Multi-polymer controlled drug releasing devices and methods

Abstract

The present disclosure relates generally to bioactive releasing membranes utilized with implantable devices, such as devices for the detection of analyte concentrations in a biological sample. More particularly, the disclosure relates to novel bioactive releasing membranes, to devices and implantable devices including these membranes, methods for forming the bioactive releasing membranes on or around the implantable devices, and to methods for monitoring analyte levels in a biological fluid sample using an implantable analyte detection device.

Description

Attorney Docket No.: 0935-PCT01-0240MULTI-POLYMER CONTROLLED DRUG RELEASING DEVICES AND METHODSTechnical Field

[0001] The present disclosure relates generally to innplantable devices with drug releasing or eluting layers or membranes, such as devices for the detection of analyte concentrations in a biological sample. More particularly, the disclosure relates to wound exudate diffusion adjustment layers adjacent such drug releasing membranes, to devices and implantable devices including these layers, compositions and methods for forming the diffusion adjustment layers, and methods of improving and / or extending sensor life while monitoring one or more analyte levels in a biological fluid sample using an implantable analyte detection device.BACKGROUND

[0002] One of the most heavily investigated analyte sensing devices is the implantable glucose device for detecting glucose levels in hosts with diabetes. Despite the increasing number of individuals diagnosed with diabetes and recent advances in the field of implantable glucose monitoring devices, currently used devices are unable to provide data safely and reliably for certain periods of time, such as soon after implantation and for extended periods of time due to local tissue responses. By way of example, there are two commonly used types of subcutaneously implantable glucose sensing devices. These types include those that are implanted transcutaneously and those that are wholly implanted.SUMMARY

[0003] In examples, a device for measurement of a concentration of an analyte is provided, the device comprising an analyte sensing portion configured to generate a signal associated with the concentration of the analyte, at least one polymer coating, and a prodrug form of a bioactive agent. In examples, the prodrug form is pharmacologically less active than the bioactive agent. In aspects, alone or in combination with any of the previous aspects, the prodrug form of the bioactive agent is coupled to the at least one polymer coating and configured to release the bioactive agent from the at least one polymer coating after implantation in a subject.Attorney Docket No.: 0935-PCT01-0240

[0004] In aspects, alone or in combination with any of the previous aspects, the prod rug form of the bioactive agent is configured to couple with the at least one polymer or a polymerizable monomer of the at least one polymer via a biodegradable linkage.

[0005] In aspects, alone or in combination with any of the previous aspects, the biodegradable linkage comprises an enzymatically degradable functional group. In aspects, alone or in combination with any of the previous aspects, the biodegradable linkage comprises a pH degradable functional group. In aspects, alone or in combination with any of the previous aspects, the biodegradable linkage comprises a temperature-degradable functional group.

[0006] In aspects, alone or in combination with any of the previous aspects, the biodegradable linkage comprises a peroxide-degradable functional group. In aspects, alone or in combination with any of the previous aspects, the biodegradable linkage comprises an unsaturated carbon-carbon functional group. In aspects, alone or in combination with any of the previous aspects, the biodegradable linkage comprises an ester functional group. In aspects, alone or in combination with any of the previous aspects, the biodegradable linkage comprises an carbonate functional group. In aspects, alone or in combination with any of the previous aspects, the prodrug form of the bioactive agent is selected from the group:

[0007] In aspects, alone or in combination with any of the previous aspects, the prodrug form of dexamethasone or dexamethasone acetate is configured to couple with the at least one polymer or polymerizable monomer of the at least one polymer coating. In aspects, alone or in combination with any of the previous aspects, the prodrug form of dexamethasone or dexamethasone acetate is configured to covalently couple with the at least one polymer or polymerizable monomer of the at least one polymer coating.

[0008] In aspects, alone or in combination with any of the previous aspects, the at least one polymer or polymerizable monomer comprises a zwitterionic functional group. InAttorney Docket No.: 0935-PCT01-0240aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer chain having one or more zwitterionic compounds.

[0009] In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer chain having polyurethane and / or polyurea segments. In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer chain having both hydrophilic and hydrophobic regions.

[0010] In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer with a heterocyclic group. In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly(2-vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers quaternized forms thereof. In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a copolymer including styrene.

[0011] In other examples, a device for measurement of a concentration of an analyte is provided, the device comprising an implantable analyte sensing portion configured to generate a signal associated with the concentration of the analyte, the device comprising at least one drug-releasing polymer layer configured to release at least one drug, and a diffusion adjustment layer adjacent the at least one drug-releasing polymer layer configured to modulate the release of the at least one drug after implantation of the implantable analyte sensing portion.

[0012] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer covers the implantable analyte sensing portion.

[0013] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer covers one or more membranes adjacent the implantable analyte sensing portion. In examples, the diffusion adjustment layer is configured to biodegrade after implantation.

[0014] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a cellulose polymer. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises hydroxypropyl methylcellulose polymer. In aspects, alone or in combination with any of theAttorney Docket No.: 0935-PCT01-0240previous aspects, the diffusion adjustment layer comprises a poly lactic acid polymer or copolymer.

[0015] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a poly glycolic acid polymer or copolymer. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises poly(lactic-co-glycolic acid) copolymer or blend.

[0016] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a hydrophilic hydrogel, the hydrophilic hydrogel being at least partly crosslinked and dissolvable or swellable in ISF. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a hydrolytically degradable biopolymer. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a hydrophilic hydrogel, the hydrophilic hydrogel is at least partly crosslinked and dissolvable in biological fluid.

[0017] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion is present on a planar substrate or a wire substrate. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer is present on a planar substrate or a wire substrate.

[0018] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer and the analyte sensing portion are spatially separated along a longitudinal axis of the wire substrate or the planar substrate.

[0019] In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer chain having polyurethane and / or polyurea segments. In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer chain having both hydrophilic and hydrophobic regions. In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer chain having one or more zwitterionic compounds.

[0020] In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer with a heterocyclic group. In aspects, alone or in combination with any of the previous aspects, the one or more membranes comprises a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly(2-vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers quaternized forms thereof. In aspects, alone orAttorney Docket No.: 0935-PCT01-0240in combination with any of the previous aspects, the one or more membranes comprises a copolymer including styrene.

[0021] In aspects, alone or in combination with any of the previous aspects, the drugreleasing coating comprises an anti-inflammatory compound or tissue response modifier. In aspects, alone or in combination with any of the previous aspects, the drug-releasing coating comprises pilocarpine, dexamethasone, a derivative form of dexamethasone, dexamethasone acetate, or a combination of dexamethasone with a derivative form of dexamethasone or dexamethasone acetate.

[0022] In other examples, a method of modulating an amount of a drug from an implanted device is provided, the method comprising providing an implantable device, the device comprising at least one polymer coating comprising at least one drug moiety wherein the at least one drug moiety is reversibly contained within a portion of the at least one polymer coating, at least one diffusion adjustment polymer coating adjacent the least one polymer coating, and modulating a release of an amount of the at least one drug moiety from the at least one polymer coating after implantation of the implanted device.

[0023] In examples, the device comprising a wire or planar substrate. In aspects, alone or in combination with any of the previous aspects, the device is an implantable analyte sensor. In aspects, alone or in combination with any of the previous aspects, the device is an implantable glucose or ketone sensor.

[0024] In aspects, alone or in combination with any of the previous aspects, modulating the release of the amount of the drug delays a bolus release thereof. In aspects, alone or in combination with any of the previous aspects, modulating the release of the amount of the drug is over predetermined time interval.

[0025] In aspects, alone or in combination with any of the previous aspects, modulating the release of the amount of the drug is during the first 5 minutes after implantation of the implanted device. In aspects, alone or in combination with any of the previous aspects, modulating the release of the amount of the drug is during the first 10 minutes after implantation of the implanted device. In aspects, alone or in combination with any of the previous aspects, modulating the release of the amount of the drug is during the first 20 minutes after implantation of the implanted device. In aspects, alone or in combination withAttorney Docket No.: 0935-PCT01-0240any of the previous aspects, modulating the release of the amount of the drug is during the first 30 minutes after implantation of the implanted device.

[0026] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer is configured to biodegrade after implantation.

[0027] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer covers the implantable analyte sensing portion. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer covers one or more membranes adjacent the implantable analyte sensing portion.

[0028] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a cellulose polymer. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises hydroxypropyl methylcellulose polymer.

[0029] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a poly lactic acid polymer or copolymer. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a poly glycolic acid polymer or copolymer. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises poly(lactic-co-glycolic acid) copolymer or blend.

[0030] In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a hydrophilic hydrogel, the hydrophilic hydrogel being at least partly crosslinked and dissolvable or swellable in ISF. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a hydrolytically degradable biopolymer. In aspects, alone or in combination with any of the previous aspects, the diffusion adjustment layer comprises a hydrophilic hydrogel, the hydrophilic hydrogel is at least partly crosslinked and dissolvable in biological fluid.

[0031] In aspects, alone or in combination with any of the previous aspects, the at least one drug moiety is an anti-inflammatory or a tissue response modifier. In aspects, alone or in combination with any of the previous aspects, the anti-inflammatory or the tissue response modifier is pilocarpine, dexamethasone, dexamethasone acetate, or salt thereof.

[0032] In aspects, alone or in combination with any of the previous aspects, the method further comprises providing analyte sensor performance within one day of implantation thatAttorney Docket No.: 0935-PCT01-0240is substantially equivalent to analyte sensor performance without the at least one drug moiety.

[0033] In yet other examples, a device for measurement of an analyte concentration is provided, the device comprising an analyte sensing portion configured for subcutaneous insertion and to generate a signal associated with a concentration of an analyte, and at least one wound extrudate absorbing coating configured to absorb wound extrudate upon subcutaneous insertion.

[0034] In examples, the at least one wound extrudate absorbing coating comprises a biocompatible hydrophilic coating. In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating comprises a cellulose polymer. In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating comprises hydroxypropyl methylcellulose polymer.

[0035] In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating comprises a poly lactic acid polymer or copolymer.

[0036] In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating comprises a poly glycolic acid polymer or copolymer. In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating comprises poly(lactic-co-glycolic acid) copolymer or blend.

[0037] In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating comprises a hydrophilic hydrogel, the hydrophilic hydrogel is at least partly crosslinked and dissolvable or swellable in biological fluid.

[0038] In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating reaches over 90% of equilibrium water absorption in less than 2 hrs. In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating reaches over 90% of equilibrium water absorption in less than 1 hr. In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating reaches over 90% of equilibrium water absorption in less than 30 min.

[0039] In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating comprises a betaine group.Attorney Docket No.: 0935-PCT01-0240

[0040] In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating is adjacent the analyte sensing portion.

[0041] In aspects, alone or in combination with any of the previous aspects, the conductive substrate is a planar substrate having a proximal end and a distal end, wherein the analyte sensing portion is positioned between the proximal end and the distal end. In aspects, alone or in combination with any of the previous aspects, the at least one wound extrudate absorbing coating extends proximal, distal, or both proximal and distal from the analyte sensing portion. In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion is positioned on a wire or a planar substrate comprising a most distal tip and the at least one wound extrudate absorbing coating is located at the most distal tip.

[0042] In aspects, alone or in combination with any of the previous aspects, the device further comprises a tissue response or anti-inflammatory agent releasing portion configured to release at least one tissue response or anti-inflammatory agent from the device upon subcutaneous insertion. In aspects, alone or in combination with any of the previous aspects, the anti-inflammatory comprises pilocarpine, a derivative form of dexamethasone, dexamethasone acetate, or a combination of a derivative form of dexamethasone or dexamethasone acetate with dexamethasone.

[0043] In aspects, alone or in combination with any of the previous aspects, the device further comprising at least one vasodilator releasing portion configured to release at least one vasodilator. In aspects, alone or in combination with any of the previous aspects, the at least one vasodilator releasing portion comprises a nitric oxide (NO) releasing molecule, polymer, or oligomer. In aspects, alone or in combination with any of the previous aspects, the nitric oxide (NO) releasing molecule is selected from N-diazeniumdiolates and S-nitrosothiols, or N-diazeniumdiolates.In aspects, alone or in combination with any of the previous aspects, the at least one vasodilator comprises a nitric oxide (NO) releasing molecule, polymer, or oligomer, phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, Hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L- arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-Attorney Docket No.: 0935-PCT01-0240N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, and combinations thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG. 1A is a perspective view schematic illustrating the layers of an in vivo portion of a continuous analyte sensor, as shown and described herein.

[0045] FIG. IB is a perspective view schematic illustrating an in vivo portion of a continuous analyte sensor, as shown and described herein.

[0046] FIG. 1C is a side view schematic illustrating an in vivo portion of an exemplary continuous analyte sensor, as shown and described herein.

[0047] FIG. ID is a cross-sectional / side-view schematic illustrating an in vivo portion of an exemplary continuous analyte sensor, as shown and described herein.

[0048] FIG. IE is a perspective-view schematic illustrating an in vivo portion of an exemplary continuous analyte sensor as disclosed and described herein.

[0049] FIG. IF is a perspective-view schematic illustrating an in vivo portion of an exemplary continuous multi-electrode, multi-analyte sensor.

[0050] FIG. 1G is an expanded perspective schematic of section 1G the distal portion of the sensor example illustrated in FIG. IF.

[0051] FIGS. 2A-2C are cross-sectional views of a sensor illustrating various embodiments of an exemplary membrane system coated as shown and described herein.

[0052] FIGs. 3A-3C are a schematic illustrating an exemplary elongated analyte sensor body multi-polymer drug coating construct as disclosed and described herein.

[0053] FIGs. 4A-4C are a schematic illustrating another exemplary elongated analyte sensor body multi-polymer drug coating construct as disclosed and described herein.

[0054] FIGs. 5A and 5B are a schematic illustrations of an exemplary elongated analyte sensor body construct as disclosed and described herein.

[0055] FIG. 6 shows examples of sustained release kinetics of drugs from a polymer as Type I, Type II and Type III.

[0056] FIG. 7 is a graphical illustration of drug release data for an exemplary polymer delayed drug release coating construct as disclosed and described herein.

[0057] FIG. 8 is a schematic illustrating polymer-coupled drug release coating construct as disclosed and described herein.Attorney Docket No.: 0935-PCT01-0240

[0058] FIG. 9 is a schematic illustrating experimental data from an exemplary polymer-coupled drug release coating construct and delayed drug release coating construct as disclosed and described herein.

[0059] FIG. 10 is a diagram illustrating certain embodiments of an example continuous transcutaneous analyte sensor system communicating with at least one display device in accordance with various technologies described in the present disclosure.DETAILED DESCRIPTION

[0060] The following description and examples illustrate a preferred example of the present disclosure in detail. Those of skill in the art will recognize that there are numerous variations and modifications of this disclosure that are encompassed by its scope.Accordingly, the description of an example should not be deemed to limit the scope of the present disclosure.

[0061] In order to facilitate an understanding of the disclosed examples, a number of terms are defined below.Definitions

[0062] In order to facilitate an understanding of the disclosed examples, a number of terms are defined below.

[0063] The term "about" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not be limited to a special or customized meaning), and refers without limitation to allowing for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The phrase "substantially free of" as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that about 0 wt. % to about 5 wt. % of the composition is the material, or about 0 wt. % to about 1 wt. %, or about 5 wt. % or less, or less than or equal to about 4.5 wt. %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt. % or less, or about 0 wt. %.Attorney Docket No.: 0935-PCT01-0240

[0064] The term "adhere" and "attach" as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not be limited to a special or customized meaning), and refer without limitation to hold, bind, or stick, for example, by gluing, bonding, grasping, interpenetrating, or fusing.

[0065] The term "agent" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to modulators, drugs, physiological stimulators, and other substances that brings about a chemical or physical effect or causes a chemical reaction.

[0066] The terms "analyte" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a substance or chemical constituent in a biological fluid (e.g., blood, interstitial fluid, cerebral spinal fluid, lymph fluid, urine, sweat, saliva, etc.) that can be analyzed. Analytes can include naturally occurring substances, artificial substances, drugs, toxins, metabolites, and / or reaction products. Exemplary analytes include troponin, BNP, insulin, GLP-1, dopamine, serotonin, and L-DOPA.

[0067] The phrases "analyte-measuring device," "analyte-monitoring device," "analytesensing device," "continuous analyte sensing device," "continuous analyte sensor device," and / or "multi-analyte sensor device" as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to an apparatus and / or system responsible for the detection of, or transduction of a signal associated with, a particular analyte, or combination of analytes. For example, these phrases may refer without limitation to an instrument responsible for detection of a particular analyte or combination of analytes. In examples, the instrument includes a sensor coupled to circuitry disposed within a housing, and configure to process signals associated with analyte concentrations into information. In examples, such apparatuses and / or systems are capable of providing specific quantitative, semi-quantitative, qualitative, and / or semi qualitative analytical information using a biological recognition element combined with a transducing and / or detecting element.Attorney Docket No.: 0935-PCT01-0240

[0068] The phrase and term "bioactive agent" and "bioactive" as used herein is a broad phrase and a broad term, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to any substance that has an effect on or elicits a response from living tissue, for example, drugs, biologies, reactive oxygen scavenger (ROS), and metal ions.

[0069] The phrases "biointerface membrane," "biointerface domain," and "biointerface layer" as used interchangeably herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a permeable membrane (which can include multiple domains) or layer that functions as a bioprotective interface between host tissue and an implantable device. The terms "biointerface" and "bioprotective" are used interchangeably herein.

[0070] The terms "biosensor" and / or "sensor" as used herein are broad terms and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a part of an analyte measuring device, analyte-monitoring device, analyte sensing device, continuous analyte sensing device, continuous analyte sensor device, and / or multi-analyte sensor device responsible for the detection of, or transduction of a signal associated with, a particular analyte or combination of analytes. In examples, the biosensor or sensor generally comprises a body, a working electrode (also referred to herein as "WE"), a reference electrode (also referred to herein as "RE"), and / or a counter electrode (also referred to herein as "CE") coupled to body and forming surfaces configured to provide signals during electrochemically reactions. One or more membranes can be affixed to the body and cover electrochemically reactive surfaces. In examples, such biosensors and / or sensors are capable of providing specific quantitative, semi-quantitative, qualitative, semi qualitative analytical signals using a biological recognition element combined with a detecting and / or transducing element.

[0071] The term "biostable" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to beAttorney Docket No.: 0935-PCT01-0240limited to a special or customized meaning), and refers without limitation to materials that are relatively resistant to degradation by processes that are encountered in vivo.

[0072] The term "co-adsorbate" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to materials that absorb, associate, or couple via covalent, ionic, or molecular interaction to a substrate surface (absorbent).

[0073] The term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0074] The term "continuous" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an uninterrupted or unbroken portion, domain, coating, or layer.

[0075] The phrase "continuous analyte sensing" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the period in which monitoring of an analyte concentration is continuously, continually, and / or intermittently (but regularly) performed, for example, from about every 5 seconds or less to about 10 minutes or more. In further examples, continuous monitoring of analyte concentration is performed from about every 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 second to about 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, 4.00, 4.25, 4.50, 4.75, 5.00, 5.25, 5.50, 5.75, 6.00, 6.25, 6.50, 6.75, 7.00, 7.25, 7.50, 7.75, 8.00, 8.25, 8.50, 8.75, 9.00, 9.25, 9.50 or 9.75 minutes. In further examples, continuous monitoring of analyte concentration is performed daily and can be performed for weeks.

[0076] The term "coupled" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to two or more system elements or components that are configured to be at least one of electrically, mechanically, thermally, operably, chemically or otherwise attached. Similarly, the phrases "operably connected", "operably linked", and "operably coupled" as used herein may refer to one orAttorney Docket No.: 0935-PCT01-0240more components linked to another component(s) in a manner that facilitates transmission of at least one signal between the components. In some examples, components are part of the same structure and / or integral with one another (i.e. "directly coupled"). In other examples, components are connected via remote means. For example, one or more electrodes can be used to detect an analyte in a sample and convert that information into a signal; the signal can then be transmitted to an electronic circuit. In this example, the electrode is "operably linked" to the electronic circuit. The phrase "removably coupled" as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached and detached without damaging any of the coupled elements or components. The phrase "permanently coupled" as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached but cannot be uncoupled without damaging at least one of the coupled elements or components.

[0077] The term "discontinuous" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to disconnected, interrupted, or separated portions, layers, coatings, or domains.

[0078] The term "distal" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region spaced relatively far from a point of reference, such as an origin or a point of attachment.

[0079] The term "domain" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region of the membrane system that can be a layer, a uniform or non-uniform gradient (for example, an anisotropic region of a membrane), or a portion of a membrane that is capable of sensing one, two, or more analytes. The domains discussed herein can be formed as a single layer, as two or more layers, as pairs of bi-layers, or as combinations thereof.

[0080] The term "drift" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to aAttorney Docket No.: 0935-PCT01-0240special or customized meaning), and refers without limitation to a progressive increase or decrease in signal over time that is unrelated to changes in host systemic analyte concentrations. While not wishing to be bound by theory, it is believed that drift may be the result of a local decrease in analyte transport to the sensor, for example, due to a formation of a foreign body capsule (FBC). It is also believed that an insufficient amount of interstitial fluid surrounding the sensor may result in reduced transport to the sensor. In examples, an increase in local interstitial fluid may slow or reduce drift and thus improve sensor performance. Drift may also be the result of sensor electronics, or algorithmic models used to compensate for noise or other anomalies that can occur with electrical signals in ranges including the milliampere range, microampere range, picoampere range, nanoampere range, and femtoampere range, likewise with faradic, capacitance, and voltage measurements.

[0081] The phrases "bioactive releasing membrane" and "drug releasing layer" and "bioactive releasing domain" and "bioactive agent releasing membrane" are used interchangeably herein and are each a broad phrase, and each are to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane which is permeable to one or more bioactive agents. In examples, the "bioactive releasing membrane" and "drug releasing layer" and "bioactive releasing domain" and "bioactive agent releasing membrane" can be comprised of two or more domains and is typically of a few microns thickness or more. In examples the bioactive releasing membrane and / or bioactive releasing membrane and / or bioactive agent releasing membrane and / or and bioactive agent releasing membrane are substantially the same as the biointerface layer and / or biointerface membrane. In other examples, the bioactive releasing membrane and / or bioactive releasing membrane and / or bioactive agent releasing membrane and / or and bioactive agent releasing membrane are distinct from the biointerface layer and / or biointerface membrane.

[0082] The term "electrochemically reactive surface" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the surface of an electrode where an electrochemical reaction takes place. In otherAttorney Docket No.: 0935-PCT01-0240examples, electron transfer is provided using a redox moiety associated with an aptamer conjugate, where the redox moiety is capable of undergoing reduction-oxidation (redox) that is related to a reversible binding interaction of the aptamer and an analyte proportional to the analyte concentration.

[0083] The term "gain" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a differential measure between signal OFF state and signal ON state. For example, a typical range of gain is 1-200% of a signal percentage change produced by analyte of certain concentration as compared to zero analyte concentration. Analyte concentration is typically quantified in micromolar (uM), nanomolar (nM), nanograms / milliliter (ng / mL) or picograms / milliliter (pg / mL).

[0084] The phrase "hard segment" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an element of a copolymer, for example, a polyurethane, a polycarbonate polyurethane, or a polyurethane urea copolymer, which imparts resistance properties, e.g., resistance to bending or twisting. The term "hard segment" can be further characterized as a crystalline, semi-crystalline, or glassy material with a glass transition temperature ("Tg") determined by dynamic scanning calorimetry typically above ambient temperature, and is typically made of diisocyanate with or without chain extender.

[0085] The term "host" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to mammals, for example humans.

[0086] The terms "implanted" or "implantable" as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to objects (e.g., sensors) that are inserted subcutaneously (i.e. in the layer of fat between the skin and the muscle) or transcutaneously (i.e. penetrating, entering, or passing through intact skin), which may result in a sensor that has an in vivo portion and an ex vivo portion.Attorney Docket No.: 0935-PCT01-0240

[0087] The terms "interfe rants" and "interfering species" as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to effects and / or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement. In examples of an electrochemical aptamer sensor, interfering species are compounds with a redox (reduction-oxidation) potential that overlaps with the analyte to be measured or one or more redox moieties associated with one or more aptamers.

[0088] The term "in vivo" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of the portion of a device (for example, a sensor) adapted for insertion into and / or existence within a living body of a host.

[0089] The term "ex vivo" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of a portion of a device (for example, a sensor) adapted to remain and / or exist outside of a living body of a host.

[0090] The term "linker" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of a chemical group or a molecule linking two molecules or moieties. In examples, the linker is positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond, thus connecting the two. In examples, the linker is an oligonucleotide, biotin, maleimide (NHS) esters, polyethylene glycol-NHS esters, or a "click" chemistry component.

[0091] The term "membrane" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a structure configured to perform functions including, but not limited to, protection of the exposed electrode surface from the biological environment, diffusion resistance (limitation) of theAttorney Docket No.: 0935-PCT01-0240analyte, service as a matrix for a catalyst for enabling an enzymatic reaction, limitation or blocking of interfering species, provision of hydrophilicity at the electrochemically reactive surfaces of the sensor interface, service as an interface between host tissue and the implantable device, modulation of host tissue response via drug (or other substance) release, and combinations thereof. When used herein, the terms "membrane" and "matrix" are meant to be interchangeable.

[0092] The phrase "membrane system" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can be comprised of two or more domains, layers, or layers within a domain, and is typically constructed of materials of a few microns thickness or more, which is permeable to analyte. In examples, the membrane system comprises an immobilized or encapsulated aptamer, which enables transduction to occur between the aptamer and analyte whereby a concentration of analyte can be measured.

[0093] The term "micro," as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a small object or scale of approximately 10-6 m that is not visible without magnification. The term "micro" is in contrast to the term "macro," which refers to a large object that may be visible without magnification. Similarly, the term "nano" refers to a small object or scale of approximately 10-9 m.

[0094] The term "noise," as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a signal detected by the sensor or sensor electronics that is unrelated to analyte concentration and can result in reduced sensor performance. One type of noise has been observed during the few hours (e.g., about 2 to about 24 hours) after sensor insertion. Afterthe first 24 hours, the noise may disappear or diminish, but in some hosts, the noise may last for about three to four days. In some cases, noise can be reduced using predictive modeling, artificial intelligence, and / or algorithmic means. In other cases, noise can be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as using a bioactive releasing membrane with at least one bioactive agent. For example, noise of one or more exemplary biosensors asAttorney Docket No.: 0935-PCT01-0240presently disclosed can be determined and then compared qualitatively or quantitatively. By way of example, by obtaining a raw signal timeseries with a fixed sampling interval (in units of picoampere (pA)), a smoothed version of the raw signal timeseries can be obtained, e.g., by applying a 3rd order lowpass digital Chebyshev Type II filter. Others smoothing algorithms can be used. At each sampling interval, an absolute difference, in units of pA, can be calculated to provide a smoothed timeseries. This smoothed timeseries can be converted into units (the unit of "noise"), using, for example, an analyte sensitivity timeseries, where the analyte sensitivity timeseries is derived by using a mathematical model between the raw signal and reference blood analyte measurements. Optionally, the timeseries can be aggregated as desired, e.g., by hour or day. Comparison of corresponding timeseries between different exemplary biosensors with the presently disclosed bioactive releasing membrane and one or more bioactive agents provides for qualitative or quantitative determination of improvement of noise.

[0095] The term "optional" or "optionally" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and, without limitation, means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0096] The phrase "polymerization group" used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a functional group that permits polymerization of the monomer with itself to form a homopolymer or together with different monomers to form a copolymer. Depending on the type of polymerization methods employed, the polymerization group can be selected from alkene, alkyne, epoxide, lactone, amine, hydroxyl, isocyanate, carboxylic acid, anhydride, silane, halide, aldehyde, and carbodiimide.

[0097] The term "polyzwitterions" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to polymers where a repeating unit of the polymer chain is a zwitterionic moiety. Polyzwitterions are also known as polybetaines. Since polyzwitterions have both cationic and anionic groups,Attorney Docket No.: 0935-PCT01-0240they are a type of polyampholytic polymer. They are unique, however, because the cationic and anionic groups are both part of the same repeating unit, which means a polyzwitterion has the same number of cationic groups and anionic groups whereas other polyampholytic polymers can have more of one ionic group than the other. Also, polyzwitterions have the cationic group and anionic group as part of a repeating unit. Polyampholytic polymers need not have cationic groups connected to anionic groups; they can be on different repeating units and thus may be distributed apart from one another at random intervals, or one ionic group may outnumber the other.

[0098] The term "proximal" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference. For example, some examples of a device include a membrane system having a biointerface layer and an enzyme layer. If the sensor is deemed to be the point of reference and the enzyme layer is positioned nearer to the sensor than the biointerface layer, then the enzyme layer is more proximal to the sensor than the biointerface layer.

[0099] The phrase and term "processor module" and "microprocessor" as used herein are each a broad phrase and term, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a computer system, state machine, processor, or the like designed to perform arithmetic or logic operations using logic circuitry that responds to and processes the basic instructions that drive a computer.

[0100] The term "semi-continuous" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a portion, coating, domain, or layer that includes one or more continuous and noncontinuous portions, coatings, domains, or layers. For example, a coating disposed around a sensing region but not about the sensing region is "semi-continuous."

[0101] The phrases "sensing portion," "sensing membrane," "sensing region," "sensing domain," and / or "sensing mechanism" as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and areAttorney Docket No.: 0935-PCT01-0240not to be limited to a special or customized meaning), and refer without limitation to the part of a biosensor and / or a sensor responsible for the detection of, or transduction of a signal associated with, a particular analyte or combination of analytes. In examples, the sensing portion, sensing membrane, and / or sensing mechanism generally comprise an electrode configured to provide signals during electrochemically reactions with one or more membranes covering electrochemically reactive surface. In examples, such sensing portions, sensing membranes, and / or sensing mechanisms are capable of providing specific quantitative, semi-quantitative, qualitative, semi qualitative analytical signals using a biological recognition element combined with a detecting and / or transducing element.

[0102] In examples, the sensing region or sensing portion can comprise at least a portion of a conductive substrate or at least a portion of a conductive surface, for example, a wire or conductive trace or a substantially planar substrate including substantially planar trace(s), and a membrane. In examples, the sensing region or sensing portion can comprise a non-conductive body, a working electrode, a reference electrode, and a counter electrode (optional), forming an electrochemically reactive surface at one location on the body and an electronic connection at another location on the body, and a sensing membrane affixed to the body and covering the electrochemically reactive surface. In general, it should be understood that the disclosed examples are applicable to a variety of analyte sensor configurations. While some figures herein illustrate sensors that may have a coaxial core and a circular or elliptical cross-section, in other examples of sensor systems, such as those including the described edema suppressing biointerface layer, the sensor may be a substantially planar sensor having a rectangular cross-section.

[0103] In examples, multiple working electrodes can be employed. For example, a second working electrode comprising a plurality of different analyte (e.g., analyte 1, analyte2, etc.) aptamer conjugates on the second working electrode to correct for sensor drift and / or interference. Likewise, a second working electrode comprising a non-selective aptamer conjugate to a plurality of different analytes (e.g., analyte 1, analyte2, etc.) on the second working electrode can be used to correct for sensor drift and / or interference.

[0104] In other examples, the sensing region can comprise one or more periplasmic binding protein (PBP) or mutant or fusion protein thereof having one or more analyte binding regions, each region capable of specifically and reversibly binding to at least oneAttorney Docket No.: 0935-PCT01-0240analyte. Mutations of the PBP can contribute to or alter one or more of the binding constants, extended stability of the protein, including thermal stability, to bind the protein to a special encapsulation matrix, membrane or polymer, or to attach a detectable reporter group or "label" to indicate a change in the binding region. Specific examples of changes in the binding region include, but are not limited to, hydrophobic / hydrophilic environmental changes, three-dimensional conformational changes, changes in the orientation of amino acid side chains in the binding region of proteins, and redox states of the binding region. Such changes to the binding region provide for transduction of a detectable signal corresponding to the one or more analytes present in the biological fluid.

[0105] In examples, the sensing region determines the selectivity among one or more analytes, so that only the analyte which has to be measured leads to (transduces) a detectable signal. The selection may be based on any chemical or physical recognition of the analyte by the sensing region, where the chemical composition of the analyte is unchanged, or in which the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.

[0106] The sensing region transduces the recognition of analytes into a semi-quantitative or quantitative signal. Thus, "transducing" or "transduction" and their grammatical equivalents as are used herein encompasses optical, electrochemical, acoustical / mechanical, or colorimetrical technologies and methods. Electrochemical properties include current and / or voltage, capacitance, and potential. Optical properties include absorbance, fluorescence / phosphorescence, wavelength shift, phase modulation, bio / chemiluminescence, reflectance, light scattering, and refractive index.

[0107] The term "sensitivity" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an amount of signal (e.g., in the form of electrical current and / or voltage) produced by a predetermined amount (unit) of the measured analyte. For example, an amperometric sensor has a sensitivity (or slope) of from about 1 to about 100 picoAmps of current for every 1 mg / dL of analyte.

[0108] The phrases and terms "small diameter sensor," "small structured sensor," and "micro-sensor" as used herein are broad phrases and terms, and are to be given theirAttorney Docket No.: 0935-PCT01-0240ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to sensing mechanisms that are less than about 2 mm in at least one dimension. In further examples, the sensing mechanisms are less than about 1 mm in at least one dimension. In some examples, the sensing mechanism (sensor) is less than about 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm. In some examples, the maximum dimension of an independently measured length, width, diameter, thickness, or circumference of the sensing mechanism does not exceed about 2 mm. In some examples, the sensing mechanism is a needle-type sensor, wherein the diameter is less than about 1 mm, see, for example, U.S. Pat. No. 6,613,379 to Ward et al. and U.S. Pat. No. 7,497,827 to Brister et al., both of which are incorporated herein by reference in their entireties. In some alternate examples, the sensing mechanism includes electrodes deposited on a substantially planar substrate, wherein the thickness of the implantable portion is less than about 1 mm, see, for example U.S. Pat. No. 6,175,752 to Say et al. and U.S. Pat. No. 5,779,665 to Mastrototaro et. al., both of which are incorporated herein by reference in their entireties. Examples of methods of forming the sensors (sensor electrode layouts and membrane) and sensor systems discussed herein may be found in currently pending U.S. Pat. Pub. No. 2019-0307371, which is incorporated by reference in its entirety herein.

[0109] The phrase "soft segment" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an element of a copolymer, for example, a polyurethane, a polycarbonate polyurethane, or a polyurethane urea copolymer, which imparts flexibility to the chain. The phrase "soft segment" can be further characterized as an amorphous material with a low Tg, e.g., a Tg not typically higher than ambient temperature or normal mammalian body temperature.

[0110] The phrase "solid portions" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to portions of a membrane's material having a mechanical structure that demarcates cavities, voids, or other non-solid portions.Attorney Docket No.: 0935-PCT01-0240

[0111] The term and phrases "zwitterion" and "zwitterionic compound" as used herein are each a broad term and phrase, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to compounds in which a neutral molecule of the compound has a unit positive and unit negative electrical charge at different locations within the molecule. Such compounds are a type of dipolar compound, and are also sometimes referred to as "inner salts."

[0112] The phrases "zwitterion precursor" or "zwitterionic compound precursor" as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to any compound that is not itself a zwitterion, but can become a zwitterion in a final or transition state through chemical reaction. In some examples described herein, devices comprise zwitterion precursors that can be converted to zwitterions prior to in vivo implantation of the device. Alternately, in some examples described herein, devices comprise zwitterion precursors that can be converted to zwitterions by some chemical reaction that occurs after in vivo implantation of the device. Such reactions are known to a person of ordinary skill in the art and include ring opening reaction, addition reaction such as Michael addition. This method is especially useful when the polymerization of betaine containing monomer is difficult due to technical challenges such as solubility of betaine monomer to achieve desired physical properties such as molecular weight and mechanical strength. Post-polymerization modification or conversion of betaine precursor can be a practical way to achieve desired polymer structure and composition. Examples of such as precursors include tertiary amines, quaternary amines, pyridines, and others detailed herein.

[0113] The phrases "zwitterion derivative" or "zwitterionic compound derivative" as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to any compound that is not itself a zwitterion, but rather is the product of a chemical reaction where a zwitterion is converted to a nonzwitterion. Such reactions can be reversible, such that under certain conditions zwitterion derivatives can act as zwitterion precursors. For example, hydrolysable betaine estersAttorney Docket No.: 0935-PCT01-0240formed from zwitterionic betaines are cationic zwitterion derivatives that under the appropriate conditions are capable of undergoing hydrolysis to revert to zwitterionic betaines.

[0114] The phrases "zwitterionic repeating group" as used herein is a broad phrase, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to, independently, two or more zwitterionic compounds, zwitterion derivatives or zwitterionic compound derivatives in the same compound or polymer. Coatings applied to a sensor or an elongated body are generally described herein after the coating has dried or cured on the sensor or an elongated body, unless noted otherwise. Coatings can improve the sensor function and mitigate degradation during in vivo use.

[0115] One reason for functional degradation of implantable continuous analyte monitoring devices is the immunological response to the implanted portion thereof, which results in a progressive degeneration of the signal during operation. For implantable sensors with electrochemically active sites, a hydrophobic coating layer containing a releasable active agent, for example, proximal to an in vivo electrochemically active site of the implantable continuous analyte monitoring devices has been shown to suppress / inhibit the immunological response and extend the end-of-life (EOL) of the implantable sensor, however, close proximity of the hydrophobic coating layer containing a releasable active agent to the active site may result in measurable drift and lag time response.

[0116] Minimizing insertion trauma is one way of reducing a local analyte diluting effect, for example, using a less invasive needle (tuohy needle) and / or a slow insertion speed. It will not, however, eliminate the acute insertion trauma and local wound response created by the insertion. Wound exudates will fill in the wound tract, thus, diluting interstitial fluid (ISF) analyte concentrations (edema dilution impact) and deviating from an established ISF-blood analyte correlation. Such deviations typically recover overtime as the analyte concentration reestablishes equilibrium but nonetheless, pose a challenge to providing analyte concentration readings during the initial introduction of the implantable portion of the sensor. The devices and methods disclosed herein provide for reducing or eliminating edema dilution impact at or near an implantable portion of a continuous analyte monitoring device. The devices and methods disclosed herein include an edema suppressingAttorney Docket No.: 0935-PCT01-0240biointerface layer on at least a portion of the implantable portion of the continuous analyte monitoring device. The edema suppressing biointerface layer according to the devices and methods disclosed herein is configured to absorb or otherwise contain wound exudates and thus reduces or eliminates edema dilution impact.

[0117] The addition of drug releasing layers to implantable continuous analyte monitoring devices has shown improvement in EOL for some implantable continuous analyte monitoring devices, however, functional limitations in drift and lag time response at implantation can occur with the use of such drug releasing layers. In some situations, a hydrophobic material is used in combination with a drug as a drug releasing layer. While not to be held by any particular theory, the hydrophobic nature of the hydrophobic materials may cause a delay in hydration of the implantable sensor resulting in at least: (1) a lag in the dynamic analyte concentration per unit time reaching a transducing component of the sensor, thus causing delayed break-in; and / or (2) a phase difference in transduced signal (e.g., intensity vs time) resulting in signal reduction and signal generation delay.

[0118] In examples, the devices and methods disclosed herein provide for reducing or eliminating lag or phase difference in transduced signal from implantable sensors by using an edema suppressing biointerface layer. In examples, the edema suppressing biointerface layer rapidly reaches equilibrium with wound site exudate post subcutaneous insertion of at least the implantable portion of the implantable continuous analyte monitoring devices. In examples, the edema suppressing biointerface layer instantly begins equilibrating with wound site exudate post subcutaneous insertion of at least the implantable portion of the implantable continuous analyte monitoring devices.

[0119] In examples, the edema suppressing biointerface layer is positioned adjacent a drug releasing layer, such that drug release from the drug releasing layer is delayed or attenuated over a period of time while the edema suppressing biointerface layer equilibrates with wound exudate post subcutaneous insertion. In examples, the edema suppressing biointerface layer is positioned adjacent a drug releasing layer, such that drug release from the drug releasing layer is delayed or attenuated over a period of time until the edema suppressing biointerface layer at least partially equilibrates with wound exudate post subcutaneous insertion. In examples, the edema suppressing biointerface layer reaches about 50%, about 60%, about 70%, about 80%, or 90% of equilibrium water absorption postAttorney Docket No.: 0935-PCT01-0240subcutaneous insertion in less than 2 hours, less than 1 hour, less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 30 min.

[0120] In examples, the edema suppressing biointerface layer is positioned adjacent a drug releasing layer, such that upon equilibrating with the wound site exudate, a mass transport rate of one or more drugs from the drug releasing layer through the edema suppressing biointerface layer is increased relative to the mass transport rate of one or more drugs before the edema suppressing biointerface layer has equilibrated, post subcutaneous insertion, with the wound exudate.

[0121] In examples, an edema suppressing biointerface layer comprises a biocompatible hydrophilic coating configured to absorb local wound exudates and to improve ISF-venous analyte equilibrium. In examples, edema suppressing biointerface layer is biostable for up to at least 14 days post subcutaneous insertion. In examples, the edema suppressing biointerface layer is biologically degraded within 14 days post subcutaneous insertion.

[0122] In examples, the edema suppressing biointerface layer comprises a betaine containing moiety. The betaine containing moiety can be a betaine containing polymer or oligomer. In examples, the betaine containing moiety is present at the end of the polymer or oligomer and / or along the backbone of the polymer or oligomer in a random or repeating manner. Examples of betaine containing polymers suitable for the edema suppressing biointerface layer are found in U.S. Patent Appl. Pub. No. 2022 / 0214300, which is incorporated herein by reference in its entirety.

[0123] In examples, the edema suppressing biointerface layer is configured to adhere to an adjacent layer, for example, a drug releasing layer. A plurality of edema suppressing biointerface layers can be stacked, with each of the edema suppressing biointerface layers independently comprising the same or different compositions of absorbing material, or collectively providing a gradient configuration of absorbing material.

[0124] In examples, the edema suppressing biointerface layer is configured to allow facile and rapid transport of one or more analytes. In examples, the edema suppressing biointerface layer can be positioned at the distal tip end of an implantable portion of the sensor. In other examples, the edema suppressing biointerface layer covers the working electrode area and / orthe sensing membrane, and can extend further proximally from the working electrode area.Attorney Docket No.: 0935-PCT01-0240

[0125] FIGS. 1A through ID illustrate an exemplary configurations of an in vivo portion of a continuous analyte sensor 100, which includes an elongated conductive body 101 configured to comprise an implantable portion 102. The elongated conductive body 101 includes a core 110 (see FIG. IB) and a first layer 112 at least partially surrounding the core. The first layer includes a working electrode (for example, located in window 106) and a sensing membrane 400 located over the working electrode. In some examples, the core and first layer can be of a single material (such as, for example, platinum). In some examples, the elongated conductive body is a composite of at least two materials, such as a composite of two conductive materials, or a composite of at least one conductive material and at least one non-conductive material. In some examples, the elongated conductive body comprises a plurality of layers. In certain examples, there are at least two concentric or annular layers, such as a core formed of a first material and a first layer formed of a second material.However, additional layers can be included in some examples. In some examples, the layers are coaxial.

[0126] The elongated conductive body can be long and thin, yet flexible and strong. For example, in some examples, the smallest dimension of the elongated conductive body is less than about 0.1 inches (2.54 mm), 0.075 inches (1.90 mm), 0.05 inches (1.27 mm), 0.025 inches (0.635 mm), 0.01 inches (0.254 mm), 0.004 inches (0.1 mm), or 0.002 inches (0.05 mm). While the elongated conductive body is illustrated in FIGS. 1A through 1C as having a circular cross-section, in other examples the cross-section of the elongated conductive body can be planar, ovoid, rectangular, triangular, polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-Shaped, irregular, or the like. In examples, a conductive wire electrode is employed as a core. To such a clad electrode, two additional conducting layers can be added (e.g., with intervening insulating layers provided for electrical isolation). The conductive layers can be comprised of any suitable material. In certain examples, it can be desirable to employ a conductive layer comprising conductive particles (i.e., particles of a conductive material) in a polymer or other binder.

[0127] In examples, the implantable portion 102 has a length of about 1 mm to about 20 mm. In other examples, the implantable portion 102 has a length of about 2 mm to about 14 mm. In further examples, the implantable portion 102 has a length of about 4 mm to about 12 mm. For example, the implantable portion 102 has a length of at least about anyAttorney Docket No.: 0935-PCT01-0240of the following: 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19 mm and / or at most about 20, 19, 18, 17, 16, 15, 4, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, and 2 mm (e.g., about 1-15 mm, about 5-18 mm, etc.).

[0128] The materials used to form the elongated conductive body (such as, for example, stainless steel, titanium, tantalum, platinum, platinum-iridium, iridium, nitinol, certain polymers, and / or combinations thereof) can be strong and hard, and therefore are resistant to breakage. In some examples, the sensor's small diameter provides flexibility to these materials, and therefore to the sensor as a whole. Thus, the sensor can withstand repeated forces applied to it by surrounding tissue.

[0129] In addition to providing structural support, resiliency and flexibility, in some examples, the core 110, or a component thereof, provides electrical conduction for an electrical signal from the working electrode to sensor electronics (not shown). In some examples, the core 110 comprises a conductive material, such as nitinol, stainless steel, titanium, tantalum, a conductive polymer, and / or the like. However, in other examples, the core is formed from a non-conductive material, such as a non-conductive polymer. In yet other examples, the core comprises a plurality of layers of materials. For example, in examples the core includes an inner core and an outer core. In further examples, the inner core is formed of a first conductive material and the outer core is formed of a second conductive material. For example, in some examples, the first conductive material is stainless steel, titanium, tantalum, a conductive polymer, an alloy, and / orthe 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 attach the first layer to the core (that is, if the first layer is formed of a material that does not attach well to the core material). In other examples, the core is formed of a non-conductive material (such as, for example, a non-conductive metal and / or a non-conductive polymer) and the first layer is formed of a conductive material, such as nitinol, stainless steel, titanium, tantalum, a conductive polymer, and / or the like. The core and the first layer can be of a single (or same) material, such as platinum. One skilled in the art appreciates that additional configurations are possible.

[0130] First layer 112 can be formed of a conductive material and the working electrode can be an exposed portion of the surface of the first layer 112. Accordingly, the first layerAttorney Docket No.: 0935-PCT01-0240112 can be formed of a material configured to provide a suitable electroactive surface for the working electrode, a material such as, but not limited to, platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, an alloy and / or the like.

[0131] As illustrated in FIG. IB and FIG. 1C, a second layer 104 surrounds at least a portion of the first layer 112, thereby defining the boundaries of the working electrode. In some examples, the second layer 104 serves as an insulator and is formed of an insulating material, such as polyimide, polyurethane, parylene, or any other known insulating materials. For example, in examples the second layer is disposed on the first layer and configured such that the working electrode is exposed via window 106. In some examples, an elongated conductive body, including the core, the first layer and the second layer, is provided. A portion of the second layer can be removed to form a window 106, through which the electroactive surface of the working electrode (that is, the exposed surface of the first layer 112) is exposed. In some examples, a portion of the second and (optionally) third layers can be removed to form the window 106, thus exposing the working electrode.Removal of coating materials from one or more layers of the elongated conductive body (for example, to expose the electroactive surface of the working electrode) can be performed by hand, excimer lasing, chemical etching, laser ablation, grit-blasting, or the like.

[0132] The sensor can further comprise a third layer 114 comprising a conductive material. For example, the third layer 114 can comprise a reference electrode, which can be formed of a silver-containing material that is applied onto the second layer 104 (that is, the insulator).

[0133] The elongated conductive body 101 can further comprise one or more intermediate layers (not shown) located between the core 110 and the first layer 112. For example, the intermediate layer can be one or more of an insulator, a conductor, a polymer, and / or an adhesive. In some examples, the core 110 comprises a non-conductive polymer and the first layer 112 comprises a conductive material. Such a sensor configuration can advantageously provide reduced material costs, in that it replaces a typically expensive material with an inexpensive material. For example, the core 110 can be formed of a non-conductive polymer, such as, a nylon or polyester filament, string or cord, which can be coated and / or plated with a conductive material, such as platinum, platinum-iridium, gold,Attorney Docket No.: 0935-PCT01-0240palladium, iridium, graphite, carbon, a conductive polymer, and allows or combinations thereof.

[0134] Referring to FIG. IB and FIG. 1C, the reference electrode 114 can comprise a silver-containing material (e.g., silver / silver chloride) applied over at least a portion of the insulating material 104, as discussed in greater detail elsewhere herein. For example, the silver-containing material can be applied using the presently disclosed coating methods described herein. In examples, the silver-containing material can be applied using the presently disclosed coating methods in combination with thin film and / or thick film techniques, such as but not limited to the methods disclosed herein, dipping, spraying, printing, electro-depositing, vapor deposition, spin coating, and sputter deposition. For example, a silver or silver chloride-containing paint (or similar formulation) can be applied to a reel of the insulated conductive core using the presently disclosed coating methods.

[0135] As illustrated in FIG. IB, FIG. 1C, and FIG. ID, the sensor can also include a sensing membrane 400, such as those discussed elsewhere herein, for example, with reference to FIGS. 2A through 2C. The sensing membrane 400 can include an enzyme layer (not shown), as described elsewhere herein. For example, the sensing membrane 400 can include a catalyst or enzyme configured to react with an analyte. For example, the sensing membrane 400 can be an immobilized enzyme-containing layer including glucose oxidase, glucose dehydrogenase, 3-hydroxy butyrate dehydrogenase, or lactate dehydrogenase. In other examples, the sensing membrane 400 can be impregnated with other oxidases, including, for example, galactose oxidase, cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate oxidase, aspartate oxidase, or uricase. In examples, the sensing membrane 400 can include one or more of glucose dehydrogenase, lactate dehydrogenase, malate dehydrogenase, glycerol dehydrogenase, alcohol dehydrogenase, sorbitol dehydrogenase, and an amino acid dehydrogenase comprising L-amino acid dehydrogenase, asparaginase, or superoxide dismutase.

[0136] In examples, the enzyme layer can include (3-hydroxybutyrate dehydrogenase (HBD) enzyme, a nicotinamide adenine dinucleotide (NAD+) and a metal or non-metal mediator. In examples, the sensing membrane 400 comprises p-hydroxybutyrate dehydrogenase (HBDH) enzyme, a nicotinamide adenine dinucleotide (NAD+) and a metal or non-metal mediator in combination with glucose oxidase or glucose dehydrogenase.Attorney Docket No.: 0935-PCT01-0240

[0137] In examples, the sensing membrane 400 comprises aspartate oxidase and / or asparaginase. In examples, the sensing membrane 400 comprises aspartate oxidase and / or asparaginase in combination with glucose oxidase or glucose dehydrogenase or (3-hydroxy butyrate dehydrogenase (HBD) enzyme, a nicotinamide adenine dinucleotide (NAD+) and a metal or non-metal mediator.

[0138] Combinations of the above enzymes can be combined in the same layer or provided in separated layers vertically and / or horizontally separated about the elongated body are envisaged with the coating methods disclosed herein. Combinations of the above enzymes can be combined in the same layer or provided in separated layers vertically and / or horizontally separated with one or more intervening layers about the elongated body are envisaged with the coating methods disclosed herein.

[0139] FIG. IE is a perspective view of the in vivo portion of a multi-electrode, multianalyte capable sensor. In this example, the insulated elongated body comprises three conductive cores 210A, 210B, 210C located in (e.g., embedded in, coated with) the insulator 104. In this example, a plurality of windows is formed in and / or through the insulator, such that each window exposes a portion of a core. As a non-limiting example, window 206 is formed in the insulator such that a portion of core 210A is exposed. Similarly, window 208 is formed in the insulator such that a portion of core 210B is exposed. The windows can be staggered and / or non-staggered along the longitudinal length of the sensor. In further examples, each conductive core includes an inner core and an outer core, such as described elsewhere herein.

[0140] In examples, the first conductive core is formed of platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer and / or an alloy, and a first window 206 is configured and arranged to expose an electroactive portion of the first conductive core. The second conductive core is formed of a silver-containing material (e.g., a silver or silver / silver-chloride wire, or a silver-containing wire-shaped a silver-containing material body), and a second window 208 is configured and arranged to expose an electroactive portion of the second conductive core. In some examples, instead of a bulk metal wire, the first conductive core comprises an inner core and an outer core. For example, to reduce material costs, the inner core is formed of a material that is relatively less expensive than platinum, such as stainless steel, titanium, tantalum and / or a polymer,Attorney Docket No.: 0935-PCT01-0240and the outer core is formed of a material that provides an appropriate electroactive surface, such as but not limited to platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer and / or an alloy. In some examples, the membrane covers the exposed electroactive portion of the first conductive core. In further examples, the membrane covers the in vivo portion of the sensor. In some examples, a third conductive core is embedded in the insulator. In some examples, the third conductive core is configured and arranged as a second working electrode, which can be configured as a redundant working electrode, a non-analyte signal-measuring working electrode (e.g., no transducing element as described below), as a counter working electrode, to detect a second analyte, and / or the like.

[0141] FIG. IF is a perspective view of the in vivo portion of an example of a multielectrode sensor system 300 comprising at least one working electrode and at least one reference / counter electrode. The sensor system 300 comprises first and second elongated bodies El, E2, each formed of a conductive core or of a core with a conductive layer deposited thereon. In this particular example, a wire-based sensor is shown, however, a planar arrangement is also envisaged. In this particular example, an insulating layer 310, a conductive layer 320 e.g., a reference electrode, and any one of the previously described membranes (not shown) are deposited on top of the elongated bodies El, E2. The insulating layer 310 separates the conductive layer 320 from the elongated body. The materials selected to form the insulating layer 310 may include any of the insulating materials described elsewhere herein, including polyurethane and polyimide. The materials selected to form the conductive layer 320 may include any of the conductive materials described elsewhere herein, including silver / silver chloride, platinum, gold, etc. Working electrodes 302, 303 are formed by removing portions of the conductive layer 320 and the insulating layer 310, thereby exposing electroactive surface of the elongated bodies El, E2, respectively. FIG. 1G provides a close perspective view of the distal portion of the elongated bodies El, E2.

[0142] In examples, the two elongated bodies illustrated in FIG. IF are fabricated to have substantially the same shape and dimensions. In examples, the two elongated bodies illustrated in FIG. IF are fabricated to have substantially the same shape and dimensions. In examples, one elongated body has no enzyme or a deactivated enzyme and a drug releasingAttorney Docket No.: 0935-PCT01-0240layer with diffusion adjustment layer, whereas the other elongated body includes an active enzyme without a drug releasing layer. In other examples, first elongated body has no enzyme ora deactivated enzyme and a drug releasing layer with diffusion adjustment layer, whereas second elongated body includes an active enzyme with a drug releasing layer having a different drug composition, different drug concentration, different polymer matrix, or different thickness than first elongated body. In other examples, first elongated body has no enzyme or a deactivated enzyme and a drug releasing layer with diffusion adjustment layer, whereas second elongated body includes an active enzyme with a drug releasing layer having a different diffusion adjustment layer, e.g., different polymer matrix, different biodegradability, or different thickness than the diffusion adjustment layer of the first elongated body.

[0143] In another example, the two elongated bodies illustrated in FIG. IF, but with one elongated body having no window and a drug releasing layer, whereas the other elongated body includes a window 106 and sensing membrane with an active enzyme without a drug releasing layer.

[0144] In some examples, the working electrodes of FIG. IF are fabricated to have the same properties, thereby providing a sensor system capable of providing redundancy of signal measurements or providing unique signals representing two or more different analytes. In other examples, the working electrodes, associated with the elongated bodies El, E2, may each have one or more characteristics that distinguish each working electrode from the other. For example, in examples, each of the elongated bodies El, E2 may be different conductive surfaces, so that each working electrode has a different electrochemical property than the other working electrode. In addition, in examples, each of the elongated bodies El, E2 may be covered with different membrane(s), so that each working electrode has a different membrane property than the other working electrode.

[0145] Although not shown in FIGS. 1F-1G, in certain examples, the exposed distal ends 330, 331 of the core portions of the elongated bodies El, E2 may be covered with an insulating material (e.g., polyurethane or polyimide). In alternative examples, the exposed distal ends 330, 331 of the core portions are covered with any of the previously described membrane system and / or serve as additional or "secondary" working electrode surface area.Attorney Docket No.: 0935-PCT01-0240

[0146] Regarding fabrication of the sensor system illustrated in FIG. 1F-1G, in one example, the elongated bodies El, E2 may be formed as an elongated conductive core, or alternatively as a core (conductive or non-conductive) having at least one conductive material deposited thereon. Next, an insulating layer 310 is deposited onto each of the elongated bodies El, E2. Thereafter, a conductive layer 320 is deposited over the insulating layer 310. The conductive layer 320 may serve as a reference / counter electrode and may be formed of silver / silver chloride, or any other material that may be used for a reference electrode. In alternative examples, the conductive layer 320 may be formed of a different conductive material, and may be used another working electrode. After these steps, a layer removal process is performed to remove portions of the deposited layers (i.e., the conductive layer320 and / orthe insulating layer 310). Any of the techniques described elsewhere herein (e.g., laser ablation, chemical etching, grit blasting) may be used. In the example illustrated in FIGS. IF and 1G, layers of the conductive layer 320 and the insulating layer 310 are removed to form the working electrodes 302, 303. Although in the example shown, layer removal is performed across the entire cross-sectional perimeter (e.g., circumference) of the deposited layer, it is contemplated that in other examples, layer removal may be performed across a preselected section of the cross-sectional perimeter, instead of across the entire cross-sectional perimeter.

[0147] Contacts 304 can be used to provide electrical connection between the working electrodes and other components of the sensor system may be formed in a similar manner. As shown, contacts 304 are separated from each other to prevent an electrical connection therebetween. Because the layer removal process is performed on each individual elongated body El, E2, instead of a single geometrically complicated elongated body, this particular sensor design (i.e., two elongated bodies placed side by side) may provide ease of manufacturing, as compared to the manufacturing processes involved with other multielectrode systems having other geometries.

[0148] After the conductive and insulating layers are deposited onto the elongated body, and after selected portions of the deposited layers have been removed, one or more membranes are applied onto at least a portion of the elongated bodies using the apparatuses and method disclosed herein, either alone or in combination with the apparatuses and method disclosed herein or with other coating apparatuses and methods.Attorney Docket No.: 0935-PCT01-0240In certain examples, any of the aforementioned membrane systems are applied only to the working electrodes, but in other examples any of the aforementioned membrane systems are applied to the entire elongated body. In examples, any of the aforementioned membrane systems are deposited onto the two working electrodes simultaneously while they are placed together (e.g., by bundling), but in other examples, any of the aforementioned membrane systems are deposited onto each individual working electrode first, and the two working electrodes are then placed together.

[0149] FIG. 2A is a cross-sectional view through the exemplary sensor of FIG. 1A-1D, illustrating examples of sensing membrane 400. In this particular non-limiting example, the membrane system includes an electrode layer 420, an enzyme layer 440, a diffusion resistance layer 460, and a biointerface layer 480 and / or drug releasing layer 470, all of which are located around a working electrode of the sensor, and all of which are described in more detail elsewhere herein. In some examples, a unitary diffusion resistance domain and biointerface layer and / or drug releasing layer can be included in the membrane system (e.g., wherein the functionality of both layers is incorporated into one domain). In some examples, the sensor is configured for short-term implantation (e.g., from about 1 to 30 days). However, it is understood that the sensing membrane 400 can be modified and / or used in other devices, for example, by including only one or more of the domains, or including additional domains.

[0150] FIG. 2B is a cross-sectional view through examples of the sensor, illustrating another example of the sensing membrane 400. In this particular example, the membrane system includes an interference reduction or blocking layer 430, an enzyme layer 440, a diffusion resistance layer 460, and a biointerface layer 480 and / or drug releasing layer 470 located around the working electrode of the sensor, all of which are described in more detail elsewhere herein.

[0151] FIG. 2C is a cross-sectional view through examples of the sensor, illustrating still another example of the sensing membrane 400. In this particular example, the membrane system includes an interferent reduction or blocking layer 430, an enzyme layer 440, and a unitary diffusion resistance / biointerface layer 480 located around the working electrode of a sensor and drug releasing layer 470 (not shown), all of which are described in more detail elsewhere herein.Attorney Docket No.: 0935-PCT01-0240

[0152] Sensing membrane 400 of some examples can also include a plurality of domains or layers including, for example, an optional electrode domain (e.g., as illustrated in the FIG.2A), an interference reduction or blocking domain (e.g., as illustrated in FIGS. 2B and 2C), enzyme domain 108, or a cell disruptive domain (not shown).

[0153] FIGs. 3A-3C show exemplary edema suppressing biointerface layer constructs. FIG. 3A shows elongated body 101 having isolated reference electrode 114, window 106 having electroactive surface 103, terminating at distal end 305. Edema suppressing biointerface layer 475 is shown covering at least a portion of distal end 305, sensing membrane 400, and reference electrode 114. Edema suppressing biointerface layer 475 is configured not to substantially interfere with sensing membrane 400, thus allowing at least partial coverage of the sensing membrane.

[0154] FIG. 3B shows elongated body 101 having isolated reference electrode 114, window 106 having electroactive surface 103, terminating at distal end 305 with edema suppressing biointerface layer 475 coated to the same extent as sensing membrane 400 along elongated body 101. In examples, edema suppressing biointerface layer 475 is configured not to substantially interfere with sensing membrane 400, thus allowing at least partial coverage of the sensing membrane.

[0155] FIG. 3C shows elongated body 101 having isolated reference electrode 114, window 106 having electroactive surface 103, terminating at distal end 305 with edema suppressing biointerface layer 475 exposing sensing membrane 400 along elongated body 101.

[0156] FIGs. 4A-4C show alternate exemplary edema suppressing biointerface layer constructs. FIG. 4A shows elongated body 101 having isolated reference electrode 114, window 106 having electroactive surface 103, terminating at distal end 305. Edema suppressing biointerface layer 475 is shown covering at least a portion of distal end 305, sensing membrane 400, drug releasing layer 470, and reference electrode 114. Edema suppressing biointerface layer 475 is configured not to substantially interfere with sensing membrane 400, thus allowing at least partial coverage of the sensing membrane, however, drug releasing layer 470 is positioned away from window 106, electroactive surface 103 and sensing membrane 400 positioned adjacent thereto. FIGs. 4B and 4C depict coatingAttorney Docket No.: 0935-PCT01-0240constructs where edema suppressing biointerface layer 475 and drug releasing layer 470 can be arranged along elongated body 101.

[0157] The configurations shown in FIGs. 3A-4C can be constructed using dip coating, meniscus coating, or electrospray and / or microfluidic coating techniques, such as are disclosed in co-assigned Attorney Docket No. 0931_US01PR_0212, the disclosure of which is incorporated by reference. The configurations shown in FIGs. 3A-4C depict an elongated body sensor, such as a wire substrate, but planar elongated body configurations are encompassed by the present disclosure.

[0158] In aspects, multi-polymer construct for a continuous analyte monitoring device is provided, the multi-polymer composed of a polymer drug releasing coating loading with releasable anti-inflammatory drug (e.g., dexamethasone acetate) and an additional polymer layer adjacent the drug release layer, where the additional polymer layer is configured as a diffusion adjustment layer to delay, attenuate, or modulate drug release of the drug from the drug release layer.

[0159] FIGs. 5A and 5B are a schematic illustrations of an exemplary elongated analyte sensor body 300 with a distal tip dual drug coating construct, where elongated body 101 includes window 106 having sensing membrane 400 and a distal tip 306 extending distally therefrom. Distal tip 306 includes one or more distally positioned layers 350 (from sensing membrane 400) introduced, for example, via dip coating, meniscus coating or electrofluidic coating methods. As illustrated, drug releasing layer 470 is most proximal to distal tip 306, diffusion adjustment layer 485 is positioned adjacent drug releasing layer 470. In examples, diffusion adjustment layer 485 at least partially covers drug releasing layer 470. In examples, diffusion adjustment layer 485 completely covers drug releasing layer 470.

[0160] In examples, diffusion adjustment layer 485 is one or more biodegradable polymers configured to break down and / or disintegrate in the ISF environment. In examples, the one or more biodegradable polymers are derived from natural materials like cornstarch, sugarcane, or potato starch, alone or are mixed with other substances. Upon contact with ISF fluids and / or enzymes in the ISF, they can be broken down into components that will allow the transport of substances from adjacent layers, such as, one or more drugs from an adjacent drug releasing layer 470.Attorney Docket No.: 0935-PCT01-0240

[0161] In examples, diffusion adjustment layer 485 is one or more hydrophilic biodegradable materials, for example a poly(lactic-co-glycolic) acid polymer (PLGA) or copolymer, cellulose-based polymer or copolymer, polyhydroxybutyrate, (PHB)poly (3-hyd roxy butyrate - co-P-hydroxy valerate (PHBV), a hydrophilic hydrogel, the hydrophilic hydrogel is at least partly crosslinked and dissolvable or swellable in biological fluid, and the like. In examples, diffusion adjustment layer 485 is hydroxypropyl methylcellulose (HPMC), poly (lactic-co-glycolic) acid (PLGA), poly lactic acid (PLA) or combinations thereof.

[0162] The thickness of diffusion adjustment layer 485 can be adjusted so as to control the beginning of drug release and / or the rate of drug release from drug releasing layer 470 or to allow the drug to have a drug action, drug effect, e.g., a biochemical or physiological effect. One or more additives can be dispersed or distributed in the diffusion adjustment layer 485 to facilitate and / or catalyze the composition or degradation of the diffusion adjustment layer after contact with ISF.

[0163] FIG. 6 shows examples of sustained release kinetics of drugs from a polymer as Type I, Type II and Type III. Release kinetics or adjustable by manipulation of the hydrophilic and hydrophobic composition polymers or blending of polymers and / or copolymers. Certain drug polymer interactions, e.g., some hydrogen bonding interactions, cause fast release shortly after insertion into the ISF (Kinetics Type II and Type I shown in Fig. 6).

[0164] To achieve delayed release, the present disclosure provides for hydrophilic biodegradable and biocompatible materials adjacent the drug releasing layer configured to suppress burst / bolus release of drugs shortly after insertion into the ISF. The delay time is controllable by degradation kinetics, surface topology, thickness, and surface hydrophilicity of diffusion adjustment coating, among other things.

[0165] Design of hydrophilic biodegradable and biocompatible materials, for example, PLGA polymer chemical composition, includes selecting a mole ratio of lactide acid and glycolic acid in PLGA, molecular weight, and stereochemistry of lactide monomers that allows for tailoring the degradation kinetics of PLGA coatings. With careful design and control of PLGA formulations, desired delayed drug release kinetics (Type III shown in Figure 6) are achievable.

[0166] In examples, an exemplary PLGA based diffusion adjustment layer 485 was evaluated on a bare wire, using a thermoplastic polyurethane (TPU) or TPU-urea distal tipAttorney Docket No.: 0935-PCT01-0240coated drug releasing layer 470 having about 45 weight percent of dexamethasone acetate covering the entire tip and working electrode area. A PLGA diffusion adjustment layer was dipped to cover the drug releasing coating. Different PLGA coating thickness were evaluated (20 um, 10 um and 5 um) and are shown in FIG. 7.

[0167] As shown in FIG. 7 , a uniform PLGA coating applied on the top of a drug releasing layer provided controlled diffusion resistance of dexamethasone acetate release rate from the drug diffusion layer. The PLGA overcoat thickness is controllable by dipping parameters (such as retracting speed) and formulations (e.g., PLGA polymer concentration, solvent type, and viscosity). Various solvents for PLGA formulations can be used, such as dichloromethane, chloroform, THF, ethanol, ethyl acetate or combination of those.

[0168] With the exemplary PLGA diffusion adjustment layer, the delayed release kinetics were observed compared to control group without diffusion adjustment layer. In first 2 days, controls 601, 602 having drug releasing layers without PLGA overcoat had 15 wt. % dexamethasone acetate released. In contrast, samples 603, 605 with PLGA diffusion adjustment layer, the release kinetics were suppressed, with less than 2 wt.% dexamethasone acetate released. It was observed that the thickness of the PLGA diffusion adjustment layer at little impact on release kinetics.

[0169] After 5 days, the example PLGA diffusion adjustment layer coated sensors showed similar dexamethasone acetate release kinetics compared to control. The real time drug release kinetics demonstrates that applying a diffusion adjustment layer over a drug releasing layer of a implantable sensors suppress day 1 release and achieves controlled sustained release profiles through EOL.

[0170] In aspects, a multi-polymer coated continuous analyte monitoring sensor is provided having at least one layer comprising one or more anti-inflammatory or tissue response modifier drugs coupled to a polymer backbone. Coupled to the polymer backbone can be covalent or ionic. In examples, the one or more anti-inflammatory or tissue response modifier drugs are covalently coupled to a polymer backbone via a linker. In examples, the linker is biologically degradable in the presence of ISF.

[0171] In examples, the one or more anti-inflammatory or tissue response modifier drugs coupled to a polymer backbone can be considered pro-drugs, as when they are conjugated to polymer backbone, substantially no appreciable anti-inflammatory or tissueAttorney Docket No.: 0935-PCT01-0240response modification function is provided. When the linker is cleaved and the one or more anti-inflammatory or tissue response modifier drugs are released to the surrounding environment, the one or more anti-inflammatory or tissue response modifier drugs become active.

[0172] In other examples, when the one or more anti-inflammatory or tissue response modifier drugs are coupled to polymer backbone, at least some anti-inflammatory or tissue response modification function is provided, whereas, post insertion, the linker is cleaved and the one or more anti-inflammatory or tissue response modifier drugs are released to the surrounding environment, the anti-inflammatory or tissue response modification function is increased relative to the coupled analog.

[0173] FIG. 8 shows a drug releasing layer 471 construct comprising polymer backbone 501 having linker moiety 502 coupling drug 503 to the polymer backbone. Linker moiety 502 and coupled drug 503 can be randomly or sequentially arranged along the backbone 501. In examples, biodegradable linker moiety 502 comprises one or more chemical bonds between drug 503 and polymer backbone 501 configured to be susceptible to enzymatic degradation or other biological processes in the ISF.

[0174] In examples, linker moiety 502 is configured to gradually release drug 503 over time. In other examples, linker moiety 502 is configured to rapidly release drug 503 over time. In other examples, a first linker moiety 502 is configured to gradually release drug 503 over time while a second linker moiety 502 is configured to rapidly release drug 503 over time. One or more linker moieties 502 can be employed to achieve a desired drug rate profile, for example, a bolus release followed by a sustained-release profile. By varying the nature of the chemical constituents of the linker moieties 502 (esters, amides, ethers, etc. and their pH and / or enzyme sensitivity) the rate of release of drug 503 can be controlled.

[0175] In examples, at least two chemically or therapeutically different antiinflammatory or tissue response modifier drugs are coupled to polymer backbone 501. In examples, the at least two chemically or therapeutically different anti-inflammatory or tissue response modifier drugs are coupled to polymer backbone 501 with different linker moiety chemistries so as to control the temporal release and / or release rate of the chemically different drugs.Attorney Docket No.: 0935-PCT01-0240

[0176] In examples, at least one of the at least two chemically or therapeutically different anti-inflammatory or tissue response modifier drugs are covalently coupled via the linker moiety 502 to polymer backbone 501. In examples, at least one of the at least two chemically or therapeutically different anti-inflammatory or tissue response modifier drugs are ionically coupled via the linker moiety 502 to polymer backbone 501.

[0177] FIG. 9 shows an exemplary membrane stack comprising the polymer coupled anti-inflammatory or tissue response modifying drug layer 471 adjacent sensing membrane or hundred which can include blocking layer 430, enzyme layer 440, and diffusion resistance layer 460 provided on an elongated substrate 101, which can be of a wire or planer construction. Optional diffusion adjustment layer 475 can be employed adjacent at least part of drug layer 471 to further adjust or control drug release. As mentioned above, diffusion adjustment layer 475 and be configured to degrade in the presence of ISF and provide one or more degradation products capable of assisting or catalyzing degradation of the linker moiety 502.

[0178] Nonlimiting examples of one or more anti-inflammatory ortissue response modifying drugs configured for coupling to a polymer backbone, using dexamethasone structure with a modifiable OH functional group are shown in Scheme II:Scheme II

[0179] where the OH functional groups are modified with unsaturated esters. The ester group provides for a biodegradable linker moiety configured to release dexamethasone in certain environments, (ex. low pH, ISF present enzymes). In examples, unsaturated linkage as shown in Scheme II is configured for click-chemistry with a suit city functionalized or functionalizable polymer backbone.Attorney Docket No.: 0935-PCT01-0240

[0180] Examples of functionalized drug-linker moieties and functionalized polymer backbones for click-chemistry include CuAAC (Copper-Catalyzed Azide-Alkyne Cycloaddition) Reaction; Strain-promoted azide-alkyne cycloaddition (SPAAC); Thiol-Ene Reaction; Diels-Alder Reaction; and Tetrazine Click Chemistry.

[0181] In examples, the functionalized drug-linker moieties and functionalized polymer backbones are configured for click-to-release, where a click reaction triggers the release of the drug from the linker, for example, drug-linker CuAAC or SPAAC, that releases the drug. Click-to-release is highly selective and can be tailored to release the drug molecule under specific conditions, such as in response to a particular enzyme or pH level.Sensing Membrane

[0182] In examples, a sensing membrane 400 is disposed over the electroactive surface 103 of the continuous analyte sensor 100 and includes one or more domains or layers. In general, the sensing domain functions to control the flux of a biological fluid there through and / or to protect sensitive regions of the sensor from contamination by the biological fluid, provide a matrix for one or more enzymes, and interface with the in vivo environment, for example. Some conventional electrochemical enzyme-based analyte sensors generally include a sensing domain that controls the flux of the analyte being measured, protects the electrodes from contamination of the biological fluid, and / or provides an enzyme that catalyzes the reaction of the analyte with a co-factor, for example. See, e.g., U.S. Patent Publication No. 2005 / 0245799, filed May 3, 2004 entitled “IMPLANTABLE ANALYTE SENSOR" and U.S. Patent No. 7,497,827, filed Mar. 10, 2005 and entitled "TRANSCUTANEOUS ANALYTE SENSOR" which are incorporated herein by reference in their entireties.

[0183] The sensing domains of the present disclosure can include any membrane configuration suitable for use with any analyte sensor. In general, the sensing domains of the present disclosure include one or more domains, all or some of which can be adhered to or deposited on the analyte sensor as is appreciated by one skilled in the art. In examples, the sensing domain generally provides one or more of the following functions: 1) protection of the exposed electrode surface from the biological environment, 2) diffusion resistance (limitation) of the analyte, 3) a catalyst for enabling an enzymatic reaction, 4) limitation or blocking of interfering species, and 5) hydrophilicity at the electrochemically reactiveAttorney Docket No.: 0935-PCT01-0240surfaces of the sensor interface, such as described in the above-referenced co-pending U.S. patent applications.

[0184] Accordingly, in examples, the sensing membrane is designed with a sensitivity of from about 1 pA / mg / dL to about 100 pA / mg / dL, preferably from about 5 pA / mg / dL to 25 pA / mg / dL, and more preferably from about 4 to about 7 pA / mg / dL. While not wishing to be bound by any particular theory, it is believed that membrane systems designed with a sensitivity in the preferred ranges permit measurement of the analyte signal in low analyte and / or low oxygen situations. Namely, conventional analyte sensors have shown reduced measurement accuracy in low analyte ranges due to lower availability of the analyte to the sensor and / or have shown increased signal noise in high analyte ranges due to insufficient oxygen necessary to react with the amount of analyte being measured. While not wishing to be bound by theory, it is believed that the membrane systems of the present disclosure, in combination with the electronic circuitry design and exposed electrochemical reactive surface area design, support measurement of the analyte in the picoampere range or less, which enables an improved level of resolution and accuracy in both low and high analyte ranges not seen in the prior art.Electrode Domain

[0185] In some examples, the membrane system comprises an optional electrode domain. The electrode domain is provided to ensure that an electrochemical reaction occurs between the electroactive surface 103 of the working electrode and the reference electrode, and thus the electrode domain is preferably situated more proximal to the electroactive surface 103 than the enzyme domain. Preferably, the electrode domain includes a semipermeable coating that maintains a layer of water at the electrochemically reactive surfaces of the sensor, for example, a humectant in a binder material can be employed as an electrode domain; this allows for the full transport of ions in the aqueous environment. The electrode domain can also assist in stabilizing the operation of the sensor by overcoming electrode start-up and drifting problems caused by inadequate electrolyte. The material that forms the electrode domain can also protect against pH-mediated damage that can result from the formation of a large pH gradient due to the electrochemical activity of the electrodes.Attorney Docket No.: 0935-PCT01-0240

[0186] In certain examples, the electrode domain is formed of a curable mixture of a urethane polymer and a hydrophilic polymer. Particularly preferred coatings are formed of a polyurethane polymer having carboxylate functional groups and non-ionic hydrophilic polyether segments, wherein the polyurethane polymer is crosslinked with a water soluble carbodiimide (e.g., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC))) in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

[0187] Although an independent electrode domain is described herein, in some examples, sufficient hydrophilicity can be provided in the interference domain and / or enzyme domain (the domain adjacent to the electroactive surface 103) so as to provide for the full transport of ions in the aqueous environment (e.g. without a distinct electrode domain).Interference Domain

[0188] In some examples, an optional interference domain is provided, which generally includes a polymer domain that restricts the flow of one or more interferants. In some examples, the interference domain functions as a molecular sieve that allows analytes and other substances that are to be measured by the electrodes to pass through, while preventing passage of other substances, including interferants such as ascorbate and urea (see U.S. Pat. No. 6,001,067 to Shults). Some known interferants for a glucose-oxidase based electrochemical sensor include acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid.

[0189] Several polymer types that can be utilized as a base material for the interference domain include polyurethanes, polymers having pendant ionic groups, and polymers having controlled pore size, for example. In examples, the interference domain includes a thin, hydrophobic membrane that is non-swellable and restricts diffusion of low molecular weight species. The interference domain is permeable to relatively low molecular weight substances, such as hydrogen peroxide, but restricts the passage of higher molecular weight substances, including glucose and ascorbic acid. Other systems and methods for reducing or eliminating interference species that can be applied to the membrane system of the present disclosure are described in U.S. Patent No. 7,074,307 filed Jul. 21, 2004 and entitled "ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS," Patent Publication No.Attorney Docket No.: 0935-PCT01-02402005 / 0176136, filed Nov. 16, 2004 and entitled, "AFFINITY DOMAIN FOR AN ANALYTE SENSOR," Patent No. 7,081,195, filed Dec. 7, 2004 and entitled "SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS" and Patent No. 7,715,893, filed Dec. 3, 2004 and entitled, "CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR." In some alternative examples, a distinct interference domain is not included. Enzyme Domain

[0190] In examples, the membrane system further includes an enzyme domain disposed more distally from the electroactive surface 103 than the interference domain (or electrode domain when a distinct interference is not included). In some examples, the enzyme domain is directly deposited onto the electroactive surface 103 (when neither an electrode or interference domain is included). In examples, the enzyme domain provides an enzyme to catalyze the reaction of the analyte and its co-reactant, as described in more detail below. Preferably, the enzyme domain includes glucose oxidase; however other oxidases, for example, galactose oxidase or uricase oxidase, can also be used.

[0191] For an enzyme-based electrochemical glucose sensor to perform well, the sensor's response is preferably limited by neither enzyme activity nor co-reactant concentration. Because enzymes, including glucose oxidase, are subject to deactivation as a function of time even in ambient conditions, this behavior is compensated for in forming the enzyme domain. Preferably, the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme. However, in alternative examples the enzyme domain is constructed from an oxygen enhancing material, for example, silicone, or fluorocarbon, in order to provide a supply of excess oxygen during transient ischemia. Preferably, the enzyme is immobilized within the domain. See U.S. Patent No. 7,379,765 filed on Jul. 21, 2004 and entitled "Oxygen Enhancing Membrane Systems for Implantable Device."Resistance Domain

[0192] In examples, the membrane system includes a resistance domain disposed more distal from the electroactive surface 103 than the enzyme domain. Although the following description is directed to a resistance domain fora glucose sensor, the resistance domain can be modified for other analytes and co-reactants as well.Attorney Docket No.: 0935-PCT01-0240

[0193] There exists a molar excess of glucose relative to the amount of oxygen in blood; that is, for every free oxygen molecule in extracellular fluid, there are typically more than 100 glucose molecules present (see Updike et al., Diabetes Care 5:207-21(1982)). However, an immobilized enzyme-based glucose sensor employing oxygen as co-reactant is preferably supplied with oxygen in non-rate-limiting excess in order for the sensor to respond linearly to changes in glucose concentration, while not responding to changes in oxygen concentration. Specifically, when a glucose-monitoring reaction is oxygen limited, linearity is not achieved above minimal concentrations of glucose. Without a semipermeable membrane situated over the enzyme domain to control the flux of glucose and oxygen, a linear response to glucose levels can be obtained only for glucose concentrations of up to about 40 mg / dL. However, in a clinical setting, a linear response to glucose levels is desirable up to at least about 400 mg / dL.

[0194] The resistance domain includes a semi-permeable membrane that controls the flux of oxygen and glucose to the underlying enzyme domain, preferably rendering oxygen in a non-rate-limiting excess. As a result, the upper limit of linearity of glucose measurement is extended to a much higher value than that which is achieved without the resistance domain. In examples, the resistance domain exhibits an oxygen to glucose permeability ratio of from about 50:1 or less to about 400:1 or more, preferably about 200:1. As a result, onedimensional reactant diffusion is adequate to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (See Rhodes et al., Anal. Chem., 66:1520-1529 (1994)).

[0195] In a preferred example, the resistance domain includes a polyurethane membrane with both hydrophilic and hydrophobic regions to control the diffusion of glucose and oxygen to an analyte sensor, the membrane being fabricated easily and reproducibly from commercially available materials. A suitable hydrophobic polymer component is a polyurethane, or polyetherurethaneurea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxylcontaining material. A polyurethaneurea is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material. Preferred diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be useful in the preparationAttorney Docket No.: 0935-PCT01-0240of the polymer and copolymer components of the membranes of the present disclosure. The material that forms the basis of the hydrophobic matrix of the resistance domain can be any of those known in the art as appropriate for use as membranes in sensor devices and as having sufficient permeability to allow relevant compounds to pass through it, for example, to allow an oxygen molecule to pass through the membrane from the sample under examination in order to reach the active enzyme or electrochemical electrodes. Examples of materials which can be used to make non-polyurethane type membranes include vinyl polymers, polyethers, polyesters, polyamides, inorganic polymers such as polysiloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein-based materials, and mixtures or combinations thereof.

[0196] In a preferred example, the hydrophilic polymer component of the resistance domain is polyethylene oxide. For example, one useful hydrophobic-hydrophilic copolymer component is a polyurethane polymer that includes about 20% hydrophilic polyethylene oxide. The polyethylene oxide portions of the copolymer are thermodynamically driven to separate from the hydrophobic portions of the copolymer and the hydrophobic polymer component. The 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend affects the water pick-up and subsequent glucose permeability of the membrane.Interference-Free Membrane Systems

[0197] Although sensors of some examples described herein include an optional interference domain in order to block or reduce one or more interferants, sensors with the membrane system of the present disclosure, including an electrode domain, an enzyme domain, and a resistance domain, have been shown to inhibit ascorbate without an additional interference domain. Namely, the membrane system of the present disclosure, including an electrode domain, an enzyme domain, and a resistance domain, has been shown to be substantially non-responsive to ascorbate in physiologically acceptable ranges. While not wishing to be bound by theory, it is believed that the process of depositing the resistance domain by spray coating, as described herein, results in a structural morphology that is substantially resistance resistant to ascorbate.

[0198] In general, it is believed that appropriate solvents and / or deposition methods can be chosen for one or more of the domains of the membrane system that form one orAttorney Docket No.: 0935-PCT01-0240more transitional domains such that interferants do not substantially permeate there through. Thus, sensors can be built without distinct or deposited interference domains, which are non-responsive to interferants. While not wishing to be bound by theory, it is believed that a simplified multilayer membrane system, more robust multilayer manufacturing process, and reduced variability caused by the thickness and associated analyte sensitivity of the deposited micron-thin interference domain can be provided. Additionally, the optional polymer-based interference domain, which usually inhibits hydrogen peroxide diffusion, is eliminated, thereby enhancing the amount of hydrogen peroxide that passes through the membrane system.Sensing Membrane Compositions

[0199] In some examples, one or more domains of the sensing systems are formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polyureas, polyurethane ureas, polyethers, polypropylene (PP), polyvinylchloride (PVC), polyvinyl pyridine, polyvinyl pyridine-co-polystyrene, polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), cellulosic polymers, polyethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers. U.S. Publication No. 2005 / 0245799, which is incorporated herein by reference in its entirety, describes biointerface and sensing domain configurations and materials that may be applied to the presently disclosed sensor.

[0200] In other examples, on or more membranes, domains, or layers of the sensing system is a block copolymer, e.g., a polyurethane block polymer with a hard segment and a soft segment, where the soft segment can comprise a hydrophobic portion, a hydrophilic portion, or a combination of hydrophobic / hydrophilic portion. Each of the of hydrophobic / hydrophilic portions can independently be of a different average molecular weight or chain length. In other examples, the diffusion adjustment membrane is a segmented block copolymer of hydrophobic / hydrophilic portions and one or more independent hard segments, e.g. an aliphatic or aromatic diisocyanate such as norbornane diisocyanate (NBDI), isophorone diisocynate (I PDI), tolylene diisocynate (TDI), 1,3-phenyleneAttorney Docket No.: 0935-PCT01-0240diisocyanate (MPDI), trans-l,3-bis(isocynatomethyl) cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocynate(HMDI), 4,4'-Diphenylmethane diisocynate (MDI), trans-l,4-bis(isocynatomethyl) cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocynate (CHDI), 1,4-phenylene diisocynate (PPDI), 3,3'-Dimethyl-4,4'-biphenyldiisocyanate (TODI), 1,6-hexamethylene diisocyanate ( H DI), or combinations thereof.

[0201] In other examples, the diffusion adjustment membrane is a multi-block copolymer. In other examples, the diffusion adjustment membrane is annealed to provide stable separated phases and / or diffusion channels for release of bioactive agent. In examples, the diffusion adjustment membrane is continuously, semi-continuously, or segmentally (randomly or in a pattern) applied over the bioactive releasing membrane 470.

[0202] The sensing membrane can be deposited on the electroactive surface 103 of the electrode material using known thin or thick film techniques (for example, spraying, electrodepositing, dipping, or the like) or by meniscus coating or microfluidic coating method, for example, as disclosed in co-assigned Attorney Docket No. 0931_US01PR_0212. It is noted that the sensing membrane that surrounds the working electrode does not have to be the same structure as what surrounds a reference electrode, etc. For example, the enzyme domain deposited over the working electrode does not necessarily need to be deposited over the reference and / or counter electrodes.

[0203] In examples, the sensor is an enzyme-based electrochemical sensor, wherein the working electrode measures electronic current, e.g. detection of hydrogen peroxide H2O2 as a by-product, or via direct electron transfer of a redox system, e.g., a "wired enzyme" system. One or more potentiostats is employed to monitor the electrochemical reaction at the electroactive surface 103 of the working electrode(s). The potentiostat applies a constant potential to the working electrode and its associated reference electrode to determine the current produced at the working electrode. The current that is produced at the working electrode (and flows through the circuitry to the counter electrode) is substantially proportional to the amount of H2O2 that diffuses to the working electrode or analyte that facilitates electron transfer in the wired enzyme system. The output signal is typically a raw data stream that is used to provide a useful value of the measured analyte concentration in a host to the host or doctor, for example.Attorney Docket No.: 0935-PCT01-0240

[0204] Some alternative analyte sensors that can benefit from the systems and methods of the present disclosure include U.S. Pat. No. 5,711,861 to Ward et al., U.S. Pat. No.6,642,015 to Vachon et al., U.S. Pat. No. 6,654,625 to Say et al., U.S. Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,514,718 to Heller, U.S. Pat. No. 6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,185 to Offenbacher et al., U.S. Pat. No. 5,310,469 to Cunningham et al., and U.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No. 6,579,690 to Bonnecaze et al., U.S. Pat. No. 6,484,046 to Say et al., U.S. Pat. No. 6,512,939 to Colvin et al., U.S. Pat. No. 6,424,847 to Mastrototaro et al., U.S. Pat. No. 6,424,847 to Mastrototaro et al., for example. All of the above patents are incorporated in their entireties herein by reference and are not inclusive of all applicable analyte sensors; in general, it should be understood that the disclosed examples are applicable to a variety of analyte sensor configurations.

[0205] The sensor of the present disclosure may be inserted into a variety of locations on the host's body, such as the abdomen, the thigh, the upper arm, and the neck or behind the ear. Although the present disclosure may suggest insertion through the abdominal region, the systems and methods described herein are limited neither to the abdominal nor to the subcutaneous insertions. One skilled in the art appreciates that these systems and methods may be implemented and / or modified for other insertion sites and may be dependent upon the type, configuration, and dimensions of the analyte sensor.

[0206] Transcutaneous / subcutaneous continuous analyte sensors can be used in vivo over various lengths of time. For example, the device includes a sensor, for measuring the analyte in the host, a porous, biocompatible matrix covering at least a portion of the sensor, and an applicator, for inserting the sensor through the host's skin. In some examples, the sensor has architecture with at least one dimension less than about 1 mm. However, one skilled in the art will recognize that alternative configurations are possible and may be desirable, depending upon factors such as intended location of insertion, for example. The sensor is inserted through the host's skin and into the underlying tissue, such as soft tissue or fatty tissue.

[0207] After insertion, fluid moves into the spacer, e.g., a biocompatible matrix or membrane, such as the bioactive releasing membrane 470 and / or biointerface membrane 480, creating a fluid-filled pocket therein. This process may occur immediately or may take place over a period of time, such as several minutes or hours post insertion. A signal fromAttorney Docket No.: 0935-PCT01-0240the sensor is then detected, such as by the sensor electronics unit located in the mounting unit on the surface of the host's skin. In general, the sensor may be used continuously for a period of days, such as 1 to 7 days, 14 days, or 21 days. After use, the sensor is simply removed from the host's skin. In examples, the host may repeat the insertion and detection steps as many times as desired. In some implementations, the sensor may be removed after about 14 days or more, and then another sensor inserted, and so on. Similarly, in other implementations, the sensor is removed after about 3, 5, 7, 10 or 21 days, followed by insertion of a new sensor, and so on.

[0208] Some examples of transcutaneous analyte sensors are described in U.S. Pat. No.8,133,178 to Brauker et al., which is incorporated herein by reference in its entirety, as well as U.S. Pat. Nos. 8,828,201, Simpson, et al.; 9,131,885 Simpson, et al.; 9,237,864, Simpson, et al.; and 9,763, 608, Simpson, et al., each of which is incorporated by reference in its entirety herein. In general, transcutaneous analyte sensors comprise the sensor and a mounting unit with electronics associated therewith.

[0209] PCT Publication No. WO2024144921 and U.S. Publication No. 2024 / 0090802, which are incorporated herein by reference in their entireties, describe drug releasing-, biointerface-, and sensing-membrane configurations and materials that are to be applied to elongated bodies. Suitable bioactive agents include those which are known to discourage or prevent inflammation, bacterial growth and infection, for example, anti-inflammatory agents, antimicrobials, antibiotics, or the like.Biointerface Membrane / Layer

[0210] In examples, the sensor includes a porous material disposed over some portion thereof, which modifies the host's tissue response to the sensor. In some examples, the porous material surrounding the sensor advantageously enhances and extends sensor performance and lifetime by slowing or reducing cellular migration to the sensor and associated degradation that would otherwise be caused by cellular invasion if the sensor were directly exposed to the in vivo environment. Alternatively, the porous material can provide stabilization of the sensor via tissue ingrowth into the porous material in the long term. Suitable porous materials include silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymersAttorney Docket No.: 0935-PCT01-0240of polyurethanes, polyureas, polyurethane ureas, polyethers, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyamides, cellulosic polymers, poly(ethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers, as well as metals, ceramics, cellulose, hydrogel polymers, poly(2-hydroxyethyl methacrylate, pHEMA), hydroxyethyl methacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC), high density polyethylene, acrylic copolymers, nylon, polyvinyl difluoride, polyanhydrides, poly(l-lysine), poly(L-lactic acid), hydroxyethyl metharcrylate, hydroxyapeptite, alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium, titanium alloy, nintinol, stainless steel, and CoCr alloy, or the like, such as are described in co-pending U.S. Patent No.7,875,293, filed May 10, 2004 and entitled, "BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVE AGENTS" and U.S. Patent No. 7,192,450filed Aug. 22, 2003 and entitled "POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES," which are incorporated by reference herein in their entireties.

[0211] When used herein, the terms "membrane" and "layer" are meant to be interchangeable. In these examples, the aforementioned porous material is a biointerface membrane comprising a first domain that includes an architecture, including cavity size, configuration, and / or overall thickness, that modifies the host's tissue response, for example, by creating a fluid pocket, encouraging vascularized tissue ingrowth, disrupting downward tissue contracture, resisting fibrous tissue growth adjacent to the device, and / or discouraging barrier cell formation. The biointerface membrane in examples covers at least the sensing mechanism of the sensor and can be of any shape or size, including uniform, asymmetrically, or axi-symmetrically covering or surrounding a sensing mechanism or sensor.

[0212] A second domain of the biointerface membrane is optionally provided that is impermeable to cells and / or cell processes. A bioactive agent is optionally provided that is incorporated into the at least one of the first domain, the second domain, the sensing domain, or other part of the implantable device, wherein the bioactive agent is configured to modify a host tissue response. In examples, the biointerface includes a bioactive agent,Attorney Docket No.: 0935-PCT01-0240the bioactive agent being incorporated into at least one of the first and second domains of the biointerface membrane, or into the device and adapted to diffuse through the first and / or second domains, in order to modify the tissue response of the host to the membrane.

[0213] Due to the small dimension(s) of the sensor (sensing mechanism) of the present disclosure, some conventional methods of porous membrane formation and / or porous membrane adhesion are inappropriate for the formation of the biointerface membrane onto the sensor as described herein. Accordingly, the following examples exemplify systems and methods for forming and / or adhering a biointerface membrane onto a small structured sensor as defined herein. For example, the biointerface membrane or release membrane of the present disclosure can be formed onto the sensor using techniques such as electrospinning, molding, weaving, direct-writing, lyophilizing, wrapping, and the like.

[0214] In examples wherein the biointerface is directly-written onto the sensor, a dispenser dispenses a polymer solution using a meniscus coater, microfluidic coater, or nozzle with a valve, or the like, for example as described in U.S. Publication No.2004 / 0253365 Al and Attorney Docket No. 0931_US01PR_0212. In general, a variety of nozzles and / or dispensers can be used to dispense a polymeric material to form the the biointerface membrane.Bioactive Agent / Bioactive Agent Releasing Layer

[0215] It is understood that "bioactive agent" is used herein to encompass antiinflammatory drugs or tissue response modifiers and vasodilation drugs as disclosed herein. It is understood that "bioactive agent releasing layer" is used herein to encompass the drug releasing layer 470 and / or diffusion adjustment layer 485.

[0216] In general, bioactive agents that are believed to modify tissue response include anti-inflammatory agents, anti-infective agents, anti-proliferative agents, anti-histamine agents, anesthetics, inflammatory agents, growth factors, angiogenic (growth) factors, adjuvants, immunosuppressive agents, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-barrier cell compounds, vascularization compounds, anti-sense molecules, vasodilation agents, and the like. In some examples, bioactive agents include SIP (Sphingosine-l-phosphate), Monobutyrin, Cyclosporin A, Anti-thrombospondin-2, Rapamycin (and its derivatives), NLRP3 inflammasome inhibitors such as MCC950, andAttorney Docket No.: 0935-PCT01-0240Dexamethasone (and its derivatives). However, other bioactive agents, biological materials (for example, proteins), or even non-bioactive substances can incorporated into the membranes of the present disclosure.

[0217] Bioactive agents suitable for use in the present disclosure are loosely organized into two groups: anti-barrier cell agents and vascularization agents. These designations reflect functions that are believed to provide short-term solute transport through the one or more membranes of the presently disclosed sensor, and additionally extend the life of a healthy vascular bed and hence solute transport through the one or more membranes long term in vivo. However, not all bioactive agents can be clearly categorized into one or other of the above groups; rather, bioactive agents generally comprise one or more varying mechanisms for modifying tissue response and can be generally categorized into one or both of the above-cited categories.

[0218] In examples, dexamethasone, dexamethasone salts, or dexamethasone derivatives in particular, dexamethasone acetate, which, for example, abates the intensity of the FBC response at the device-tissue interface, is incorporated into the bioactive releasing membrane 470. In other examples, a combination of dexamethasone and dexamethasone acetate is incorporated into the bioactive releasing membrane 470. In other examples, dexamethasone and / or dexamethasone acetate combined with one or more other anti-inflammatory and / or immunosuppressive agents is incorporated into the bioactive releasing membrane 470. Alternatively, Rapamycin, which is a potent specific inhibitor of some macrophage inflammatory functions, can be incorporated into the release membrane alone or in combination with dexamethasone, dexamethasone salts, dexamethasone derivatives in particular, dexamethasone acetate.

[0219] Other suitable medicaments, pharmaceutical compositions, therapeutic agents, or other desirable substances can be incorporated into the bioactive releasing membrane 470 of the present disclosure, including, but not limited to, anti-inflammatory agents, anti-infective agents, necrosing agents, and anesthetics.

[0220] Generally, anti-inflammatory agents reduce acute and / or chronic inflammation adjacent to the implant, in order to decrease the formation of a FBC capsule to reduce or prevent barrier cell layer formation. Suitable anti-inflammatory agents include but are not limited to, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) such asAttorney Docket No.: 0935-PCT01-0240acetometaphen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflu nisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-IO, IL-6 mutein, anti-IL-6 iNOS inhibitors (for example, L-NAME or L-NMDA), Interferon, ketoprofen, ketorolac, leflunomide, melenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin; and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethesone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, NLRP3 inflammasome inhibitors such as MCC950, dexamethasone, and dexamethasone acetate.

[0221] Generally, immunosuppressive and / or immunomodulatory agents interfere directly with several key mechanisms necessary for involvement of different cellular elements in the inflammatory response. Suitable immunosuppressive and / or immunomodulatory agents include anti-proliferative, cell-cycle inhibitors, (for example, paclitaxol (e.g., Sirolimus), cytochalasin D, infiximab), taxol, actinomycin, mitomycin, thospromote VEGF, estradiols, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methothrexate, mycophenolic acid, angiopeptin, vincristing, mitomycine, statins, C MYC antisense, sirolimus (and analogs), RestenASE, 2-chloro-deoxyadenosine, proliferating cell nuclear antigen (PCNA) Ribozyme, batimstat, prolyl hydroxylase inhibitors, PPARy ligands (for example troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catchins, glycating agents, endothelin inhibitors (for example, Ambrisentan, Tesosentan, Bosentan), Statins (for example, Cerivasttin), E. coli heat-labile enterotoxin, and advanced coatings.

[0222] Generally, anti-infective agents are substances capable of acting against infection by inhibiting the spread of an infectious agent or by killing the infectious agent outright, which can serve to reduce immuno-response without inflammatory response at the implant site. Anti-infective agents include, but are not limited to, anthelmintics (mebendazole), antibiotics including aminoclycosides (gentamicin, neomycin, tobramycin), antifungalAttorney Docket No.: 0935-PCT01-0240antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcil lin), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; colistimethate sodium; polymyxin b sulfate; vancomycin; antivirals including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum; gatifloxacin; and sulfa methoxazole / trimethoprim.

[0223] Generally, necrosing agents are any drug that causes tissue necrosis or cell death. Necrosing agents include cisplatin, BCNU, taxol or taxol derivatives, and the like.Vascularization Agents

[0224] Generally, vascularization agents include substances with direct or indirect angiogenic properties. In some cases, vascularization agents may additionally affect formation of barrier cells in vivo. By indirect angiogenesis, it is meant that the angiogenesis can be mediated through inflammatory or immune stimulatory pathways. It is not fully known how agents that induce local vascularization indirectly inhibit barrier-cell formation; however it is believed that some barrier-cell effects can result indirectly from the effects of vascularization agents.

[0225] Vascularization agents include mechanisms that promote neovascularization around the membrane and / or minimize periods of ischemia by increasing vascularization close to the device-tissue interface. Sphingosine-l-Phosphate (SIP), which is a phospholipid possessing potent angiogenic activity, is incorporated into a biointerface membrane or release membrane of examples. Monobutyrin, which is a potent vasodilator and angiogenic lipid product of adipocytes, is incorporated into a biointerface membrane or release membrane of other examples. In other examples, an anti-sense molecule (for example, thrombospondin-2 anti-sense), which increases vascularization, is incorporated into a biointerface membrane or release membrane.Attorney Docket No.: 0935-PCT01-0240

[0226] Vascularization agents can include mechanisms that promote inflammation, which is believed to cause accelerated neovascularization in vivo. In examples, a xenogenic carrier, for example, bovine collagen, which by its foreign nature invokes an immune response, stimulates neovascularization, and is incorporated into a biointerface membrane or release membrane of the present disclosure. In other examples, Lipopolysaccharide, which is a potent immunostimulant, is incorporated into a biointerface membrane or release membrane. In other examples, a protein, for example, a bone morphogenetic protein (BMP), which is known to modulate bone healing in tissue, is incorporated into a biointerface membrane or release membrane of examples.

[0227] Generally, angiogenic agents are substances capable of stimulating neovascularization, which can accelerate and sustain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include, but are not limited to, copper ions, iron ions, tridodecylmethylammonium chloride, Basic Fibroblast Growth Factor (bFGF), (also known as Heparin Binding Growth Factor-ll and Fibroblast Growth Factor II), Acidic Fibroblast Growth Factor (aFGF), (also known as Heparin Binding Growth Factor-1 and Fibroblast Growth Factor-1), Vascular Endothelial Growth Factor (VEGF), Platelet Derived Endothelial Cell Growth Factor BB (PDEGF-BB), Angiopoietin-1, Transforming Growth Factor Beta (TGF-Beta), Transforming Growth Factor Alpha (TGF-Alpha), Hepatocyte Growth Factor, Tumor Necrosis Factor-Alpha (TNF-Alpha), Placental Growth Factor (PLGF), Angiogenin, lnterleukin-8 (IL-8), Hypoxia Inducible Factor-1 (HIF-1), Angiotensin-Converting Enzyme (ACE) Inhibitor Quinaprilat, Angiotropin, Thrombospondin, Peptide KGHK, Low Oxygen Tension, Lactic Acid, Insulin, Copper Sulphate, Estradiol, prostaglandins, cox inhibitors, endothelial cell binding agents (for example, decorin or vimentin), glenipin, hydrogen peroxide, nicotine, and Growth Hormone.

[0228] Generally, pro-inflammatory agents are substances capable of stimulating an immune response in host tissue, which can accelerate or sustain formation of a mature vascularized tissue bed. For example, pro-inflammatory agents are generally irritants or other substances that induce chronic inflammation and chronic granular response at the implantation-site. While not wishing to be bound by theory, it is believed that formation of high tissue granulation induces blood vessels, which supply an adequate or rich supply ofAttorney Docket No.: 0935-PCT01-0240analytes to the device-tissue interface. Pro-inflammatory agents include, but are not limited to, xenogenic carriers, Lipopolysaccharides, S. aureus peptidoglycan, and proteins.

[0229] Other substances that can be incorporated into membranes of the present disclosure include various pharmacological agents, excipients, and other substances well known in the art of pharmaceutical formulations. For example, one or more vasodilators can be incorporated into membranes of the present disclosure, including phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, Hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L-arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, and combinations thereof.

[0230] Although the bioactive agent in some examples is incorporated into the biointerface membrane or release membrane and / or implantable device, in some examples the bioactive agent can be administered concurrently with, prior to, or after implantation of the device systemically, for example, by oral administration, or locally, for example, by subcutaneous injection near the implantation site. A combination of bioactive agent incorporated in the biointerface membrane and bioactive agent administration locally and / or systemically can be preferred in certain examples.

[0231] In examples, the drug releasing layer 470 and / or diffusion adjustment layer 485 functions as the biointerface layer 480. In other examples, the bioactive releasing layer 470 is chemically distinct from the biointerface layer 480, or no biointerface layer 480 is used. In such examples, one or more bioactive agents are incorporated into the bioactive releasing layer 470 or both the biointerface layer 480 and the bioactive releasing layer 470.

[0232] Generally, numerous variables can affect the pharmacokinetics of bioactive agent release. The bioactive agents of the present disclosure can be optimized for short- and / or extended release. In some examples, the bioactive agents of the present disclosure are designed to aid or overcome factors associated with short-term effects (for example, acute inflammation) of the foreign body response, which can begin as early as the time of implantation and extend up to about one month after implantation. In some examples, the bioactive agents of the present disclosure are designed to aid or overcome factors associated with extended effects, for example, chronic inflammation, barrier cell layer formation, or build-up of fibrotic tissue of the foreign body response, which can begin asAttorney Docket No.: 0935-PCT01-0240early as about one week after implantation and extend for the life of the implant, for example, months to years. In some examples, the bioactive agents of the present disclosure combine short- and extended release to exploit the benefits of both. Published U.S.Publication No. 2005 / 0031689 Al to Shults et al. discloses a variety of systems and methods for release of the bioactive agents.

[0233] The amount of loading of the bioactive agent into the release membrane can depend upon several factors. For example, the bioactive agent dosage and duration can vary with the intended use of the release membrane, for example, cell transplantation, analyte measuring-device, and the like; differences among hosts in the effective dose of bioactive agent; location and methods of loading the bioactive agent; and release rates associated with bioactive agents and optionally their chemical composition and / or bioactive agent loading. Therefore, one skilled in the art will appreciate the variability achieving a reproducible and controlled release of the one or more bioactive agents, at least for the reasons described above. U.S. Publication No. 2005 / 0031689 Al to Shults et al. that discloses a variety of systems and methods for loading of the bioactive agents.

[0234] In examples, multiple layers or discrete or semi-discrete rings or bands of the bioactive releasing membrane are employed to specifically tailor the drug release of the bioactive agent for the intended sense of life. Thus, in examples, two or more layers of the multilayer bioactive releasing membrane differs in one or more aspects, for example: of hydrophobicity / hydrophilicity content or ratio of the segments of a soft-hard segmented polymer or copolymer; compositional makeup or weight percent of two or more different polymers or copolymers or blends of different polymers and / or copolymers in each layer or their vertical or horizontal distribution in one or more layers; bioactive loading and / or distribution (vertically or longitudinally within the coated membrane) in each layer; membrane thickness of each layer; composition and loading amount of two or more distinct bioactive agents (e.g., a neutral, derivative and / or salt form or a primary form and derivative form of the bioactive agent); the solvent system used to cast or deposit or dip coat the individual bioactive releasing membrane layers; and the relative position(s) (continuous, semicontinuous, or noncontinuous positioning) of the bioactive releasing membrane layers along the length of the sensor.Attorney Docket No.: 0935-PCT01-0240

[0235] Suitable bioactive releasing membranes are those membranes which provide a therapeutically effective amount and release rate of bioactive agent beginning with the insertion of the sensor and throughout the life of the sensor. In examples, the bioactive releasing membrane in combination with an amount of bioactive agent provides for extending the useful life of the sensor when compared to an equivalent sensor the bioactive releasing membrane without the bioactive agent (or compared to the absence of the bioactive releasing membrane and bioactive agent). As used herein a therapeutically effective amount of the bioactive agent is an amount capable of inducing an intended therapeutic effect. An intended therapeutic effect is one that can be readily determined using conventional diagnostic methods. For example, an intended therapeutic effect encompasses suppressing unwanted foreign body response to an implant (foreign body) including, but not limited to inflammation and / or fibrous capsule formation.

[0236] In some examples, the wetting property of the membrane (and by extension the extent of sensor drift exhibited by the sensor) can be adjusted and / or controlled by creating covalent cross-links between surface-active group-containing polymers, functional-group containing polymers, polymers with zwitterionic groups (or precursors or derivatives thereof), and combinations thereof. Cross-linking can have a substantial effect on film structure, which in turn can affect the film's surface wetting properties. Crosslinking can also affect the film's tensile strength, mechanical strength, water absorption rate and other properties.

[0237] Cross-linked polymers can have different cross-linking densities. In certain examples, cross-linkers are used to promote cross-linking between layers. In other examples, in replacement of (or in addition to) the cross-linking techniques described above, heat is used to form cross-linking. For example, in some examples, imide and amide bonds can be formed between two polymers as a result of high temperature. In some examples, photo cross-linking is performed to form covalent bonds between the polycationic layers(s) and polyanionic layer(s). One major advantage to photo-cross-linking is that it offers the possibility of patterning. In certain examples, patterning using photocross linking is performed to modify the film structure and thus to adjust the wetting property of the membrane.Attorney Docket No.: 0935-PCT01-0240

[0238] Polymers with domains or segments that are functionalized to permit crosslinking can be made by methods known in the art. For example, polyurethaneurea polymers with aromatic or aliphatic segments having electrophilic functional groups (e.g., carbonyl, aldehyde, anhydride, ester, amide, isocyano, epoxy, allyl, or halo groups) can be crosslinked with a crosslinking agent that has multiple nucleophilic groups (e.g., hydroxyl, amine, urea, urethane, or thio groups). In further examples, polyurethaneurea polymers having aromatic or aliphatic segments having nucleophilic functional groups can be crosslinked with a crosslinking agent that has multiple electrophilic groups. Still further, polyurethaneurea polymers having hydrophilic segments having nucleophilic or electrophilic functional groups can be crosslinked with a crosslinking agent that has multiple electrophilic or nucleophilic groups. Unsaturated functional groups on the polyurethane urea can also be used for crosslinking by reacting with multivalent free radical agents. Non-limiting examples of suitable cross-linking agents include isocyanate, carbodiimide, glutaraldehyde, aziridine, silane, or other aldehydes, epoxy, acrylates, free-radical based agents, ethylene glycol diglycidyl ether (EGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). In examples, from about 0.1% to about 15% w / w of cross-linking agent is added relative to the total dry weights of cross-linking agent and polymers added when blending the ingredients (in examples, about 1% to about 10%). During the curing process, substantially all of the cross-linking agent is believed to react, leaving substantially no detectable unreacted cross-linking agent in the final film.

[0239] Polymers disclosed herein can be formulated into mixtures that can be drawn into a film or applied to a surface using any method known in the art (e.g., spraying, painting, dip coating, vapor depositing, molding, 3-D printing, lithographic techniques (e.g., photolithograph), micro- and nano-pipetting printing techniques, silk-screen printing, etc.). The mixture can then be cured under high temperature (e.g., 50-150° C.). Other suitable curing methods can include ultraviolet or gamma radiation, for example.

[0240] In examples, the weight of bioactive agent associated with the sensor is 1-120 pL, 2-110 pL, 3-100 pL, 4-90 pL, 5-80 pL, 6-70 pL, 7-60 pL, 8-50 pL, 9-40 pL, or 10-30 pL. In other examples, the weight of two or more bioactive agents associated with the sensor, independently or collectively is 1-120 pL, 2-110 pL, 3-100 pL, 4-90 pL, 5-80 pL, 6-70 pL, 7-60 pL, 8-50 pL, 9-40 pL, or 10-30 pL.Attorney Docket No.: 0935-PCT01-0240

[0241] In examples, the weight percent loading of bioactive agent in the bioactive releasing membrane 470 is about 10 weight percent to about 90 weight percent. In examples, the weight percent loading of bioactive agent in the bioactive releasing membrane 470 is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, of the total weight of the bioactive releasing membrane plus bioactive agent (as a deposited membrane on a sensor). In examples, the weight percent loading of bioactive agent in the bioactive releasing membrane 470 is 30%, 40%, 50%, or 60%, of the total weight of the bioactive releasing membrane plus bioactive agent (as a deposited membrane on a sensor).Depending on the nature of the bioactive releasing membrane, for example, the ratio of hydrophobic / hydrophilic soft segments, the weight percent of the bioactive agent is chosen based on solubility / miscibility / dispersion of the bioactive agent with the bioactive releasing membrane and any solvent or solvent system used to dispense the bioactive releasing membrane and bioactive agent onto the sensor. Too high a loading of bioactive agent in a particular bioactive releasing membrane can result in precipitation of the bioactive agent, and / or poor coating quality. Too low a loading of bioactive agent in the bioactive releasing membrane can result in inefficient therapeutic effect over the intended lifetime of the sensor, which can manifest itself as poor signal-to-noise initially and / or prior to the designed EOL of the sensor, reduction or fluctuation of sensitivity of the sensor to the target analyte(s) shortly after insertion and / or prior to the designed EOL of the sensor, among other things.

[0242] In examples, the bioactive releasing membrane is configured to release, in weight percent, after insertion and up to the EOL of the sensor, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, up to and including 100% of the initial loading of the bioactive agent. In examples, the bioactive releasing membrane is configured to release, after insertion and up to the EOL of the sensor, between 60-90 weight percent of the bioactive agent. In other examples, the bioactive releasing membrane is configured to release, after insertion and up to the EOL of the sensor, between 75-85 weight percent of the bioactive agent.

[0243] In examples, the bioactive releasing membrane of the present disclosure provides for release of the bioactive agent from the bioactive releasing membrane commensurate with a bolus amount of the bioactive agent. In other examples, the bioactiveAttorney Docket No.: 0935-PCT01-0240releasing membrane of the present disclosure provides for release of the bioactive agent from the bioactive releasing membrane commensurate with a therapeutically effective amount of the bioactive agent. In examples, the bioactive releasing membrane of the present disclosure provides for release of the bioactive agent from the bioactive releasing membrane commensurate with a non-therapeutically effective amount where the non-therapeutically effective amount follows one or more of a release of a bolus amount or therapeutic amount of the bioactive agent.

[0244] In examples, the bioactive releasing membrane of the present disclosure provides for a bolus release of the bioactive agent essentially immediately upon insertion of the sensor for a first time period or range (for example, minutes, hours, days, weeks, etc.), the first time period or range initiated at a first time point (for example, a second or less) into the subject's soft tissue. In examples, the bioactive releasing membrane of the present disclosure provides for release of a bolus amount of the bioactive agent essentially immediately upon insertion of the sensor, for the first time period initiated at the first time point, into the subject's soft tissue followed by release of a therapeutically effective amount of the bioactive agent beginning at a second time point for a second time period, the second time period overlapping with or subsequent to the first time period. In examples, the second time point is subsequent to the first time point by at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes or more. In examples, the bioactive releasing membrane of the present disclosure provides for release of a bolus amount of the bioactive agent essentially immediately upon insertion of the sensor, forthe first time period initiated at the first time period, into the subject's soft tissue followed by release of a therapeutically effective amount of the bioactive agent beginning at a second time point for a second time period, the second time period overlapping with or subsequent to the first time period, followed by a release of a non-therapeutically effective amount of the bioactive agent beginning at a third time point for a third time period, the third time period overlapping with or subsequent to the second time period. In examples, the third time point is subsequent to the second time point by at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes or more.

[0245] Release rates of the bioactive agent in any of the aforementioned first, second or third time periods can be the same or different. Release rates of the bioactive agent in anyAttorney Docket No.: 0935-PCT01-0240of the aforementioned first, second or third time periods can be configured to occur at a substantially constant rate or a variable rate (intermittent, periodic, and / or random) by modifying one or more of membrane chemistry, structure, and / or morphology, bioactive agent loading, bioactive chemistry, for example. Release rates (the concentration or amount of bioactive released over time) of the bioactive agent in any of the aforementioned time periods can be configured to change after implantation overtime by modifying one or more of membrane chemistry, structure, and / or morphology, bioactive agent loading, bioactive chemistry, for example.

[0246] In examples, the release rate of the bioactive agent from the bioactive releasing membrane initially or during the first time period is greater than the release rate of the bioactive agent from the bioactive releasing membrane initially or during the second time period. In examples, the release rate of the bioactive agent from the bioactive releasing membrane initially or during the second time period is greater than the release rate of the bioactive agent from the bioactive releasing membrane initially or during the third time period. In examples, the release rate of the bioactive agent from the bioactive releasing membrane initially or during the first time period is greater than the release rate of the bioactive agent from the bioactive releasing membrane initially or during the second time period and the and release rate of the bioactive agent from the bioactive releasing membrane initially or during the second time period is greater than the release rate of the bioactive agent from the bioactive releasing membrane initially the third time period.

[0247] Suitable bioactive releasing membranes of the present disclosure capable of the aforementioned release rates and released amounts of the bioactive agents can be selected from silicone polymers, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polyureas, polyurethane ureas, polyethers, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyamides, cellulosic polymers and copolymers and blends thereof, poly(ethylene oxide) and copolymers and blends thereof, polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block,Attorney Docket No.: 0935-PCT01-0240tri-block, alternating, random and graft copolymers cellulose, hydrogel polymers, poly(2-hydroxyethyl methacrylate, pHEMA) and copolymers and blends thereof, hydroxyethyl methacrylate, (HEMA) and copolymers and blends thereof, polyacrylonitrile-polyvinyl chloride (PAN-PVC) and copolymers and blends thereof, acrylic copolymers and copolymers and blends thereof, nylon and copolymers and blends thereof, polyvinyl difluoride, polyanhydrides, poly(l-lysine), poly( L-lactic acid), hydroxyethyl metharcrylate and copolymers and blends thereof, and hydroxyapeptite and copolymers and blends thereof.

[0248] A suitable bioactive releasing membrane is a polyurethane, or polyetherurethaneurea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxyl-containing material. A polyurethaneurea is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material. Exemplary diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be useful in the preparation of the polymer and copolymer components of the bioactive releasing membranes of the present disclosure. The material that forms the basis of the hydrophobic matrix of the bioactive releasing membrane or its domains can be any of those known in the art as appropriate for use as membranes in sensor devices. In examples, the bioactive releasing membrane is different from the other membranes of the sensor system in that the bioactive releasing membrane is less sufficient in its permeability to relevant compounds, for example, to allow an glucose molecule to pass through the membrane.

[0249] Examples of other materials which can be used to make non-polyurethane type bioactive releasing membranes include vinyl polymers, polyethers, polyesters, polyamides, polysilicones poly(dialkylsiloxanes), poly(alkylarylsiloxanes), poly(diarylsiloxanes), polycarbosiloxanes, polycarbonate, polyvinyl pyridine, polyvinyl pyridine-co-polystyrene, natural polymers such as cellulosic and protein-based materials, and mixtures, copolymers, or combinations thereof with or without the aforementioned polyurethane, or polyetherurethaneurea polymers.

[0250] In other examples, the bioactive agent is minoxidil, hydralazine, nitroglycerin alone or in combination with at least one of dexamethasone, dexamethasone and aAttorney Docket No.: 0935-PCT01-0240derivative or salt. Dexamethasone derivatives include dexamethasone acetate, or dexamethasone acetate salt.

[0251] In examples, suitable bioactive releasing membranes 470 are hard-soft segmented polymers, where hard segments include polymer segments providing crystallinity or crystalline like structure and a soft segments providing an amorphous or amorphous-like structure. In examples the bioactive releasing membrane 470 is a hard-soft segmented copolymer where the soft segment comprises a hydrophilic polymer or hydrophilic polymer segment. In examples the bioactive releasing membrane 470 of the present disclosure is a hard-soft segmented copolymer where the soft segment comprises a hydrophilic polymer or hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. Various confirmations and distributions of the hydrophobic domains and hydrophilic domains are envisioned depending on the relative concentrations of each domain and whether there is non-stoichiometric or stoichiometric amounts of each domain. In examples, the soft segment of the bioactive releasing membrane 470 comprises a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent.

[0252] In examples, the bioactive releasing membrane 470 comprises a hard-soft segmented polyurethane copolymer. In other examples, the bioactive releasing membrane 470 comprises a hard-soft segmented polyurethane urea copolymer. In examples the bioactive releasing membrane 470 is a hard-soft segmented polyurethane or polyurethane urea copolymer where the soft segment comprises a hydrophilic polymer, or hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. In examples the bioactive releasing membrane 470 of the present disclosure is a hard-soft segmented polyurethane or polyurethane urea copolymer blend where at least one of the individual polymers of the polymer blend comprises a soft segment comprises a hydrophilic polymer or hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. In examples the bioactive releasing membrane 470 of the present disclosure is a hard-soft segmented polyurethane or polyurethane urea copolymer blend, where at least one of the individual polymers of the polymer blend comprises a soft segment comprises a hydrophilic polymer segment only and at least oneAttorney Docket No.: 0935-PCT01-0240polymer of the polymer blend comprises a soft segment comprising hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment.

[0253] In some examples, the hard segment of the copolymer may have a molecular weight of from about 160 daltons to about 10,000 daltons, or from about 200 daltons to about 2,000 daltons. In some examples, the molecular weight of the soft segment may be from about 200 daltons to about 100,000 daltons, or from about 500 daltons to about 500,000 daltons, or from about 5,000 daltons to about 20,000 daltons.

[0254] In examples, aliphatic or aromatic diisocyanates are used to prepare the hard segment of bioactive releasing membrane 470. In examples, the aliphatic or aromatic diisocyanate used to provide the hard segment of bioactive releasing membrane 470 is norbornane diisocyanate (NBDI), isophorone diisocynate (I PDI), tolylene diisocynate (TDI), 1.3-phenylene diisocyanate (MPDI), trans-l,3-bis(isocynatomethyl) cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocynate(HMDI), 4,4'-Diphenylmethane diisocynate (M DI), trans-l,4-bis(isocynatomethyl) cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocynate (CHDI), 1.4-phenylene diisocynate (PPDI), 3,3'-Dimethyl-4,4'-biphenyldiisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0255] In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises polysiloxane or copolymer thereof. In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises poly(dialkyl)siloxane, poly(diphenyl)siloxane, poly(alkylphenyl)siloxane or copolymer thereof. In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises poly(alkyl)oxy polymer, poly (alkylene)oxide, or copolymers thereof. In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises polyfa Iky I )oxide, poly(ethylene)oxide, poly(propylene)oxide, poly(ethylene-propylene) oxide, poly(tetraalkylene)oxide, poly(tetramethylene)oxide polymer or copolymers or blends thereof. The soft segments can be comprised of hydrophilic and / or hydrophobic oligomers of, for example, polyalkylene glycols, polycarbonates, polyesters, polyethers, polyvinylalcohol, polyvinypyrrolidone, polyoxazoline, and the like.

[0256] In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises polysiloxane or copolymer thereof andAttorney Docket No.: 0935-PCT01-0240poly(alkylene)oxy polymer or copolymers thereof. In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises poly(dialkyl)siloxane, poly(diphenyl)siloxane, poly(alkylphenyl)siloxane or copolymer and poly(alkyl)oxide, poly(ethylene) oxide, poly(propylene)oxide, poly(ethylene-propylene) oxide, poly(tetraalkylene)oxide, poly(tetramethylene)oxide polymer or copolymers or blends thereof.

[0257] In examples, the bioactive releasing membrane 470 has a hard segment weight percent content of between about 20-60%, 30-50%, or 35-45% so as to achieve a 70A-55D durometer. In other examples, the bioactive releasing membrane 470 has a hard segment weight percent content of between about 20-60%, 30-50%, or 35-45% so as to achieve a target modulus. In examples, the durometer and / or modulus of the bioactive releasing membrane 470 is provided in a single copolymer or blends of copolymers.

[0258] In examples, the bioactive releasing membrane 470 comprises a soft segment-hard segment copolymer comprising less than 70 weight percent of soft segment, not including zero weight percent. In examples, the releasing membrane comprises a soft segment-hard segment copolymer comprising a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising less than 70 weight percent of soft segment, not including zero weight percent.

[0259] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer comprising a hydrophilic segment weight percent that is greater than the hydrophobic segment weight percent thereof. In examples, the releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment weight percent of a soft segment-hard segment that is greater than the hydrophobic segment weight percent thereof.

[0260] In examples, the hydrophilic segment weight percent of the soft segment-hard segment copolymer is less than the hydrophobic segment weight percent thereof. In examples, the hydrophilic segment weight percent of the soft segment-hard segment polyurethane or polyurethane urea copolymer is less than the hydrophobic segment weight percent thereof.

[0261] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer that is blends of different soft segment-hard segment copolymers. InAttorney Docket No.: 0935-PCT01-0240examples, the bioactive releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer that is blends of different soft segment-hard segment copolymers.

[0262] In examples, the bioactive releasing membrane comprises a blend of different soft segment-hard segment copolymers that is a first soft segment-hard segment copolymer comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent, blended with another second soft segment-hard segment copolymer comprising a hydrophilic segment weight percent greater than a hydrophobic segment weight percent. In examples, the bioactive releasing membrane comprises a blend of different soft segment-hard segment polyurethane or polyurethane urea copolymers that comprise a first soft segment-hard segment copolymer comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent, blended with another soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment weight percent greater than a hydrophobic segment weight percent.

[0263] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent, blended with another soft segment-hard segment copolymer comprising a hydrophilic segment weight percent less than a hydrophobic segment weight percent. In examples, the bioactive releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent, blended with another soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment weight percent less than a hydrophobic segment weight percent.

[0264] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer and a soft segment-hard segment copolymer, each comprising less than 70 weight percent of soft segment, not including zero weight percent, and each comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent. In examples, the bioactive releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer and another,Attorney Docket No.: 0935-PCT01-0240different, soft segment-hard segment polyurethane or polyurethane urea copolymer, each comprising less than 70 weight percent of soft segment, not including zero weight percent, and each comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent.

[0265] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer blended with a hydrophobic polymer and / or a hydrophilic polymer. In examples, the bioactive releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer blended with a hydrophobic polymer and / or a hydrophilic polymer.

[0266] In examples, the bioactive releasing membrane 470 is substantially impervious to analyte transport there through. In other examples, the bioactive releasing membrane 470 is less permeable to the analyte than an interference layer of the sensing membrane 400. In such examples, the bioactive releasing membrane 470 is deposited on portions of the sensor adjacent to but not covering the electroactive portion of the sensor.

[0267] In examples, the bioactive releasing membrane 470 is loaded with bioactive agent prior to depositing on the sensor 100 and / or sensing membrane 400. In examples, the bioactive agent is dissolved in one or more solvents that are miscible with the bioactive releasing membrane 470. Mild heating can be used to facilitate dissolution, distribution, or dispersing of the bioactive agent in the bioactive releasing membrane 470. Suitable solvents include THF, alcohols, ketones, ethers, acetates, NMP, methylene chloride, heptane, hexane, and combinations thereof.

[0268] In examples, the bioactive releasing membrane 470 is deposited onto at least a portion of the sensing membrane 400. In other examples, the bioactive releasing membrane 470 is deposited adjacent to but not directly on sensing membrane 400. In examples, the bioactive releasing membrane is deposited so as to provide a membrane thickness of from about 0.05 micron or more to about 50 microns or less. In other examples, the bioactive releasing membrane is deposited so as to provide a membrane thickness of from about 0.5 to 50 microns, 1 to 50 microns, 2 to 50 microns, 3 to 50 microns, 4 to 50 microns, 5 to 50 microns, 6 to 50 microns, 7 to 50 microns, 8 to 50 microns, 9 to 50 microns, 10 to 50 microns, 10 to 40 microns, 10 to 30 microns, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 microns.Attorney Docket No.: 0935-PCT01-0240

[0269] In examples, the bioactive releasing membrane 470 is deposited onto the enzyme domain by spray coating, brush coating, pad printing, meniscus coating, microfluidic coating, or dip coating. In examples, the bioactive releasing membrane 470 is deposited on the sensing membrane 400 by meniscus-, microfluidic-, or spray-coating a solution of from about 1 wt. % to about 50 wt. % polymer and from about 50 wt. % to about 99 wt. % solvent. In spraying a solution of bioactive releasing membrane 470, including a solvent, onto the sensing domain, it is desirable to mitigate or substantially reduce any contact with enzyme of any solvent in the spray solution that can deactivate the underlying enzyme of the enzyme domain. Tetrahydrofuran (THF) is one solvent, alone or in combination with one or more alcohols, that minimally or negligibly affects the enzyme of the enzyme domain upon spraying. Other solvents can also be suitable for use, as is appreciated by one skilled in the art.

[0270] The at least one polymer layer of the bioactive releasing membrane 470 can include any suitable polymeric materials discussed previously herein. In examples, the at least one polymer layer of the bioactive releasing membrane 470 comprises one or more epoxides, polyolefins, polysiloxanes, polyamide, polystyrene, polyacrylate, polyethers, polyvinyl pyridines, polyvinyl pyridine-co-polystyrene, polyvinylimidazoles, polyesters, polycarbonates, polyurethane, polyurethaneurea, and copolymers thereof. In other examples, the at least one polymer layer of the bioactive releasing membrane 470 comprises one or more zwitterionic repeating units associated with the at least one bioactive agent, the at least one bioactive agent configured to be released from the one or more zwitterionic repeating units to modify tissue response of a subject.

[0271] The at least one bioactive agent includes any suitable bioactive agent discussed previously herein. In examples, the at least one bioactive agent comprises an antiinflammatory compound or a tissue response modifier. In examples, the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier in combination with a vasodilator. For instance, in examples, the at least one bioactive agent comprises at least one of dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or any combination thereof with at least one of minoxidil, hydralazine, and nitroglycerin.Attorney Docket No.: 0935-PCT01-0240Sensor Electronics

[0272] The sensor electronics includes hardware, firmware, and / or software that enable measurement of levels of the analyte via the sensor. For example, the sensor electronics can comprise a potentiostat, a power source for providing power to the sensor, other components useful for signal processing, and preferably an RF module for transmitting data from the sensor electronics to a receiver. Electronics can be affixed to a printed circuit board (PCB), or the like, and can take a variety of forms. For example, the electronics can take the form of an integrated circuit (IC), such as an Application-Specific Integrated Circuit (ASIC), a microcontroller, ora processor. Preferably, sensor electronics comprise systems and methods for processing sensor analyte data. Examples of systems and methods for processing sensor analyte data are described in more detail below and in U.S. Patent No.7,778,680 filed Aug. 1, 2003, and entitled, "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA."

[0273] In this example, after insertion of the sensor using the applicator, and subsequent release of the applicator from the mounting unit, the sensor electronics are configured to releasably mate with the mounting unit. In examples, the electronics are configured with programming, for example initialization, calibration reset, failure testing, or the like, each time it is initially inserted into the mounting unit and / or each time it initially communicates with the sensor.

[0274] In some embodiments, sensitivity loss may be indicative of EOL. Sensitivity loss may occur towards the sensor EOL due to physiological wound healing and foreign body mechanisms around the sensor or other mechanisms including reference electrode capacity, enzyme depletion, membrane changes, or the like.

[0275] In some embodiments, sensor sensitivity may be computed in using an analysis of uncalibrated sensor data (e.g., raw or filtered). In examples, a slow moving average or median of raw count starts showing negative trends, the sensor may be losing sensitivity. Loss of sensitivity may be computed by calculating a short term (e.g. ~6-8 hours) average (or median) of the sensor output and normalizing it by the expected longer term (48 hours) average sensor sensitivity. If the ratio of short term to longterm sensitivity is smaller than 70%, there may be a risk of sensor losing sensitivity. Loss of sensitivity may be translatedAttorney Docket No.: 0935-PCT01-0240into an EOL risk factor value, for example a value of about 1 until the ratio is about 70%, reducing to 0.5 at 50% and <0.1 at 25%.

[0276] In some embodiments, sensor sensitivity may be computed by comparing sensor data (e.g., calibrated sensor data) with reference blood glucose (BG). For example, calibration algorithms adjust the glucose estimates based on the systematic bias between sensor and a reference BG. End of life algorithms may use this bias, called error at calibration or downward drift, to quantify or qualify EOL symptoms. The error at calibration may be normalized to account for irregular calibration times and smoothed to give more weight to recent data (e.g., moving average or exponential smoothing). In some embodiments, EOL risk factor value is determined based on the resulting smoothed error at calibration. In such embodiments, EOL risk factor value is 1 for all values of error at calibration>-0.3, and reduces to 0.5 at error at calibration=-0.4, and to <0.1 for error at calibration=-0.6. In some examples, one more of a downward drift in sensor sensitivity over time, an amount of non-symmetrical, nonstationary noise, and a duration of noise can be employed, for example, as disclosed in co-assigned U.S. Patent Application 2021 / 0209497, which is incorporated herein by reference.

[0277] In some embodiments, sensor sensitivity may be computed in using an analysis of uncalibrated sensor data (e.g., raw or filtered). In examples, a slow moving average or median of raw count starts showing negative trends, the sensor may be losing sensitivity. Loss of sensitivity may be computed by calculating a short term (e.g. ~6-8 hours) average (or median) of the sensor output and normalizing it by the expected longer term (48 hours) average sensor sensitivity. If the ratio of short term to long term sensitivity is smaller than 70%, there may be a risk of sensor losing sensitivity. Loss of sensitivity may be translated into an EOL risk factor value, for example a value of about 1 until the ratio is about 70%, reducing to 0.5 at 50% and <0.1 at 25%.

[0278] FIG. 10 is a diagram depicting an example continuous transcutaneous analyte monitoring system 100 configured to measure one or more analytes and / or electrophysiological indicators (e.g., blood pressure, heart rate, core temperature, etc.). The monitoring system includes a continuous transcutaneous analyte sensor system 124 operatively connected to a host 120 and a plurality of display devices 134 a-e according to certain aspects of the present disclosure. It should be noted that display device 134eAttorney Docket No.: 0935-PCT01-0240alternatively or in addition to being a display device, may be a medicament delivery device that can act cooperatively with the continuous transcutaneous analyte sensor system 124 to deliver medicaments to host 120. The continuous transcutaneous analyte sensor system 124 may include a sensor electronics module 126 and a continuous transcutaneous analyte sensor 122 associated with the sensor electronics module 126. The sensor electronics module 126 may be in direct wireless communication with one or more of the plurality of the display devices 134a-e via wireless communications signals. In one example, display devices 134a-e may also communicate amongst each other and / or through each other to continuous transcutaneous analyte sensor system 124. For ease of reference, wireless communications signals from analyte sensor system 124 to display devices 134a-e can be referred to as "uplink" signals 128. Wireless communications signals from, e.g., display devices 134a-e to continuous transcutaneous analyte sensor system 124 can be referred to as "downlink" signals 130. Wireless communication signals between two or more of display devices 134a-e may be referred to as "crosslink" signals 132. Additionally, wireless communication signals can include data transmitted by one or more of display devices 134a-d via "long-range" uplink signals 136 (e.g., cellular signals) to one or more remote servers 140 or network entities, such as cloud-based servers or databases, and receive long-range downlink signals 138 transmitted by remote servers 140.

[0279] The sensor electronics module 126 includes sensor electronics that are configured to process sensor information and generate transformed sensor information. In certain examples, the sensor electronics module 126 includes electronic circuitry associated with measuring and processing data from continuous transcutaneous analyte sensor 122, including prospective algorithms associated with processing and calibration of the continuous transcutaneous analyte sensor data. The sensor electronics module 126 can be integral with (non-releasably attached to) or releasably attachable to the continuous transcutaneous analyte sensor 122 achieving a physical connection therebetween. The sensor electronics module 126 may include hardware, firmware, and / or software that enables analyte level measurement. For example, the sensor electronics module 126 can include a potentiostat, a power source for providing power to continuous transcutaneous analyte sensor 122, other components useful for signal processing and data storage, and a telemetry module for transmitting data from itself to one or more display devices 134a-e.Attorney Docket No.: 0935-PCT01-0240Electronics can be affixed to a printed circuit board (PCB), or the like, and can take a variety of forms. For example, the electronics can take the form of an integrated circuit (IC), such as an Application-Specific Integrated Circuit (ASIC), a microcontroller, and / or a processor. Examples of systems and methods for processing sensor analyte data are described in more detail herein and in U.S. Pat. Nos. 7,310,544 and 6,931,327 and U.S. Patent Publication Nos.2005 / 0043598, 2007 / 0032706, 2007 / 0016381, 2008 / 0033254, 2005 / 0203360, 2005 / 0154271, 2005 / 0192557, 2006 / 0222566, 2007 / 0203966 and 2007 / 0208245, each of which are incorporated herein by reference in their entirety for all purposes.

[0280] Display devices 134a-e are configured for displaying, alarming, and / or basing medicament delivery on the sensor information that has been transmitted by the sensor electronics module 126 (e.g., in a customized data package that is transmitted to one or more of display devices 134a-e based on their respective preferences). Each of the display devices 134a-e can include a display such as a touchscreen display for displaying sensor information to a user (most often host 120 or a caretaker / medical professional) and / or receiving inputs from the user. In some examples, the display devices 134a-e may include other types of user interfaces such as a voice user interface instead of or in addition to a touchscreen display for communicating sensor information to the user of the display device 134a-e and / or receiving user inputs. In some examples, one, some or all of the display devices 134a-e are configured to display or otherwise communicate the sensor information as it is communicated from the sensor electronics module 126 (e.g., in a data package that is transmitted to respective display devices 134a-e), without any additional prospective processing required for calibration and real-time display of the sensor information.

[0281] In the example of FIG. 10, one of the plurality of display devices 134a-e may be a custom display device 134a specially designed for displaying certain types of displayable sensor information associated with analyte values received from the sensor electronics module 126 (e.g., a numerical value and an arrow, in some examples). In some examples, one of the plurality of display devices 134a-e may be a handheld device 134c, such as a mobile phone based on the Android, iOS operating system or other operating system, a palm-top computer and the like, where handheld device 134c may have a relatively larger display and be configured to display a graphical representation of the continuous sensor data (e.g., including current and historic data). Other display devices can include other hand-Attorney Docket No.: 0935-PCT01-0240held devices, such as a tablet 134d, a smart watch 134b, a medicament delivery device 134e, a blood glucose meter, and / or a desktop or laptop computers.

[0282] As alluded to above, because the different display devices 134a-e provide different user interfaces, content of the data packages (e.g., amount, format, and / or type of data to be displayed, alarms, and the like) can be customized (e.g., programmed differently by the manufacture and / or by an end user) for each particular display device and / or display device type. Accordingly, in the example of FIG. 10, one or more of display devices 134a-e can be in direct or indirect wireless communication with the sensor electronics module 126 to enable a plurality of different types and / or levels of display and / or functionality associated with the sensor information, which is described in more detail elsewhere herein.

[0283] All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

[0284] The term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0285] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0286] The above description discloses several methods and materials of the present disclosure. This disclosure is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure orAttorney Docket No.: 0935-PCT01-0240practice of the disclosure disclosed herein. Consequently, it is not intended that this disclosure be limited to the specific examples disclosed herein, but that it covers all modifications and alternatives coming within the true scope and spirit of the disclosure.

[0287] While certain examples of the present disclosure have been illustrated with reference to specific combinations of elements, various other combinations may also be provided without departing from the teachings of the present disclosure. Thus, the present disclosure should not be construed as being limited to the particular exemplary examples described herein and illustrated in the Figures, but may also encompass combinations of elements of the various illustrated examples and aspects thereof.

Claims

1. Attorney Docket No.: 0935-PCT01-0240WE CLAIM:

1. A device for measurement of a concentration of an analyte, the device comprising:an analyte sensing portion configured to generate a signal associated with the concentration of the analyte;at least one polymer coating; anda prodrug form of a bioactive agent wherein the prodrug form is pharmacologically less active than the bioactive agent;wherein the prodrug form of the bioactive agent is coupled to the at least one polymer coating and configured to release the bioactive agent from the at least one polymer coating after implantation in a subject.

2. The device of claim 1, wherein the prodrug form of the bioactive agent is configured to couple with the at least one polymer or a polymerizable monomer of the at least one polymer via a biodegradable linkage.

3. The device of any one of the previous claims, wherein the biodegradable linkage comprises an enzymatically degradable functional group.

4. The device of any one of the previous claims, wherein the biodegradable linkage comprises a pH degradable functional group.

5. The device of any one of the previous claims, wherein the biodegradable linkage comprises a temperature-degradable functional group.

6. The device of any one of the previous claims, wherein the biodegradable linkage comprises a peroxide-degradable functional group.

7. The device of any one of the previous claims, wherein the biodegradable linkage comprises an unsaturated carbon-carbon functional group.

8. The device of any one of the previous claims, wherein the biodegradable linkage comprises an ester functional group.Attorney Docket No.: 0935-PCT01-02409. The device of any one of the previous claims, wherein the biodegradable linkage comprises an carbonate functional group.

10. The device of any one of the previous claims, wherein the prodrug form of the bioactive agent is selected from the group:and11. The device of any one of the previous claims, wherein the prodrug form is at least one of dexamethasone or dexamethasone acetate and is configured to couple with the at least one polymer or polymerizable monomer of the at least one polymer coating.

12. The device of any one of the previous claims, wherein the prodrug form of is at least one of dexamethasone or dexamethasone acetate and is configured to covalently couple with the at least one polymer or polymerizable monomer of the at least one polymer coating.

13. The device of any one of the previous claims, wherein the at least one polymer or polymerizable monomer comprises a zwitterionic functional group.

14. The device of any one of the previous claims, further comprising one or more membranes comprising a polymer chain having polyurethane and / or polyurea segments.

15. The device of any one of the previous claims, further comprising one or more membranes comprising a polymer chain having both hydrophilic and hydrophobic regions.

16. The device of any one of the previous claims, further comprising one or more membranes comprising a polymer chain having one or more zwitterionic compounds.

17. The device of any one of the previous claims, further comprising one or more membranes comprising a polymer with a heterocyclic group.Attorney Docket No.: 0935-PCT01-024018. The device of any one of the previous claims, further comprising one or more membranes comprising a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly(2-vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers quaternized forms thereof.

19. The device of any one of the previous claims, further comprising one or more membranes comprising a copolymer including styrene.

20. A device for measurement of a concentration of an analyte, the device comprising:an implantable analyte sensing portion configured to generate a signal associated with the concentration of the analyte, the device comprising at least one drug-releasing polymer layer configured to release at least one anti-inflammatory compound or tissue response modifier; anda diffusion adjustment layer adjacent the at least one drug-releasing polymer layer configured to modulate the release of the at least one anti-inflammatory compound or tissue response modifier after implantation of the implantable analyte sensing portion.

21. The device of claim 20, wherein the diffusion adjustment layer covers the implantable analyte sensing portion.

22. The device of any one of claims 20-21, wherein the diffusion adjustment layer is configured to biodegrade after implantation.

23. The device of any one of claims 20-22, wherein the diffusion adjustment layer covers one or more membranes adjacent the implantable analyte sensing portion.

24. The device of any one of claims 20-23, wherein the diffusion adjustment layer comprises a cellulose polymer.

25. The device of any one of claims 20-24, wherein the diffusion adjustment layer comprises hydroxypropyl methylcellulose polymer.

26. The device of any one of claims 20-25, wherein the diffusion adjustment layer comprises a poly lactic acid polymer or copolymer.

27. The device of any one of claims 20-26, wherein the diffusion adjustment layer comprises a poly glycolic acid polymer or copolymer.Attorney Docket No.: 0935-PCT01-024028. The device of any one of claims 20-27, wherein the diffusion adjustment layer comprises poly(lactic-co-glycolic acid) copolymer or blend.

29. The device of any one of claims 20-28, wherein the diffusion adjustment layer comprises a hydrophilic hydrogel, the hydrophilic hydrogel being at least partly crosslinked and dissolvable or swellable in interstitial fluid (ISF).

30. The device of any one of claims 20-29, wherein the diffusion adjustment layer comprises a hydrolytically degradable biopolymer.

31. The device of any one of claims 20-30, wherein the diffusion adjustment layer comprises a hydrophilic hydrogel, the hydrophilic hydrogel being at least partly crosslinked and dissolvable in biological fluid.

32. The device of any one of claims 20-31, wherein the analyte sensing portion is present on a planar substrate or a wire substrate.

33. The device of any one of claims 20-32, wherein the at least one drug-releasing polymer layer and the analyte sensing portion are spatially separated along a longitudinal axis of the wire substrate or the planar substrate.

34. The device of any one of claims 20-33, wherein the diffusion adjustment layer and the analyte sensing portion are spatially separated along a longitudinal axis of the wire substrate or the planar substrate.

35. The device of any one of claims 20-34, further comprising one or more membranes comprising a polymer chain having polyurethane and / or polyurea segments.

36. The device of any one of claims 20-35, further comprising one or more membranes comprising a polymer chain having both hydrophilic and hydrophobic regions.

37. The device of any one of claims 20-36, further comprising one or more membranes further comprising a polymer chain having one or more zwitterionic compounds.

38. The device of any one of claims 20-37, further comprising one or more membranes comprising a polymer with a heterocyclic group.Attorney Docket No.: 0935-PCT01-024039. The device of any one of claims 20-38, further comprising one or more membranes comprising a polymer chain having poly(l-vinyl imidazole), poly (4-vinyl pyridine), polypvinyl pyridine), acrylonitrile, acrylamide, and / or copolymers quaternized forms thereof.

40. The device of any one of claims 20-39, further comprising one or more membranes comprising a copolymer including styrene.

41. The device of any one of claims 20-40, wherein the diffusion adjustment layer comprises an amount of the anti-inflammatory compound ortissue response modifier.

42. The device of any one of claims 20-41, wherein the at least one anti-inflammatory compound or tissue response modifier comprises pilocarpine, dexamethasone, a derivative form of dexamethasone, dexamethasone acetate, or a combination of dexamethasone with a derivative form of dexamethasone or dexamethasone acetate.

43. A method of modulating an amount of a drug from an implanted device, the method comprising:providing an implantable device, the implantable device comprising:at least one polymer coating comprising at least one drug moiety wherein the at least one drug moiety is reversibly contained within a portion of the at least one polymer coating; andat least one diffusion adjustment polymer coating adjacent the least one polymer coating; andmodulating a release of an amount of the at least one drug moiety from the at least one polymer coating after implantation of the implanted device.

44. The method of claim 43, wherein the implantable device comprises a wire or planar substrate.

45. The method of any one of claims 43-44, wherein the implantable device is an implantable analyte sensor.

46. The method of any one of claims 43-45, wherein the implantable device is an implantable glucose or ketone sensor.Attorney Docket No.: 0935-PCT01-024047. The method of any one of claims 43-46, wherein modulating the release of the amount of the at least one drug moiety delays a bolus release thereof.

48. The method of any one of claims 43-47, wherein modulating the release of the amount of the at least one drug moiety is over a predetermined time interval.

49. The method of any one of claims 43-48, wherein modulating the release of the amount of the at least one drug moiety is during the first 5 minutes after implantation of the implantable device.

50. The method of any one of claims 43-49, wherein modulating the release of the amount of the at least one drug moiety is during the first 10 minutes after implantation of the implantable device.

51. The method of any one of claims 43-50, wherein modulating the release of the amount of the at least one drug moiety is during the first 20 minutes after implantation of the implantable device.

52. The method of any one of claims 43-51, wherein modulating the release of the amount of the at least one drug moiety is during the first 30 minutes after implantation of the implantable device.

53. The method of any one of claims 43-52, wherein the diffusion adjustment polymer coating is configured to biodegrade after implantation.

54. The method of any one of claims 43-53, wherein the diffusion adjustment polymer coating covers the at least one polymer coating.

55. The method of any one of claims 43-54, wherein the diffusion adjustment polymer coating covers one or more membranes adjacent the at least one polymer coating.

56. The method of any one of claims 43-55, wherein the diffusion adjustment polymer coating comprises a cellulose polymer.

57. The method of any one of claims 43-56, wherein the diffusion adjustment polymer coating comprises hydroxypropyl methylcellulose polymer.

58. The method of any one of claims 43-57, wherein the diffusion adjustment polymer coating comprises a poly lactic acid polymer or copolymer.Attorney Docket No.: 0935-PCT01-024059. The method of any one of claims 43-58, wherein the diffusion adjustment polymer coating comprises a poly glycolic acid polymer or copolymer.

60. The method of any one of claims 43-59, wherein the diffusion adjustment polymer coating comprises poly(lactic-co-glycolic acid) copolymer or blend.

61. The method of any one of claims 43-60, wherein the diffusion adjustment polymer coating comprises a hydrophilic hydrogel, the hydrophilic hydrogel being at least partly crosslinked and dissolvable or swellable in interstitial fluid (ISF).

62. The method of any one of claims 43-61, wherein the diffusion adjustment polymer coating comprises a hydrolytically degradable biopolymer.

63. The method of any one of claims 43-62, wherein the diffusion adjustment polymer coating comprises a hydrophilic hydrogel, the hydrophilic hydrogel being at least partly crosslinked and dissolvable in biological fluid.

64. The method of any one of claims 43-63, wherein the at least one drug moiety is an anti-inflammatory or a tissue response modifier.

65. The method of any one of claims 43-64, wherein the anti-inflammatory or the tissue response modifier is pilocarpine, dexamethasone, dexamethasone acetate, or a salt thereof.

66. The method of any one of claims 43-65, further comprising providing implantable device performance within one day of implantation that is substantially equivalent to implantable device performance without the at least one drug moiety.

67. A device for measurement of an analyte concentration, the device comprising:an analyte sensing portion configured for subcutaneous insertion and configured to generate a signal associated with the concentration of the analyte; andat least one wound extrudate absorbing coating configured to absorb wound extrudate upon subcutaneous insertion of the analyte sensing portion.

68. The device of claim 67, wherein the at least one wound extrudate absorbing coating comprises a biocompatible hydrophilic coating.

69. The device of any one of claims 67-68, wherein the at least one wound extrudate absorbing coating comprises a cellulose polymer.Attorney Docket No.: 0935-PCT01-024070. The device of any one of claims 67-69, wherein the at least one wound extrudate absorbing coating comprises hydroxypropyl methylcellulose polymer.

71. The device of any one of claims 67-70, wherein the at least one wound extrudate absorbing coating comprises a poly lactic acid polymer or copolymer.

72. The device of any one of claims 67-71, wherein the at least one wound extrudate absorbing coating comprises a poly glycolic acid polymer or copolymer.

73. The device of any one of claims 67-72, wherein the at least one wound extrudate absorbing coating comprises poly ( lactic-co-glycolic acid) copolymer or blend.

74. The device of any one of claims 67-73, wherein the at least one wound extrudate absorbing coating comprises a hydrophilic hydrogel, the hydrophilic hydrogel being at least partly crosslinked and dissolvable or swellable in biological fluid.

75. The device of any one of claims 67-74, wherein the at least one wound extrudate absorbing coating reaches over 90% of equilibrium water absorption in less than 2 hours.

76. The device of any one of claims 67-75, wherein the at least one wound extrudate absorbing coating reaches over 90% of equilibrium water absorption in less than 1 hour.

77. The device of any one of claims 67-76, wherein the at least one wound extrudate absorbing coating reaches over 90% of equilibrium water absorption in less than 30 minutes.

78. The device of any one of claims 67-77, wherein the at least one wound extrudate absorbing coating comprises a betaine group.

79. The device of any one of claims 67-78, wherein the at least one wound extrudate absorbing coating is positioned adjacent the analyte sensing portion.

80. The device of any one of claims 67-79, further comprising a conductive substrate, wherein the conductive substrate is a planar substrate having a proximal end and a distal end, and wherein the analyte sensing portion is positioned between the proximal end and the distal end.Attorney Docket No.: 0935-PCT01-024081. The device of any one of claims 67-80, wherein the at least one wound extrudate absorbing coating extends proximal, distal, or both proximal and distal from the analyte sensing portion.

82. The device of any one of claims 67-81, wherein the analyte sensing portion is positioned on a wire or a planar substrate comprising a distal-most tip and the at least one wound extrudate absorbing coating is located at the distal-most tip.

83. The device of any one of claims 67-82, further comprising a tissue response or an anti-inflammatory agent releasing portion configured to release at least one tissue response or anti-inflammatory agent from the device upon subcutaneous insertion.

84. The device of any one of claims 67-83, wherein the anti-inflammatory agent comprises pilocarpine, a derivative form of dexamethasone, dexamethasone acetate, or a combination of a derivative form of dexamethasone or dexamethasone acetate with dexamethasone.

85. The device of any one of claims 67-84, further comprising at least one vasodilator releasing portion configured to release at least one vasodilator.

86. The device of any one of claims 67-85, wherein the at least one vasodilator releasing portion comprises a nitric oxide (NO) releasing molecule, polymer, or oligomer.

87. The device of any one of claims 67-86, wherein the nitric oxide (NO) releasing molecule is selected from N-diazeniumdiolates and S-nitrosothiols, or N-diazeniumdiolates.

88. The device of any one of claims 67-87, wherein the at least one vasodilator comprises a nitric oxide (NO) releasing molecule, polymer, or oligomer, phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, Hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L-arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, and combinations thereof.

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