Bioactive releasing membranes for analyte sensors.

Abstract

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

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 244,644, filed September 15, 2021, and this application also claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 318,901, filed March 11, 2022, all of which are incorporated by reference in their entireties herein.

[0002] The present disclosure relates generally to bioactive release or elution layers or films utilized with implantable devices, such as devices for the detection of analyte concentrations in biological samples. More particularly, the disclosure relates to novel bioactive release films, devices and implantable devices including these films, methods for forming bioactive release films on or around implantable devices, methods for improving and / or extending sensor lifetime, and methods for monitoring one or more analyte levels in a biological fluid sample using implantable analyte detection devices. [Background technology]

[0003] One of the most intensively investigated analyte sensing devices is an implantable glucose device for detecting glucose levels in a diabetic host. Summary of the Invention [Problem to be solved by the invention]

[0004] 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 safely and reliably provide data over a period of time due to local tissue responses. As an example, there are two commonly used types of subcutaneously implantable glucose sensing devices. These types include transcutaneously implantable and fully implantable. [Means for solving the problem]

[0005] In one aspect, a device for measuring a concentration of an analyte is provided comprising a sensor substrate comprising a distal end separated from a proximal end and at least one sensor portion positioned between the distal end and the proximal end, the sensor portion configured to generate a signal associated with the concentration of the analyte, and a bioactive-releasing membrane adjacent to the sensor substrate, the bioactive-releasing membrane including at least one releasable bioactive agent capable of modifying a tissue response of a subject.

[0006] In one aspect, the distal end has an outer surface and the bioactive releasing membrane is positioned on the outer surface.

[0007] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive releasing membrane is positioned only at the distal end.

[0008] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release membrane is directly adjacent to the resistive membrane.

[0009] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive releasing membrane is immediately adjacent to the interference membrane.

[0010] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive releasing membrane is directly adjacent to the electrode membrane.

[0011] In one aspect, alone or in combination with any one of the previous aspects, the device further comprises a dissolvable coating adjacent to the bioactive releasing membrane.

[0012] In one embodiment, alone or in combination with any one of the previous embodiments, the dissolvable coating further comprises a releasable bioactive agent.

[0013] In one aspect, alone or in combination with any one of the previous aspects, the at least one releasable bioactive agent is a first releasable bioactive agent and the dissolvable coating further comprises a second releasable bioactive agent, wherein the first releasable bioactive agent is the same as or different from the second releasable bioactive agent.

[0014] In one embodiment, alone or in combination with any one of the previous embodiments, the dissolvable coating comprises a second releasable bioactive agent in combination with nanoparticles comprising one or more anti-inflammatory agents.

[0015] In one embodiment, alone or in combination with any one of the previous embodiments, the dissolvable coating provides a bolus release of both the second releasable bioactive agent and the nanoparticles.

[0016] In one aspect, alone or in combination with any one of the previous aspects, the dissolvable coating is hydrophilic.

[0017] In one aspect, alone or in combination with any one of the previous aspects, the dissolvable coating is analyte-diffusible.

[0018] In one aspect, alone or in combination with any one of the previous aspects, the device further comprises a diffusion-controlling membrane adjacent to the bioactive release membrane, the diffusion-controlling membrane being different from the bioactive release membrane.

[0019] In one embodiment, alone or in combination with any one of the previous embodiments, the diffusion-regulating membrane is directly adjacent to the bioactive releasing membrane.

[0020] In one embodiment, alone or in combination with any one of the previous embodiments, the diffusion-controlling membrane is a block copolymer.

[0021] In one embodiment, alone or in combination with any one of the previous embodiments, the diffusion-controlling membrane is a segmented block copolymer.

[0022] In one embodiment, alone or in combination with any one of the previous embodiments, the diffusion control membrane is a multi-block copolymer.

[0023] In one embodiment, alone or in combination with any one of the preceding embodiments, the diffusion-controlling membrane is annealed.

[0024] In one embodiment, alone or in combination with any one of the previous embodiments, the annealed diffusion-controlling membrane comprises a stable separate phase.

[0025] In one embodiment, alone or in combination with any one of the previous embodiments, the stable separate phase provides a diffusion channel for at least one releasable bioactive agent.

[0026] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film includes a soft segment and a hard segment, the hard segment including a urethane group, a urea group, or a combination of a urethane group and a urea group.

[0027] In one embodiment, alone or in combination with any one of the previous embodiments, the soft segments are two or more different polymer segments.

[0028] In one embodiment, alone or in combination with any one of the previous embodiments, the soft segment comprises a hydrophobic block and a hydrophilic block.

[0029] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film comprises a multi-component soft segment comprising two or more different polymer segments.

[0030] In one embodiment, alone or in combination with any one of the previous embodiments, the multi-component soft segment comprises hydrophobic and hydrophilic blocks of at least one of polysiloxane, polyalkylcarbonate, and polycarbonate in combination with polyalkylether, polyalkylester.

[0031] In one embodiment, alone or in combination with any one of the preceding embodiments, the soft segments include one or more combinations of polysiloxane, polyalkyl ether, polyalkyl ester, polyalkyl carbonate, polycarbonate, and polysiloxane-polyalkyl ether segmented blocks, and the hard segments include norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene diisocynate (TDI), 1,3-phenylene diisocyanate (1,3-phenylene diisocyanate ... diisocyanate (MPDI), trans-1,3-bis(isocynatomethyl)cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocynate (HMDI), 4,4'-diphenylmethane diisocynate (MDI), trans-1,4-bis(isocynatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocynate (CHDI), 1,4-phenylene diisocyanate (1,4-phenylene diisocyanate) diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyldiisocyanate (TODI), and 1,6-hexamethylene diisocyanate (HDI).

[0032] In one embodiment, alone or in combination with any one of the previous embodiments, the soft segment comprises a polysiloxane, a polyalkyl ether, a polyalkyl ester, a polyalkyl carbonate, a polycarbonate, or a polysiloxane-polyalkyl ether segmented block.

[0033] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film further comprises a chain extender.

[0034] In one aspect, alone or in combination with any one of the previous aspects, the bioactive release membrane is a polyurethaneurea.

[0035] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film comprises, based on the total weight of the bioactive release film, about 10% to 30% by weight polysiloxane and about 10% to 30% by weight polyalkyl ether, 40% to 60% by weight hard segments comprising urethane groups, urea groups, or a combination of urethane and urea groups, and the remaining weight percent is a chain extender.

[0036] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film comprises about 20% to 30% by weight polysiloxane, about 20% to 30% by weight polyalkyl ether, and about 40% to 60% by weight hard segment, based on the total weight of the bioactive release film, with any remaining weight percentage being chain extender.

[0037] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film comprises a soft segment comprising about 10% to 30% by weight polysiloxane, about 10% to 30% by weight polyalkyl ether, and about 0% to 10% by weight chain extender, based on the total weight of the bioactive release film.

[0038] In one aspect, alone or in combination with any one of the previous aspects, the polyalkyl ether is represented by repeating units of formula (I): -(R5-O)-, where R5 is a linear or branched alkyl group having 2 to 6 carbon atoms.

[0039] In one embodiment, alone or in combination with any one of the preceding embodiments, the bioactive release film has a water uptake of 1% to 4% by weight at equilibrium.

[0040] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film has a water uptake of less than 3% by weight at equilibrium.

[0041] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release membrane is an excipient for at least one releasable bioactive agent.

[0042] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release membrane comprises a hydrophobic soft segment, at least one hydrophilic soft segment, and a hard segment comprising a urethane group, a urea group, or a combination of a urethane group and a urea group.

[0043] In one aspect, alone or in combination with any one of the previous aspects, the bioactive release film comprises a hard segment and a soft segment, wherein the hard segment has a closer Hildebrand solubility parameter to at least one releasable bioactive agent than the soft segment.

[0044] In one aspect, alone or in combination with any one of the previous aspects, the distal end of the substrate includes a wire singulation, a planar singulation, or a substantially planar singulation.

[0045] In one aspect, alone or in combination with any one of the previous aspects, the device further comprises an electrically insulating end cap adjacent the distal end.

[0046] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is a hydrophobic coating.

[0047] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is impermeable to electrochemically active species.

[0048] In one aspect, alone or in combination with any one of the preceding aspects, the electrically insulating end cap is impermeable to the analyte.

[0049] In one aspect, alone or in combination with any one of the previous aspects, an electrically insulating end cap extends longitudinally from the distal end.

[0050] In one aspect, alone or in combination with any one of the previous aspects, an electrically insulating end cap extends from the distal end to the sensor portion.

[0051] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, urethane acrylate, polybutadiene modified urethane, polyethylene vinyl acetate, silicone, or a combination thereof.

[0052] In another example, a method is provided for reducing or delaying an immune response in a tissue of a subject, the method including: (i) providing a continuous analyte sensing device, the device comprising an insertable portion operably coupled to a non-insertable portion, the insertable portion comprising a sensing portion configured to be inserted into a tissue, the insertable portion having an insertable surface area and an insertable volume, and at least one bioactive release membrane disposed on a portion of the insertable surface area, the bioactive release membrane being spatially separated from the sensing portion, the at least one bioactive release membrane comprising at least one bioactive agent; (ii) forming a tissue insert volume in the tissue by inserting the insertable portion, the tissue insert volume being equal to or greater than the insertable volume; (iii) releasing the at least one bioactive agent from the at least one bioactive release membrane into the tissue insert volume at an average release rate of about 0.1 μg / day to about 5 μg / day; and (iv) reducing or delaying the immune response in the tissue.

[0053] In one aspect, the bioactive emitting membrane is spatially separated from the sensing moiety.

[0054] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release membrane further comprises a non-releasable bioactive agent.

[0055] In one aspect, alone or in combination with any one of the preceding aspects, the bioactive release film comprises a polymer and the weight / weight ratio of the at least one bioactive agent to the polymer is from about 0.1 to about 2, including all ranges and subranges therebetween.

[0056] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifying agent.

[0057] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, a dexamethasone acetate, or a combination of a dexamethasone salt, a dexamethasone derivative, or a dexamethasone acetate with dexamethasone.

[0058] In another example, a method is provided for reducing signal noise in a continuous analyte sensing device caused by a foreign body response, the method including providing a continuous analyte sensing device comprising a substrate having an insertable portion operably coupled to a non-insertable portion, the insertable portion having a distal end, at least one sensing portion positioned proximally from the distal end, and at least one bioactive emitting membrane disposed on at least a portion of the distal end, the bioactive emitting membrane including at least one bioactive agent capable of attenuating the foreign body response, and reducing signal noise during use of the continuous analyte sensing device.

[0059] In one embodiment, the method further comprises releasing or exposing at least one bioactive agent to the tissue.

[0060] In one aspect, alone or in combination with any one of the previous aspects, the method further includes attenuating a foreign body response proximate the distal end.

[0061] In one aspect, alone or in combination with any one of the previous aspects, the analyte is glucose and the signal noise is maintained below 4 mg / dL for at least 10 days.

[0062] In one aspect, alone or in combination with any one of the previous aspects, the analyte is glucose and the signal noise is maintained below 4 mg / dL for at least 15 days.

[0063] In one aspect, alone or in combination with any one of the previous aspects, the analyte is glucose and the signal noise is maintained below 4 mg / dL for at least 21 days.

[0064] In one aspect, alone or in combination with any one of the previous aspects, the insertable portion comprises an insertable surface area and an insertable volume.

[0065] In one aspect, alone or in combination with any one of the previous aspects, the at least one bioactive release membrane is disposed over a portion of the insertable surface area, and the at least one bioactive release membrane has at least one of the bioactive release membrane surface areas less than or equal to the insertable surface area.

[0066] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive release membrane comprises a polymer and the weight ratio of the polymer to the total amount of the at least one bioactive agent is from about 0.1 to about 2.

[0067] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifying agent.

[0068] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or a combination of a dexamethasone salt, a dexamethasone derivative, or dexamethasone acetate with dexamethasone.

[0069] In one aspect, alone or in combination with any one of the previous aspects, the insertable portion and the non-insertable portion are disposed on a substrate, and the substrate is a wire; in one aspect, alone or in combination with any one of the previous aspects, the planar substrate or substantially planar substrate, and the distal end further comprises singulation.

[0070] In one aspect, alone or in combination with any one of the previous aspects, the method further comprises an electrically insulating end cap adjacent the distal end.

[0071] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is a hydrophobic coating.

[0072] In one aspect, alone or in combination with any one of the previous aspects, an electrically insulating end cap extends longitudinally from the distal end.

[0073] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is impermeable to electrochemically active species.

[0074] In one aspect, alone or in combination with any one of the preceding aspects, the electrically insulating end cap is impermeable to the analyte.

[0075] In one aspect, alone or in combination with any one of the previous aspects, an electrically insulating end cap extends from the distal end to the sensor portion.

[0076] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, urethane acrylate, polybutadiene modified urethane, polyethylene vinyl acetate, silicone, or a combination thereof.

[0077] In yet another example, a method is provided for reducing the onset of sensitivity loss in a continuous analyte sensing device caused by a foreign body response in tissue during use, the method comprising: providing a continuous analyte sensing device comprising a substrate including an insertable portion having a distal end operably coupled to a non-insertable portion, at least one sensing portion positioned proximally from the distal end and distally from the non-insertable portion, and at least one bioactive emitting membrane disposed on a portion of the distal end, the at least one bioactive emitting membrane comprising at least one bioactive agent capable of attenuating the foreign body response, and reducing the onset of sensitivity loss of the continuous analyte sensing device during use.

[0078] In one embodiment, the method further comprises releasing or exposing at least one bioactive agent to the tissue.

[0079] In one embodiment, alone or in combination with any one of the previous embodiments, the reduction in onset of sensitivity loss is for at least 14 days.

[0080] In one aspect, alone or in combination with any one of the previous aspects, the reduction in the onset of sensitivity loss is at least 20 days.

[0081] In one aspect, alone or in combination with any one of the previous aspects, the reduction in the onset of sensitivity loss is for at least 30 days.

[0082] In one aspect, alone or in combination with any one of the previous aspects, the substrate is a wire, a planar substrate, or a substantially planar substrate, and the distal end further comprises a singulation.

[0083] In one aspect, alone or in combination with any one of the previous aspects, the method further comprises an electrically insulating end cap adjacent the distal end.

[0084] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is distinct from the bioactive releasing membrane.

[0085] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is a hydrophobic coating.

[0086] In one aspect, alone or in combination with any one of the previous aspects, an electrically insulating end cap extends longitudinally from the distal end.

[0087] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is impermeable to electrochemically active species.

[0088] In one aspect, alone or in combination with any one of the preceding aspects, the electrically insulating end cap is impermeable to the analyte.

[0089] In one aspect, alone or in combination with any one of the previous aspects, an electrically insulating end cap extends longitudinally from the distal end to the sensor portion.

[0090] In one aspect, alone or in combination with any one of the previous aspects, the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, urethane acrylate, polybutadiene modified urethane, polyethylene vinyl acetate, silicone, or a combination thereof.

[0091] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifying agent.

[0092] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or a combination of a dexamethasone salt, a dexamethasone derivative, or dexamethasone acetate with dexamethasone.

[0093] In yet another example, a device for measuring a concentration of an analyte is provided, the device comprising: a sensor portion configured to generate a signal associated with the concentration of the analyte; and a bioactive-releasing membrane proximate to the sensor portion, the bioactive-releasing membrane configured to form a complex with at least one bioactive agent, the at least one bioactive agent configured to be released from the bioactive-releasing membrane to modify a tissue response in a subject.

[0094] In one embodiment, the complex with at least one bioactive agent is covalently or non-covalently bonded.

[0095] In one embodiment, alone or in combination with any one of the previous embodiments, the complex with the at least one bioactive agent is ionic.

[0096] In one aspect, alone or in combination with any one of the previous aspects, the complex has at least one bioactive agent and is a bioactive agent conjugate.

[0097] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifying agent.

[0098] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, a dexamethasone acetate, or a combination of a dexamethasone salt, a dexamethasone derivative, or a dexamethasone acetate with dexamethasone.

[0099] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent is a nitric oxide releasing molecule, polymer, or oligomer.

[0100] In one embodiment, alone or in combination with any one of the previous embodiments, the nitric oxide releasing molecule is selected from N-diazeniumdiolates and S-nitrosothiols.

[0101] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent is covalently bound Factor H.

[0102] In one aspect, alone or in combination with any one of the previous aspects, the complex is a borate ester or boronate-containing bioactive agent conjugate.

[0103] In one embodiment, alone or in combination with any one of the previous embodiments, the complex is a bioactive agent conjugate that includes at least one cleavable linker that is cleavable by a subcutaneous stimulus.

[0104] In one aspect, alone or in combination with any one of the previous aspects, the subcutaneous stimulus is a matrix metallopeptidase or protease attack.

[0105] In one aspect, alone or in combination with any one of the previous aspects, the bioactive release membrane comprises a hydrophilic hydrogel, which is at least partially crosslinked and dissolvable in biological fluids.

[0106] In one embodiment, alone or in combination with any one of the previous embodiments, the hydrophilic hydrogel comprises hyaluronic acid crosslinked with divinylsulfone or polyethylene glycol divinylsulfone.

[0107] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive releasing film comprises silver nanoparticles.

[0108] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release membrane comprises biodegradable polymeric nanoparticles selected from PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphoesters, or PEO-b-polypeptides comprising at least one bioactive agent.

[0109] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release membrane comprises an organic gel carrier and / or an inorganic gel carrier.

[0110] In one aspect, alone or in combination with any one of the previous aspects, a bioactive release membrane configured to form a complex with at least one bioactive agent includes a combination of at least one bioactive agent encapsulated within the bioactive release membrane and at least one bioactive agent covalently bonded to the bioactive release membrane.

[0111] In one aspect, alone or in combination with any one of the previous aspects, a bioactive releasing membrane configured to form a complex with at least one bioactive agent includes a spatially distal drug depot of the at least one bioactive agent.

[0112] In one aspect, alone or in combination with any one of the previous aspects, a bioactive release membrane configured to form a complex with at least one bioactive agent comprises a hydrolytically degradable biopolymer that includes at least one bioactive agent.

[0113] In one embodiment, alone or in combination with any one of the previous embodiments, the hydrolytically degradable biopolymer comprises a salicylic polyanhydride ester.

[0114] In one aspect, alone or in combination with any one of the preceding aspects, the bioactive release film comprises a polyurethane segment and / or a polyurea segment, and the polyurethane segment and / or the polyurea segment is about 15% by weight to about 75% by weight, based on the total weight of the bioactive release film, including all ranges and subranges therebetween.

[0115] In one aspect, alone or in combination with any one of the previous aspects, the bioactive release membrane comprises at least one polymer segment, the at least one segment being selected from the group consisting of epoxides, polyolefins, polysiloxanes, polyamides, polystyrenes, polyacrylates, polyethers, polypyridines, polyesters, polyalkyl esters, polyalkyl carbonates, polycarbonates, polyethylene vinyl acetates, polyvinyl alcohols, and copolymers thereof.

[0116] In one aspect, alone or in combination with any one of the previous aspects, the bioactive release membrane comprises polyethylene oxide segments.

[0117] In one embodiment, alone or in combination with any one of the previous embodiments, the polyethylene oxide segment is about 5% to about 60% by weight, based on the total weight of the bioactive release film.

[0118] In one aspect, alone or in combination with any one of the preceding aspects, the base polymer of the bioactive release membrane has an average molecular weight of about 10 kDa to about 500 kDa, including all ranges and subranges therebetween.

[0119] In one embodiment, alone or in combination with any one of the preceding embodiments, the bioactive release film has a polydispersity index of 1 to about 10, including all ranges and subranges therebetween.

[0120] In one embodiment, alone or in combination with any one of the preceding embodiments, the bioactive release film has a contact angle of from about 90° to about 160°, including all ranges and subranges therebetween.

[0121] In yet another example, a device for measuring a concentration of an analyte is provided, the device comprising: a sensor portion configured to generate a signal associated with the concentration of the analyte; and a bioactive releasing membrane proximate to the sensor portion, the bioactive releasing membrane including one or more zwitterionic repeat units complexed with at least one bioactive agent, the at least one bioactive agent configured to be released from the one or more zwitterionic repeat units to modify a tissue response in a subject.

[0122] In one embodiment, one or more of the zwitterionic repeat units comprises a betaine compound or a derivative thereof.

[0123] In one embodiment, alone or in combination with any one of the previous embodiments, one or more of the zwitterionic repeat units comprises a betaine compound or a precursor thereof.

[0124] In one embodiment, alone or in combination with any one of the previous embodiments, the one or more zwitterionic repeat units comprise at least one moiety selected from the group consisting of carboxylbetaines, sulfobetaines, phosphabetaines, and derivatives thereof.

[0125] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifying agent.

[0126] In one embodiment, alone or in combination with any one of the previous embodiments, the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, a dexamethasone acetate, or a combination of a dexamethasone salt, a dexamethasone derivative, or a dexamethasone acetate with dexamethasone.

[0127] In one embodiment, alone or in combination with any one of the previous embodiments, one or more of the zwitterionic repeat units is derived from a monomer selected from the group consisting of:

[0128] [ka] wherein Z is a branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl; R1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R2, R3, and R4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and one or more of R1, R2, R3, R4, and Z are substituted with a polymerizable group.

[0129] In one embodiment, alone or in combination with any one of the previous embodiments, the polymerizable group is selected from an alkene, an alkyne, an epoxide, a lactone, an amine, a hydroxyl, an isocyanate, a carboxylic acid, an anhydride, a silane, a halide, an aldehyde, a carbodiimide, or a combination thereof.

[0130] In one embodiment, alone or in combination with any one of the previous embodiments, the one or more zwitterionic repeat units are at least about 1 wt %, based on the total weight of the bioactive releasing membrane.

[0131] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film further comprises one or more zwitterions selected from the group consisting of cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, caprylyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly(carboxybetaine), poly(sulfobetaine), and derivatives thereof.

[0132] In one embodiment, alone or in combination with any one of the previous embodiments, the bioactive release membrane comprises polymer chains having zwitterionic groups at the ends and along the polymer chain.

[0133] In one aspect, alone or in combination with any one of the previous aspects, the bioactive release membrane comprises a polymer chain having both hydrophilic and hydrophobic regions, and the one or more zwitterionic compounds are present at the ends of the polymer chains, and the bioactive release membrane comprises a base polymer selected from polyolefins, polystyrenes, polyoxymethylenes, polysiloxanes, polyethers, polyacrylics, polymethacrylics, polyesters, polyalkylesters, polyalkylcarbonates, polycarbonates, polyamides, polypyridines, poly(etherketones), poly(etherimides), polyurethanes, polyurethaneureas, polyethylenevinylacetates, polyvinylalcohols, or copolymers or blends thereof.

[0134] In one aspect, alone or in combination with any one of the preceding aspects, the base polymer of the bioactive release membrane has an average molecular weight of about 10 kDa to about 500 kDa, including all ranges and subranges therebetween.

[0135] In one embodiment, alone or in combination with any one of the preceding embodiments, the base polymer of the bioactive release membrane has a polydispersity index of from about 1 to about 10, including all ranges and subranges therebetween.

[0136] In one embodiment, alone or in combination with any one of the preceding embodiments, the base polymer of the bioactive release film has a dynamic contact angle of from about 90° to about 160°, including all ranges and subranges therebetween. [Brief description of the drawings]

[0137] [Figure 1A] 1A-1C are cross-sectional views of exemplary embodiments of a continuous analyte sensing device. [Figure 1B]1A-1C are cross-sectional views of exemplary embodiments of a continuous analyte sensing device. [Figure 2A] FIG. 1 is a perspective view of an exemplary continuous analyte sensing device as disclosed and described herein. [Figure 2B] 2B is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along section line BB of FIG. 2A. [Figure 2C] 2B is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along section line BB of FIG. 2A showing an exemplary bioactive emissive layer. [Figure 2D] 2B is a cross-sectional view through the continuous analyte sensing device of FIG. 2A on line DD of FIG. 2A showing an exemplary bioactive releasing membrane as disclosed and described herein. [Figure 2E] 2B is a cross-sectional view through the continuous analyte sensing device of FIG. 2A on line DD of FIG. 2A showing another exemplary bioactive releasing membrane as disclosed and described herein. [Figure 2F] FIG. 2 is a perspective schematic diagram illustrating an in vivo portion of an exemplary continuous analyte sensing device as disclosed and described herein. [Figure 2G] FIG. 2F is a side schematic diagram illustrating an in vivo portion of the exemplary sensor of FIG. 2F as disclosed and described herein. [Figure 2H] FIG. 2 is a cross-sectional plan view of a continuous analyte sensing device as disclosed and described herein in one embodiment. [Figure 2I] FIG. 1 is a cross-sectional view of a continuous analyte sensing device in one embodiment as disclosed and described herein. [Figure 2J] FIG. 1 is a cross-sectional view of a continuous analyte sensing device in one embodiment as disclosed and described herein. [Figure 3A] FIG. 1 is a side schematic view of an embodiment of a transdermal continuous analyte sensing device as disclosed and described herein. [Figure 3B] FIG. 2 is a side schematic view of an alternative transdermal continuous analyte sensing device as disclosed and described herein. [Figure 3C]FIG. 2 is a side schematic view of an implantable portion of an implantable continuous analyte sensing device in one embodiment. [Figure 3D] FIG. 13 is a schematic side view of an implantable portion of an implantable analyte sensor in an alternative embodiment. [Figure 3E] FIG. 13 is a side schematic view of an implantable portion of a continuous analyte sensing device in another alternative embodiment. [Figure 3F] FIG. 1 is a side view of one embodiment of a continuous analyte sensing device inductively coupled to an electronics unit within a functionally useful distance on the skin of a host. [Figure 3G] FIG. 1 is a side view of one example of an implantable portion of a continuous analyte sensing device inductively coupled to an electronics unit implanted within the tissue of a host at a functionally useful distance. [Figure 3H] FIG. 13 is a side schematic view of an implantable portion of a continuous analyte sensing device in another alternative embodiment. [Figure 3I] FIG. 13 is a cross-sectional view of an implantable portion of a continuous analyte sensing device in another alternative embodiment. [Figure 3J] FIG. 13 is a cross-sectional view of an implantable portion of a continuous analyte sensing device in another alternative embodiment. [Figure 3K] FIG. 2 is a side schematic view of an implantable portion of a continuous analyte sensing device. [Figure 3L] FIG. 13 is a side schematic view of an implantable portion of a continuous analyte sensing device in an alternative embodiment. [Figure 3M] FIG. 13 is a side schematic view of an implantable portion of a continuous analyte sensing device in another alternative embodiment. [Figure 3N] FIG. 13 is a side schematic view of an implantable portion of a continuous analyte sensing device in another alternative embodiment. [Figure 3O] FIG. 13 is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative embodiment. [Figure 3P] 1 is a graphical representation of in vivo bioactive agent release over time from a bioactive release film as disclosed and described herein. [Figure 3Q] 1 is a graphical representation of in vivo bioactive agent release over time from a bioactive release film as disclosed and described herein. [Figure 4A] FIG. 1 is a schematic diagram of a hard-soft segmented polymer as disclosed and described herein. [Figure 4B] FIG. 4C is a cross-sectional view through an exemplary membrane showing a 3D volume 4C. [Figure 4C] FIG. 4C is a schematic side view of the 3D volume 4C of FIG. 4B. [Figure 5A] 1 is a graphical representation of the cumulative release rate of a bioactive agent over time from a bioactive release film as disclosed and described herein. [Figure 5B] 1 is a graphical representation of the cumulative release rate of a bioactive agent over time from a bioactive release film as disclosed and described herein. [Figure 5C] 1 is a graphical representation of the cumulative release rate of a bioactive agent over time from a bioactive release film as disclosed and described herein. [Figure 6A] 1 is a graphical representation of bioactive agent release from different bioactive releasing films in relation to their water uptake, as disclosed and described herein. [Figure 6B] 1 is a graphical representation of the normalized sensitivity of sensors with and without a bioactive releasing membrane over an 18 day period, as disclosed and described herein. [Figure 6C] 1 is a graphical representation of the normalized sensitivity of sensors with and without a bioactive releasing film over a 30 day period, as disclosed and described herein. [Figure 6D] 1 is a survival plot representation of normalized sensitivity of sensors with and without a bioactive releasing membrane, as disclosed and described herein. [Figure 6E] 1 is a survival plot representation of normalized sensitivity of sensors having different bioactive emissive films as disclosed and described herein. [Figure 7A] 1 is a graphical representation of the average absolute noise over time from a sensor having a bioactive emitting membrane as disclosed and described herein. [Figure 7B] 1 is a survival plot representation of the mean absolute noise of sensors with and without a bioactive emitting membrane, as disclosed and described herein. [Figure 7C] 1 is a survival plot representation of the mean absolute noise of sensors having different bioactive emitting membranes as disclosed and described herein. [Figure 8A] 13 is a histological image of a foreign body response from a sensor without a bioactive-releasing membrane. [Figure 8B] 1 is a histological image of a foreign body response from a sensor having a bioactive emitting membrane as disclosed and described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0138] The following description and examples illustrate preferred embodiments of the present disclosure in detail. Those skilled in the art will recognize that there are many variations and modifications of the present invention that are encompassed by the scope of the present disclosure. Therefore, the description of the examples should not be considered as limiting the scope of the present disclosure.

[0139] (definition) To facilitate understanding of the disclosed embodiments, several terms are defined below.

[0140] As used herein, the term "about" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to allowing for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of the stated limits of a stated value or range, including, but not limited to, the precisely stated value or range. As used herein, the term "substantially" refers to a majority or majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the phrase "substantially free" can mean having no or an insignificant amount of the material such that the amount of the material present does not affect the material properties of the composition including the material, and may be from about 0% to about 5% by weight of the composition being the material, or from about 0% to about 1%, or about 5% by weight or less, or about 4.5% by weight or less, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001% by weight or less, or about 0% by weight.

[0141] As used herein, the terms "adhere" and "attach" are broad terms and are to be given their ordinary and accustomed meaning to those of skill in the art (and are not to be limited to any special or customized meaning), including, but not limited to, holding, joining, or fastening, for example, by adhering, bonding, grasping, interpenetrating, or fusing.

[0142] As used herein, the term "analyte" is a broad term and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, a substance or chemical constituent in a biological fluid (e.g., blood, interstitial fluid, cerebrospinal fluid, lymphatic fluid, urine, sweat, saliva, etc.) that can be analyzed. Analytes can include naturally occurring substances, man-made substances, metabolites, and / or reaction products. In some examples, the analyte measured by the sensing region, devices, and methods is glucose. However, other analytes are contemplated as well, including acarboxyprothrombin; acylcarnitines; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profile (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); bilirubin; biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-β hydroxy-cholic acid; cortisol; creatine; creatine kinase; creatine MM isoenzyme;creatinine;cyclosporine A;d-penicillamine;deethylchloroquine;dehydroepiandrosterone sulfate;DNA (acetylation polymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne / Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber's hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol);desbutylhalofantrine;dihydropteridine reductase;diphtheria / tetanus antitoxin;erythrocyte arginase;erythrocyte protoporphyrin;esterase D;Fatty acids / acylglycines;Free beta-human chorionic gonadotropin;Free erythrocyte porphyrins;Free thyroxine (FT4);Free tri-iodothyronine (FT3);Fumarylacetoacetase;Galactose / gal-1-phosphate;Galactose-1-phosphate uridyltransferase;Gentamicin;Glucose-6-phosphate dehydrogenase;Glutathione;Glutathione peroxidase;Glycerol;Glycocholate;Glycosylated hemoglobin;Halofantrine;Hemoglobin variants;Hexosaminidase A;Human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone ron;hypoxanthine phosphoribosyltransferase;immunoreactive trypsin;beta-hydroxybutyrate;ketones;lactate;lead;lipoproteins ((a), B / A-1, β);lysozyme;mefloquine;netilmicin;oxygen;phenobarbitone;phenytoin;phytanic acid / pristanic acid;potassium, sodium, and / or other blood electrolytes;progesterone;prolactin;prolidase;purine nucleoside phosphorylase;quinine;reverse triiodothyronine tri-iodothyronine, rT3); selenium; serum pancreatic lipase; sisomicin; somatomedin C; specific antibodies (adenovirus, antinuclear antibody, anti-zeta antibody, arbovirus, pseudorabies virus, dengue virus, dracunculiasis, tapeworm, ameba granulosus, enterovirus, giardiasis, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, Leptospirosis, measles / mumps / Rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, Parainfluenza virus, Plasmodium falciparum, Poliovirus, Pseudomonas aeruginosa, Respiratory syncytial virus, Rickettsia scrub typhus, Schistosoma mansoni, Toxoplasma gondii, Treponema pallidum, Trypanosoma cruzi / rangeli, Vesicular stomatitis virus, Wuchereria bancrofti, Yellow fever virus); Specific antigens (Hepatitis B virus, HIV-1); Succinylacetone; Sulfadoxine; Theophylline; Thyrotropin (TSH); Thyroxine (T4);Analytes that are naturally present in the blood or interstitial fluid may also constitute analytes in certain embodiments. Analytes may be naturally present in the biological fluid or may be endogenous, e.g., metabolites, hormones, antigens, antibodies, etc. Alternatively, the analyte can be introduced into the body or can be exogenous, such as a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including, but not limited to, insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, RITALIN®, CYLERT®, PRELUDIN®, DIDREX®, PRESTATE®, VORANIL®, SANDREX®, PLEGINE®); anti-cancer drugs. stimulants (barbiturates, methaqualone, tranquilizers such as VALIUM®, LIBRIUM®, MILTOWN®, SERAX®, EQUANIL®, TRANZENE®); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, PERCOCET®, PERCODAN®, TUSSIONEX®, fentanyl, DARVON®, TALWIN, LOMOTIL®); synthetic narcotics (fentanyl, meperidine, amphetamine, methamphetamine, and phencyclidine analogues, e.g., ecstasy); anabolic steroids;Analytes that are useful for the analysis of analytes include, but are not limited to, nicotine, serotonin, and nicotine. Metabolites of drugs and pharmaceutical compositions are also contemplated analytes. Analytes such as neurochemicals and other chemicals produced in the body, such as ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (FHIAA), and histamine, can also be analyzed.

[0143] As used herein, the phrases "analyte measuring device", "analyte monitoring device", "analyte sensing device", "sequential analyte sensing device", "sequential analyte sensor device" and / or "multi-analyte sensor device" are broad terms and are given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning) and refer to, but are not limited to, analyte apparatus and / or systems responsible for detecting a particular analyte or combination of analytes or converting a signal associated therewith. For example, these phrases may refer to, but are not limited to, an instrument responsible for detecting a particular analyte or combination of analytes. In one embodiment, the instrument includes a sensor coupled to a circuit disposed within a housing and configured to process a signal associated with an analyte concentration into information. In one embodiment, such an apparatus and / or system is capable of providing specific quantitative, semi-quantitative, qualitative, and / or semi-qualitative analytical information using a biorecognition element combined with a transduction and / or detection element.

[0144] As used herein, the phrase "barrier cell layer" is a broad phrase that is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning) and refers, without limitation, to the portion of the foreign body reaction that forms a coherent monolayer of cells (e.g., macrophages and foreign body giant cells) that substantially blocks the transport of molecules and other substances into the implantable device.

[0145] As used herein, the phrases and terms "bioactive agent" and "bioactive" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning) and refer to any substance that has an effect on or elicits a response from living tissue, such as, but not limited to, drugs, biologics, reactive oxygen scavengers (ROS), and metal ions.

[0146] As used interchangeably herein, the phrases "biointerface membrane," "biointerface domain," and "biointerface layer" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning), including, but not limited to, a permeable membrane (which may include multiple domains) or layer that serves as a bioprotective interface between a host tissue and an implantable device. The terms "biointerface" and "bioprotection" are used interchangeably herein.

[0147] As used herein, the terms "biosensor" and / or "sensor" are broad terms and are given their ordinary and customary meaning to those skilled in the art (not limited to any special or customized meaning) and refer to, but are not limited to, a part of an analyte measuring device, an analyte monitoring device, an analyte sensing device, a continuous analyte sensing device, a sequential analyte sensing device, and / or a multi-analyte sensing device that is responsible for detecting a specific analyte or combination of analytes or converting a signal associated therewith. In an embodiment, a biosensor or sensor generally comprises a body and a working electrode, a reference electrode, and / or a counter electrode that are coupled to the body and form a surface configured to provide a signal during an electrochemical reaction. One or more membranes can be attached to the body and cover the electrochemically reactive surface. In an embodiment, such biosensors and / or sensors can provide a specific quantitative, semi-quantitative, qualitative, semi-qualitative analytical signal using a biorecognition element combined with a detection and / or conversion element.

[0148] As used herein, the term "biostable" is a broad term that is to be given its ordinary and accustomed meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, materials that are relatively resistant to degradation by processes encountered in vivo.

[0149] As used herein, the phrase "cell process" is a broad phrase and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, the pseudopodia of cells.

[0150] As used herein, the phrase "cell attachment" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the adhesion of cells and / or cell processes to a material at a molecular level and / or the attachment of cells and / or cell processes to a microporous or macroporous material surface. One example of a material used in the prior art that promotes cell attachment to a porous surface is the BIOPORE™ cell culture support marketed by Millipore (Bedford, MA) and described in U.S. Patent No. 5,741,330 to Brauker et al.

[0151] As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0152] As used herein, the term "conjugate" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning) and refers to a bioactive agent covalently attached to a carrier such as a polymer or nanocarrier (e.g., a bioactive releasing membrane or a biointerface layer) through a linker, but is not limited to the linker being biologically active so as to allow for separation of the drug from the carrier when exposed to or presented in a biological environment such as a subcutaneous or transdermal environment. As used herein, conjugate encompasses drug releasing layer-bioactive agent conjugates and nanoparticle polymer-bioactive agent conjugates. Suitable carriers / nanocarriers include PEG and N-(2-hydroxypropyl)methacrylamide (HPMA), polyglutamic acid (PGA) and their copolymers. As used herein, conjugate encompasses drug release layer-bioactive agent conjugates and nanoparticle polymer-bioactive agent conjugates present in the drug release layer. In embodiments, the bioactive release film includes domains having drug release-bioactive agent conjugates and domains having bioactive agent depots, which can be spatially arranged vertically or horizontally.

[0153] As used herein, the term "continuous" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, an uninterrupted or unbroken portion, domain, coating, or layer.

[0154] As used herein, the phrase "continuous analyte sensing" is a broad phrase that is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, continuous, continuous, and / or intermittent (but periodic) monitoring of analyte concentration, for example, for periods of time that are performed from about 5 seconds or less to about 10 minutes or more. In further embodiments, monitoring of the analyte concentration is performed every about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds 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.

[0155] As used herein, the term "coupled" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, two or more system elements or components that are configured to be electrically, mechanically, thermally, operatively, chemically, or otherwise attached to at least one. Similarly, as used herein, the phrases "operably connected," "operably linked," and "operably coupled" may refer to one or more components that are coupled to another component in a manner that facilitates the transmission of at least one signal between the components. In some examples, the components are part of the same structure and / or are integrated with each other (i.e., "directly coupled"). In other examples, the components are connected via remote means. For example, one or more electrodes can be used to detect analytes in a sample and convert that information into a signal, which can then be transmitted to an electronic circuit. In this example, the electrodes are "operably linked" to the electronic circuit. As used herein, the phrase "removably coupled" may refer to two or more system elements or components that are configured or configured to be electrically, mechanically, thermally, operatively, chemically, or otherwise attached and removed without damaging any of the coupled elements or components. As used herein, the phrase "permanently coupled" may refer to two or more system elements or components that are configured or attached electrically, mechanically, thermally, operatively, chemically, or otherwise attached, but cannot be separated without damaging at least one of the coupled elements or components.

[0156] As used herein, the phrase "defined edge" is a broad phrase that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, an abrupt, distinct edge or boundary between layers, domains, coatings, or portions. A "defined edge" is in contrast to a gradual transition between layers, domains, coatings, or portions.

[0157] As used herein, the term "discontinuous" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, cut, interrupted, or separated portions, layers, coatings, or domains.

[0158] As used herein, the term "distal" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, an area that is spaced relatively far from a reference point such as an origin or attachment point.

[0159] As used herein, the term "domain" is a broad term and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, a region of a membrane system that may be a layer, a uniform or non-uniform gradient (e.g., 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 a pair of bilayers, or as a combination thereof.

[0160] As used herein, the term "drift" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, a gradual increase or decrease in a signal over time that is unrelated to changes in a host's systemic analyte concentration, such as, for example, the host's postprandial glucose concentration. Without wishing to be bound by theory, it is believed that drift may be the result of a local decrease in glucose transport to the sensor, for example, due to the formation of a foreign body capsule (FBC). It is also believed that an insufficient amount of interstitial fluid surrounding the sensor may decrease the transport of oxygen and / or glucose to the sensor. In one embodiment, an increase in local interstitial fluid may slow or reduce drift, thus improving sensor performance. Drift may also be the result of the sensor electronics or algorithmic models used to compensate for noise or other anomalies that may occur with electrical signals in ranges including the microampere range, the picoampere range, the nanoampere range, and the femtoampere range.

[0161] The phrases "bioactive release film", "drug release layer", "bioactive release domain" and "bioactive agent releasing film" are used interchangeably herein and are each broad terms and are given their ordinary and customary meaning to one of skill in the art (and are not limited to any special or customized meaning), including, but not limited to, a permeable or semi-permeable film that is permeable to one or more bioactive agents. In embodiments, the "bioactive release film", "drug release layer", "bioactive release domain" and "bioactive agent releasing film" can include two or more domains and are typically several microns or more thick. In embodiments, the bioactive release film and / or the bioactive release film and / or the bioactive agent releasing film and / or the bioactive agent releasing film are substantially the same as the biointerface layer and / or the biointerface membrane. In another embodiment, the bioactive release film and / or the bioactive release film and / or the bioactive agent releasing film and / or the bioactive agent releasing film are different from the biointerface layer and / or the biointerface membrane.

[0162] As used herein, the term "electrochemically reactive surface" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, the surface of an electrode on which an electrochemical reaction occurs. In an embodiment, hydrogen peroxide produced by an enzyme-catalyzed reaction of an analyte, the reaction being detected, can create a measurable electronic current. For example, in the detection of glucose, glucose oxidase produces hydrogen peroxide (H2O2) as a by-product. H2O2 reacts with the surface of the working electrode to release two protons (2H + ), 2 electrons (2e - ), and one oxygen molecule (O2), which generates an electronic current that is detected. At the counter electrode, a reducible species, e.g., O2, is reduced at the electrode surface to balance the current generated by the working electrode. In another embodiment, electron transfer is provided using a mediator or "wired enzyme" during reduction-oxidation (redox) of the transducer and analyte.

[0163] As used herein, the phrase "hard segment" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, an element of a copolymer, such as a polyurethane, polycarbonate polyurethane, or polyurethane urea copolymer, that imparts resistance properties, such as resistance to bending or twisting. The term "hard segment" can be further characterized as a crystalline, semi-crystalline, or glassy material that has a glass transition temperature, typically determined by dynamic scanning calorimetry ("Tg"), above ambient temperature, and is typically made from diisocyanates with or without chain extenders.

[0164] As used herein, the term "host" is a broad term and is given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to a mammal, such as, but not limited to, a human.

[0165] As used herein, the terms "implanted" or "implantable" are broad terms that are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning) and refer to an object (e.g., a sensor) that is inserted subcutaneously (i.e., within the fatty layer between the skin and the muscle) or percutaneously (i.e., penetrating, penetrating, or passing through intact skin), which can result in a sensor having an in vivo portion and an ex vivo portion.

[0166] As used herein, the phrase "insertable surface area" is a broad phrase that is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, the surface area of ​​the insertable portion of an analyte sensor, including the surface area of ​​flat (substantially planar) substrates and / or wire substrates utilized in the analyte sensors described herein.

[0167] As used herein, the phrase "insertable volume" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, the volume in front of and to the sides of the insertion path of the insertable portion of the analyte sensor, as described herein, and the incision made in the skin for inserting the insertable portion of the analyte sensor. The insertable volume also includes up to 5 mm radially or perpendicularly to the volume in front of and to the sides of the insertion path.

[0168] As used herein, the terms "interfering substance" and "interfering species" are broad terms and are to be given their ordinary and customary meaning to one of skill in the art (and are not to be limited to any special or customized meaning), and refer to, but are not limited 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 the example of an electrochemical sensor, an interfering species is a compound that has an oxidation potential that overlaps with the analyte or one or more mediators being measured.

[0169] As used herein, the term "in vivo" is intended to be broad and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and encompasses, but is not limited to, portions of a device (e.g., a sensor) that are adapted for insertion into and / or presence within the body of a host.

[0170] As used herein, the term "ex vivo" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and encompasses, but is not limited to, a portion of a device (e.g., a sensor) that is adapted to reside and / or exist outside the host organism.

[0171] As used herein, the term "membrane" is a broad term and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning) and refers to a structure configured to perform functions including, but not limited to, protecting exposed electrode surfaces from the biological environment, resisting (limiting) diffusion of analytes, acting as a matrix for catalysts to enable enzymatic reactions, limiting or blocking interfering species, providing hydrophilicity at electrochemically reactive surfaces of the sensor interface, acting as an interface between host tissue and the implantable device, modulating host tissue response by drug (or other substance) release, and combinations thereof. As used herein, the terms "membrane" and "matrix" are meant to be interchangeable.

[0172] As used herein, the phrase "membrane system" is a broad phrase and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning) and refers, without limitation, to a permeable or semi-permeable membrane that may be composed of two or more domains, layers, or layers within domains, typically composed of materials several microns or more thick, and that is permeable to oxygen and, optionally, for example, to glucose or another analyte. In an embodiment, the membrane system includes an immobilized glucose oxidase enzyme that allows a reaction to occur between glucose and oxygen, thereby allowing glucose concentration to be measured.

[0173] As used herein, the term "micro" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to a size of approximately 10 microns that is not visible without magnification. -6 "Micro" refers to objects or scales that are small, but not limited to, those on the order of 10 mm. The term "micro" is in contrast to the term "macro", which refers to objects that are large enough to be seen without magnification. Similarly, the term "nano" refers to objects that are large enough to be seen on the order of 10 mm.-9 Refers to a small object or scale of m.

[0174] As used herein, the term "noise" is a broad term and is used in its ordinary sense, including, but not limited to, signals detected by the sensor or sensor electronics that are independent of analyte concentration and may result in degradation of sensor performance. Some types of noise are observed for several hours (e.g., about 2 hours to about 24 hours) after sensor insertion. After the first 24 hours, the noise may disappear or decrease, but in some hosts, the noise may persist for about 3 to 4 days. In some cases, the noise can be reduced using predictive modeling, artificial intelligence, and / or algorithmic means. In other cases, the noise can be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as using a bioactive releasing membrane having at least one bioactive agent. For example, the noise of one or more exemplary biosensors as disclosed herein can be determined and then compared qualitatively or quantitatively. As an example, by acquiring a raw signal time series at a fixed sampling interval (in picoamperes (pA)), a smoothed version of the raw signal time series can be obtained, for example, by applying a third order low pass digital Chebyshev Type II filter. Other smoothing algorithms can also be used. At each sampling interval, an absolute difference in pA can be calculated to provide a smoothed time series. This smoothed time series can be converted to units of mg / dL (units of "noise") using the glucose sensitivity time series in units of pA / mg / dL, which is derived by using a mathematical model between the raw signal and a reference blood glucose measurement (e.g., obtained from a glucometer). Optionally, the time series can be aggregated, for example, by hour or day, as desired. Comparison of corresponding time series between different exemplary biosensors having a bioactive-releasing membrane and one or more bioactive agents of the present disclosure provides a qualitative or quantitative determination of the noise improvement.

[0175] As used herein, the terms "optional" or "optionally" are intended to be broad and to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning) and to mean, without limitation, that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when it does not occur.

[0176] As used herein, the term "polyampholyte polymer" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, polymers that contain both cationic and anionic groups. Such polymers can be prepared to have an approximately equal number of positive and negative charges, and thus the surface of such polymers can be approximately net neutrally charged. Alternatively, such polymers can be prepared to have either an excess of positive or negative charges, and thus the surface of such polymers can be net positive or net negative, respectively. "Polyampholyte polymer" encompasses polyampholyte polymers.

[0177] As used herein, the phrase "polymerizable group" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, a functional group that allows for the polymerization of a monomer with itself to form a homopolymer, or with a different monomer to form a copolymer. Depending on the type of polymerization method used, the polymerizable group can be selected from alkenes, alkynes, epoxides, lactones, amines, hydroxyls, isocyanates, carboxylic acids, anhydrides, silanes, halides, aldehydes, and carbodiimides.

[0178] As used herein, the term "polyzwitterion" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, polymers in which the repeat units of the polymer chain are zwitterionic moieties. Polyzwitterions are also known as polybetaines. Polyzwitterions are a type of polyampholytic polymer because they have both cationic and anionic groups. However, they are unique because the cationic and anionic groups are both part of the same repeat unit, which means that polyzwitterions have the same number of cationic and anionic groups, whereas other polyampholytic polymers can have more of one ionic group than the other. Polyzwitterions also have cationic and anionic groups as part of the repeat unit. A polyampholytic polymer need not have cationic groups attached to anionic groups; they can be on different repeat units and thus distributed apart from one another at random intervals, or one ionic group can outnumber the other.

[0179] As used herein, the term "proximal" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the spatial relationship between various elements compared to a particular reference point. For example, some embodiments of the device include a membrane system having a biointerface layer and an enzyme layer. If the sensor is considered to be the reference point and the enzyme layer is positioned closer to the sensor than the biointerface layer, then the enzyme layer is more proximal to the sensor than the biointerface layer.

[0180] As used herein, the phrases and terms "processor module" and "microprocessor" are each broad phrases and terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning) and refer to, but are not limited to, a computer system, state machine, processor, or the like, designed to perform arithmetic or logical operations using logic circuitry that responds to and processes the basic instructions that drive a computer.

[0181] As used herein, the term "semi-continuous" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, a portion, coating, domain, or layer that includes one or more continuous and discontinuous portions, coatings, domains, or layers. For example, a coating that is disposed around but not over a sensing area is "semi-continuous."

[0182] As used herein, the terms "sensing moiety," "sensing membrane," "sensing region," "sensing domain," and / or "sensing mechanism" are broad terms and are given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, biosensors and / or sensors responsible for detecting or transducing a signal associated with a particular analyte or combination of analytes. In an embodiment, the sensing moiety, sensing membrane, and / or sensing mechanism generally comprises an electrode configured to provide a signal during an electrochemical reaction with one or more membranes covering an electrochemically reactive surface. In an embodiment, such sensing moiety, sensing membrane, and / or sensing mechanism can provide a specific quantitative, semi-quantitative, qualitative, semi-qualitative analytical signal using a biorecognition element combined with a detection and / or transduction element.

[0183] During typical operation of an analyte measuring device, biosensor, sensor, sensing region, sensing moiety, or sensing mechanism, a biological sample, e.g., blood or interstitial fluid, or a component thereof, contacts, either directly or after passing through one or more membranes, an enzyme, e.g., glucose oxidase, or a protein, e.g., one or more periplasmic binding proteins (PBPs) or variants or fusion proteins thereof, having one or more analyte binding regions, each region capable of specifically and reversibly binding at least one analyte. The interaction of the biological sample or a component thereof with the analyte measuring device, biosensor, sensor, sensing region, sensing moiety, or sensing mechanism results in the transduction of a signal that allows for a qualitative, semi-qualitative, quantitative, or semi-qualitative determination of the analyte level, e.g., glucose, in the biological sample.

[0184] In examples, the sensing area or sensing portion may comprise at least a portion of a conductive substrate, or at least a portion of a conductive surface, e.g., a substantially planar substrate including wires or conductive traces, or substantially planar traces, and a membrane. In examples, the sensing area or sensing portion may comprise a non-conductive body, a working electrode, a reference electrode, and a counter electrode (optional) that form an electrochemically reactive surface at one location on the body and electronic connections at another location on the body, and a sensing membrane affixed to the body and covering the electrochemically reactive surface. In some examples, the sensing membrane further comprises an enzyme domain, e.g., an enzyme layer, and an electrolyte phase, e.g., a free-flowing liquid phase including an electrolyte-containing fluid as further described below. These terms are broad enough to include the entire device, or just the sensing portion thereof (or anything in between).

[0185] In another example, the sensing region can include one or more periplasmic binding proteins (PBPs) or mutants or fusion proteins thereof with one or more analyte binding regions, each region capable of specifically and reversibly binding at least one analyte. Mutations of the PBPs can contribute to or alter one or more of the binding constant, 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 "tag" to indicate changes 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 the protein, and redox state of the binding region. Such changes to the binding region provide a transduction of a detectable signal corresponding to one or more analytes present in the biological fluid.

[0186] In an embodiment, the sensing region determines selectivity between one or more analytes such that only the analyte that must be measured results in (transduces) a detectable signal. This selection can be based on any chemical or physical recognition of the analyte by the sensing region, where the chemical composition of the analyte does not change, or where the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.

[0187] The sensing region converts the recognition of the analyte into a semi-quantitative or quantitative signal. Thus, as used herein, "transducing" or "transduction" and their grammatical equivalents encompass optical, electrochemical, acoustic / mechanical, or colorimetric techniques and methods. Electrochemical properties include current and / or voltage, capacitance, and electric potential. Optical properties include absorbance, fluorescence / phosphorescence, wavelength shift, phase modulation, bio / chemiluminescence, reflectance, light scattering, and refractive index.

[0188] As used herein, the term "sensitivity" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, the amount of signal (e.g., in the form of current and / or voltage) generated by a given amount (unit) of analyte measured. For example, a sensor may have a sensitivity (or slope) of about 1 picoamp to about 100 picoamps of current per mg / dL of glucose analyte.

[0189] As used herein, the phrases and terms "small diameter sensor", "miniature structured sensor", and "microsensor" are broad phrases and terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not to be limited to any special or customized meaning) and refer to, but are not limited to, a sensing mechanism that has at least one dimension that is less than about 2 mm. In further embodiments, the sensing mechanism is less than about 1 mm in at least one dimension. In some embodiments, 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 embodiments, the maximum independently measured length, width, diameter, thickness, or circumference dimension of the sensing mechanism does not exceed about 2 mm. In some embodiments, the sensing mechanism is a needle-type sensor with a diameter of less than about 1 mm, see, e.g., U.S. Patent No. 6,613,379 to Ward et al. and U.S. Patent No. 7,497,827 to Brister et al., both of which are incorporated by reference in their entirety. In some alternative embodiments, the sensing mechanism includes an electrode deposited on a substantially planar substrate, and the thickness of the embedded portion is less than about 1 mm, see, e.g., U.S. Patent No. 6,175,752 to Say et al. and U.S. Patent No. 5,779,665 to Mastrototaro et al., both of which are incorporated by reference in their entirety. Examples of sensors (sensor electrode layouts and films) and methods of forming the sensor systems discussed herein can be found in currently pending U.S. Patent Application Publication No. 2019 / 0307371 to Boock et al., which is incorporated by reference in its entirety.

[0190] As used herein, the phrase "soft segment" is a broad phrase and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, an element of a copolymer, such as, for example, a polyurethane, a polycarbonate polyurethane, or a polyurethane urea copolymer, that imparts flexibility to the chain. The phrase "soft segment" can be further characterized as an amorphous material having a low Tg, e.g., a Tg that is typically no higher than ambient temperature or normal mammalian body temperature.

[0191] As used herein, the phrase "solid portion" is a broad phrase that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, that portion of the material of the membrane that has a mechanical structure that defines a cavity, void, or other non-solid portion.

[0192] As used herein, the terms and phrases "zwitterion" and "zwitterionic compound" are broad terms and phrases, respectively, that are to be given their ordinary and accustomed meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning) and refer to, but are not limited to, compounds in which a neutral molecule of the compound has a unit positive charge and a unit negative charge at different locations within the molecule. Such compounds are a type of zwitterionic compound and are sometimes referred to as "inner salts."

[0193] As used herein, the phrase "zwitterion precursor" or "zwitterionic compound precursor" is a broad phrase and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, any compound that is not itself a zwitterion, but can become a zwitterion in a final or transition state by a chemical reaction. In some examples described herein, the device includes a zwitterion precursor that can be converted to a zwitterion prior to in vivo implantation of the device. Alternatively, in some examples described herein, the device includes a zwitterion precursor that can be converted to a zwitterion by some chemical reaction that occurs after in vivo implantation of the device. Such reactions are known to those of skill in the art and include ring-opening reactions, addition reactions such as Michael addition, and the like. The method is particularly useful when polymerization of betaine-containing monomers is difficult due to technical challenges such as solubility of the betaine monomer to achieve desired physical properties such as molecular weight and mechanical strength. Post-polymerization modification or conversion of the betaine precursor can be a practical method to achieve desired polymer structures and compositions. Examples of such precursors include tertiary amines, quaternary amines, pyridine, and others detailed herein.

[0194] As used herein, the phrase "zwitterionic derivative" or "zwitterionic compound derivative" is a broad phrase and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, any compound that is not itself a zwitterion, but rather is the product of a chemical reaction in which a zwitterion is converted to a non-zwitterion. Such reactions can be reversible, such that under certain conditions the zwitterionic derivative can act as a zwitterionic precursor. For example, a hydrolyzable betaine ester formed from a zwitterionic betaine is a cationic zwitterionic derivative that can undergo hydrolysis back to the zwitterionic betaine under appropriate conditions.

[0195] Devices and probes that are percutaneously inserted or implanted into subcutaneous tissue traditionally induce a foreign body response (FBR), which includes the infiltration of inflammatory cells that ultimately form a foreign body capsule (FBC) as part of the body's response to the introduction of a foreign body. The continuous monitoring systems discussed herein include continuous analyte monitoring systems configured to simultaneously, sequentially, and / or randomly (comprising events that can occur independently in picoseconds, nanoseconds, milliseconds, seconds, or minutes) monitor one, two, or more analytes to predict health-related events and health system performance (e.g., current and future performance of a system of the human body, such as a cardiovascular, respiratory, digestive, or other system, or combination of organs or systems). In an embodiment, the insertion or implantation of a device, e.g., a glucose sensing device, may result in an acute inflammatory response that resolves into chronic inflammation with the concomitant construction of fibrous tissue, as described in detail above. Eventually, over a period of time, a mature FBC, mainly comprising contractile fibrous tissue, forms around the device. See Shanker and Greisler, Inflammation and Biomaterials in Greco RS, ed., "Implantation Biology: The Host Response and Biomedical Devices" pp 68-80, CRC Press (1994). FBCs surrounding conventional implanted devices have been shown to impede or block analyte transport across the device-tissue interface. Thus, continuous extended-life analyte transport in vivo (e.g., beyond the first few days) has traditionally been considered unreliable or impossible.

[0196] In some embodiments, certain aspects of the FBR in the first few days may play a role in the noise. Some sensors have been observed to function more poorly during the first few hours after insertion than they do later. This is exemplified by noise and / or suppression of the signal during the first few hours after insertion (e.g., about 2 to about 24 hours). These anomalies often resolve naturally, after which the sensor becomes less noisy, has improved sensitivity, and is more accurate than initially. Some transcutaneous and fully implantable sensors have been observed to be noisy for a period of time after application to the host (i.e., inserted percutaneously or fully implanted under the skin).

[0197] When the sensor is first inserted or implanted into the subcutaneous tissue, it comes into contact with a wide variety of possible tissue structures. The subcutaneous tissue in different hosts may be relatively fat-free in the case of very athletic people, or may be composed mostly of fat in the majority of people. Fat comes in a wide range of textures, from very white fluffy fat to very dense fibrous fat. Some fat is very yellow and appears thick, some is very clear, fluffy, and appears white, while in other cases it is more red or brown. The fat may be several inches thick or only a centimeter thick. It may be very vascular or relatively non-vascular. Many hosts with diabetes have some subcutaneous scar tissue due to years of insulin pump use or insulin injections. Sometimes the sensor may rest within such scar regions during insertion. The subcutaneous tissue may even vary greatly from one location to another in a given host's abdomen. Furthermore, by chance, the sensor may rest near a more densely vascularized area or in a less vascularized area of ​​a given host. Without wishing to be bound by theory, it is believed that the creation of space between the sensor surface and the surrounding cells, including the formation of a fluid pocket surrounding the sensor, may enhance sensor performance. Thus, the continuous analyte monitoring systems discussed herein provide extended life without compromising accuracy, which may also improve the host experience.

[0198] 1A is a side schematic view of an adipocyte in contact with an inserted transcutaneous or implanted sensor 34. In this case, the sensor 34 is tightly inserted into a small space with the adipocyte pressed against the surface. Close association of the adipocyte with the sensor can also occur, for example, if the sensor surface is hydrophobic. For example, adipocytes 200 and / or inflammatory cells, and / or other tissue types such as the dermis, fascia, and / or connective tissue, may create an active metabolic interface that can physically block access to the sensor surface and / or working electrode 38.

[0199] Typically, fat cells can be about 120 microns in diameter and are typically fed by small capillaries 205. When the sensor is pressed against the fat tissue, very few capillaries can actually come close to the surface of the sensor. This can be similar to covering the surface of the sensor with an impermeable material such as cellophane. Even if there were a few small holes in the cellophane, the function of the sensor would likely be compromised. Additionally, the surrounding tissue has a low metabolic rate and therefore does not require large amounts of glucose and oxygen. Without wishing to be bound by theory, it is believed that during this initial period the sensor signal may be noisy and may be suppressed due to the close association of the sensor surface with the fat cells and the reduced availability of oxygen and glucose for both physical-mechanical and physiological reasons.

[0200] Referring now to the extended functionality of the sensor, after a few days or weeks of implantation, these devices typically lose their functionality. In some applications, cellular attack or migration of cells to the sensor can cause a decrease in sensitivity and / or functionality of the device, especially after the first day of implantation. See also, for example, U.S. Pat. No. 5,791,344 and Gross et al. and "Performance Evaluation of the MiniMed Continuous Monitoring System During Host home Use," Diabetes Technology and Therapeutics, (2000) 2(1):49-56, which report a glucose oxidase-based device approved by the U.S. Food and Drug Administration for use in humans that works well for a few days after implantation, but rapidly loses functionality after a few days (e.g., from a few days to about 14 days).

[0201] Without being bound by any theory, this performance degradation of device function is most likely due to cells such as polymorphonuclear cells and monocytes that migrate to the sensor site during the first few days after implantation. These cells consume, among other things, local glucose and oxygen. If such cells are present in excess, they may deplete glucose and / or oxygen before they can reach the device enzyme layer, thereby reducing the sensitivity of the device or rendering it non-functional. Further inhibition of device function may be due to inflammatory cells, e.g., macrophages, which associate with the implanted device and adjacent tissue, e.g., at the interface, and physically block and / or attenuate glucose transport / flux into the device, e.g., by forming a barrier cell layer. Additionally, these inflammatory cells can biodegrade many artificial biomaterials, some of which were thought to be non-biodegradable until recently. When activated by foreign bodies, tissue macrophages degranulate, releasing hypochlorite (a bleaching agent) and other oxidizing species, enzymes, and superperoxide anions, hydroxyl ion / radical generating moieties known to degrade a variety of polymers.

[0202] 1B is a schematic side view of a biointerface membrane of an inserted transcutaneous or implanted sensor in one exemplary embodiment. In this view, a biointerface membrane 68 surrounds the sensor 34 and covers the working electrode 38. In one embodiment, the biointerface membrane 68 is used in combination with a bioactive release membrane 70, which is adjacent to or at least partially covers a portion of the biointerface membrane 68. In another embodiment, the bioactive release membrane 70 is at least partially covered by the biointerface membrane 68. In another embodiment, the bioactive release membrane 70 is used without the biointerface membrane 68.

[0203] Thus, for example, sensors that include a biointerface, including but not limited to porous biointerface materials, mesh cages, etc. (all of which are described in more detail elsewhere), can be used to improve sensor function (e.g., during the first hours to days).

[0204] In some situations, for example, in an expanded sensor, it is believed that the foreign body response is a primary event surrounding the expanded implantation of the implanted device and can be managed or engineered to support analyte transport rather than impeding or blocking it. In another aspect, to extend the life of the sensor, an embodiment uses a material that promotes vascularized tissue ingrowth, for example, in a porous biointerface membrane. For example, tissue ingrowth into a porous biointerface material surrounding an expanded sensor can promote sensor function over an extended period of time (e.g., weeks, months, or years). It has been observed that tissue ingrowth and formation of a tissue bed can take up to three weeks. It is believed that tissue ingrowth and tissue bed formation are part of the foreign body response. As discussed herein, the foreign body response can be engineered by the use of a porous biointerface material that surrounds the sensor and promotes ingrowth of tissue and microvasculature over time.

[0205] (sensing mechanism) In general, the analyte sensors of the present disclosure include a sensing mechanism 36 having, at least in part, a miniature structure (e.g., a miniature structured sensor, a microsensor, or a small diameter sensor), e.g., a needle-type sensor. As used herein, "miniature structure" preferably refers to an architecture having at least one dimension less than about 1 mm. The miniature structured sensing mechanism can be wire-based substrate, substrate-based, or any other architecture. In some alternative embodiments, the term "miniature structure" can also refer to slightly larger structures, such as those having a minimum dimension greater than about 1 mm, but where the architecture (e.g., mass or size) is designed to minimize foreign body reactions due to size and / or mass. In one embodiment, a biointerface membrane is formed on the sensing mechanism 36, as described in more detail below. In another embodiment, a bioactive-releasing membrane 70 is formed on the sensing mechanism 36 adjacent to the working electrode 38. In another embodiment, the bioactive-releasing membrane 70 is used in combination with a biointerface layer 68. In another embodiment, the bioactive-releasing membrane 70 is used without a biointerface layer 68.

[0206] 2A is a close-up view of an exemplary embodiment of a continuous analyte sensor 34, also referred to as a transcutaneous analyte sensor or needle-type sensor, specifically showing the sensing mechanism 36. Preferably, the sensing mechanism comprises a miniature structure as defined herein and is adapted for insertion under the skin of a host, while the remaining body of the sensor (e.g., electronics, etc.) can reside ex vivo. In the illustrated embodiment, the continuous analyte sensor 34 includes two electrodes, a working electrode 38 and at least one additional electrode that may function as a counter electrode and / or a reference electrode 30, hereafter referred to as the reference electrode 30.

[0207] In some exemplary embodiments, each electrode is formed from a thin wire having a diameter of, for example, about 0.001 inch or less to about 0.010 inch or more, and may be formed from, for example, plated insulation, plated wire, or bulk conductive material. While the illustrated electrode configuration and associated text describes one preferred method of forming a transcutaneous sensor, a variety of known transcutaneous sensor configurations can be used with the transcutaneous analyte sensor system of the present disclosure, such as those described in U.S. Pat. No. 6,695,860 to Ward et al., U.S. Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,248,067 to Causey III et al., and U.S. Pat. No. 6,514,718 to Heller et al.

[0208] In an embodiment, the working electrode comprises a wire formed from a conductive material, such as platinum, platinum-iridium, palladium, graphite, gold, carbon, conductive polymers, alloys, etc. Although the electrodes can be formed by a variety of manufacturing techniques (bulk metal processing, deposition of metal on a substrate, etc.), it may be advantageous to form the electrodes from plated wire (e.g., platinum on steel wire) or bulk metal (e.g., platinum wire). Electrodes formed from bulk metal wires are believed to offer superior performance (e.g., as opposed to deposited electrodes), including increased assay stability, simplified manufacturability, resistance to contamination (e.g., that may be introduced in the deposition process), and improved surface reactions without peeling or delamination (e.g., due to the purity of the material).

[0209] The working electrode 38 is configured to measure the concentration of one or more analytes. For example, in an enzymatic electrochemical sensor for detecting glucose, the working electrode measures hydrogen peroxide produced by an enzyme-catalyzed reaction of the analyte being detected, generating a measurable electronic current. For example, in the detection of glucose, where glucose oxidase produces hydrogen peroxide as a by-product, the hydrogen peroxide reacts with the surface of the working electrode to release two protons (2H + ), 2 electrons (2e - ) and one oxygen molecule (O2), which generates an electronic current that is detected.

[0210] The working electrode 38 is covered with an insulating material, such as a non-conductive polymer. Dip coating, spray coating, vapor deposition, or other coating or deposition techniques can be used to deposit the insulating material on the working electrode. In one embodiment, the insulating material includes parylene, which can be a polymer coating that is advantageous for its strength, lubricity, and electrical insulation properties. Generally, parylene is produced by vapor deposition and polymerization of paraxylylene (or its substituted derivatives). However, any suitable insulating material can be used, such as fluorinated polymers, polyethylene terephthalate, polyurethane, polyimide, other non-conductive polymers, and the like. Glass or ceramic materials can also be used. Other materials suitable for use include surface energy modification coating systems, such as those commercially available under the trade names AMC18, AMC148, AMC141, and AMC321 by Advanced Materials Components Express of Bellafonte, Pennsylvania. However, in some alternative embodiments, the working electrode may not require a coating of an insulator.

[0211] Preferably, the reference electrode 30, which may function as a reference electrode alone or as a dual reference and counter electrode, is formed from silver, silver / silver chloride, or the like. Preferably, the electrodes are juxtaposed and / or twisted on or around each other, although other configurations are possible. In one example, the reference electrode 30 is spirally wound around the working electrode 38, as illustrated in FIG. 1B. The assembly of wires may then optionally be coated with an insulating material similar to that described above to provide an insulating attachment (e.g., to secure the working and reference electrodes together).

[0212] In embodiments where an outer insulator 35 is disposed, a portion of the coated assembly structure may be stripped or otherwise removed, for example, by hand, excimer laser, chemical etching, laser ablation, grit blasting (e.g., with sodium bicarbonate, solid carbon dioxide, or other suitable grit), etc., to expose the electrochemically active surfaces. Alternatively, a portion of the electrodes may be masked prior to depositing the insulator to maintain exposed electrochemically active surface area. In one exemplary embodiment, grit blasting is implemented to expose the electrochemically active surfaces, preferably utilizing a grit material that is hard enough to ablate the polymeric material, but soft enough to minimize or avoid damage to the underlying metal electrodes (e.g., platinum electrodes). While a variety of "grit" materials (e.g., sand, talc, walnut shells, crushed plastic, sea salt, solid carbon dioxide, etc.) can be used, in some embodiments, sodium bicarbonate is an advantageous grit material, as it is hard enough to ablate, for example, the parylene coating, without damaging, for example, the underlying platinum conductor. One additional benefit of sodium bicarbonate blasting includes its abrasive action on metal as it strips away the polymer layer, thereby eliminating a cleaning step that might otherwise be necessary.

[0213] In some embodiments, a radial window is formed through the insulating material to expose a circumferential electrochemically active surface of the working electrode. In addition, a section of the electrochemically active surface of the reference electrode is exposed. For example, the section of the electrochemically active surface can be masked during deposition of the outer insulating layer or can be etched after deposition of the outer insulating layer.

[0214] In some applications, cellular attack or migration to the sensor may cause degradation of the device's sensitivity and / or function, especially after the first day of implantation. However, when the exposed electroactive surface is distributed circumferentially around the sensor (e.g., as in radial windows), the surface area available for reaction can be sufficiently distributed to minimize the effect of local cellular invasion of the sensor on the sensor signal. Alternatively, a tangentially exposed electrochemically active window can be formed, for example, by peeling only one side of the coated assembly structure. In other alternative embodiments, a window can be provided at the tip of the coated assembly structure such that the electrochemically active surface is exposed at the tip of the sensor. Other methods and configurations for exposing the electrochemically active surface can also be used.

[0215] Preferably, the sensors exemplified above have an overall diameter of about 0.020 inches (about 0.51 mm) or less, more preferably about 0.018 inches (about 0.46 mm) or less, and most preferably about 0.016 inches (0.41 mm) or less. In some embodiments, the working electrode has a diameter of about 0.001 inches or less to about 0.010 inches or more, preferably about 0.002 inches to about 0.008 inches, more preferably about 0.004 inches to about 0.005 inches, including all ranges and subranges therebetween. The length of the window can be from about 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078 inches) or more, preferably about 0.5 mm (about 0.02 inches) to about 0.75 mm (0.03 inches), including all ranges and subranges therebetween. In such embodiments, the exposed surface area of ​​the working electrode is preferably about 0.000013 inches (about 0.000013 inches). 2 (0.0000839cm 2 ) below approximately 0.0025in 2 (0.016129cm 2) or greater (assuming a diameter of about 0.001 inches to about 0.010 inches and a length of about 0.004 inches to about 0.078 inches), including all ranges and subranges therebetween. The exposed surface area of ​​the working electrode is selected to generate an analyte signal having a current in the femtoamp range, picoamp range, nanoamp range, or microamp range, as described in more detail elsewhere herein. However, currents below the picoamp range can depend on a variety of factors, such as the electronic circuit design (e.g., sample rate, current draw, A / D converter bit resolution, etc.), the membrane system (e.g., analyte permeability through the membrane system), and the exposed surface area of ​​the working electrode. Thus, the exposed electrochemically active working electrode surface area can be selected to have a value greater than the aforementioned ranges or less than the aforementioned ranges, taking into account modifications in the membrane system and / or electronic circuitry. In an embodiment of a glucose sensor, it may be advantageous to minimize the surface area of ​​the working electrode while maximizing the diffusivity of glucose in order to optimize the signal-to-noise ratio while maintaining sensor performance in both high and low glucose concentration ranges.

[0216] In some alternative embodiments, the exposed surface area of ​​the working (and / or other) electrodes can be increased by modifying the cross-section of the electrode itself. For example, in some embodiments, the cross-section of the working electrode can be defined by a cross, star, cloverleaf, rib, dimple, ridge, irregular, or other non-circular configuration, thus achieving a certain increased surface area (compared to the area achieved by a circular cross-section) for any given length of the electrode. Increasing the surface area of ​​the working electrode can be advantageous in providing an increased signal in response to analyte concentration, which in turn can help to improve, for example, the signal-to-noise ratio.

[0217] In some alternative embodiments, additional electrodes can be included in the assembly, such as a three-electrode system (working, reference, and counter electrodes) and / or additional working electrodes (e.g., an electrode that can be used to generate oxygen, an electrode configured as a baseline subtraction electrode, or an electrode configured to measure an additional analyte). U.S. Pat. No. 7,081,195, filed Dec. 7, 2004, entitled "SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS," and U.S. Pat. No. 7,715,893, filed Dec. 3, 2004, entitled "CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR," describe several systems and methods for implementing and using additional working, counter, and / or reference electrodes. In one implementation where the sensor comprises two working electrodes, the two working electrodes are juxtaposed (e.g., extending parallel to one another) around which the reference electrode is disposed (e.g., wound in a spiral). In some examples where more than one working electrode is provided, the working electrodes can be formed in a double, triple, quadruple, etc. spiral configuration along the length of the sensor (e.g., surrounding a reference electrode, an insulating rod, or other support structure). The resulting electrode system can be configured with a suitable membrane system, where the first working electrode is configured to measure a first signal including glucose and a baseline, and the additional working electrode is configured to measure a baseline signal consisting of only the baseline (e.g., configured substantially similarly to the first working electrode without the enzyme disposed thereon). In this manner, the baseline signal can be subtracted from the first signal to generate a glucose-only signal that is substantially free of variations in baseline and / or interfering species on the signal. Thus, the dimensions described above can be modified as desired. Although the present disclosure discloses one electrode configuration including one bulk metal wire helically wound around another bulk metal wire, other electrode configurations are contemplated. In an alternative embodiment, the working electrode comprises a tube having a reference electrode disposed or coiled therein with an insulator therebetween.Alternatively, the reference electrode comprises a tube having the working electrode disposed or coiled therein with an insulator therebetween. In another alternative embodiment, a polymeric (e.g., insulating) rod is provided and the electrodes are deposited (e.g., electroplated) thereon. In yet another alternative embodiment, a metal (e.g., steel) rod coated with an insulating material is provided and the working and reference electrodes are deposited thereon. In yet another alternative embodiment, one or more working electrodes are spirally wound around the reference electrode.

[0218] The methods of the present disclosure are particularly suitable for use with miniature structured sensors, microsensors, or small diameter sensors, although the methods may be suitable for use with larger diameter sensors, such as sensors having a diameter of 1 mm to about 2 mm or more.

[0219] In some alternative embodiments, the sensing mechanism includes electrodes deposited on a planar substrate and the thickness of the implantable portion is less than about 1 mm, see, e.g., 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 by reference in their entireties herein.

[0220] (sensing membrane) In an embodiment, the sensing membrane 32 is disposed on the electrochemically active surface of the continuous analyte sensor 34 and includes one or more domains or layers. In general, the sensing membrane functions, for example, to control the flow of biological fluid therethrough and / or to protect the sensitive area of ​​the sensor from contamination by the biological fluid. Some conventional electrochemical enzyme-based analyte sensors generally include a sensing membrane that, for example, controls the flow of the analyte to be measured, protects the electrodes from contamination by the biological fluid, and / or provides an enzyme that catalyzes the reaction of the analyte with a cofactor. See, for example, U.S. Patent Application Publication No. 2005 / 0245799, entitled "IMPLANTABLE ANALYTE SENSOR," filed May 3, 2004, and U.S. Patent No. 7,497,827, entitled "TRANSCUTANEOUS ANALYTE SENSOR," filed March 10, 2005, each of which is incorporated herein by reference in its entirety.

[0221] The sensing membrane of the present disclosure can include any membrane configuration suitable for use with any analyte sensor (as described in more detail above). In general, the sensing membrane of the present disclosure includes one or more domains, all or some of which can be adhered or deposited on the analyte sensor, as will be understood by those skilled in the art. In embodiments, the sensing membrane generally provides one or more of the following functions, as described in the above-referenced U.S. patent publications: 1) protection of exposed electrode surfaces from the biological environment, 2) analyte diffusion resistance (limitation), 3) catalysis to enable enzymatic reactions, 4) limiting or blocking interfering species, and 5) hydrophilicity at the electrochemically reactive surface of the sensor interface.

[0222] (Electrode domain) In some embodiments, the membrane system comprises an electrode membrane with an optional electrode domain. The electrode domain is provided to ensure that the electrochemical reaction occurs between the electrochemically active surface of the working electrode and the reference electrode, and therefore the electrode domain is preferably located closer to the electrochemically active surface than the enzyme domain. Preferably, the electrode domain comprises a semi-permeable coating that maintains a layer of water on the electrochemically reactive surface of the sensor, for example, a wetting agent in a binder material can be used as the electrode domain, which allows complete transport of ions in an aqueous environment. The electrode domain can also help stabilize the operation of the sensor by overcoming problems of electrode start-up and drift caused by insufficient electrolyte. The material forming the electrode domain can also protect against pH-mediated damage that may result from the formation of a large pH gradient due to the electrochemical activity of the electrode.

[0223] In embodiments, the electrode domain comprises a flexible, water-swellable hydrogel film having a "dry film" thickness of about 0.05 microns or less to about 20 microns or more, more preferably about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, more preferably about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns, including all ranges and subranges therebetween. "Dry film" thickness refers to the thickness of a cured film cast from a coating formulation by standard coating techniques.

[0224] In a particular embodiment, the electrode domain is formed from a curable mixture of a urethane polymer and a hydrophilic polymer. A particularly preferred coating is formed from a polyurethane polymer having carboxylate functional groups and non-ionic hydrophilic polyether segments, where the polyurethane polymer is crosslinked with a water-soluble carbodiimide (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

[0225] Preferably, the electrode domain is deposited by spraying or dip coating the electrochemically active surface of the sensor. More preferably, the electrode domain is formed by dip coating the electrochemically active surface in an electrode solution and curing the domain at a temperature of about 40° C. to about 55° C. for about 15 minutes to about 30 minutes (and may be accomplished under vacuum (e.g., 20 mmHg to 30 mmHg)), including all ranges and subranges therebetween. In embodiments where dip coating is used to deposit the electrode domain, a preferred insertion speed of about 1 inch / min to about 3 inches / min, a preferred residence time of about 0.5 minutes to about 2 minutes, and a preferred withdrawal speed of about 0.25 inches / min to about 2 inches / min provide a functional coating, including all ranges and subranges therebetween. However, values ​​other than those listed above may be acceptable or even desirable in certain embodiments, depending, for example, on viscosity and surface tension, as will be appreciated by those skilled in the art. In one embodiment, the electrochemically active surface of the electrode system is dip coated once (one layer) and cured at 50° C. for 20 minutes under vacuum.

[0226] Although separate electrode domains are described herein, in some examples, sufficient hydrophilicity can be provided in the interference domain and / or enzyme domain (domains adjacent to the electrochemically active surface) to provide complete transport of ions in an aqueous environment (e.g., without a separate electrode domain).

[0227] (Interference domain) In some embodiments, an optional interference domain is provided, which generally comprises a polymer domain that restricts the flow of one or more interfering substances. In some embodiments, the interference domain functions as a molecular sieve that allows the passage of the analyte and other substances measured by the electrode, but prevents the passage of other substances, including interfering substances such as ascorbate and urea (see U.S. Patent No. 6,001,067 to Shults). Some known interfering substances for glucose oxidase-based electrochemical sensors include acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylic acid, tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid.

[0228] Some polymer types that can be utilized as base materials for the interference domain include, for example, polyurethanes, polymers with pendant ionic groups, and polymers with controlled pore size. In one embodiment, the interference domain comprises a thin hydrophobic membrane that is non-swelling and limits the diffusion of low molecular weight species. The interference domain is permeable to relatively low molecular weight substances such as hydrogen peroxide, but restricts the passage of higher molecular weight substances including glucose and ascorbic acid. Other systems and methods for reducing or eliminating interfering species that may be applied to the membrane systems of the present disclosure are described in U.S. Pat. No. 7,074,307, entitled "ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS," filed July 21, 2004; U.S. Patent Application Publication No. 2005 / 0176136, entitled "AFFINITY DOMAIN FOR AN ANALYTE SENSOR," filed November 16, 2004; U.S. Pat. No. 7,081,195, entitled "SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS," filed December 7, 2004; and U.S. Pat. No. 7,715,893, entitled "CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR," filed December 3, 2004. In some alternative embodiments, a separate interference domain is not included.

[0229] In embodiments, the interference domain is deposited on the electrode domain (or directly on the electrochemically active surface when no separate electrode domain is included) with a domain thickness of from about 0.05 microns or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, more preferably from about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns, including all ranges and subranges therebetween. Thicker membranes can also be useful, but thinner membranes are generally preferred as they have less effect on the rate of diffusion of hydrogen peroxide from the enzyme membrane to the electrode. Unfortunately, the small thickness of the interference domains previously used can introduce variability in membrane system processing: for example, if too many or too few interference domains are incorporated into a membrane system, the performance of the membrane can be adversely affected.

[0230] (enzyme domain) In one embodiment, the membrane system further comprises an enzyme domain disposed more distally from the electrochemically active surface than the interference domain (or the electrode domain when no separate interference is included). In some embodiments, the enzyme domain is deposited directly on the electrochemically active surface (when neither is included in the electrode or interference domain). In one embodiment, the enzyme domain provides an enzyme that catalyzes the reaction of the analyte and its co-reactant, as described in more detail below. Preferably, the enzyme domain comprises glucose oxidase, however, other oxidases, such as galactose oxidase, lactate oxidase, or uricase oxidase, may also be used.

[0231] For an enzyme-based electrochemical glucose sensor to perform well, it is preferred that the sensor response is not limited by either the enzyme activity or the co-reactant concentration. Since enzymes, including glucose oxidase, undergo inactivation as a function of time even in ambient conditions, this behavior is compensated for in forming an enzyme domain. Preferably, the enzyme domain is composed of an aqueous dispersion of colloidal polyurethane polymer containing the enzyme. However, in an alternative embodiment, the enzyme domain is constructed from an oxygen enhancing material, such as silicone or fluorocarbon, to provide an excess supply of oxygen during transient ischemia. Preferably, the enzyme is immobilized within the domain. See U.S. Patent No. 7,379,765, entitled "Oxygen Enhancing Membrane Systems for Implantable Devices," filed July 21, 2004.

[0232] In embodiments, the enzyme domain is deposited on the interference domain at a domain thickness of about 0.05 microns or less to about 20 microns or more, more preferably about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, more preferably about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns, including all ranges and subranges therebetween. However, in some embodiments, the enzyme domain is deposited directly on the electrode domain or on the electrochemically active surface. Preferably, the enzyme domain is deposited by spray coating or dip coating. More preferably, the enzyme domain is formed by dip coating the electrode domain into the enzyme domain solution and curing the domain at a temperature of about 40 to about 55° C. for about 15 to about 30 minutes (and may be accomplished under vacuum (e.g., 20 mmHg to 30 mmHg)), including all ranges and subranges therebetween. In examples where dip coating is used to deposit the enzyme domain at room temperature, a preferred insertion speed of about 1 in / min to about 3 in / min, a preferred residence time of about 0.5 min to about 2 min, and a preferred withdrawal speed of about 0.25 in / min to about 2 in / min provide a functional coating, including all ranges and subranges therebetween. However, values ​​other than those recited above may be acceptable or even desirable in certain examples, depending, for example, on viscosity and surface tension, as will be appreciated by those of skill in the art. In one example, the enzyme domain is formed by dip coating twice into the coating solution (i.e., forming two layers) and curing under vacuum at 50° C. for 20 minutes. However, in some embodiments, the enzyme domain can be formed by dip coating and / or spray coating one or more layers at a predetermined concentration of coating solution, insertion rate, residence time, withdrawal rate, and / or desired thickness.

[0233] (Resistance Domain) In one embodiment, the membrane system includes a resistance domain located more distally from the electrochemically active surface than the enzyme domain. Although the following description is directed to a resistance domain for a glucose sensor, the resistance domain can be similarly modified for other analytes and co-reactants.

[0234] There is a molar excess of glucose relative to the amount of oxygen in the blood, i.e., for each free oxygen molecule in the extracellular fluid, there are typically more than 100 glucose molecules (see Updike et al., Diabetes Care 5:207-21 (1982)). However, immobilized enzyme-based glucose sensors that use oxygen as a coreactant are preferably supplied with a non-rate-limiting excess of oxygen so that the sensor responds linearly to changes in glucose concentration but not to changes in oxygen concentration. Specifically, when the glucose monitoring reaction is oxygen-limited, linearity is not achieved above a minimum concentration of glucose. In the absence of a semi-permeable membrane placed over the enzyme domain to control the flux of glucose and oxygen, a linear response to glucose levels can only be obtained for glucose concentrations 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.

[0235] The resistance domain includes a semi-permeable membrane that controls the flux of oxygen and glucose to the underlying enzyme domain, preferably making the oxygen non-rate-limiting excess. As a result, the upper linearity limit of glucose measurement is extended to values ​​much higher than that achieved without the resistance domain. In an embodiment, the resistance domain exhibits an oxygen to glucose permeability ratio of about 50:1 or less to about 400:1 or more, preferably about 200:1, including all ranges and subranges therebetween. As a result, one-dimensional reactant diffusion is sufficient to provide an excess of oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (see Rhodes et al., Anal. Chem., 66:1520-1529 (1994)).

[0236] In an alternative embodiment, a lower ratio of oxygen to glucose can be sufficient to provide excess oxygen by using a high oxygen solubility domain (e.g., silicone or fluorocarbon based materials or domains) to enhance oxygen supply / transport to the enzyme domain. Also, if more oxygen is supplied to the enzyme, more glucose can be supplied to the enzyme without creating an oxygen-limiting excess. In an alternative embodiment, the resistance domain is formed from a silicone composition such as described in U.S. Patent Publication No. 2005 / 0090607, entitled "SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE," filed October 28, 2003.

[0237] In a preferred embodiment, the resistive domain comprises a polyurethane membrane having both hydrophilic and hydrophobic regions for controlling the diffusion of glucose and oxygen to the analyte sensor, which membrane is easily and reproducibly manufactured from commercially available materials. A suitable hydrophobic polymer component is a polyurethane, or a polyetherurethane urea. Polyurethanes are polymers produced by the condensation reaction of diisocyanates with difunctional hydroxyl-containing materials. Polyurethane ureas are polymers produced by the condensation reaction of diisocyanates with difunctional amine-containing materials. In some embodiments, exemplary diisocyanates include aliphatic diisocyanates containing about 4 to about 8 methylene units. Diisocyanates containing alicyclic moieties can also be useful in preparing the polymer and copolymer components of the membranes of the present disclosure. The material that forms the base of the hydrophobic matrix of the resistive domain can be any known in the art as suitable for use as a membrane in a continuous analyte sensor device and having sufficient permeability to allow the relevant compounds to pass through it, for example, sufficient permeability to allow oxygen molecules from the test sample to pass through the membrane to reach the active enzyme or electrochemical electrode. Examples of materials that can be used to make non-polyurethane type membranes include inorganic polymers such as vinyl polymers, polyethylene vinyl acetate copolymers, polyethers, polyalkyl carbonates, polycarbonates, polyalkyl esters, polyesters, polyamides, polysiloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein-based materials, and mixtures or combinations thereof.

[0238] In a preferred embodiment, the hydrophilic polymer component of the resistance domain is polyethylene oxide. For example, one useful hydrophobic-hydrophilic copolymer component is a polyurethane polymer containing about 20% hydrophilic polyethylene oxide. The polyethylene oxide portion of the copolymer is thermodynamically driven to separate from the hydrophobic portion of the copolymer and the hydrophobic polymer component. The 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend affects the water uptake and subsequent glucose permeability of the membrane.

[0239] In embodiments, the resistance domain is deposited on the enzyme domain to obtain a domain thickness of about 0.05 microns or less to about 20 microns or more, more preferably about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, more preferably about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns, including all ranges and subranges therebetween. Preferably, the resistance domain is deposited on the enzyme domain by spray coating or dip coating. In certain embodiments, spray coating is the preferred deposition technique. The spraying process atomizes and mistizes the solution, so that most or all of the solvent evaporates before the coating material settles on the underlying domain, thereby minimizing contact between the solvent and the enzyme. One additional advantage of spray coating the resistance domain as described in this disclosure includes the formation of a membrane system that substantially blocks or resists ascorbate, a known electrochemical interferent in hydrogen peroxide measuring glucose sensors. Without wishing to be bound by theory, it is believed that during the process of depositing the resistance domain as described in this disclosure, a structural morphology is formed that is characterized by a substantial impermeability to ascorbate.

[0240] In an embodiment, the resistance domain is deposited on the enzyme domain by spray coating a solution of about 1% to about 5% by weight polymer and about 95% to about 99% by weight solvent, including all ranges and subranges therebetween. When spraying a solution of resistance domain material containing a solvent onto the enzyme domain, it is desirable to mitigate or substantially reduce any contact with the enzyme of any solvent in the spray solution that may inactivate the enzyme underlying the enzyme domain. Tetrahydrofuran (THF) is one solvent that has minimal or negligible effect on the enzyme of the enzyme domain when sprayed. Other solvents may also be suitable for use, as will be appreciated by those skilled in the art.

[0241] Although a variety of spraying or deposition techniques can be used, spraying the resistive domain material and rotating the sensor at least once 180° can provide sufficient coverage by the resistive domain. Spraying the resistive domain material and rotating the sensor at least twice 120° provides even greater coverage (one layer of 360° coverage), thereby ensuring resistance to glucose, as described in more detail above.

[0242] In an embodiment, the resistive domain is spray coated and then cured at a temperature of about 40 to about 60° C. for about 15 minutes to about 90 minutes (which can be accomplished under vacuum (e.g., 20 mmHg to 30 mmHg)), including all ranges and subranges therebetween. Curing times of up to about 90 minutes or more can be advantageous to ensure complete drying of the resistive domain. Without wishing to be bound by theory, it is believed that complete drying of the resistive domain helps stabilize the sensitivity of the glucose sensor signal. It reduces drift in signal sensitivity over time, and complete drying is believed to stabilize the performance of the glucose sensor signal in lower oxygen environments.

[0243] In an embodiment, the resistance domain is formed by spray coating at least six layers (i.e., rotating the sensor 17 times by 120° for at least six layers of 360° coverage) and curing for 60 minutes under vacuum at 50° C. However, the resistance domain can be formed by dip coating or spray coating any layer or layers depending on the concentration of the solution, insertion speed, dwell time, withdrawal speed, and / or desired thickness of the resulting film.

[0244] Advantageously, sensors having the membrane system of the present disclosure, including an electrode domain and / or interference domain, an enzyme domain, and a resistance domain, provide a stable signal response to increasing glucose levels from about 40 mg / dL to about 400 mg / dL, including all ranges and subranges therebetween, and sustained functionality (at least 90% signal strength) even at low oxygen levels (e.g., about 0.6 mg / LO2). Without wishing to be bound by theory, it is believed that the resistance domain provides sufficient resistivity or the enzyme domain provides sufficient enzyme such that oxygen limitation is seen at much lower oxygen concentrations compared to prior art sensors.

[0245] In examples, sensor signals having currents in the picoamp range or below are provided, which are described in more detail elsewhere herein. However, the ability to generate signals with currents in the picoamp range can depend on a combination of factors, including electronic circuit design (e.g., A / D converter, bit resolution, etc.), membrane system (e.g., permeability of analyte through the resistive domain, enzyme concentration, and / or electrolyte availability for electrochemical reactions at the electrode), and exposed surface area of ​​the working electrode. For example, the resistive domain can be designed to be more or less restrictive for the analyte, depending on the design of the electronic circuit, membrane system, and / or exposed electrochemically active surface area of ​​the working electrode.

[0246] Thus, in embodiments, the membrane system is designed with a sensitivity of about 1 pA / mg / dL to about 100 pA / mg / dL, preferably about 5 pA / mg / dL to 25 pA / mg / dL, more preferably about 4 pA / mg / dL to about 7 pA / mg / dL, including all ranges and subranges therebetween. Without wishing to be bound by any theory, it is believed that the membrane system designed with a sensitivity in the preferred range allows for measurement of analyte signals in low analyte and / or low oxygen conditions. That is, conventional analyte sensors have shown reduced measurement accuracy in the low analyte range due to low availability of analyte to the sensor, and / or increased signal noise in the high analyte range due to insufficient oxygen required to react with the amount of analyte being measured. Without wishing to be bound by theory, it is believed that the membrane system of the present disclosure, in combination with the electronic circuitry design and exposed electrochemically reactive surface area design, supports the measurement of analytes in the picoamp range and below, which allows for improved levels of resolution and accuracy in both the low and high analyte ranges not seen in the prior art.

[0247] Although some embodiment sensors described herein include an optional interference domain to block or reduce one or more interfering substances, sensors having 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 additional interference domains. That is, the membrane system of the present disclosure including an electrode domain, an enzyme domain, and a resistance domain has been shown to be substantially unresponsive to ascorbate in a physiologically acceptable range. Without wishing to be bound by theory, it is believed that the process of depositing the resistance domain by spray coating described herein results in a structural form that is substantially resistant to ascorbate.

[0248] (Membrane systems without interference domains) In general, it is believed that suitable solvents and / or deposition methods can be selected for one or more domains of the membrane system that form one or more transition domains so that the interfering substances are substantially impermeable. Thus, the sensor can be constructed without separate or deposited interference domains that are non-responsive to the interfering substances. Without wishing to be bound by theory, it is believed that a simplified multilayer membrane system, a more robust multilayer manufacturing process, and a reduction in the variability caused by the thickness of the deposited micron-thin interference domains and the associated oxygen and glucose sensitivity can be provided. Additionally, the optional polymer-based interference domains that normally inhibit the diffusion of hydrogen peroxide are eliminated, thereby enhancing the amount of hydrogen peroxide passing through the membrane system.

[0249] (Oxygen Tube) As mentioned above, certain sensors rely on enzymes in a membrane system through which the host's bodily fluid passes and an analyte (e.g., glucose) in the bodily fluid reacts in the presence of a co-reactant (e.g., oxygen) to produce a product. This product is then measured using electrochemical methods, and thus the output of the electrode system serves as a measurement of the analyte. For example, when the sensor is a glucose oxidase-based glucose sensor, the species measured at the working electrode is H2O2. The enzyme glucose oxidase catalyzes the conversion of oxygen and glucose to hydrogen peroxide and gluconic acid according to the following reaction: glucose + O2 -> gluconic acid + H2O2.

[0250] For each glucose molecule reacted, there is a proportional change in the product, H2O2, so that the change in H2O2 can be monitored to determine the glucose concentration. The oxidation of H2O2 by the working electrode is balanced by the reduction of ambient oxygen, enzymatically generated H2O2, and other reducible species, for example, at the counter electrode. See Fraser, DM, "An Introduction to In vivo Biosensing: Progress and Problems"; see "Biosensors and the Body," DM Fraser, ed., 1997, pp. 1-56 John Wiley and Sons, New York).

[0251] In vivo, glucose concentrations are generally about 100 times higher than oxygen concentrations. As a result, oxygen is the limiting reactant in the electrochemical reaction, and the sensor is unable to accurately measure glucose concentrations when insufficient oxygen is supplied to the sensor. Thus, reduced sensor function or inaccuracy is believed to be the result of problems in the availability of oxygen to the enzyme and / or electrochemically active surfaces.

[0252] Thus, in an alternative embodiment, an oxygen conduit (e.g., a high oxygen solubility domain formed from silicone or fluorochemical) is provided that extends from the ex vivo portion of the sensor to the in vivo portion of the sensor to increase the availability of oxygen to the enzyme. The oxygen conduit can be formed as part of the coating (insulating) material or can be a separate conduit associated with the assembly of wires that forms the sensor.

[0253] 2B is a cross-sectional view of the sensor of FIG. 2A at line BB, showing a core 39 with an exposed electrochemically active surface of at least the working electrode 38 surrounded by the sensing membrane 32. The core 39 is configured for multi-axis bending and can be stainless steel, titanium, tantalum, or a polymer. Generally, the sensing membrane of the present disclosure includes multiple domains or layers, e.g., an interference domain 44, an enzyme domain 46, and a resistive domain 48, and may include additional domains, such as an electrode domain, a cell impermeable domain (not shown), an oxygen domain (not shown), a bioactive release membrane 70, and / or a biointerface membrane 68 (not shown), as described in more detail below and / or in the U.S. patent publications cited above. However, it is understood that sensing membranes modified for other sensors, e.g., by including fewer or additional domains, are within the scope of the present disclosure.

[0254] (Membrane System) In some embodiments, one or more domains of the sensing membrane are formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefins, polyesters, polyalkylesters, polyalkylcarbonates, polycarbonates, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethane or polyethylene urea copolymers, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyethylene vinyl acetate, polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, poly(ethylene oxide), poly(propylene oxide), and copolymers and blends thereof, polysulfones and block copolymers thereof, including, for example, diblock, triblock, alternating, random, and graft copolymers. US Patent Application Publication No. 2005 / 0245799, incorporated herein by reference in its entirety, describes biological interfaces and sensing membrane configurations and materials that may be applied to the sensors of the present disclosure.

[0255] The sensing membrane can be deposited on the electrochemically active surface of the electrode material using known thin or thick film techniques (e.g., spraying, electrodeposition, dipping, etc.). Note that the sensing membrane surrounding the working electrode need not be of the same structure as the sensing membrane surrounding the reference electrode, etc. For example, an enzyme domain deposited on the working electrode does not necessarily need to be deposited on the reference and / or counter electrodes.

[0256] In the illustrated embodiment, the sensor is an enzyme-based electrochemical sensor, and the working electrode 38 measures the electronic current; for example, detection of glucose utilizing glucose oxidase produces hydrogen peroxide as a by-product, and H2O2 reacts with the surface of the working electrode to produce two protons (2H + ), 2 electrons (2e - ), and one oxygen molecule (O2) that generates an electronic current that is detected, or via direct electron transfer in a redox system, e.g., a "wired enzyme" system as described in more detail above and understood by those of skill in the art. One or more potentiostats are used to monitor the electrochemical reaction at the electrochemically active surface of the working electrode. 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 generated at the working electrode (and flows through the circuit to the counter electrode) is substantially proportional to the amount of H2O2 that diffuses to the working electrode or the analyte that facilitates the 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 the host, for example, to a host or physician.

[0257] Some alternative analyte sensors that can benefit from the systems and methods of the present disclosure are described, for example, in 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. 6,465,066 to Offenbacher et al., and U.S. Pat. No. 6,520,313 to Benjamin et al. No. 6,214,185 to Cunningham et al., U.S. Patent No. 5,310,469 to Cunningham et al., U.S. Patent No. 5,683,562 to Shaffer et al., U.S. Patent No. 6,579,690 to Bonnecaze et al., U.S. Patent No. 6,484,046 to Say et al., U.S. Patent No. 6,512,939 to Colvin et al., U.S. Patent No. 6,424,847 to Mastrototaro et al., and U.S. Patent No. 6,424,847 to Mastrototaro et al., all of which are incorporated herein by reference in their entireties and are not intended to be exhaustive of all applicable analyte sensors, although it should be understood that in general, the disclosed embodiments are applicable to a variety of analyte sensor configurations.

[0258] (Exemplary Sensor Configurations) 2C is a cross-sectional view of the sensor of FIG. 2A along line BB, showing the unexposed electrochemically active surface of at least the working electrode 38 surrounded by a sensing membrane including multiple domains or layers, e.g., interference domain 44, enzyme domain 46, and resistive domain 48, and may include additional domains / membranes, such as an electrode domain, a cell impermeable domain (not shown), an oxygen domain (not shown), a bioactive emissive membrane 70, and / or a biointerface membrane 68 (not shown), as described in more detail below. The bioactive emissive membrane 70 is positioned adjacent to the working electrode 38 surface and does not cover the multiple domains or layers, e.g., interference domain 44, enzyme domain 46, and resistive domain 48, of the working electrode 38 or the sensing membrane 32 adjacent to the working electrode surface. In one embodiment, the bioactive emissive membrane 70 is positioned at the distal end 37 of the sensor 34. In another embodiment, the bioactive emissive membrane 70 spans the electrochemically active portion of the working electrode 38 and does not cover the sensing membrane 32 associated with the working electrode 38.

[0259] 2D is a cross-sectional view through the sensor of FIG. 2A on line DD of an exemplary bioactive emissive film deposition of sensor 34, where bioactive emissive film 70 is more distal from electrode 38 than resistive domain 48 and / or biointerface domain 68, and adjacent to but not covering enzyme domain 46 or transducer element and / or interference domain 44, and / or sensing region or electrochemically active surface of the sensing region. Bioactive emissive film 70 can be arranged on sensor 34 as shown in FIG. 2D using one or more of screen printing, spray coating, or dip coating methods.

[0260] 2E is a cross-sectional view through the sensor of FIG. 2A on line BB of another exemplary bioactive emissive film deposition, where the bioactive emissive film 70 is more distal from the electrode 38 than the resistive layer 48 and / or the biointerface layer 68, and is adjacent to and generally covering only the tip or distal end 37 of the sensor 34, close to and adjacent to, but not covering, the enzyme domain 46 or the transducer element and / or interference domain 44, and / or the sensing region or electrochemically active surfaces of the sensing region. The bioactive emissive film 70 can be disposed on the sensor 34 as shown in FIG. 2E using one or more of a screen printing, spray coating, or dip coating method.

[0261] FIG. 2F can be considered to build on the general structure as depicted in FIG. 2A in that two or more additional layers are added to form one or more additional electrodes. Also, a method of selectively removing two or more windows to form two or more electrodes can be used. For example, by adding another conductive layer 38b and an insulating layer 35b under the reference electrode layer 30, two electrodes (such as a first and (optional) second working electrode) can be formed, resulting in a dual-electrode sensor or a multi-electrode sensor. The same concept can be applied to create, for example, a counter electrode, an electrode for measuring an additional analyte (e.g., oxygen), etc. FIG. 2G illustrates a sensor with an additional electrode 38b, where the window has been selectively removed to expose the working electrodes 38a, 38b between the reference electrode (including multiple segments) 30, and a small amount of insulator 35a, 35b exposed between them.

[0262] Although some figures herein illustrate sensors that may have a coaxial core and a circular or elliptical cross section, in other examples of sensor systems that include a bioactive emitting membrane, the sensor may be a substantially planar sensor, as shown in cross section for illustrative purposes in FIG. 2H. For example, as shown in FIG. 2H, a continuous analyte sensing device 100 may include a substantially planar substrate 142, and an interference domain 144, an enzyme domain 146, a resistive domain 148, and a biointerface / bioprotective domain 168 and / or a bioactive emitting domain 170 arranged in a substantially planar fashion around the substantially planar substrate 142 having one or more working electrodes. Referring to FIGS. 2G-2H, in some examples, the reference electrode 30 includes a silver-containing material applied onto at least a portion of the insulating material 35. In some examples, the silver-containing material is applied using thin and / or thick film techniques, such as, but not limited to, dipping, spraying, printing, electrodeposition, vapor deposition, spin coating, and sputter deposition, as described elsewhere herein. For example, a silver or silver chloride containing paint (or similar formulation) is applied, by way of example, to a reel of insulated conductive core. In another embodiment, a reel of insulated elongated body (or core) is cut (e.g., "singulated") into single unit pieces and a silver containing ink is pad printed thereon. In yet another embodiment, the silver containing material is applied as a silver foil. For example, an adhesive can be applied to the insulated elongated body and then a silver foil can be wrapped around it. Alternatively, the sensor can be rolled within an Ag / AgCl particle such that a sufficient amount of silver is attached to and / or embedded in and / or otherwise adhered to the adhesive for the particle to function as a reference electrode. In some embodiments, the reference electrode of the sensor includes a sufficient amount of silver chloride for the sensor to measure and / or detect an analyte for at least three days.

[0263] In some embodiments, the sensor is formed from an elongated body 33 (e.g., an elongated conductive body) as shown in Figure 2G, which includes a core 39, a first layer 38a, an insulator 35a, and a layer of silver-containing material 30. In some embodiments, as shown in Figure 2H, the electrochemically active surface of the elongated body (e.g., also the (electroactive) surface of the first layer 38a) is exposed by the formation of a window 31 through both the silver-containing material and the insulator. In one exemplary embodiment, the elongate body of FIG. 2G has a length (e.g., less than or greater than 0.5, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, or 24 inches) and is provided as an extended length on a reel that is singulated into multiple pieces appropriate for a selected sensor configuration. For example, a first sensor configured for percutaneous implantation may use a length of 2.5 inches, and a second sensor configured for percutaneous implantation may use a length of 3 inches. In another example, a first sensor configured for implantation in a peripheral vein of an adult host may use a length of 3 inches, while a second sensor configured for implantation in a central vein of an adult host may use a length of 12 inches. A window is formed on each sensor, such as by milling and / or etching a radial window through the silver-containing material and insulator such that a platinum surface (e.g., an electrochemically active surface of a "working electrode") is exposed. In some examples, a reel of elongate bodies is singulated and then the window is formed. In other examples, a window is formed along the length of a reel of elongate bodies and then singulated. In further examples, additional manufacturing steps are performed prior to singulation. The sensing membrane 32 is applied to the exposed electrochemically active surface (e.g., working electrode) defined by the edge of the window such that the electrochemically active surface can function as the working electrode of the sensor (e.g., when the sensor is in contact with a host sample) and generate a signal associated with the analyte.Alternative manufacturing techniques and / or sequences of steps can be used to produce a sensor having the configuration shown in FIG. 2H, including but not limited to masking a portion of the elongated body (or core) prior to application of the insulator and silver-containing material.

[0264] FIG. 2G illustrates the layers that have been cut away, but in a manufacturing process, material typically results with all layers terminating at a tip. A step of removing layers 30 and 30 may be performed to form a window. FIG. 2I illustrates the result of this removal / cutting process in a side / cross-sectional view. The removal process may be accomplished by methods already described or other methods known in the art. In one embodiment, the removal step is performed, for example, by laser skiving, and may be performed in a reel-to-reel process on a continuous strand. The removed area may be stepped, for example, by removing different layers at different lengths (FIG. 2I). In such a fabrication method with a continuous strand, the sensor may be singulated after the removal step creating singulation 29 (FIGS. 7A-7C). In some embodiments, if the core is metallic, an end cap of insulating or other isolating material may be employed on the tip, for example, by dipping, spraying, shrink tubing, crimp wrapping, etc. If the core is polymeric (e.g., a hydrophobic material), an end cap may not be necessary. For example, in the sensor depicted in FIG. 2I, an end cap 40 (eg, of a polymer or insulating material) or other structure may be provided over the core (eg, if the core 39 is not insulating).

[0265] FIG. 2J can be considered to build on the general structure as depicted in FIG. 2G in that two or more additional layers are added to create one or more additional electrodes. Also, a method of selectively removing two or more windows to form two or more electrodes can be used. For example, by adding another conductive layer 38b and an insulating layer 35b under the reference electrode layer 30, two electrodes (first and second working electrodes) can be formed, resulting in a dual electrode sensor. The same concept can be applied to create, for example, a counter electrode, an electrode for measuring an additional analyte (e.g., oxygen), etc.

[0266] Figure 2K illustrates a sensor with an additional electrode 38b (compared to Figures 2G-2I) where windows have been selectively removed to expose the working electrodes 38a, 38b between the reference electrodes (including multiple segments) 30 and a small amount of insulator 35a, 35b therebetween. Figure 2L illustrates another example where selective removal of various layers is done in stages to expose the electrodes 38a, 38b and insulators 35a, 35b along the length of the elongated body.

[0267] 2J is a cross-sectional view through an alternative sensor configuration, showing the unexposed electrochemically active surface of at least the working electrode 38 surrounded by the sensing membrane 32 including multiple domains or layers, e.g., interference domain 44, enzyme domain 46, and resistive domain 48, and including additional domains / membranes, such as an electrode domain, a cell impermeable domain (not shown), an oxygen domain (not shown), a bioactive release membrane 70, and / or a biointerface membrane 68 (not shown), as described in more detail below. The bioactive release membrane 70 is positioned adjacent to the working electrode 38 surface and does not cover the working electrode 38 or multiple domains or layers, e.g., interference domain 44, enzyme domain 46, and resistive domain 48, of the sensing membrane 32 associated with the working electrode. As shown in FIG. 2J, a bioactive diffusion-controlling membrane 73 is provided adjacent to the bioactive release membrane 70. In one embodiment, the diffusion-controlling membrane 73 is directly adjacent to the bioactive release membrane 70. In another embodiment, the diffusion-controlling membrane 73 is chemically, structurally, or functionally distinct from the bioactive release membrane 70. In another embodiment, the diffusion control membrane 73 is a block copolymer, such as a polyurethane block polymer having hard and soft segments, where the soft segments can include hydrophobic portions, hydrophilic portions, or a combination of hydrophobic / hydrophilic portions, each of which can be independently of a different average molecular weight or chain length.In another embodiment, the diffusion control membrane 73 is a polyol (polyethylene oxide, polyethylene propylene oxide, polytetrahydrofuran or polytetramethylene oxide, polyether, polysiloxane, polyamine, polysiloxane amine, polyester, polyalkyl ester, polyalkyl carbonate, polycarbonate) having a hydrophobic / hydrophilic portion and one or more independent hard segments, such as norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (TDI), cyclohexane diisocyanate (CD ... and 4,4'-bicyclohexylmethane diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0268] In another embodiment, the diffusion controlling membrane 73 is a multi-block copolymer. In another embodiment, the diffusion controlling membrane is annealed to provide stable separate phases and / or diffusion channels for releasing the bioactive agent. In an embodiment, the diffusion controlling membrane 73 is applied continuously, semi-continuously, or segmentally (randomly or in a pattern) over the bioactive releasing membrane 70.

[0269] In some embodiments, the silver-containing material is applied to the sensor (e.g., the insulated conductive core) in a substantially continuous process as described elsewhere herein. Thus, in some embodiments, the silver-containing material is applied in a fully automated process. In other embodiments, the silver-containing material is applied in a semi-automated process.

[0270] The methods of the present disclosure are particularly suitable for use with miniature structured sensors, microsensors, or small diameter sensors, although the methods may be suitable for use with larger diameter sensors, such as sensors having a diameter of 1 mm to about 2 mm or more.

[0271] 3A is a side schematic view of a transcutaneous analyte sensor 50 in one embodiment. The sensor 50 includes a mounting unit 52 adapted for mounting to the skin of a host, a small (diameter) structure sensor 34 (as defined herein) adapted for transcutaneous insertion through the skin of the host, and electrical connections configured to provide reliable electrical contact between the sensor and electronics preferably housed within the mounting unit 52. In general, the mounting unit 52 is designed to maintain the integrity of the sensor in the host so as to reduce or eliminate translation of motion between the mounting unit, the host, and / or the sensor. See U.S. Patent Publication No. 2006 / 0020187, entitled "TRANSCUTANEOUS ANALYTE SENSOR," filed March 10, 2005, which is incorporated herein by reference in its entirety. In one embodiment, a bioactive emissive membrane is formed on the sensing mechanism 36, as described in more detail below.

[0272] 3B is a side schematic view of a transdermal analyte sensor 54 in an alternative embodiment. The transdermal analyte sensor 54 includes a mounting unit 52, with a sensing mechanism 36 comprising a miniature structure as defined herein and tethered to the mounting unit 52 via a cable 56 (alternatively, a wireless connection can be utilized). The mounting unit is adapted for mounting to the skin of a host and operably connected, such as via a tether, to a miniature structured sensor 34 adapted for transdermal insertion through the skin of the host and measurement of an analyte therein, see, for example, U.S. Pat. No. 6,558,330 to Causey III et al., which is incorporated herein by reference in its entirety. In one embodiment, a bioactive emissive membrane 70 is formed over at least a portion of the sensing mechanism 36, as described in more detail below.

[0273] The sensors of the present disclosure may be inserted at various locations on the host's body, such as the abdomen, thigh, upper arm, and behind the neck or ear. Although the present disclosure may suggest insertion through the abdominal region, the systems and methods described herein are not limited to abdominal or subcutaneous insertion. Those skilled in the art will understand that these systems and methods may be implemented and / or modified for other insertion sites and may depend on the type, configuration, and size of the analyte sensor.

[0274] Transcutaneous continuous analyte sensors can be used in vivo for various lengths of time. For example, the device includes a sensor for measuring an analyte in a host, a porous biocompatible matrix covering at least a portion of the sensor, and an applicator for inserting the sensor through the skin of the host. In some embodiments, the sensor has an architecture with at least one dimension less than about 1 mm. Examples of such structures are shown in Figures 3A and 3B, as described elsewhere herein. However, one skilled in the art will recognize that alternative configurations are possible and may be desirable depending on factors such as, for example, the intended location of insertion. The sensor is inserted through the skin of the host into underlying tissue, such as soft tissue or fatty tissue.

[0275] After insertion, the fluid migrates to the spacer, a biocompatible matrix or membrane, such as the bioactive releasing membrane 70 and / or the biointerface membrane 68, creating a fluid-filled pocket therein. This process can occur immediately or over a period of time, such as minutes or hours after insertion. The signal from the sensor is then detected, for example, by a sensor electronics unit located in a mounting unit on the surface of the host's skin. Generally, the sensor can be used continuously for a period of several days, such as 1-7 days, 14 days, or 21 days. After use, the sensor is simply removed from the host's skin. In one embodiment, the host can repeat the insertion and detection steps as many times as desired. In some implementations, the sensor can be removed after about 3 days, and then another sensor can be inserted, and so on. Similarly, in other implementations, the sensor can be removed after about 3, 5, 7, 10, or 14 days, followed by insertion of a new sensor, and so on.

[0276] Some examples of transcutaneous analyte sensors are described in U.S. Patent No. 8,133,178 to Brauker et al., which is incorporated herein by reference in its entirety, as well as U.S. Patent No. 8,828,201 to Simpson et al., U.S. Patent No. 9,131,885 to Simpson et al., U.S. Patent No. 9,237,864 to Simpson et al., and U.S. Patent No. 9,763,608 to Simpson et al., each of which is incorporated herein by reference in its entirety. Generally, a transcutaneous analyte sensor comprises a sensor and a mounting unit having associated electronics.

[0277] In general, the mounting unit includes a base adapted for mounting to the skin of a host, a sensor adapted for transcutaneous insertion through the skin of the host, and one or more contacts configured to provide reliable electrical contact between the sensor and the sensor electronics. The mounting unit is designed to maintain the integrity of the sensor in the host so as to reduce or eliminate translation of motion between the mounting unit, the host, and / or the sensor. The base can be formed from a variety of hard or soft materials, and preferably has a low profile to minimize protrusion of the device from the host during use. In some examples, the base is formed at least in part from a flexible material, which is believed to provide numerous advantages over conventional transcutaneous sensors, but unfortunately may be subject to motion-related artifacts associated with host motion when the host is using the device. For example, when a transcutaneous analyte sensor is inserted into a host, various movements of the sensor (e.g., relative movement between the in vivo and ex vivo portions, movement of the skin, and / or movement within the host (dermis or subcutaneous)) can cause stress on the device and generate noise in the sensor signal. Even small movements of the skin can be translated into discomfort and / or motion-related artifacts that could be reduced or eliminated by a flexible or articulating base. Thus, by providing flexibility and / or articulation of the device relative to the host's skin, better compatibility of the sensor system with the host's normal use and movement can be achieved. It is believed that the flexibility or articulation increases the adhesion of the mounting unit onto the skin (with the use of adhesive pads), thereby reducing motion-related artifacts and reduced sensor performance that could otherwise be translated from host motion.

[0278] In certain embodiments, the mounting unit is provided with an adhesive pad, preferably including a peelable backing layer disposed on the underside of the mounting unit. Thus, by removing the backing layer and pressing the base portion of the mounting unit onto the host's skin, the mounting unit adheres to the host's skin. Additionally or alternatively, an adhesive pad can be positioned over some or all of the sensor system to ensure adhesion and, optionally, an air-tight or water-tight seal around the wound exit site (or sensor insertion site) after sensor insertion is complete. A suitable adhesive pad can be selected and designed to stretch, stretch, conform to, and / or aerate the area (e.g., the host's skin).

[0279] In embodiments, the adhesive pad is formed from spunlace, open or closed cell foam, and / or nonwoven fibers and includes an adhesive disposed thereon, although a variety of adhesive pads suitable for adhesion to the skin of a host can be used as will be understood by those skilled in the art of medical adhesive pads. In some embodiments, a double-sided adhesive pad is used to adhere the mounting unit to the skin of the host. In other embodiments, the adhesive pad includes a foam layer, for example, a layer of foam disposed between the side edges of the adhesive pad to act as a shock absorber.

[0280] In some embodiments, the surface area of ​​the adhesive pad is greater than the surface area of ​​the back surface of the mounting unit. Alternatively, the adhesive pad can be sized to have substantially the same surface area as the back surface of the base portion. Preferably, the adhesive pad has a surface area of ​​the side that is mounted on the host's skin that is greater than about 1, 1.25, 1.5, 1.75, 2, 2.25, or 2.5 times the surface area of ​​the back surface of the mounting unit base. Such a greater surface area can increase adhesion between the mounting unit and the host's skin, minimize migration between the mounting unit and the host's skin, and / or protect the wound exit site (sensor insertion site) from environmental and / or biological contamination. However, in some alternative embodiments, the adhesive pad can have a smaller surface area than the back surface, assuming sufficient adhesion can be achieved.

[0281] In some embodiments, the adhesive pad is substantially the same shape as the underside of the base, although other shapes, e.g., butterfly, round, square, or rectangular, can also be advantageously used. The adhesive pad backing can be designed for a two-step peel, e.g., a primary peel where only a portion of the adhesive pad is first exposed to allow adjustable positioning of the device, and a secondary peel where the remaining adhesive pad is later exposed to firmly and securely adhere the device to the host's skin once properly positioned. The adhesive pad is preferably waterproof. Preferably, a stretch-release adhesive pad is provided on the underside of the base portion so that it can be easily peeled off from the host's skin at the end of the sensor's usable life.

[0282] It has been found that in some circumstances, conventional bonding between the adhesive pad and the mounting unit may not be sufficient, for example due to humidity, which can cause delamination of the adhesive pad from the mounting unit. Thus, in some embodiments, the adhesive pad can be bonded using a bonding agent that is activated or accelerated by UV curing, sonic curing, radio frequency curing, or moisture curing. In some embodiments, a eutectic bond of the first and second composite materials can form a strong bond. In some embodiments, the surface of the mounting unit can be pre-treated using ozone, plasma, chemicals, etc. to enhance the bonding properties of the surface.

[0283] The bioactive agent is preferably applied locally at the insertion site prior to or during sensor insertion. Suitable bioactive agents include those known to inhibit or prevent bacterial growth and infection, such as anti-inflammatory agents, antibacterial agents, antibiotics, etc. It is believed that the diffusion or presence of the bioactive agent can aid in the prevention or elimination of bacteria adjacent to the exit site. Additionally or alternatively, the bioactive agent can be integrated with or coated onto the adhesive pad, or no bioactive agent can be used at all.

[0284] In some embodiments, an applicator is provided for inserting the sensor through the skin of the host at a suitable insertion angle with the aid of a needle, and for subsequent removal of the needle using a successive push-pull motion. Preferably, the applicator includes an applicator body base with an applicator body that guides the applicator and configured to mate with a mounting unit during insertion of the sensor into the host. The mating between the applicator body base and the mounting unit can use any known mating configuration, e.g., a snap fit, a press fit, an interference fit, etc., to prevent separation during use. One or more release latches allow for release of the applicator body base, e.g., when the applicator body base is snap-fit ​​into the mounting unit.

[0285] The sensor electronics includes hardware, firmware, and / or software that allows for the measurement of the level of an analyte via the sensor. For example, the sensor electronics can include a potentiostat, a power supply 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. The electronics can be affixed to a printed circuit board (PCB) or the like and can take a variety of forms. For example, the electronics can take the form of an integrated circuit (IC), such as an application-specific integrated circuit (ASIC), a microcontroller, and / or a processor. Preferably, the sensor electronics includes 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 August 1, 2003, entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA."

[0286] In this embodiment, the sensor electronics are configured to releasably mate with the mounting unit following insertion of the sensor using the applicator and subsequent release of the applicator from the mounting unit. In an embodiment, the electronics are configured with programming, e.g., initialization, calibration reset, fault testing, etc., each time the electronics is initially inserted into the mounting unit and / or initially communicates with the sensor.

[0287] (Sensor Electronics) The following description of the electronics associated with the sensor is applicable to a variety of continuous analyte sensors, such as non-invasive, minimally invasive, and / or invasive (e.g., transcutaneous and fully implantable) sensors. For example, the sensor electronics and data processing and receiver electronics and data processing described below may be incorporated into the fully implantable glucose sensors disclosed in U.S. Patent Application Publication No. 2005 / 0245799, entitled "IMPLANTABLE ANALYTE SENSOR," filed May 3, 2004, and U.S. Patent Application Publication No. 2006 / 0015020, entitled "SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM," filed July 6, 2004.

[0288] In one embodiment, a potentiostat operably connected to the electrode system (as described above) provides a voltage to the electrodes, which biases the sensor and allows measurement of a current signal indicative of the analyte concentration in the host (also referred to as the analog portion). In some embodiments, the potentiostat includes a resistor that converts the current to a voltage. In some alternative embodiments, a current-to-frequency converter is provided that is configured to continuously integrate the measured current, for example using a charge counting device. An A / D converter digitizes the analog signal into a digital signal, also referred to as "counts," for processing. The resulting raw data stream in counts, also referred to as raw sensor data, is thus directly related to the current measured by the potentiostat.

[0289] The processor module includes a central control unit that controls the processing of the sensor electronics. In some embodiments, the processor module includes a microprocessor, although computer systems other than a microprocessor can be used to process data as described herein, for example, an ASIC can be used for some or all of the sensor's central processing. The processor typically provides semi-permanent storage of data, such as storage of data such as a sensor identifier (ID), and programming for processing the data stream (e.g., programming for data smoothing and / or signal artifact replacement, as described in U.S. Patent No. 8,010,174, entitled "SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM," filed August 22, 2003). The processor can additionally be used for system cache memory, for example, to temporarily store recent sensor data. In some embodiments, the processor module includes memory storage components such as ROM, RAM, dynamic RAM, static RAM, non-static RAM, EEPROM, rewriteable ROM, flash memory, etc.

[0290] In some embodiments, the processor module comprises a digital filter, e.g., an IIR or FIR filter, configured to smooth the raw data stream from the A / D converter. Generally, the digital filter is programmed to filter the sampled data at predefined time intervals (also referred to as the sample rate). In some embodiments, the potentiostat is configured to measure the analyte at discrete time intervals, these time intervals determining the sample rate of the digital filter. In some alternative embodiments, where the potentiostat is configured to measure the analyte continuously, e.g., using a current-to-frequency converter as described above, the processor module can be programmed to request digital values ​​from the A / D converter at predefined time intervals, also referred to as acquisition times. In these alternative embodiments, the values ​​acquired by the processor are advantageously averaged over the acquisition time due to the continuity of the current measurements. Thus, the acquisition time determines the sample rate of the digital filter. In one embodiment, the processor module is configured with a programmable acquisition time, i.e., the predefined time interval for requesting digital values ​​from the A / D converter is programmable by a user within the digital circuitry of the processor module. An acquisition time of about 2 seconds to about 512 seconds is preferred, however, any acquisition time can be programmed into the processor module. Programmable acquisition times are advantageous for optimizing noise filtering, time lag, and processing / battery power.

[0291] Preferably, the processor module is configured to construct a data packet for transmission to an external source, for example, RF transmission to a receiver as described in more detail below. Generally, the data packet comprises a number of bits that may include a sensor ID code, raw data, filtered data, and / or error detection or correction. The processor module can be configured to transmit any combination of raw data and / or filtered data.

[0292] In some embodiments, the processor module further comprises a transmitter portion, which determines the interval for transmission of the sensor data to the receiver, etc. In some embodiments, the transmitter portion, which determines the interval for transmission, is configured to be programmable. In one such embodiment, a coefficient can be selected (e.g., a number between about 1 and about 100, or more), and the coefficient is multiplied by the acquisition time (or sampling rate) as described above to define the transmission interval for the data packets. Thus, in some embodiments, the transmission interval is programmable between about 2 seconds and about 850 minutes, more preferably between about 30 seconds and 5 minutes, although any transmission interval is programmable or can be programmed into the processor module. However, various alternative systems and methods for providing a programmable transmission interval can also be used. By providing a programmable transmission interval, the data transmission can be customized to meet various design criteria (e.g., reduced battery consumption, timeliness of reporting sensor values, etc.).

[0293] Conventional glucose sensors measure current in the nanoamp range. In contrast to conventional glucose sensors, the sensors of the present disclosure are configured to measure current in the picoamp range, and in some embodiments, femtoamps. That is, at least one picoamp of current is measured for every unit (mg / dL) of glucose measured. Preferably, the analog portion of the A / D converter is configured to continuously measure the current flowing at the working electrode and convert the current measurement into a digital value representing the current. In an embodiment, the current flow is measured by a charge counting device (e.g., a capacitor). Thus, a signal is provided, whereby high sensitivity maximizes the signal received with a minimum amount of measured hydrogen peroxide (e.g., minimum glucose requirement without sacrificing accuracy even in the low glucose range) and reduces sensitivity to oxygen limitation in vivo (e.g., in oxygen-dependent glucose sensors).

[0294] A battery is operably connected to the sensor electronics and powers the sensor. In an embodiment, the battery is a lithium manganese dioxide battery, but any suitable size and power battery (e.g., AAA, nickel-cadmium, zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium ion, zinc-air, zinc-mercury oxide, silver-zinc, and / or sealed) can be used. In some embodiments, the battery is rechargeable and / or multiple batteries can be used to power the system. The sensor can be powered transcutaneously, for example, via inductive coupling. In some embodiments, the quartz crystal is operably connected to the processor and maintains system time throughout the computer system, for example, during a programmable acquisition time in the processor module.

[0295] An optional temperature probe can be provided, located on the electronics assembly or on the glucose sensor itself. The temperature probe can be used to measure the ambient temperature near the glucose sensor. This temperature measurement can be used to add temperature compensation to the calculated glucose value.

[0296] The RF module is operatively connected to the processor and transmits sensor data from the sensor via the antenna to the receiver in a wireless transmission. In some embodiments, the second crystal provides a time reference for an RF carrier frequency used for data transmission from the RF transceiver. However, in some alternative embodiments, data may be transmitted and / or received using other mechanisms, such as light, infrared radiation (IR), ultrasound, etc.

[0297] In the RF telemetry module of the present disclosure, the hardware and software are designed for low power requirements to increase the device's longevity (e.g., allowing a longevity of about 3 months to about 24 months or more) with maximum RF penetration from in vivo to ex vivo environments for fully implanted sensors (e.g., distances of about 1 meter to 10 meters or more). Preferably, a high frequency carrier signal of about 402 MHz to about 433 MHz is used to maintain the lower power requirements. Additionally, in fully implanted devices, the carrier frequency is adapted to physiological attenuation levels, which is achieved by tuning the RF module in a simulated in vivo environment to ensure RF functionality after implantation, and thus preferred glucose sensors can sustain sensor functionality for 3 months, 6 months, 12 months, or 24 months or more.

[0298] In some embodiments, the output signal (from the sensor electronics) is transmitted to a receiver (e.g., a computer or other communication station). The output signal is typically a raw data stream that is used, for example, to provide a patient or physician with a useful value of the measured analyte concentration. In some embodiments, the raw data stream may be algorithmically smoothed or otherwise modified, continuously or periodically, to reduce outlying points that do not accurately represent the analyte concentration, for example, due to signal noise or other signal artifacts, as described in U.S. Patent No. 6,931,327, filed August 1, 2003, entitled "SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM," which is incorporated herein by reference in its entirety.

[0299] When the sensor is first implanted in the host tissue, the sensor and receiver are initialized. This may be referred to as a wake-up mode, which optionally includes resetting the sensor data and calibrating the sensor. In selected embodiments, mating the electronics unit to the mounting unit triggers the wake-up mode. In other embodiments, the wake-up mode is triggered by the receiver.

[0300] (Receiver) In some embodiments, the sensor electronics are wirelessly connected to the receiver, such as via one-way or two-way RF transmission. However, wired connections are also contemplated. The receiver provides much of the processing and display of the sensor data, and can be selectively worn and / or removed at the host's convenience. Thus, the sensor system can be unobtrusively worn, and the receiver, which provides much of the processing and display of the sensor data, can be selectively worn and / or removed at the host's convenience. In particular, the receiver includes programming for retroactively and / or prospectively initiating calibration, converting sensor data, updating calibration, evaluating received reference and sensor data, and evaluating the calibration of the analyte sensor, as described in more detail with reference to U.S. Pat. No. 7,778,680, entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA," filed Aug. 1, 2003.

[0301] FIG. 3C is a schematic side view of a fully implantable analyte sensor 53 in one embodiment. The sensor includes a sensor body 60 suitable for subcutaneous implantation and includes a miniaturized structured sensor 34 as defined herein. U.S. Patent Application Publication No. 2004 / 0199059 to Brauker et al. describes systems and methods suitable for the sensor body 60 and is incorporated herein by reference in its entirety. In one embodiment, a biointerface membrane 68 is formed on the sensing mechanism 36, as described in more detail elsewhere herein. The sensor body 60 includes the sensor electronics and preferably communicates with a receiver, as described in more detail above. As shown in FIG. 3C, a bioactive emitting membrane 70 is disposed on at least a portion of the biointerface membrane 68 and / or the sensing membrane 32.

[0302] 3D is a side schematic view of a fully implantable analyte sensor 62 in an alternative embodiment. The fully implantable analyte sensor 62 includes a sensor body 60 and a miniature structured sensor 34 as defined herein. The sensor body 60 includes the sensor electronics and preferably communicates with a receiver, as described in more detail above.

[0303] In one embodiment, the biointerface membrane 68 is formed on the sensing mechanism 36, as described in more detail elsewhere herein. In another embodiment, the bioactive release membrane 70 is formed on at least a portion of the sensing mechanism 36. In another embodiment, the bioactive release membrane 70 is formed on a separate, isolated portion of the sensing mechanism 36. In yet another embodiment, the biointerface membrane 68 is formed on at least a portion of the bioactive release membrane 70. In yet another embodiment, the bioactive release membrane 70 is formed on at least a portion of the biointerface membrane 68. In one embodiment, the matrix or framework 64 surrounds the sensing mechanism 36 to protect the sensor from some foreign body protrusions, for example, by causing tissue to compress against or around the framework 64 rather than the sensing mechanism 36.

[0304] In general, the optional protective framework 64 is formed from a two- or three-dimensional flexible, semi-rigid, or rigid matrix (e.g., a mesh) and includes spaces or pores through which the analyte can pass. In some embodiments, the framework is incorporated as part of the biointerface membrane, although a separate framework can be provided. Without wishing to be bound by theory, it is believed that the framework 64 protects the miniature structured sensing mechanism from mechanical forces generated in vivo.

[0305] 3E is a side schematic view of a fully implantable analyte sensor 66 in another alternative embodiment. The sensor 66 includes a sensor body 60 and a miniature structured sensor 34 as defined herein having a biological interface membrane 68 and / or a bioactive release membrane 70 as described in more detail elsewhere herein. Preferably, the framework 64 protects the sensing mechanism 36 as described in more detail above. The sensor body 60 includes the sensor electronics and preferably communicates with a receiver as described in more detail above.

[0306] In certain embodiments, the sensing device is adapted to be fully implanted within the host, such as in the soft tissue beneath the skin, for example, implanted subcutaneously, such as in the abdomen of the host. One of ordinary skill in the art will appreciate the variety of suitable implantation sites available due to the small size of the sensor. In some embodiments, the sensor architecture is a wire-based sensor having at least one dimension less than about 0.5 mm, for example, a diameter less than about 0.5 mm. In another exemplary embodiment, the sensor may be, for example, 0.5 mm thick, 3 mm long, and 2 cm wide, which may be a thin substrate, needle, wire, rod, sheet, or pocket. In another exemplary embodiment, multiple wires about 1 mm wide and about 5 mm long may be connected at their first ends to create a fork-shaped sensor structure. In yet another embodiment, a 1 mm wide sensor may be wound into a coil to create a planar spiral sensor structure. Although several embodiments are cited above, numerous other useful embodiments are contemplated by the present disclosure, as will be appreciated by those skilled in the art.

[0307] After implantation, a period of time is allowed for tissue ingrowth within the biointerface. The length of time required for tissue ingrowth varies from host to host, such as from about 1 week to about 3 weeks, although other time periods are possible. Once a mature bed of vascularized tissue has grown into the biointerface, a signal can be detected from the sensor, as described elsewhere herein and in U.S. Patent Application Publication No. 2005 / 0245799 to Brauker et al., entitled "IMPLANTABLE ANALYTE SENSOR," which is incorporated herein in its entirety. Long-term sensors, as described in the above-referenced patent applications, can remain implanted and generate glucose signal information for months to years.

[0308] In certain embodiments, the device is configured such that the sensing unit is separated from the electronics unit by a tether or cable, similar to that illustrated in FIG. 3B, or similar structure. Those skilled in the art will recognize that various known useful means can be used to tether the sensor to the electronics. Without wishing to be bound by theory, it is believed that the FBR to the electronics unit alone may be greater than the FBR to the sensing unit alone, for example, due to the greater mass of the electronics unit. Thus, separation of the sensing unit and the electronics unit effectively reduces the FBR to the sensing unit, resulting in improved device function. As described elsewhere herein, the architecture and / or composition of the sensing unit (e.g., inclusion of a bioactive releasing membrane having a certain bioactive agent) can be implemented to further reduce foreign body reactions to the tethered sensing unit.

[0309] In another embodiment, the analyte sensor is designed with separate electronics and sensing units, and the sensing unit is inductively coupled to the electronics unit. In this embodiment, the electronics unit provides power to the sensing unit and / or enables communication of data therebetween. Figures 3F and 3G illustrate an exemplary system using inductive coupling between the electronics unit 52 and the sensing unit 58.

[0310] 3F is a side view of an embodiment of an implanted sensor inductively coupled to an electronics unit within a functionally useful distance on the host's skin. FIG. 3F illustrates a sensing unit 58 including a sensing mechanism 36, a biointerface membrane 68 and a bioactive release membrane 70 at the distal end 37 of the sensor 34, and a miniature electronics chip 216 implanted in the host's tissue 210 and beneath the host's skin 212. In this embodiment, the majority of the electronics associated with the sensor are contained within an electronics unit 52 (also referred to as a mount unit) that is located in suitable proximity to the host's skin. The electronics unit 52 is inductively coupled to the miniature electronics chip 216 on the sensing unit 58, for example, to transfer power to the sensor and / or collect data. A miniature electronics chip 216 coupled to the sensing unit 58 may provide the necessary electronics to provide bias potentials to the sensors, measure signal outputs, and / or other necessary requirements to enable the mechanisms of the sensing unit 58 to function (e.g., the chip 216 may include an ASIC (application specific integrated circuit), an antenna, and other necessary components as would be understood by one of ordinary skill in the art).

[0311] In yet another embodiment, the implanted sensor additionally includes a capacitor to provide the power necessary for the device to function, and a handheld scanner (e.g., a wand-like device) is used to collect the data stored in the circuitry and / or to recharge the device.

[0312] Generally, as described herein, inductive coupling allows power to be transferred to the sensor for continuous powering, recharging, etc. Additionally, inductive coupling utilizes antennas (e.g., coils) that are appropriately spaced and oriented on the sensing unit and electronics unit to efficiently transmit / receive power (e.g., current) and / or data communication therebetween. One or more coils on each of the sensing and electronics units can provide the necessary power induction and / or data transmission.

[0313] In this example, the sensing mechanism may be, for example, a wire-based sensor as described in more detail with reference to Figures 2A and 2B and in U.S. Patent Application Publication No. 2006 / 0020187, or a planar substrate-based sensor as described in U.S. Patent No. 6,175,752 to Say et al. and U.S. Patent No. 5,779,665 to Mastrototaro et al., all of which are incorporated herein by reference in their entireties. The biointerface membrane 68 may be any suitable biointerface as described in more detail elsewhere herein, for example, a layer of porous biointerface membrane material, a mesh cage, etc. In one illustrative example, the biointerface membrane 68 is a single or multi-layer sheet (e.g., a pocket) of a porous membrane material such as ePTFE, with the sensing mechanism 36 incorporated therein.

[0314] Figure 3G is a side view of one embodiment of an implanted sensor inductively coupled to an electronics unit implanted in the tissue of a host at a functionally useful distance. Figure 3G illustrates a sensing unit 58 and electronics unit 52 similar to those described with reference to Figure 3F above, but both implanted in suitable proximity beneath the skin of the host.

[0315] In general, it is believed that there will be a smaller foreign body reaction surrounding the sensing unit (e.g., compared to devices of greater mass, e.g., devices that include certain electronics and / or power sources) when the electronics unit 52, which carries the majority of the mass of the implantable device, is separate from the sensing unit 58. Thus, the configuration of the sensing unit, including the biointerface membrane and / or bioactive release membrane, can be optimized to minimize and / or modify host tissue response, e.g., with minimal mass, as described in more detail elsewhere.

[0316] (Biointerface membrane / layer) In one embodiment, the sensor includes a porous material disposed on some portion thereof, which modifies the host tissue response to the sensor. In some embodiments, the porous material surrounding the sensor advantageously enhances and extends the performance and lifespan of the sensor by slowing or reducing cell migration to the sensor and associated degradation that would be caused by cell invasion if the sensor were directly exposed to an in vivo environment. Alternatively, the porous material can provide stabilization of the sensor through tissue ingrowth into the porous material over time. Suitable porous materials are disclosed in U.S. Patent No. 7,875,293, entitled "BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVE AGENTS," filed May 10, 2004, and U.S. Patent No. 7,192,433, filed August 22, 2003, and incorporated herein by reference.As described in No. 450, entitled "POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES," the following materials may be used: silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefins, polyesters, polyalkyl carbonates, polycarbonates, biostable polytetrafluoroethylene, homopolymers, copolymers, and terpolymers of polyurethane, polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (polyvinyl Polysulfones and their block copolymers, including diblock, triblock, alternating, random and graft copolymers, as well as polymers and blends thereof, such as polysulfones and their block copolymers, including diblock, triblock, alternating, random and graft copolymers, as well as polymers and blends thereof, such as polyvinyl alcohol (PVA), polybutylene terephthalate (PBT), polymethyl methacrylate (PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes, polyurethane urea copolymers, cellulosic polymers, poly(ethylene oxide), poly(propylene oxide) and copolymers and blends thereof, such as diblock, triblock, alternating, random and graft copolymers, as well as polymers and blends thereof, such as polysulfones and their block copolymers, including ... polysulfones and their block copolymers, chloride, PAN-PVC), high density polyethylene, acrylic copolymers, nylon, polyvinyl fluoride, polyanhydrides, poly(L-lysine), poly(L-lactic acid), hydroxyethyl methacrylate, hydroxyapeptide, alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium, titanium alloys, tinol, stainless steel, and CoCr alloys.

[0317] In some embodiments, the porous material surrounding the sensor provides unique advantages in vivo (e.g., 1-14 days) that can be used to enhance and extend the performance and lifespan of the sensor. However, such materials can also provide advantages in the long term (e.g., beyond 14 days). In particular, the in vivo portion of the sensor (the portion of the sensor that is implanted in the host's tissue) is encapsulated (partially or completely) in the porous material. The porous material can be wrapped around the sensor (e.g., by wrapping the porous material around the sensor or by inserting the sensor into a section of the porous material sized to receive the sensor). Alternatively, the porous material can be deposited on the sensor (e.g., by electrospinning a polymer directly onto it). In yet other alternative embodiments, the sensor is inserted into a selected section of the porous biomaterial. Other methods for surrounding the in vivo portion of the sensor with the porous material can also be used as will be understood by those skilled in the art.

[0318] The porous material surrounding the sensor advantageously retards or reduces cell migration to the sensor and associated degradation that would be caused by cell invasion if the sensor were directly exposed to the in vivo environment. That is, the porous material provides a barrier that makes cell migration towards the sensor more tortuous and therefore slower. This is believed to reduce or slow the loss of sensitivity typically observed over time.

[0319] In embodiments where the porous material is a high oxygen solubility material such as porous silicone, the high oxygen solubility porous material surrounds some or all of the in vivo portion of the sensor. In some embodiments, a lower ratio of oxygen to glucose can be sufficient to provide excess oxygen by using a high oxygen solubility domain (e.g., silicone or fluorocarbon-based material) to enhance oxygen supply / transport to the enzyme membrane and / or electroactive surface. It is believed that some signal noise typically seen with conventional sensors may be due to oxygen deficiency. Silicone has high oxygen permeability, thus facilitating oxygen transport to the enzyme layer. By enhancing oxygen supply through the use of silicone compositions, for example, glucose concentration may not be a limiting factor. In other words, if more oxygen is supplied to the enzyme and / or electrochemically active surface, more glucose can also be supplied to the enzyme without creating an oxygen-limiting excess. Without being bound to any particular theory, it is believed that silicone materials provide enhanced biostability compared to other polymeric materials such as polyurethane.

[0320] In another embodiment, the porous material further comprises a bioactive agent that is released upon insertion. In an embodiment, the porous structure provides access for glucose permeation while allowing for bioactive agent release / elution. In an embodiment, as the bioactive agent is released / eluted from the porous structure, glucose transport may increase to counteract any attenuation of glucose transport from, for example, the immune response factors discussed above.

[0321] As used herein, the terms "membrane" and "matrix" are meant to be interchangeable. In these examples, the aforementioned porous material is a biointerface membrane with a first domain that includes an architecture, including cavity size, configuration, and / or overall thickness, that modifies the host tissue response, for example, by forming fluid pockets, promoting vascularized tissue ingrowth, breaking down underlying tissue contracture, resisting fibrotic tissue growth adjacent to the device, and / or preventing barrier cell formation. The biointerface membrane, in examples, can be of any shape or size, including covering at least the sensing mechanism of the sensor, and covering or surrounding the sensing mechanism or sensor uniformly, asymmetrically, or axially symmetrically.

[0322] A second domain of the biointerface membrane that is impermeable to cells and / or cell processes is optionally provided. A bioactive agent is optionally provided that is incorporated into at least one of the first domain, the second domain, the sensing membrane, or other portions of the implantable device, the bioactive agent being configured to modify a host tissue response. In an embodiment, the biointerface includes a bioactive agent that is 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 domain to modify a host tissue response to the membrane.

[0323] Due to the small dimensions of the sensor (sensing mechanism) of the present disclosure, some conventional methods of porous membrane formation and / or porous membrane adhesion are inappropriate for forming a biointerface membrane on a sensor as described herein. Therefore, the following examples illustrate systems and methods for forming and / or adhering a biointerface membrane on a miniature structured sensor as defined herein. For example, the biointerface membrane or release membrane of the present disclosure can be formed on a sensor using techniques such as electrospinning, molding, weaving, direct writing, freeze-drying, wrapping, etc.

[0324] In embodiments where the biointerface is written directly onto the sensor, the dispenser dispenses the polymer solution using a nozzle having a valve or the like, for example, as described in U.S. Patent Application Publication No. 2004 / 0253365. In general, a variety of nozzles and / or dispensers may be used to dispense the polymer material to form the woven or nonwoven fibers of the biointerface membrane.

[0325] (Bioactive release membrane / layer - Inflammatory response control) In general, the inflammatory response to biomaterial implants can be divided into two phases. The first phase consists of the recruitment of mast cells followed by the infiltration of mainly polymorphonuclear (PMN) cells. This phase is called the acute inflammatory phase. Over a period of days to weeks, chronic cell types that comprise the second phase of inflammation replace the PMNs. Macrophages and lymphoid cells predominate during this phase. Without wishing to be bound by any particular theory, it is believed that limiting vasodilation and / or blocking pro-inflammatory signaling, short-term stimulation of angiogenesis, or short-term inhibition of scar formation or barrier cell layer formation, provides protection from scar tissue formation and / or reduces acute inflammation, thereby providing a stable platform for sustained maintenance of, for example, an altered foreign body response.

[0326] Thus, bioactive intervention can modify the foreign body response in the early weeks of foreign body capsule formation and change the long-term behavior of the foreign body capsule. Additionally, in some situations, it is believed that the biointerface membranes of the present disclosure may benefit from bioactive intervention to overcome the sensitivity of the membrane to implant procedures, implant movement, or other factors that are otherwise known to cause inflammation, scarring, and impede device function in vivo.

[0327] In general, bioactive agents that are believed to modify tissue responses include anti-inflammatory agents, anti-infective agents, anti-proliferative agents, antihistamines, anesthetics, inflammatory agents, growth factors, angiogenic (growth) factors, adjuvants, immunosuppressants, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-barrier cell compounds, angiogenic compounds, antisense molecules, etc. In some examples, preferred bioactive agents include S1P (sphingosine-1-phosphate), monobutyrin, cyclosporin A, anti-thrombospondin-2, rapamycin (and its derivatives), NLRP3 inflammasome inhibitors such as MCC950, and dexamethasone. However, other bioactive agents, biological materials (e.g., proteins), or even non-bioactive substances can be incorporated into the membranes of the present disclosure.

[0328] Bioactive agents suitable for use in the present disclosure are broadly organized into two groups, anti-barrier cell agents and angiogenic agents. These names reflect their function of providing short-term solute transport through one or more membranes of the sensor of the present disclosure and additionally extending the lifespan of healthy vascular beds, thus extending solute transport through one or more membranes in vivo long-term. However, not all bioactive agents can be clearly classified into one or the other of the above groups; rather, bioactive agents generally comprise one or more different mechanisms for modifying tissue response and can generally be classified into one or both of the above cited categories.

[0329] (Anti-barrier cell agent) Generally, anti-barrier cell agents include compounds that exhibit effects against macrophages and foreign body giant cells (FBGCs). Anti-barrier cell agents are believed to prevent the closure of the barrier to solute transport presented by macrophages and FBGCs at the device-tissue interface during FBC maturation.

[0330] Anti-barrier cell agents generally include mechanisms for inhibiting foreign body giant cells and / or occlusive cell layers. For example, Super Oxide Dismutase (SOD) mimics utilize a manganese catalytic center in a porphyrin-like molecule to mimic native SOD and effectively scavenge superoxide over an extended period of time, thereby inhibiting FBGC formation at the surface of biomaterials in vivo, and are incorporated into preferred embodiments of the biointerface or release membrane.

[0331] Anti-barrier cell agents may include anti-inflammatory and / or immunosuppressive mechanisms that affect early FBC formation. Cyclosporine, which stimulates very high levels of neovascularization around the biomaterial, may be incorporated into the biointerface membrane (see U.S. Patent No. 5,569,462 to Martinson et al.) or into the release membrane of a preferred embodiment.

[0332] In an embodiment, dexamethasone, dexamethasone salts, or dexamethasone derivatives, particularly dexamethasone acetate, for example, which attenuates the strength of the FBC response at the device-tissue interface, are incorporated into the bioactive release membrane 70. In another embodiment, a combination of dexamethasone and dexamethasone acetate is incorporated into the bioactive release membrane 70. In another embodiment, dexamethasone and / or dexamethasone acetate in combination with one or more other anti-inflammatory and / or immunosuppressant agents is incorporated into the bioactive release membrane 70. Alternatively, rapamycin, a potent specific inhibitor of several macrophage inflammatory functions, can be incorporated into the release membrane alone or in combination with dexamethasone, dexamethasone salts, dexamethasone derivatives, particularly dexamethasone acetate.

[0333] Other suitable drugs, pharmaceutical compositions, therapeutic agents, or other desirable substances can be incorporated into the bioactive release film 70 of the present disclosure, including, but not limited to, anti-inflammatory agents, anti-infective agents, necrotic agents, and anesthetic agents.

[0334] Generally, anti-inflammatory agents reduce acute and / or chronic inflammation adjacent to the implant in order to reduce the formation of the FBC capsule and reduce or prevent barrier cell layer formation. Suitable anti-inflammatory agents include, for example, nonsteroidal anti-inflammatory drugs such as acetomethaphine, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 muteins, anti-IL-6 iNOS inhibitors (e.g., L-NAME or L-NMDA), interferons, ketoprofen, ketorolac, leflunomide, melenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin. These include, but are not limited to, corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximethasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, NLRP3 inflammasome inhibitors such as MCC950, dexamethasone, and dexamethasone acetate.

[0335] Generally, immunosuppressants and / or immunomodulators directly interfere with several important mechanisms required for the involvement of different cellular elements in the inflammatory response. Suitable immunosuppressants and / or immunomodulators include antiproliferative agents, cell cycle inhibitors (e.g., paclitaxel (e.g., sirolimus), cytochalasin D, infiximab), taxol, actinomycin, mitomycin, thospromote VEGF, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopeptin, vincristine, mitomycin, statins, C These include MYC antisense, sirolimus (and analogs), restenase, 2-chlorodeoxyadenosine, PCNA ribozyme, batimustat, prolyl hydroxylase inhibitors, PPARγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catchin, glycation agents, endothelin inhibitors (e.g., ambrisentan, tesosentan, bosentan), statins (e.g., cerivastatin), E. coli burn enterotoxin, and advanced coatings.

[0336] Generally, anti-infectives are substances that can act against infection by inhibiting the spread of the infectious agent or by killing the infectious agent altogether, which can act to reduce the immune response without an inflammatory reaction at the implant site. Anti-infectives include anthelmintics (mebendazole), aminoglycoside-containing antibiotics (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolide antibiotics (azithromycin, clarithromycin, erythromycin), penicillin antibiotics (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticac ... lucirin), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; colistin metasodium; polymyxin b sulfate; vancomycin; antivirals including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolone antibacterials (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum; gatifloxacin; and sulfamethoxazole / trimethoprim.

[0337] Generally, a necrotic agent is any drug that causes tissue necrosis or cell death. Necrotic agents include cisplatin, BCNU, taxol or taxol derivatives.

[0338] (angiogenic agent) Generally, angiogenic agents include substances that have direct or indirect angiogenic properties. In some cases, angiogenic agents may additionally affect the formation of barrier cells in vivo. Indirect angiogenesis means that angiogenesis may be mediated through inflammatory or immune stimulatory pathways. It is not entirely known how agents that induce local angiogenesis indirectly inhibit barrier cell formation, however, it is believed that some barrier cell effects may result indirectly from the effects of angiogenic agents.

[0339] The angiogenic agent includes mechanisms to promote neovascularization around the membrane and / or minimize ischemic periods by increasing angiogenesis close to the device-tissue interface. Sphingosine-1-Phosphate (S1P), a phospholipid with potent angiogenic activity, is incorporated into the biointerface membrane or release membrane of preferred embodiments. Monobutyrin, a potent vasodilator and angiogenic lipid product of adipocytes, is incorporated into the biointerface membrane or release membrane of preferred embodiments. In another embodiment, an antisense molecule that increases angiogenesis (e.g., thrombospondin-2 antisense) is incorporated into the biointerface membrane or release membrane.

[0340] Angiogenic agents may include mechanisms that promote inflammation, which is believed to lead to accelerated neovascularization in vivo. In one embodiment, a heterologous carrier, such as bovine collagen, which by its foreign nature induces an immune response and stimulates neovascularization, is incorporated into the biointerface membrane or release membrane of the present disclosure. In another embodiment, lipopolysaccharide, a potent immune stimulant, is incorporated into the biointerface membrane or release membrane. In another embodiment, proteins, such as bone morphogenetic proteins (BMPs), which are known to regulate bone healing in tissues, are incorporated into the biointerface membrane or release membrane of the preferred embodiment.

[0341] 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 copper ions, iron ions, tridodecylmethylammonium chloride, Basic Fibroblast Growth Factor (bFGF), (also known as Heparin Binding Growth Factor II and Fibroblast Growth Factor II), Acidic Fibroblast Growth Factor (aFGF), (also known as Heparin Binding Growth Factor-I and Fibroblast Growth Factor-I), Vascular Endothelial Growth Factor (VEGF), Platelet Derived Endothelial 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 (PGF), and the like. These include, but are not limited to, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49 ...9, IL-40, IL-41, IL-42, IL-43,

[0342] Generally, pro-inflammatory agents are substances capable of stimulating an immune response in the host tissue, which can accelerate or sustain the 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 responses at the implantation site. Without wishing to be bound by theory, it is believed that the formation of advanced tissue granulation induces blood vessels, which provide an adequate or abundant supply of analytes to the device-tissue interface. Pro-inflammatory agents include, but are not limited to, heterologous carriers, lipopolysaccharides, Staphylococcus aureus peptidoglycan, and proteins.

[0343] Other substances that can be incorporated into the membranes of the present disclosure include various drugs, excipients, and other substances well known in the art of pharmaceutical formulations.

[0344] While the bioactive agent in some embodiments is incorporated into the biointerface membrane or release membrane and / or implantable device, in some embodiments the bioactive agent can be administered simultaneously with, prior to, or after implantation of the device, either systemically, e.g., by oral administration, or locally, e.g., by subcutaneous injection near the implantation site. The combination of bioactive agent incorporated into the biointerface membrane and local and / or systemic bioactive agent administration can be preferred in certain embodiments.

[0345] In one embodiment, bioactive release membrane 70 functions as a biointerface membrane. In another embodiment, bioactive release membrane 70 is chemically distinct from biointerface membrane 68, or biointerface membrane 68 is not used. In such an embodiment, one or more bioactive agents are incorporated into bioactive release membrane 70, or into both biointerface membrane 68 and bioactive release membrane 70.

[0346] In general, numerous variables can affect the pharmacokinetics of bioactive agent release. Bioactive agents of the present disclosure can be optimized for short-term and / or extended release. In some examples, bioactive agents of the present disclosure are designed to supplement or overcome factors associated with short-term effects of a foreign body response (e.g., acute inflammation), which can begin as early as the time of implantation and extend up to about one month after implantation. In some examples, bioactive agents of the present disclosure are designed to supplement or overcome factors associated with long-term effects, such as chronic inflammation, barrier cell layer formation, or fibrous tissue construction of a foreign body response, which can begin as early as about one week after implantation and extend over the life of the implant, for example, months to years. In some examples, bioactive agents of the present disclosure combine short-term and extended release to exploit the benefits of both. U.S. Patent Application Publication No. 2005 / 0031689 to Shults et al. discloses various systems and methods for the release of bioactive agents.

[0347] The loading amount of bioactive agent in the release film can depend on various factors. For example, the dosage and duration of the bioactive agent can vary depending on the intended use of the release film, such as cell transplantation, analyte measuring device, etc., the host-to-host difference in effective dosage of the bioactive agent, the location and method of loading the bioactive agent, and the release rate associated with the bioactive agent, and optionally their chemical composition and / or bioactive agent loading amount. Thus, those skilled in the art will understand the variability of achieving a reproducible and controlled release of one or more bioactive agents, at least for the reasons mentioned above. U.S. Patent Application Publication No. 2005 / 0031689 to Shults et al. discloses various systems and methods for loading bioactive agents.

[0348] In an embodiment, multiple layers or individual or semi-individual rings or bands of bioactive-releasing membranes are used to specifically tailor the release of bioactive agents to the intended biological sensing. Thus, in an embodiment, two or more layers of a multi-layer bioactive-releasing membrane differ in one or more aspects, such as the hydrophobic / hydrophilic content or ratio of segments of a soft-hard segmented polymer or copolymer, the composition 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, the loading and / or distribution of bioactive agents in each layer (vertically or longitudinally within the coated membrane), the membrane thickness of each layer, the composition and loading of two or more distinct bioactive agents (e.g., neutral, derivative and / or salt forms, or primary and derivative forms of the bioactive agents), the solvent system used to cast or deposit or dip coat the individual bioactive-releasing membrane layers, and the relative position (continuous, semi-continuous or non-continuous positioning) of the bioactive-releasing membrane layers along the length of the sensor.

[0349] (Formation of bioactive releasing film / layer on the sensor) The membrane systems disclosed herein are suitable for use in implantable devices that contact biological fluids. For example, the membrane systems can be utilized with implantable devices such as devices for monitoring and determining analyte levels in biological fluids, e.g., devices for monitoring glucose levels for individuals with diabetes. In some embodiments, the analyte measuring device is a continuous device. The analyte measuring device can use any suitable sensing element to provide a raw signal, including, but not limited to, enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, potentiometric, calorimetric, radiometric, immunochemical, and the like elements.

[0350] Although some of the following description is directed to glucose measurement devices including the described membrane systems and methods of their use, these membrane systems are not limited to use in devices that measure or monitor glucose. These membrane systems are suitable for use in any of a variety of devices, including, for example, devices that detect and quantify other analytes present in biological fluids (e.g., cholesterol, amino acids, alcohol, galactose, and lactate), cell transplantation devices (see, for example, U.S. Pat. Nos. 6,015,572, 5,964,745, and 6,083,523), drug delivery devices (see, for example, U.S. Pat. Nos. 5,458,631, 5,820,589, and 5,972,369), and the like, which are incorporated herein by reference in their entirety for the teachings of the membrane systems.

[0351] A suitable bioactive releasing membrane is one that provides a therapeutically effective amount and release rate of a bioactive agent beginning with the insertion of the sensor and continuing throughout the life of the sensor. In one embodiment, a bioactive releasing membrane in combination with an amount of a bioactive agent provides an extension of the useful life of the sensor when compared to a comparable sensor bioactive releasing membrane without a bioactive agent (or compared to the absence of a bioactive releasing membrane and bioactive agent). As used herein, a therapeutically effective amount of a bioactive agent is an amount that is capable of inducing an intended therapeutic effect. The intended therapeutic effect is one that can be readily determined using conventional diagnostic methods. For example, the intended therapeutic effect includes suppressing undesirable foreign body reactions to the implant (foreign body), including but not limited to inflammation and / or fibrous capsule formation.

[0352] In some examples, the wetting properties of the membrane (and thus the degree of sensor drift exhibited by the sensor) can be tuned and / or controlled by creating covalent crosslinks between surface active group-containing polymers, functional group-containing polymers, polymers with zwitterionic groups (or precursors or derivatives thereof), and combinations thereof. Crosslinking can have a substantial effect on the film structure, which in turn can affect the surface wetting properties of the film. Crosslinking can also affect the tensile strength, mechanical strength, water absorption rate, and other properties of the film.

[0353] The crosslinked polymers can have different crosslink densities. In certain embodiments, a crosslinking agent is used to promote crosslinking between layers. In other embodiments, instead of (or in addition to) the crosslinking techniques described above, heat is used to form crosslinks. For example, in some embodiments, imide and amide bonds can be formed between two polymers as a result of high temperatures. In some embodiments, photocrosslinking is performed to form covalent bonds between the polycation layer and the polyanion layer. One major advantage of photocrosslinking is that it offers the possibility of patterning. In certain embodiments, patterning using photocrosslinking is performed to modify the film structure and thus adjust the wetting properties of the membrane.

[0354] Polymers with domains or segments functionalized to allow crosslinking can be made by methods known in the art. For example, polyurethaneurea polymers with aromatic or aliphatic segments with electrophilic functional groups (e.g., carbonyl, aldehyde, anhydride, ester, amide, isocyano, epoxy, allyl, or halo groups) can be crosslinked with a crosslinker with multiple nucleophilic groups (e.g., hydroxyl, amine, urea, urethane, or thio groups). In further examples, polyurethaneurea polymers with aromatic or aliphatic segments with nucleophilic functional groups can be crosslinked with a crosslinker with multiple electrophilic groups. Furthermore, polyurethaneurea polymers with hydrophilic segments with nucleophilic or electrophilic functional groups can be crosslinked with a crosslinker with multiple electrophilic or nucleophilic groups. Unsaturated functional groups on the polyurethaneurea can also be used for crosslinking by reacting with a multivalent free radical agent. Non-limiting examples of suitable crosslinkers include isocyanates, carbodiimides, glutaraldehyde, aziridines, silanes or other aldehydes, epoxies, acrylates, free radical based agents, ethylene glycol diglycidyl ether (EGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). In embodiments, from about 0.1% w / w to about 15% w / w of crosslinker is added based on the total dry weight of crosslinker and polymer added when blending the components (in embodiments, from about 1% to about 10%), including all ranges and subranges therebetween. During the curing process, it is believed that substantially all of the crosslinker reacts leaving substantially no detectable unreacted crosslinker in the final film.

[0355] The polymers disclosed herein can be formulated into a mixture that can be stretched into a film or applied to a surface using any method known in the art (e.g., spraying, painting, dip coating, vapor deposition, molding, 3D printing, lithography techniques (e.g., photolithography), micro- and nano-pipetting printing techniques, silk screen printing, etc.). The mixture can then be cured under elevated temperatures (e.g., 50° C. to 150° C.). Other suitable curing methods can include, for example, ultraviolet light or gamma radiation.

[0356] In one embodiment, the weight of the bioactive agent associated with the sensor is between 1 and 120 μL, between 2 and 110 μL, between 3 and 100 μL, between 4 and 90 μL, between 5 and 80 μL, between 6 and 70 μL, between 7 and 60 μL, between 8 and 50 μL, between 9 and 40 μL, or between 10 and 30 μL. In another embodiment, the weight of two or more bioactive agents associated with the sensor is, independently or collectively, between 1 and 120 μL, between 2 and 110 μL, between 3 and 100 μL, between 4 and 90 μL, between 5 and 80 μL, between 6 and 70 μL, between 7 and 60 μL, between 8 and 50 μL, between 9 and 40 μL, or between 10 and 30 μL.

[0357] In one embodiment, the weight percent loading of the bioactive agent in the bioactive release film 70 is between about 10 weight percent and about 90 weight percent. In an embodiment, the weight percent loading of the bioactive agent in the bioactive release film 70 is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the total weight of the bioactive release film plus the bioactive agent (as a film deposited on the sensor). In an embodiment, the weight percent loading of the bioactive agent in the bioactive release film 70 is 30%, 40%, 50%, or 60% of the total weight of the bioactive release film plus the bioactive agent (as a film deposited on the sensor). Depending on the nature of the bioactive release film, e.g., the ratio of hydrophobic / hydrophilic soft segments, the weight percent of the bioactive agent is selected based on the solubility / miscibility / dispersion of the bioactive agent with any solvent or solvent system used to dispense the bioactive release film and the bioactive agent onto the bioactive release film and the sensor. Too high a loading of a bioactive agent in a particular bioactive-releasing film can result in precipitation of the bioactive agent and / or poor coating quality. Too low a loading of a bioactive agent in a bioactive-releasing film can result in an inefficient therapeutic effect over the intended life of the sensor, which can manifest as, among other things, insufficient signal-to-noise initially and / or prior to the designed life of the sensor, a decrease or shift in the sensitivity of the sensor to the target analyte immediately after insertion and / or prior to the designed life of the sensor.

[0358] In some embodiments, the bioactive releasing membrane is configured to release up to 100% of the initial loading of bioactive agent, including at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, by weight percent, after insertion and until the end of the sensor's life. In some embodiments, the bioactive releasing membrane is configured to release 60-90% by weight of the bioactive agent after insertion and until the end of the sensor's life. In other embodiments, the bioactive releasing membrane is configured to release 75-85% by weight of the bioactive agent after insertion and until the end of the sensor's life.

[0359] In one embodiment, the bioactive release films of the present disclosure provide for release of a bioactive agent from the bioactive release film in accordance with a bolus amount of the bioactive agent. In another embodiment, the bioactive release films of the present disclosure provide for release of a bioactive agent from the bioactive release film in accordance with a therapeutically effective amount of the bioactive agent. In an embodiment, the bioactive release films of the present disclosure provide for release of a bioactive agent from the bioactive release film in accordance with a non-therapeutically effective amount, the non-therapeutically effective amount following one or more of release of a bolus amount or a therapeutic amount of the bioactive agent.

[0360] In examples, the bioactive releasing membrane of the present disclosure provides a bolus release of a bioactive agent essentially immediately upon insertion of a sensor for a first time period or range (e.g., minutes, hours, days, weeks, etc.), the first time period or range beginning at a first time point (e.g., 1 second or less) into the soft tissue of the subject. In examples, the bioactive releasing membrane of the present disclosure provides a release of a bolus amount of a bioactive agent essentially immediately upon insertion of a sensor into the soft tissue of the subject for a first time period beginning at the first time point, followed by a release of a therapeutically effective amount of a bioactive agent beginning at a second time point for a second time period, the second time period overlapping with or following the first time period. In examples, the second time point is at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, or more after the first time point. In one embodiment, the bioactive releasing membrane of the present disclosure provides release of a bolus amount of bioactive agent to the soft tissue of a subject essentially immediately upon insertion of the sensor for a first time period beginning at a first time period, followed by release of a therapeutically effective amount of bioactive agent for a second time period beginning at a second time point for a second time period overlapping or following the first time period, followed by release of a non-therapeutically effective amount of bioactive agent for a third time period beginning at a third time point for a third time period overlapping or following the second time period. In embodiments, the third time point is at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes or more after the second time point.

[0361] In an embodiment, the bolus release of the bioactive is combined with the release of a non-active pharmaceutical ingredient (non-API), such as a hydrophilic material (zwitterionic species, hydrogel particles or spheres), to modify the environment created within the tissue by the presence of the sensor volume. Without wishing to be bound by theory, it is believed that the hydrophilic material can attract fluid to the environment, reduce biofouling, slow metabolic degradation of the bioactive, and / or increase cellular uptake of the bioactive. The release of such a non-API may, among other benefits, help delay foreign body reactions and / or facilitate the release of the bioactive from the bioactive-releasing membrane.

[0362] The release rate of the bioactive agent during any of the first, second, or third time periods can be the same or different. The release rate of the bioactive agent during any of the first, second, or third time periods can be configured to occur at a substantially constant rate or at a variable rate (intermittent, periodic, and / or random), for example, by modifying one or more of the membrane chemistry, structure, and / or morphology, bioactive agent loading, and bioactive agent chemistry. The release rate of the bioactive agent during any of the time periods (concentration or amount of bioactive agent released over time) can be configured to vary over time after implantation, for example, by modifying one or more of the membrane chemistry, structure, and / or morphology, bioactive agent loading, and bioactive agent chemistry.

[0363] In one embodiment, the release rate of the bioactive agent from the bioactive release film during the initial or first time period is greater than the release rate of the bioactive agent from the bioactive release film during the initial or second time period. In one embodiment, the release rate of the bioactive agent from the bioactive release film during the initial or second time period is greater than the release rate of the bioactive agent from the bioactive release film during the initial or third time period. In one embodiment, the release rate of the bioactive agent from the bioactive release film during the initial or first time period is greater than the release rate of the bioactive agent from the bioactive release film during the initial or second time period, and the release rate of the bioactive agent from the bioactive release film during the initial or second time period is greater than the release rate of the bioactive agent from the bioactive release film during the initial or second time period.

[0364] Suitable bioactive release membranes of the present disclosure that are capable of the aforementioned release rates and amounts of bioactive agent include silicone polymers, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefins, polyesters, polyalkyl esters, polyalkylcarbonates, polycarbonates, biostable polytetrafluoroethylene, homopolymers, copolymers, and terpolymers of polyurethane, polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (PVA), polyethylene vinyl acetate (EVA), polybutylene terephthalate (PBT), polymethyl methacrylate (PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes and copolymers and blends thereof, polyurethaneurea polymers and copolymers and blends thereof, cellulose polymers and copolymers and blends thereof, and mixtures thereof. The polymer may be selected from poly(ethylene oxide) and copolymers and blends thereof, poly(propylene oxide) and copolymers and blends thereof, for example, polysulfones and block copolymers thereof, including diblock, triblock, alternating, random and graft copolymer 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 methacrylate and copolymers and blends thereof, hydroxyapeptite and copolymers and blends thereof.

[0365] A suitable bioactive releasing membrane is a polyurethane, or a polyether urethane urea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate with a difunctional hydroxyl-containing material. Polyurethane urea is a polymer produced by the condensation reaction of a diisocyanate with a difunctional amine-containing material. Exemplary diisocyanates include aliphatic diisocyanates containing about 4 to about 8 methylene units. Diisocyanates containing alicyclic moieties may also be useful in preparing the polymer and copolymer components of the bioactive releasing membrane of the present disclosure. The material forming the basis of the hydrophobic matrix of the bioactive releasing membrane or its domains may be any known in the art as suitable for use as a membrane in a continuous analyte sensing device. In one embodiment, the bioactive releasing membrane differs from other membranes of the sensor system in that the bioactive releasing membrane is less permeable to related compounds, for example, to allow glucose molecules to pass through the membrane.

[0366] Examples of other materials that can be used to make non-polyurethane type bioactive release films include vinyl polymers, polyethylene vinyl acetate, polyethylene vinyl acetate copolymers, polyethers, polyesters, polyalkyl esters, polyamides, polysilicones, poly(dialkylsiloxanes), poly(alkylarylsiloxanes), poly(diarylsiloxanes), polycarbosiloxanes, polyalkylcarbonates, polycarbonates, natural polymers such as cellulosic and protein-based materials, as well as mixtures, copolymers, or combinations thereof with or without the aforementioned polyurethane or polyether urethane urea polymers.

[0367] In an embodiment, the bioactive release membrane comprises a soft segment and a hard segment, the hard segment comprising a urethane group, a urea group, or a combination of a urethane group and a urea group. The soft segment can be two or more different polymer segments. The soft segment can comprise a hydrophobic block and a hydrophilic block. The soft segment can comprise a polysiloxane, a polyalkyl ether, a polyalkyl ester, a polyalkyl carbonate, a polycarbonate, or a polysiloxane-polyalkyl ether segmented block.

[0368] In embodiments, the soft segments are independently a combination of hydrophobic / hydrophilic moieties, such as polyols (polyethylene oxide "PEO", polyethylene propylene oxide, polytetrahydrofuran or polytetramethylene oxide), polyethers, polysiloxanes, polyamines, polysiloxane amines, polyesters, polyalkyl esters, polyalkylcarbonates, polycarbonates, and one or more independent hard segments, such as norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI). , trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0369] In an embodiment, the bioactive release film can further include a chain extender. The chain extender can be, for example, a diol, a diamine, a silicon hydride, or a multifunctional epoxide. Exemplary diols include aliphatic or aromatic low molecular weight diols, such as glycol, propylene glycol, diethylene glycol, and 1,4-butanediol, and other exemplary chain extenders include dialkylamines, such as ethylenediamine, 1,6-hexamethylenediamine, 4,4'-diaminodiphenylmethane, triethylenediamine, putrescine, and diaminopropane, or hydroxylamines.

[0370] In other embodiments, the bioactive release film further comprises one or more zwitterionic repeat units selected from the group consisting of cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, caprylyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly(carboxybetaine), poly(sulfobetaine), and derivatives thereof. In another embodiment, alone or in combination with any one of the previous embodiments, the bioactive release film does not comprise zwitterionic groups only at the ends of polymer chains.

[0371] In an embodiment, one or more of the zwitterionic repeat units is derived from a monomer selected from the group consisting of:

[0372] [ka]

[0373] wherein Z is a branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl; R1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R2, R3, and R4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R 1 , R 2 , R 3 , R 4 and where one or more of Z are substituted with a polymerizable group are used as at least a portion of the bioactive release membrane.

[0374] In an embodiment, the polymerizable group is selected from an alkene, an alkyne, an epoxide, a lactone, an amine, a hydroxyl, an isocyanate, a carboxylic acid, an anhydride, a silane, a halide, an aldehyde, and a carbodiimide. In another embodiment, the one or more zwitterionic repeat units is at least about 1 wt %, based on the total weight of the polymer.

[0375] In one embodiment, a minimum of one bioactive agent is covalently associated with the bioactive release membrane. In another embodiment, at least one bioactive agent is ionically associated with the bioactive release membrane. In another embodiment, the bioactive agent is a conjugate.

[0376] In another embodiment, the at least one bioactive agent is a nitric oxide (NO) releasing molecule, polymer, or oligomer. In another embodiment, alone or in combination with any one of the previous embodiments, the nitric oxide releasing molecule is selected from N-diazeniumdiolates and S-nitrosothiols. In an embodiment, the nitric oxide releasing molecule is covalently or non-covalently attached to the polymer or oligomer. In an embodiment, the N-diazeniumdiolates are of the structure RR'N-N2O2, where R and R' are independently alkyl, aryl, phenyl, alkylaryl, alkylphenyl, or functionalized N-alkylaminotrialkoxysilane. In an embodiment, at least one of the R and R' groups of the N-diazeniumdiolates of the structure RR'N-N2O2 is sufficiently lipophilic to remain in the hydrophobic region of the bioactive releasing membrane while providing a source of nitric oxide at the insertion site. In an embodiment, at least one of R and R' is sufficiently functionalized to bind to a bioactive release membrane while providing a source of nitric oxide at the insertion site. In an embodiment, the S-nitrosothiol is an S-nitrosothiol derivative of S-nitroso-glutathione (GSNO) or penicillamine.

[0377] In another embodiment, the bioactive agent is a borate ester or boronate. In one embodiment, the bioactive agent-borate ester or boranate is covalently attached to the bioactive release film. In another embodiment, the bioactive agent-borate ester or boranate is non-covalently attached to the bioactive release film. In one embodiment, the bioactive agent-borate ester or boranate is covalently attached to the bioactive agent and covalently attached to the bioactive release film. In another embodiment, the bioactive agent-borate ester or boranate is covalently attached to the bioactive agent and non-covalently attached to the bioactive release film. In another embodiment, the bioactive agent is a borate ester or boronate of dexamethasone, a dexamethasone salt, or a dexamethasone derivative, particularly dexamethasone acetate or dexamethasone acetate.

[0378] In another embodiment, the bioactive agent is a conjugate comprising at least one linker cleavable by a subcutaneous stimulus. In another embodiment, the bioactive agent is a conjugate of dexamethasone, a dexamethasone salt, or a dexamethasone derivative, in particular dexamethasone acetate, or dexamethasone acetate, comprising at least one linker cleavable by a subcutaneous stimulus. For example, the bioactive agent conjugate comprising at least one cleavable linker is cleaved by a subcutaneous stimulus after inserting the analyte sensor into the subcutaneous domain of the host. In one embodiment, the subcutaneous stimulus is a chemical attack by one or more members of the metzincin superfamily, a matrix metalloproteinase (MMP), or a matrix metallopeptidase or matrixin, or any other protease. In an embodiment, the MMP is a calcium or zinc-dependent endopeptidase, an adalysin, an astacin, or a serralysin.

[0379] In another embodiment, the bioactive release membrane comprising a bioactive agent (alone or as a conjugate or associated with the bioactive release membrane) comprises a hydrophilic hydrogel that is at least partially crosslinked and dissolvable in biological fluids. In another embodiment, the bioactive release membrane comprising a bioactive agent (alone or as a conjugate) comprises a hydrophilic hydrogel associated or bonded with dexamethasone, a dexamethasone salt, or a dexamethasone derivative, particularly dexamethasone acetate, or dexamethasone acetate, that is at least partially crosslinked and dissolvable in biological fluids to provide for release of dexamethasone, a dexamethasone salt, or a dexamethasone derivative, particularly dexamethasone acetate, or dexamethasone acetate.

[0380] In an embodiment, the hydrophilic hydrogel at least partially dissolves in biological fluids within 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or more and provides continuous, semi-continuous or bolus release of dexamethasone, a dexamethasone salt or a dexamethasone derivative, particularly dexamethasone acetate or dexamethasone acetate. In an embodiment, the hydrophilic hydrogel comprises hyaluronic acid (HA) crosslinked with divinylsulfone or polyethylene glycol divinylsulfone. In an embodiment, the hydrophilic hydrogel comprises a hydrogel conjugate of dexamethasone, a dexamethasone salt or a dexamethasone derivative, particularly dexamethasone acetate or dexamethasone acetate.

[0381] In another embodiment, the bioactive release film comprises silver nanoparticles or nanogels as the bioactive agent, alone or in combination with dexamethasone, dexamethasone salts, or dexamethasone derivatives, or mixtures thereof, particularly dexamethasone acetate or dexamethasone acetate salts. In one embodiment, the nanoparticles are biodegradable. For example, biodegradable polymer nanoparticles include PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphoesters, or PEO-b-polypeptides, which contain at least one bioactive agent. In an embodiment, the bioactive release film comprises copper and / or zinc nanoparticles or nanogels as the bioactive agent. The silver, copper, or zinc nanoparticles / nanogels can be spatially distributed or dispersed throughout the bioactive release film, and the spatial distribution or dispersion can be uniform or non-uniform and / or can vary vertically and / or horizontally with a gradient.

[0382] In an embodiment, bacterial cellulose with self-assembled nanoparticles / nanogels of silver, zinc, or copper are used as a bioactive release membrane to provide release of dexamethasone, dexamethasone salts, or dexamethasone derivatives, particularly dexamethasone acetate, or dexamethasone acetate, either alone or in combination with any one of the polyurethane / polyurethane urea membranes disclosed herein. In another embodiment, chitosan oligosaccharide / poly(vinyl alcohol) nanoparticles / nanogels or nanofibers of silver, zinc, or copper are used as a bioactive release membrane to provide release of dexamethasone, dexamethasone salts, or dexamethasone derivatives, particularly dexamethasone acetate, or dexamethasone acetate.

[0383] In an embodiment, the bioactive release membrane comprises biodegradable polymeric nanoparticles selected from PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphoesters, PEO-b-polypeptides, and the polymeric nanoparticles / nanogels comprise covalently or non-covalently associated dexamethasone, a dexamethasone salt, or a dexamethasone derivative, in particular dexamethasone acetate, or dexamethasone acetate.

[0384] In another embodiment, the bioactive release membrane comprises an organic and / or inorganic sol-gel, or an organic-inorganic hybrid sol-gel, or a poloxamer-based carrier that provides release of dexamethasone, a dexamethasone salt, or a dexamethasone derivative, particularly dexamethasone acetate, or dexamethasone acetate. In another embodiment, the bioactive release membrane comprises a thermosensitive controlled release hydrogel or poloxamer, for example, poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) hydrogel.

[0385] In one embodiment, the bioactive release membrane comprises a combination of at least one bioactive agent encapsulated in the bioactive release membrane and at least one bioactive agent covalently bonded to the bioactive release membrane, hi another embodiment, the bioactive release membrane comprises a spatially distal drug depot of at least one bioactive agent, either as a conjugate or associated with the bioactive release membrane disclosed herein.

[0386] In another embodiment, the bioactive release film comprises a hydrolytically degradable biopolymer comprising at least one bioactive agent, hi one embodiment, the hydrolytically degradable biopolymer comprises a salicylic acid polyanhydride ester (Structure I), which can be hydrolyzed to salicylic acid and adipic acid.

[0387] [ka]

[0388] In one embodiment, a suitable bioactive release membrane 70 is a hard-soft segmented polymer. Referring to FIG. 4A, an exemplary hard-soft segmented copolymer is depicted having a hard segment 72 where there is a close association of polymer segments that provides a crystalline or crystalline-like structure, and a soft segment 74 that provides an amorphous or amorphous-like structure. In one embodiment, the bioactive release membrane 70 of the present disclosure is a hard-soft segmented copolymer 71, where the soft segment 74 includes a hydrophilic polymer or hydrophilic polymer segment. In one embodiment, the bioactive release membrane 70 of the present disclosure is a hard-soft segmented copolymer 71, where the soft segment 74 includes a hydrophilic polymer or hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. 4B and 4C, a hard-soft segmented copolymer, in which the soft segment 74 comprises a hydrophilic polymer or hydrophilic polymer segment combined with a hydrophobic polymer or hydrophobic polymer segment, is shown diagrammatically as a three-dimensional volume 4C of the bioactive release membrane 70 of the sensing membrane 32 depicting the arrangement of hydrophobic domains 76 and hydrophilic domains 78. Various configurations and distributions of hydrophobic and hydrophilic domains are envisioned depending on the relative concentration of each domain and whether there is a non-stoichiometric or stoichiometric amount of each domain. In an embodiment, the soft segment of the bioactive release membrane 70 comprises a hydrophilic segment that does not include zero weight percent and a hydrophobic segment that includes zero weight percent.

[0389] In one embodiment, the bioactive release membrane 70 comprises a hard-soft segmented polyurethane copolymer. In another embodiment, the bioactive release membrane 70 comprises a hard-soft segmented polyurethane urea copolymer. In an embodiment, the bioactive release membrane 70 of the present disclosure is a hard-soft segmented polyurethane or polyurethane urea copolymer, where the soft segment 74 comprises a hydrophilic polymer or a hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. In an embodiment, the bioactive release membrane 70 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 74 comprising a hydrophilic polymer or a hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. In an embodiment, the bioactive release membrane 70 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 74 comprising only hydrophilic polymer segments, where at least one of the polymers of the polymer blend comprises a soft segment comprising a hydrophobic polymer or a hydrophilic polymer segment in combination with a hydrophobic polymer segment.

[0390] In an embodiment, the bioactive release membrane 70 comprises a hard-soft segmented polyurethane copolymer or polyurethane-urea copolymer that contains a pharmaceutical amount of a bioactive agent and provides a release of the bioactive with a release profile (bolus, bolus followed by controlled release, etc.). The bioactive may be dexamethasone ((11β,16α)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), a dexamethasone salt (e.g., sodium phosphate), or a dexamethasone derivative (or analog), particularly dexamethasone acetate; dexamethasone acetate; dexamethasone 17-propionate; dexamethasone enol-pyruvylaldehyde; (Z)-2-((8S,9R ,10S,11S,13S,14S,16R)-9-fluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-3,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-ylidene)-2-hydroxyacetaldehyde;2-((10R,13S,16S,17R)-11,17-dihydroxy-10,13,16-trimethyl-4,9,10,11,12, 13,14,15,16,17-Decahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxolane]-17-yl)-2-oxoethyl acetate;(8S,9R,10R,11S,13S,14S,16R,17R)-9-fluoro-1,11,17-trihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetra ... It can be tradecahydro-3H-cyclopenta[a]phenanthren-3-one; dexamethasone glyoxal; or 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoacetic acid.

[0391] In some embodiments, the hard segments of the copolymers can have an average or number average molecular weight of from about 160 Daltons (DA) to about 10,000 DA, or from about 200 DA to about 2,000 DA, including all ranges and subranges therebetween. In some embodiments, the average or number average molecular weight of the soft segments can be from about 200 DA to about 100,000 DA, or from about 500 DA to about 500,000 DA, or from about 5,000 DA to about 20,000 DA, including all ranges and subranges therebetween.

[0392] In some embodiments, the base polymer of the bioactive release membrane has an average molecular weight or number average molecular weight of about 200 DA to about 10,000 DA, about 10,000 DA to about 50,000 DA, about 50,000 DA to about 100,000 DA, about 100,000 DA to about 150,000 DA, about 150,000 DA to about 250,000 DA, or about 250,000 DA to about 500,000 DA, including all ranges and subranges therebetween.

[0393] In an embodiment, an aliphatic or aromatic diisocyanate is used to prepare the hard segment 72 of the bioactive release film 70. In an embodiment, the aliphatic or aromatic diisocyanate used to provide the hard segment 72 of the bioactive release film 70 is norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocyanate (B6XDI), cyclohexane ... diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or a combination thereof.

[0394] In an embodiment, the soft segment 74 of the hard-soft segmented polyurethane or polyurethaneurea copolymer comprises a polysiloxane or copolymer thereof. In an embodiment, the soft segment 74 of the hard-soft segmented polyurethane or polyurethaneurea copolymer comprises a poly(dialkyl)siloxane, a poly(diphenyl)siloxane, a poly(alkylphenyl)siloxane, or copolymers thereof. In an embodiment, the soft segment 74 of the hard-soft segmented polyurethane or polyurethaneurea copolymer comprises a poly(alkyl)oxy polymer, a poly(alkylene)oxide, or copolymers thereof. In an embodiment, the soft segment 74 of the hard-soft segmented polyurethane or polyurethaneurea copolymer comprises a poly(alkyl)oxide, a poly(ethylene)oxide, a poly(propylene)oxide, a poly(ethylene-propylene)oxide, a poly(tetraalkylene)oxide, a poly(tetramethylene)oxide polymer, or copolymers or blends thereof. The soft segments may be composed of hydrophilic and / or hydrophobic oligomers, such as, for example, polyalkylene glycols, polyalkylcarbonates, polycarbonates, polyesters, polyethers, polyvinyl alcohols, polyvinylpyrrolidones, polyoxazolines, and the like.

[0395] In an embodiment, the soft segment 74 of the hard-soft segmented polyurethane or polyurethaneurea copolymer includes a polysiloxane or copolymer thereof and a poly(alkylene)oxy polymer or copolymer thereof. In an embodiment, the soft segment 74 of the hard-soft segmented polyurethane or polyurethaneurea copolymer includes a poly(dialkyl)siloxane, poly(diphenyl)siloxane, poly(alkylphenyl)siloxane or copolymer, and a 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.

[0396] In one embodiment, the bioactive release film 70 has a hydrophilic segment with a static contact angle greater than 90 degrees. In one embodiment, the bioactive release film 70 has a hydrophobic segment with a static contact angle less than 90 degrees. Examples of hydrophilic polymers suitable for at least a portion of the soft segment of the bioactive release film 70 to provide a static contact angle of 90 degrees or greater include, but are not limited to, polyvinylpyrrolidone, polyvinylpyridine, proteins, cellulose, polyethers, polyetherimines. Examples of hydrophobic polymers suitable for at least a portion of the soft segment of the bioactive release film 70 to provide a static contact angle less than 90 degrees include, but are not limited to, polyurethanes, silicones, polyurethaneureas, polyesters, polyamides, polyalkylcarbonates, polycarbonates, and copolymers thereof.

[0397] At least a portion of the surface of the biointerface / bioactive release membrane can be hydrophobic as measured by contact angle. For example, the biointerface / bioactive release membrane can have a contact angle of about 90° to about 160°, about 95° to about 155°, about 100° to about 150°, about 105° to about 145°, about 110° to about 140°, at least about 100°, at least about 110°, or at least about 120°, including all ranges and subranges therebetween. In an embodiment, the dynamic contact angle, i.e., the contact angle that occurs during the wetting (advancing angle) or dewetting (receding angle) of the surface of the biointerface / bioactive release membrane, has an advancing contact angle of about 100° to about 150°. In another embodiment, the dynamic contact angle, i.e., the contact angle that occurs during the wetting (advancing angle) or dewetting (receding angle) of the surface of the biointerface / bioactive release membrane, has an advancing contact angle of about 105° to about 130°, or 110° to about 120°, including all ranges and subranges therebetween. In yet another embodiment, the dynamic contact angle, i.e., the contact angle that occurs during the wetting (advancing angle) or dewetting (receding angle) of the surface of the biointerface / bioactive release membrane, has a receding contact angle of about 40° to about 80°. In another embodiment, the dynamic contact angle, i.e., the contact angle that occurs during the wetting (advancing angle) or dewetting (receding angle) of the surface of the biointerface / bioactive release membrane, has a receding contact angle of about 45° to about 75°. In yet another embodiment, the dynamic contact angle, i.e., the contact angle that occurs during the wetting (advancing angle) or dewetting (receding angle) of the surface of the biointerface / bioactive release membrane, has a receding contact angle of about 50° to about 70°. In some examples, dynamic contact angle measurements and surface roughness measurements (correlated to contact angle hysteresis, which arises from surface chemical and topographical heterogeneity, solution impurities absorbed onto the surface, or surface swelling, rearrangement, or modification by solvents) on the bioactive releasing film after placement on the analyte sensor and after sterilization can be performed using a Sigma 701 force tensiometer and performing one or more of advancing contact angle measurements, receding contact angle measurements, hysteresis measurements, and combinations thereof. The force tensiometer measures the mass that impacts the balance and calculates and automatically subtracts the effects of buoyancy and the weight of the probe so that the only remaining force measured by the balance is the wetting force.

[0398] In an embodiment, the bioactive release membrane 70 has a hard segment weight percent content of about 20%-60%, 30%-50%, or 35%-45% to achieve a hardness of 70A-55D durometer. In another embodiment, the bioactive release membrane 70 has a hard segment weight percent content of about 20%-60%, 30%-50%, or 35%-45% to achieve a target modulus. In one embodiment, the durometer and / or modulus of the bioactive release membrane 70 is provided by a single copolymer or blend of copolymers.

[0399] In one embodiment, the bioactive release membrane 70 comprises a soft segment-hard segment copolymer comprising less than 70 weight percent, including but not including zero weight percent, of a soft segment. In one embodiment, the release 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, including but not including zero weight percent, of a soft segment.

[0400] In one embodiment, the bioactive release membrane comprises a soft segment-hard segment copolymer comprising a weight percent of hydrophilic segment greater than its weight percent of hydrophobic segment, hi an embodiment, the release membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a soft segment-hard segment with a weight percent of hydrophilic segment greater than its weight percent of hydrophobic segment.

[0401] In one embodiment, the weight percent of the hydrophilic segments of a soft segment-hard segment copolymer is less than the weight percent of its hydrophobic segments. In one embodiment, the weight percent of the hydrophilic segments of a soft segment-hard segment polyurethane or polyurethane urea copolymer is less than the weight percent of its hydrophobic segments.

[0402] In one embodiment, the bioactive release membrane comprises a soft segment-hard segment copolymer that is a blend of different soft segment-hard segment copolymers.In one embodiment, the bioactive release membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer that is a blend of different soft segment-hard segment copolymers.

[0403] In one embodiment, the bioactive release membrane comprises a blend of different soft segment-hard segment copolymers, where a first soft segment-hard segment copolymer comprising no more than zero weight percent of a hydrophilic segment and zero weight percent of a hydrophobic segment is blended with another second soft segment-hard segment copolymer comprising a weight percent of a hydrophilic segment greater than the weight percent of the hydrophobic segment. In one embodiment, the bioactive release membrane comprises a blend of different soft segment-hard segment polyurethane or polyurethane urea copolymers, where a first soft segment-hard segment copolymer comprising no more than zero weight percent of a hydrophilic segment and zero weight percent of a hydrophobic segment is blended with another soft segment-hard segment polyurethane or polyurethane urea copolymer with a weight percent of a hydrophilic segment greater than the weight percent of the hydrophobic segment.

[0404] In one embodiment, the bioactive release membrane comprises a soft segment-hard segment copolymer comprising no more than zero weight percent of a hydrophilic segment and zero weight percent of a hydrophobic segment blended with another soft segment-hard segment copolymer comprising a weight percent of a hydrophilic segment less than the weight percent of a hydrophobic segment.In one embodiment, the bioactive release membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising no more than zero weight percent of a hydrophilic segment and zero weight percent of a hydrophobic segment blended with another soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a weight percent of a hydrophilic segment less than the weight percent of a hydrophobic segment.

[0405] In one embodiment, the bioactive release membrane comprises a soft segment-hard segment copolymer and a soft segment-hard segment copolymer, each comprising less than 70 weight percent and including zero weight percent of a soft segment, each comprising less than zero weight percent of a hydrophilic segment and zero weight percent of a hydrophobic segment. In one embodiment, the bioactive release membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer and another different soft segment-hard segment polyurethane or polyurethane urea copolymer, each comprising less than 70 weight percent and including zero weight percent of a soft segment, each comprising less than zero weight percent of a hydrophilic segment and zero weight percent of a hydrophobic segment.

[0406] In one embodiment, the bioactive release membrane comprises a soft segment-hard segment copolymer blended with a hydrophobic and / or hydrophilic polymer.In one embodiment, the bioactive release membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer blended with a hydrophobic and / or hydrophilic polymer.

[0407] In one embodiment, the bioactive emitting film 70 is substantially impermeable to analyte transport therethrough. In another embodiment, the bioactive emitting film 70 is less permeable to analytes than the interference film 44 of the sensing membrane 32. In such an embodiment, the bioactive emitting film 70 is deposited on a portion of the sensor adjacent to, but not covering, the electrochemically active portion of the sensor.

[0408] In one embodiment, the bioactive emitting film 70 is doped with a bioactive agent prior to deposition on the sensor 34 and / or sensor film 32. In one embodiment, the bioactive agent is dissolved in one or more solvents that are miscible with the bioactive emitting film 70. Mild heating can be used to facilitate dissolution, distribution, or dispersion of the bioactive agent in the bioactive emitting film 70. Suitable solvents include THF, alcohols, ketones, ethers, acetates, NMP, methylene chloride, heptane, hexane, and combinations thereof.

[0409] In one embodiment, the bioactive emitting film 70 is deposited over at least a portion of the sensing film 32. In another embodiment, the bioactive emitting film 70 is deposited adjacent to, but not directly on, the sensing film 32. In an embodiment, the bioactive emitting film is deposited to provide a film thickness of about 0.05 microns or more to about 50 microns or less, including all ranges and subranges therebetween. In another embodiment, the bioactive release film is deposited to provide a film thickness of about 0.5-50 microns, 1-50 microns, 2-50 microns, 3-50 microns, 4-50 microns, 5-50 microns, 6-50 microns, 7-50 microns, 8-50 microns, 9-50 microns, 10-50 microns, 10-40 microns, 10-30 microns, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 microns, including all ranges and subranges therebetween.

[0410] In embodiments, the bioactive release film 70 is deposited on the enzyme domain by spray coating, brush coating, pad printing, or dip coating. In certain embodiments, the bioactive release film 70 is deposited using spray coating and / or dip coating. In embodiments, the bioactive release film 70 is deposited on the sensing membrane 32 by pad printing a mixture of about 1% to about 80% by weight of the polymer / drug combination and about 20% to about 99% by weight of solvent, including all ranges and subranges therebetween.

[0411] In contacting the solvent-containing solution of bioactive release membrane 72 onto the sensing membrane, it is desirable to reduce or substantially reduce any contact of any solvent in the pad printing mixture with the enzyme that may inactivate the enzyme underlying the enzyme domain. Tetrahydrofuran (THF) is one solvent that, alone or in combination with one or more alcohols, has minimal or negligible effect on the enzyme in the enzyme domain when sprayed. Other solvents may also be suitable for use, as will be appreciated by those skilled in the art.

[0412] In an embodiment, the bioactive release film 70 is deposited on the sensing membrane 32 by spray coating a solution of about 1% to about 50% by weight polymer and about 50% to about 99% by weight solvent, including all ranges and subranges therebetween. In spraying the solution of the bioactive release film 72 containing the solvent onto the sensing membrane, it is desirable to reduce or substantially reduce any contact with the enzyme of any solvent in the spray solution that may inactivate the enzyme underlying the enzyme domain. Tetrahydrofuran (THF) is one solvent that, alone or in combination with one or more alcohols, has minimal or negligible effect on the enzyme of the enzyme domain when sprayed. Other solvents may also be suitable for use, as will be appreciated by those skilled in the art.

[0413] Bioactive Release Film / Layer Composition - Bioactive Agent Release Profile The present disclosure provides for providing controlled release or release profiles of bioactive agents from bioactive release films. As examples, exemplary bioactive agent / bioactive release film systems, such as dexamethasone and / or dexamethasone acetate / soft segment-hard segment polyurethaneurea copolymers or blends, are used, although other combinations of bioactive agents and bioactive release films are envisioned.

[0414] Referring to Figure 5A, an exemplary in vitro bioactive release profile for dexamethasone acetate is shown using an exemplary bioactive release membrane 70. The percent cumulative release of dexamethasone acetate can be determined using HPLC, for example, using a Phenomenex Kinetex 5μ EVO C18 100 Å, 50×3.0 mm column held at 25° C. with a 254 nm UV detector and an elution gradient of A: water with 0.1% formic acid / B: acetonitrile with 0.1% formic acid (vol / vol), where the gradient from time 0 to 2 minutes is 90% A / 10% B, the gradient from 2 to 5 minutes is 10% A / 90% B, and the gradient from 5 minutes is 90% A / 10% B. Dexamethasone acetate and dexamethasone HPLC standards are prepared at concentrations of about 0.1 to 20 ug / mL.

[0415] FIG. 5A shows the correlation between in vitro 77 release and in vivo 79 release of dexamethasone acetate in a bioactive release membrane 70 of the present disclosure over a 15 day period, demonstrating the feasibility of the in vitro data to approximate the in vivo data of the system of the present disclosure.

[0416] Referring to FIG. 5B, experimental data is shown in which the release rate of the bioactive agent (dexamethasone acetate) from the bioactive-releasing film 70 during an initial or first time period is greater than the release rate of the bioactive agent from the bioactive-releasing film during an initial or second time period, and the release rate of the bioactive agent from the bioactive-releasing film during an initial or second time period is greater than the release rate of the bioactive agent from the bioactive-releasing film during an initial or third time period.

[0417] Thus, Figure 5B shows the exemplary in vitro bioactivity release profile of Figure 5A, with a first release rate shown corresponding to a time period (e.g., bolus) associated with sensor insertion and extending over approximately 2 days or more, followed by a second release rate shown corresponding to a second time period associated with a time period (within the therapeutic range, or "sustained therapeutic amount") extending over 15 days or more, e.g., beginning approximately 2 days after sensor insertion. Sub-therapeutic, e.g., non-therapeutic, release continues until the end of the sensor's life for a time period of approximately 18 days or more after sensor insertion (data not shown). As can be seen from the graphical data of Figure 5B, the first release rate corresponds to a bolus release of approximately 50% of the initial load of dexamethasone acetate over approximately 2 days, followed by a second release rate corresponding to a release of approximately 40% of the initial load of dexamethasone acetate over approximately 13 days. This is followed by a third release rate corresponding to the release of the remaining amount of dexamethasone acetate (approximately 10%) over a period of 16 to 35 days.

[0418] Thus, for example, if a therapeutically effective amount or greater release per day is targeted, with an initial loading of 50 μg-100 μg dexamethasone acetate (DexAc) per sensor, the bioactive release membrane 70 of the present disclosure can provide a bolus therapeutic release of an amount of DexAc immediately after insertion (approximately 3-20 μg / sensor / day, 4-18 μg / sensor / day, 5-16 μg / sensor / day, 6-14 μg / sensor / day), followed by an extended therapeutic release of an amount of DexAc for a period thereafter (approximately 0.5-10 μg / sensor / day, 0.6-9 μg / sensor / day, 0.4-7 μg / sensor / day, 0.5-8 μg / sensor / day), followed by an extended non-therapeutic release of an amount of DexAc (approximately less than 0.5 μg / sensor / day) until the end of the sensor's life.

[0419] Referring to Figure 5C, initial and sustained bioactive release rates using different bioactive release membranes are presented. As shown, examples of polyurethane polymer membranes having various amounts of polysiloxane component in the soft segment ranging from about 10% to about 40% by weight, with each example having 40-55% by weight of hard segment, demonstrated unique release rates of dexamethasone acetate over an initial 10-48 hour period, as well as different total release amounts over extended periods of up to 15 days, as summarized below: Sample 120 - 10% by weight polysiloxane: 50% by weight hard segment Sample 121 - 22 - 25% by weight polysiloxane: 50% by weight hard segment Sample 122 - 25% by weight polysiloxane: 50% by weight hard segment Sample 123 - 25% by weight polysiloxane: 50% by weight hard segment Sample 124 - 25% by weight polysiloxane: 50% by weight hard segment Sample 125 - 25% by weight polysiloxane: 50% by weight hard segment Sample 126 - 25% by weight polysiloxane: 50% by weight hard segment Sample 127 - 25% by weight polysiloxane: 50% by weight hard segment Sample 128 - 25% by weight polysiloxane: 50% by weight hard segment Sample 129 - 25% by weight polysiloxane: 50% by weight hard segment Sample 23 - 25% by weight polysiloxane: 50% by weight hard segment Sample 24 - 25% by weight polysiloxane: 50% by weight hard segment Sample 25 - 25% by weight polysiloxane: 50% by weight hard segment Sample 26 - 25% by weight polysiloxane: 50% by weight hard segment Sample 27 - 25% by weight polysiloxane: 50% by weight hard segment Sample 28 - 25% by weight Amount % polysiloxane: 55 wt% hard segment, sample 122-25 wt% polysiloxane: 50 wt% hard segment, sample 123-27 wt% polysiloxane: 45 wt% hard segment, sample 124-30 wt% polysiloxane: 40 wt% hard segment, sample 125-30 wt% polysiloxane: 45 wt% hard segment, sample 126-30 wt% polysiloxane: 50 wt% hard segment, sample 127-40 wt% polysiloxane: 40 wt% hard segment. For example, the 10 wt% polysiloxane-containing film provided a rapid initial release rate and a sustained high total release rate, in contrast to the 35 wt% polysiloxane-containing film, which provided a more linear release rate and a sustained low total release rate. The data in Figure 5C further demonstrates the effect of the hard segment weight percentage in combination with the polysiloxane-containing film to tailor the bioactive release rate to the initial and sustained release time. Thus, a desired or targeted bioactive release profile commensurate with a bioactive treatment regimen can be obtained by modifying the chemical makeup of the bioactive release film 70 .

[0420] With reference to FIG. 6A, the effect of the chemistry of the bioactive releasing film 70 on the bioactive release correlates with the water uptake of the film. In one embodiment, at least a portion of the bioactive releasing film 70 (e.g., the hard segment) has a Hildebrand solubility parameter that is closer to the releasable bioactive agent than another portion of the bioactive releasing film (e.g., the soft segment). For example, the bioactive releasing film 70 can include a hydrophobic soft segment, at least one hydrophilic soft segment, and a hard segment that includes a urethane group, a urea group, or a combination of urethane and urea groups, where the hard segment has a Hildebrand solubility parameter that is closer to the releasable bioactive agent than either of the soft segment portions. FIG. 6A shows various samples of bioactive releasing film 70 with different hard segment portions (and different weight % ranges) and hydrophobic and hydrophilic soft segment portions with various weight % ranges. Thus, samples 130, 136 and 137, which comprise a polyurethane block polymer having 40% to 60% by weight of a hard segment (e.g., cyclic isophorone diisocyanate (IPDI)), 10% to 30% by weight of a hydrophobic soft segment portion (e.g., polysiloxane), and 20% to 50% by weight of a hydrophilic soft segment portion (e.g., polyalkyl ether), displayed desirable release rates for a selected bioactive (e.g., dexamethasone acetate). In contrast, samples 131, 132, 133, 134 and 135, which comprise polyurethane block polymers having 40% to 60% by weight of hard segment (e.g., linear 1,6-hexamethylene diisocyanate (HDI)), 10% to 30% by weight of hydrophobic soft segment portion (e.g., polysiloxane) and 0% to 50% by weight of hydrophilic soft segment portion (e.g., polyalkyl ether), displayed rapid release for selected bioactives (e.g., dexamethasone acetate). This data demonstrates that the water uptake of the bioactive release layer, e.g., the correlation of the hard segment solubility, which is similar to the releasable bioactive, with the water uptake of the bioactive can be used to tailor the release rate / profile of the bioactive.

[0421] In an embodiment, the chemistry of the bioactive release membrane 70 includes a soft segment and a hard segment, the hard segment including a urethane group, a urea group, or a combination of a urethane group and a urea group. The soft segment is two or more different polymer segments. The soft segment includes a hydrophobic block and a hydrophilic block. The soft segment includes a polysiloxane, a polyalkyl ether, a polyalkyl ester, a polyalkyl carbonate, a polycarbonate, or a polysiloxane-polyalkyl ether segmented block.

[0422] In an embodiment, the chemistry of bioactive release film 70 further includes a chain extender. The chain extender includes a diol, a diamine, a silicon hydride, or a multifunctional epoxide.

[0423] In an embodiment, the chemistry of bioactive release membrane 70 is a polyurethaneurea.

[0424] In an embodiment, the chemistry of the bioactive release film 70 includes, based on the total weight of the bioactive release film, about 10% to 30% by weight polysiloxane and about 10% to 30% by weight polyalkyl ether, 40% to 60% by weight hard segments comprising urethane groups, urea groups, or a combination of urethane and urea groups, and any remaining weight percent is a chain extender.

[0425] In an embodiment, the chemistry of bioactive release film 70 includes about 20% to 30% by weight polysiloxane, about 20% to 30% by weight polyalkyl ether, and about 40% to 60% by weight hard segment, based on the total weight of the bioactive release film, with any remaining weight percentage being chain extender.

[0426] In an embodiment, the chemistry of bioactive release film 70 includes a soft segment comprising about 10%-30% by weight polysiloxane, about 10%-30% by weight polyalkyl ether, and about 0%-10% by weight chain extender, based on the total weight of the bioactive release film.

[0427] In the examples, the polyalkyl ethers are represented by repeating units of formula (I): -(R5-O)-, where R5 is a straight or branched chain alkyl group having from 2 to 6 carbon atoms.

[0428] 6B, a study in living host study sensitivity data is presented comparing an exemplary experimental sensor 82 comprising a bioactive releasing membrane 70 of the present disclosure having an effective amount of dexamethasone acetate (DexAc) (e.g., approximately 40-50 weight percent loading: bioactive releasing membrane) over a 15 day period to a control sensor 84 having a membrane 70 without DexAc. As shown, the experimental sensor 82 provided consistent normalized sensitivity sustainability over a 15 day period after insertion, while the control sensor 84 exhibited a decrease in normalized sensitivity approximately 10 days after insertion.

[0429] 6C, a study in living host study sensitivity data is presented comparing an exemplary experimental sensor 83 comprising a bioactive releasing membrane 70 of the present disclosure having an effective amount of dexamethasone acetate (DexAc) (e.g., approximately 40-50 weight percent loading: bioactive releasing membrane) over a 30 day period to a control sensor 85 without DexAc. As shown, the experimental sensor 83 provided improved normalized sensitivity sustainability of greater than 60% over a 30 day period after insertion, while the control sensor 84 exhibited a decrease in normalized sensitivity below 60% approximately 20 days after insertion.

[0430] In some embodiments, the loss of sensitivity may indicate end of life. Sensitivity loss may occur toward the end of the sensor's life due to physiological wound healing and foreign body mechanisms surrounding the sensor, or other mechanisms including reference electrode capacitance, enzyme depletion, membrane changes, etc.

[0431] In some embodiments, sensor sensitivity may be calculated using analysis of uncalibrated sensor data (e.g., raw or filtered). In an example, if a slow moving average or median of raw counts begins to show a negative trend, the sensor may be losing sensitivity. Sensitivity loss may be calculated by calculating the short-term (e.g., about 6-8 hours) average (or median) of the sensor output and normalizing it by the expected long-term (48 hours) average sensor sensitivity. If the ratio of short-term sensitivity to long-term sensitivity is less than 70%, the sensor may be at risk of losing sensitivity. Sensitivity loss may be converted to an end-of-life risk factor value, e.g., with a value of about 1 until the ratio is about 70%, reducing to 0.5 at 50% and <0.1 at 25%.

[0432] In some embodiments, the sensor sensitivity may be calculated by comparing the sensor data (e.g., calibrated sensor data) to a reference blood glucose. For example, a calibration algorithm adjusts the glucose estimate based on a systematic bias between the sensor and the reference blood glucose. An end-of-life algorithm may use this bias, called calibration error or downward drift, to quantify or qualify end-of-life symptoms. The calibration error may be normalized to account for irregular calibration times and may be smoothed (e.g., moving average or exponential smoothing) to give more weight to recent data. In some embodiments, an end-of-life risk factor value is determined based on the smoothed error obtained at calibration. In such an embodiment, the end-of-life risk factor value is 1 for all values ​​of error at calibration > -0.3, reduces to 0.5 for errors at calibration = -0.4, and reduces to < 0.1 for errors at calibration = -0.6. In some examples, one or more of the downward drift of sensor sensitivity over time, the amount of asymmetric non-stationary noise, and the duration of noise may be used, for example, as disclosed in commonly owned U.S. Patent Application Publication No. 2021 / 0209497, which is incorporated by reference herein.

[0433] In some embodiments, sensor sensitivity may be calculated using analysis of uncalibrated sensor data (e.g., raw or filtered). In an example, if a slow moving average or median of raw counts begins to show a negative trend, the sensor may be losing sensitivity. Loss of sensitivity may be calculated by calculating the short-term (e.g., about 6-8 hours) average (or median) of the sensor output and normalizing it by the expected long-term (48 hours) average sensor sensitivity. If the ratio of short-term sensitivity to long-term sensitivity is less than 70%, the sensor may be at risk of losing sensitivity. Loss of sensitivity may be converted to an end-of-life risk factor value that has a value of about 1 until the ratio is about 70%, reducing to 0.5% at 50% and <0.1 at 25%.

[0434] 6C, a survival plot of a continuous analyte sensor 90 (with bioactive emitting membrane 70) versus a control 91 (no membrane) and a sensor 92 (with membrane but no bioactivity present) is shown. As shown, the sensor with the bioactive emitting membrane 70 outperforms the control and the sensor with only a membrane for at least five days, with less than 80% sensitivity indicating significant end of life (EOL).

[0435] With reference to the survival plots in Figure 6D, improvements to sensitivity retention were demonstrated by adjusting modifications to the bioactive release membrane chemistry, e.g., weight percent of the hard segment, soft segment, weight percent of the hydrophobic portion of the soft segment, etc., to vary the release rate of bioactivity from the bioactive release membrane 70, generally characterized as fast, medium, or slow release of bioactivity, including any bolus release or absence of bolus release. Thus, Figure 6D shows a slow release rate membrane 93 of bioactivity (exemplified by dexamethasone acetate) with less than 80% sensitivity retention after 14 days, a control 94 (without membrane) with less than 80% sensitivity retention after 18 days, a medium release rate membrane 95 with less than 80% sensitivity retention after 19 days, and a fast release rate membrane 96 with less than 80% sensitivity retention after 20 days.

[0436] 7A, a study in living hosts of mean absolute noise data is presented comparing an exemplary experimental sensor 86 comprising a bioactive release membrane 70 of the present disclosure having an effective amount of dexamethasone acetate (DexAc) (e.g., approximately 40-50 weight percent loading: bioactive release membrane) over a 22 day period with a control sensor 84 without DexAc, and a comparative sensor 87 having a bioactive release membrane 70 without dexamethasone acetate. As shown, the experimental sensor 86 provided relatively consistent mean absolute noise sustainability over the 22 day period after insertion, while the control sensor 88 and the comparative sensor 87 showed an increase in mean absolute noise approximately 8-10 days after insertion. This data illustrates the ability of the combination of the bioactive release membrane and bioactive agent of the present disclosure to minimize noise increases in implantable sensors over extended periods of time.

[0437] 7B, a survival plot is presented for a continuous analyte sensor 90 (with bioactive emitting membrane 70) versus a control 91 (no membrane) and a sensor 92 (with membrane but no bioactivity). As shown, the sensor with bioactive emitting membrane 70 outperforms the control and the sensor with membrane only for at least 10 days, with less than 80% noise indicating significant end of life (EOL).

[0438] With reference to the survival plots in Figure 7C, improvements in minimizing noise increase were demonstrated by adjusting modifications to the bioactive release film chemistry, such as the weight percent of the hard segment, the soft segment, the weight percent of the hydrophobic portion of the soft segment, etc., to vary the release rate of bioactivity from the bioactive release film 70, generally characterized as fast, medium, or slow release of bioactivity, including any bolus release or absence of bolus release, as previously described in Figure 6D. Thus, Figure 7C shows a slow release rate film 93 of bioactivity (exemplified by dexamethasone acetate) with a noise increase of over 80% after 5 days, a control 94 (without film) with a noise increase of over 80% after 4 days, a medium release rate film 95 with a noise increase of over 80% after 8 days, and a fast release rate film 96 with a noise increase of over 80% after 8 days. This data illustrates the ability of the bioactive release film and bioactive agent combination of the present disclosure to minimize noise increase in an implantable sensor over an extended period of time relative to a control or non-bioactive film.

[0439] Additional experiments were performed using dexamethasone salts in different bioactive release membrane combinations. For example, dexamethasone sodium phosphate in a water-soluble cellulose-based polymer provided a bolus release profile. Dexamethasone phosphate incorporated into a biointerface polymer membrane as disclosed herein provided a sustained release of about 2 days. Dexamethasone acetate in a hard-soft segmented polyurethaneurea copolymer with zero weight percent hydrophobic soft segment provided a sustained release of about 5 days. Dexamethasone acetate in a hard-soft segmented polyurethaneurea copolymer with approximately equal weight percentages of hydrophobic / hydrophilic segments provided a sustained release of approximately 15 days. Dexamethasone acetate in a hard-soft segmented polyurethaneurea copolymer with a weight percentage of hydrophobic soft segment greater than the weight percentage of hydrophilic soft segment provided a slow sustained release of more than 15 days. Dexamethasone acetate in a cellulose polymer provided a slow sustained (continuous or semi-continuous) release of more than 15 days. Using combinations of the aforementioned bioactive releasing films, the release rate and / or release profile of the bioactive agent can be tailored specifically to a particular sensor and its intended end-of-life, while providing sustained sensitivity and low noise performance.

[0440] This data illustrates the ability of the disclosed bioactive-releasing film / bioactive agent combination to minimize decay / reduction in sensitivity of implantable sensors over extended periods of time. The disclosed bioactive-releasing film / bioactive agent combination may be configured for other sensor platforms besides electrochemical-based sensor systems, such as optical-based sensor systems, as well as other medical devices intended for long-term implantation that subsequently need to be removed from a subject.

[0441] As shown in Figure 3H, the continuous analyte sensing device 100 includes an analyte sensor having an insertable portion 102 operably coupled to a non-insertable portion 104, where the continuous analyte sensing device 100 is configured to deploy the insertable portion 102. The insertable portion 102 has at least one of an insertable surface area and an insertable volume. At least one sensing domain 112 is positioned at least partially about the insertable portion 102 (e.g., the insertable surface area and / or the insertable volume). The insertable portion 102 also includes a bioactive-releasing membrane 70 formed thereon.

[0442] In some embodiments, the insertable portion 102 has a length of about 1 mm to about 20 mm, including all ranges and subranges therebetween. In other embodiments, the insertable portion 102 has a length of about 2 mm to about 14 mm. In further embodiments, the insertable portion 102 has a length of about 4 mm to about 12 mm. For example, the insertable portion 102 has a length of at least any of 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 up to 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.).

[0443] As shown in FIG. 3I, the insertable portion includes a bioactive release membrane 70. In one embodiment, the bioactive release membrane 70 includes at least one polymer layer disposed on a portion of the insertable portion 102 (and thus a portion of the insertable surface area and / or the insertable volume). The bioactive release membrane 70 includes at least one bioactive agent 110 dispersed therein. In one embodiment, the bioactive release membrane 70 is configured to associate with and / or release the at least one bioactive agent 110. The at least one bioactive agent 110 can be configured to be non-releasable from the bioactive release membrane and to modify the tissue response of the subject. The at least one bioactive agent 110 can be configured to be independently non-releasable in some form as well as releasable from the bioactive agent-releasing membrane and to modify the tissue response of the subject.

[0444] At least one polymer layer of bioactive release membrane 70 can include any suitable polymeric material as previously described herein. In an embodiment, at least one polymer layer of bioactive release membrane 70 includes one or more of epoxides, polyolefins, polysiloxanes, polyamides, polystyrenes, polyacrylates, polyethers, polyvinylpyridines, polyvinyl-co-polystyrenes, polyvinyl imidazoles, polyesters, polyalkyl esters, polyalkyl carbonates, polycarbonates, polyurethanes, polyurethane ureas, polyethylene vinyl acetate (EVA), polyvinyl alcohols, and copolymers or blends thereof. In another embodiment, at least one polymer layer of bioactive release membrane 70 includes one or more zwitterionic repeat units associated with at least one bioactive agent, the at least one bioactive agent being configured to be released from the one or more zwitterionic repeat units to modify a tissue response in a subject.

[0445] In one aspect, alone or in combination with any one of the previous aspects, the bioactive release membrane comprises polyethylene oxide segments.

[0446] In one aspect, a...

Claims

1. 1. A device for measuring the concentration of an analyte, comprising: a sensor substrate comprising: a distal end separated from a proximal end; and at least one sensor portion positioned between the distal end and the proximal end, the sensor portion configured to generate a signal associated with the concentration of the analyte; a bioactive-release membrane adjacent to the sensor substrate, the bioactive-release membrane comprising at least one releasable bioactive agent capable of modifying a tissue response in a subject.

2. The device of claim 1 , wherein the distal end has an outer surface and the bioactive-releasing membrane is positioned on the outer surface.

3. The device of claim 1 , wherein the bioactive emitting membrane is positioned only at the distal end.

4. 10. The device of claim 1, wherein the bioactive emissive film is directly adjacent to a resistive film, the bioactive emissive film is directly adjacent to an electrode film, or the bioactive emissive film is directly adjacent to an interference film.

5. The device of claim 1 further comprising a dissolvable coating adjacent to the bioactive releasing membrane.

6. The device of claim 5 , wherein the dissolvable coating further comprises a releasable bioactive agent.

7. 10. The device of claim 1, wherein the at least one releasable bioactive agent is a first releasable bioactive agent and the dissolvable coating further comprises a second releasable bioactive agent, the first releasable bioactive agent being different from the second releasable bioactive agent.

8. 10. The device of claim 1, further comprising a diffusion-regulating membrane adjacent to the bioactive release membrane, the diffusion-regulating membrane being different from the bioactive release membrane.

9. The device of claim 1 , wherein the diffusion-regulating membrane is directly adjacent to the bioactive-releasing membrane.

10. The device of claim 1 , wherein the diffusion-controlling membrane is a block copolymer.

11. The device of claim 1 , wherein the diffusion-controlling membrane is a segmented block copolymer.

12. 10. The device of claim 1, wherein the bioactive release membrane comprises a soft segment and a hard segment, the hard segment comprising urethane groups, urea groups, or a combination of urethane and urea groups.

13. The device of claim 1 , wherein the bioactive release film comprises a multi-component soft segment comprising two or more different polymer segments.

14. 10. The device of claim 1, wherein the multi-component soft segment comprises hydrophobic and hydrophilic blocks of at least one of polysiloxane, polyalkyl carbonate, and polycarbonate in combination with polyalkyl ether, polyalkyl ester.

15. The device of claim 1 , wherein the bioactive release membrane is a polyurethaneurea.

16. 10. The device of claim 1, wherein the bioactive releasing membrane has a water uptake at equilibrium of 1% to 4% by weight.

17. 10. The device of claim 1, wherein the bioactive release film has a water uptake of less than 3% by weight at equilibrium.

18. The device of any one of claims 1 to 17, wherein the bioactive release membrane is an excipient for the at least one releasable bioactive agent.

19. 10. The device of claim 1, wherein the bioactive release membrane comprises a hydrophobic soft segment, at least one hydrophilic soft segment, and a hard segment comprising a urethane group, a urea group, or a combination of urethane and urea groups.

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