the thickness of a cured film cast from a coating formulation by standard coating techniques.
  • the electrode domain is formed of a curable mixture of a urethane polymer and a hydrophilic polymer.
  • Particularly preferred coatings are formed of a polyurethane polymer having carboxylate functional groups and non-ionic hydrophilic polyether segments, wherein the polyurethane polymer is crosslinked with a water soluble carbodiimide (e.g., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC))) in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 50° C.
  • a water soluble carbodiimide e.g., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
  • the electrode domain is deposited by spray or dip-coating the electroactive surfaces of the sensor. More preferably, the electrode domain is formed by dip-coating the electroactive surfaces in an electrode solution and curing the domain for a time of from about 15 to about 30 minutes at a temperature of from about 40 to about 55° C. (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)).
  • a preferred insertion rate of from about 1 to about 3 inches per minute, with a preferred dwell time of from about 0.5 to about 2 minutes, and a preferred withdrawal rate of from about 0.25 to about 2 inches per minute provide a functional coating.
  • an optional interference domain is provided, which generally includes a polymer domain that restricts the flow of one or more interferants.
  • the interference domain functions as a molecular sieve that allows analytes and other substances that are to be measured by the electrodes to pass through, while preventing passage of other substances, including interferants such as ascorbate and urea (see U.S. Pat. No. 6,001,067 to Shults).
  • Some known interferants for a glucose-oxidase based electrochemical sensor include acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid.
  • the interference domain includes a thin, hydrophobic membrane that is non-swellable and restricts diffusion of low molecular weight species.
  • the interference domain is permeable to relatively low molecular weight substances, such as hydrogen peroxide, but restricts the passage of higher molecular weight substances, including glucose and ascorbic acid.
  • the interference domain is deposited onto the electrode domain (or directly onto the electroactive surfaces when a distinct electrode domain is not included) for a domain thickness of from about 0.05 micron or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns.
  • Thicker membranes can also be useful, but thinner membranes are generally preferred because they have a lower impact on the rate of diffusion of hydrogen peroxide from the enzyme membrane to the electrodes.
  • the thin thickness of the interference domains conventionally used can introduce variability in the membrane system processing. For example, if too much or too little interference domain is incorporated within a membrane system, the performance of the membrane can be adversely affected.
  • the sensor's response is preferably limited by neither enzyme activity nor co-reactant concentration. Because enzymes, including glucose oxidase, are subject to deactivation as a function of time even in ambient conditions, this behavior is compensated for in forming the enzyme domain.
  • the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme.
  • the enzyme domain is constructed from an oxygen enhancing material, for example, silicone, or fluorocarbon, in order to provide a supply of excess oxygen during transient ischemia.
  • the enzyme is immobilized within the domain. See U.S.
  • the enzyme domain is deposited onto the interference domain for a domain thickness of from about 0.05 micron or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns.
  • the enzyme domain is deposited onto the electrode domain or directly onto the electroactive surfaces.
  • the enzyme domain is deposited by spray or dip coating.
  • the enzyme domain is formed by dip-coating the electrode domain into an enzyme domain solution and curing the domain for from about 15 to about 30 minutes at a temperature of from about 40 to about 55° C. (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)).
  • a preferred insertion rate of from about 1 inch per minute to about 3 inches per minute, with a preferred dwell time of from about 0.5 minutes to about 2 minutes, and a preferred withdrawal rate of from about 0.25 inch per minute to about 2 inches per minute provide a functional coating.
  • the enzyme domain is formed by dip coating two times (namely, forming two layers) in a coating solution and curing at 50° C. under vacuum for 20 minutes.
  • the enzyme domain can be formed by dip-coating and/or spray-coating one or more layers at a predetermined concentration of the coating solution, insertion rate, dwell time, withdrawal rate, and/or desired thickness.
  • the membrane system includes a resistance domain disposed more distal from the electroactive surfaces than the enzyme domain.
  • a resistance domain disposed more distal from the electroactive surfaces than the enzyme domain.
  • an immobilized enzyme-based glucose sensor employing oxygen as co-reactant is preferably supplied with oxygen in non-rate-limiting excess in order for the sensor to respond linearly to changes in glucose concentration, while not responding to changes in oxygen concentration. Specifically, when a glucose-monitoring reaction is oxygen limited, linearity is not achieved above minimal concentrations of glucose.
  • a linear response to glucose levels can be obtained only for glucose concentrations of up to about 40 mg/dL. However, in a clinical setting, a linear response to glucose levels is desirable up to at least about 400 mg/dL.
  • the resistance domain includes a semi-permeable membrane that controls the flux of oxygen and glucose to the underlying enzyme domain, preferably rendering oxygen in a non-rate-limiting excess.
  • the resistance domain exhibits an oxygen to glucose permeability ratio of from about 50:1 or less to about 400:1 or more, preferably about 200:1.
  • one-dimensional reactant diffusion is adequate to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (See Rhodes et al., Anal. Chem., 66:1520-1529 (1994)).
  • a lower ratio of oxygen-to-glucose can be sufficient to provide excess oxygen by using a high oxygen solubility domain (for example, a silicone or fluorocarbon-based material or domain) to enhance the supply/transport of oxygen to the enzyme domain. If more oxygen is supplied to the enzyme, then more glucose can also be supplied to the enzyme without creating an oxygen rate-limiting excess.
  • the resistance domain is formed from a silicone composition, such as is described in co-pending U.S. application Ser. No. 10/695,636 filed Oct. 28, 2003 and entitled,
  • the resistance domain includes a polyurethane membrane with both hydrophilic and hydrophobic regions to control the diffusion of glucose and oxygen to an analyte sensor, the membrane being fabricated easily and reproducibly from commercially available materials.
  • a suitable hydrophobic polymer component is a polyurethane, or polyetherurethaneurea.
  • Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxylcontaining material.
  • a polyurethaneurea is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material.
  • Preferred diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units.
  • Diisocyanates containing cycloaliphatic moieties can also be useful in the preparation of the polymer and copolymer components of the membranes of the present disclosure.
  • the material that forms the basis of the hydrophobic matrix of the resistance domain can be any of those known in the art as appropriate for use as membranes in sensor devices and as having sufficient permeability to allow relevant compounds to pass through it, for example, to allow an oxygen molecule to pass through the membrane from the sample under examination in order to reach the active enzyme or electrochemical electrodes.
  • non-polyurethane type membranes examples include vinyl polymers, polyethers, polyesters, polyamides, inorganic polymers such as polysiloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein-based materials, and mixtures or combinations thereof.
  • the hydrophilic polymer component of the resistance domain is polyethylene oxide.
  • one useful hydrophobic-hydrophilic copolymer component is a polyurethane polymer that includes about 20% hydrophilic polyethylene oxide.
  • the polyethylene oxide portions of the copolymer are thermodynamically driven to separate from the hydrophobic portions of the copolymer and the hydrophobic polymer component.
  • the 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend affects the water pick-up and subsequent glucose permeability of the membrane.
  • the resistance domain is deposited onto the enzyme domain to yield a domain thickness of from about 0.05 micron or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns.
  • the resistance domain is deposited onto the enzyme domain by spray coating or dip coating.
  • spray coating is the preferred deposition technique.
  • the spraying process atomizes and mists the solution, and therefore most or all of the solvent is evaporated prior to the coating material settling on the underlying domain, thereby minimizing contact of the solvent with the enzyme.
  • One additional advantage of spraycoating the resistance domain as described in the present disclosure includes formation of a membrane system that substantially blocks or resists ascorbate (a known electrochemical interferant in hydrogen peroxide-measuring glucose sensors). While not wishing to be bound by theory, it is believed that during the process of depositing the resistance domain as described in the present disclosure, a structural morphology is formed, characterized in that ascorbate does not substantially permeate there through.
  • the resistance domain is deposited on the enzyme domain by spray-coating a solution of from about 1 wt. % to about 5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent.
  • a solution of resistance domain material including a solvent
  • Tetrahydrofuran (THF) is one solvent that minimally or negligibly affects the enzyme of the enzyme domain upon spraying.
  • Other solvents can also be suitable for use, as is appreciated by one skilled in the art.
  • the resistance domain is spray-coated and subsequently cured for a time of from about 15 to about 90 minutes at a temperature of from about 40 to about 60° C. (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)).
  • a cure time of up to about 90 minutes or more can be advantageous to ensure complete drying of the resistance domain. While not wishing to be bound by theory, it is believed that complete drying of the resistance domain aids in stabilizing the sensitivity of the glucose sensor signal. It reduces drifting of the signal sensitivity over time, and complete drying is believed to stabilize performance of the glucose sensor signal in lower oxygen environments.
  • the resistance domain is formed by spray-coating at least six layers (namely, rotating the sensor seventeen times by 120° for at least six layers of 360° coverage) and curing at 50° C. under vacuum for 60 minutes.
  • the resistance domain can be formed by dip-coating or spray-coating any layer or plurality of layers, depending upon the concentration of the solution, insertion rate, dwell time, withdrawal rate, and/or the desired thickness of the resulting film.
  • sensors with the membrane system of the present disclosure including an electrode domain and/or interference domain, an enzyme domain, and a resistance domain, provide stable signal response to increasing glucose levels of from about 40 to about 400 mg/dL, and sustained function (at least 90% signal strength) even at low oxygen levels (for example, at about 0.6 mg/L 02). While not wishing to be bound by theory, it is believed that the resistance domain provides sufficient resistivity, or the enzyme domain provides sufficient enzyme, such that oxygen limitations are seen at a much lower concentration of oxygen as compared to prior art sensors.
  • the membrane system is designed with a sensitivity of from about 1 pA/mg/dL to about 100 pA/mg/dL, preferably from about 5 pA/mg/dL to 25 pA/mg/dL, and more preferably from about 4 to about 7 pA/mg/dL. While not wishing to be bound by any particular theory, it is believed that membrane systems designed with a sensitivity in the preferred ranges permit measurement of the analyte signal in low analyte and/or low oxygen situations.
  • sensors can be built without distinct or deposited interference domains, which are non-responsive to interferants. While not wishing to be bound by theory, it is believed that a simplified multilayer membrane system, more robust multilayer manufacturing process, and reduced variability caused by the thickness and associated oxygen and glucose sensitivity of the deposited micron-thin interference domain can be provided. Additionally, the optional polymer-based interference domain, which usually inhibits hydrogen peroxide diffusion, is eliminated, thereby enhancing the amount of hydrogen peroxide that passes through the membrane system.
  • the senor includes a porous material disposed over some portion thereof, which modifies the host's tissue response to the sensor.
  • the porous material surrounding the sensor advantageously enhances and extends sensor performance and lifetime by slowing or reducing cellular migration to the sensor and associated degradation that would otherwise be caused by cellular invasion if the sensor were directly exposed to the in vivo environment.
  • the porous material can provide stabilization of the sensor via tissue ingrowth into the porous material in the long term.
  • the porous material surrounding the sensor provides unique advantages in vivo (e.g., one to 14 days) that can be used to enhance and extend sensor performance and lifetime. However, such materials can also provide advantages in the long term too (e.g., greater than 14 days).
  • the in vivo portion of the sensor (the portion of the sensorthat is implanted into the host's tissue) is encased (partially or fully) in a porous material.
  • the porous material can be wrapped around the sensor (for example, by wrapping the porous material around the sensor or by inserting the sensor into a section of porous material sized to receive the sensor).
  • the porous material can be deposited on the sensor (for example, by electrospinning of a polymer directly thereon).
  • the sensor is inserted into a selected section of porous biomaterial.
  • Other methods for surrounding the in vivo portion of the sensor with a porous material can also be used as is appreciated by one skilled in the art.
  • the porous material surrounding the sensor advantageously slows or reduces cellular migration to the sensor and associated degradation that would otherwise be caused by cellular invasion if the sensor were directly exposed to the in vivo environment.
  • the porous material provides a barrier that makes the migration of cells towards the sensor more tortuous and therefore slower. It is believed that this reduces or slows the sensitivity loss normally observed over time.
  • the porous material is a high oxygen solubility material, such as porous silicone
  • the high oxygen solubility porous material surrounds some of or the entire in vivo portion of the sensor.
  • a lower ratio of oxygen-to-glucose can be sufficient to provide excess oxygen by using a high oxygen soluble domain (for example, a silicone- or fluorocarbon-based material) to enhance the supply/transport of oxygen to the enzyme membrane and/or electroactive surfaces. It is believed that some signal noise normally seen by a conventional sensor can be attributed to an oxygen deficit. Silicone has high oxygen permeability, thus promoting oxygen transport to the enzyme layer.
  • glucose concentration can be less of a limiting factor.
  • more oxygen can also be supplied to the enzyme without creating an oxygen rate-limiting excess.
  • silicone materials provide enhanced biostability when compared to other polymeric materials such as polyurethane.
  • the aforementioned porous material is a biointerface membrane comprising a first domain that includes an architecture, including cavity size, configuration, and/or overall thickness, that modifies the host's tissue response, for example, by creating a fluid pocket, encouraging vascularized tissue ingrowth, disrupting downward tissue contracture, resisting fibrous tissue growth adjacent to the device, and/or discouraging barrier cell formation.
  • the biointerface membrane in one example covers at least the sensing mechanism of the sensor and can be of any shape or size, including uniform, asymmetrically, or axi-symmetrically covering or surrounding a sensing mechanism or sensor.
  • a second domain of the biointerface membrane is optionally provided that is impermeable to cells and/or cell processes.
  • a bioactive agent is optionally provided that is incorporated into the at least one of the first domain, the second domain, the sensing membrane, or other part of the implantable device, wherein the bioactive agent is configured to modify a host tissue response.
  • the biointerface includes a bioactive agent, the bioactive agent being incorporated into at least one of the first and second domains of the biointerface membrane, or into the device and adapted to diffuse through the first and/or second domains, in order to modify the tissue response of the host to the membrane.
  • biointerface membrane or release membrane of the present disclosure can be formed onto the sensor using techniques such as electrospinning, molding, weaving, direct-writing, lyophilizing, wrapping, and the like.
  • a dispenser dispenses a polymer solution using a nozzle with a valve, or the like, for example as described in U.S. Publication No. 2004/0253365 Al.
  • a variety of nozzles and/or dispensers can be used to dispense a polymeric material to form the woven or non-woven fibers of the biointerface membrane.
  • the inflammatory response to biomaterial implants can be divided into two phases.
  • the first phase consists of mobilization of mast cells and then infiltration of predominantly polymorphonuclear (PMN) cells.
  • This phase is termed the acute inflammatory phase.
  • chronic cell types that comprise the second phase of inflammation replace the PMNs.
  • Macrophage and lymphocyte cells predominate during this phase. While not wishing to be bound by any particular theory, it is believed that restricting vasodilation and/or blocking pro-inflammatory signaling, short-term stimulation of vascularization, or short-term inhibition of scar formation or barrier cell layer formation, provides protection from scar tissue formation and/or reduces acute inflammation, thereby providing a stable platform for sustained maintenance of the altered foreign body response, for example.
  • bioactive intervention can modify the foreign body response in the early weeks of foreign body capsule formation and alter the extended behavior of the foreign body capsule. Additionally, it is believed that in some circumstances the biointerface membranes of the present disclosure can benefit from bioactive intervention to overcome sensitivity of the membrane to implant procedure, motion of the implant, or other factors, which are known to otherwise cause inflammation, scar formation, and hinder device function in vivo.
  • preferred bioactive agents include SIP (Sphingosine-l-phosphate), Monobutyrin, Cyclosporin A, Anti-thrombospondin-2, Rapamycin (and its derivatives), NLRP3 inflammasome inhibitors such as MCC950, and Dexamethasone.
  • SIP Sphingosine-l-phosphate
  • Monobutyrin Cyclosporin A
  • Anti-thrombospondin-2 Rapamycin (and its derivatives)
  • NLRP3 inflammasome inhibitors such as MCC950
  • Dexamethasone Dexamethasone
  • Bioactive agents suitable for use in the present disclosure are loosely organized into two groups: anti-barrier cell agents and vascularization agents. These designations reflect functions that are believed to provide short-term solute transport through the one or more membranes of the presently disclosed sensor, and additionally extend the life of a healthy vascular bed and hence solute transport through the one or more membranes long term in vivo. However, not all bioactive agents can be clearly categorized into one or other of the above groups; rather, bioactive agents generally comprise one or more varying mechanisms for modifying tissue response and can be generally categorized into one or both of the above-cited categories.
  • a combination of dexamethasone and dexamethasone acetate is incorporated into the drug releasing membrane.
  • dexamethasone and/or dexamethasone acetate combined with one or more other antiinflammatory and/or immunosuppressive agents is incorporated into the drug releasing membrane.
  • Rapamycin which is a potent specific inhibitor of some macrophage inflammatory functions, can be incorporated into the release membrane alone or in combination with dexamethasone, dexamethasone salts, dexamethasone derivatives in particular, dexamethasone acetate.
  • Suitable medicaments, pharmaceutical compositions, therapeutic agents, or other desirable substances can be incorporated into the drug releasing membrane 70 of the present disclosure, including, but not limited to, anti-inflammatory agents, anti-infective agents, necrosing agents, and anesthetics. It is to be understood that the different membrane/membrane systems described above can be applied to any of the sensors/sensor systems described herein. Additionally, it is also to be understood that any of the membranes (including membrane layers and domains), membrane properties, and membrane-derived results can be used with any of the sensors/sensor systems described herein.
  • bioactive agent in some examples is incorporated into the biointerface membrane or release membrane and/or implantable device
  • the bioactive agent can be administered concurrently with, prior to, or after implantation of the device systemically, for example, by oral administration, or locally, for example, by subcutaneous injection near the implantation site.
  • a combination of bioactive agent incorporated in the biointerface membrane and bioactive agent administration locally and/or systemically can be preferred in certain examples.
  • the drug release membrane functions as the biointerface membrane.
  • the drug releasing membrane is chemically distinct from the biointerface membrane, or no biointerface membrane is used.
  • one or more bioactive agents are incorporated into the drug releasing membrane or both the biointerface membrane and the drug releasing membrane.
  • Such drug releasing membranes are disclosed in co-assigned PCT/US2022/043641, which is incorporated herein by reference in its entirety.
  • a single working electrode sensor can be configured to measure and detect various in vivo analyte concentrations in combination with properties and physiological changes and conditions associated with the indwelling electrode. Such types of electrode and sensor can, for example, be coupled with or integrated with or in communication with devices or systems that measure and detect in combination various in vivo properties and physiological conditions sequentially, concurrently or randomly.
  • a single-working-electrode-based sensor system is capable of measuring both an analyte concentration and physiological changes/conditions in a sensor environment through bias potential methods as disclosed herein.
  • a single-working- electrode-based sensor system is capable of measuring both an analyte concentration and physiological changes/conditions in a sensor environment through bias potential methods alone or in combination with impedance methods as disclosed herein.
  • FIG. 8 is a perspective-view schematic illustrating an in vivo portion of a singleworking-electrode analyte sensor 1200, wherein the elongated body E comprises a plurality of working electrodes 1202' exposed through windows.
  • window can be formed by completely removing (360 degrees around the perimeter of the elongated body) a portion of a conductive layer 1214 and an insulating layer 1204, thereby exposing an electroactive surface of the window.
  • Windows can be formed by removing a cut portion (i.e., a cut that does not correspond to 360 degrees around the perimeter of the elongated body) of the conductive layer 1214 and a portion of the insulating layer 1204, thereby exposing electroactive surfaces of elongated body E. All the working electrodes 1202' and 1202 share a common electrical connection.
  • the conductive layer 1214 may function as a reference electrode and may be formed of any of a variety of materials and be in various forms, such as, Ag/AgCl-polymer pastes, paints, polymer-based conducting mixture, and/or inks that are commercially available, for example.
  • a portion of the coated assembly structure can be stripped or otherwise removed, for example, by hand, excimer lasing, chemical etching, laser ablation, grit-blasting, or the like, to expose the electroactive surfaces.
  • a portion of the electrode can be masked prior to depositing the insulator in order to maintain an exposed electroactive surface area.
  • a radial window is formed through the insulating material to expose a circumferential electroactive surface of the working electrode.
  • sections of electroactive surface of the reference electrode are exposed.
  • the sections of electroactive surface can be masked during deposition of an outer insulating layer or etched after deposition of an outer insulating layer.
  • cellular attack or migration of cells to the sensor can cause reduced sensitivity or function of the device, particularly after the first day of implantation.
  • the exposed electroactive surface is distributed circumferentially about the sensor (e.g. as in a radial window)
  • the available surface area for reaction can be sufficiently distributed so as to minimize the effect of local cellular invasion of the sensor on the sensor signal.
  • a tangential exposed electroactive window can be formed, for example, by stripping only one side of the coated assembly structure.
  • the window can be provided at the tip of the coated assembly structure such that the electroactive surfaces are exposed at the tip of the sensor.
  • Other methods and configurations for exposing electroactive surfaces can also be employed.
  • the configuration of FIG. 8 can employ any of the membrane structures disclosed herein.
  • the single working electrode When powered at its normal bias potential, the single working electrode is in a mode for analyte concentration (e.g., glucose concentration) measurement.
  • the bias potential may be changed as described herein.
  • the bias potential may be decreased, or the frequency of the applied bias potential can be altered, to a level such that the working electrode can no longer oxidize the measured species (e.g., hydrogen peroxide that is indicative of glucose concentration) or provide electron transfer in a mediated redox system. Nonetheless, at a lower bias potential, the working electrode may be capable of measuring or detecting some other parameter that is indicative of biofouling and/or physiological conditions or changes.
  • the working electrode's bias potential may alternate from one bias potential (e.g., for measuring glucose or redox current) to another bias potential (for measuring/detecting biofouling and/or another parameter, such as a parameter related to sensor environment).
  • the timing and frequency of the changes in applied bias potential is dependent on certain parameters that are indicative of a possible change involving the sensor environment, e.g., biofouling.
  • the system if the system detects a high rate of signal drift or increase in impedance, the system is configured to apply an alternate bias potential as described herein to commence cleaning of the electrode(s).
  • the bias potential may be altered as described herein (e.g., increased) to measure oxygen concentration and oxygen concentration changes, which may be indicative of certain physiological changes to the sensor environment (e.g., encapsulation/biofouling of the sensor).
  • implantable sensors are the result of differences in patient physiology that impacts sensor performances (like differences in in vitro/in vivo sensitivity), especially as they relate to tissue composition and the hydration status of the sensor's environment.
  • this limitation has been one of the major challenges to creating a factory calibrated glucose sensor.
  • two sensors tested to an identical sensitivity on the bench may exhibit two very different in vivo sensitivities in two different patients (or even the same patient at two different time periods). Accordingly, this may complicate predictions of in vivo behavior based solely on bench test data alone.
  • impedance measurements can be used to detect a wound healing response, excess edema, buildup of biomaterials, or encapsulation, which in turn can be used to identify temporary or permanent loss of sensor sensitivity. Impedance measurements can also be indicative of loss of signal due to tissue compression and displacement of the sensor. In some examples, a single impedance measurement can be compared to known or expected impedance values to evaluate whether impedance is abnormal. Alternatively, multiple impedance measurements can be taken at varying frequencies. Additionally, multiple impedance measurements can be taken over time to monitor changes in the tissue. For example, encapsulation of the sensor by surrounding tissue can be indicated by abnormally high resistivity or increasing resistivity, and thus a high impedance value or an increase in impedance can be used to identify encapsulation tissue.
  • I mpedance measurements can indicate, independently or in combination with the methods disclosed herein, certain physiological conditions within the host.
  • impedance measurements e.g., impedance measurements between the bottom surface of the sensor housing 602, 702 (skin surface) and the tip of the sensor 606, 706— individual patient physiologic information may be provided to an algorithm used to calculate analyte concentration.
  • Such use of physiologic information can provide, to the sensor system, adjustments (e.g., adjustments to processing of sensor signal) that accounts for differences in physiology between patients.
  • sensor algorithm prediction of in vivo sensor performance is segregated by impedance states, such as high body fat, low hydration states, and/or high hydration states. In one example, this information is used to select certain algorithm parameters/predictions states to improve accuracy and overall sensor performance and also to improve the reliability of bench data prediction of in vivo sensor use.
  • Fouling can occur several ways, which are dictated by chemical properties of the fouling agent, electrode properties of substances in proximity to the electrode surface, and applied potential amount and duration.
  • the result of fouling includes, for example, reducing the conductivity of the electrode surface or by preventing one or more analytes of interest from reaching the surface of the electrode and thus lowering the current generated by the reaction of that analyte and the electrode (sensitivity).
  • Many compounds, such as proteins and neurotransmitters, that are present in-vivo can cause fouling of electrodes presented to such environments.
  • the biological media In addition to the presence of many compounds that cause electrode fouling, the biological media also often possesses extremely low concentrations of the target analyte with respect to other background species. This means that even minor degradation of the electrode surface characteristics or analyte contact to the electrode surface could manifest in significant performance issues for the system. Due to the unique fouling properties of molecules found in-vivo a universal method to detect and compensate for fouling is necessary for biosensor technology.
  • Electrochemical activation can be applied to sensing technologies in real time to improve accuracy and reliability of readings during the wear period, for example, until end of life.
  • Bench evidence demonstrates the electrode fouling of bare wires can be reversed through electrochemical cleaning. Electrochemical cleaning was facilitated through a technique called cyclic voltammetry (CV), in which voltage is swept forwards and backwards, in this process, chemicals adsorbed to the surface can be removed.
  • CV cyclic voltammetry
  • the presently disclosed device and method utilizing electrochemical activation/detection/cleaning obviates the need for anti-fouling layers, e.g., polymer layers such as a polyvinylchloride-("PVC") and/or a poly-vinylpyridine (“PVP").
  • polymer layers such as a polyvinylchloride-("PVC") and/or a poly-vinylpyridine (“PVP").
  • the methods disclosed herein provide for measuring current at a plurality of potentials for determining the oxidation and or reduction potential of one or more redox active moiety or moieties associated with or immobilized on an electroactive surface.
  • voltammetry is used.
  • cyclic voltammetry, pulse voltammetry, normal pulse voltammetry, square wave voltammetry, differential pulse voltammetry linear voltammetry, or square wave voltammetry is used.
  • a source for supplying a plurality of potentials is a potentiostat, for example, a potentiostat capable of applying square waves for square wave voltammetry, etc.
  • the senor is configured to perform voltammetry by periodically sweeping or scanning the bias potential and recording the signal response.
  • pulse voltammetry is performed at about 2.5, 10, 20, 22.5, 30, and 40 hours after sensor activation. With each pulse voltammetry performed, a curved plot is obtained. Any of a variety of voltammetry techniques (e.g., cyclic voltammetry, squarewave voltammetry, and staircase voltammetry) may also be used in replacement of (or in addition) to pulse voltammetry. Certain sections of the plot may be more important than other others in terms of analysis for identifying biofouled electroactive surfaces of an electrode event.
  • the section of the plot near 600 mV can be important.
  • the section of the plot near the bias potential can be important to indicate biofouling of the electroactive surface of the electrode.
  • a biofouled electroactive surfaces of an electrode can be identified when the most recent plot(s) have a shape or a shift in a certain section (e.g., corresponding to a target mV) that is substantially different from those of other plots made during an earlier time. For example, in FIG. 11, at a section near a bias potential of 600 mV, the plots corresponding to 30 and 40 hour post sensor activation show a shift that is not insubstantial.
  • the sensor system may be programmed to have a certain threshold corresponding to shift, such that if the shift exceeds such threshold, the possibility of an biofouled electroactive surfaces of an electrode event for the electroactive surface is identified.
  • the sensor system after a threshold is exceeded, commences one or more of the foulant removal methods as disclosed herein.
  • a potentiostat which is operably connected to an electrode system (such as described above) provides a voltage to the electrodes, which biases the sensor to enable measurement of an current signal indicative of the analyte concentration in the host (also referred to as the analog portion).
  • the potentiostat includes a resistor that translates the current into voltage.
  • a current to frequency converter is provided that is configured to continuously integrate the measured current, for example, using a charge counting device.
  • An A/D converter digitizes the analog signal into a digital signal, also referred to as "counts" for processing. Accordingly, the resulting raw data stream in counts, also referred to as raw sensor data, is directly related to the current measured by the potentiostat.
  • a processor module includes the central control unit that controls the processing of the sensor electronics.
  • the processor module includes a microprocessor, however a computer system other than a microprocessor can be used to process data as described herein, for example an ASIC can be used for some or all of the sensor's central processing.
  • the processor typically provides semi-permanent storage of data, for example, storing data such as sensor identifier (ID) and programming to process data streams (for example, programming for data smoothing and/or replacement of signal artifacts such as is described in co-pending U.S. patent application Ser. No. 10/648,849, filed Aug.
  • the processor additionally can be used for the system's cache memory, for example for temporarily storing recent sensor data.
  • the processor module comprises memory storage components such as ROM, RAM, dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flash memory, or the like.
  • the processor module comprises a digital filter, for example, an HR or FIR filter, configured to smooth the raw data stream from the A/D converter.
  • digital filters are programmed to filter data sampled at a predetermined time interval (also referred to as a sample rate).
  • a predetermined time interval also referred to as a sample rate.
  • the potentiostat is configured to measure the analyte at discrete time intervals, these time intervals determine the sample rate of the digital filter.
  • the processor module can be programmed to request a digital value from the A/D converter at a predetermined time interval, also referred to as the acquisition time.
  • the values obtained by the processor are advantageously averaged over the acquisition time due the continuity of the current measurement. Accordingly, the acquisition time determines the sample rate of the digital filter.
  • the processor module is configured with a programmable acquisition time, namely, the predetermined time interval for requesting the digital value from the A/D converter is programmable by a user within the digital circuitry of the processor module.
  • An acquisition time of from about 2 seconds to about 512 seconds is preferred; however any acquisition time can be programmed into the processor module.
  • a programmable acquisition time is advantageous in optimizing noise filtration, time lag, and processing/battery power.
  • the processor module is configured to build the data packet for transmission to an outside source, for example, an RF transmission to a receiver as described in more detail below.
  • the data packet comprises a plurality of bits that can include a sensor ID code, raw data, filtered data, and/or error detection or correction.
  • the processor module can be configured to transmit any combination of raw and/or filtered data.
  • the processor module further comprises a transmitter portion that determines the transmission interval of the sensor data to a receiver, or the like.
  • the transmitter portion which determines the interval of transmission, is configured to be programmable.
  • a coefficient can be chosen (e.g., a number of from about 1 to about 100, or more), wherein the coefficient is multiplied by the acquisition time (or sampling rate), such as described above, to define the transmission interval of the data packet.
  • the transmission interval is programmable between about 2 seconds and about 850 minutes, more preferably between about 30 second and 5 minutes; however, any transmission interval can be programmable or programmed into the processor module.
  • a variety of alternative systems and methods for providing a programmable transmission interval can also be employed.
  • data transmission can be customized to meet a variety of design criteria (e.g., reduced battery consumption, timeliness of reporting sensor values, etc.)
  • design criteria e.g., reduced battery consumption, timeliness of reporting sensor values, etc.
  • Conventional glucose sensors measure current in the nanoampere range.
  • the presently disclosed sensors are configured to measure the current flow in the picoampere range, and in some examples, femtoamps. Namely, for every unit (mg/dL) of glucose measured, at least one picoampere of current is measured.
  • the analog portion of the A/D converter is configured to continuously measure the current flowing at the working electrode and to convert the current measurement to digital values representative of the current.
  • the current flow is measured by a charge counting device (e.g., a capacitor).
  • a charge counting device e.g., a capacitor.
  • a signal is provided, whereby a high sensitivity maximizes the signal received by a minimal amount of measured hydrogen peroxide (e.g., minimal glucose requirements without sacrificing accuracy even in low glucose ranges), reducing the sensitivity to oxygen limitations in vivo (e.g., in oxygendependent glucose sensors).
  • a battery is operably connected to the sensor electronics and provides the power for the sensor.
  • the battery is a lithium manganese dioxide battery; however, any appropriately sized and powered battery can be used (for example, AAA, nickel-cadmium, zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion, zinc-air, zinc-mercury oxide, silver-zinc, and/or hermetically-sealed).
  • the battery is rechargeable, and/or a plurality of batteries can be used to power the system.
  • the sensor can be transcutaneously powered via an inductive coupling, for example.
  • a quartz crystal is operably connected to the processor and maintains system time for the computer system as a whole, for example for the programmable acquisition time within the processor module.
  • Optional temperature probe can be provided, wherein the temperature probe is located on the electronics assembly or the glucose sensor itself.
  • the temperature probe can be used to measure ambient temperature in the vicinity of the glucose sensor. This temperature measurement can be used to add temperature compensation to the calculated glucose value.
  • An RF module is operably connected to the processor and transmits the sensor data from the sensor to a receiver within a wireless transmission via antenna.
  • a second quartz crystal provides the time base for the RF carrier frequency used for data transmissions from the RF transceiver.
  • other mechanisms such as optical, infrared radiation (IR), ultrasonic, or the like, can be used to transmit and/or receive data.
  • the hardware and software are designed for low power requirements to increase the longevity of the device (for example, to enable a life of from about 3 to about 24 months, or more) with maximum RF transmittance from the in vivo environment to the ex vivo environment for wholly implantable sensors (for example, a distance of from about one to ten meters or more).
  • a high frequency carrier signal of from about 402 MHz to about 433 MHz is employed in order to maintain lower power requirements.
  • the carrier frequency is adapted for physiological attenuation levels, which is accomplished by tuning the RF module in a simulated in vivo environment to ensure RF functionality after implantation; accordingly, the preferred glucose sensor can sustain sensor function for 3 months, 6 months, 12 months, or 24 months or more.
  • output signal (from the sensor electronics) is sent to a receiver (e.g., a computer or other communication station).
  • the output signal is typically a raw data stream that is used to provide a useful value of the measured analyte concentration to a patient or a doctor, for example.
  • the raw data stream can be continuously or periodically algorithmically smoothed or otherwise modified to diminish outlying points that do not accurately represent the analyte concentration, for example due to signal noise or other signal artifacts, such as described in co-pending U.S. patent application Ser. No. 10/632,537 entitled, "SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM," filed Aug. 22, 2003, which is incorporated herein by reference in its entirety.
  • start-up mode When a sensor is first implanted into host tissue, the sensor and receiver are initialized. This can be referred to as start-up mode, and involves optionally resetting the sensor data and calibrating the sensor. In selected examples, mating the electronics unit to the mounting unit triggers a start-up mode. In other examples, the start-up mode is triggered by the receiver.
  • the sensor electronics are wirelessly connected to a receiver via one- or two-way RF transmissions or the like.
  • a wired connection is also contemplated.
  • the receiver provides much of the processing and display of the sensor data, and can be selectively worn and/or removed at the host's convenience.
  • the sensor system can be discreetly worn, and the receiver, which provides much of the processing and display of the sensor data, can be selectively worn and/or removed at the host's convenience.
  • the receiver includes programming for retrospectively and/or prospectively initiating a calibration, converting sensor data, updating the calibration, evaluating received reference and sensor data, and evaluating the calibration for the analyte sensor, such as described in more detail with reference to co-pending U.S.
  • a processing module or sensor electronics, is used to determine and identify electrode fouling present.
  • the sensor electronics may include a potentiostat, A/D converter, RAM, ROM, transceiver, processor, and/or the like.
  • the potentiostat is used to provide a bias to the electrodes for de-fouling/cleaning.
  • FIG. 13 is a diagram depicting an example continuous transcutaneous analyte monitoring system 110 configured to measure one or more analytes and/or electrophysiological indicators (e.g., blood pressure, heart rate, core temperature, etc.) as discussed herein.
  • the monitoring system includes a continuous transcutaneous analyte sensor system 124 operatively connected to a host 120 and a plurality of display devices 134 a-e according to certain aspects of the present disclosure.
  • display device 134e alternatively or in addition to being a display device, may be a medicament delivery device that can act cooperatively with the continuous transcutaneous analyte sensor system 124 to deliver medicaments to host 120.
  • the continuous transcutaneous analyte sensor system 124 may include a sensor electronics module 126 and a continuous transcutaneous analyte sensor 122 associated with the sensor electronics module 126.
  • the sensor electronics module 126 may be in direct wireless communication with one or more of the plurality of the display devices 134a-e via wireless communications signals.
  • display devices 134a-e may also communicate amongst each other and/or through each other to continuous transcutaneous analyte sensor system 124.
  • wireless communications signals from analyte sensor system 124 to display devices 134a-e can be referred to as "uplink" signals 128.
  • Wireless communications signals from, e.g., display devices 134a-e to continuous transcutaneous analyte sensor system 124 can be referred to as "downlink" signals 130.
  • Wireless communication signals between two or more of display devices 134a-e may be referred to as “crosslink” signals 132.
  • wireless communication signals can include data transmitted by one or more of display devices 134a- d via "long-range" uplink signals 136 (e.g., cellular signals) to one or more remote servers 140 or network entities, such as cloud-based servers or databases, and receive long-range downlink signals 138 transmitted by remote servers 140.
  • long-range uplink signals 136 e.g., cellular signals
  • the sensor electronics module 126 includes sensor electronics that are configured to process sensor information and generate transformed sensor information.
  • the sensor electronics module 126 includes electronic circuitry associated with measuring and processing data from continuous transcutaneous analyte sensor 122, including prospective algorithms associated with processing and calibration of the continuous transcutaneous analyte sensor data.
  • the sensor electronics module 126 can be integral with (non-releasably attached to) or releasably attachable to the continuous transcutaneous analyte sensor 122 achieving a physical connection therebetween.
  • the sensor electronics module 126 may include hardware, firmware, and/or software that enables analyte level measurement.
  • the sensor electronics module 126 can include a potentiostat, a power source for providing power to continuous transcutaneous analyte sensor 122, other components useful for signal processing and data storage, and a telemetry module for transmitting data from itself to one or more display devices 134a-e.
  • Electronics can be affixed to a printed circuit board (PCB), or the like, and can take a variety of forms.
  • the electronics can take the form of an integrated circuit (IC), such as an Application-Specific Integrated Circuit (ASIC), a microcontroller, and/or a processor.
  • IC integrated circuit
  • ASIC Application-Specific Integrated Circuit
  • Display devices 134a-e are configured for displaying, alarming, and/or basing medicament delivery on the sensor information that has been transmitted by the sensor electronics module 126 (e.g., in a customized data package that is transmitted to one or more of display devices 134a-e based on their respective preferences).
  • Each of the display devices 134a-e can include a display such as a touchscreen display for displaying sensor information to a user (most often host 120 or a care taker/medical professional) and/or receiving inputs from the user.
  • the display devices 134a-e may include other types of user interfaces such as a voice user interface instead of or in addition to a touchscreen display for communicating sensor information to the user of the display device 134a-e and/or receiving user inputs.
  • one, some or all of the display devices 134a-e are configured to display or otherwise communicate the sensor information as it is communicated from the sensor electronics module 126 (e.g., in a data package that is transmitted to respective display devices 134a-e), without any additional prospective processing required for calibration and real-time display of the sensor information.
  • one of the plurality of display devices 134a-e may be a custom display device 134a specially designed for displaying certain types of displayable sensor information associated with analyte values received from the sensor electronics module 126 (e.g., a numerical value and an arrow, in some examples).
  • one of the plurality of display devices 134a-e may be a handheld device 134c, such as a mobile phone based on the Android, iOS operating system or other operating system, a palm-top computer and the like, where handheld device 134c may have a relatively larger display and be configured to display a graphical representation of the continuous sensor data (e.g., including current and historic data).
  • Other display devices can include other handheld devices, such as a tablet 134d, a smart watch 134b, a medicament delivery device 134e, a blood glucose meter, and/or a desktop or laptop computers.
  • display devices 134a-e provide different user interfaces
  • content of the data packages e.g., amount, format, and/or type of data to be displayed, alarms, and the like
  • content of the data packages can be customized (e.g., programmed differently by the manufacture and/or by an end user) for each particular display device and/or display device type.
  • one or more of display devices 134a-e can be in direct or indirect wireless communication with the sensor electronics module 126 to enable a plurality of different types and/or levels of display and/or functionality associated with the sensor information, which is described in more detail elsewhere herein.
  • Interference testing of various substances was conducted using a sensor system equivalent to a commercial sensor. Dose response testing was conducted to assess interference/biofouling effect on sensor performance at increments of 55, 120 and 250 mg/dL glucose using a concentration of interferent equivalent to a maximum dose. Changes to calculated glucose readings of less than about 1 mg/dL, 5 mg/dL or 10 mg/dL was considered non-significant interference/biofouling whereas changes to calculated glucose readings of greater than about 10 mg/dL was considered significant interference/biofouling.
  • FIG. 9 depicts an exemplary sensor configuration comprising a Ag/AgCl counterreference electrode and a bare Pt Working electrode system where 600 mV is applied between the two electrodes when exposed to control ferrocyanide solution and with added.
  • the reaction of interest being facilitated is the conversion of hydrogen peroxide to oxygen, hydrogen, and 2 free electrons which can generate a current. This process requires the electrodes to have ample amounts of electrochemically active surface area for reaction to occur and function for extended periods of time.
  • FIG. 11 shows the bare platinum electrode wire surface of the sensor of FIG. 9 responding to ferricyanide before and after exposure to N-Acetylcysteine (NAC).
  • NAC N-Acetylcysteine
  • NAC forms a monolayer around the electrodes and/or electrode surface upon exposure.
  • the resulting monolayer, of reduced conductivity causes a decrease in electrochemically active surface area available for reactions to occur.
  • the resulting monolayer, of reduced conductivity also causes an increase in impedance of electrochemically active surface of the electrode.
  • CV was performed in the original ferrocyanide solution. All other cycles in FIG. 11 (Curves 1-5 "after NAC exposure") show the electrode performance approaches the same current magnitudes as before exposure. This indicates the fouling agent is being removed from the surface of the electrode, essentially reversing the fouling effect using the methods herein disclosed.
  • CV can be implemented for electrochemical cleaning in-situ, and provides a widely applicable and dynamic solution for electrode fouling in-vivo.
  • EIS Electrochemical Impedance Spectroscopy.
  • FIG. 12 shows the change in Impedance modulus and Phase Angle of an electrode "before” and “after” exposure to NAC fouling agent.
  • the difference in phase angle measured at 1 kHz can be used to detect if fouling has occurred in the electrode system and can be combined with the de-fouling/cleaning methods disclosed herein.

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Abstract

L'invention concerne un système de capteur de surveillance transcutanée continue comprenant une zone de capteur comprenant une électrode de travail, l'électrode de travail ayant une zone de surface électrochimiquement active au moins partiellement implantée, au moins une membrane adjacente à la zone de surface électrochimiquement active, et un dispositif de commande configuré pour fournir une plage de potentiel balayé à la zone de surface électrochimiquement active au moins partiellement implantée. L'invention concerne également un procédé de détection continue d'encrassement et d'élimination électrochimique de l'encrassement d'une électrode de détection implantable.
PCT/US2024/048484 2023-10-05 2024-09-25 Dispositifs et procédés pour détecter et compenser l'encrassement dans des systèmes de détection électrochimique Pending WO2025075851A1 (fr)

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