WO2025075851A1

WO2025075851A1 - Devices and methods to detect and compensate for fouling in electrochemical sensing systems

Info

Publication number: WO2025075851A1
Application number: PCT/US2024/048484
Authority: WO
Inventors: Hifza NAJIB; Wenjie LAN; Ellese ROBERTS; Forrest GOODWIN
Original assignee: Dexcom Inc
Current assignee: Dexcom Inc
Priority date: 2023-10-05
Filing date: 2024-09-25
Publication date: 2025-04-10
Anticipated expiration: 2026-04-05

Abstract

A continuous transcutaneous monitoring sensor system comprising a sensor area comprising a working electrode, the working electrode having an electrochemically active surface area at least partially implanted, 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 is disclosed. A method of continually detecting fouling and electrochemically removing fouling of an implantable sensing electrode is also disclosed.

Description

DEVICES AND METHODS TO DETECT AND COMPENSATE FOR FOULING IN ELECTROCHEMICAL SENSING SYSTEMS

Technical Field

[0001] 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.

BACKGROUND

[0002] Electrode fouling in electroactive systems involves the passivation of an electrode surface through various mechanisms that are dependent on the electrochemical nature of the fouling agent and electrode surface. Most methods that address reducing fouling include changing the characteristics of the electrode surface such that interaction between the fouling agent and electrode surface is no longer kinetically or thermodynamically favorable. Examples of methods to reduce or eliminate electrode fouling include physically modifying electrode surfaces and/or creating a protective layer around electrode surface.

[0003] Another technique to address electrode fouling involves electrochemical methods, such as electrochemical activation of the electrode. Electrochemical activation involves applying electrical pulses to remove adsorbed material off the surface in real time. [0004] 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.

[0005] In all of the above, complex polymeric membrane chemistry was not considered or incorporated in the analysis of the data, nor were the above coupled to continuously sensing analyte, continuously detecting fouling in combination with cleaning electrode surfaces in real time, in vivo.

[0006] N-acetyl cysteine (NAC) 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.

SUMMARY

[0007] In one example, a continuous monitoring sensor system is provided, the 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.

[0008] In one aspect, 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.

[0009] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises covalently coupled mediator. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane comprises covalently coupled mediator.

[0010] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0011] In one aspect, alone or in combination with any one of the previous aspects, 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. [0012] In one aspect, alone or in combination with any one of the previous aspects, the controller is configured to provide a plurality of swept potential ranges to the implanted electrochemically active surface area. In one aspect, alone or in combination with any one of the previous aspects, 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. In one aspect, alone or in combination with any one of the previous aspects, the first potential value and the fifth potential value are equal or different.

[0013] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0014] In one aspect, alone or in combination with any one of the previous aspects, the controller is configured to provide a bias voltage to the implanted electrochemically active surface area. In one aspect, alone or in combination with any one of the previous aspects, 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..

[0015] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0016] In one aspect, alone or in combination with any one of the previous aspects, the controller is configured to provide a bias voltage to the implanted electrochemically active surface area. In one aspect, alone or in combination with any one of the previous aspects, 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. [0017] In another example, a continuous monitoring sensor system is provided, the 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.

[0018] In one aspect, 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.

[0020] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises covalently coupled mediator.

[0021] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area is in contact with at least one membrane. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane comprises covalently coupled mediator. In one aspect, alone or in combination with any one of the previous aspects, 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.

[0022] In one aspect, alone or in combination with any one of the previous aspects, the sinusoidal potential range is modulated in a frequency range. In one aspect, alone or in combination with any one of the previous aspects, the frequency range is between about 1 MHz (megahertz) to about 1 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 (kilohertz). 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.

[0023] In one aspect, alone or in combination with any one of the previous aspects, the sinusoidal potential range is applied continuously, semi-continuously, intermittently, or randomly.

[0024] In another example, a method of in-vivo reversing or reducing biofouling of an implanted biosensor electrode is provided, the method comprising applying a swept potential across an electrochemically active surface of an implanted electrochemical biosensor, at least a portion of the electrochemically active surface being covered by at least one foulant; electrochemically removing at least one foulant from the electrochemically active surface.

[0025] In one aspect, 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.

[0027] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises covalently coupled mediator.

[0028] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area is in contact with at least one membrane. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane comprises covalently coupled mediator. In one aspect, alone or in combination with any one of the previous aspects, 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. [0029] In one aspect, alone or in combination with any one of the previous aspects, the foulant is endogenous. In one aspect, alone or in combination with any one of the previous aspects, the foulant is exogenous.

[0030] 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.

[0031] 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.

[0032] In another example a method of detecting biofouling of an implanted biosensor system is provided, the method 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.

[0033] In one aspect, the method further comprises determining a baseline measurement corresponding to the at least one property. In one aspect, alone or in combination with any one of the previous aspects, where (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.

[0034] In one aspect, alone or in combination with any one of the previous aspects, the method further comprises applying a swept potential to the electrochemically active surface of an implanted electrochemical biosensor after detecting the change.

[0035] In one aspect, alone or in combination with any one of the previous aspects, the method further comprises determining a baseline measurement corresponding to the at least one property.

[0036] In one aspect, alone or in combination with any one of the previous aspects, where (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. [0037] In one aspect, alone or in combination with any one of the previous aspects, the method further comprises applying a swept potential to the electrochemically active surface of an implanted electrochemical biosensor after detecting the change.

[0038] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0039] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area comprises covalently coupled mediator.

[0040] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area is in contact with at least one membrane. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane comprises covalently coupled mediator.

[0041] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0042] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0043] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0045] In one aspect, alone or in combination with any one of the previous aspects, the at least one sinusoidal signal is applied continuously, semi-continuously, intermittently, or randomly.

[0046] In another example, a method of continually detecting fouling and electrochemically removing fouling of an implantable sensing electrode is provided, the method 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.

[0047] In one aspect, 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.

[0048] In one aspect, alone or in combination with any one of the previous aspects, the electrochemically active surface area is in contact with at least one membrane. In one aspect, alone or in combination with any one of the previous aspects, the at least one membrane comprises coupled mediator.

[0049] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0050] In one aspect, alone or in combination with any one of the previous aspects, the sinusoidal potential range is modulated in a frequency range. In one aspect, alone or in combination with any one of the previous aspects, 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.

[0051] In one aspect, alone or in combination with any one of the previous aspects, 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.

[0052] In one aspect, alone or in combination with any one of the previous aspects, the foulant is endogenous. In one aspect, alone or in combination with any one of the previous aspects, the foulant is exogenous.

[0053] 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.

[0054] In one aspect, alone or in combination with any one of the previous aspects, the at least one sinusoidal potential range is applied continuously, semi-continuously, intermittently, or randomly. In one aspect, alone or in combination with any one of the previous aspects, the swept potential range is applied continuously, semi-continuously, intermittently, or randomly. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] In order to understand and to see how the present disclosure may be carried out in practice, examples will now be described, by way of non-limiting examples only, with reference to the accompanying drawings, in which:

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] FIG. 8 is a perspective-view schematic illustrating an in vivo portion of a singleworking-electrode analyte sensor

[0064] FIG. 9 illustrates an exemplary sensor construct for testing in accordance with the broadest aspect of the present disclosure.

[0065] FIG. 10 illustrates plots that record pulse voltammetry conducted intermittently between 2.5 and 40 hours post sensor activation.

[0066] FIG. 11 illustrates Cyclic Voltammetry (CV) on an electrode in Ferrocyanide solution before and after exposure to foulant.

[0067] FIG. 12 illustrates an Electrochemical Impedance Spectroscopy (EIS) measurements on an electrode before and after exposure to foulant.

[0068] 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. DETAILED DESCRIPTION

[0069] 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.

[0070] In order to facilitate an understanding of the disclosed examples, a number of terms are defined below.

[0071] The terms and phrases "analyte measuring device," "analyte sensing device," "biosensor," "sensor," "sensing region," "sensing portion," and "sensing mechanism" 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. In one example, 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. In one example, 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.

[0072] 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%. The phrase "substantially free of" as used herein 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.%.

[0073] The term "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.

[0074] The term "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. Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some examples, the analyte measured by the sensing regions, devices, and methods is glucose. However, other analytes are contemplated as well, including but not limited to 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-|3 hydroxy-cholic acid; cortisol; creatine; creatine kinase; creatine kinase MM isoenzyme; creatinine; cyclosporin A; d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcohol dehydrogenase, alpha 1-antitry psin, cystic fibrosis, Duchenne/Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D- Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids/acylglycines; free |3-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine (FT3); fumarylacetoacetase; galactose/gal-l-phosphate; galactose-l-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycerol; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-alpha- hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; beta-hydroxybutyrate; ketones; lactate; lead; lipoproteins ((a), B/A-l, 0); lysozyme; mefloquine; netilmicin; oxygen; phenobarbitone; phenytoin; phytanic/pristanic acid; potassium, sodium, and/or other blood electrolytes; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3); selenium; serum pancreatic lipase; sissomicin; somatomedin C; specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus medinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, leptospira, measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma pal lid iu m, Trypanosoma cruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uric acid; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. 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. Alternately, the analyte can be introduced into the body, or exogenous, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbiturates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine, amphetamines, methamphetamines, and phencyclidine, for example, Ecstasy); anabolic steroids; and nicotine. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes. 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.

[0075] The term "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.

[0076] The phrases "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. The terms "biointerface" and "bioprotective" are used interchangeably herein.

[0077] The term "continuous" 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 an uninterrupted or unbroken portion, domain, coating, or layer.

[0078] The phrase "continuous analyte sensing" 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 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

1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, 4.00, 4.25, 4.50, 4.75, 5.00,

5.25, 5.50, 5.75, 6.00, 6.25, 6.50, 6.75, 7.00, 7.25, 7.50, 7.75, 8.00, 8.25, 8.50, 8.75, 9.00,

9.25, 9.50 or 9.75 minutes.

[0079] The term "coupled" 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 two or more system elements or components that are configured to be at least one of electrically, mechanically, thermally, operably, chemically or otherwise attached. Similarly, 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"). In other examples, components are connected via remote means. For example, 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. In this example, the electrode is "operably linked" to the electronic circuit. The phrase "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. The phrase "permanently 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 but cannot be uncoupled without damaging at least one of the coupled elements or components.

[0080] The term "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.

[0081] The term "distal" 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 region spaced relatively far from a point of reference, such as an origin or a point of attachment.

[0082] The term "domain" 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 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.

[0083] The term "drift" 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 progressive increase or decrease in signal over time that is unrelated to changes in host systemic analyte concentrations, for example, such as a host postprandial glucose concentrations. While not wishing to be bound by theory, it is believed that drift may be the result of a local decrease in glucose transport to the sensor, for example, due to a formation of a foreign body capsule (FBC). It is also believed that an insufficient amount of interstitial fluid surrounding the sensor may result in reduced oxygen and/or glucose transport to the sensor. In one example, an increase in local interstitial fluid may slow or reduce drift and thus improve sensor performance. Drift may also be the result of sensor electronics, or algorithmic models used to compensate for noise or other anomalies that can occur with electrical signals in ranges including the, microampere range, picoampere range, nanoampere range, and femtoampere range.

[0084] The phrases "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. In one example, 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. In one example the drug releasing layer and/or drug releasing membrane are substantially the same as the biointerface layer and/or biointerface membrane. In another example, the drug releasing layer and/or drug releasing membrane are distinct from the biointerface layer and/or biointerface membrane.

[0085] Further examples of drug releasing layers and membranes may be found in pending U.S. Provisional Application No. Application Number: 63/318901, titled "DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR," filed March 11, 2022, incorporated by reference in its entirety herein.

[0086] The phrases "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. In one example, hydrogen peroxide produced by an enzyme-catalyzed reaction of an analyte being detected reacts can create a measurable electronic current. For example, in the detection of glucose, glucose oxidase produces hydrogen peroxide (H2O2) as a byproduct. The 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. In another example, electron transfer is provided using a mediator or "wired enzyme" during reduction-oxidation (redox) of the transducing element and the analyte.

[0087] The terms "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. [0088] 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.

[0089] The term "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.

[0090] The terms "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. In one example of an electrochemical sensor, interfering species are compounds with an oxidation potential that overlaps with the analyte to be measured or one or more mediators.

[0091] The term "in vivo" 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 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.

[0092] The term "ex vivo" 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 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. [0093] The term "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. When used herein, the terms "membrane" and "matrix" are meant to be interchangeable.

[0094] The phrase "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. In one example, 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.

[0095] The term "noise," as used herein, 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. In some cases, noise can be reduced using predictive modeling, artificial intelligence, and/or algorithmic means. In other cases, noise can be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as using a drug releasing layer with at least one bioactive agent. For example, noise of one or more exemplary biosensors as presently disclosed can be determined and then compared qualitatively or quantitatively. By way of example, by obtaining a raw signal timeseries with a fixed sampling interval (in units of picoampere (pA)), 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. At each sampling interval, 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). Optionally, 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.

[0096] The term "optional" or "optionally" 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, without limitation, means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. [0097] The term "potentiostat," 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 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.

[0098] The term "proximal" 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 the spatial relationship between various elements in comparison to a particular point of reference. For example, 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.

[0099] The phrase and term "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.

[0100] The term "semi-continuous" 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 portion, coating, domain, or layer that includes one or more continuous and noncontinuous portions, coatings, domains, or layers. For example, a coating disposed around a sensing region but not about the sensing region is "semi-continuous."

[0101] The phrase "sensing membrane" 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 comprise one or more domains, layers, or layers within domains and that is constructed of materials having a thickness of a few microns or more, and that are permeable to reactants and/or co-reactants employed in determining the analyte of interest. As an example, a sensing membrane can comprise an immobilized glucose oxidase enzyme, which catalyzes an electrochemical reaction with glucose and oxygen to permit measurement of a concentration of glucose.

[0102] During general operation of the analyte measuring device, biosensor, sensor, sensing region, sensing portion, or sensing mechanism, a biological sample, for example, blood or interstitial fluid, or a component thereof contacts, either directly, or after passage through one or more membranes, an enzyme, for example, glucose oxidase, or a protein, for example, one or more periplasmic binding protein (PBP) or mutant or fusion protein thereof having one or more analyte binding regions, each region capable of specifically and reversibly binding to at least one analyte. 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.

[0103] In one example, 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. In one example, 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. In some examples, the sensing membrane further comprises an enzyme domain, for example, an enzyme layer, and an electrolyte phase, for example, a free-flowing liquid phase comprising an electrolyte-containing fluid described further below. The terms are broad enough to include the entire device, or only the sensing portion thereof (or something in between). [0104] In another example, the sensing region can comprise one or more periplasmic binding protein (PBP) or mutant orfusion protein thereof having one or more analyte binding regions, each region capable of specifically and reversibly binding to at least one analyte. 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. Specific examples of 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.

[0105] In one example, 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. [0106] The sensing region transduces the recognition of analytes into a semi- quantitative or quantitative signal. Thus, "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.

[0107] The term "sensitivity" 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 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. For example, in one example, 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.

[0108] The phrase "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.

[0109] Electrochemical sensing technology, in an example, utilizes electrodes to apply potential to a system to facilitate a desired chemical reaction. When surface area is diminished on an electrode, for example, by fouling, the performance of the electrochemical system can be affected. For example, the desired analyte cannot reach the electrode surface for electron transfer and/or surface area of the system can be diminished by fouling. In one example, 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. Typically, 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.

[0110] In one example, 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. [0111] 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. With reference to FIGs. 1-3, a general summary of the methods of the present disclosure are provided. Thus, as depicted in FIG. 1, 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.

[0112] 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. In one example, 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 and step 204 comprises correlating the change of the least one property with biofouling.

[0113] 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. In one example of 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. [0114] In some examples, a combination of direct current (DC) and alternating current (AC) are applied or measured in the methods and devices disclosed herein. In one example, DC is used for analyte detection whereas AC is used for de-fouling/cleaning of an electrode surface. In some examples, DC is used for analyte detection and clea nsing/anti-fou ling, whereas AC is used for detection only. In one example, Electrochemical Impedance Spectroscopy (EIS) 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. In one example, cyclic voltammetry (CV) is employed where DC current is applied in a predetermined sequence. In some examples 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

[0115] Currently, all 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. Examples of 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.

Sensor/Sensor System

[0116] FIGS. 4-6 illustrate exemplary examples of a single working electrode continuous transcutaneous analyte sensor 800. In one example, 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. In some examples, the core and first layer can be of a single material (e.g., platinum). In some examples, 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. In some examples, the elongated conductive body comprises a plurality of layers. In certain examples, there are at least two concentric (e.g., annular) layers, such as a core formed of a first material and a first layer formed of a second material. However, additional layers can be included in some examples. In some examples, the layers are coaxial.

[0117] The elongated conductive body may be long and thin, yet flexible and strong. For example, in some examples, 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. While 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. In one example, a conductive wire electrode is employed as a core. To such a clad electrode, two additional conducting layers may be added (e.g., with intervening insulating layers provided for electrical isolation). The conductive layers can be comprised of any suitable material. In certain examples, it can be desirable to employ a conductive layer comprising conductive particles (i.e., particles of a conductive material) in a polymer or other binder. In other examples, the conductive body can be configured in a linear or planar arrangement, e.g., on a generally flat surface or substrate.

[0118] In addition to providing structural support, resiliency and flexibility, in some examples, 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. In some examples, the core 810 comprises a conductive material, such as titanium, stainless steel, tantalum, a conductive polymer, and/or the like. However, in other examples, the core is formed from a non-conductive material, such as a non-conductive polymer. In yet other examples, the core comprises a plurality of layers of materials. For example, in one example the core includes an inner core and an outer core. In a further example, the inner core is formed of a first conductive material and the outer core is formed of a second conductive material. For example, in some examples, the first conductive material is stainless steel, titanium, tantalum, a conductive polymer, an alloy, and/or the like, and 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). In another example, 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. One skilled in the art appreciates that additional configurations are possible. [0119] Referring again to FIGS. 4-6, in some examples, the first layer 812 is formed of a conductive material. The working electrode is an exposed portion of the surface of the first layer. Accordingly, 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.

[0120] As illustrated in FIGS. 4-6, a second layer 804 surrounds a least a portion of the first layer 812, thereby defining the boundaries of the working electrode. In some examples, 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. Other materials 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. In some alternative examples, however, the working electrode may not require a coating of insulator.

[0121] In one example, the second layer is disposed on the first layer and configured such that the working electrode is exposed via window 806. In another example, an elongated conductive body, including the core, the first layer and the second layer, is provided, and the working electrode is exposed (i.e., formed) by removing a portion of the second layer, thereby forming the window 806 through which the electroactive surface of the working electrode (e.g., the exposed surface of the first layer) is exposed. In some examples, the working electrode is exposed by (e.g., window 806 is formed by) removing a portion of the second and (optionally) third layers. Removal of coating materials from one or more layers of elongated conductive body (e.g., to expose the electroactive surface of the working electrode) can be performed by hand, excimer lasing, chemical etching, laser ablation, grit-blasting, or the like.

[0122] In some examples, the sensor further comprises a third layer 814 comprising a conductive material. In further examples, 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. In one exemplary example, 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. In some examples, multiple coating steps are used to build up the coating to a predetermined thickness.

[0123] In some examples, 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. In certain examples, 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%. In some examples, 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. [0124] In one example, 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). In some examples, 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). In such examples, 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. However, 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. Accordingly, 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. In one example of a glucose sensor, it can be advantageous to minimize the surface area of the working electrode while maximizing the diffusivity of glucose in order to optimize the signal-to-noise ratio while maintaining sensor performance in both high and low glucose concentration ranges.

[0125] In some alternative examples, the exposed surface area of the working (and/or other) electrode can be increased by altering the cross-section of the electrode itself. For example, in some examples 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.

[0126] In some examples, the elongated conductive body further comprises one or more intermediate layers located between the core and the first layer. For example, in some examples, the intermediate layer is an insulator, a conductor, a polymer, and/or an adhesive.

[0127] In certain example, the core comprises a non-conductive polymer and the first layer comprises a conductive material. Such a sensor configuration can sometimes provide reduced material costs, in that it replaces a typically expensive material with an inexpensive material. For example, in some examples, 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.

[0128] As illustrated in FIG. 4, the sensor 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.

[0129] Exemplary sensor configurations, may be applied to any planar or non-planar surface, for example. In another 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.

[0130] FIG. 7A is a cross-sectional view through a sensor, illustrating one example of the membrane system 908. In this particular example, 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.

[0131] As illustrated in FIG. 7B, in some examples, 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. In some examples, 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). In some examples, the sensor is configured for implantation from about 1 to 30 days). However, it is understood that 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.

[0132] As illustrated in FIG. 7C, in some examples, 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.

[0133] A wide variety of configurations and combinations for the various layers in the membrane system are encompassed by the preferred examples. In various examples, any of the domains illustrated in FIGS. 7A-7C may be omitted, altered, substituted for, and/or incorporated together without departing from the spirit of the preferred examples. It is to be understood that sensing membranes modified for other sensors, for example, may include fewer or additional layers. For example, in some examples, the membrane system may comprise one electrode layer, one enzyme layer, and two bioprotective layers, but in other examples, the membrane system may comprise one electrode layer, two enzyme layers, and one bioprotective layer. In some examples, the bioprotective layer may be configured to function as the diffusion resistance domain and control the flux of the analyte (e.g., glucose) to the underlying membrane layers.

[0134] In some examples, 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. [0135] In one example, a sensing membrane is disposed over the electroactive surfaces of the continuous transcutaneous analyte sensor and includes one or more domains or layers of a membrane system. In general, the sensing membrane functions to control the flux of a biological fluid there through and/or to protect sensitive regions of the sensor from contamination by the biological fluid, for example. Some conventional electrochemical enzyme-based analyte sensors generally include a sensing membrane that controls the flux of the analyte being measured, protects the electrodes from contamination of the biological fluid, and/or provides an enzyme that catalyzes the reaction of the analyte with a co-factor, for example. See, e.g., co-pending U.S. patent application Ser. No. 10/838,912, filed May 3, 2004 entitled "IMPLANTABLE ANALYTE SENSOR" and U.S. patent application Ser. No. 11/077,715, filed Mar. 10, 2005 and entitled "TRANSCUTANEOUS ANALYTE SENSOR" which are incorporated herein by reference in their entirety.

[0136] The sensing membranes of the present disclosure can include any membrane configuration suitable for use with any analyte sensor (such as described in more detail above). In general, the sensing membranes of the present disclosure include one or more domains, all or some of which can be adhered to or deposited on the analyte sensor as is appreciated by one skilled in the art. In one example, 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. Membrane Systems

[0137] In some examples, 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. Co-pending U.S. patent application Ser. No. 10/838,912, which is incorporated herein by reference in its entirety, describes biointerface and sensing membrane configurations and materials that may be applied to the presently disclosed sensor. Electrode Domain

[0138] In some examples, the membrane system comprises an optional electrode domain. The electrode domain 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 is preferably situated more proximal to the electroactive surfaces than the enzyme domain. Preferably, the electrode domain includes a semipermeable coating that maintains a layer of water at the electrochemically reactive surfaces of the sensor, for example, a humectant in a binder material can be employed as an electrode domain; this allows for the full transport of ions in the aqueous environment. The electrode domain can also assist in stabilizing the operation of the sensor by overcoming electrode start-up and drifting problems caused by inadequate electrolyte. The material that forms the electrode domain can also protect against pH-mediated damage that can result from the formation of a large pH gradient due to the electrochemical activity of the electrodes.

[0139] In one example, 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.

[0140] In certain examples, 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.

[0141] Preferably, 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)). In examples wherein dip-coating is used to deposit the electrode domain, 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. However, values outside of those set forth above can be acceptable or even desirable in certain examples, for example, dependent upon viscosity and surface tension as is appreciated by one skilled in the art. In one example, the electroactive surfaces of the electrode system are dip-coated one time (one layer) and cured at 50° C. under vacuum for 20 minutes.

[0142] Although an independent electrode domain is described herein, in some examples, sufficient hydrophilicity can be provided in the interference domain and/or enzyme domain (the domain adjacent to the electroactive surfaces) so as to provide for the full transport of ions in the aqueous environment (e.g. without a distinct electrode domain). Interference Domain

[0143] In some examples, an optional interference domain is provided, which generally includes a polymer domain that restricts the flow of one or more interferants. In some examples, 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.

[0144] Several polymer types that can be utilized as a base material for the interference domain include polyurethanes, polymers having pendant ionic groups, and polymers having controlled pore size, for example. In one example, 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. Other systems and methods for reducing or eliminating interference species that can be applied to the membrane system of the present disclosure are described in co-pending U.S. patent application Ser. No. 10/896,312 filed Jul. 21, 2004 and entitled "ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS," Ser. No. 10/991,353, filed Nov. 16, 2004 and entitled, "AFFINITY DOMAIN FOR AN ANALYTE SENSOR," Ser. No. 11/007,635, filed Dec. 7, 2004 and entitled "SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS" and Ser. No. 11/004,561, filed Dec. 3, 2004 and entitled, "CALIBRATION TECHNIQUES FOR A CONTINUOUS TRANSCUTANEOUS ANALYTE SENSOR." In some alternative examples, a distinct interference domain is not included.

[0145] In one example, 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. Unfortunately, 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.

Enzyme Domain

[0146] In one example, the membrane system further includes an enzyme domain disposed more distally from the electroactive surfaces than the interference domain (or electrode domain when a distinct interference is not included). In some examples, the enzyme domain is directly deposited onto the electroactive surfaces (when neither an electrode or interference domain is included). In one example, the enzyme domain provides an enzyme to catalyze the reaction of the analyte and its co-reactant, as described in more detail below. Preferably, the enzyme domain includes glucose oxidase; however other oxidases, for example, galactose oxidase or uricase oxidase, can also be used.

[0147] For an enzyme-based electrochemical glucose sensor to perform well, 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. Preferably, the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme. However, in alternative examples 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. Preferably, the enzyme is immobilized within the domain. See U.S. patent application Ser. No. 10/896,639 filed on Jul. 21, 2004 and entitled "Oxygen Enhancing Membrane Systems for Implantable Device."

[0148] In one example, 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. However in some examples, the enzyme domain is deposited onto the electrode domain or directly onto the electroactive surfaces. Preferably, the enzyme domain is deposited by spray or dip coating. More preferably, 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)). In examples wherein dip-coating is used to deposit the enzyme domain at room temperature, 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. However, values outside of those set forth above can be acceptable or even desirable in certain examples, for example, dependent upon viscosity and surface tension as is appreciated by one skilled in the art. In one example, 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. However, in some examples, 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.

Resistance Domain [0149] In one example, the membrane system includes a resistance domain disposed more distal from the electroactive surfaces than the enzyme domain. Although the following description is directed to a resistance domain for a glucose sensor, the resistance domain can be modified for other analytes and co-reactants as well.

[0150] There exists a molar excess of glucose relative to the amount of oxygen in blood; that is, for every free oxygen molecule in extracellular fluid, there are typically more than 100 glucose molecules present (see Updike et al., Diabetes Care 5:207-21(1982)). However, 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. Without a semipermeable membrane situated over the enzyme domain to control the flux of glucose and oxygen, 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.

[0151] 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. As a result, the upper limit of linearity of glucose measurement is extended to a much higher value than that which is achieved without the resistance domain. In one example, 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. As a result, 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)).

[0152] In alternative examples, 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. In alternative examples, 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,

"SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE."

[0153] In a preferred example, 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. Examples of materials which can be used to make non-polyurethane type membranes 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.

[0154] In a preferred example, the hydrophilic polymer component of the resistance domain is polyethylene oxide. For example, 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.

[0155] In one example, 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.

Preferably, the resistance domain is deposited onto the enzyme domain by spray coating or dip coating. In certain examples, 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.

[0156] In one example, 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. In spraying a solution of resistance domain material, including a solvent, onto the enzyme domain, it is desirable to mitigate or substantially reduce any contact with enzyme of any solvent in the spray solution that can deactivate the underlying enzyme of the enzyme domain. 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.

[0157] Although a variety of spraying or deposition techniques can be used, spraying the resistance domain material and rotating the sensor at least one time by 180° can provide adequate coverage by the resistance domain. Spraying the resistance domain material and rotating the sensor at least two times by 120 degrees provides even greater coverage (one layer of 360° coverage), thereby ensuring resistivity to glucose, such as is described in more detail above.

[0158] In one example, 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.

[0159] In one example, 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. However, 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.

[0160] Advantageously, 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.

[0161] In one example, a sensor signal with a current in the picoampere range or less is provided, which is described in more detail elsewhere herein. However, the ability to produce a signal with a current in the picoampere range can be dependent upon a combination of factors, including the electronic circuitry design (e.g., A/D converter, bit resolution, and the like), the membrane system (e.g., permeability of the analyte through the resistance domain, enzyme concentration, and/or electrolyte availability to the electrochemical reaction at the electrodes), and the exposed surface area of the working electrode. For example, the resistance domain can be designed to be more or less restrictive to the analyte depending upon to the design of the electronic circuitry, membrane system, and/or exposed electroactive surface area of the working electrode.

[0162] Accordingly, in one example, 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. Namely, conventional analyte sensors have shown reduced measurement accuracy in low analyte ranges due to lower availability of the analyte to the sensor and/or have shown increased signal noise in high analyte ranges due to insufficient oxygen necessary to react with the amount of analyte being measured. While not wishing to be bound by theory, it is believed that the membrane systems of the present disclosure, in combination with the electronic circuitry design and exposed electrochemical reactive surface area design, support measurement of the analyte in the picoampere range or less, which enables an improved level of resolution and accuracy in both low and high analyte ranges not seen in the prior art.

[0163] Although sensors of some examples described herein include an optional interference domain in order to block or reduce one or more interferants, sensors with the membrane system of the present disclosure, including an electrode domain, an enzyme domain, and a resistance domain, have been shown to inhibit ascorbate without an additional interference domain. Namely, the membrane system of the present disclosure, including an electrode domain, an enzyme domain, and a resistance domain, has been shown to be substantially non-responsive to ascorbate in physiologically acceptable ranges. While not wishing to be bound by theory, it is believed that the process of depositing the resistance domain by spray coating, as described herein, results in a structural morphology that is substantially resistance resistant to ascorbate.

Interference-Free Membrane Systems

[0164] In general, it is believed that appropriate solvents and/or deposition methods can be chosen for one or more of the domains of the membrane system that form one or more transitional domains such that interferants do not substantially permeate there through. Thus, 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. Biointerface Membrane/Layer

[0165] In one example, the sensor includes a porous material disposed over some portion thereof, which modifies the host's tissue response to the sensor. In some examples, 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. Alternatively, the porous material can provide stabilization of the sensor via tissue ingrowth into the porous material in the long term. Suitable porous materials include silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyamides, 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, as well as metals, ceramics, cellulose, hydrogel polymers, poly(2-hydroxyethyl methacrylate, pHEMA), hydroxyethyl methacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC), high density polyethylene, acrylic copolymers, nylon, polyvinyl difluoride, polyanhydrides, poly(l-lysine), poly(L-lactic acid), hydroxyethyl metharcrylate, hydroxyapeptite, alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium, titanium alloy, nintinol, stainless steel, and CoCr alloy, or the like, such as are described in co-pending U.S. patent application Ser. No. 10/842,716, filed May 10, 2004 and entitled, "BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVE AGENTS" and U.S. patent application Ser. No. 10/647,065 filed Aug. 22, 2003 and entitled "POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES."

[0166] In some examples, 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). Particularly, 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). Alternately, the porous material can be deposited on the sensor (for example, by electrospinning of a polymer directly thereon). In yet other alternative examples, 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.

[0167] 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. Namely, 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.

[0168] In an example wherein 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. In some examples, 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. By enhancing the oxygen supply through the use of a silicone composition, for example, glucose concentration can be less of a limiting factor. In other words, if more oxygen is supplied to the enzyme and/or electroactive surfaces, then more glucose can also be supplied to the enzyme without creating an oxygen rate-limiting excess. While not being bound by any particular theory, it is believed that silicone materials provide enhanced biostability when compared to other polymeric materials such as polyurethane.

[0169] In another example, the porous material further comprises a bioactive agent that releases upon insertion. In one example, the porous structure provides access for glucose permeation while allowing drug release/elute. In one example, as the bioactive agent releases/elutes from the porous structure, glucose transport may increase, for example, so as to offset any attenuation of glucose transport from the aforementioned immune response factors. [0170] When used herein, the terms "membrane" and "matrix" are meant to be interchangeable. In these examples, 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.

[0171] 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. In one example, 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.

[0172] Due to the small dimension(s) of the sensor (sensing mechanism) of the present disclosure, some conventional methods of porous membrane formation and/or porous membrane adhesion are inappropriate for the formation of the biointerface membrane onto the sensor as described herein. Accordingly, the following examples exemplify systems and methods for forming and/or adhering a biointerface membrane onto a small structured sensor as defined herein. For example, the 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.

[0173] In examples wherein the biointerface is directly-written onto the sensor, 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. In general, 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. Drug Release Membrane/Layer -Inflammatory Response Control

[0174] In general, 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. Over the course of days to weeks, 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.

[0175] Accordingly, 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.

[0176] In general, bioactive agents that are believed to modify tissue response include anti-inflammatory agents, anti-infective agents, anti-proliferative agents, anti-histamine agents, anesthetics, inflammatory agents, growth factors, angiogenic (growth) factors, adjuvants, immunosuppressive agents, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-barrier cell compounds, vascularization compounds, anti-sense molecules, and the like. In some examples, 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. However, other bioactive agents, biological materials (for example, proteins), or even non-bioactive substances can incorporated into the membranes of the present disclosure.

[0177] 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.

[0178] In one example, dexamethasone, dexamethasone salts, or dexamethasone derivatives in particular, dexamethasone acetate, which, for example, abates the intensity of the FBC response at the device-tissue interface, is incorporated into any of the previously disclosed membranes, in the biointerfacing membrane or is provided in a separate membrane adjacent the biointerfacing membrane.

[0179] In another example, a combination of dexamethasone and dexamethasone acetate is incorporated into the drug releasing membrane. In another example, dexamethasone and/or dexamethasone acetate combined with one or more other antiinflammatory and/or immunosuppressive agents is incorporated into the drug releasing membrane. Alternatively, 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.

[0180] Other 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.

[0181] Although the bioactive agent in some examples is incorporated into the biointerface membrane or release membrane and/or implantable device, in some examples 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.

[0182] In one example, the drug release membrane functions as the biointerface membrane. In another example, the drug releasing membrane is chemically distinct from the biointerface membrane, or no biointerface membrane is used. In such examples, 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.

[0183] In some examples, 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. In one example, 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. In one example, 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.

[0184] 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. In this embodiment, 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. In certain embodiments, 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.

[0185] In examples wherein an outer insulator is disposed, 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. Alternatively, a portion of the electrode can be masked prior to depositing the insulator in order to maintain an exposed electroactive surface area.

[0186] In some examples, a radial window is formed through the insulating material to expose a circumferential electroactive surface of the working electrode. Additionally, sections of electroactive surface of the reference electrode are exposed. For example, the sections of electroactive surface can be masked during deposition of an outer insulating layer or etched after deposition of an outer insulating layer. In some applications, 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. However, when 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.

Alternatively, a tangential exposed electroactive window can be formed, for example, by stripping only one side of the coated assembly structure. In other alternative examples, 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.

[0187] When powered at its normal bias potential, the single working electrode is in a mode for analyte concentration (e.g., glucose concentration) measurement. With this example, at certain times, the bias potential may be changed as described herein. For example, 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. With this example, 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). In one example, 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.

[0188] In one example, 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). In another example, 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).

Measuring Impedance - Correlation with Biofouling

[0189] One limitation of implantable sensors is 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. Heretofore, this limitation has been one of the major challenges to creating a factory calibrated glucose sensor. For example, 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.

[0190] In some examples, 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.

[0191] Many devices and systems can be used to measure impedance. A typical analyte sensor may have a working and reference electrode implanted into tissue, often anchored to the skin by a housing or base plate. As an example, this type of typical analyte sensor can be modified in a variety of ways to measure impedance through nearby tissue. In some examples, one or more additional electrodes can be placed in various positions, including for example, on the surface of the skin. The one or more additional electrodes enable measurement of electrical impedance of tissue surrounding the sensor to determine the condition of the tissue. In one example, a third electrode can be placed on the surface of the skin. In some preferred examples, the additional electrode can be placed under the surface of the housing or base plate. In another example, multiple additional electrodes can be placed on the surface of the skin, and in some examples all additional electrodes are located underthe surface of the housing or base plate.

[0192] I mpedance measurements can indicate, independently or in combination with the methods disclosed herein, certain physiological conditions within the host. In some examples, through use of 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. In some examples, 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] In one example, 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").

[0197] In one example, 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. In one example, voltammetry is used. In one example, cyclic voltammetry, pulse voltammetry, normal pulse voltammetry, square wave voltammetry, differential pulse voltammetry linear voltammetry, or square wave voltammetry is used. In one example, 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.

[0198] To identify this decrease in electroactive surface capacity, in some examples, the sensor is configured to perform voltammetry by periodically sweeping or scanning the bias potential and recording the signal response. In FIG. 10, 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. For example, for an electrochemicalbased glucose sensor that employs a bias potential of about 600 mV and that measures glucose concentration by measuring oxidized hydrogen peroxide, the section of the plot near 600 mV can be important. Likewise, for a mediated electrochemical-based glucose sensor that employs a bias potential of about 200 mV, 100 mV, 50mV, 40mV or less and that measures glucose concentration by mediated redox reactions, the section of the plot near the bias potential can be important to indicate biofouling of the electroactive surface of the electrode.

[0199] In one example, 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. In certain examples, 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. In one example, the sensor system, after a threshold is exceeded, commences one or more of the foulant removal methods as disclosed herein.

Electronics

[0200] The following description of electronics associated with the sensor is applicable to a variety of continuous transcutaneous analyte sensors, such as non-invasive, minimally invasive, and/or invasive (e.g., transcutaneous and wholly implantable) sensors. For example, the sensor electronics and data processing as well as the receiver electronics and data processing described below can be incorporated into the wholly implantable glucose sensor disclosed in co-pending U.S. patent application Ser. No. 10/838,912, filed May 3, 2004 and entitled "IMPLANTABLE ANALYTE SENSOR" and U.S. patent application Ser. No. 10/885,476 filed Jul. 6, 2004 and entitled, "SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM". [0201] In one example, 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). In some examples, the potentiostat includes a resistor that translates the current into voltage. In some alternative examples, 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.

[0202] A processor module includes the central control unit that controls the processing of the sensor electronics. In some examples, the processor module includes a microprocessor, however a computer system other than a microprocessor 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. 22, 2003, and entitled, "SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM"). The processor additionally can be used for the system's cache memory, for example for temporarily storing recent sensor data. In some examples, 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.

[0203] In some examples, 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. Generally, digital filters are programmed to filter data sampled at a predetermined time interval (also referred to as a sample rate). In some examples, wherein the potentiostat is configured to measure the analyte at discrete time intervals, these time intervals determine the sample rate of the digital filter. In some alternative examples, wherein the potentiostat is configured to continuously measure the analyte, for example, using a current-to- frequency converter as described above, 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. In these alternative examples, 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. In one example, 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.

[0204] Preferably, 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. Generally, 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.

[0205] In some examples, the processor module further comprises a transmitter portion that determines the transmission interval of the sensor data to a receiver, or the like. In some examples, the transmitter portion, which determines the interval of transmission, is configured to be programmable. In one such example, 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. Thus, in some examples, 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. However, a variety of alternative systems and methods for providing a programmable transmission interval can also be employed. By providing a programmable transmission interval, data transmission can be customized to meet a variety of design criteria (e.g., reduced battery consumption, timeliness of reporting sensor values, etc.) [0206] Conventional glucose sensors measure current in the nanoampere range. In contrast to conventional glucose sensors, 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. Preferably, 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. In one example, the current flow is measured by a charge counting device (e.g., a capacitor). Thus, 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).

[0207] A battery is operably connected to the sensor electronics and provides the power for the sensor. In one example, 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). In some examples, 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. In some examples, 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.

[0208] 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.

[0209] 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. In some examples, a second quartz crystal provides the time base for the RF carrier frequency used for data transmissions from the RF transceiver. In some alternative examples, however, other mechanisms, such as optical, infrared radiation (IR), ultrasonic, or the like, can be used to transmit and/or receive data.

[0210] In the RF telemetry module of the present disclosure, 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). Preferably, a high frequency carrier signal of from about 402 MHz to about 433 MHz is employed in order to maintain lower power requirements. Additionally, in wholly implantable devices, 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.

[0211] In some examples, 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. In some examples, 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.

[0212] 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.

Receiver

[0213] In some examples, the sensor electronics are wirelessly connected to a receiver via one- or two-way RF transmissions or the like. However, 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. Thus, 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. Particularly, 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. patent application Ser. No. 10/633,367, filed Aug. 1, 2003 and entitled, "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA."

[0214] In one example, 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. In one example, the potentiostat is used to provide a bias to the electrodes for de-fouling/cleaning.

[0215] 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. It should be noted that 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. In one example, display devices 134a-e may also communicate amongst each other and/or through each other to continuous transcutaneous analyte sensor system 124. For ease of reference, 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. Additionally, 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.

[0216] The sensor electronics module 126 includes sensor electronics that are configured to process sensor information and generate transformed sensor information. In certain examples, 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. For example, 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. For example, 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.

Examples of systems and methods for processing sensor analyte data are described in more detail herein and in U.S. Pat. Nos. 7,310,544 and 6,931,327 and U.S. Patent Publication Nos. 2005/0043598, 2007/0032706, 2007/0016381, 2008/0033254, 2005/0203360, 2005/0154271, 2005/0192557, 2006/0222566, 2007/0203966 and 2007/0208245, each of which are incorporated herein by reference in their entirety for all purposes.

[0217] 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. In some examples, 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. In some examples, 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.

[0218] In the example of FIG. 13, 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). 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.

[0219] As alluded to above, because the different 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) 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. Accordingly, in the example of FIG. 13, 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. Experimental Data

[0220] 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. [0221] The following substances (and their metabolites) did not introduce significant interference or biofouling on the sensor based on acceptance criteria: albuterol, amoxicillin, ascorbic acid, atenolol, azithromycin, bilirubin, bupropion, captopril, carbidopa, cimetidine, ciprofloxacin, creatinine, diltiazem, d-mannitol, dopamine, enalapril, enoxaparin, erythritol, escita lopram, ethacrynic acid, fenofibric acid, folic acid, fructose, furosemide, gabapentin, galactose, gentisic acid (2,5-dihydroxybenzoic acid), heparin, ibuprofen, iron sucrose, isosorbide mononitrate, ketorolac, levodopa, levofloxacin, lisinopril, lovastatin, magnesium, maltose, mesalamine, methyldopa, methyl-prednisolone, metoprolol, olsalazine, omeprazole, ondansetron, oseltamivir, pantoprazole, pindolol, pioglitazone, potassium chloride, rosuvastatin, salicylate, SINEMET® Tablet (levodopa lOOmg and carbidopa 25mg), sorbitol, sota lol, tolazamide, tolbutamide, uric acid (7.9 mg/dl), vancomycin, warfarin, xylitol. Whereas N-Acetyl Cysteine (NAC) or its metabolite introduced interference and/or biofouling on the sensor based on acceptance criteria.

[0222] 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). While not being held to any particular theory, it is believed that 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.

[0223] In the experiment show above, cyclic voltammetry (CV) was performed on G6 bare wires before exposure to NAC. The resulting trace (labelled "before") represents electrode signature for ferricyanide before any exposure to NAC. The electrode was then exposed to NACs for two hours and a potential of 0.6V was applied; NAC attaches to the electrode under these conditions.

[0224] After exposure, 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. Thus, CV can be implemented for electrochemical cleaning in-situ, and provides a widely applicable and dynamic solution for electrode fouling in-vivo.

[0225] Another technique that can be used to detect changes in electrode surfaces that can results from fouling is Electrochemical Impedance Spectroscopy. (EIS) EIS spectrums illustrated in FIG. 12 were taken using a potentiostat before and after exposure to NAC of an exemplary commercial sensor configuration as disclosed herein. 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, by way of example, 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.

[0226] While certain examples of the present disclosure have been illustrated with reference to specific combinations of elements, various other combinations may also be provided without departing from the teachings of the present disclosure. Thus, the present disclosure should not be construed as being limited to the particular exemplary examples described herein and illustrated in the Figures, but may also encompass combinations of elements of the various illustrated examples and aspects thereof.

Claims

WE CLAIM

1. 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; at least one membrane adjacent the electrochemically active surface area; and a controller configured to provide a swept potential range to the electrochemically active surface area.

2. The continuous monitoring sensor system of any one of the previous claims, wherein the electrochemically active surface area comprises metal.

3. The continuous monitoring sensor system of any one of the previous claims, wherein the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof.

4. The continuous monitoring sensor system of any one of the previous claims, wherein the electrochemically active surface area comprises metal and carbon.

5. The continuous monitoring sensor system of any one of the previous claims, wherein the electrochemically active surface area comprises carbon.

6. The continuous monitoring sensor system of any one of the previous claims, wherein the electrochemically active surface area comprises a covalently coupled mediator.

7. The continuous monitoring sensor system of any one of the previous claims, wherein the at least one membrane comprises a covalently coupled mediator.

8. The continuous monitoring sensor system of any one of the previous claims, wherein the at least one membrane is an interference membrane.

9. The continuous monitoring sensor system of any one of the previous claims, wherein the at least one membrane is biosensing membrane.

10. The continuous monitoring sensor system of any one of the previous claims, wherein the at least one membrane is a resistance membrane.

11. The continuous monitoring sensor system of any one of the previous claims, wherein the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.

12. The continuous monitoring sensor system of any one of the previous claims, wherein the swept potential range is between about -2.0 volts to about 2.0 volts verses a reference electrode.

13. The continuous monitoring sensor system of any one of the previous claims, wherein the swept potential range is between about -1.0 volts to about 1.0 volts verses a reference electrode.

14. The continuous monitoring sensor system of any one of the previous claims, wherein the swept potential range is between about -0.5 volts to about 1.0 volts verses a reference electrode.

15. The continuous monitoring sensor system of any one of the previous claims, wherein the swept potential range applied continuously, semi-continuously, intermittently, or randomly.

16. The continuous monitoring sensor system of any one of the previous claims, wherein the controller is configured to provide a plurality of swept potential ranges to the electrochemically active surface area.

17. The continuous monitoring sensor system of any one of the previous claims, wherein 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.

18. The continuous monitoring sensor system of any one of the previous claims, wherein the first potential value and the fifth potential value are equal or unequal.

19. The continuous monitoring sensor system of any one of the previous claims, wherein the controller is configured to measure a current response to the swept potential range.

20. The continuous monitoring sensor system of any one of the previous claims, wherein the controller is configured to measure plurality of current values corresponding a plurality of potential values.

21. The continuous monitoring sensor system of any one of the previous claims, wherein the controller is configured to provide a bias voltage to the electrochemically active surface area.

22. The continuous monitoring sensor system of any one of the previous claims, wherein 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.

23. The continuous monitoring sensor system of any one of the previous claims, wherein the controller is configured to provide a plurality of swept potential ranges to the electrochemically active surface area.

24. The continuous monitoring sensor system of any one of the previous claims, wherein 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.

25. The continuous monitoring sensor system of any one of the previous claims, wherein the first potential value and the fifth potential value are equal or unequal.

26. The continuous monitoring sensor system of any one of the previous claims, wherein the controller is configured to measure a current response to the swept potential range.

27. The continuous monitoring sensor system of any one of the previous claims, wherein the controller is configured to measure plurality of current values corresponding a plurality of potential values.

28. The continuous monitoring sensor system of any one of the previous claims, wherein the controller is configured to provide a bias voltage to the electrochemically active surface area.

29. The continuous monitoring sensor system of any one of the previous claims, wherein 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.

30. 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.

31. The continuous monitoring sensor system of claim 30, wherein the electrochemically active surface area comprises metal.

32. The continuous monitoring sensor system of any one of claims 30-31, wherein the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof.

33. The continuous monitoring sensor system of any one of claims 30-32, wherein the electrochemically active surface area comprises metal and carbon.

34. The continuous monitoring sensor system of any one of claims 30-33, wherein the electrochemically active surface area comprises carbon.

35. The continuous monitoring sensor system of any one of claims 30-34, wherein the electrochemically active surface area comprises covalently coupled mediator.

36. The continuous monitoring sensor system of any one of claims 30-35, wherein the electrochemically active surface area is in contact with at least one membrane.

37. The continuous monitoring sensor system of any one of claims 30-36, wherein the at least one membrane comprises covalently coupled mediator.

38. The continuous monitoring sensor system of any one of claims 30-37, wherein the at least one membrane is an interference membrane.

39. The continuous monitoring sensor system of any one of claims 30-38, wherein the at least one membrane is biosensing membrane.

40. The continuous monitoring sensor system of any one of claims 30-39, wherein the at least one membrane is a resistance membrane.

41. The continuous monitoring sensor system of any one of claims 30-40, wherein the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.

42. The continuous monitoring sensor system of any one of claims 30-41, wherein the sinusoidal potential range is modulated in a frequency range.

43. The continuous monitoring sensor system of any one of claims 30-42, wherein the frequency range is between about 1 MHz to about 10 MHz.

44. The continuous monitoring sensor system of any one of claims 30-43, wherein the frequency range is between about 10 MHz to about 100 kHz.

45. The continuous monitoring sensor system of any one of claims 30-44, wherein the frequency range is between about 100 MHz to about 10 kHz.

46. The continuous monitoring sensor system of any one of claims 30-45, wherein the sinusoidal potential range is applied continuously, semi-continuously, intermittently, or randomly.

47. A method of in-vivo reversing or reducing biofouling of an implanted biosensor electrode, the method comprising: applying a swept potential across an electrochemically active surface of an implanted electrochemical biosensor, at least a portion of the electrochemically active surface being covered by at least one foulant; and electrochemically removing at least one foulant from the electrochemically active surface.

48. The method of claim 47, wherein the electrochemically active surface area comprises metal.

49. The method of any one of claims 47-48, wherein the electrochemically active surface area comprises metal and carbon.

50. The method of any one of claims 47-49, wherein the electrochemically active surface area comprises carbon.

51. The method of any one of claims 47-50, wherein the electrochemically active surface area comprises covalently coupled mediator.

52. The method of any one of claims 47-51, wherein the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof.

53. The method of any one of claims 47-52, wherein the electrochemically active surface area is in contact with at least one membrane.

54. The method of any one of claims 47-53, wherein the at least one membrane comprises covalently coupled mediator.

55. The method of any one of claims 47-54, wherein the at least one membrane is an interference membrane.

56. The method of any one of claims 47-55, wherein the at least one membrane is biosensing membrane.

57. The method of any one of claims 47-56, wherein the at least one membrane is a resistance membrane.

58. The method of any one of claims 47-57, wherein the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.

59. The method of any one of claims 47-58, wherein the foulant is endogenous.

60. The method of any one of claims 47-59, wherein the foulant is exogenous.

61. The method of any one of claims 47-60, wherein the foulant comprises a thiol group.

62. The method of any one of claims 47-61, wherein the foulant comprises a cystine group.

63. The method of any one of claims 47-62, wherein the foulant is N-acetylcysteine.

64. The method of any one of claims 47-63, wherein the swept potential range applied continuously, semi-continuously, intermittently, or randomly.

65. 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);

(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.

66. The method of claim 65, further comprising: determining a baseline measurement corresponding to the at least one property.

67. The method of any one of claims 65-66, wherein (c) detecting a change of the at least one property of the electrochemically active surface area includes comparingthe at least one property to the baseline measurement.

68. The method of any one of claims 65-67, further comprising: applying a swept potential to the electrochemically active surface of an implanted electrochemical biosensor after detecting the change.

69. The method of any one of claims 65-68, further comprising: determining a baseline measurement corresponding to the at least one property.

70. The method of any one of claims 65-69, wherein (c) detecting a change of the at least one property of the electrochemically active surface area includes comparingthe at least one property to the baseline measurement.

71. The method of any one of claims 65-70, further comprising: applying a swept potential to the electrochemically active surface of an implanted electrochemical biosensor after detecting the change.

72. The method of any one of claims 65-71, wherein the electrochemically active surface area comprises metal.

73. The method of any one of claims 65-72, wherein the electrochemically active surface area comprises metal and carbon.

74. The method of any one of claims 65-73, wherein the electrochemically active surface area comprises carbon.

75. The method of any one of claims 65-74, wherein the electrochemically active surface area comprises covalently coupled mediator.

76. The method of any one of claims 65-75, wherein the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof.

77. The method of any one of claims 65-76, wherein the electrochemically active surface area is in contact with at least one membrane.

78. The method of any one of claims 65-77, wherein the at least one membrane comprises covalently coupled mediator.

79. The method of any one of claims 65-78, wherein the at least one membrane is an interference membrane.

80. The method of any one of claims 65-79, wherein the at least one membrane is biosensing membrane.

81. The method of any one of claims 65-80, wherein the at least one membrane is a resistance membrane.

82. The method of any one of claims 65-81, wherein the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.

83. The method of any one of claims 65-82, wherein the at least one property is electrical resistance.

84. The method of any one of claims 65-83, wherein the at least one property is an impedance modulus value.

85. The method of any one of claims 65-84, wherein the at least one property is a phase angle value.

86. The method of any one of claims 65-85, wherein the foulant is endogenous.

87. The method of any one of claims 65-86, wherein the foulant is exogenous.

88. The method of any one of claims 65-87, wherein the foulant comprises a thiol group.

89. The method of any one of claims 65-88, wherein the foulant comprises a cystine group.

90. The method of any one of claims 65-89, wherein the foulant is N-acetylcysteine.

91. The method of any one of claims 65-90, wherein the at least one sinusoidal signal is applied continuously, semi-continuously, intermittently, or randomly.

92. A method of continually detecting fouling and electrochemically removing fouling of an implantable sensing electrode, the method 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;

(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.

93. The method of claim 92, wherein the electrochemically active surface area comprises metal and carbon.

94. The method of any one of claims 92-93, wherein the electrochemically active surface area comprises carbon.

95. The method of any one of claims 92-94, wherein the electrochemically active surface area comprises covalently coupled mediator.

96. The method of any one of claims 92-95, wherein the electrochemically active surface area comprises gold, platinum, palladium, or binary or tertiary alloys thereof.

97. The method of any one of claims 92-96, wherein the electrochemically active surface area is in contact with at least one membrane.

98. The method of any one of claims 92-97, wherein the at least one membrane comprises coupled mediator.

99. The method of any one of claims 92-98, wherein the at least one membrane is an interference membrane.

100. The method of any one of claims 92-99, wherein the at least one membrane is biosensing membrane.

101. The method of any one of claims 92-100, wherein the at least one membrane is a resistance membrane.

102. The method of any one of claims 92-101, wherein the at least one membrane is a combination of at least two of an interference membrane, a biosensing membrane, and a resistance membrane.

103. The method of any one of claims 92-102, wherein the sinusoidal potential range is modulated in a frequency range.

104. The method of any one of claims 92-103, wherein the frequency range is between about 1 MHz to about 10 MHz.

105. The method of any one of claims 92-104, wherein the frequency range is between about 10 MHz to about 100 kHz.

106. The method of any one of claims 92-105, wherein the frequency range is between about 100 MHz to about 10 kHz.

107. The method of any one of claims 92-106, wherein the at least one property is electrical resistance.

108. The method of any one of claims 92-107, wherein the at least one property is an impedance modulus value.

109. The method of any one of claims 92-108, wherein the at least one property is a phase angle value.

110. The method of any one of claims 92-109, wherein the foulant is endogenous.

111. The method of any one of claims 92-110, wherein the foulant is exogenous.

112. The method of any one of claims 92-111, wherein the foulant comprises a thiol group.

113. The method of any one of claims 92-112, wherein the foulant comprises a cystine group.

114. The method of any one of claims 92-113, wherein the foulant is N-acetylcysteine.

115. The method of any one of claims 92-114, wherein the at least one sinusoidal potential range is applied continuously, semi-continuously, intermittently, or randomly.

116. The method of any one of claims 92-115, wherein the swept potential range is applied continuously, semi-continuously, intermittently, or randomly.