Biointerface Layer for an Analyte Sensor

Abstract

To provide: devices for measuring a biological analyte in a host which are able to reduce inaccuracy in an implanted sensor that can be caused by biomaterial-associated inflammation, and which are able to increase the life of an implanted device; and components of such devices.SOLUTION: Devices for determining an analyte concentration (e.g., glucose) comprise a sensor configured to generate a signal associated with a concentration of an analyte, and a sensing membrane located over the sensor. The sensing membrane comprises a biointerface layer which interfaces with a biological fluid containing the analyte to be measured. In the devices, the biointerface layer comprises a biointerface polymer, where the biointerface polymer may comprise polyurethane and / or polyurea segments and one or more zwitterionic repeating units.SELECTED DRAWING: None

Description

Technical Field

[0001] Incorporation by reference of related applications Any and all priority claims identified in the application data sheet, or any corrections thereto, are hereby incorporated by reference into this specification under 37 CFR 1.57. This application claims the benefit of U.S. Provisional Application No. 62 / 273,155, filed Dec. 30, 2015, U.S. Provisional Application No. 62 / 273,142, filed Dec. 30, 2015, and U.S. Provisional Application No. 62 / 273,219, filed Dec. 30, 2015. Each of the foregoing applications is hereby incorporated by reference in its entirety into this specification and each thereby becomes expressly a part hereof.

[0002] The subject matter disclosed herein relates to devices for measuring biological analytes in a host and components of such devices.

Background Art

[0003] Electrochemical sensors are useful for determining the presence or concentration of biological analytes such as blood glucose. Such sensors are effective, for example, in monitoring glucose in diabetic patients and lactate during life-saving emergencies.

[0004] Difficulties associated with the long-term use of continuous sensors and other medical devices are biomaterial-related inflammation, which is inflammation caused by implanting foreign objects into the body. Biomaterial-related inflammation is a result of the dynamic microenvironment around the implanted device, including initial injury, neutrophil and macrophage recruitment, foreign body giant cell (FBGC) response, neovascularization, fibroblast recruitment, and downstream fibrosis. The formation of a barrier cell layer around the implanted device can result in tissue integration failure.

[0005] In the case of continuous sensors, biocompatibility inflammation can impair analyte transport from tissue to the sensor surface by creating either a diffusion barrier or active consumption of the analyte. The FBGC response to implantable materials results in the formation of a fibrous capsule that interferes with sensor function by regulating glucose diffusion through a high-density fibrous "scar tissue" layer. Other components of the biocompatibility inflammation cascade, such as inflammatory cytokines and other small molecules, may act as interferents to sensor performance. These interferents can cause sensor inaccuracies due to periodic changes in transport properties at the sensor / tissue interface. In addition to diffusion limitations, there are active cellular components of the biocompatibility inflammation cascade, including inflammatory and wound healing cells, and these cells, which can be activated by the implanted material, actively consume glucose and produce H2O2, which can also lead to sensor inaccuracies. Therefore, reduction of biocompatibility inflammation is important for the creation of long-term stable implantable sensors and devices. Accordingly, there is a need for methods and compositions that can reduce the inaccuracies of implanted sensors that can be caused by biocompatibility inflammation. There is also a need for methods and compositions that can extend the lifespan of implanted devices. The methods and compositions disclosed herein address these and other needs.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0007] In accordance with the objectives of the disclosed materials and methods, the disclosed subject matter, as embodied and broadly described herein, in one aspect, relates to compounds, compositions, and methods of making and using devices containing the compounds and compositions. In a first aspect, there is provided a device for determining an analyte concentration (e.g., glucose), the device comprising a sensor configured to generate a signal related to the concentration of the analyte, and a sensing film located on the sensor. The sensing film includes a biointerface layer that interfaces with a biological fluid containing the analyte to be measured. In the device of this aspect, the biointerface layer includes a biointerface polymer, and the biointerface polymer may include polyurethane and / or polyurea segments and one or more zwitterionic repeating units.

[0008] The biointerface layer increases the lifespan of the sensor and reduces sensor inaccuracy by inhibiting the accumulation of cells, proteins, and other biological species on the outermost layer of the sensor. Early attenuation of these events in the biomaterial-related inflammatory cascade can reduce the overall sensitivity of the response, so that the inaccuracy of the in vivo sensor can be reduced.

[0009] In a further embodiment of the disclosed device, the sensing film further includes an enzyme domain including an enzyme selected from the group consisting of glucose oxidase, glucose dehydrogenase, galactose oxidase, cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate oxidase, and uricase. In certain embodiments, the enzyme is glucose oxidase.

[0010] In an embodiment of the device of this aspect, the one or more zwitterionic repeating units include a betaine compound or a derivative thereof. In an example of the device of this aspect, the one or more zwitterionic repeating units include a betaine compound or a precursor thereof.

[0011] In an embodiment of the device of this aspect, the one or more zwitterionic repeating units include at least one moiety selected from the group consisting of carboxybetaine, sulfobetaine, phosphobetaine, and derivatives thereof.

[0012] In an embodiment of the device of this aspect, one or more zwitterionic repeating units are derived from monomers selected from the group consisting of

Chemical formula

[0013] In an embodiment of the device of this aspect, one or more zwitterionic repeating units are derived from monomers selected from the group consisting of

Chemical formula

[0014] In an embodiment of the device of this aspect, the polymerizable group is selected from alkene, alkyne, epoxide, lactone, amine, hydroxyl, isocyanate, carboxylic acid, anhydride, silane, halide, aldehyde, and carbodiimide.

[0015] In an embodiment of the device of this aspect, one or more zwitterionic repeating units are at least about 1 wt% based on the total weight of the polymer.

[0016] In an embodiment of the device of this aspect, the polyurethane and / or polyurea segment is about 15 wt% to about 75 wt% based on the total weight of the polymer.

[0017] In an embodiment of the device of this aspect, the biointerface polymer further comprises at least one segment selected from the group consisting of epoxide, polyolefin, polysiloxane, polyamide, polystyrene, polyacrylate, polyether, polyester, and polycarbonate.

[0018] In an embodiment of the device of this aspect, the biointerface polymer further includes a polyethylene oxide segment and, in some examples, is from about 5 wt% to about 60 wt% based on the total weight of the biointerface polymer.

[0019] In an embodiment of the device of this aspect, the biointerface polymer has a molecular weight of about 10 kDa to about 500,000 kDa, a polydispersity index of about 1.4 to about 3.5, and / or a contact angle of about 20° to about 90°.

[0020] In a second aspect, there is provided a device in which the biointerface layer further includes one or more zwitterions selected from cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, caprylyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly(carboxybetaine), poly(sulfobetaine), and derivatives thereof.

[0021] In an embodiment of the second aspect, there is provided a device in which the biointerface layer further includes a pharmaceutical or a biological agent.

[0022] In a third aspect, there is provided a device for determining an analyte concentration, the device comprising a sensor configured to generate a signal related to the concentration of the analyte and a sensing membrane located on the sensor. The sensing membrane includes a biointerface layer that interfaces with a biological fluid containing the analyte to be measured. In the device of this aspect, the biointerface domain includes a biointerface polymer, and the biointerface polymer includes a polymer chain having both a hydrophilic region and a hydrophobic region. The hydrophilic region includes a linear polymer chain to which a hydrophilic oligomer is attached, and the linear polymer is grafted onto the biointerface polymer.

[0023] In a fourth aspect, there is provided a device for determining an analyte concentration, the device comprising a sensor configured to generate a signal related to the concentration of the analyte, and a sensing film located on the sensor. The sensing film includes a biointerface layer that interfaces with a biological fluid containing the analyte to be measured. In the device of this aspect, the biointerface layer includes a biointerface polymer, and the biointerface polymer includes a fluorescent moiety covalently bonded to the biointerface polymer.

[0024] In a fifth aspect, there is provided a device for determining an analyte concentration, the device comprising a sensor configured to generate a signal related to the concentration of the analyte, and a sensing film located on the sensor. The sensing film includes a biointerface layer that interfaces with a biological fluid containing the analyte to be measured. In the device of this aspect, the biointerface layer includes a base polymer and a surface-modified polymer, the surface-modified polymer including a polymer chain having both a hydrophilic region and a hydrophobic region, as well as one or more zwitterionic compounds, and the base polymer being selected from silicone, epoxide, polyolefin, polystyrene, polyoxymethylene, polysiloxane, polyether, polyacrylic acid, polymethacrylic acid, polyester, polycarbonate, polyamide, poly(ether ketone), poly(ether imide), polyurethane, and polyurethane urea.

[0025] In all of the devices disclosed herein, they can be configured for continuous measurement of analyte concentration.

[0026] Additional advantages will be described in part in the following description, become apparent in part from the description, or can be learned by practice of the aspects below. The advantages below are recognized and achieved by the elements and combinations particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

[0027] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects described below.

Brief Description of the Drawings

[0028]

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Mode for Carrying Out the Invention

[0029] The methods, compositions, and devices described in this specification can be more readily understood by reference to the following detailed description of specific aspects of the disclosed subject matter, as well as the examples and drawings contained therein.

[0030] Before the methods, compositions, and devices are disclosed and described, it is to be understood that the following aspects are not limited to a particular synthesis method or particular reagents, and as such, can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0031] Also, various publications are referenced throughout this specification. The disclosures of these publications are hereby incorporated by reference in their entirety into this application to more fully describe the state of the art to which the disclosed matter pertains. The disclosed references are also individually and specifically incorporated by reference herein for the materials contained therein, as discussed in the context in which that reference is relied upon.

[0032] Definitions As used herein, and in the following claims, reference is made to a number of terms that are defined to have the following meanings.

[0033] As used herein, the term "about" is intended to identify the numerical value it modifies, and is shown as such a value being variable within an error. When no specific error, such as a standard deviation relative to an average value shown in a data chart or table, is recited, the term "about" is understood to mean, taking significant figures into account, the range encompassing the recited value and the ranges included by rounding up or down that number as well.

[0034] As used herein, the term "analyte" is a broad term, and its ordinary and customary meaning is indicated to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to substances or chemical components in biological fluids that can be analyzed (e.g., blood, interstitial fluid, cerebrospinal fluid, lymph, urine, sweat, saliva, etc.), but is not limited thereto. Analytes can include naturally occurring substances, artificial substances, metabolites, and / or reaction products. In some embodiments, the analyte for measurement by the detection region, device, and method is glucose. However, other analytes are equally contemplated, including carboxyprothrombin, acylcarnitine, adenine phosphoribosyltransferase, adenosine deaminase, albumin, alpha-fetoprotein, amino acid profile (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan), androstenedione, antipyrine, arabinitol enantiomers, arginase, benzoylecgonine (cocaine), biotinidase, biopterin, c-reactive protein, carnitine, carnosinase, CD4, ceruloplasmin, chenodeoxycholic acid, chloroquine, cholesterol, cholinesterase, conjugated 1-beta-hydroxychenodeoxycholic acid, cortisol, creatine kinase, creatine kinase MM isozyme, cyclosporin A, d-penicillamine, de-ethylchloroquine, dehydroepiandrosterone sulfate, DNA (acetylation polymorphism, alcohol dehydrogenase, alpha1-antitrypsin, cystic fibrosis, Duchenne / Becker muscular dystrophy, analyte-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 malariae, sex differentiation, 21-deoxycortisol), desbutylhalofantrine, dihydropteridine reductase, diphtheria / tetanus antitoxin, erythrocyte arginase, erythrocyte protoporphyrin, esterase D, fatty acid / acylglycine, free beta-human chorionic gonadotropin, free erythrocyte protoporphyrin,Free thyroxine (FT4), free triiodothyronine (FT3), fumarylacetoacetase, galactose / gal-1-phosphate, galactose-1-phosphate uridyltransferase, gentamicin, analyte-6-phosphate dehydrogenase, glutathione, glutathione peroxidase, glycolic acid, glycosylated hemoglobin, halofantrine, hemoglobin variants, hexosaminidase A, human erythrocyte carbonic anhydrase I, 17-α-hydroxyprogesterone, hypoxanthine phosphoribosyltransferase, immunoreactive trypsin, lactate, lead, lipoproteins ((a), B / A-1, β), lysozyme, mefloquine, netilmicin, phenobarbital, phenytoin, phytanic acid / pristanic acid, progesterone, prolactin, prolidase, purine nucleoside phosphorylase, kinins, reverse triiodothyronine (rT3), selenium, serum pancreatic lipase, sisomicin, somatomedin C, specific antibodies (adenovirus, antinuclear antibody, anti-zeta antibody, arbovirus, OESK virus, dengue virus, guinea worm, tapeworm, Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic diseases), influenza virus, Leishmania donovani, leptospira, measles / mumps / rubella, mycoplasma pneumoniae, myoglobin, Trichinella spiralis, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, respiratory rash virus, Rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Treponoma pallidium, Trypanosoma cruzi / Langerhans, 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, uroporphyrinogen I synthase, vitamin A, white blood cells, and zinc protoporphyrin are mentioned,Not limited to these. Salts, sugars, proteins, fats, vitamins, and hormones that occur naturally in blood or interstitial fluid can also constitute analytes in certain embodiments. Analytes, such as metabolites, hormones, antigens, antibodies, etc., can be naturally present in biological fluids or can be endogenous. Alternatively, analytes, such as contrast agents for imaging diagnostics, radioisotopes, chemical agents, fluorocarbon-based artificial blood, or drugs or pharmaceutical compositions, can be introduced into the body or can be exogenous, including insulin, ethanol, cannabis (marijuana, tetrahydrocannabinol, hashish), inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorinated hydrocarbons, hydrocarbons), cocaine (crack cocaine), stimulants (amphetamine, methamphetamine, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine), depressants (barbiturates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene), hallucinogens (fenciclovir, lysergic acid, mescaline, peyote, psilocybin), narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil), designer drugs (analogs of fentanyl, meperidine, amphetamine, methamphetamine, and fenciclovir such as Ecstasy), anabolic steroids, and nicotine, but not limited to these. Metabolites of drugs and pharmaceutical compositions can also be contemplated as analytes. For example, analytes such as ascorbic acid, uric acid, dopamine, norepinephrine, 3-methoxythyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA), etc., neurochemicals and other chemicals generated in the body can also be analyzed.

[0035] As used herein, the term "baseline" is a broad term, and its ordinary and customary meaning is indicated to those skilled in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, components of an analyte sensor signal that are not related to analyte concentration. In one example of a glucose sensor, the baseline is substantially composed of signal contributions due to factors other than glucose (e.g., interfering species, non-reaction related hydrogen peroxide, or other electroactive species having an oxidation potential overlapping with hydrogen peroxide). In some embodiments where calibration is defined by solving the equation y = mx + b, the value of b represents the baseline of the signal.

[0036] As used herein, the term "continuous (or ongoing) analyte sensing" is a broad term, and its ordinary and customary meaning is indicated to those skilled in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, a period during which monitoring of analyte concentration is performed continuously, continuously, and / or intermittently (but regularly), for example, every about 5 - 10 minutes.

[0037] As used herein, the term "count" is a broad term, and its ordinary and customary meaning is indicated to those skilled in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, a unit of measurement of a digital signal. In one example, the raw data stream measured in counts is directly related to voltage (e.g., converted by an A / D converter), which is directly related to the current from the working electrode. In another example, the counter electrode voltage measured in counts is directly related to voltage.

[0038] As used herein, the terms "dipole" or "dipolar compound" are broad terms, and their ordinary and customary meanings are indicated to those skilled in the art (and are not limited to special or customized meanings), and refer to, but are not limited to, compounds in which the neutral molecules of the compound have positive and negative charges at different positions within the molecule. The positive and negative charges within the molecule can be any non-zero charge less than or equal to a full unit charge.

[0039] As used herein, the term "distal" is a broad term, and its ordinary and customary meanings are indicated to those skilled in the art (and are not limited to special or customized meanings), and refers to, but is not limited to, the spatial relationship between various elements compared to a specific reference point. For example, some embodiments of the sensor include a membrane system having a biointerface domain and an enzyme domain. If the sensor is considered the reference point and the biointerface domain is positioned farther from the sensor than the enzyme domain, the biointerface domain is distal to the enzyme domain with respect to the sensor.

[0040] As used herein, the term "domain" is a broad term, and its ordinary and customary meanings are indicated to those skilled in the art (and are not limited to special or customized meanings), and refers to, but is not limited to, a region of a membrane that can be a layer of uniform or non-uniform gradient (i.e., anisotropic) or can be provided as part of a membrane.

[0041] As used herein, the term "potential" is a broad term, and its ordinary and customary meanings are indicated to those skilled in the art (and are not limited to special or customized meanings), and refers to, but is not limited to, the potential difference between two points in a circuit that causes a flow of current.

[0042] As used herein, the terms "electrochemical reaction surface" or "electroactive surface" are broad terms, their ordinary and customary meanings being those indicated to one of ordinary skill in the art (and not being limited to special or customized meanings), and refer to, but are not limited to, the surface of an electrode at which an electrochemical reaction occurs. As an example, at a working electrode, H2O2 (hydrogen peroxide) generated by an enzyme-catalyzed reaction of an analyte to be detected reacts, thereby creating an electrical circuit that can be measured. For example, in the detection of glucose, glucose oxidase generates H2O2 as a byproduct. H2O2 reacts with the surface of the working electrode to produce two protons (2H + ), two electrons (2e - ), and one oxygen molecule (O2), which generates a detectable current. In the case of a counter electrode, a reducible species, such as O2, is reduced at the electrode surface to balance the current generated by the working electrode.

[0043] As used herein, the term "host" is a broad term, its ordinary and customary meanings being those indicated to one of ordinary skill in the art (and not being limited to special or customized meanings), and refers to, but is not limited to, animals (e.g., humans) and plants. In some embodiments, hosts can include companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mice, rabbits, rats, guinea pigs, etc.), and birds. In other embodiments, hosts can include mammals such as primates or humans.

[0044] As used herein, the terms "interferent" and "interfering species" are broad terms, their ordinary and customary meanings being those indicated to one of ordinary skill in the art (and not being limited to special or customized meanings), and refer to, but are not limited to, an effect or species that interferes with the measurement of an analyte of interest in a sensor and produces a signal that does not accurately represent the analyte measurement value. In an exemplary electrochemical sensor, interfering species can include compounds having an oxidation potential that overlaps with the oxidation potential of the analyte being measured.

[0045] As used herein, the terms "zwitterion dipole" and "zwitterionic compound" are broad terms, and their ordinary and customary meanings are indicated to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to compounds in which the neutral molecules of the compound have positive and negative charges at different positions within the molecule, but are not limited thereto. The positive and negative charges within the molecule are less than a full unit but can be any non-zero charge.

[0046] As used herein, the terms "operably connected", "operably coupled", and "operably linked" are broad terms, and their ordinary and customary meanings are indicated to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to one or more components that are connected to another component (s) in a manner that enables the transmission of signals between the components, but are not limited thereto. For example, one or more electrodes can be used to detect the amount of an analyte in a sample and convert that information into a signal, which can then be transmitted to a circuit. In this case, the electrodes are "operably linked" to the electronic circuit.

[0047] The term "any" or "optionally" means that the event or situation described later may or may not occur, and that the description includes both the case where the event or situation occurs and the case where it does not occur.

[0048] As used herein, the term "ampholytic polymer electrolyte" is a broad term, with its ordinary and customary meaning being indicated to those of ordinary skill in the art (and not being limited to a special or customized meaning), and refers to, but is not limited to, polymers that contain both cationic and anionic groups. Such polymers can be prepared to have approximately equal numbers of positive and negative charges, and thus the surface of such polymers can be substantially net charge neutral. Alternatively, such polymers can be prepared to have an excess of either positive or negative charge, and thus the surface of such polymers can be net positively or negatively charged, respectively.

[0049] As used herein, the term "polyzwitterion" is a broad term, with its ordinary and customary meaning being indicated to those of ordinary skill in the art (and not being limited to a special or customized meaning), and refers to, but is not limited to, polymers in which the repeating units of the polymer chain are zwitterionic moieties. Polyzwitterions are also known as polybetaines. Since polyzwitterions have both cationic and anionic groups, they are a type of ampholytic polymer electrolyte. However, since both the cationic and anionic groups are part of the same repeating unit, they are integral, which means that polyzwitterions have the same number of cationic and anionic groups, while other ampholytic polymer electrolytes can have more of one ionic group than the other. Also, polyzwitterions have cationic and anionic groups as part of the repeating unit. Ampholytic polymer electrolytes do not necessarily have cationic groups attached to anionic groups; they can be on different repeating units and thus can be distributed randomly spaced apart from each other, or one ionic group can outnumber the others.

[0050] As used herein, the term "proximal" is a broad term, and its ordinary and customary meaning is provided to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, the spatial relationship between various elements as compared to a particular reference point. For example, some embodiments of a device include a membrane system having a biointerface layer and an enzyme layer. If the sensor is considered the reference point and the enzyme layer is positioned closer to the sensor than the biointerface layer, the enzyme layer is proximal to the biointerface layer relative to the sensor.

[0051] As used herein, the terms "raw data stream" and "data stream" are broad terms, and their ordinary and customary meaning is provided to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refer to, but are not limited to, analog or digital signals directly related to the measured glucose concentration from a glucose sensor. In one example, the raw data stream is digital data in "counts" (e.g., voltage or amperage) converted from an analog signal by an A / D converter and represents the glucose concentration. These terms broadly encompass multiple time-spaced data points from a substantially continuous glucose sensor, which includes individual measurements taken at time intervals ranging from less than 1 second to, for example, up to 1, 2, or 5 minutes or more.

[0052] As used herein, the terms "sensing membrane" and "membrane system" are broad terms, and their ordinary and customary meaning is provided to those of ordinary skill in the art (and is not limited to a special or customized meaning), and may include one or more domains or layers, and refer to, but are not limited to, a permeable or semi-permeable membrane composed of a material having a thickness of several microns or more that is permeable to oxygen and may or may not be permeable to the analyte of interest. In one example, the sensing membrane or membrane system may include an immobilized glucose oxidase enzyme, which enables an electrochemical reaction to occur to measure the concentration of glucose.

[0053] As used herein, the terms "detection region", "sensor", and "detection mechanism" are broad terms, and their ordinary and customary meanings are provided to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to, but are not limited to, the regions or mechanisms of a monitoring device involved in the detection of a particular analyte.

[0054] As used herein, the term "sensitivity" is a broad term, and its ordinary and customary meaning is provided to those of ordinary skill in the art (and is not limited to special or customized meanings), and refers to, but is not limited to, the amount of signal (e.g., in the form of current and / or voltage) generated by a measured amount (unit) of an analyte. For example, in one embodiment, the sensor has a sensitivity (or slope) of about 1 to about 100 picoamperes of current per 1 mg / dL of glucose analyte.

[0055] As used herein, the terms "zwitterion" and "zwitterionic compound" are broad terms, and their ordinary and customary meanings are provided to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to, but are not limited to, compounds in which the neutral molecules of the compound have a unit positive charge and a unit negative charge at different positions within the molecule. Such compounds are a type of bipolar compound and may also be referred to as "inner salts".

[0056] As used herein, the terms "zwitterionic precursor" or "zwitterionic compound precursor" are broad terms, their ordinary and customary meanings being those indicated to one of ordinary skill in the art (and not limited to special or customized meanings), and refer to any compound that is not itself a zwitterion but can become a zwitterion in its final or transitional state through a chemical reaction, including but not limited to. In some embodiments described herein, the device includes a zwitterionic precursor that can be converted to a zwitterion prior to in vivo implantation of the device. Alternatively, in some embodiments described herein, the device includes a zwitterionic precursor that can be converted to a zwitterion by some chemical reactions that occur after in vivo implantation of the device. Such reactions are known to those of ordinary skill in the art and include addition reactions such as ring-opening reactions and Michael additions. This method is particularly useful when the polymerization of betaine-containing monomers is difficult due to technical difficulties such as the solubility of betaine monomers in order to achieve desired physical properties such as molecular weight and mechanical strength. Post-polymerization modification or conversion of betaine precursors can be a practical method for achieving desired polymer structures and compositions. Examples of such precursors include tertiary amines, quaternary amines, pyridines, and others detailed herein.

[0057] As used herein, the terms "zwitterionic derivative" or "zwitterionic compound derivative" are broad terms, their ordinary and customary meanings being those indicated to one of ordinary skill in the art (and not limited to special or customized meanings), and refer to any compound that is not itself a zwitterion but rather the product of a chemical reaction in which a zwitterion is converted to a non-zwitterion, including but not limited to. Since such reactions can be reversible, under certain conditions, a zwitterionic derivative can act as a zwitterionic precursor. For example, a hydrolyzable betaine ester formed from a zwitterionic betaine is a cationic zwitterionic derivative that can undergo hydrolysis to return to zwitterionic betaine under appropriate conditions.

[0058] As used herein, the following abbreviations apply: Eq and Eqs (equivalent), mEq (milliequivalent), M (mole), mM (millimole), μM (micromole), N (normal), mol (mole), mmol (millimole), μmol (micromole), nmol (nanomole), g (gram), mg (milligram), μg (microgram), Kg (kilogram), L (liter), mL (milliliter), dL (deciliter), μL (microliter), cm (centimeter), mm (millimeter), μm (micrometer), nm (nanometer), h and hr (hour), min (minute), s and sec (second), °C (Celsius temperature).

[0059] Sensor system FIG. 1 is a schematic diagram of a continuous analyte sensor system 100 attached to a host and communicating with a number of other exemplary devices 110-113. A transdermal analyte sensor system is shown that includes an on-skin sensor assembly 600 that is secured to the host's skin via a disposable housing (not shown). The system includes a transdermal analyte sensor 200 and an electronics unit (alternatively referred to as a "sensor electronics" or "transmitter") 500 for wirelessly transmitting analyte information to a receiver. During use, the sensing portion of the sensor 200 is under the host's skin and the contacting portion of the sensor 200 is operably connected (e.g., electrically connected) to the electronics unit 500. The electronics unit 500 engages a housing attached to an adhesive patch secured to the host's skin.

[0060] The on-skin sensor assembly 600 may be attached to the host using an applicator adapted to provide a convenient and safe application. Such an applicator can also be used to insert the sensor 200 through the host's skin. Once the sensor 200 is inserted, the applicator is detached from the sensor assembly.

[0061] Generally, the continuous analyte sensor system 100 includes any sensor configuration that provides an output signal indicative of the concentration of an analyte. The output signal (including sensor data such as, for example, raw data streams, filtered data, smoothed data, and / or sensor data converted in other ways) is transmitted to a receiver, which can be, for example, a smartphone, a smartwatch, a dedicated device, etc. In one embodiment, the analyte sensor system 100 includes a transcutaneous glucose sensor as described in U.S. Patent Publication No. US-2011-0027127-A1, the content of which is incorporated herein by reference in its entirety. In some embodiments, the sensor system 100 includes a continuous glucose sensor, including, for example, a transcutaneous sensor as described in U.S. Patent No. 6,565,509 to Say et al. In another embodiment, the sensor system 100 includes a continuous glucose sensor, including, for example, a subcutaneous sensor as described with reference to U.S. Patent No. 6,579,690 to Bonnecaze et al. and U.S. Patent No. 6,484,046 to Say et al. In another embodiment, the sensor system 100 includes a continuous glucose sensor, including, for example, a subcutaneous sensor as described with reference to U.S. Patent No. 6,512,939 to Colvin et al. In another embodiment, the sensor system 100 includes a continuous glucose sensor, including, for example, an intravascular sensor as described with reference to U.S. Patent No. 6,477,395 to Schulman et al. In another embodiment, the sensor system 100 includes a continuous glucose sensor, including, for example, an intravascular sensor as described with reference to U.S. Patent No. 6,424,847 to Mastrototaro et al. Other signal processing techniques and embodiments of glucose monitoring systems suitable for use with the embodiments described herein are described in U.S. Patent Publication No. US-2005-0203360-A1 and U.S. Patent Publication No. US-2009-0192745-A1, the contents of which are incorporated herein by reference in their entirety. The sensor extends through a housing that maintains the sensor on the skin and is provided in an electronics unit to provide an electrical connection between the sensor and the sensor electronics.

[0062] In one embodiment, the sensor is formed from a wire or is in the form of a wire. For example, the sensor can include an elongated conductor such as a bare, elongated conductive core (e.g., a metal wire) or an elongated conductive core coated with one, two, three, four, five, or more layers of material, each of which may or may not be conductive. The elongated sensor can be long and thin, yet flexible and strong. For example, in some embodiments, the minimum dimension of the elongated conductor is less than about 0.1 inch (0.3 cm), less than about 0.075 inch (0.20 cm), less than about 0.05 inch (0.13 cm), less than about 0.025 inch (0.06 cm), less than about 0.01 inch (0.03 cm), less than about 0.004 inch (0.01 cm), or less than about 0.002 inch (0.005 cm). The sensor can have a circular cross-section. In some embodiments, the cross-section of the elongated conductor can be oval, rectangular, triangular, polygonal, star-shaped, C-shaped, T-shaped, X-shaped, Y-shaped, irregular, etc. In one embodiment, a conductive wire electrode is used as the core. One or two additional conductive layers may be added to such a clad electrode (e.g., by interposing an insulating layer provided for electrical isolation). The conductive layer can be composed of any suitable material. In certain embodiments, it may be desirable to use a conductive layer that includes conductive particles (i.e., particles of a conductive material) in a polymer or other binder.

[0063] In certain embodiments, the materials used to form the elongated conductor (e.g., stainless steel, titanium, tantalum, platinum, platinum-iridium, iridium, certain polymers, and / or the like) can be strong and hard to prevent damage. For example, in some embodiments, the maximum tensile strength of the elongated conductor is from about 80 kPsi to about 500 kPsi. In another example, in some embodiments, the Young's modulus of the elongated conductor is from about 160 GPa to about 220 GPa. In yet another example, in some embodiments, the yield strength of the elongated conductor is from about 60 kPsi to about 2200 kPsi. In some embodiments, the small diameter of the sensor provides flexibility to these materials and thus to the sensor as a whole (e.g., confers, enables). Thus, the sensor can withstand the repeated forces applied to it by the surrounding tissue.

[0064] In addition to providing structural support, elasticity, and flexibility, in some embodiments, the core (or its components) provides electrical conduction for electrical signals from the working electrode to sensor electronics (not shown). In some embodiments, the core comprises a conductive material such as stainless steel, titanium, tantalum, a conductive polymer, and / or the like. However, in other embodiments, the core is formed from a non-conductive material such as a non-conductive polymer. In still other embodiments, the core comprises a plurality of material layers. For example, in one embodiment, the core comprises an inner core and an outer core. In a further embodiment, 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 embodiments, the first conductive material is stainless steel, titanium, tantalum, a conductive polymer, an alloy, and / or the like, and the second conductive material is a conductive material selected to provide electrical conduction between the core and the first layer and / or to adhere the first layer to the core (e.g., if the first layer is formed of a material that does not adhere well to the core material). In another embodiment, 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 stainless steel, titanium, tantalum, a conductive polymer, and / or the like. The core and the first layer can be of a single (or the same) material, e.g., platinum. Those skilled in the art will understand that additional configurations are possible.

[0065] In the illustrated embodiment, the electronic device unit 500 is removably attachable to the sensor 200. The electronic device unit 500 includes electronic device circuitry related to the measurement and processing of continuous analyte sensor data and is configured to execute algorithms related to the processing and calibration of sensor data. For example, the electronic device unit 500 can provide various aspects related to the functionality of a sensor electronics module as described in U.S. Patent Publication No. US-2009-0240120-A1 and U.S. Patent Application No. 13 / 247,856, filed September 28, 2011, entitled "ADVANCED CONTINUOUS ANALYTE MONITORING SYSTEM", the contents of which are hereby incorporated by reference in their entirety. The electronic device unit 500 can include hardware, firmware, and / or software that enables the measurement of analyte levels via a glucose sensor such as analyte sensor 200. For example, the electronic device unit 500 can include a potentiostat, a power source for providing power to the sensor 200, other components useful for signal processing and data storage, and preferably a telemetry module for one-way or two-way data communication between the electronic device unit 500 and one or more receivers, repeaters, and / or display devices such as devices 110-113. The electronic device can be fixed to a printed circuit board (PCB) or the like and can take various forms. For example, the electronic device can take the form of an integrated circuit (IC) such as an application specific integrated circuit (ASIC), a microcontroller, and / or a processor. The electronic device unit 500 can include sensor electronics configured to process sensor information, e.g., store data, analyze data streams, calibrate analyte sensor data, estimate analyte values, compare estimated analyte values to time-corresponding measured analyte values, and analyze various estimated analyte values.Examples of systems and methods for processing sensor analyte data are described in more detail herein and in U.S. Patent No. 7,310,544, U.S. Patent No. 6,931,327, U.S. Patent Publication No. 2005-0043598-A1, U.S. Patent Publication No. 2007-0032706-A1, U.S. Patent Publication No. 2007-0016381-A1, U.S. Patent Publication No. 2008-0033254-A1, U.S. Patent Publication No. 2005-0203360-A1, U.S. Patent Publication No. 2005-0154271-A1, U.S. Patent Publication No. 2005-0192557-A1, U.S. Patent Publication No. 2006-0222566-A1, U.S. Patent Publication No. 2007-0203966-A1, and U.S. Patent Publication No. 2007-0208245-A1, the contents of which are hereby incorporated by reference in their entirety.

[0066] One or more repeaters, receivers, and / or display devices, such as key fob repeater 110, medical device receiver 111 (e.g., insulin delivery device and / or dedicated glucose sensor receiver), smartphone 112, portable computer 113, etc., are operably connected to the electronic device unit, which is also referred to herein as the transmitter and / or sensor electronic device body, receive data from the electronic device unit 500, and in some embodiments, transmit data to the electronic device unit 500. For example, sensor data can be transmitted from the sensor electronic device unit 500 to one or more of key fob repeater 110, medical device repeater 111, smartphone 112, portable computer 113, etc. In one embodiment, the display device includes an input module having a crystal crystal operably connected to an RF transceiver (not shown) that functions together to transmit, receive, and synchronize data streams from the electronic device unit 500. However, the input module can be configured in any manner capable of receiving data from the electronic device unit 500. Once received, the input module transmits the data stream to a processor that processes the data stream, as described in more detail below. The processor is a central control unit that performs processes such as storing data, analyzing data streams, calibrating analyte sensor data, estimating analyte values, comparing estimated analyte values with time-corresponding measured analyte values, analyzing fluctuations in estimated analyte values, downloading data, and controlling the user interface by providing analyte values, prompts, messages, warnings, alarms, etc. The processor includes hardware for performing the processes described herein. For example, read-only memory (ROM) provides permanent or semi-permanent storage of data, storage of data such as sensor ID (sensor identifier), receiver ID (receiver identifier), etc., and programming for processing data streams (e.g., programming for performing estimations and other algorithms described elsewhere herein), and random access memory (RAM) stores the system's cache memory and is useful for data processing.An output module that can be integrated with and / or operably connected to a processor includes programming (and any processing that occurs within the processor) for generating an output based on sensor data received from an electronic device unit.

[0067] In some embodiments, the analyte value is displayed on a display device. In some embodiments, a prompt or message can be displayed on the display device to communicate information such as an out-of-range value, a request for a reference analyte value, a treatment recommendation, a deviation of a measured analyte value from an estimated analyte value, etc. to the user. Further, a prompt can be displayed to guide the user through calibration or calibration troubleshooting.

[0068] Furthermore, the data output from the output module can provide wired or wireless one-way or two-way communication between the receiver and an external device. The external device can be any device that interfaces with or communicates with the receiver. In some embodiments, the external device is a computer and the receiver can download current or past data for retrospective analysis, for example, by a physician. In some embodiments, the external device is a modem and the receiver can transmit alerts, warnings, emergency messages, etc., to a counterpart such as a physician or family member via a communication line. In some embodiments, the external device is an insulin pen and the receiver can communicate treatment recommendations such as insulin dosage and time to the insulin pen. In some embodiments, the external device is an insulin pump and the receiver can communicate treatment recommendations such as insulin dosage and time to the insulin pump. The external device can include other technical or medical devices such as, for example, a pacemaker, an implantable analyte sensor patch, other infusion devices, telemetry devices, etc. The receiver can communicate with the external device and / or any number of additional devices via any suitable communication protocol including radio frequency, Bluetooth®, Universal Serial Bus (USB), Wireless Local Area Network (WLAN) communication standards (including IEEE802.11, 802.15, 802.20, 802.22, and other 802 communication protocols), ZigBee, wireless (e.g., cellular) telecommunications, paging network communication, magnetic induction, satellite data communication, GPRS, ANT, and / or proprietary communication protocols.

[0069] The implementations described herein generally discuss sensors constituted by one or more sensor wires. However, it will be understood that the sensors are not limited to such wire-like or linear arrangements. Rather, the sensors can be implemented as planar sensors, volume sensors, point sensors, or in other shapes understood in view of this description.

[0070] Membrane system The membrane systems disclosed herein are suitable for use with implantable devices that contact biological fluids. For example, the membrane systems can be utilized with implantable devices for monitoring and determining analyte levels in biological fluids, such as devices for monitoring glucose levels in individuals with diabetes. In some embodiments, the analyte measurement device is a continuous device. The analyte measurement device provides a raw signal using any suitable sensing element, including but not limited to those involving enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, calorimetric, radiometric, immunochemical, or similar elements.

[0071] Part of the following description is directed to glucose measurement devices, including the described membrane systems and their methods of operation, but these membrane systems are not limited to use in devices for measuring or monitoring glucose. These membrane systems are suitable for use in any of a variety of devices, such as devices for detecting and quantifying other analytes present in biological fluids (e.g., cholesterol, amino acids, alcohols, galactose, and lactate), cell implantation devices (see, e.g., U.S. Patent Nos. 6,015,572, 5,964,745, and 6,083,523), drug delivery devices (see, e.g., U.S. Patent Nos. 5,458,631, 5,820,589, and 5,972,369), and the like, the disclosures of which patents are hereby incorporated by reference in their entirety with respect to the teachings of their membrane systems.

[0072] In one embodiment, the analyte measurement device is an implantable glucose sensor as described with reference to U.S. Patent No. 6,001,067 and U.S. Patent Publication No. US-2005-0027463-A1 (which are hereby incorporated by reference in their entirety). In another embodiment, the analyte measurement device is a glucose sensor as described with reference to U.S. Patent Publication No. US-2006-0020187-A1 (which is hereby incorporated by reference in its entirety). In yet other embodiments, the sensor is configured to be implanted in a host blood vessel or configured extracorporeally as described in U.S. Patent Publication Nos. US-2007-0027385-A1, US-2008-0119703-A1, US-2008-0108942-A1, and US-2007-0197890-A1 (which are hereby incorporated by reference in their entirety). In some embodiments, the sensor is configured as a dual electrode sensor as described in U.S. Patent Publication Nos. US-2005-0143635-A1, US-2007-0027385-A1, US-2007-0213611-A1, and US-2008-0083617-A1 (which are hereby incorporated by reference in their entirety). In one alternative embodiment, the continuous glucose sensor includes, for example, a sensor as described in U.S. Patent No. 6,565,509 to Say et al. In another alternative embodiment, the continuous glucose sensor includes, for example, a subcutaneous sensor as described with reference to U.S. Patent No. 6,579,690 to Bonnecaze et al. or U.S. Patent No. 6,484,046 to Say et al. In another alternative embodiment, the continuous glucose sensor includes, for example, a refillable subcutaneous sensor as described with reference to U.S. Patent No. 6,512,939 to Colvin et al. In yet another alternative embodiment, the continuous glucose sensor includes, for example, an intravascular sensor as described with reference to U.S. Patent No. 6,477,395 to Schulman et al.In another alternative embodiment, the continuous glucose sensor includes an intravascular sensor as described with reference to U.S. Patent No. 6,424,847 to Mastrototaro et al. In some embodiments, the electrode system can be used with any of a variety of known in vivo analyte sensors or monitors, such as those described in U.S. Patent No. 7,157,528 to Ward, U.S. Patent No. 6,212,416 to Ward et al., U.S. Patent No. 6,119,028 to Schulman et al., U.S. Patent No. 6,400,974 to Lesho, U.S. Patent No. 6,595,919 to Berner et al., U.S. Patent No. 6,141,573 to Kurnik et al., U.S. Patent No. 6,122,536 to Sun et al., European Patent Publication No. EP1153571 to Varall et al., U.S. Patent No. 6,512,939 to Colvin et al., U.S. Patent No. 5,605,152 to Slate et al., U.S. Patent No. 4,431,004 to Bessman et al., U.S. Patent No. 4,703,756 to Gough et al., U.S. Patent No. 6,514,718 to Heller et al., U.S. Patent No. 5,985,129 to Gough et al., PCT International Publication No. WO4 / 021877 to Caduff, U.S. Patent No. 5,494,562 to Maley et al., U.S. Patent No. 6,120,676 to Heller et al., and U.S. Patent No. 6,542,765 to Guy et al., which are hereby incorporated by reference in their entirety. Generally, the disclosed embodiments are applicable to a variety of continuous analyte measurement device configurations.

[0073] In some embodiments, long-term sensors (e.g., fully implantable or intravascular) are configured and arranged to function over a period of about 30 days or less to about 1 year or more (e.g., a sensor session). In some embodiments, short-term sensors (e.g., those that are transcutaneous or intravascular) are configured and arranged to function over a period of about several hours to about 30 days, including periods of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 days (e.g., a sensor session). As used herein, the term "sensor session" is a broad term and refers to, but is not limited to, the period during which a sensor is applied (e.g., implanted) in a host or used to obtain sensor values. For example, in some embodiments, a sensor session extends from the time of sensor implantation (e.g., including insertion of the sensor into subcutaneous tissue and arranging the sensor in fluid communication with the host's circulatory system) to the time the sensor is removed.

[0074] Generally, a membrane system includes a plurality of domains, such as an electrode domain, an interference domain, an enzyme domain, a resistance domain, and a biointerface domain. The membrane system can be deposited on an exposed electroactive surface using known thin-film techniques, such as vapor deposition, spraying, electrodeposition, dipping, brush coating, film coating, droplet coating, etc. Following the deposition of the membrane material, additional steps, such as drying, firing, and curing (e.g., UV curing, thermal curing, moisture curing, radiation curing, etc.) can be applied to enhance certain properties, such as mechanical properties, signal stability, and selectivity. In a typical process, when depositing a resistive layer membrane, the biointerface layer has a "dry film" thickness of about 0.05 μm or less to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 μm. The "dry film" thickness refers to the thickness of the cured film casting from a coating formulation by standard coating techniques.

[0075] In certain embodiments, the biointerface layer is formed of a biointerface polymer, which includes polyurethane and / or polyurea segments and one or more zwitterionic repeating units. In some embodiments, the biointerface layer coating is formed of a polyurethane urea having carboxybetaine groups incorporated into the polymer and nonionic hydrophilic polyethylene oxide segments, and this polyurethane urea polymer is dissolved in an organic or non-organic solvent system by a given coating formulation, crosslinked with an isocyanate crosslinking agent, and cured at a medium temperature of about 50 °C. The solvent system can be a single solvent or a mixture of solvents that aids in the dissolution or dispersion of the polymer. The solvent can be one selected as the polymerization medium or one added after polymerization is complete. The solvent is preferably selected from those having a lower boiling point to facilitate drying and having low toxicity for implant applications. Examples of these solvents include fat-soluble ketones, esters, ethers, alcohols, carbohydrates, and the like. Depending on the final thickness of the biointerface layer and the solution viscosity (related to the percentage of polymer solids), the coating can be applied in a single step or multiple repeated steps of a selected process such as dipping to build the desired thickness. In yet other embodiments, the biointerface polymer is formed of a polyurethane urea having carboxylic acid groups, carboxybetaine groups, and nonionic hydrophilic polyethylene oxide segments incorporated into the polymer, and the polyurethane urea polymer is decomposed in an organic or non-organic solvent system in the coating formulation and crosslinked with a carbodiimide (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) and cured at a moderate temperature of about 50 °C.

[0076] In other embodiments, the biointerface layer coating is formed of a polyurethane urea having sulfobetaine groups incorporated into the polymer and nonionic hydrophilic polyethylene oxide segments, and this polyurethane urea polymer is dissolved in an organic or non-organic solvent system by a given coating formulation, crosslinked with an isocyanate crosslinking agent, and cured at a medium temperature of about 50 °C. The solvent system can be a single solvent or a mixture of solvents that aids in the dissolution or dispersion of the polymer. The solvent can be one selected as the polymerization medium or added after the polymerization is completed. The solvent is preferably selected from those having a lower boiling point to facilitate drying and having low toxicity for implant applications. Examples of these solvents include fat-soluble ketones, esters, ethers, alcohols, carbohydrates, and the like. Depending on the final thickness of the biointerface layer and the solution viscosity (related to the percentage of polymer solids), the coating can be applied in a single step or multiple repeated steps of a selected process such as dipping to build the desired thickness. Still in other embodiments, the biointerface polymer is formed of a polyurethane urea having unsaturated hydrocarbon groups and sulfobetaine groups incorporated into the polymer, and nonionic hydrophilic polyethylene oxide segments, and this polyurethane urea polymer is dissolved in an organic or non-organic solvent system in the coating formulation and crosslinked by heat and irradiation including UV, LED light sources, and electron beams in the presence of an initiator and cured at a medium temperature of about 50 °C. Examples of unsaturated hydrocarbons include allyl groups, vinyl groups, acrylates, methacrylates, alkenes, alkynes, and the like. FIGS. 3A - 3C show embodiments of the in vivo portion of a continuous analyte sensor 400 including an elongated conductor 402. The elongated conductor 402 includes a core 410 (see FIG. 3B) and a first layer 412 that at least partially surrounds the core. The first layer includes a working electrode (e.g., located within window 406) and a membrane 408 located on the working electrode. In some embodiments, the core and the first layer can be a single material (e.g., platinum, etc.).In some embodiments, the elongated conductor 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 embodiments, the elongated conductor includes a plurality of layers. In certain embodiments, there are at least two concentric or annular layers, such as a core formed of a first material and a first layer formed of a second material. However, in some embodiments, additional layers may be included. In some embodiments, the layers are coaxial.

[0077] The elongated conductor is long and thin, but can be flexible and strong. For example, in some embodiments, the minimum dimension of the elongated conductor is less than about 0.1 inch, 0.075 inch, 0.05 inch, 0.025 inch, 0.01 inch, 0.004 inch, or 0.002 inch. The elongated conductor is shown as having a circular cross-section in FIGS. 3A-3C, but in other embodiments, the cross-section of the elongated conductor can be oval, rectangular, triangular, polygonal, star-shaped, C-shaped, T-shaped, X-shaped, Y-shaped, irregular, etc. In one embodiment, a conductive wire electrode is used as the core. Two additional conductive layers may be added to such a clad electrode (e.g., by interposing an insulating layer provided for electrical separation). The conductive layer can be composed of any suitable material. In certain embodiments, it may be desirable to use a conductive layer that includes conductive particles (i.e., particles of a conductive material) in a polymer or other binder.

[0078] The materials used to form the elongated conductor (e.g., stainless steel, titanium, tantalum, platinum, platinum-iridium, iridium, certain polymers, and / or the like) can be strong and rigid to prevent breakage. In some embodiments, the small diameter of the sensor provides flexibility to these materials and thus to the sensor as a whole. Thus, the sensor can withstand the repeated forces applied to it by the surrounding tissue.

[0079] In addition to providing structural support, elasticity, and flexibility, in some embodiments, the core 410 or its components provide electrical conduction for electrical signals from the working electrode to sensor electronics (not shown). In some embodiments, the core 410 includes a conductive material such as stainless steel, titanium, tantalum, a conductive polymer, and / or the like. However, in other embodiments, the core is formed from a non-conductive material such as a non-conductive polymer. In still other embodiments, the core includes a plurality of material layers. For example, in one embodiment, the core includes an inner core and an outer core. In a further embodiment, 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 embodiments, the first conductive material is stainless steel, titanium, tantalum, a conductive polymer, an alloy, and / or the like, and the second conductive material is a conductive material selected to provide electrical conduction between the core and the first layer and / or to adhere the first layer to the core (i.e., in the case where the first layer is formed of a material that does not adhere well to the core material). In another embodiment, the core is formed of a non-conductive material (e.g., a non-conductive metal and / or a non-conductive polymer, etc.), and the first layer is formed of a conductive material such as stainless steel, titanium, tantalum, a conductive polymer, and / or the like. The core and the first layer can be of a single (or the same) material, e.g., platinum. Those skilled in the art will understand that additional configurations are possible.

[0080] Referring again to FIGS. 3A - 3C, the first layer 412 can be formed of a conductive material, and the working electrode can be an exposed portion of the surface of the first layer 412. Thus, the first layer 412 is a material configured to provide an electrochemically active surface suitable for the working electrode and can be formed of materials including, but not limited to, platinum, platinum - iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, an alloy, and / or the like.

[0081] As shown in FIGS. 3B and 3C, the second layer 404 surrounds at least a portion of the first layer 412, thereby defining the boundary of the working electrode. In some embodiments, the second layer 404 functions as an insulator and is formed of an insulating material such as polyimide, polyurethane, parylene, or any other known insulating material. For example, in one embodiment, the second layer is disposed on the first layer and configured such that the working electrode is exposed through the window 406. In some embodiments, an elongated conductor is provided that includes a core, a first layer, and a second layer. A portion of the second layer can be removed to form the window 406, thereby exposing the electroactive surface of the working electrode (i.e., the exposed surface of the first layer 412). In some embodiments, a portion of the second layer and (optionally) a third layer can be removed to form the window 406, thus exposing the working electrode. Removal of the coating material from one or more layers of the elongated conductor (e.g., exposing the electroactive surface of the working electrode) can be performed by hand, excimer laser treatment, chemical etching, laser ablation, grit blasting, or the like.

[0082] The sensor may further include a third layer 414 that includes a conductive material. For example, the third layer 414 may include a reference electrode formed of a silver-containing material and is applied over the second layer 404 (i.e., the insulator).

[0083] The elongated conductor 402 may further include one or more intermediate layers (not shown) located between the core 410 and the first layer 412. For example, the intermediate layer can be one or more of an insulator, a conductor, a polymer, and / or an adhesive.

[0084] The ratio of the thickness of the silver / silver chloride layer to the thickness of the insulator (e.g., polyurethane or polyimide, etc.) layer can be controlled to allow for defects in the sensor (e.g., defects resulting from an etching process that cuts deeper than intended, thereby exposing the electroactive surface unintentionally), certain errors (i.e., errors associated with the etching process). This ratio can vary depending on the type of etching process used, whether it is laser ablation, grit blasting, chemical etching, or some other etching method. In one embodiment where laser ablation is performed to remove the silver / silver chloride layer and the polyurethane layer, the ratio of the thickness of the silver / silver chloride layer to the thickness of the polyurethane layer can be from about 1:5 to about 1:1, or from about 1:3 to about 1:2.

[0085] In some embodiments, the core 410 comprises a non-conductive polymer and the first layer 412 comprises a conductive material. Such a sensor configuration advantageously provides reduced material costs in terms of typically replacing expensive materials with inexpensive materials. For example, the core 410 can be formed of a non-conductive polymer such as a nylon or polyester filament, string, or cord that can be coated and / or plated with a conductive material such as platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, and alloys, or combinations thereof.

[0086] As shown in FIGS. 3C and 3D, the sensor can also include a membrane 408 such as those discussed elsewhere herein with reference to FIGS. 2A-2C, etc. The membrane 408 can include an enzyme layer (not shown) described elsewhere herein. For example, the enzyme layer can include a catalyst or enzyme configured to react with an analyte. For example, the enzyme layer can be an immobilized enzyme layer containing glucose oxidase. In other embodiments, the enzyme layer can be impregnated with other oxidases including, for example, galactose oxidase, cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate oxidase, or uricase.

[0087] FIG. 3B is a schematic diagram showing an embodiment of an elongated conductor 402 or an elongated body, the elongated conductor being formed from at least two materials and / or layers of conductive material, as will be described in more detail elsewhere in this specification. The term "electrode" may be used herein to refer to an elongated conductor that includes an electroactive surface for detecting an analyte. In some embodiments, the elongated conductor provides an electrical connection between the electroactive surface (i.e., the working electrode) and sensor electronics (not shown). In certain embodiments, each electrode (i.e., the elongated conductor having an electroactive surface located thereon) is formed from a thin wire having a diameter of about 0.001 inches (0.003 cm) or less to about 0.01 inches (0.03 cm) or more. Each electrode may be formed, for example, from a plated insulator, a plated wire, or a bulk conductive material. For example, in some embodiments, the wire and / or elongated conductor used to form the working electrode has a diameter of about 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, or 0.045 inches.

[0088] Further, the first layer may include an electroactive surface (i.e., the portion exposed through window 406). The exposed electroactive surface may be a working electrode. For example, if the sensor is an enzymatic electrochemical analyte sensor, the analyte enzymatically reacts with an enzyme within a film that coats at least a portion of the electroactive surface. This reaction generates electrons (e - ) that can be detected as a measurable current at the electroactive surface. For example, in the detection of glucose where glucose oxidase produces hydrogen peroxide as a byproduct, hydrogen peroxide reacts with the surface of the working electrode to produce two protons (2H + ), two electrons (2e - ), and one oxygen molecule (O2), which generates the current that is detected.

[0089] Referring to FIG. 3A described above and as shown in FIG. 3C, the insulator 404 is disposed on at least a portion of the elongated conductor 402. In some embodiments, the sensor is configured and arranged such that the elongated body includes a core 410 and a first layer 412, and a portion of the first layer 412 is exposed through a window 406 of the insulator 404. In other embodiments, the sensor is configured and arranged such that the elongated body 402 includes a core 410 embedded in the insulator 404, and a portion of the core 410 is exposed through a window 406 of the insulator 404. For example, the insulating material may be applied to the elongated body 402 (e.g., by screen printing, inkjet printing, and / or block printing) in a configuration designed such that at least a portion of the surface of the first layer 412 (or the surface of the core 410) remains exposed. For example, the insulating material may be printed in a pattern that does not cover a portion of the elongated body 402. Alternatively, a portion of the elongated body 402 may be masked prior to application of the insulating material. Removal of the mask after application of the insulating material may expose a portion of the elongated body 402.

[0090] In some embodiments, the insulating material 404 includes a polymer, such as a non-conductive (i.e., dielectric) polymer. Immersion coating, spray coating, vapor deposition, printing, and / or other thin film and / or thick film coating or deposition techniques can be used to deposit the insulating material onto the elongated body 402 and / or the core 410. For example, in some embodiments, the insulating material is applied as a layer having a thickness of less than about 5 μm, or from about 5, about 10, or about 15 μm to about 20, about 25, about 30, or about 35 μm or more. The insulator can be applied as a single layer of material, or as two or more layers composed of the same or different materials, as described elsewhere in this specification. Alternatively, the conductive core does not require a coating of insulator. In some embodiments, the insulating material defines the electroactive surface of the analyte sensor (i.e., the working electrode). For example, the surface of the conductive core (e.g., a portion of the first layer 412, etc.) can remain exposed during insulator application, or as described above, a portion of the applied insulator can be removed to expose a portion of the surface of the conductive core.

[0091] In some embodiments having an insulator disposed on an elongated body or conductive structure where the sensor is insulated, a portion of the insulating material can be removed or otherwise removed, for example, by hand, excimer laser treatment, chemical etching, laser ablation, grit blasting (e.g., using sodium bicarbonate or other suitable grit), etc., to expose the electroactive surface. In an exemplary embodiment, grit blasting is implemented to utilize a grit material that is hard enough to cut, for example, a polymeric material, but soft enough to minimize or avoid damage to underlying metal electrodes (e.g., platinum electrodes) to expose the electroactive surface(s). A variety of "grit" materials (e.g., sand, talc, walnut shells, crushed plastic, sea salt, etc.) can be used, and in some embodiments, sodium bicarbonate is an advantageous grit material because it is hard enough to cut, for example, a parylene coating, without damaging underlying platinum conductors. An additional advantage of sodium bicarbonate blasting is that its abrasive action on the metal, since it peels the polymer layer, thereby eliminating a cleaning step that may be essential in other methods. Alternatively, a portion of the electrode or other conductor can be masked prior to depositing the insulator to maintain the exposed electroactive surface area.

[0092] The electroactive surface of the working electrode can be exposed by the formation of window 406 in insulator 404. The electroactive window 406 of the working electrode can be configured to measure the concentration of the analyte.

[0093] In some embodiments, a silver wire is formed on and / or fabricated within the sensor and later chlorinated to form a silver / silver chloride reference electrode. Advantageously, the chlorination of the silver wire described herein enables the fabrication of reference electrodes with good in vivo performance. By controlling the amount and quantity of silver chlorination to form silver / silver chloride, in some embodiments, improved discontinuity, reference electrode stability, and extended lifespan can be obtained. Further, the use of silver chloride described above enables a relatively inexpensive and simple fabrication of the reference electrode.

[0094] Referring to FIGS. 3B and 3C, the reference electrode 414 can include a silver-containing material (e.g., silver / silver chloride) applied over at least a portion of the insulating material 404, as discussed in more detail elsewhere in this specification. For example, the silver-containing material can be applied using thin film and / or thick film techniques such as, but not limited to, dipping, spraying, printing, electroplating, vapor deposition, spin coating, and sputter deposition, as described elsewhere in this specification. For example, a silver or silver chloride-containing paint (or similar formulation) can be applied to a reel of insulated conductive cores. Alternatively, a reel of insulated elongated body (or core) is cut into single unit pieces (i.e., "singularized") and silver-containing ink is pad printed thereon. In yet other embodiments, the silver-containing material is applied as silver foil. For example, an adhesive can be applied to the insulated elongated body and then silver foil can be wrapped around it. Alternatively, the sensor is wound with Ag / AgCl particles such that a sufficient amount of silver adheres to, and / or is embedded in, and / or otherwise adheres to the adhesive such that the particles function as a reference electrode. In some embodiments, the reference electrode of the sensor includes a sufficient amount of silver chloride for the sensor to measure and / or detect an analyte for at least three days.

[0095] Figure 2A is a cross-sectional view through a sensor showing one embodiment of the membrane system 32. In this particular embodiment, the membrane system includes an electrode layer 42, an enzyme layer 44, a diffusion resistance layer 46, and a biointerface layer 48, all of which are located around the working electrode of the sensor 38, and all of which are described in further detail elsewhere in this specification. In some embodiments, an integrated diffusion resistance domain and biointerface layer may be included in the membrane system (e.g., the functionality of both layers is incorporated into one domain). In some embodiments, the sensor is configured for short-term implantation (e.g., about 1 to 30 days). However, the membrane system 32 may be modified for use in other devices, for example, by including only one or more of the domains or by including additional domains.

[0096] Figure 2B is a cross-sectional view through an embodiment of a sensor showing another embodiment of the membrane system 32. In this particular embodiment, the membrane system includes an interference reduction or blocking layer 43, an enzyme layer 44, a diffusion resistance layer 46, and a biointerface layer 48 located around the working electrode of the sensor 38, all of which are described in more detail elsewhere in this specification.

[0097] Figure 2C is a cross-sectional view through an embodiment of a sensor showing yet another embodiment of the membrane system 32. In this particular embodiment, the membrane system includes an interference reduction or blocking layer 43, an enzyme layer 44, and an integrated diffusion resistance / biointerface layer 47 located around the working electrode of the sensor, all of which are described in more detail elsewhere in this specification.

[0098] In some embodiments, the membrane system may include a biointerface layer 48 that includes a surface-modified biointerface polymer, which is described in more detail elsewhere in this specification. However, the sensing membrane 32 of some embodiments may include a plurality of domains or layers, such as, for example, an electrode domain (e.g., as shown in FIG. 2A), an interference reduction or blocking domain (e.g., as shown in FIGS. 2B and 2C), or a cell disruption domain (not shown), which is described in more detail elsewhere in this specification and in U.S. Patent Publication No. US-2006-0036145-A1, which is hereby incorporated by reference in its entirety.

[0099] For example, it is understood that a sensing membrane modified for use with other sensors may include fewer or additional layers. For example, in some embodiments, the membrane system may include one electrode layer, one enzyme layer, and two biointerface layers, while in other embodiments, the membrane system may include one electrode layer, two enzyme layers, and one biointerface layer. In some embodiments, the biointerface layer is configured to function as a diffusion resistance domain and can control the flow of an analyte (e.g., glucose) to the underlying membrane layer.

[0100] In some embodiments, one or more domains of the sensing membrane may be formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymer, copolymer, terpolymer of polyurethane, polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethyl methacrylate (PMMA), polyetheretherketone (PEEK), polyurethane, polyurethane urea, cellulose polymer, poly(ethylene oxide), poly(propylene oxide), and their copolymers and blends, polysulfone and its block copolymers (including, for example, diblock, triblock, alternating, random, and graft copolymers).

[0101] In some embodiments, the sensing film can be deposited on the electroactive surface of the electrode material using known thin-film or thick-film techniques (e.g., spraying, electrodeposition, dipping, etc.). It should be understood that the sensing film located on the working electrode does not necessarily have the same structure as the sensing film located on the reference electrode. For example, the enzyme domain deposited on the working electrode does not necessarily have to be deposited on the reference electrode or the counter electrode.

[0102] The exemplary embodiments shown in FIGS. 2A - 2C involve extending the membrane system circumferentially, but the membranes described herein can be applied to any planar or non-planar surface.

[0103] Sensor electronics Generally, an analyte sensor system has associated electronic devices, also referred to as a "computer system", which may include hardware, firmware, or software that enables the measurement and processing of data related to analyte levels in a host. In an exemplary embodiment of an electrochemical sensor, the electronic devices include a potentiostat, a power source for providing power to the sensor, and other components useful for signal processing. In additional embodiments, some or all of the electronic devices may communicate wired or wirelessly with the sensor or other parts of the electronic device. For example, a potentiostat disposed on the device may be wired to the remaining electronic devices (e.g., a processor, a recorder, a transmitter, a receiver, etc.) at the bedside. In another example, a portion of the electronic device is wirelessly connected to another portion of the electronic device (e.g., a receiver) by, for example, infrared (IR) or radio frequency (RF). Other embodiments of the electronic devices are contemplated to be useful for providing sensor data outputs such as those described in U.S. Patent Publication Nos. US-2005-0192557-A1, US-2005-0245795-A1, US-2005-0245795-A1, US-2005-0245795-A1, US-2008-0119703-A1, and US-2008-0108942-A1, each of which is incorporated herein by reference in its entirety.

[0104] In a preferred embodiment, the potentiostat is operably connected to an electrode (s) (e.g., as described elsewhere in this specification) and deflects the sensor to enable measurement of a current signal indicative of the analyte concentration (also referred to as the analog portion) in the host. In some embodiments, the potentiostat includes a resistor that converts current to voltage. In some alternative embodiments, for example, a current-to-frequency converter configured to continuously integrate the measured current using a charge counting device is provided. In some embodiments, the electronic device includes an A / D converter that digitizes an analog signal, also referred to as a "count" for processing, into a digital signal. Thus, the resulting raw data stream in counts (also referred to as raw sensor data) is directly related to the current measured by the potentiostat.

[0105] Generally, the electronic device includes a processor module that includes a central control unit that controls the processing of the sensor system. In some embodiments, the processor module includes a microprocessor, but other computer systems besides a microprocessor can be used to process the data described herein, for example, an ASIC can be used for part or all of the central processing of the sensor. The processor typically provides semi-permanent storage of data, e.g., storage of data such as sensor identifiers (IDs) and programming for processing data streams (e.g., programming for data smoothing or replacement of signal artifacts as described in US Patent Publication No. US-2005-0043598-A1). Further, the processor can be used to temporarily store the system's cache memory, e.g., recent sensor data. In some embodiments, the processor module includes memory storage components, such as ROM, RAM, dynamic RAM, static RAM, non-volatile RAM, EEPROM, rewritable ROM, flash memory, and the like.

[0106] In some embodiments, the processor module includes a digital filter configured to smooth the raw data stream, such as an infinite impulse response (IIR) or finite impulse response (FIR) filter. Generally, the digital filter is programmed to filter data sampled at a predetermined time interval (also referred to as the sampling rate). In some embodiments where the potentiostat is configured to measure the analyte at discrete time intervals, these time intervals determine the sampling rate of the digital filter. In some alternative embodiments where the potentiostat is configured to continuously measure the analyte using, for example, the current - to - frequency converter described above, the processor module can be programmed to request digital values from the A / D converter at a predetermined time interval, also referred to as the acquisition time. In these alternative embodiments, the values obtained by the processor are advantageously averaged over the acquisition time due to the continuity of the current measurement. Thus, the acquisition time determines the sampling rate of the digital filter.

[0107] In some embodiments, the processor module is configured to construct data packets for transmission to an external source, such as RF transmission to a receiver. Generally, the data packet includes a plurality of bits that can include a unique identifier (e.g., a sensor ID code) preamble identifying the electronic device unit, the receiver, or both, data (e.g., raw data, filtered data, or integrated values), or error detection or correction. Preferably, the data (transmission) packet has a length of about 8 bits to about 128 bits, preferably about 48 bits, although in certain embodiments, larger or smaller packets may be desirable. The processor module can be configured to transmit any combination of raw data or filtered data. In an exemplary embodiment, the transmission packet includes a fixed preamble unique ID of the electronic device unit, a single 5 - minute average (e.g., integrated) sensor data value, and a cyclic redundancy check (CRC).

[0108] In some embodiments, the processor further performs operations such as storing data, analyzing data streams, calibrating analyte sensor data, estimating analyte values, comparing the estimated analyte values with time-corresponding measured analyte values, analyzing fluctuations in the estimated analyte values, downloading data, and controlling the user interface by providing analyte values, prompts, messages, warnings, alarms, etc. In such cases, the processor includes hardware for performing the operations described herein. For example, flash memory provides for permanent or semi-permanent storage of data, storage of data such as sensor IDs, receiver IDs, etc., and programming for processing data streams (e.g., programming for performing the estimations and other algorithms described elsewhere herein), and random access memory (RAM) stores the system's cache memory and aids in data processing. Alternatively, some portions of the data processing (e.g., as described elsewhere herein with reference to the processor) can be accomplished in another (e.g., remote) processor and can be configured to be connected thereto, either wired or wirelessly.

[0109] In some embodiments, an output module integrated with or operably connected to the processor includes programming for generating an output based on a data stream received from the sensor system and the processing occurring within the processor. In some embodiments, the output is generated via the user interface.

[0110] Interferent Interfering substances are molecules or other species that can cause a sensor to generate false positive or false negative analyte signals (e.g., non-analyte related signals). Some interfering substances are reduced or oxidized at the electrochemical reaction surface of the sensor, while other interfering substances interfere with the ability of the enzyme being used (e.g., glucose oxidase) to react with the analyte being measured. Still other interfering substances react with the enzyme (e.g., glucose oxidase) to produce electrochemically active by-products. Interfering substances can exaggerate or mask the response signal, thereby leading to false or misleading results. For example, a false positive signal can make the host's analyte concentration (e.g., glucose concentration) appear higher than the true analytical concentration. False positive signals can pose clinically significant problems in some conventional sensors. For example, in a critical hypoglycemic situation where the host has ingested an interfering substance (e.g., acetaminophen), the resulting artificially high glucose signal can lead the host to believe that they are normoglycemic or hyperglycemic. In response, the host may make inappropriate treatment decisions by injecting excessive insulin, or by doing nothing, if the appropriate course of action is to start a meal. In turn, this inappropriate action or inaction can lead to a dangerous hypoglycemic episode for the host. Accordingly, certain embodiments contemplated herein include membrane systems that substantially reduce or eliminate the effect of interfering substances on analyte measurements. These membrane systems can include one or more domains that can block or substantially reduce the flow of interfering substances onto the electroactive surface of the electrode and, as described in more detail in U.S. Patent Publication No. US-2009-0247856-A1, can reduce noise and improve sensor accuracy.

[0111] Drift As used herein, the term "drift" is used in a broad sense and its ordinary and customary meaning is provided to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, changes in the sensitivity of a sensor over time. Drift can be driven by changes in the permeability of the sensor membrane system, which can be particularly evident in embodiments using a polyurethane diffusion resistance domain. Without being bound by theory, it is believed that changes in permeability in such systems result from the rearrangement of the diffusion resistance domain polyurethane polymer chains to provide a more hydrophilic component to the surface, or otherwise from a rearrangement that allows for better access to hydrophilic polymer components during hydration of the membrane system. Thus, an increase in the rate of hydration or an increase in the wettability of the membrane system reduces system drift.

[0112] Due to electrostatically induced hydration, the polymers and crosslinked coatings of zwitterionic compounds have near-instantaneous wettability. As discussed in more detail below, including one or more zwitterionic compounds, precursors or derivatives thereof (hydrolyzable cationic esters) in the outermost domain of the membrane system, or applying a coating of such compounds to the surface of the membrane system, results in reduced sensor drift.

[0113] Membrane Fabrication The polymers of the preferred embodiments can be processed by solution-based techniques such as spraying, dipping, casting, electrospinning, vapor deposition, spin coating, coating, etc. Aqueous polymer emulsions can be manufactured to form membranes in a manner similar to that used for solvent-based materials. In both cases, the evaporation of the volatile liquid (e.g., an organic solvent or water) leaves a film of the polymer. Crosslinking of the deposited film or layer can be done in many ways through the use of multifunctional reactive components. The liquid system can be cured by heat, moisture, high energy irradiation, ultraviolet light, or by completing a reaction that produces the final polymer within the mold or substrate being coated.

[0114] In some embodiments, the wettability of the membrane (and by extension, the degree of sensor drift indicated by the sensor) can be adjusted and / or controlled by creating covalent cross-links between a surface-active group-containing polymer, a functional-group-containing polymer, a polymer having zwitterionic groups (or a precursor or derivative thereof), and combinations thereof. The cross-linking can have a substantial effect on the film structure, which in turn can affect the wettability of the film surface. The cross-linking can also affect the film tensile strength, mechanical strength, water absorption rate, and other properties.

[0115] Cross-linked polymers can have different cross-linking densities. In certain embodiments, cross-linking is used to facilitate cross-linking between layers. In other embodiments, heat is used to form cross-links instead of (or in addition to) the cross-linking techniques described above. For example, in some embodiments, imide and amide bonds can be formed between two polymers as a result of high temperatures. In some embodiments, photocross-linking is performed to form covalent bonds between the polycationic layer(s) and the polyanionic layer(s). One major advantage of photocross-linking is that it provides the possibility of patterning. In certain embodiments, patterning using photocross-linking is performed to modify the film structure and thus adjust the wettability of the membrane.

[0116] Polymers having domains or segments that are functionalized to allow crosslinking can be made by methods known in the art. For example, a polyurethane urea polymer having an aromatic or aliphatic segment with an electrophilic functional group (e.g., carbonyl, aldehyde, anhydride, ester, amide, isocyano, epoxy, allyl, or halo group) can be crosslinked with a crosslinking agent having a plurality of nucleophilic groups (e.g., hydroxyl, amine, urea, urethane, or thio group). In a further embodiment, a polyurethane urea polymer having an aromatic or aliphatic segment with a nucleophilic functional group can be crosslinked with a crosslinking agent having a plurality of electrophilic groups. Still further, a polyurethane urea polymer having a hydrophilic segment with a nucleophilic or electrophilic functional group can be crosslinked with a crosslinking agent having a plurality of electrophilic or nucleophilic groups. Unsaturated functional groups on the polyurethane urea can also be used for crosslinking by reacting with a polyvalent free radical agent. Non-limiting examples of suitable crosslinking agents include isocyanate, carbodiimide, glutaraldehyde, aziridine, silane, or other aldehydes, epoxies, acrylates, free radical-based agents, ethylene glycol diglycidyl ether (EGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). In one embodiment, about 0.1% to about 15% w / w of the crosslinking agent is added based on the total dry weight of the crosslinking agent, and the polymer is added when blending the components (in one example, about 1% to about 10%). During the curing process, it is believed that substantially all of the crosslinking agent reacts, leaving substantially no detectable unreacted crosslinking agent in the final film.

[0117] The polymers disclosed herein can be drawn into films or incorporated into mixtures that can be applied to surfaces using any method known in the art (e.g., spraying, painting, dip coating, vapor deposition, molding, 3D printing, lithographic techniques (e.g., photolithography), micro- and nanopipetting printing techniques, silk screen printing, etc.). The mixture can then be cured at an elevated temperature (e.g., 50 - 150 °C). Other suitable curing methods can include, for example, ultraviolet or γ irradiation.

[0118] Biointerface domain The biointerface layer is a domain or layer of an implantable device configured to interface (i.e., contact) with a biological fluid when implanted in or connected to a host (e.g., via an intravascular access device that provides access to a blood vessel). When present on an analyte sensor, e.g., a continuous analyte sensor implanted in a host, the biointerface layer can increase the lifespan of the sensor and reduce sensor inaccuracies by reducing a biomaterial-related inflammatory response. The antifouling properties of the biointerface layer can inhibit the accumulation of cells, proteins, and other biological species on the sensor. Without being bound by theory, zwitterionic groups in the biointerface layer can attract, retain, and organize the structure of water at the polymer-biological interface, thereby resulting in reversible adsorption, absence or reduction of protein denaturation, and absence or reduction of cell activation (see FIG. 12). Another possible mechanism for the antifouling properties of the biointerface layer is significant swelling, which can fill voids at the implantation site and act as a buffer zone (see FIG. 16).

[0119] The biointerface layer disclosed herein is mechanically robust, prevents damage during implantation, and can withstand degradation during sensor implantation. Further, the disclosed biointerface layer does not substantially affect the response time of the sensor or the properties of the diffusion resistance layer. Also, the disclosed biointerface layer can have hydrophilicity with high water absorption, fast water absorption, and rapid stabilization, thereby not adversely affecting the startup of the sensor. The disclosed biointerface layer is also permeable to analytes (e.g., glucose) but prevents protein adsorption.

[0120] Some embodiments described herein may include a film that includes a biointerface layer 48 (see FIGS. 2A and 2B).

[0121] Furthermore, the disclosed biointerface layer can be a host for pharmaceuticals or bioactive agents that can effectively reduce or delay inflammation upon release from the biointerface layer to the local tissue. The anti-inflammatory agent can be a steroid or non-steroid drug and can be a scavenger of reactive oxygen species (ROS). Suitable anti-inflammatory agents include, but are not limited to, for example, non-steroidal anti-inflammatory drugs (NSAIDs) such as acetometaphen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 mutein, anti-IL-6 iNOS inhibitor (e.g., L-NAME or L-NMDA), interferon, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and trametin; and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone, betamethasone dipropionate, betamethasone valerate, desonide, desoxymethasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, and dexamethasone. In a further example, the biointerface layer can include a material that repels the adhesion and / or adsorption of carbohydrates. Without being bound by theory, the adhesion or adsorption of carbohydrates on the sensor membrane can affect the operation of the sensor. Thus, having a material that repels the adhesion and / or adsorption of carbohydrates can help alleviate this problem.

[0122] In a further example, factor H can be covalently conjugated to the surface of the biointerface layer. Factor H is one of the main regulators of the complement system, which plays a crucial role in the immune response. Its normal functions include the control of proteins that generate inflammatory anaphylatoxins; distinguishing "self" from "non-self" and maintaining tissue integrity by utilizing direct anti-inflammatory properties. Thus, factor H is an important protein that regulates complement activation. This regulation occurs through multiple mechanisms, including the decay of C3 convertase formation and the promotion of its inactivation. Factor H also acts as a cofactor for factor I in the degradation of C3b and competes with factor B for binding to C3b.

[0123] Factor H, for use as a surface coating of a medical device, may be beneficial due to its relevance between complement-induced inflammation, which is the regulatory role of factor H in halting complement-induced inflammation and tissue damage.

[0124] In this embodiment, factor H can be covalently conjugated to the surface of the biointerface layer by the methods disclosed herein. Factor H can then be released upon environmental changes and control inflammation. The control of inflammation can help reduce problems associated with signal decline or loss on the first day after the sensor is implanted. Factor H can also help extend lifespan and reduce in vivo variability.

[0125] For this reason, sensors including a biointerface layer with active factor H covalently bonded to the surface of the biointerface layer are disclosed herein in certain embodiments. The covalent bond can be a linker, such as alkyl, alkoxyl, ester, triazole, polyether, polyester, polyalkene oxide, and the like. In some examples, the linker can be sensitive to cleavage by internal or external stimuli such as pH, heat, UV-Vis, or protease attack. The linker can also be an oligopeptide sequence that can be cleaved by MMP (matrix metallopeptidase), which is upregulated in atherosclerosis and inflammation. A schematic diagram of the biointerface layer with conjugated factor H is shown in FIG. 33. The layer includes the following three parts: (I) the biointerface polymer disclosed herein; (ii) a stimulus-responsive linker that can be cleaved by environmental changes; and (iii) active factor H covalently bonded to the linker.

[0126] The biointerface layer includes a biointerface polymer. In some embodiments, the biointerface polymer is a polyzwitterion. A polyzwitterion is a polymer in which the repeating unit of the polymer chain is a zwitterionic moiety. As such, these polymers have an equal number of cationic and anionic groups due to each zwitterionic repeating unit having both a positive and a negative charge, and thus often have an overall zero charge over a wide pH range.

[0127] Polyzwitterions are distinguished from other polyelectrolytes in that the polyelectrolytes contain anionic and cationic groups, but the ionic groups are not correlated with each other as part of the same repeating unit. Therefore, the anionic and cationic groups can be distributed randomly at intervals away from each other, or one ionic group can be more than the other ionic group. Thus, it is typical for polyelectrolytes to have a net charge, except perhaps over a somewhat narrow pH range.

[0128] The disclosed polyzwitterions can have various repeating units, shown as i) to vii) below, where n is an integer from 2 to 1000. [Chemical formula] In structures i) to iv), the zwitterion unit is connected to the backbone chain (~~~~), and the charges are on side groups suspended from the chain. In structures v) to vii), the zwitterion unit is such that one or both charges are on the chain itself.

[0129] Examples of suitable zwitterion monomers that can be used to generate any of the polyzwitterions of structures i) to vii) include ammonio phosphate (phosphobetaine or lecithin analog), ammonio phosphonate (phosphonobetaine), or ammonio phosphinate (phosphinobetaine), each having the following structures [Chemical formula] wherein Z is branched or linear alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, and R 1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 2 , R 3 , and R 4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and one or more of R 1 , R 2 , R 3 , R 4 , and Z are substituted with a polymerizable group ammonio sulfonate (sulfobetaine), ammonio sulfate each have the following structures [Chemical formula] In the formula, Z is a branched or straight-chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, and R 1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 2 and R 3 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and one or more of R 1 , R 2 , R 3 and Z are substituted with a polymerizable group, The ammonium carboxylate has the following structure:

Chemical formula

[0130] As used herein, the term "polymerizable group" is a broad term, and its ordinary and customary meaning is indicated to those skilled in the art (and is not limited to a special or customized meaning), and refers to a functional group that enables a monomer to polymerize with itself to form a homopolymer or with a different monomer to form a copolymer, but is not limited thereto. Depending on the type of polymerization method used, the polymerizable group can be selected from alkenes, alkynes, epoxides, lactones, amines, hydroxyls, isocyanates, carboxylic acids, anhydrides, silanes, halides, aldehydes, and carbodiimides.

[0131] In step-growth polymerization, a matching pair of functional groups is selected to promote polymerization, for example, to polymerize a dihydroxyl group carrying a zwitterionic monomer, and a comonomer containing a diisocyanate, epoxide, or dicarboxylic acid group can be selected to supply a polymer formed of urethane, ether, and ester bonds.

[0132] Additional examples of zwitterionic precursors formed into monomers for the modified and disclosed biointerface polymers include ammoniocarboxylates (carboxybetaines) or ammoniosulfonates (sulfobetaines), phosphobetaines (ammoniophosphates or lecithin analogs), phosphatidylcholines, poly(carboxybetaines), poly(sulfobetaines), and precursors or derivatives; trigonelline, ectoine, 3-dimethylsulfoniopropanoate, arsenobetaine, ammoniophosphonates (phosphonobetaines), ammoniophosphinates (phosphinobetaines), ammoniosulfonamides, ammoni-sulfone-imides, guanidinium carboxylates (asparagine analogs), pyridinium carboxylates, ammonio(alokoxy)dicyanoenolates, ammonioboronate, sulfonium carboxylates, phosphoniosulfonates, phosphoniocarboxylates, squalene dyes, and oxypyridine betaines.

[0133] These monomers can be prepared by methods known to those skilled in the art, for example, as detailed in Laschewsky, ″Structures and synthesis of zwitterionic polymers,″ Polymers 6:1544-1601, 2014. In certain embodiments, the disclosed polyzwitterions can have repeating zwitterionic units obtained from any of the zwitterionic monomers disclosed above.

[0134] The biointerface polymer can also include polyurethane and / or polyurea segments. For example, the biointerface polymer can include polyurethane copolymers such as polyether-urethane-urea, polycarbonate-urethane, polyether-urethane, silicone-polyether-urethane, silicone-polycarbonate-urethane, polyester-urethane, polyurethane-urea, etc. These polyurethane and / or polyurea segments include urea and / or urethane bonds formed from polyisocyanates and short-chain polyols or polyamines, which are moieties rich in hydrogen bonds. Therefore, these segments are referred to herein as "hard segments." These segments can also be relatively hydrophobic.

[0135] In addition to the polyurethane and / or polyurea hard segments, the disclosed biointerface polymer can also include soft segments with relatively poor hydrogen bonding. Soft segments are usually composed of polyols such as polycarbonate, polyester, polyether, polyarylene, and polyalkylene. Soft segments can be either hydrophobic or hydrophilic.

[0136] The biointerface polymer in some embodiments includes polyurethane and / or polyurea, but in other embodiments, the biointerface polymer can be a polymer that does not include polyurethane and / or polyurea.

[0137] Biointerface polymers useful in certain embodiments can include linear or branched polymers on the backbone structure of the polymer. Thus, either the hard or soft segments can include a branched or linear backbone.

[0138] Zwitterionic monomers can be part of either, or both, the hard or soft segments, as described herein.

[0139] In some embodiments, the hard segment portion of the biointerface polymer can include from about 5 wt% to about 50 wt% of the polymer, sometimes from about 15 wt% to 20 wt%, and other times from about 25 wt% to 40 wt%. The hard segment can have a molecular weight from about 160 Daltons to about 10,000 Daltons, and sometimes from about 200 Daltons to about 2,000 Daltons. In some embodiments, the molecular weight of the soft segment can be from about 200 Daltons to about 10,000,000 Daltons, sometimes from about 500 Daltons to about 5,000 Daltons, and sometimes from about 500 Daltons to about 2,000 Daltons.

[0140] As described, the hard segment can be a polyurethane or a polyurea. A polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxyl-containing material. A polyurea 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 9 methylene units. Alicyclic moieties containing diisocyanates can also be useful in the preparation of the polymer and copolymer components of the membranes of preferred embodiments.

[0141] The soft segments used in the preparation of the biointerface polymer can be polyfunctional aliphatic polyols, polyfunctional aliphatic or aromatic amines, etc. that can be useful in providing permeability to analytes (e.g., glucose) therethrough, such as polyoxazoline, poly(ethylene glycol) (PEG), polyacrylamide, polyimine, polypropylene oxide (PPO), PEG-co-PPO diol, silicone-co-PEG diol, silicone-co-PPO diol, polyethyl acrylate (PEA), polyvinyl pyrrolidone (PVP), and their copolymers, blends, and / or modifications (e.g., PVP vinyl acetate), where PEG, and its copolymers, blends, and / or modifications can be suitable due to their hydrophilicity.

[0142] In some of the embodiments, the soft segment portion of the biointerface polymer can contain from about 5 wt% to about 50 wt%, sometimes from about 15 wt% to 20 wt%, and other times from about 25 wt% to 40 wt% of the polymer. The soft segment can have a molecular weight of from about 160 Daltons to about 10,000 Daltons, and sometimes from about 200 Daltons to about 2,000 Daltons. In some embodiments, the molecular weight of the soft segment can be from about 200 Daltons to about 10,000,000 Daltons, sometimes from about 500 Daltons to about 5,000 Daltons, and sometimes from about 500 Daltons to about 2,000 Daltons.

[0143] In some embodiments, the biointerface polymer containing hard and soft segments, as well as zwitterionic repeating units, can have a molecular weight of from about 10 kDa to about 500,000 kDa, such as from about 10 kDa to about 100,000 kDa, from about 1000 kDa to about 500,000 kDa, from about 10,000 kDa to about 100,000 kDa, and from about 100,000 kDa to about 500,000 kDa.

[0144] The hard and soft segments can each be selected for their properties, including but not limited to, tensile strength, flex life, modulus of elasticity, etc. For example, polyurethane is relatively strong, provides many reaction pathways, and its properties can be advantageous as the bulk properties for the membrane domain of a continuous sensor.

[0145] In some specific examples, the segments can be selected to yield a biointerface polymer with a high Tg. Having segments or polymers with a high Tg in the biointerface layer can result in stronger mechanical properties. Additionally, segments or polymers with a high Tg can enable more hydrophilic and flexible segments, which can in turn enable the incorporation of bioactive agents such as anti-inflammatory drugs (e.g., dexamethasone). As an example, the zwitterionic nature of betaine can bind more efficiently to the salt form of dexamethasone due to electrostatic interactions. Thus, examples of biointerface polymers that can be composed of a hydrophilic polymer (e.g., polycarbonate) with a high glass transition temperature (T g ) of hydrophobic segments are disclosed herein. The hydrophobic segments with a high T g can have strong mechanical properties and thus can construct a porous scaffold that can absorb and encapsulate water and drugs internally for continuous drug delivery. These materials can also co-incorporate functional reactive groups (these groups include carboxylic acid, azide, alkyne, alkene, thiol) for further chemical reactions or crosslinking.

[0146] As described above, the biointerface polymer includes one or more zwitterionic repeating units, and thus these groups are "internal" with respect to the polymer backbone. Such "internal" repeating units are distinguished from the materials found at the ends of the polymer chains, since such moieties are only attached to the polymer chain at one position. The disclosed biointerface polymers may, in some embodiments, have one or more zwitterionic groups at the termini of the polymer chains, but such groups are not the only zwitterionic groups in the chain, as there is at least one internal zwitterionic group in the backbone.

[0147] In some preferred embodiments, the zwitterionic moiety is selected for desirable properties such as, for example, non-steady state noise blocking ability, intermittency (reduced), ability to repel charge species, cationic or ionic blocking, surface wetting, antifouling, etc. In some embodiments, the zwitterion or zwitterionic precursor is present as a zwitterionic group, but the device is in vivo. As such, these groups present a mixed charge area of the device surface to the surrounding environment, thereby increasing the surface hydration of the device and potentially reducing non-specific protein adsorption and cell attachment.

[0148] In some embodiments, the biointerface polymer comprises at least about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt% to about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, or about 55 wt% zwitterionic repeating units.

[0149] The zwitterionic repeating units can be betaines such as carboxyl, sulfo, or phosphobetaine compounds, precursors or derivatives thereof (e.g., alkylbetaine or aminobetaine). These segments or portions can be incorporated into the biointerface polymer, for example, up to about 55 wt% of the biointerface polymer, in the hard segment, the soft segment, or both.

[0150] In some embodiments, two or more different zwitterionic or zwitterionic precursor segments or portions are used, while in other embodiments, a single zwitterionic or zwitterionic precursor segment or portion can be used in the biointerface polymer.

[0151] Some examples of biointerface polymers are schematically illustrated in FIG. 4. Generally, a biointerface polymer includes one or more hard segments and one or more soft segments. The hard segments can be aliphatic or aromatic monomers. The soft segments can be hydrophilic or hydrophobic oligomers such as polyalkylene glycols, polycarbonates, polyesters, polyethers, polyvinyl alcohol, polyvinyl pyrrolidone, polyoxazolines, etc. Zwitterionic groups (e.g., betaine) can be part of the soft segment, the hard segment, or both. As illustrated in FIG. 4, various hard and soft segments can be present, allowing for tuning of the properties of the biointerface polymer by using different segments, different segment lengths, functionalization of a particular segment, crosslinking of a particular segment, etc. In some embodiments, a biocompatible segmented block polyurethane copolymer containing hard and soft segments can be used for the biointerface layer.

[0152] Incorporation of these zwitterionic repeating units into the polymer can be achieved by using zwitterionic monomers having a diol or diamine (e.g., in the Z position), or can be attached to the diol or diamine in any of R 1 ~R 4 . Attachment to the diol or diamine in R 1 ~R 4 can be achieved by reacting the corresponding precursor with a halo-substituted diamine or halo-substituted diol. Examples of such monomers are shown below,

Chemical Formula

[0153] These compounds can react with diisocyanates to form polyurethanes or polyureas. Alternatively, carboxylate, sulfonate, phosphinate, or phosphonate moieties can be protected and then the protecting groups can be removed after polymerization. In another alternative, the amine can be a tertiary amine and then quaternized by alkylation after polymerization.

[0154] Another method involves radical polymerization of zwitterionic monomers having an unsaturated moiety substituted at the Z position in the monomers shown above. In other embodiments, zwitterionic monomers in which the unsaturated moiety is attached to an ammonium group can be used in radical polymerization. Examples of such monomers are shown below,

Chemical formula

[0155] Additional examples of suitable zwitterionic monomers include N-(2-methacryloyloxy)ethyl-N,N-dimethylammoniopropanesulfonate, N-(3-methacryloylimino)propyl-N,N-dimethylammoniopropanesulfonate, 2-(methacryloyloxy)ethyl phosphatidylcholine, and 3-(2'-vinyl-pyridino)propanesulfonate.

[0156] In other embodiments, the biointerface polymer is crosslinked. For example, a polyurethane urea polymer having an aromatic or aliphatic segment with an electrophilic functional group (e.g., carbonyl, aldehyde, anhydride, ester, amide, isocyanate, epoxy, allyl, or halo group) can be crosslinked with a crosslinking agent having a plurality of nucleophilic groups (e.g., hydroxyl, amine, urea, urethane, or thio group). In a further embodiment, a polyurethane urea polymer having an aromatic or aliphatic segment with a nucleophilic functional group can be crosslinked with a crosslinking agent having a plurality of electrophilic groups. Still further, a polyurethane urea polymer having a hydrophilic segment with a nucleophilic or electrophilic functional group can be crosslinked with a crosslinking agent having a plurality of electrophilic or nucleophilic groups. Unsaturated functional groups on the polyurethane urea can also be used for crosslinking by reacting with a polyvalent free radical agent.

[0157] Non-limiting examples of suitable crosslinking agents include isocyanates, carbodiimides, glutaraldehyde, or other aldehydes, aziridines, silanes, epoxies, acrylates, free radical agents, ethylene glycol diglycidyl ether (EGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). In one embodiment, from about 0.1% to about 15% w / w of a crosslinking agent is added based on the total dry weight of the crosslinking agent, and the polymer is added when the components are blended (in one example, from about 1% to about 10%). During the curing process, it is believed that substantially all of the crosslinking agent reacts, leaving substantially no detectable unreacted crosslinking agent in the final layer.

[0158] Furthermore, the disclosed biointerface layer can have zwitterions trapped or embedded within the polymer network by non-covalent interactions. Thus, in a further embodiment, the disclosed biointerface layer can include a biointerface polymer and additional betaines blended therewith. For example, the biointerface polymer can be blended with cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, caprylyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly(carboxybetaine) (pCB), and poly(sulfobetaine) (pSB). It will be understood that many more zwitterionic compounds or their precursors or derivatives may be applicable and that this exemplary list of betaines is not intended to limit the scope of the embodiments.

[0159] The biointerface layer may further include a biointerface domain, which includes a surface-modified polymer attached to a base polymer, where the surface-modified polymer includes polymer chains having both hydrophilic and hydrophobic regions, and one or more zwitterionic compounds are covalently bonded to the interior region of the polymer, and the base polymer may be selected from silicone, epoxy, polyolefin, polystyrene, polyoxymethylene, polysiloxane, polyether, polyacrylic, polymethacrylic, polyester, polycarbonate, polyamide, poly(ether ketone), poly(ether imide), polyurethane, and polyurethane urea.

[0160] In some embodiments, the biointerface layer may include a combination of one or more biointerface polymers, e.g., polyurethane or polyurethane urea and one or more hydrophilic polymers, e.g., PVA, PEG, polyacrylamide, polyacetate, polyzwitterion, PEO, PEA, PVP, and their copolymers, blends, and / or variants (e.g., PVP vinyl acetate), as, for example, a physical blend or admixture, where each polymer maintains its own chemical properties.

[0161] In some embodiments, the biointerface layer 48 is positioned most distally with respect to the sensing region, such that its outermost domain contacts the biological fluid when inserted in vivo. In some embodiments, the biointerface layer is resistant to cell attachment, impermeable to cells, and may be composed of a biostable material. Without being bound by theory, if the biointerface domain 48 is resistant to cell attachment (e.g., attachment by inflammatory cells such as macrophages, and thus held at a sufficient distance from other domains, such as enzyme domains), hypochlorite and other oxidizing species are short-lived chemical species in vivo and biodegradation generally does not occur. Further, the materials preferred for forming the biointerface domain 48 may be resistant to the effects of these oxidizing species and are thus referred to as biopersistent. In some embodiments, the biointerface domain controls the flow of oxygen and other analytes (e.g., glucose) to the underlying enzyme domain (e.g., the functionality of a diffusion resistance domain is incorporated into the biointerface domain, obviating the need for a separate diffusion resistance domain).

[0162] In some embodiments, one or more zwitterionic compounds or precursors thereof applied to the surface of the membrane system are hydrolyzable cationic esters of zwitterionic compounds. In these embodiments, the hydrolyzable cationic esters provide the added benefit that hydrolysis of the cationic ester to a non-fouling zwitterionic group can kill microorganisms (such as bacteria) or condense DNA. Further, the resulting mixed charge nature of the zwitterionic group results in inhibition of non-specific protein adsorption on the surface of the sensor. In these embodiments, cationic betaine esters, such as cationic pCB esters, are preferred.

[0163] In certain embodiments, the biointerface polymer can include reactive groups that can be used for further functionalization. For example, unsaturated functional groups such as alkynes can be used to attach various moieties that are attached to dipolar groups such as azides to various moieties to form covalent bonds. Such Huisgen cycloaddition chemical reactions are often referred to as click chemical reactions. Thus, in certain embodiments herein, the biointerface layer can include alkyne functional groups pendant from the polymer backbone. Preservatives such as proteins, cytokines, anti-inflammatory agents, steroids, and other bioactive agents disclosed herein that are attached to dipolar groups such as azides can be conveniently attached to the polymer, resulting in a triazole group. Thus, sensors are disclosed herein that include such layers that include the biointerface layer, alkyne, triazole, or both. These reactive groups can be present in zwitterionic repeat units (e.g., as substituents on Z or Y). A schematic of these products is shown in FIG. 17.

[0164] Incorporating zwitterions or zwitterion precursor segments or moieties within the polymer backbone can be difficult due to solubility issues associated with the monomers of such zwitterions or zwitterion precursors. Such groups typically can only dissolve in highly polar solvents such as methanol and water, which are not preferred for the synthesis of some biointerface polymers (e.g., polyurethanes). Thus, the available functional groups that could be chemically incorporated into the backbone of biointerface polymers by solution-based polycondensation synthesis were limited. As an alternative method of incorporating zwitterions or zwitterion precursor segments or moieties into the backbone of a base polymer, precursors or derivatives of such zwitterions or zwitterion precursors can be used. For example, zwitterion precursors and / or zwitterion derivatives having more desirable solubility characteristics in low-polarity organic solvents can be used as monomers. Biointerface polymers (e.g., polyurethane ureas) can be synthesized by polycondensation reactions to form well-defined polymers having high molecular weights and low polydispersity indices. These polymers can then be converted to zwitterion groups contained within the polymer via chemical reactions (hydrolysis, deprotection, heat-induced rearrangement, and UV-induced degradation) or biologically induced reactions after in vivo implantation of the device.

[0165] In some embodiments, the hydrophilic segment of the biointerface domain includes a "brush" polymer in which the linear polymer backbone is functionalized with oligomers (e.g., PEG) of hydrophilic branches. That is, in the biointerface domain, the biointerface polymer can include a polymer chain having both a hydrophilic region and a hydrophobic region, the hydrophilic region can include a linear polymer chain to which a hydrophilic oligomer is attached, and the linear polymer can be grafted to the biointerface polymer. The linear polymer can be a non-biodegradable polymer, such as a polyacrylate, that is functionalized at one end (e.g., azide) to enable attachment to a functional group located on the backbone of the biointerface domain. For example, multiple brush polymers can be attached to alkynyl functional groups on the biointerface domain using a copper-catalyzed Huisgen addition cyclization reaction (CuAAC). The brush polymers can be prepared by atom transfer radical polymerization from homopolymers (e.g., PEG acrylate monomers) with defined chain lengths. In some embodiments, the biointerface layer is grafted onto surface functional groups in an adjacent layer (e.g., a resist layer) (see FIG. 14).

[0166] In another embodiment, the biointerface layer can include an amphiphilic copolymer of a hydrophobic hyperbranched fluoropolymer (HBFP) and a hydrophilic polymer, such as a polyalkylene oxide, polyvinyl alcohol, or polyester (see, e.g., FIG. 15). These networks can be prepared from hyperbranched fluoropolymers (1-100 kDa, e.g., Mn of 5-15 kDa) by atom transfer radical self-condensing vinyl copolymerization and linear diamine-terminated hydrophilic polymers, such as diamino-poly(ethylene glycol) (Mn of 1-20,000 Da). Accordingly, a continuous analyte sensor is disclosed herein that includes an amphiphilic copolymer comprising a hyperbranched fluoropolymer segment and a hydrophilic polyethylene glycol segment. Examples of such polymers are disclosed in Gudipati et al., J. Polymer Sci. (42:6193-6208, (2004)), and Muller et al., Macromolecules 31:776, (1998), which are hereby incorporated by reference herein for their teachings regarding amphiphilic polymers containing HBFP.

[0167] In another embodiment, a fluorescent dye (e.g., rhodamine) can be incorporated into the biointerface domain in common. This domain can enable tracking of the domain, the sensing layer, and / or the sensor by a confocal microscope. This feature can be useful for tracking the degradation or phase separation of the polymer in the sensing membrane. Such polymers can be prepared by two-step polycondensation. In certain embodiments, the fluorescent dye incorporated into the biointerface domain can be combined and blended with other biointerface domains disclosed herein. Examples of suitable fluorescent dyes include benzoporphyrin; azabenzoporphyrin; naphthoporphyrin; phthalocyanine; polycyclic aromatic hydrocarbons such as perylene, perylenediamine, pyrene; azo dyes; xanthene dyes; boron dipyrromethene, aza-boron dipyrromethene, cyanine dyes, metal-ligand complexes such as ruthenium and iridium bipyridine, bipyridyl, phenanthroline, coumarin, and acetylacetonate; acridine, oxazine derivatives such as benzophenoxazine; aza-annulene, squaraine; 8-hydroxyquinoline, polymethine, luminescent nanoparticles such as quantum dots, nanocrystals; carbostyryl; terbium complexes; inorganic phosphors; ionophores such as crown ether-related or derivatized dyes; or combinations thereof, but are not limited thereto. Specific examples of suitable fluorescent dyes include Pd(II) octaethylporphyrin; Pt(II)-octaethylporphyrin; Pd(II) tetraphenylporphyrin; Pt(II) tetraphenylporphyrin; Pd(II) meso-tetraphenylporphyrin tetratetrabenzoporphyrin; Pt(II) meso-tetraphenylmetrylbenzoporphyrin; Pd(II) octaethylporphyrin ketone; Pt(II) octaethylporphyrin ketone; Pd(II) meso-tetra(pentafluorophenyl)porphyrin; Pt(II) meso-tetra(pentafluorophenyl)porphyrin; Ru(II)tris(4,7-diphenyl-1,10-phenanthroline) (Ru(dpp)3);Ru(II) tris(1,10-phenanthroline) (Ru(phen)3), tris(2,2'-bipyridine) ruthenium(II) hexahydrate chloride (Ru(bpy)3); erythrosine B; fluorescein; eosin; iridium(III) ((N-methyl-benzimidazol-2-yl)-7-(diethylamino)-coumarin)); indium(III) ((benzothiazol-2-yl)-7-(diethylamino)-coumarin))-2-(acetylacetonate); Lumogen dye; Macroflex fluorescent red; Macrolex fluorescent yellow; Texas Red; rhodamine B; rhodamine 6G; sulfur rhodamine; m-cresol; thymol blue; xylenol blue; cresol red; chlorophenol blue; bromocresol green; bromocresol red; bromothymol blue; Cy2; Cy3; Cy5; Cy5.5; Cy7; 4-nitrophenol; alizarin; phenolphthalein; o-cresolphthalein; chlorophenol red; carmagite; bromo-xylenol; phenol red; neutral red; nitrazine; 3,4,5,6-tetrabromophenolphthalein; congo red; fluorescein; eosin; 2',7'-dichlorofluorescein; 5(6)-carboxy-fluorescein; carboxynaphthofluorescein; 8-hydroxypyrene-1,3,6-trisulfonic acid; semi-naphthorhodafluor; semi-naphthofluorescein; tris(4,7-diphenyl-1,10-phenanthroline) ruthenium(II) dichloride; (4,7-diphenyl-1,10-phenanthroline) ruthenium(II) tetraphenylboron; platinum(II) octaethylporphyrin; dialkylcarbocyanine; and dioctadecylcycloxacarbocyanine; or derivatives or combinations thereof, but not limited thereto.;

[0168] The fluorescently labeled biointerface domain can contain from about 0.05 wt% to about 20 wt% of a fluorescent dye, such as about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, or about 20 wt%, and any of the recited values can form the upper or lower endpoint of the range.

[0169] In certain embodiments, the thickness of the biointerface domain can be from about 0.1, about 0.5, about 1, about 2, about 4, about 6, about 8 μm or less to about 10, about 15, about 20, about 30, about 40, about 50, about 75, about 100, about 125, about 150, about 175, about 200, or about 250 μm or more. In some of these embodiments, the thickness of the biointerface domain can sometimes be from about 1 to about 5 μm and sometimes from about 2 to about 7 μm. In other embodiments, the biointerface domain can be from about 20 or about 25 μm to about 50, about 55, or about 60 μm in thickness. In some embodiments, the glucose sensor can be configured for transdermal or short-term subcutaneous implantation and can have a thickness from about 0.5 μm to about 8 μm and sometimes from about 4 μm to about 6 μm. In one glucose sensor configured to be in fluid communication with the host's circulatory system, the thickness can be from about 1.5 μm to about 25 μm and sometimes from about 3 to about 15 μm. In some embodiments, the biointerface layer or any other layer of the electrode can have a consistent thickness, although in other embodiments it is contemplated that the thickness can vary. For example, in some embodiments, the thickness of the biointerface layer can vary along the longitudinal axis of the electrode end.

[0170] The biointerface layer can be hydrophilic as measured by the contact angle. For example, the biointerface layer can have a contact angle from about 20° to about 90°, about 60 to about 90°, about 70 to about 90°, about 80 to about 90°, about 60 to about 80°, at least about 50°, at least about 60°, or at least about 70°.

[0171] The biointerface layer can also have a low polydispersity index. For example, the polymer can have a polydispersity index of from about 1.4 to about 3.5, from about 1.75 to about 2.25, from about 1.75 to about 2.5, or about 2. The biointerface layer can also not substantially affect the T95 response time of the sensor. The T95 response time is the amount of time required for the electrical response to reach 95% of the difference between the response of the first glucose step and the response of the second glucose step. For example, a sensor having the biointerface layer disclosed herein can have a T95 response time that is the same as or within 5% of the T95 response time of a sensor that is identical except for not having the biointerface layer.

[0172] Diffusion resistance domain In some embodiments, a diffusion resistance domain 46, also referred to as a diffusion resistance layer, can be used and positioned closer to the device that can be embedded relative to the biointerface layer. In some embodiments, the functionality of the diffusion resistance domain can be incorporated into a biointerface layer that includes a polyzwitterionic biointerface polymer. Thus, it should be noted that the description of the diffusion resistance domain herein can also apply to the biointerface layer. The diffusion resistance domain functions to control the flow of oxygen and other analytes (e.g., glucose) to the underlying enzyme domain. As described in more detail elsewhere herein, there is a molar excess of glucose relative to the amount of oxygen in the blood, i.e., typically more than 100 glucose molecules per free oxygen molecule in extracellular fluid (see Updike et al., Diabetes Care 5:207-21 (1982)). However, in an immobilized enzyme-based sensor that uses oxygen as a cofactor, oxygen is supplied in a non-rate-limiting excess such that it responds linearly to changes in glucose concentration but not to changes in oxygen partial pressure. More specifically, when the glucose monitoring reaction is oxygen-limited, linearity is not achieved at glucose concentrations above the minimum. Without a semipermeable membrane located on the enzyme domain to control the flow of glucose and oxygen, a linear response to glucose levels can be obtained up to only about 40 mg / dL maximum. However, in a clinical setting, a linear response to glucose levels is desirable up to at least about 500 mg / dL maximum. In some embodiments, the diffusion resistance domain can be formed of the diffusion resistance domain described in U.S. Provisional Application No. 62 / 273,219, filed Dec. 30, 2015, which is hereby incorporated by reference in its entirety.

[0173] The diffusion resistance domain 46 includes a semi-permeable membrane that controls the flow of oxygen and glucose to the underlying enzyme domain 44, preferably making the oxygen non-rate limiting in excess. As a result, the upper limit of the linearity of glucose measurement is extended to a much higher value than the value achieved without the diffusion resistance domain. In some embodiments, the diffusion resistance domain exhibits an oxygen to glucose permeability ratio of approximately 200:1, while in other embodiments, the oxygen to glucose permeability ratio can be approximately 100:1, 125:1, 130:1, 135:1, 150:1, 175:1, 225:1, 250:1, 275:1, 300:1, or 500:1. As a result of the high oxygen to glucose permeability ratio, one-dimensional reactant diffusion can provide sufficient excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (see Rhodes et al., Anal. Chem., 66:1520-1529 (1994)). In some embodiments, a lower oxygen to glucose ratio may be sufficient to provide excess oxygen by using a high oxygen solubility domain (e.g., a silicone material) to enhance the supply / transport of oxygen to the enzyme membrane or electroactive surface. By enhancing the oxygen supply through the use of a silicone composition, for example, the glucose concentration is not as much of a limiting factor. In other words, when more oxygen is supplied to the enzyme or electroactive surface, then more glucose can also be supplied to the enzyme without resulting in an oxygen rate limiting excess.

[0174] In some embodiments, the diffusion resistance domain is formed of a base polymer synthesized to include a polyurethane membrane having both hydrophilic and hydrophobic regions to control the diffusion of glucose and oxygen to the analyte sensor. Suitable hydrophobic polymer components can be polyurethane or polyether urethane urea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a bifunctional hydroxyl-containing material. Polyurea is a polymer produced by the condensation reaction of a diisocyanate and a bifunctional amine-containing material. Preferred diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units. Alicyclic moieties containing diisocyanates may also be useful in the preparation of the polymer and copolymer components of the membranes of preferred embodiments. The material forming the basis of the hydrophobic matrix of the diffusion resistance domain is suitable for use as a membrane within the sensor device and allows related compounds to pass through it, e.g., to reach an active enzyme or an electrochemical electrode, and has sufficient permeability to allow oxygen molecules to pass through the membrane from the sample under examination, and can be any of those known in the art. Examples of materials that 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 cellulose and protein-based materials), and mixtures or combinations thereof.

[0175] In one embodiment of the polyurethane-based resistance domain, the hydrophilic soft segment polymer component can be polyethylene oxide. For example, one useful hydrophilic copolymer component is a polyurethane polymer containing about 20% hydrophilic polyethylene oxide. The polyethylene oxide portion of the copolymer is thermodynamically driven to separate from the hydrophobic portion 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 water absorption and subsequent glucose permeability of the membrane.

[0176] Alternatively, in some embodiments, the diffusion resistance domain can include a combination of a base polymer (e.g., polyurethane) and one or more hydrophilic polymers (e.g., PVA, PEG, polyacrylamide, acetate, PEO, PEA, PVP, and their copolymers, blends, and / or modifications). Any of various combinations of polymers can be used to provide the desired blend with glucose, oxygen, and interference permeability characteristics. For example, in some embodiments, the diffusion resistance domain can be formed from a blend of a silicone polycarbonate-urethane base polymer and a PVP hydrophilic polymer, although in other embodiments, a blend of polyurethane, or another base polymer, and one or more hydrophilic polymers can be used instead. In some of the embodiments involving the use of PVP, the PVP portion of the polymer blend can include from about 5 wt% to about 50 wt%, sometimes from about 15 wt% to about 20 wt%, and other times from about 25 wt% to about 40 wt% of the polymer blend. It is contemplated that PVPs of various molecular weights can be used. For example, in some embodiments, the molecular weight of the PVP used can be from about 25,000 Daltons to about 5,000,000 Daltons, sometimes from about 50,000 Daltons to about 2,000,000 Daltons, and other times from about 6,000,000 Daltons to about 10,000,000 Daltons.

[0177] In some embodiments, the diffusion resistance domain 46 can be formed as an integral structure having a biointerface domain 48, i.e., the inherent properties of the diffusion resistance domain 46 are incorporated into the biointerface domain 48, whereby the biointerface domain 48 functions as the diffusion resistance domain 46.

[0178] In certain embodiments, the thickness of the diffusion resistance domain can be from about 0.05 μm or less to about 200 μm or more. In some of these embodiments, the thickness of the diffusion resistance domain is about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 6, about 8 μm to about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 19.5, about 20, about 30, about 40, about 50, about 60, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 μm. In some embodiments, the thickness of the diffusion resistance domain is about 2, about 2.5, or about 3 μm to about 3.5, about 4, about 4.5, or about 5 μm for a transdermally implanted sensor, or about 20 or about 25 μm to about 40 or about 50 μm for an overall implanted sensor.

[0179] Enzyme domain In some embodiments, an enzyme domain 44, also referred to as an enzyme layer, can be used, which is located closer to the electrochemical reaction surface than the diffusion resistance domain 46. The enzyme domain includes a catalyst configured to react with an analyte. In one embodiment, the enzyme domain is an immobilized enzyme domain 44 that includes glucose oxidase. In other embodiments, the enzyme domain 44 can be impregnated with other oxidases, such as galactose oxidase, cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate oxidase, or uricase. For example, for a sensor based on an enzyme system for electrochemically detecting glucose to operate well, the response of the sensor should not be limited by enzyme activity or cofactor concentration.

[0180] As described above, the enzyme domain can include one surfactant-terminated polymer or a blend of two or more (e.g., two, three, four, or more) surfactant-terminated polymers. For example, in some embodiments, the enzyme domain can include one surfactant-terminated polymer that includes surfactant termini that are zwitterions or their precursors or derivatives. In other embodiments, one surfactant terminus in a blend of two or more surfactant group-containing polymers includes a zwitterionic surfactant group or its precursors or derivatives. In other embodiments, the blend can include a polymer having a positively charged surfactant group and a polymer having a negatively charged surfactant group. In some embodiments, the enzyme domain may be formed of the enzyme domain described in U.S. Provisional Application No. 62 / 273,155, filed Dec. 30, 2015, which is hereby incorporated by reference in its entirety.

[0181] In some embodiments where the enzyme domain contains one or more zwitterionic surfactant groups, or precursors or derivatives thereof, the zwitterionic surfactant group may contain a betaine moiety, such as a carboxyl, sulfo, or phosphobetaine group, or a precursor or derivative thereof (e.g., alkyl betaine or amino betaine), for example, up to about 0.1, about 0.2, about 0.5, about 1, about 2, or about 5 weight % of the domain. Exemplary betaines include cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, caprylyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly(carboxybetaine) (pCB), and poly(sulfobetaine) (pSB). It will be understood that many other zwitterionic groups, or precursors or derivatives thereof, may be applicable and that this list of exemplary betaines is not intended to limit the scope of the embodiments. In some embodiments, the hydrolyzable cationic esters of the zwitterionic groups (discussed elsewhere) may be used at similar concentrations for incorporation into the enzyme domain.

[0182] In some other embodiments, a blend of polymers containing two or more surfactant groups contains one surfactant group with a negative charge and one surfactant group with a positive charge. In some embodiments, the number of negatively and positively charged surfactant groups is such that the enzyme domain formed from the blend has a net neutral charge. In other embodiments, the number of positively and negatively charged surfactant groups may not be equal, and either the positively or negatively charged surfactant group may be present in greater amounts.

[0183] In some embodiments, the catalyst (enzyme) can be impregnated with a biointerface or diffusion resistance domain or immobilized in other ways, such that a separate enzyme domain 44 is not required (e.g., here, an integrated domain is provided that includes the functionality of the biointerface domain, diffusion resistance domain, and enzyme domain). In some embodiments, the enzyme domain 44 is formed from a polyurethane, e.g., an aqueous dispersant of a colloidal polyurethane polymer containing the enzyme.

[0184] In some embodiments, the thickness of the enzyme domain can be from about 0.01, about 0.05, about 0.6, about 0.7, or about 0.8 μm to about 1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.1, about 2.2, about 2.5, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 μm. In more preferred embodiments, the thickness of the enzyme domain can be from about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 4, or about 5 μm to about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 19.5, about 20, about 25, or about 30 μm. In even more preferred embodiments, the thickness of the enzyme domain can be about 2, about 2.5, or about 3 μm to about 3.5, about 4, about 4.5, or about 5 μm for a transdermally implanted sensor and about 6, about 7, or about 8 μm to about 9, about 10, about 11, or about 12 μm for a fully implanted sensor.

[0185] Interference domain In some embodiments, for example, in the sensor configuration shown in FIG. 2B, an interference domain 43, also referred to as an interference layer, is contemplated to be provided in addition to (or instead of) the biointerface layer. The interference domain 43 can substantially reduce the permeation of one or more interfering substances to the electrochemical reaction surface. The interference domain 43 can be configured to have a much lower permeability to one or more of the interfering substances than the measured species. In some embodiments where interference blocking can be provided by the biointerface layer (e.g., via a polymer containing surface active groups of the biointerface layer), there is no separate interference domain. In other embodiments, the membrane includes both an interference domain and a biointerface layer, and both domains are configured to reduce the permeation of one or more interfering substances. In further embodiments, the interference domain and the biointerface layer are each configured to reduce the permeation of different interfering species. For example, the interference domain can have better specificity than the biointerface layer with respect to reducing the permeation of a certain interfering species, while the biointerface layer can have better specificity than the interference domain with respect to reducing the permeation of a different interfering species. In some embodiments, both the interference domain and the biointerface layer are configured to target a specific interfering species for permeation reduction.

[0186] In certain embodiments, an implantable sensor uses a membrane system that includes a resistance domain, an enzyme domain, and an interference domain. The interference domain can be proximal to the sensor, the resistance domain can be distal to the sensor, and the enzyme domain is therebetween. The interference domain can consist of a single layer or multiple layers of the same material. However, in some embodiments, the interference domain includes layers of two or more different species in an alternating configuration. For example, the first species of layer can be represented by X, the second species of layer can be represented by Y, and the third species of layer can be represented by Z. The interference domain including alternating layers can have the following exemplary configurations.

Chemical formula

[0187] The above-described configurations are merely illustrative and show various embodiments. In certain embodiments, the first and last layers are the same (e.g., X and X), and in other embodiments, the first and last layers are different (e.g., X and Y). A domain may include one or more layers and may be integral (i.e., a single layer is deposited, e.g., X) or composite (e.g., a first material layer is deposited, followed by layers such as a second and third of the same material deposited on top of the first layer, e.g., XXX). The pattern of alternating layers may be regular (e.g., XYXYXYXYXY) or irregular (e.g., ZYXZXYZYZ).

[0188] In some embodiments, the alternating layers include a polyanion layer and a polycation layer. The following are exemplary interference domain configurations, where the polyanion layer (integral, composite, and / or continuous with the same or different polyanions) is represented by A and the polycation layer (integral, composite, and / or continuous with the same or different polyanions) is represented by C.

Chemical formula

Chemical formula

[0189] Other configurations (e.g., those including additional layers and / or additional materials) are also contemplated for some embodiments. In some embodiments, each A layer is a single or composite layer of the same polyanion, and each C layer is a single or composite layer of the same polycation. Both of the outermost layers of the interference domain can be polycation layers, and the polyanion layer can exist only as an internal layer. Any suitable number of alternative layers, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more bilayer (defined as a polycation layer adjacent to a polyanion layer) can be used in the interference domain. In some embodiments, a final polycation layer is added to result in an interference domain having a polycation layer as the outermost layer. In other embodiments, a final anion layer is added to result in an interference domain having a polyanion layer as the outermost layer.

[0190] Polyanions and polycations belong to a class of polymers generally referred to as polyelectrolyte-polymers, where at least some of the repeating units (or monomers) contain one or more ionic moieties. A polyelectrolyte carrying both cationic and anionic moieties is generally referred to as a polyampholyte. Certain polyelectrolytes form self-assembled monolayers where one end of the molecule exhibits a specific reversible affinity for the substrate, whereby a closely packed monolayer of the polyelectrolyte can be deposited.

[0191] The polycation can be any biocompatible polycationic polymer. In some embodiments, the polycation is a biocompatible water-soluble polycationic polymer. In certain embodiments, the water solubility can be enhanced by grafting the polycationic polymer with a water-soluble poly(non-ionic) material such as polyethylene glycol. Representative polycationic materials can include, for example, natural and non-natural polyamino acids having a net positive charge at neutral pH, positively charged polysaccharides, and positively charged synthetic polymers. Additional examples of suitable polycationic materials include polyamines having amine groups either in the polymer backbone or in the polymer side chains, such as poly-L-lysine and other positively charged polyamino acids of natural or synthetic amino acids or mixtures of amino acids (including poly(D-lysine), poly(ornithine), poly(arginine), and poly(histidine)), as well as non-peptidic polyamines, such as poly(aminostyrene), poly(aminoacrylate), poly(N-methylaminoacrylate), poly(N-ethylaminoacrylate), poly(N,N-dimethylaminoacrylate), poly(N,N-diethylaminoacrylate), poly(diallyldimethylammonium chloride), poly(aminomethacrylate), poly(N-methylamino-methacrylate), poly(N-ethylaminomethacrylate), poly(N,N-dimethylaminomethacrylate), poly(N,N-diethylaminomethacrylate), poly(ethyleneimine), polymers of quaternary amines, such as poly(N,N,N-trimethylaminoacrylate chloride), poly(methylacrylamidepropyltrimethylammonium chloride), as well as natural or synthetic polysaccharides, such as chitosan, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(vinylbenzyltrimethylamine), polyaniline or sulfonic acid polyaniline, (p-type doped), polypyrrole (p-type doped), polyallylamine gluconolactone, and poly(pyridinium acetylene).

[0192] The polyanion material can be any biocompatible polyanion polymer, for example, any polymer having carboxylic acid groups attached as pendant groups. The polyion layer can be hydrophilic (e.g., a material or a portion thereof that would associate more readily with water than with lipids). In some embodiments, the polyanion polymer is a biocompatible water-soluble polyanion polymer. Suitable materials include, but are not limited to, alginate, carrageenan, furcellaran, pectin, xanthan, hyaluronic acid, heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, dextran sulfate, polymethacrylic acid, polyacrylic acid, poly(vinyl sulfate), poly(thiophene-3-acetic acid), poly(4-styrenesulfonate), poly(styrenesulfonate), (poly[1-[4-(3-carboxy-4-hydroxy-phenylazo)benzenesulfonamide]-1,2-ethanediyl, sodium salt]), poly(4-[4-({4-[3-amino-2-(4-hydroxy-phenyl)propylcarbamoyl]-5-oxo-pentyl-}-methyl-amino)-phenylazo]-benzenesulfonic acid), oxidized cellulose, carboxymethyl cellulose, and croscarmellose, synthetic polymers, and copolymers containing pendant carboxyl groups, such as those containing maleic acid or fumaric acid in the backbone. Polyamino acids that are predominantly negatively charged are also suitable. Examples of these materials include polyaspartic acid, polyglutamic acid, and copolymers with other natural and non-natural amino acids. Polyphenol materials such as tannins and lignins can be used if they are sufficiently biocompatible.

[0193] The molecular weight of the polyion material can vary to change coating characteristics such as coating thickness. As the molecular weight is increased, the coating thickness generally increases. However, increasing the molecular weight can make handling more difficult. To achieve a balance of coating thickness, material handling, and other design considerations, the polyion material can have a specific average molecular weight Mn. In some embodiments, the average molecular weight of the polyion material used is from about 1,000, 10,000, or 20,000 to about 25,000, 50,000, 100,000, or 150,000 g / mol.

[0194] In some embodiments, the interference domain can be prepared using the layer-by-layer method, where a substrate (e.g., a sensor or a film layer on a sensor, such as a resistive layer or an enzyme layer) is first immersed in one polyelectrolyte bath and then in a polyelectrolyte bath of opposite charge. Optionally, the substrate can be immersed in a cleaning solution bath before or after being immersed in the polyelectrolyte bath. During each immersion, a small amount of polyelectrolyte is adsorbed and the surface charge is reversed, thereby enabling the stepwise and controlled construction of an electrostatically cross-linked (or hydrogen-bonded) film of alternating polycation-polyanion layers. This method provides functionality as well as techniques for controlling film thickness and functionality. For example, it can be used to deposit a film as thin as one monolayer or for thicker layers. FIG. 26B illustrates an embodiment of the layer-by-layer method for creating the structure illustrated in FIG. 26A using the alternate adsorption of polycations and polyanions. Operationally, the embodiment shown in FIG. 26B occurs through the successive exposure of substrate 938 to polycation and polyanion solutions, with washing after each deposition step to remove unadsorbed polymer. In the first step, polycation 942 is deposited onto substrate 938 (e.g., a wire or flat wafer substrate having an electroactive surface), forming polycation layer 942. As described in more detail elsewhere herein, layer deposition can be performed using any of a variety of techniques, such as immersion and / or spraying. In the second step, washing is performed after the deposition of polycation layer 942 to remove unadsorbed polymer. Next, in the third step, polyanion 944 is deposited onto polycation layer 942. Thereafter, in the fourth step, washing is performed after the deposition of polyanion layer 944 to remove unadsorbed polymer. These steps can be repeated until the desired interference domain configuration and / or structure is achieved. In an alternative embodiment, instead of depositing a polycation layer as the first layer onto substrate 938, a polyanion layer is deposited instead. Thereafter, a second layer formed of polycation is deposited onto the first layer, i.e., the polyanion layer. This process is continued until a particular desired interference domain configuration and / or structure is achieved.

[0195] In some embodiments, the method can also use other interactions such as hydrogen bonds or covalent bonds. Depending on the nature of the polyelectrolyte, polyelectrolyte crosslinking can occur, where a single polyelectrolyte chain adsorbs to two (or more) oppositely charged macroions, thereby establishing a molecular crosslink. If only a single monolayer of each polyelectrolyte adsorbs in each deposition step, an electrostatically crosslinked hydrogel-like material can be constructed on the surface only a few microns at a time. If the substrate is not completely cleaned during the application of the polyion film, a thicker hydrogel-like structure can be deposited.

[0196] In some embodiments, the interference blocking ability provided by alternating polycation layer(s) and polyanion layer(s) can be adjusted and / or controlled by creating covalent bonds between the polycation layer(s) and the polyanion layer(s). Crosslinking can have a substantial effect on the mechanical properties and structure of the film and, in turn, can affect the interference blocking ability of the film. Crosslinked polymers can have different crosslinking densities. In certain embodiments, crosslinking is used to facilitate crosslinking between layers. In other embodiments, instead of (or in addition to) the crosslinking techniques described above, heat is used to form crosslinks. For example, in some embodiments, imide and amide bonds can be formed between the polycation layer and the polyanion layer as a result of high temperature. In some embodiments, photocrosslinking is performed to form covalent bonds between the polycation layer(s) and the polyanion layer(s). One of the main advantages of photocrosslinking is that it provides the possibility of patterning. In certain embodiments, patterning using photocrosslinking is performed to modify the film structure and, in so doing, adjust the interference blocking ability of the interference domain. The blocking ability can correspond, without limitation, to the ability to reduce the transport of certain interfering species or the selectivity of the transport of a desired species (e.g., H2O2) over the interfering species. Post-deposition reactions such as crosslinking and reduction of metal ions to form nanoparticles provide additional ways to modify film properties. In some embodiments, crosslinking can be performed during the deposition of adjacent polycation or polyanion layers instead of (or in addition to) a post-deposition crosslinking process.

[0197] The overall thickness of the interference layer can affect its permeability to the interfering substance. The overall thickness of the interference domain can be controlled by adjusting the number of layers and / or the degree of cleaning between the layers. By layer deposition through spraying, control of the droplet size and density can provide a coating of the desired selected thickness without necessarily requiring cleaning between the layers. Further, excess (unbound) material can be removed via other means, e.g., by an air jet. When residual polyelectrolytes from the previous layer are substantially removed before adding the subsequent layer, the thickness per layer decreases. Thus, in one embodiment, the surface is first coated with a polycation, then the excess polycation is removed by cleaning the surface, then a polyanion is added, then the excess is removed, and this process is repeated as necessary. In some embodiments, the polycations or polyanions from different adjacent layers may be intertwined. In further embodiments, they can be intertwined over several layers.

[0198] In some embodiments, the level of ionization of the polyion can be controlled, for example, by controlling the pH in the immersion solution containing the polycation or polyanion. By varying the level of ionization of these polyions, the interference blocking ability of a particular layer may be altered and / or controlled. For example, a first polycation layer having a higher level of ionization than a second polycation layer will interact better with the first interfering species and reduce its transport, while the second polycation will interact better with the second interfering species and may reduce its transport. Changes in the level of ionization of the charge groups of the polyion can also affect mechanical properties, structural properties, and other particular properties (e.g., diffusion properties), which can affect the ability of the interference domain to reduce (or entirely block) the transport of the interfering species. For example, an alternating bilayer containing both a polycation and a polyanion having a high level of ionization can bind more tightly than the corresponding bilayer having a low level of ionization. Thus, the structural differences between these two membranes, which can be in the form of mechanical properties or other properties (e.g., domain thickness), can affect the performance of the interference domain.

[0199] In some embodiments, the linear charge density of the polyelectrolyte can be at least partially controlled by the average charge spacing along the polyion chain. The space between the charge groups on the polycationic polymer and / or polyanionic polymer forming the interference domain can be controlled by polyelectrolyte polymer selection or polymer synthesis. How far apart the charge groups are can significantly affect the structural properties of the interference domain. For example, a polyion having charge groups interposed close to each other can result in small-diameter pores in the interference domain, thereby excluding the passage of medium- and large-diameter interfering species therethrough, but resulting in a structure that allows the passage of small-diameter pores therethrough. Conversely, a polyion having charge groups interposed at a moderate distance from each other can result in medium-diameter pores that exclude large-diameter interfering species and allow the passage of medium- and small-diameter interfering species therethrough. In certain embodiments, the linear charge density of the polyanionic polymer is about 1-50 e / Å, sometimes about 10-25 e / Å, sometimes about 2-10 e / Å, and sometimes 2-3 e / Å, where e is the elementary charge of an electron / proton and Å is the distance in angstroms. In some embodiments, the linear charge density of the polyanionic polymer is about 1-50 e / Å, sometimes about 10-15 e / Å, sometimes about 2-10 e / Å, and sometimes 2-3 e / Å.

[0200] In some embodiments, the linear charge density of the polyanionic polymer is substantially the same as the linear charge density of the polycationic polymer. For example, in one embodiment, the polyanionic layer is formed of (i) poly(acrylic acid) having an average linear charge density of about 2.5 e / Å and (ii) poly(allylamine hydrochloride) having an average linear charge density of about 2.5 e / Å as well. In certain embodiments, the polycationic layer and the polyanionic layer can have substantially equal average linear charge densities that are about 1-50 e / Å, sometimes about 2-25 e / Å, sometimes about 5-10 e / Å, other times about 10-15 e / Å, and still other times about 15-25 e / Å.

[0201] By providing interference domains having different linear charge densities, interference domains can be formed that include different polycation / polyanion bilayers specifically designed to exclude different interfering species based on certain characteristics of the targeted interfering species (e.g., molecular diameter). For example, in one embodiment, the outermost bilayer of the interference domain is designed to have an intermediate average charge spacing, thereby resulting in a bilayer that excludes only large molecular diameter species but allows the passage of medium and small molecular diameter species therethrough. Conversely, the innermost bilayer of the interference domain may be designed to have a low average charge spacing, thereby resulting in a bilayer that excludes all molecules except those having a very small molecular diameter, e.g., H2O2.

[0202] In some embodiments, the polycation layer can be formed of the same or substantially the same material (e.g., poly(allylamine hydrochloride) (PAH) in the case of polycations, or poly(acrylic acid) (PAA) in the case of polyanions), but having different levels of ionization. For example, in one embodiment, the interference domain includes seven alternating polyelectrolyte layers, where the first, third, fifth, and seventh layers are polycation layers, and the second, fourth, and sixth layers are polyanion layers, where the first and seventh layers form the outer layers of the interference domain. In one embodiment, each or some of the polycation layers can have different levels of ionization. For example, in one embodiment, the first, third, fifth, and seventh layers can each have different levels of ionization, where the first layer has the highest level of ionization and the seventh layer has the lowest level of ionization, or vice versa. In an alternative embodiment, some of the polycation layers can share substantially the same level of ionization. For example, in one embodiment, the first and seventh layers can have substantially the same level of ionization, but the third and fifth layers can have a different level of ionization from the others. As described elsewhere herein, the ionization level of the polyion can be controlled by controlling the pH in the immersion solution containing the polycation or polyanion. By changing the ionization levels of these polyions, the interference blocking ability of a particular layer can be changed and / or controlled.

[0203] The design of the interference domain with layers having levels of ionization can be similarly applied to the polyanion layer. For example, in one embodiment having seven alternating polyelectrolyte layers, the second, fourth, and sixth layers are each polyanion layers, which can each have different levels of ionization, where the second layer has the highest level of ionization and the sixth layer has the lowest level of ionization, or vice versa. In an alternative embodiment, some of the polyanion layers can share substantially the same level of ionization. For example, in one embodiment, the second and fourth layers can have substantially the same level of ionization, but the sixth layer can have a substantially different level of ionization from the others.

[0204] In certain embodiments, the particular polycation layer(s) and / or polyanion layer(s) selected to form the interference layer may depend at least in part on their ability to block, reduce, or impede the passage of one or more interfering substances therethrough. For example, a polyanion layer may be selected for its ability to block, reduce, or impede the passage of a first interfering substance, while a polycation layer may be selected for its ability to block, reduce, or impede the passage of a second interfering substance. The layer may be designed to slow down but not block the passage of interfering substances therethrough, or may be designed to substantially block (e.g., capture) interfering substances therein. Additional polyion layers may still be included in interference domains that have specific selectivity for different interfering substances. Depending on the location of the interference domain in the membrane system relative to the electrode or electroactive surface of the sensor, the permeability of the layer to substances other than interfering substances may be important. In a sensor system where H2O2 (hydrogen peroxide) is produced by an enzyme-catalyzed reaction of the analyte being detected, the interference domain should be designed to allow H2O2 to pass with minimal impedance if the interference domain is positioned between the electroactive surface and the enzyme layer. On the other hand, in different membrane designs, if the interference domain is positioned distally (with respect to the electroactive surface) relative to the enzyme layer, in some embodiments, the interference domain may be designed to block H2O2 that is not produced by the enzyme-catalyzed reaction from passing therethrough. Further, with this particular membrane design, the interference domain may be configured to allow the analyte and oxygen to pass with minimal impedance.

[0205] The application of layers in forming an interference domain can be achieved by various methods known in the art. Embodiments of one coating process simply involve dipping coating and dipping washing steps. Embodiments of another coating process simply involve spray coating and spray washing steps. However, many alternative embodiments involve various uses of combinations of spray coating, dipping coating, and / or washing steps. For example, one dipping coating method involves applying a coating of a first polyionic material to a substrate by dipping the substrate into a first solution of the first polyionic material (e.g., a sensor or a film layer on a sensor, such as a resistive layer or an enzyme layer), washing the substrate by dipping the substrate into a washing solution, and optionally drying the substrate. Then, to form a polyion double layer, this procedure is repeated using a second polyionic material, which has a charge opposite to that of the first polyionic material. This double layer formation process can be repeated multiple times to generate an interference domain. In some embodiments, the number of double layers can be from 1 to about 16 double layers, sometimes from 1 to about 10 double layers, and sometimes from about 3 to about 7 double layers. In certain embodiments, a final layer of the oppositely charged polyionic material can be deposited, such that the first layer and the final layer have the same charge (both positive or both negative). The dipping time for each of the coating and washing steps can vary depending on many factors. For example, the dipping of the substrate into the polyionic solution can occur over a period of about 1 to 30 minutes, or about 2 to 20 minutes, or about 1 to 5 minutes. Washing can be achieved in one step, but multiple washing steps can also be used. A series of about 2 to 5 washing steps can be used, and each dipping into the washing solution takes, for example, about 1 to about 3 minutes. In some embodiments, several polycation solutions and / or several polyanion solutions may be used.For example, in certain embodiments, the dip coating sequence may require applying a coating of a first polycationic material to a substrate to form a first layer, then applying a first anionic material to the first layer to form a second layer, then applying a second polycationic material to the second layer to form a third layer, then applying a second polyanionic material to form a fourth layer, and then applying the first or second polycationic material to the fourth layer to form a fifth layer. In some of these embodiments, the dip coating sequence may intersperse cleaning steps between coating steps. Any of a variety of permutations involving the steps and materials described may be used. In alternative embodiments, the materials used to form the polycation layers and / or polyanion layers may be substantially the same. However, individual polycation layers may have different levels of ionization from one or more other polycation layers in the interference domain, and individual polyanion layers may also have different levels of ionization from one or more other polyanion layers. For example, in one embodiment, the dip coating sequence method involves the use of a first solution at a first pH containing a polycationic material, a second solution at a second pH containing a polyanionic material, a third solution at a third pH containing the aforementioned polycationic material, a fourth solution at a fourth pH containing the aforementioned polyanionic material, and a fifth solution at a fifth pH containing the aforementioned polycationic material. Even when the same polycationic material is used to form the first, third, and fifth layers, the ionization levels of the first, third, and fifth layers are different because the solutions used to form the first, third, and fifth layers have different pH values. Similarly, even when the same polyanionic material is used to form the second and fourth layers, the ionization levels of the second and fourth layers are different because the solutions used to form the second and fifth layers have different pH values. This difference in ionization levels can affect, among other things, the mechanical properties of the film, the structural properties of the film (e.g., porosity, roughness), the diffusion properties of the film, and the selectivity of a particular polyelectrolyte layer for a particular interfering species over another interfering species.All of these effects affect the ability of the individual polyelectrolyte layers and interference domains to reduce the transport of the various interference species. In certain embodiments, at least two polycation layers and / or two polyanion layers of the interference domain are formed from the same polycationic / polyanionic material, but through the use of solutions at different pHs. In some of these embodiments, the first polycation layer has a higher selectivity for a particular interference species than for other interference species, while the second polycation layer has a higher selectivity for a different interference species than for other interference species.

[0206] Alternatively, or additionally, spray coating techniques can be used. In one embodiment, the coating process generally includes applying a coating of a first polyionic material to a substrate by contacting the substrate with a first solution of the first polyionic material, spraying a cleaning solution onto the substrate to clean the substrate, and (optionally) drying the substrate. Similar to the dip coating process, the spray coating process can then be repeated with a second polyionic material, which has a charge opposite to that of the first polyionic material. Contact of the substrate with either the polyionic material or the cleaning solution can occur through a variety of methods. For example, the substrate may be immersed in both solutions. One alternative is to apply the solution in spray or mist form. Of course, various combinations are possible and within the scope of the contemplated embodiments, for example, spraying the cleaning solution after immersing the substrate in the polyionic material. Spray coating application can be achieved through a number of methods known in the art. For example, a conventional spray coating arrangement may be used, i.e., the liquid material is sprayed by applying the fluid through a small diameter nozzle oriented towards the vapor deposition target, whether at elevated or reduced pressure. Another spray coating technique involves the use of ultrasonic energy, whereby the liquid is atomized by ultrasonic vibrations at the tip of the spray forming head, thereby changing it into a spray.

[0207] Yet another technique involves electrostatic spray coating, where an electric charge is carried into the fluid or droplets, increasing the efficiency of the coating. A further method of atomizing liquids for spray coating requires pure mechanical energy, for example, by contacting the liquid with a high-speed reciprocating member or a high-speed rotating disk. Yet another method of generating microdroplets for spray coating involves the use of piezoelectric elements to atomize the liquid. These techniques can be used with air assist or with elevated solution pressure. Furthermore, a combination of two or more techniques may prove more useful in certain materials and conditions. A method of spray application involves dispensing a polyanion or polycation solution into an ultrasonic dispensing head using a metering pump. The polyion layer is sprayed to allow the surface droplets to coalesce across the material surface. The resulting layer can then be allowed to interact for a period of time or can be immediately washed with water or saline solution (or other solution without polyanion or polycation).

[0208] In some embodiments, the layers of the interference domain may include a polymer with a complex π system. The polymer with a complex π system may contain a delocalized electron system and may be conductive. The layers of the polymer with a complex π system may interact with each other through intermolecular forces, such as electrostatic π-π interactions (i.e., π-stacking). The complex polymer may provide beneficial properties of the interference domain, such as increasing the rigidity, integrity, and / or reproducibility of the domain. In some embodiments, the polymer with a complex π system may be polyacetylene, polypyrrole, polythiophene, poly(p-phenylene), poly(p-phenylenevinylene), or poly(carbazole). The interference domain may include alternating layers of any of the complex polymers described above. In some embodiments, the number of layers of the complex polymer may be from 1 to about 20 layers, sometimes from about 3 to about 10 layers.

[0209] In some embodiments, the thickness of the interference domain can be from about 0.01 microns or less to about 20 microns or more. In some of these embodiments, the thickness of the interference domain can be from about 0.01, 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 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns. In some of these embodiments, the thickness of the interference domain can be from about 0.2, 0.4, 0.5, or 0.6 microns to about 0.8, 0.9, 1, 1.5, 2, 3, or 4 microns.

[0210] Polyimide film In some embodiments, a particular polymer film can be used to form an interference domain. For example, a particular polyimide prepared from 2,2′-dimethyl-4,4′-diaminobiphenyl, and the corresponding dianhydride, can be cast into a film that can be used as a hydrogen peroxide selective membrane. See, for example, Ekinci et al., Turk.J.Chem. 30(2006), 277-285. In one embodiment, the film is prepared using the following steps. First, n-methyl-2-pyrrolidone (NMP) is distilled over CaH2 under reduced pressure and stored on about 4 Å molecular sieves. Reagent grade pyromellitic dianhydride (PMDA) is sublimed under reduced pressure at about 250 °C and dried under vacuum at about 120 °C before use. The diamine is purified from ethanol via recrystallization to obtain shiny crystals. Next, 2,20-dimethyl-4,40-diaminobiphenyl (about 1.06 g, about 5 mmol) is dissolved in NMP (about 15 mL) in a 50 mL Schlenk tube equipped with a nitrogen line, an overhead stirrer, a xylene-filled Dean-Stark trap, and a condenser. Then, PMDA (about 1.09 g, about 5 mmol) is added to the amine solution, followed by stirring overnight to obtain a viscous solution. After stirring for about 3 hours, the solution is heated to reflux at about 200 °C for about 15 hours. During the polymerization process, the water generated from imidization is distilled from the reaction mixture together with about 1-2 mL of xylene. After cooling to ambient temperature, the solution is diluted with NMP and then slowly added to a vigorously stirred solution of 95% ethanol. The precipitated polymer is collected via filtration, washed with ethanol, and dried at 150 °C under reduced pressure. Before coating, the substrate (e.g., Pt electrode) is cleaned and optionally polished to about 0.05 μm with an aqueous alumina slurry. Then, about 20 μL of a polymer solution prepared by dissolving about 70 mg of polyimide in about 2 mL of NMP is dropped onto the surface of the Pt electrode and dried at room temperature for about 3 days.

[0211] Self-assembly technique Using a self-assembly process, ultrathin multilayer films can be constructed that contain alternating anionic and cationic polyelectrolytes on a charged surface. See, for example, Decher et al., Thin Solid Films, 210-211 (1992) 831-835. The ionic attraction between opposite charges is the driving force for multilayer construction. In contrast to chemisorption techniques that require a reaction yield of approximately 100% to maintain the surface functional density in each layer, covalent bonds need not be formed in the self-assembly process. Further, an advantage over classical Langmuir-Blodgett techniques is that the solution process is independent of the size and topology of the substrate. Exemplary polyelectrolytes for use in such processes include, but are not limited to, sodium polystyrene sulfonate, potassium polyvinyl sulfonate, poly-4-vinylbenzyl-(N,N-diethyl-N-methyl)-ammonium iodide, and poly(allylamine hydrochloride). The construction of the multilayer film can be carried out as follows. A solid substrate having a positively charged planar surface is immersed in a solution containing an anionic polyelectrolyte, and a monolayer of polyanion is adsorbed. Since the adsorption is carried out at a relatively high polyelectrolyte concentration, a large number of ionic groups remain exposed at the interface with the solution, and thus the surface charge is reversed. After washing with pure water, the substrate is immersed in a solution containing a cationic polyelectrolyte. Again, a monolayer is adsorbed, but here the original surface charge is restored. By repeating both steps in a cyclic manner, an alternating multilayer assembly of both polymers is obtained. This process of multilayer formation is based on the attraction of opposite charges and thus requires at least two oppositely charged molecules. As a result, as long as the charge is reversed from layer to layer, more than two molecules can be incorporated into the multilayer simply by immersing the substrate in as many polyelectrolyte solutions as desired. Micropatterned multilayer assemblies can also be readily prepared. In this regard, this technique is more versatile than the Langmuir-Blodgett technique, which is rather limited to periodically alternating layer systems. Another advantage is that the immersion procedure does not impose major limitations with respect to the size of the substrate or automation in a continuous process.

[0212] A specific example of the preparation of such films is as follows. Polystyrene sulfonate (sodium salt, Mr = 100,000), polyvinyl sulfonate (potassium salt, Mr = 245,000), and poly(allylamine hydrochloride), Mw = 50,000 - 65,000) are obtained from commercial sources and used without further purification. Poly-4-vinylbenzyl-(N,N-diethyl-N-methyl)-ammonium iodide can be synthesized as described in Decher et al., Ber. Bunsenges. Phys. Chem., 95(1992)1430. The alternating multilayer assembly of all materials can be characterized by UV / visible spectroscopy and small-angle X-ray scattering (SAXS) using techniques known in the art. Direct light microscopy and SAXS measurements can be performed using the multilayer assembly on a suitable substrate. The multilayer film can be deposited, for example, on a platinum electrode or other metal electrode, or a suitable intervening layer can be deposited on the electrode. In the case of the adsorption of the first layer, an aqueous acidic solution of polystyrene sulfonate or polyvinyl sulfonate can be used. The substrate is then washed with water. After the adsorption of the first layer, the substrate can be stored for several weeks without significant deterioration of the surface. Subsequently, the cationic polyelectrolyte polyallylamine is adsorbed from an aqueous solution. In the case of non-quaternized polyallylamine, the polycation is adsorbed from an acidic solution. All subsequent layers (odd layer numbers) of the anionic polyelectrolyte are adsorbed from an aqueous solution. In the case of a sample containing polyallylamine as the previously adsorbed layer, the polystyrene sulfonate layer can be adsorbed from an acidic solution. An adsorption time of about 20 minutes at ambient temperature can be used, although in certain embodiments, longer or shorter adsorption times may be acceptable. A range of polymer concentrations (e.g., 20 - 30 mg / approx. 10 mL of water) can provide acceptable results.

[0213] Polyelectrolytes: Multilayer molecular films of calixarenes and polyelectrolytes: cyclodextrin hosts can be fabricated by alternately adsorbing charge species in an aqueous solution onto a suitable substrate. See, for example, X. Yang, Sensors and Actuators B 45 (1997) 87-92. Using such an alternate layer molecular deposition approach, molecular recognition reagents can be incorporated into the polymer film. This deposition process is highly reproducible, and the resulting films are uniform and stable. By replacing the polyanion, highly negatively charged molecular species can be used in film fabrication. These molecular reagents can bind organic species and can be deposited as functional components in the thin film. This approach incorporates polymer and molecular elements into the film, thus resulting in a film with the physical properties of the polymer and the selectivity of the molecular film. The film can be prepared as follows. The substrate (e.g., Pt electrode) can first be treated with aminopropyltrimethoxysilane in chloroform and subsequently immersed in aqueous solutions of the polyelectrolytes to deposit PSS and then the PDDA polyelectrolyte, respectively. Thereafter, alternate deposition of the negatively charged molecular host species (e.g., calix[6]arene or p-t-butylcalix[4]arene) and PDDA can be carried out until the desired number of bilayers is reached. Between each deposition, the substrate is thoroughly washed with deionized water. The polyelectrolyte and molecular ion assembly can be monitored by UV-visible absorption spectroscopy, and the mass loading can be measured with a surface acoustic wave (SAW) device.

[0214] In some embodiments, the interference domain is formed from one or more cellulose derivatives. Generally, cellulose derivatives can include polymers such as cellulose acetate, cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate trimellitate, or blends and combinations thereof.

[0215] In some alternative embodiments, other polymer species that can be utilized as the base material of the interference domain include polyurethanes and / or polymers having a controlled pore size. In one such alternative embodiment, the interference domain includes a non-swellable thin hydrophobic membrane that restricts the 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 interfering species that can be applied to the membrane system of the preferred embodiment are described in U.S. Patent No. 7,074,307, U.S. Patent Publication No. US-2005-0176136-A1, U.S. Patent No. 7,081,195, and U.S. Patent Publication No. US-2005-0143635-A1, each of which is incorporated herein by reference in its entirety.

[0216] In some embodiments, it is contemplated that the thickness of the interference domain can be from about 0.01 μm or less to about 20 μm or more. In some of these embodiments, the thickness of the interference domain can be about 0.01, about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, or about 3.5 μm to about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 19.5 μm. In some of these embodiments, the thickness of the interference domain can be about 0.2, about 0.4, about 0.5, or about 0.6 microns to about 0.8, about 0.9, about 1, about 1.5, about 2, about 3, or about 4 microns.

[0217] Generally, the membrane systems described herein can be formed or deposited on exposed electroactive surfaces (e.g., one or more of a working electrode and a reference electrode) using known thin film techniques such as casting, spray coating, stretching, electroplating, dip coating, etc., although casting or other known application techniques can also be utilized. In some embodiments, the interference domain can be deposited by spray or dip coating. In an exemplary embodiment, the interference domain is formed by dip coating the sensor in an interference domain solution using an insertion rate of about 0.5 inches per minute to about 60 inches per minute, sometimes about 1 inch per minute, a dwell time of about 0.01 minutes to about 2 minutes, sometimes about 1 minute, and a withdrawal rate of about 0.5 inches per minute to about 60 inches per minute, sometimes about 1 inch per minute, and curing (drying) the domain for about 1 minute to about 14 hours, sometimes about 3 minutes to about 15 minutes (which can be achieved at room temperature or under vacuum, e.g., about 20 to about 30 mmHg). In an exemplary embodiment containing a cellulose acetate butyrate interference domain, a 3-minute curing (i.e., drying) time is used between each layer applied. In another exemplary embodiment using a cellulose acetate interference domain, a 15-minute curing time is used between each layer applied.

[0218] In some embodiments, the dipping process can be repeated from at least 1 time up to 10 times or more. In other embodiments, a single dip is preferred. The preferred number of repeated dipping processes can depend on the cellulose derivative(s) used, their concentrations, the conditions during deposition (e.g., dipping), and the desired thickness (e.g., a thickness sufficient to provide functional blocking of a particular interferent). In one embodiment, the interference domain is formed from 3 layers of cellulose acetate butyrate. In another embodiment, the interference domain is formed from 10 layers of cellulose acetate. In yet another embodiment, the interference domain is formed from a blend of 1 layer of cellulose acetate and cellulose acetate butyrate. In alternative embodiments, the interference domain can be formed using any known method, as well as combinations of cellulose acetate and cellulose acetate butyrate, as would be understood by one of ordinary skill in the art.

[0219] Electrode domain In some embodiments, such as the embodiment shown in FIG. 2A, any electrode domain 42, also referred to as an electrode layer, may be provided in addition to the biointerface domain and the enzyme domain, but in other embodiments, the functionality of the electrode domain may be incorporated into an integrated domain that includes the functionality of the biointerface domain, the diffusion resistance domain, the enzyme domain, and the electrode domain.

[0220] In some embodiments, the electrode domain is located closest to the electrochemical reaction surface. To facilitate the electrochemical reaction, the electrode domain may include a semi-permeable coating that maintains hydrophilicity at the electrochemical reaction surface of the sensor interface. The electrode domain can enhance the stability of adjacent domains by protecting and supporting the materials that form the adjacent domains. The electrode domain can also help to stabilize the operation of the device by overcoming electrode startup problems and drift problems caused by inappropriate electrolytes. The buffered electrolyte solution contained in the electrode domain can also protect against pH-mediated damage that can result from the formation of a large pH gradient between the substantially hydrophobic interference domain due to the electrochemical activity of the electrode and the electrode.

[0221] In some embodiments, the electrode domain comprises a flexible, hydro-expandable, substantially solid gel-like film (e.g., a hydrogel) having a “dry film” thickness of from about 0.05 μm to about 100 μm, sometimes from about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, or about 1 μm to about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 19.5, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 μm. In some embodiments, the thickness of the electrode domain can be from about 2, about 2.5, or about 3 μm to about 3.5, about 4, about 4.5, or about 5 μm for a transdermally implanted sensor, or from about 6, about 7, or about 8 μm to about 9, about 10, about 11, or about 12 μm for a fully implanted sensor. As used herein, the term “dry film thickness” is a broad term and its ordinary and customary meaning is provided to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, the thickness of a cured film cast from a coating formulation on the surface of a film by standard coating techniques. The coating formulation can include a premix of a film-forming polymer and a crosslinker and can be curable upon application of medium heat.

[0222] In certain embodiments, the electrode domain can be formed of a curable mixture of a urethane polymer and a hydrophilic polymer. In some of these embodiments, the coating is formed of a polyurethane polymer having an anionic carboxylate functional group and a nonionic hydrophilic polyether segment, which is crosslinked in the presence of polyvinylpyrrolidone and cured at a medium temperature of about 50° C.

[0223] An aqueous dispersion of a fully reacted colloidal polyurethane polymer having crosslinkable carboxyl functionality (e.g., BAYBOND™, Mobay Corporation) is particularly suitable for this purpose. These polymers are supplied in dispersion grades having a polycarbonate-polyurethane backbone containing carboxylate groups specified as XW-121 and XW-123, and a polyester-polyurethane backbone containing carboxylate groups specified as XW-110-2. In some embodiments, BAYBOND™ 123, an aqueous anionic dispersion of an aliphatic polycarbonate urethane polymer sold as a 35 wt% solution in water and the co-solvent N-methyl-2-pyrrolidone, can be used.

[0224] In some embodiments, the electrode domain is formed from a hydrophilic polymer that makes the electrode domain as hydrophilic as or more hydrophilic than the overlying domain (e.g., the interference domain, the enzyme domain). Such hydrophilic polymers can include, for example, polyamides, polylactones, polyimides, polylactams, functionalized polyamides, functionalized polylactones, functionalized polyimides, functionalized polylactams, or combinations thereof.

[0225] In some embodiments, the electrode domain is formed primarily from a hydrophilic polymer, and in some of these embodiments, the electrode domain is formed substantially from PVP. PVP is a hydrophilic water-soluble polymer and is commercially available as the PVP K(trademark) homopolymer series by BASF Wyandotte and GAF Corporation in a range of viscosity grades and average molecular weights in the range of about 18,000 to about 500,000. In certain embodiments, a PVP homopolymer having an average molecular weight of about 360,000, identified as PVP-K90 (BASF Wyandotte), can be used to form the electrode domain. Also suitable are hydrophilic film-forming copolymers of N-vinylpyrrolidone, such as copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinylpyrrolidone, ethyl methacrylate, and methacrylic acid monomers, and the like.

[0226] In certain embodiments, the electrode domain is formed entirely from a hydrophilic polymer. Useful hydrophilic polymers contemplated include, but are not limited to, poly-N-vinylpyrrolidone, poly-N-vinyl-2-piperidone, poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam, poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone, poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole, poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, poly-2-ethyl-oxazoline, copolymers thereof, and mixtures thereof. Blends of two or more hydrophilic polymers may be suitable in some embodiments.

[0227] In certain embodiments, the hydrophilic polymer used may not be crosslinked, but in other embodiments, crosslinking is used and can be achieved by any of a variety of methods, for example, by adding a crosslinking agent. In some embodiments, the polyurethane polymer can be crosslinked in the presence of PVP by preparing a premix of the polymer and adding the crosslinking agent immediately prior to film formation. Suitable crosslinking agents contemplated include, but are not limited to, carbodiimides (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and UCARLNK™ XL-25 (Union Carbide)), epoxides, and melamine / formaldehyde resins. Alternatively, it is also contemplated that crosslinking can be achieved by irradiation at a wavelength sufficient to promote crosslinking between hydrophilic polymer molecules, which is thought to create a more tortuous diffusion path through the domain.

[0228] The flexibility and hardness of the coating can be varied as needed by varying the dry weight solids of the components in the coating formulation. As used herein, the term "dry weight solids" is a broad term and its ordinary and customary meaning is indicated to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to the dry weight percentage based on the total coating composition after the crosslinking agent has been included, but is not limited thereto. In one embodiment, the coating formulation can contain about 6 to about 20 dry weight %, preferably about 8 dry weight % of PVP; about 3 to about 10 dry weight %, sometimes about 5 dry weight % of the crosslinking agent; and about 70 to about 91 weight %, sometimes about 87 weight % of the polyurethane polymer, such as a polycarbonate-polyurethane polymer. The reaction product of such a coating formulation is referred to herein as a hydroexpandable crosslinked matrix of polyurethane and PVP.

[0229] In some embodiments, beneath the electrode domain is an electrolyte phase, which, when hydrated, is a free liquid phase containing a solution of at least one compound, typically a soluble chloride salt that conducts current. In one embodiment where the membrane system is used with a glucose sensor as described herein, the electrolyte phase flows over the electrodes and is in contact with the electrode domains. It is contemplated that certain embodiments can use any suitable electrolyte solution, including standard commercially available solutions. Generally, the electrolyte phase can have the same or lower osmotic pressure than the sample being analyzed. In a preferred embodiment, the electrolyte phase comprises normal saline.

[0230] Bioactive agent It is contemplated that any of a variety of bioactive (therapeutic) agents may be used in conjunction with the analyte sensor systems described herein, such as the analyte sensor system shown in FIG. 1. In certain embodiments, the bioactive agent may be in the biointerface layer of the disclosed device. In some embodiments, the bioactive agent is an anticoagulant. As used herein, the term "anticoagulant" is a broad term and its ordinary and customary meaning is indicated to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, a substance that prevents clotting (e.g., minimizes, reduces, or stops blood clots). In these embodiments, the anticoagulant included in the analyte sensor system can prevent clotting within or on the sensor.Anticoagulants suitable for incorporation into a sensor system include, but are not limited to, vitamin K antagonists (e.g., acenocoumarol, chlorindione, dicumarol (Dicumarol, Dicoumarol), diphenadione, ethyl biscoumacetate, phenprocoumon, phenindione, thiochromarol, or warfarin), heparin-based anticoagulants (e.g., platelet aggregation inhibitors: antithrombin III, bemiparin, dalteparin, danaparoid, enoxaparin, heparin, nadroparin, parnaparin, reviparin, sordexide, tinzaparin), other platelet aggregation inhibitors (e.g., abciximab, acetylsalicylic acid (aspirin), alloxipurinol, beraprost, ditazole, carbazerat calcium, chloricromene, clopidogrel, dipyridamole, epoprostenol, eptifibatide, indobufen, iloprost, picotamide, ticlopidine, tirofiban, treprostinil, triflusal), enzymes (e.g., alteplase, ancrod, anisoylated plasminogen streptokinase activator complex (APSAC), brinase, drotrecogin alpha, fibrinolytic enzyme, protein C, reteplase, saruplase, streptokinase, tenecteplase, urokinase), direct thrombin inhibitors (e.g., argatroban, bivalirudin, desirudin, lepirudin, melagatran, ximelagatran), and other antithrombotic agents (e.g., dabigatran, defibrotide, dermatan sulfate, fondaparinux, rivaroxaban).

[0231] In one embodiment, heparin is incorporated into the analyte sensor system, for example, by dipping or spraying. Without being bound by theory, heparin coated on a catheter or sensor can prevent blood aggregation and embolism on the analyte sensor system, thereby preventing thromboembolization (e.g., prevention of blood flow by thrombus or clot) or subsequent complications. In some embodiments, heparin is admixed with one or more zwitterionic compounds or derivatives thereof, such as its hydrolyzable cationic esters (described above), prior to dipping or spraying, thus providing a mixed coating of heparin and one or more zwitterionic compounds or derivatives thereof on the sensor system.

[0232] In some embodiments, an antibacterial agent is coated on the catheter (inner or outer diameter) or sensor. In some embodiments, the antibacterial agent can be incorporated into the analyte sensor system. Contemplated antibacterial agents include, but are not limited to, antibiotics, preservatives, bactericides, and synthetic moieties, as well as combinations thereof, and other agents soluble in organic solvents such as alcohol, ketone, ether, aldehyde, acetonitrile, acetic acid, methylene chloride, and chloroform. The amount of each antibacterial agent used to impregnate the medical device varies somewhat but is at least an effective concentration to inhibit the growth of bacterial and fungal organisms such as staphylococci, gram-positive bacteria, gram-negative bacteria, and Candida.

[0233] In some embodiments, antibiotics can be incorporated into an analyte sensor system. Classes of antibiotics that can be used include tetracycline (e.g., minocycline), rifamycin (e.g., rifampin), macrolide (e.g., erythromycin), penicillin (e.g., nafcillin), cephalosporin (e.g., cefazolin), other β-lactam antibiotics (e.g., imipenem, aztreonam), aminoglycoside (e.g., gentamicin), chloramphenicol, sulfonamide (e.g., sulfamethoxazole), glycopeptide (e.g., vancomycin), quinolone (e.g., ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin, mupirocin, polyene (e.g., amphotericin B), azole (e.g., fluconazole), and β-lactam inhibitor (e.g., sulbactam).

[0234] Examples of specific antibiotics that can be used include minocycline, rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin, temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid, amphotericin B, fluconazole, itraconazole, ketoconazole, and nystatin.

[0235] In some embodiments, an antiseptic or a bactericide can be incorporated into the analyte sensor system. Examples of antiseptics and bactericides are hexachlorophene, cationic bisbiguanides (e.g., chlorhexidine, cyclohexidine), iodine and iodophors (e.g., povidone iodine), para-chloro-meta-xylenol, triclosan, furan medicaments (e.g., nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde), and alcohols. Other examples of antiseptics and bactericides will be readily presented by those skilled in the art themselves.

[0236] In some embodiments, an anti-barrier cell agent can be incorporated into the analyte sensor system. The anti-barrier cell agent can include compounds that are effective against macrophages and foreign body giant cells (FBGC). The anti-barrier cell agent is thought to prevent the closing of the barrier to the lysate transport presented by macrophages and FBGC at the device-tissue interface during FBC maturation. The anti-barrier cell agent can provide an anti-inflammatory or immunosuppressive mechanism that affects the wound healing process, for example, the healing of a wound caused by an incision into which an implantable device is inserted. Cyclosporine, which stimulates very high levels of angiogenesis around the biomaterial, can be incorporated into the biointerface membrane of a preferred embodiment (see, e.g., U.S. Patent No. 5,569,462 to Martinson et al.). Alternatively, dexamethasone, which weakens the intensity of the FBC response at the tissue-device interface, can be incorporated into the biointerface membrane of a preferred embodiment. Alternatively, rapamycin, which is a potent specific inhibitor of some macrophage inflammatory functions, can be incorporated into the biointerface membrane of a preferred embodiment.

[0237] In some embodiments, the anti-inflammatory agent can be incorporated into the analyte sensor system to reduce acute or chronic inflammation adjacent to the implant or to reduce the formation of FBC capsules, for example, to reduce the formation of the barrier cell layer. Suitable anti-inflammatory agents include, but are not limited to, for example, non-steroidal anti-inflammatory drugs (NSAIDs), such as acetaminophen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 mutein, anti-IL-6 iNOS inhibitor (e.g., L-NAME or L-NMDA), interferon, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and trametin; and corticosteroids, such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone, betamethasone dipropionate, betamethasone valerate, desonide, desoxymethasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, and dexamethasone.

[0238] In some embodiments, immunosuppressive or immunomodulatory agents can be incorporated into the analyte sensor system to directly interfere with some of the key mechanisms essential for the involvement of different cellular elements in the inflammatory response. Suitable immunosuppressive and immunomodulatory agents include, but are not limited to, antiproliferative cell cycle inhibitors (e.g., paclitaxel, cytochalasin D, infliximab), taxol, actinomycin, mitomycin, thospromote VEGF, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopep-tide, vincristine, mitomycin, statins, C MYC antisense, sirolimus (and analogs), RestenASE, 2-chloro-deoxyadenosine, PCNA ribozyme, batimastat, prolyl hydroxylase inhibitors, PPARγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catchin, glycating agents, endothelin inhibitors (e.g., ambrisentan, tesocartan, bosentan), statins (e.g., cerivastatin), E. coli heat-labile enterotoxin, and high coatings.

[0239] In some embodiments, an anti-infective agent can be incorporated into the analyte sensor system. Generally, an anti-infective agent is a substance capable of acting against an infection by inhibiting the spread of the infectious agent or by immediately killing the infectious agent, and can function, for example, to reduce the immune response without an inflammatory response at the implantation site. Anti-infective agents include, but are not limited to, anthelmintics (e.g., mebendazole), antibiotics (e.g., aminoglycosides, gentamicin, neomycin, tobramycin), antifungal antibiotics (e.g., amphotericin b, fluconazole, glycerol fluvin, itraconazole, ketoconazole, nystatin, miconazole, tolnaftate), cephalosporins (e.g., cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), β-lactam antibiotics (e.g., cefotetan, meropenem), chloramphenicol, macrolides (e.g., azithromycin, clarithromycin, erythromycin), penicillins (e.g., penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcillin), tetracyclines (e.g., doxycycline, minocycline, tetracycline), bacitracin, clindamycin, colistin methanesulfonate, polymyxin b sulfate, vancomycin, antiviral agents (e.g., acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine), quinolones (e.g., ciprofloxacin, levofloxacin), sulfonamides (e.g., sulfadiazine, sulfisoxazole), sulfones (e.g., dapsone), furazolidone, metronidazole, pentamidine, sulfanilamidum crystallinum, gatifloxacin, and sulfamethoxazole / trimethoprim.

[0240] In some embodiments, an angiogenesis agent can be incorporated into an analyte sensor system. An angiogenesis agent can generally include substances having direct or indirect angiogenesis properties. Optionally, the angiogenesis agent can additionally affect the formation of barrier cells in vivo. Indirect angiogenesis means that angiogenesis can be mediated through inflammatory or immunostimulatory pathways. Although it is not fully understood how agents that induce local angiogenesis inhibit barrier cell formation, and without being bound by theory, it is thought that some barrier cell hardening can occur indirectly from the effects of the angiogenesis agent.

[0241] The angiogenesis agent can provide a mechanism to minimize the ischemic period by promoting angiogenesis, accelerating wound healing around the membrane, or increasing angiogenesis near the tissue-device interface. Sphingosine-1-phosphate (S1P), a phospholipid with potent angiogenic activity, can be incorporated into the biointerface membrane. Monobutyrylin, a vasodilator and angiogenic lipid product of adipocytes, can also be incorporated into the biointerface membrane. In another embodiment, an antisense molecule (e.g., thrombospondin-2 antisense) that can increase angiogenesis is incorporated into the biointerface membrane.

[0242] The angiogenesis agent can provide a mechanism to promote inflammation, which is thought to accelerate angiogenesis and wound healing in vivo. In one embodiment, a heterologous carrier whose foreign nature induces an immune response, such as bovine collagen, stimulates angiogenesis and is incorporated into the biointerface membrane of some embodiments. In another embodiment, lipopolysaccharide, an immunostimulant, can be incorporated into the biointerface membrane. In another embodiment, a protein, such as a bone morphogenetic protein (BMP) that regulates bone healing in tissue, can be incorporated into the biointerface membrane.

[0243] In some embodiments, an angiogenesis agent can be incorporated into the analyte sensor system. An angiogenesis agent is a substance capable of stimulating angiogenesis, and for example, can accelerate and sustain the development of an angiogenic tissue bed at the tissue-device interface. Angiogenesis agents include, but are not limited to, basic fibroblast growth factor (bFGF) (also known as heparin-binding growth factor-II and fibroblast growth factor II), acidic fibroblast growth factor (aFGF) (also known as heparin-binding growth factor-I and fibroblast growth factor-I), vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor BB (PDEGF-BB), angiopoietin-1, transforming growth factor β (TGF-β), transforming growth factor α (TGFα), hepatocyte growth factor, tumor necrosis factor-α (TNFα), placental growth factor (PLGF), angiogenin, interleukin-8 (IL-8), hypoxia-inducible factor-I (HIF-1), angiotensin-converting enzyme (ACE) inhibitor quinaprilat, angiotropin, thrombospondin, peptide KGHK, hypoxia, lactic acid, insulin, copper sulfate, estradiol, prostaglandin, cyclooxygenase inhibitor, endothelial cell binder (e.g., decorin or vimentin), granipin, hydrogen peroxide, nicotine, and growth hormone.

[0244] In some embodiments, an inflammation promoter can be incorporated into the analyte sensor system. An inflammation promoter is generally a substance capable of stimulating an immune response in the host tissue and can accelerate or sustain the formation of a mature angiogenic tissue bed. For example, an inflammation promoter is generally a stimulant or other substance that induces chronic inflammation and a chronic granulomatous response at the site of injury. Without being bound by theory, it is believed that the formation of high tissue particles induces blood vessels that provide an adequate or abundant supply of analyte to the device-tissue interface. Inflammation promoters include, but are not limited to, heterologous carriers, lipopolysaccharides, S. aureus peptidoglycan, and proteins.

[0245] These bioactive agents can be used alone or in combination. The bioactive agents can be dispersed throughout the material of the sensor, for example, incorporated into at least a portion of the membrane system or into a device (e.g., a housing) and adapted to diffuse through the membrane.

[0246] There are various systems and methods by which bioactive agents can be incorporated into the sensor membrane. In some embodiments, the bioactive agent can be incorporated during the manufacture of the membrane system. For example, the bioactive agent can be blended before curing the membrane system or subsequent to membrane system manufacture, such as by coating, suction, solvent casting, or absorption of the bioactive agent into the membrane system. In some embodiments, the bioactive agent is incorporated into the membrane system, while in other embodiments, the bioactive agent can be administered in vivo, simultaneously with, before, or after insertion of the device, for example, by oral administration or by subcutaneous injection near the implantation site. A combination of bioactive agents incorporated into the membrane system and local or systemic bioactive agent administration can be suitable in certain embodiments.

[0247] Generally, bioactive agents can be incorporated into the membrane system or into a device and adapted to diffuse therefrom to modify the host's in vivo response to the membrane. In some embodiments, the bioactive agent can be incorporated into only a portion of the membrane system adjacent to the sensing region of the device, across the entire surface of the device excluding the sensing region, or any combination thereof, which can help control different mechanisms or stages of the in vivo response (e.g., thrombus formation). However, in some alternative embodiments, the bioactive agent can be incorporated into a device proximal to the membrane system, whereby the bioactive agent diffuses into the host's circulatory system through the membrane system.

[0248] The bioactive agent includes a carrier matrix, where the matrix includes one or more of collagen, a particulate matrix, an absorbable or non-absorbable matrix, a controlled release matrix, or a gel. In some embodiments, the carrier matrix includes a receptacle, where the bioactive agent is encapsulated within microcapsules. The carrier matrix can include a system in which the bioactive agent is physically trapped within a polymer network. In some embodiments, the bioactive agent is cross-linked to a membrane system, while in other embodiments, the bioactive agent is incorporated into the membrane system by, for example, adsorption, absorption, or suction. The bioactive agent can be deposited within or on the membrane system by, for example, coating, filling, or solvent casting. In certain embodiments, ionic and non-ionic surfactants, detergents, micelles, emulsifiers, demulsifiers, stabilizers, aqueous and oily carriers, solvents, preservatives, antioxidants, or buffering agents are used to incorporate the bioactive agent into the membrane system.

[0249] In some embodiments, the surface of the membrane system includes a binding layer found on the outermost surface of a sensor membrane to which the bioactive agent binds reversibly. In some embodiments, this binding layer includes one or more zwitterionic compounds, or precursors or derivatives thereof, which are bound to the surface-active groups of a polymer including the outermost domain of the membrane system. In some embodiments, the zwitterionic compound, or precursor or derivative thereof, includes one or more zwitterionic betaines as described above. In some embodiments, the zwitterionic compound, or precursor or derivative thereof, includes a hydrolyzable cationic ester of the zwitterionic compound as described above. In a preferred embodiment, the binding layer includes one or more hydrolyzable cationic betaine esters such as hydrolyzable cationic pCB ester.

[0250] The bioactive agent can also be incorporated into a polymer using the techniques as described above, and this polymer can be used to form a membrane system, a coating on the membrane system, a portion of the membrane system, or any portion of the sensor system.

[0251] The membrane system can be manufactured using techniques known in the art. The bioactive agent can be absorbed into the membrane system, for example, by immersing the membrane system for a period of time (e.g., from about 1 hour or less to about 1 week, or more preferably from about 4, about 8, about 12, about 16, or about 20 hours to about 1, about 2, about 3, about 4, about 5, or about 7 days).

[0252] The bioactive agent can be blended into the uncured polymer before forming the membrane system. The membrane system is then cured, whereby the bioactive agent is either cross-linked or encapsulated within the polymer forming the membrane system.

[0253] In yet another embodiment, microspheres are used to encapsulate the bioactive agent. The microspheres can be formed of biodegradable polymers, most preferably synthetic or natural polymers such as proteins and polysaccharides. As used herein, the term polymer is used to refer to both synthetic polymers and proteins. U.S. Patent No. 6,281,015 discloses some systems and methods that can be used in conjunction with the preferred embodiments. Generally, the bioactive agent can be incorporated into (1) the polymer matrix forming the microspheres, (2) the microparticles (s) surrounded by the polymer forming the microspheres, (3) the polymer core within the protein microspheres, (4) the polymer coating around the polymer microspheres, (5) the mixing with microspheres aggregated into larger forms, or (6) a combination thereof. The bioactive agent can be incorporated as a particle or by co-dissolving a factor having a polymer. The stabilizer can be incorporated by adding the stabilizer to the factor solution prior to the formation of the microspheres.

[0254] The bioactive agent can be incorporated into and coated on the hydrogel or deposited within or on the membrane system in other ways. Some hydrogels suitable for use in the preferred embodiments include cross-linked hydrophilic three-dimensional polymer networks that are highly permeable to the bioactive agent and are induced to release the bioactive agent based on a stimulus.

[0255] The bioactive agent can be incorporated into the membrane system by solvent casting, where a solution containing the dissolved bioactive agent is deposited on the surface of the membrane system and then the solvent is removed to form a coating on the membrane surface.

[0256] The bioactive agent can be formulated into a plug of material that is placed within a device such as those described in U.S. Patent No. 4,506,680 and U.S. Patent No. 5,282,844, which are hereby incorporated by reference in their entirety. In some embodiments, it is preferred to place this plug under the membrane system, such that the bioactive agent is controlled by diffusion through the membrane and provides a mechanism for the sustained release of the bioactive agent in the host.

[0257] Release of the Bioactive Agent Many variables can affect the pharmacokinetics of bioactive agent release. The bioactive agents of the disclosed embodiments can be optimized for short-term or long-term release. In some embodiments, the bioactive agents of the disclosed embodiments are designed to assist or overcome factors associated with the short-term effects of sensor insertion (e.g., acute inflammation or embolism). In some embodiments, the bioactive agent is designed to assist or overcome factors associated with long-term effects, such as chronic inflammation or the construction of fibrous tissue or plaque material. In some embodiments, the bioactive agent combines short-term and long-term release to take advantage of both benefits.

[0258] As used herein, “controlled,” “sustained,” or “long-term” release of a factor can be continuous or intermittent, linear or non-linear. This can be achieved using the selection of one or more polymer compositions, drug loading, excipients or degradation enhancers, or other modifications, administered alone, in combination, or sequentially to achieve the desired effect.

[0259] The short-term release of the bioactive agent in the disclosed embodiments generally refers to release over a period of about a few minutes or hours to about 2, about 3, about 4, about 5, about 6, or about 7 days or more.

[0260] Loading of the bioactive agent The amount of loading of the bioactive agent into the membrane system can depend on several factors. For example, the dosage and duration of the bioactive agent can vary depending on the intended use of the membrane system, such as the intended device usage period, differences in the effective dosage of the bioactive agent among patients, the location and method of loading the bioactive agent, and the release rate associated with the bioactive agent and optionally their carrier matrix. Therefore, one of ordinary skill in the art would understand the variability in the level of loading of the bioactive agent for the reasons described above.

[0261] In some embodiments where the bioactive agent is incorporated into the membrane system without a carrier matrix, the preferred level of loading of the bioactive agent into the membrane system can vary depending on the nature of the bioactive agent. The loading level of the bioactive agent is preferably high enough for a biological effect (e.g., embolism prevention) to be observed. Above this threshold, the bioactive agent can be loaded into the membrane system such that it assimilates up to 100% of the solid portion, coats all accessible surfaces of the membrane, or fills up to 100% of the accessible void space. Typically, the loading level is (based on the weight of the bioactive agent(s), membrane system, and other substances present) from about 1 ppm or less to about 1000 ppm or more, preferably from about 2, about 3, about 4, or about 5 ppm to a maximum of about 10, about 25, about 50, about 75, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, or about 900 ppm. In certain embodiments, the loading level can be from about 1 wt% or less to a maximum of about 50 wt% or more, preferably from about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, or about 20 wt% to a maximum of about 25, about 30, about 35, about 40, or about 45 wt%.

[0262] When a bioactive agent is incorporated into a membrane system together with a carrier matrix such as a gel, the gel concentration can be optimized and is, for example, loaded with one or more test loads of the bioactive agent. Generally, the gel contains from about 0.1% or less to about 50% or more by weight of the bioactive agent(s), preferably from about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9% by weight to about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, or about 45% or more by weight of the bioactive agent(s), more preferably from about 1, about 2, or about 3% by weight to about 4 or about 5% by weight of the bioactive agent(s). Substances that are not bioactive can also be incorporated into the matrix.

[0263] Referring now to microencapsulated bioactive agents, release of the drug from these polymeric systems generally occurs by two different mechanisms. The bioactive agent can be released by diffusion through aqueous filled channels created in the dosage form by dissolution of the drug or by voids created by removal of the polymer solvent or pore former during the original microencapsulation. Alternatively, release can be enhanced due to degradation of the encapsulating polymer. Over time, the polymer erodes, creating more porosity and microstructure within the device. This creates an additional pathway for release of the bioactive agent.

[0264] In some embodiments, the sensor is designed to be bio-inert, for example, by use of a bio-inert material. The bio-inert material does not substantially elicit any response from the host. As a result, cells can survive adjacent to the material but do not form a bond with it. Bio-inert materials include, but are not limited to, alumina, zirconia, titanium oxide, or other bio-inert materials commonly used in the "catheter / catheterization" art. Without being bound by theory, it is believed that inclusion of the bio-inert material within or on the sensor can reduce attachment of blood cells or proteins to the sensor, embolization, or other host responses to the sensor.

Example

[0265] Example 1: Biointerface Polymer and Property Evaluation Various biointerface polymers were prepared using different amounts of hard segment, PEG, and sulfobetaine. The hard segment (HS) was a polyurethane or polyurea prepared from a diisocyanate reacted with a diol or diamine chain extender having less than 12 carbon units. Specific formulations are shown in Table 1.

Table 1

[0266] Example 2: Property Evaluation Analysis Sensors were constructed as described in the section entitled "Sensor System". The in vitro response time was tested and compared with sensors without a biointerface layer. It was found that the sensors with a biointerface layer had the same T95 response time as the sensors without a biointerface layer, indicating that the biointerface layer did not delay the response time of the glucose sensor (Figure 5).

[0267] The in vivo response time was also tested in pigs over 15 days. Specific continuous sensors with SBL-3 and crosslinked SBL-9 biointerface layers were compared with sensors without a biointerface layer. Similarly, no difference in response time was found between sensors with and without a biointerface layer (Figure 6). This showed that the biointerface domain also did not affect the glucose sensor response time.

[0268] The calibration performance was compared between sensors without a biointerface layer and sensors dip-coated with 5 wt% SBL-8. The results are shown in Figure 7. In this calibration check test, the following characteristics were measured. i. Glucose slope (pA / mg / dL) - Ordinary least squares linear regression analysis of the electrical response of the sensor when placed in a buffer solution with increasing glucose concentration. Also referred to as glucose sensitivity. ii. Baseline equivalent (mg / dL) - mg / dL equivalent of non-glucose related signals iii. MARD (%) - Mean absolute relative difference, a measure of change away from the ideal line iv. Hypoxic response - Defined as the rate of change of the electrical response under reduced oxygen conditions compared to the signal obtained under atmospheric conditions (i.e., 0.25 ± 0.05 mg O2 / L). Also referred to as oxygen performance. v. Acetaminophen bias - mg / dL equivalent signal from 2 mg / dL concentration of acetaminophen, also referred to as glucose equivalent

[0269] Mechanical strength was also visually inspected by observing sensors having BL-8, blends of SBL-8 and SBL-10, and SBL-10. The Bl-10 layer has various inclusions, which suggests that the mechanical strength decreases as the hydrophilicity of the layer increases (Figure 8). Hydrophilicity can be adjusted by blending the biointerface layer with different hydrophilic substances (e.g., blending a more hydrophilic polymer with a less hydrophilic polymer to achieve the desired hydrophilicity and strength).

[0270] The hydrophilicity of various biointerface layers was tested by measuring the weight percentage of water they absorb. Cross-linked SBL-10 (XSBL-10) having sulfobetaine in its backbone was the most hydrophilic polymer among those tested (Figure 9). These data show that the disclosed biointerface polymers are extremely hydrophilic, much more so than current sensors that do not have such layers. Furthermore, cross-linking can be used to affect the hydrophilicity of the polymer.

[0271] The effect of crosslinking on the water absorption rate and tensile strength was also tested. Specifically, those crosslinked with sulfobetaine (XSBL-8) and those not crosslinked (SBL-8) in the backbone were immersed over time and weighed. The non-crosslinked polymer absorbed more water over time. The crosslinked polymer absorbed less water and reached equilibrium faster. The crosslinked polymer also had significantly better strength (Figures 10A and 10B).

[0272] Hydrophobicity was also measured by a contact angle experiment. Specifically, the advancing contact angle was measured using an Attension Sigma tensiometer 701 (manufactured by Biolin Scientific) on a sensor wire coated with different polymer coatings. The sensor was immersed in deionized water at 25°C, and repeatedly retracted and advanced to calculate the average value of the advancing contact angle. The more hydrophilic and wettable the surface of the coating, the lower the value. The baseline value for the sensor without the biointerface layer was 60°. The contact angles of the tested biointerface layers ranged from about 50° to about 90° (Figure 18).

[0273] The curing rates of various crosslinking agents were tested, and the data are shown in Figure 11. The curing rate is measured by the time until the conversion of functional groups such as isocyanate groups reaches 50%. In practice, a fast curing rate helps improve conversion and accelerate the process, but may sacrifice the pot life. It is desirable to select a curing chemistry and crosslinking agent that produce a balanced pot life and curing rate. This can be achieved by screening different types of crosslinking agents and selecting those that impart optimal properties.

[0274] SBL-3, CBL-8, and the film of the resistive layer (i.e., the film in which neither the biointerface layer nor the resistive layer is formed on the outermost layer) were prepared by flowing a polymer solution onto a polycarbonate sheet and drawing a bar coater to form a flat film. This process was repeated until the dried film reached the desired thickness (3 - 4 thou). Next, the film was cut into a dog-bone shape using a dog-bone punching die and a hand press. The dog-bone shaped film was subjected to a tensile test using Instron 3345 to generate a stress-strain curve. Five dog-bones were measured for each sample, and the data was represented using the average with the standard deviation as error bars. The maximum tensile strength, maximum load, and Young's modulus at 100% elongation were calculated from these curves. The maximum tensile strength of SBL-3 is higher than that of CBL-8 and the resistive layer film (Figure 28). The tensile strain at the maximum load for SBL-3 is higher than that of CBL-8 and the resistive layer film (Figure 29). The tensile strain at the maximum load for CBL-8 is significantly lower than the tensile strain of SBL-3 (400% vs. 600%). The Young's modulus at 100% elongation follows a similar trend to the maximum tensile strength, with SBL-3 having a significantly higher Young's modulus compared to both CBL-8 and the resistive layer control (Figure 30).

[0275] Regarding the bulk mechanical properties, SBL-3 has a higher maximum tensile strength, tensile strain at the break point, and Young's modulus than CBL-8. Regarding the solvent pair used in polymer synthesis, SBL-3 prepared using THF / EtOH has stronger mechanical properties than SBL-3 prepared using the THF / IPA solvent pair. In addition, dry SBL-3 with a high solvent viscosity (over 90 cps in THF / EtOH with a solid content of 10.5 wt%) showed improved mechanical properties of the film compared to the resistive layer control.

[0276] Example 3: Antifouling Properties The mechanism of protein adsorption and antifouling properties of the biointerface layer was investigated. The use of zwitterions embedded within the polymer and physically encapsulated rather than covalently bound is thought to act by these hydrophilic species migrating to the interface between the polymer and the environment. The biointerface layer made from SBL-10 was tested by X-ray photoelectron spectroscopy (XPS) when in the dry state and after immersion. It was found that the atomic concentration of sulfur on the surface of the sensor tip coated with SBL-10 did not increase before immersion (dry state, 0.3%) and after immersion (0.2%), indicating that the zwitterion segments in the polymer chains did not migrate to the surface (Figure 13). Thus, although not bound by theory, the biointerface layer is thought to create a loosely bound water layer on the surface, which prevents the adsorption of proteins and cells (Figure 12).

[0277] As another theory regarding the antifouling properties of the disclosed biointerface layer, there is the swelling ability of the biointerface layer. The ability of the disclosed biointerface layer to swell by 50 - 400% is shown in Figure 16. Although not bound by theory, the swelling ability at the implantation site is thought to help exclude cells, proteins, and cytokines from sites that could contribute to contamination by filling voids.

[0278] The amount of protein adsorption was determined for a continuous glucose sensor without a biointerface layer, a continuous glucose sensor having a polyurethane urea with betaine in the polymer main chain, and a continuous glucose sensor having a polyurethane urea with betaine only at the ends of the polymer chains. A fluorescent conjugate construct of bovine serum albumin and human fibrinogen was incubated with these sensor configurations for 1 hour. Next, these sensors were washed in DPBS and imaged as a z-stack on a laser scanning confocal microscope. A maximum intensity projection was made from this image stack, and the fluorescence intensity of the protein adsorbed on the outer membrane over the sensor active electrode region was measured, and the results (a.u.) are shown in FIG. 19. Similar tests were performed using polymers SBL-1, SBL-3, and SBL-10 and compared with a silicone polycarbonate urethane layer (RL-1) and a silicone-free polycarbonate urethane layer (RL-2) (see FIG. 20). The data indicate that having a betaine group within the polymer chain results in significantly less protein adsorption than when the betaine group is at the ends of the polymer chains.

[0279] The protein results were confirmed using an in vitro on-sensor assay using the micro BCA extraction method. The sensors were placed in human plasma for 1 hour. The protein adsorbed on the surface was extracted with a detergent solution and tested for total protein using micro BCA (bicinchoninic acid assay). Again, it was found that the polymers SBL-3 and SBL-10 resulted in a significant reduction in total protein adsorption compared to sensors without a biointerface layer (FIG. 21).

[0280] Sensors without a biointerface layer (RL-1 and RL-2), sensors without betaine or PEG in the backbone (RL-7), cross-linked versions of biointerface layers SBL-3, SBL-10, SBL-8, and SBL-9 (XSBL-10, XSL-8, and XSL-9, respectively), and sensors having cross-linked and non-cross-linked versions of SBL-3 in which sulfobetaine is replaced by carboxybetaine (XCBL-3 and CBL-3, respectively) for normalized protein adsorption of BSA or fibrinogen. A significant reduction in protein adsorption by the biointerface layer is evident (Figure 22). Z-stack images of a particular polymer were taken in the skived regions of these sensors (Figure 31). Both SBL-3 and CBL-8 perform well, and protein adsorption (shown in green) to its surface is minimal compared to both RL-7 (non-betaine control) and the resistive layer. Figure 32 provides quantification results based on the images in Figure 31.

[0281] Evaluated on spin-coated glass disks, both carboxybetaine-type coatings and sulfobetaine-type coatings dip-coated onto the sensors had significantly lower protein adsorption than both non-betaine controls and non-coated RL controls.

[0282] The thickness of the fibrous capsule was also measured. The fibrous capsule is a step in the biomaterial-related inflammatory response. It was found that the thickness of the fibrous capsule was approximately 26% smaller when using the biointerface polymer (SBL-3) compared to the case without a biointerface layer (Figure 23).

[0283] The stability of the biointerface layer 14 days post-implantation in vivo was visually confirmed. The pre-implantation layer was comparable to SBL-3 (middle row) and SBL-10 (bottom row). SBL-10 showed more severe degradation than SBL-3 (Figure 24).

[0284] The raw data from the continuous glucose sensors were plotted on the 2nd and 14th days. It was found that when there was no biointerface layer, the difference between sensors on the 14th day was greater than that of the sensors with a biointerface layer. This data suggests that when not using the biointerface layer, biofouling is a more important factor, leading to a greater dispersion of the measured values (Figure 25).

[0285] Example 4: Noise Analysis A walkable pig model was developed for in vivo evaluation of sensor performance. Hairless Yucatan pigs were used, and the sensors and the wearable pods were adhered to their skin similar to that of humans. Two 10 French external vascular access ports that enabled injection and withdrawal of liquids and blood from the central venous circulation were placed in the descending right / left jugular vein. The animals were allowed to recover for 5 - 7 days before the test. The pigs were induced with 5% isoflurane using a Surgivet anesthetic for 5 - 10 minutes. The pigs were maintained with 2.5% - 4% isoflurane during the sensor insertion period. A pulse oximeter was used to track the telemetry and pO2 of the pigs. The pigs' skin was cleaned using soap and surgical scrub of chlorohexidine. Next, after cleaning the pigs' skin with alcohol gauze, it was prepared with skin tac and air-dried. The sensor was inserted, and the active transmitter in log mode was snap-in. An animal patch overlay was used to fix the patch to the skin for long-term wear. Tegaderm (4 inches wide) was used to prevent the edges of the patch from curling and to waterproof all the sensors.

[0286] A bag of 25% glucose was prepared from a bag of 0.9% normal saline (1000 mL) mixed with 50% glucose. Blood was sampled from the vascular access port to obtain baseline measurements. The bag of 25% glucose was attached for injection into the vascular access port and started at a base drip rate of 1 - 1.5 drops per second. Measurements were obtained every 10 minutes during the exercise period. Data was downloaded from the transmitter and processed for time tag, sensitivity, noise, EOL, and MARD in MATLAB. The differences between groups regarding improvement of time lag, gradient stability, and MARD calculation were minimal. Therefore, the biointerface layer does not affect calibration checks or constant drift characteristics. Furthermore, SBL - 3 exhibits the lowest level of noise compared to the CBL - 8 group and the SBL - 3 group (Figure 27). There is no obvious loss in performance between groups regarding time lag, gradient, or MARD.

[0287] Example 5: Fluorescent Incorporation Polyurethane urea labeled with a fluorescent dye (FPUU) was synthesized by a two - step polycondensation reaction using erythrosine B dye (0.21 wt%). FPUU was prepared in a solvent mixture of ethyl acetate and isopropanol and could form a homogeneous and transparent red solution. The polymer could precipitate in hexane. The polymer precipitate was strongly bright red in color, while the supernatant hexane was colorless and transparent, indicating that all the dyes were covalently incorporated into the polymer. After immersing the polymer in water for one week, there was no leaching of free dye.

[0288] Example 6: Synthesis of SBL - 8 The biointerface polymer is a polyurethane urea synthesized by a two - step polycondensation reaction. In the first step, a homogeneous polyurethane prepolymer with isocyanate - terminal groups on both prepolymer chains was prepared. In the second step, small - molecule diamines were used as chain extenders. These diamines reacted with the prepolymer in a dilute solution to obtain a well - defined polyurethane urea with a high molecular weight.

[0289] As a representative example, prepolymers were prepared by adding isophorone diisocyanate (IPDI), polyethylene oxide diol (Ymer™ N120), polycarbonate diol (Ravecarb 107 polycarbonate diol), and sulfobetaine prepolymer to a dry 200 mL reaction flask equipped with a nitrogen injection tube and a mechanical stirrer at room temperature. The reaction solution was mechanically stirred (200 rpm) under nitrogen for 30 minutes and heated to 65 °C until all reactants were dissolved. 400 ppm of a catalyst was added to the reaction solution and held at 65 °C for 1 hour. The reaction temperature was raised to 85 °C and held for 3 hours until no bubbles were observed in the reaction mixture. The reaction mixture was further stirred at 100 °C for 2 hours to complete the formation of the prepolymer. The viscous prepolymer was cooled to 50 °C and dissolved in ethyl acetate to form a clear solution.

[0290] In the case of the chain extension step, isophorone diamine was used as the chain extender, added to a dry 700 mL reaction flask equipped with a mechanical stirrer, and diluted with an ethyl acetate / isopropanol solvent mixture. The polyurethane prepolymer solution was added dropwise to the chain extender solution at room temperature with vigorous stirring (600 rpm). During the addition of the chain extender solution, a specific amount of the solvent mixture (ethyl acetate / isopropanol) was added to the reaction mixture to maintain the reaction mixture at a suitable viscosity. After all of the prepolymer solution was added to the flask, the reaction mixture was continuously stirred at room temperature for an additional 5 hours to complete the chain extension. Similar procedures can be continued to provide other biointerface polymers, as detailed herein.

[0291] Methods and devices suitable for use in conjunction with aspects of the preferred embodiments are described in U.S. Patent No. 4,757,022, U.S. Patent No. 4,994,167, U.S. Patent No. 6,001,067, U.S. Patent No. 6,558,321, U.S. Patent No. 6,702,857, U.S. Patent No. 6,741,877, U.S. Patent No. 6,862,465, U.S. Patent No. 6,931,327, U.S. Patent No. 7,074,307, U.S. Patent No. 7,081,195, U.S. Patent No. 7,108,778, U.S. Patent No. 7,110,803, U.S. Patent No. 7,134,999, U.S. Patent No. 7,136,689, U.S. Patent No. 7,192,450, U.S. Patent No. 7,226,978, U.S. Patent No. 7,276,029, U.S. Patent No. 7,310,544, U.S. Patent No. 7,364,592, U.S. Patent No. 7,366,556, U.S. Patent No. 7,379,765, U.S. Patent No. 7,424,318, U.S. Patent No. 7,460,898, U.S. Patent No. 7,467,003, U.S. Patent No. 7,471,972, U.S. Patent No. 7,494,465, U.S. Patent No. 7,497,827, U.S. Patent No. 7,519,408, U.S. Patent No. 7,583,990, U.S. Patent No. 7,591,801, U.S. Patent No. 7,599,726, U.S. Patent No. 7,613,491, U.S. Patent No. 7,615,007, U.S. Patent No. 7,632,228, U.S. Patent No. 7,637,868, U.S. Patent No. 7,640,048, U.S. Patent No. 7,651,596, U.S. Patent No. 7,654,956, U.S. Patent No. 7,657,297, U.S. Patent No. 7,711,402, U.S. Patent No. 7,713,574, U.S. Patent No. 7,715,893, U.S. Patent No. 7,761,130, U.S. Patent No. 7,771,352, U.S. Patent No. 7,774,145, U.S. Patent No. 7,775,975, U.S. Patent No. 7,778,680, U.S. Patent No. 7,783,333, U.S. Patent No. 7,792,562, U.S. Patent No. 7,797,028, U.S. Patent No. 7,826,981, U.S. Patent No. 7,828,728, U.S. Patent No. 7,831,287, U.S. Patent No. 7,835,777, U.S. Patent No. 7,857,760, U.S. Patent No. 7,860,545, U.S. Patent No. 7,875,293, U.S. Patent No. 7,881,763, U.S. Patent No. 7,885,697, U.S. Patent No. 7,896,809, U.S. Patent No. 7,U.S. Patent No. 899,511, U.S. Patent No. 7,901,354, U.S. Patent No. 7,905,833, U.S. Patent No. 7,914,450, U.S. Patent No. 7,917,186, U.S. Patent No. 7,920,906, U.S. Patent No. 7,925,321, U.S. Patent No. 7,927,274, U.S. Patent No. 7,933,639, U.S. Patent No. 7,935,057, U.S. Patent No. 7,946,984, U.S. Patent No. 7,949,381, U.S. Patent No. 7,955,261, U.S. Patent No. 7,959,569, U.S. Patent No. 7,970,448, U.S. Patent No. 7,974,672, U.S. Patent No. 7,976,492, U.S. Patent No. 7,979,104, U.S. Patent No. 7,986,986, U.S. Patent No. 7,998,071, U.S. Patent No. 8,000,901, U.S. Patent No. 8,005,524, U.S. Patent No. 8,005,525, U.S. Patent No. 8,010,174, U.S. Patent No. 8,027,708, U.S. Patent No. 8,050,731, U.S. Patent No. 8,052,601, U.S. Patent No. 8,053,018, U.S. Patent No. 8,060,173, U.S. Patent No. 8,060,174, U.S. Patent No. 8,064,977, U.S. Patent No. 8,073,519, U.S. Patent No. 8,073,520, U.S. Patent No. 8,118,877, U.S. Patent No. 8,128,562, U.S. Patent No. 8,133,178, U.S. Patent No. 8,150,488, U.S. Patent No. 8,155,723, U.S. Patent No. 8,160,669, U.S. Patent No. 8,160,671, U.S. Patent No. 8,167,801, U.S. Patent No. 8,170,803, U.S. Patent No. 8,195,265, U.S. Patent No. 8,206,297, U.S. Patent No. 8,216,139, U.S. Patent No. 8,229,534, U.S. Patent No. 8,229,535, U.S. Patent No. 8,229,536, U.S. Patent No. 8,231,531, U.S. Patent No. 8,233,958, U.S. Patent No. 8,233,959, U.S. Patent No. 8,249,684, U.S. Patent No. 8,251,906, U.S. Patent No. 8,255,030, U.S. Patent No. 8,255,032, U.S. Patent No. 8,255,033, U.S. Patent No. 8,257,259, U.S. Patent No. 8,260,393, U.S. Patent No. 8,265,725, U.S. Patent No. 8,275,437, U.S. Patent No. 8,275,438, U.S. Patent No. 8,277,713, U.S. Patent No. 8,280,No. 475, U.S. Patent No. 8,282,549, U.S. Patent No. 8,282,550, U.S. Patent No. 8,285,354, U.S. Patent No. 8,287,453, U.S. Patent No. 8,290,559, U.S. Patent No. 8,290,560, U.S. Patent No. 8,290,561, U.S. Patent No. 8,290,562, U.S. Patent No. 8,292,810, U.S. Patent No. 8,298,142, U.S. Patent No. 8,311,749, U.S. Patent No. 8,313,434, U.S. Patent No. 8,321,149, U.S. Patent No. 8,332,008, U.S. Patent No. 8,346,338, U.S. Patent No. 8,364,229, U.S. Patent No. 8,369,919, U.S. Patent No. 8,374,667, U.S. Patent No. 8,386,004, and U.S. Patent No. 8,394,021.,

[0292] Methods and devices suitable for use in conjunction with aspects of the preferred embodiments are described in U.S. Patent Publication Nos. 2003-0032874-A1, 2005-0176136-A1, 2005-0182451-A1, 2005-0245799-A1, 2005-0033132-A1, 2005-0051427-A1, 2005-0056552-A1, 2005-0090607-A1, 2006-0015020-A1, 2006-0016700-A1, 2006-0020188-A1, 2006-0020190-A1, 2006-0020191-A1, 2006-0020192-A1, 2006-0036140-A1, 2006-0036143-A1, 2006-0040402-A1, 2006-0068208-A1, 2006-0142651-A1, 2006-0155180-A1, 2006-0198864-A1, 2006-0200020-A1, 2006-0200022-A1, 2006-0200970-A1, 2006-0204536-A1, 2006-0224108-A1, 2006-0235285-A1, 2006-0249381-A1, 2006-0252027-A1, 2006-0253012-A1, 2006-0257995-A1, 2006-0258761-A1, 2006-0263763-A1, 2006-0270922-A1, 2006-0270923-A1, 2007-0027370-A1, 2007-0032706-A1, 2007-0032718-A1, 2007-0045902-A1, 2007-0059196-A1,US Patent Publication No. 2007-0066873-A1, US Patent Publication No. 2007-0173709-A1, US Patent Publication No. 2007-0173710-A1, US Patent Publication No. 2007-0208245-A1, US 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[0293] Methods and devices suitable for use in conjunction with aspects of the preferred embodiments are disclosed in U.S. Application No. 09 / 447,227, entitled "DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS", filed on November 22, 1999, and U.S. Application No. 13 / 461,625, entitled "DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR", filed on May 1, 2012.

[0294] For ease of explanation and illustration, in some examples, the detailed description describes exemplary systems and methods with respect to a continuous glucose monitoring environment, but the scope of the present invention is not limited to that particular environment, and one of ordinary skill in the art will understand that the systems and methods described herein can be implemented in various forms. Therefore, any structural and / or functional details disclosed herein should not be construed as limiting the systems and methods, but rather as attributes of representative embodiments and / or arrangements that may be advantageous in other settings to teach one or more ways of implementing the systems and methods to those skilled in the art.

[0295] For example, without limitation, the monitoring systems and methods described may include sensors that measure the concentration of one or more analytes (e.g., glucose, lactate, potassium, pH, cholesterol, isoprene, and / or hemoglobin) in and / or related to a host and / or another individual, as well as / or other blood or body fluid components.

[0296] By way of example and without limitation, embodiments of the monitoring systems and methods described herein may include fingerstick blood sampling, blood analyte test strips, non-invasive sensors, wearable monitors (e.g., smart bracelets, smartwatches, smart rings, smart necklaces or pendants, workout monitors, fitness monitors, health and / or medical monitors, clip-on monitors, etc.), adhesive sensors, smart textiles and / or garment-integrated sensors, shoe inserts and / or insoles containing sensors, transdermal (i.e., transdermal, transcutaneous) sensors, and / or swallowable, inhalable, or implantable sensors.

[0297] In some embodiments, without limitation, the monitoring system and method may include, instead of or in addition to the sensors described herein, an inertial measurement unit including an accelerometer, a gyroscope, a magnetometer, and / or a barometer; a motion, altitude, position, and / or location sensor; a biometric sensor; an optical sensor including, for example, an optical heart monitor, a photoplethysmogram (PPG) / pulse oximeter, a fluorescence monitor, and a camera; a wearable electrode; an electrocardiogram (EKG or ECG), electroencephalogram (EEG), and / or electromyogram (EMG) sensor; a chemical sensor; a flexible sensor for measuring, for example, elongation, movement, pressure, weight, or impact; a galvanometric sensor, a capacitive sensor, an electromagnetic field sensor, a temperature / thermal sensor, a microphone, a vibration sensor, an ultrasonic sensor, a piezoelectric / piezoresistive sensor, and / or other sensors such as a transducer for measuring information about the host and / or another individual or regarding the same.

[0298] Although the present disclosure has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. The present disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the present disclosure, and the appended claims.

[0299] All references listed herein are hereby incorporated by reference in their entirety. To the extent that the incorporated publications and patents or patent applications conflict with the disclosure contained herein, the present disclosure is intended to supersede and / or take precedence over any such conflicting material.

[0300] Unless otherwise defined, all terms (including technical and scientific terms) shall have the meaning as is shown to those of ordinary skill in the art, and shall not be limited to special or customized meanings unless explicitly defined as such in this specification. When using a specific term to describe a particular feature or aspect of the present disclosure, it should be noted that it should not be construed as implying that the term is redefined in this specification if the use of the term is restricted to include any specific characteristics of the feature or aspect of the present disclosure to which the term relates. In particular, in the appended claims, the terms and phrases used in this application and their variants shall be construed as non-limiting as opposed to limiting, unless otherwise explicitly stated. As an example of the above, the term "comprising" should be construed to mean "including without limitation", "including but not limited to", etc., and the term "comprising", when used in this specification, is synonymous with "including", "containing", or "characterized by", and is inclusive or non-limiting and does not exclude additional unenumerated elements or method steps. The term "having" should be construed to mean "having at least", and the term "including" should be construed to mean "including but not limited to". The term "example" is used to provide an illustrative example rather than an inclusive or limiting list of matters under consideration. Adjectives such as "known", "ordinary", "standard", and terms of similar meaning should not be construed to limit the matters described to those available during a given period or at a given point in time, but rather should be construed to include known, ordinary, or standard techniques that may be available now or at any time in the future or may be known. The use of terms such as "preferably", "preferred", "desired", or "desirable", and terms of similar meaning should not be understood to imply that a particular feature is critical, essential, or even important to the structure or function of the invention. Rather, it is merely intended to emphasize alternative or additional features that may or may not be utilized in a particular embodiment of the invention.Similarly, a group of items connected by the conjunction "and" should not be construed as requiring each of those items to be present within the group; rather, unless otherwise specified, it should be construed as "and / or." Similarly, a group of items connected by the conjunction "or" should not be construed as requiring mutual exclusivity among the group; rather, unless otherwise specified, it should be construed as "and / or."

[0301] When a range of values is provided, it is understood that the upper and lower limits thereof, as well as each intervening value therebetween within the range, are included in the embodiments.

[0302] Regarding substantially any plural and / or singular terms herein, one of ordinary skill in the art can convert from plural to singular and / or from singular to plural as appropriate for the context and / or application. Various singular / plural substitutions may be explicitly recited herein for clarity. The indefinite articles "a" or "an" do not exclude a plural. A single processor or other unit may accomplish the functions of several items recited in the claims. The mere fact that certain criteria are recited in mutually different independent claims does not indicate that combinations of these criteria cannot be used to advantage. Reference signs in the claims should not be construed as limiting the scope.

[0303] If a particular number is intended in the description of an introduced claim, such intention will be understood by those skilled in the art to be clearly described in that claim, and in the absence of such a description, it will be further understood that no such intention exists. For example, for purposes of illustration, the following appended claims may include the use of introductory phrases "at least one" and "one or more" to introduce the description of the claim. However, the use of such phrases should not be construed to imply that the introduction of a claim description by an indefinite article such as "one or more" or "at least one" and "a" or "an" in the same claim limits a particular claim that includes such introduced claim description to embodiments that include only one such description (e.g., "a" and / or "an" should typically be construed to mean "at least one" or "one or more"), and this also applies to the use of definite articles used to introduce the description of the claim. In addition, even when a particular number of an introduced claim description is explicitly stated, those skilled in the art will recognize that such a description should typically be construed to mean at least the stated number (e.g., a mere description of "two descriptions" without other modifying phrases typically means at least two descriptions, or two or more descriptions). Further, when conventional expressions similar to "at least one of A, B, or C" are used, generally, such a construction is intended in the sense that those skilled in the art will understand such conventional expression (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B, A and C, B and C, and / or A, B, and C, etc.). When conventional expressions similar to "at least one of A, B, or C" are used, generally, such a construction is intended in the sense that those skilled in the art will understand such conventional expression (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B, A and C, B and C, and / or A, B, and C, etc.).It should be further understood by those skilled in the art that substantially any disjunctive and / or conjunctive term or phrase indicating two or more alternative terms is intended to encompass one of the terms, any of the terms, or both terms, whether in the description, claims, or drawings. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B".

[0304] All numbers representing quantities of ingredients, reaction conditions, etc. used in this specification are to be understood as being modified in all cases by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification are approximations that may vary depending upon the desired properties to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents in the scope of any claim of any application claiming priority to this application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding methods.

[0305] Furthermore, while the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain changes and modifications can be made. Accordingly, the description and examples are not to be construed as limiting the scope of the invention to the particular embodiments and examples described herein, but rather should be construed to include all modifications and alternatives falling within the true scope and spirit of the invention.

Claims

1. A device for measuring the concentration of an analyte, the device comprising: a sensor configured to generate a signal related to the concentration of the analyte; and a sensing membrane located on the sensor, the sensing membrane including a biointerface layer, the biointerface layer including a biointerface polymer including one or more internal zwitterion repeating units and a pharmaceutical or bioactive agent, the one or more internal zwitterion repeating units being present within the polymer backbone.

2. The device according to claim 1, wherein the biointerface polymer includes a crosslinked polyurethane or polyurea segment.

3. The device according to claim 1 or 2, wherein the one or more internal zwitterion repeating units include a betaine compound or a derivative thereof.

4. The device according to any one of claims 1 to 3, wherein the one or more internal zwitterion repeating units comprise 10 to 55% by weight of the biointerface polymer.

5. The device according to any one of claims 1 to 4, wherein the one or more internal zwitterion repeating units include at least one moiety selected from the group consisting of carboxybetaine, sulfobetaine, phosphobetaine, and derivatives thereof.

6. The one or more internal zwitterion repeating units are derived from monomers selected from the group consisting of: 【Chemical 1】 wherein Z is a branched or straight-chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, and R １ is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R ２ , R ３ , and R ４ are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and one or more of R １ , R ２ , R ３ , R ４ , and Z are substituted with a polymerizable group, the device according to any one of claims 1 to 5.

7. The one or more internal zwitterion repeating units are derived from monomers selected from the group consisting of: [Chemical 2] wherein Z is a branched or straight-chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, and R １ is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R ２ and R ３ are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and one or more of R １ , R ２ , R ３ , and Z are substituted with a polymerizable group, the device according to any one of claims 1 to 5.

8. The one or more internal zwitterion repeating units are derived from monomers selected from the group consisting of: 【Chemical Formula 3】 wherein Z is a branched or straight-chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, and R １ is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R ２ and R ３ are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and one or more of R １ , R ２ , R ３ and Z are substituted with a polymerizable group, the device according to any one of claims 1 to 5.

9. The device according to any one of claims 6 to 8, wherein the polymerizing group is selected from alkenes, alkynes, epoxides, lactones, amines, hydroxyls, isocyanates, carboxylic acids, anhydrides, silanes, halides, aldehydes, and carbodiimides.

10. The device according to any one of claims 1 to 9, wherein the biointerface polymer further includes at least one segment selected from the group consisting of epoxides, polyolefins, polysiloxanes, polyamides, polystyrenes, polyacrylates, polyethers, polyesters, and polycarbonates.

11. The device according to any one of claims 1 to 10, wherein the biointerface polymer has a molecular weight of about 10 kDa to about 500,000 kDa.

12. The device according to any one of claims 1 to 11, wherein the biointerface polymer has a polydispersity index of about 1.4 to about 3.

5.

13. The device according to any one of claims 1 to 12, wherein the biointerface layer has a contact angle of about 20° to about 90°.

14. The device according to any one of claims 1 to 13, wherein the biointerface layer further comprises one or more zwitterions selected from the group consisting of cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, caprylyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly(carboxybetaine), poly(sulfobetaine), and derivatives thereof.

15. The device according to any one of claims 1 to 14, wherein the pharmaceutical or bioactive agent comprises an anti-inflammatory agent or an antifouling agent.

16. The device according to any one of claims 1 to 15, wherein the pharmaceutical is dexamethasone or sodium dexamethasone phosphate.

17. The device according to any one of claims 1 to 16, wherein the sensing membrane comprises a fluorescent moiety incorporated into the biointerface domain.

18. The device according to any one of claims 1 to 17, wherein the biointerface polymer comprises a first hydrophilic component and a second hydrophilic component.

19. A device for measuring an analyte concentration, the device comprising: a sensor configured to generate a signal related to the concentration of the analyte; and a sensing membrane located on the sensor, the sensing membrane comprising a biointerface layer, the biointerface layer comprising a betaine compound or a precursor thereof, and dexamethasone or sodium dexamethasone phosphate, wherein the betaine compound or a precursor thereof is present within the polymer backbone of a polymer included in the biointerface layer.

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