CN118019491A

CN118019491A - Bioactive substance releasing membrane for analyte sensor

Info

Publication number: CN118019491A
Application number: CN202280061687.2A
Authority: CN
Inventors: 王尚儿; M·N·阿武拉; C·德林; T·T·李; X·Y·刘; S·R·帕内尔; 邹炯
Original assignee: Dexcom Inc
Current assignee: Dexcom Inc
Priority date: 2021-09-15
Filing date: 2022-09-15
Publication date: 2024-05-10

Abstract

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

Description

Bioactive substance releasing membrane for analyte sensor

Cross Reference to Related Applications

The present application claims priority and benefit from U.S. provisional application number 63/244,644, filed on day 2021, 9, and 15, and the present application claims priority and benefit from U.S. provisional application number 63/318,901, filed on day 2022, 3, and 11, all of which are incorporated herein by reference in their entirety.

Technical Field

The present disclosure relates generally to bioactive substance release or eluting layers or membranes for use with implantable devices, such as devices for detecting analyte concentrations in biological samples. More particularly, the present disclosure relates to novel bioactive substance releasing membranes, devices and implantable devices including these membranes, methods of forming bioactive substance releasing membranes on or around implantable devices, methods of improving and/or extending sensor life, and methods of monitoring one or more analyte levels in a biological fluid sample using an implantable analyte detection device.

Background

One of the most deeply studied analyte sensing devices is an implantable glucose device for detecting glucose levels in a subject suffering from diabetes (host). 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 specific period of time due to local tissue reactions. For example, there are two common types of subcutaneously implantable glucose sensing devices. These types include those of percutaneous implantation and those of total implantation.

Disclosure of Invention

In one aspect, there is provided a device for measuring the concentration of an analyte, the device comprising: a sensor substrate comprising a distal end separate 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 a concentration of an analyte; and a bioactive substance release film adjacent the sensor substrate, the bioactive substance release film comprising at least one releasable bioactive agent capable of altering a tissue response of the subject.

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

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is positioned only at the distal end.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is directly adjacent to the resistant membrane.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is directly adjacent to the interfering membrane.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is directly adjacent to the electrode membrane.

In one aspect, alone or in combination with any of the preceding aspects, the device further comprises a dissolvable coating adjacent the bioactive substance releasing film.

In one aspect, the dissolvable coating further comprises a releasable bioactive agent, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding 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, the first releasable bioactive agent being the same as or different from the second releasable bioactive agent.

In one aspect, alone or in combination with any of the preceding aspects, the dissolvable coating comprises a second releasable bioactive agent in combination with nanoparticles comprising one or more anti-inflammatory agents.

In one aspect, alone or in combination with any of the preceding aspects, the dissolvable coating provides a bolus release of both the second releasable bioactive agent and the nanoparticles.

In one aspect, the dissolvable coating is hydrophilic, alone or in combination with any of the preceding aspects.

In one aspect, the dissolvable coating is capable of diffusing an analyte, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, the device further comprises a diffusion regulating membrane adjacent to the bioactive substance releasing membrane, wherein the diffusion regulating membrane is different from the bioactive substance releasing membrane.

In one aspect, alone or in combination with any of the preceding aspects, the diffusion regulating membrane is directly adjacent to the bioactive substance releasing membrane.

In one aspect, the diffusion regulating membrane is a block copolymer, alone or in combination with any of the preceding aspects.

In one aspect, the diffusion regulating membrane is a segmented block copolymer, alone or in combination with any of the preceding aspects.

In one aspect, the diffusion regulating membrane is a multiblock copolymer, alone or in combination with any of the preceding aspects.

In one aspect, the diffusion regulating membrane is annealed, alone or in combination with any of the preceding aspects.

In one aspect, the annealed diffusion regulating membrane comprises a stable separate phase, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, the stable separate phase provides a diffusion channel for at least one releasable bioactive agent.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane includes a soft segment and a hard segment, the hard segment including urethane groups, urea groups, or a combination of urethane and urea groups.

In one aspect, the soft segment is two or more different polymer segments, alone or in combination with any of the preceding aspects.

In one aspect, the soft segment comprises a hydrophobic block and a hydrophilic block, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film comprises a multicomponent soft segment comprising two or more different polymer segments.

In one aspect, alone or in combination with any of the preceding aspects, the multicomponent soft segment comprises a hydrophobic block and a hydrophilic block of a combination of a polyalkylether, polyalkyl ester and at least one of a polysiloxane, a polyalkylcarbonate, and a polycarbonate.

In one aspect, the soft segment comprises one or more of polysiloxane, polyalkylether, polyalkylester, polyalkylcarbonate, polycarbonate, and polysiloxane-polyalkylether segmented blocks, alone or in combination with any of the preceding aspects, and wherein the hard segment comprises at least one of norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene Diisocyanate (TDI), 1, 3-phenylene diisocyanate (MPDI), trans-1, 3-bis (isocyanatomethyl) cyclohexane (1, 3-H6 XDI), dicyclohexylmethane-4, 4 '-diisocyanate (HMDI), 4' -diphenylmethane diisocyanate (MDI), trans-1, 4-bis (isocyanatomethyl) cyclohexane (1, 4-H6 XDI), 1, 4-cyclohexyl diisocyanate (CHDI), 1, 4-phenylene diisocyanate (PPDI), 3 '-dimethyl-4, 4' -biphenyl diisocyanate (TODI), and 1, 6-Hexamethylene Diisocyanate (HDI).

In one aspect, alone or in combination with any of the preceding aspects, the soft segment comprises a polysiloxane, a polyalkylether, a polyalkylester, a polyalkylcarbonate, a polycarbonate, or a polysiloxane-polyalkylether segmented block.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane further comprises a chain extender.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is a polyurethaneurea.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film comprises about 10 to 30 weight percent polysiloxane and about 10 to 30 weight percent polyalkylether, 40 to 60 weight percent hard segment, and any remaining weight percent is a chain extender, the hard segment comprising urethane groups, urea groups, or a combination of urethane groups and urea groups, based on the total weight of the bioactive substance releasing film.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film comprises about 20 to 30 weight percent polysiloxane, about 20 to 30 weight percent polyalkylether, and about 40 to 60 weight percent hard segment, based on the total weight of the bioactive substance releasing film, and any remaining weight percent is chain extender.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film comprises a soft segment comprising about 10 to 30 weight percent polysiloxane, about 10 to 30 weight percent polyalkylether, and about 0 to 10 weight percent chain extender, based on the total weight of the bioactive substance releasing film.

In one aspect, alone or in combination with any of the preceding aspects, the polyalkyl ether is represented by a repeating unit of formula (I): - (R5-O) -; wherein R5 is a linear or branched alkyl group of 2 to 6 carbons.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film has an equilibrium water absorption of 1 to 4 wt%.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film has an equilibrium water absorption of less than 3% by weight.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is at least one excipient that can release the bioactive agent.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane includes 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 a urethane group and a urea group.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film comprises a hard segment and a soft segment, the hard segment having a Hildebrand solubility parameter that is closer to the at least one releasable bioactive agent than the soft segment.

In one aspect, alone or in combination with any of the preceding aspects, the distal end of the substrate comprises a wire singulation, a planar singulation, or a substantially planar singulation.

In one aspect, alone or in combination with any of the preceding aspects, the apparatus further comprises an electrically insulating end cap adjacent the distal end.

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

In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is impermeable to the electrochemically active material.

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

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

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

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

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

In one aspect, the bioactive substance releasing membrane is spatially separated from the sensing portion.

In one aspect, the bioactive substance releasing membrane active further comprises, alone or in combination with any of the preceding aspects, a non-releasable bioactive agent.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane 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.

In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier.

In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.

In another example, a method of reducing signal noise caused by foreign body reactions in a continuous analyte sensor apparatus is provided, the method comprising: providing a continuous analyte sensing device comprising: a substrate comprising an insertable portion operably coupled to a non-insertable portion, the insertable portion having a distal end; at least one sensing portion positioned proximal to the distal end; at least one bioactive substance releasing membrane disposed on at least a portion of the distal end, the bioactive substance releasing membrane comprising at least one bioactive agent capable of attenuating a foreign body response; and reducing signal noise during use of the continuous analyte sensing device.

In one aspect, the method further comprises releasing or exposing at least one bioactive agent to the tissue.

In one aspect, alone or in combination with any of the preceding aspects, the method further comprises attenuating a foreign body response near the distal end.

In one aspect, alone or in combination with any of the preceding aspects, the analyte is glucose and the signal noise is maintained at less than 4mg/dL for at least 10 days.

In one aspect, alone or in combination with any of the preceding aspects, the analyte is glucose and the signal noise is maintained at less than 4mg/dL for at least 15 days.

In one aspect, alone or in combination with any of the preceding aspects, the analyte is glucose and the signal noise is maintained at less than 4mg/dL for at least 21 days.

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

In one aspect, alone or in combination with any of the preceding aspects, at least one bioactive substance releasing membrane is disposed on a portion of the insertable surface area, the at least one bioactive substance releasing membrane having at least one of a surface area of the bioactive substance releasing membrane that is less than or equal to the insertable surface area.

In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive substance releasing membrane comprises a polymer, and the weight ratio of the polymer to the total amount of the at least one bioactive agent is about 0.1 to about 2.

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

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

In yet another example, a method of reducing the occurrence of sensitivity loss of a continuous analyte sensor apparatus caused by foreign body reaction in tissue during use is provided, the method comprising: providing a continuous analyte sensing device comprising: a substrate comprising an insertable portion having a distal end operably coupled to a non-insertable portion; at least one sensing portion positioned proximal of the distal end and distal of the non-insertable portion; at least one bioactive substance releasing membrane disposed on a portion of the distal end, the at least one bioactive substance releasing membrane comprising at least one bioactive agent capable of attenuating a foreign body response; and reducing the occurrence of sensitivity loss of the continuous analyte sensing device during use.

In one aspect, alone or in combination with any of the preceding aspects, the reduction in the occurrence of sensitivity loss occurs for at least 14 days.

In one aspect, alone or in combination with any of the preceding aspects, the reduction in the occurrence of sensitivity loss occurs for at least 20 days.

In one aspect, alone or in combination with any of the preceding aspects, the reduction in the occurrence of sensitivity loss occurs for at least 30 days.

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

In one aspect, the electrically insulating end cap is different from the bioactive substance releasing membrane, alone or in combination with any of the preceding aspects.

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

In yet another example, there is provided an apparatus for measuring a concentration of an analyte, the apparatus comprising: a sensor portion configured to generate a signal associated with a concentration of an analyte; and a bioactive substance release membrane proximate the sensor portion, the bioactive substance release membrane configured to form a complex with at least one bioactive agent configured to be released from the bioactive substance release membrane to alter a tissue response of the subject.

In one aspect, the complex with the at least one bioactive agent is covalent or non-covalent.

In one aspect, the complex with at least one bioactive agent is ionic, alone or in combination with any of the preceding aspects.

In one aspect, the complex with at least one bioactive agent provides a bioactive agent conjugate, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent is a nitric oxide releasing molecule, polymer, or oligomer.

In one aspect, the nitric oxide releasing molecule is selected from the group consisting of N-diazeniumdiolate and S-nitrosothiols, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent is covalently coupled factor H.

In one aspect, alone or in combination with any of the preceding aspects, the complex is a bioactive agent conjugate including a borate or borate.

In one aspect, alone or in combination with any of the preceding aspects, the complex is a bioactive agent conjugate that includes at least one cleavable linker capable of cleavage by subcutaneous stimulation.

In one aspect, alone or in combination with any of the preceding aspects, the subcutaneous stimulus is a matrix metallopeptidase or protease challenge.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises a hydrophilic hydrogel that is at least partially crosslinked and is capable of dissolving in a biological fluid.

In one aspect, alone or in combination with any of the preceding aspects, the hydrophilic hydrogel comprises hyaluronic acid crosslinked by divinyl sulfone or polyethylene glycol divinyl sulfone.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises silver nanoparticles.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises biodegradable polymer nanoparticles selected from PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphates, or PEO-b-polypeptides containing at least one bioactive agent.

In one aspect, the bioactive substance releasing membrane comprises an organogel carrier and/or an inorganic gel carrier, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, a bioactive substance release membrane configured to form a complex with at least one bioactive agent includes a combination of at least one bioactive agent encapsulated in the bioactive substance release membrane and at least one bioactive agent covalently coupled to the bioactive substance release membrane.

In one aspect, alone or in combination with any of the preceding aspects, a bioactive substance release membrane configured to form a complex with at least one bioactive agent comprises a spatial distal drug reservoir of the at least one bioactive agent.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane configured to form a complex with at least one bioactive agent comprises a hydrolytically degradable biopolymer comprising at least one bioactive agent.

In one aspect, the hydrolytically degradable biopolymer comprises a poly (anhydride salicylate), alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film comprises a polyurethane segment and/or a polyurea segment, the polyurethane segment and/or the polyurea segment being about 15 wt% to about 75 wt%, including all ranges and subranges therebetween, based on the total weight of the bioactive substance releasing film.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film comprises at least one polymer segment selected from the group consisting of epoxides, polyolefins, polysiloxanes, polyamides, polystyrenes, polyacrylates, polyethers, polypyridines, polyesters, polyalkylesters, polyalkylcarbonates, polycarbonates, polyethylene vinyl acetate, polyvinyl alcohol, and copolymers thereof.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises a polyethylene oxide segment.

In one aspect, alone or in combination with any of the preceding aspects, the polyethylene oxide segment is from about 5 wt% to about 60 wt% based on the total weight of the bioactive substance releasing film.

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

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane has a polydispersity index of 1 to about 10, including all ranges and subranges therebetween.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film has a contact angle of about 90 ° to about 160 °, including all ranges and subranges therebetween.

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

In one aspect, the one or more zwitterionic repeat units comprise a betaine compound or derivative thereof.

In one aspect, alone or in combination with any of the preceding aspects, the one or more zwitterionic repeat units comprise a betaine compound or precursor thereof.

In one aspect, alone or in combination with any of the preceding aspects, the one or more zwitterionic repeat units comprise at least one moiety selected from the group consisting of carboxybetaines, sulfobetaines, phosphobetaines, and derivatives thereof.

In one aspect, alone or in combination with any of the preceding aspects, the one or more zwitterionic repeat units are derived from monomers selected from the group consisting of:

Wherein Z is branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; r1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R2, R3 and R4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and wherein one or more of R1, R2, R3, R4 and Z are substituted with a polymeric group.

In one aspect, alone or in combination with any of the preceding aspects, the polymeric group is selected from an alkene, alkyne, epoxide, lactone, amine, hydroxyl, isocyanate, carboxylic acid, anhydride, silane, halide, aldehyde, carbodiimide, or combinations thereof.

In one aspect, the one or more zwitterionic repeat units are at least about 1% by weight, based on the total weight of the bioactive substance releasing membrane, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane further comprises one or more zwitterions selected from the group consisting of: cocoamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, decyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly (carboxybetaine), poly (sulfobetaine) and derivatives thereof.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises a polymer chain having zwitterionic groups at the ends of and along the polymer chain.

In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises a polymer chain having both hydrophilic and hydrophobic regions, and wherein one or more zwitterionic compounds are present at the ends of the polymer chain; the bioactive substance releasing membrane comprises a base polymer selected from the group consisting of polyolefin, polystyrene, polyoxymethylene, polysiloxane, polyether, polyacrylic acid, polymethacrylic acid, polyester, polyalkyl ester, polyalkyl carbonate, polycarbonate, polyamide, polypyridine, poly (ether ketone), poly (ether imide), polyurethane, polyurethaneurea, polyvinyl acetate, polyvinyl alcohol, or copolymers or blends thereof.

In one aspect, alone or in combination with any of the preceding aspects, the base polymer of the bioactive substance releasing membrane has a polydispersity index of about 1 to about 10, including all ranges and subranges therebetween.

In one aspect, alone or in combination with any of the preceding aspects, the base polymer of the bioactive substance releasing membrane has a dynamic contact angle of about 90 ° to about 160 °, including all ranges and subranges therebetween.

Drawings

FIG. 1A is a cross-sectional view of an illustrative example of a continuous analyte sensing device.

FIG. 1B is a cross-sectional view of an illustrative example of a continuous analyte sensing device.

FIG. 2A is a perspective view of an exemplary continuous analyte sensing device as disclosed and described herein.

FIG. 2B is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along section line B-B of FIG. 2A.

FIG. 2C is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along section line B-B of FIG. 2A, showing an exemplary bioactive substance releasing layer.

FIG. 2D is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along line D-D of FIG. 2A, illustrating an exemplary bioactive substance releasing membrane as disclosed and described herein.

FIG. 2E is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along line D-D of FIG. 2A, illustrating another exemplary bioactive substance releasing membrane as disclosed and described herein.

Fig. 2F is a perspective schematic diagram illustrating an in vivo portion of an exemplary continuous analyte sensing device as disclosed and described herein.

Fig. 2G is a side view schematic diagram showing the in-vivo portion of the exemplary sensor of fig. 2F as disclosed and described herein.

FIG. 2H is a cross-sectional plan view of a continuous analyte sensing device in one example as disclosed and described herein.

FIG. 2I is a cross-sectional view of a continuous analyte sensing device in one example as disclosed and described herein.

FIG. 2J is a cross-sectional view of a continuous analyte sensing device in one example as disclosed and described herein.

Fig. 3A is a schematic side view of a transdermal continuous analyte sensing device in one example as disclosed and described herein.

Fig. 3B is a schematic side view of a transdermal continuous analyte sensing device in an alternative example as disclosed and described herein.

FIG. 3C is a schematic side view of an implantable portion of an implantable continuous analyte sensing device in one example.

Fig. 3D is a schematic side view of an implantable portion of an implantable analyte sensor in an alternative example.

FIG. 3E is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.

Fig. 3F is a side view of one example of a continuous analyte sensing device electrically coupled to an electronics unit within a functionally useful distance on the skin of a recipient.

Fig. 3G is a side view of one example of an implantable portion of a continuous analyte sensing device electrically coupled to an electronics unit implanted in recipient tissue at a functionally useful distance.

FIG. 3H is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.

FIG. 3I is a cross-sectional view of an implantable portion of a continuous analyte sensing device in another alternative example.

FIG. 3J is a cross-sectional view of an implantable portion of a continuous analyte sensing device in another alternative example.

FIG. 3K is a schematic side view of an implantable portion of the continuous analyte sensing device.

FIG. 3L is a schematic side view of an implantable portion of a continuous analyte sensing device in an alternative example.

FIG. 3M is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.

FIG. 3N is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.

FIG. 3O is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.

Fig. 3P is a graphical representation of in vivo release of a bioactive agent from a bioactive substance release film over time as disclosed and described herein.

Fig. 3Q is a graphical representation of in vivo release of a bioactive agent from a bioactive substance release film over time as disclosed and described herein.

Fig. 4A is a schematic diagram of a hard segment-soft segment polymer as disclosed and described herein.

Fig. 4B is a cross-sectional view through an exemplary membrane indicating a 3-D volume 4C.

Fig. 4C is a schematic side view of the 3-D volume 4C of fig. 4B.

Fig. 5A is a graphical representation of the cumulative release rate of a bioactive agent from a bioactive substance release film over time as disclosed and described herein.

Fig. 5B is a graphical representation of the cumulative release rate of a bioactive agent from a bioactive substance release film over time as disclosed and described herein.

Fig. 5C is a graphical representation of the cumulative release rate of a bioactive agent from different bioactive substance release films over time as disclosed and described herein.

Fig. 6A is a graphical representation of the release of bioactive agents from different bioactive substance releasing membranes as disclosed and described herein relative to their water absorption rate.

Fig. 6B is a graphical representation of normalized sensitivity of the sensor with and without a bioactive substance releasing membrane over 18 days as disclosed and described herein.

Fig. 6C is a graphical representation of normalized sensitivity of a sensor with and without a bioactive substance releasing membrane over 30 days as disclosed and described herein.

Fig. 6D is a survival graph representation of normalized sensitivity of a sensor with and without a bioactive substance releasing membrane as disclosed and described herein.

Fig. 6E is a survival graph representation of normalized sensitivity of a sensor with different bioactive substance releasing membranes as disclosed and described herein.

Fig. 7A is a graphical representation of average absolute noise over time from a sensor having a bioactive substance releasing membrane as disclosed and described herein.

Fig. 7B is a survival graph representation of average absolute noise of a sensor with and without a bioactive substance releasing membrane as disclosed and described herein.

Fig. 7C is a survival graph representation of average absolute noise for sensors with different bioactive substance releasing membranes as disclosed and described herein.

Fig. 8A is a tissue imaging image of a foreign body response from a sensor without a bioactive substance releasing membrane.

Fig. 8B is a tissue imaging image of a foreign body response from a sensor with a bioactive substance releasing membrane as disclosed and described herein.

Detailed Description

The following description and examples illustrate preferred examples of the present disclosure in detail. Those skilled in the art will recognize that the scope of the present disclosure encompasses many variations and modifications of the present disclosure. Accordingly, the description of the examples should not be taken as limiting the scope of the disclosure.

Definition of the definition

To facilitate an understanding of the disclosed examples, a number of terms are defined below.

The term "about" as used herein is a broad term and will give one of ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a degree of variability of a permitted value or range, e.g., within 10%, within 5% or within 1% of the value or range limit, and includes the exact 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" may mean free of or having trace amounts such that the amount of material present does not affect the material properties of a composition comprising the material such that the material comprises from about 0 wt% to about 5 wt% or from about 0 wt% to about 1 wt% or about 5 wt% or less than or equal to about 4.5 wt%, 4 wt%, 3.5 wt%, 3 wt%, 2.5 wt%, 2 wt%, 1.5 wt%, 1 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt%, 0.1 wt%, 0.01 wt% or about 0.001 wt% or less or about 0 wt% of the composition.

As used herein, the terms "adhering" and "adhering" are broad terms and will give one of ordinary and customary meaning to them (and are not limited to special or customized meanings) and refer to, but are not limited to, holding, bonding or adhering, such as by adhesive, bonding, gripping, interpenetration or fusion.

As used herein, the term "analyte" is a broad term and will give the person of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a substance or chemical component that can be analyzed in a biological fluid (e.g., blood, interstitial fluid, cerebral spinal fluid, lymph fluid, urine, sweat, saliva, etc.). Analytes may include naturally occurring substances, artificial substances, metabolites and/or reaction products. In some examples, the analyte measured by the sensing region, the sensing device, and the sensing method is glucose. However, other analytes are also contemplated, including but not limited to, carboxyprothrombin; acyl carnitines; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha fetoprotein; amino acid profile (arginine (krebs cycle), histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, tryptophan); androstenedione; antipyrine; an enantiomer of arabitol; arginase; benzoyl ecgonine (cocaine); bilirubin, biotin enzyme; biopterin; c-reactive protein; carnitine; a carnosine enzyme; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-beta hydroxy-cholic acid; cortisol; creatine; creatine kinase; creatine kinase MM isozymes; creatinine; cyclosporin a; d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylase polymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis, dunaliella/Beck muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-bystander, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, leibbean hereditary optic neuropathy, MCAD, RNA, PKU, plasmodium vivax, 21-deoxycortisol); debutyl halofanning; dihydropteridine reductase; diphtheria/tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acid/acyl glycine; free beta-human chorionic gonadotrophin; free erythrocyte porphyrin; free thyroxine (FT 4); free triiodothyronine (FT 3); fumarylacetoacetate; galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione peroxidase; glycerol; glycocholic acid; glycosylated hemoglobin; a halofanning group; a hemoglobin variant; hexosaminidase a; human erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; beta-hydroxybutyrate; a ketone; lactate; lead; lipoproteins ((a), B/A-1, beta); lysozyme; mefloquine; netilmicin; oxygen; phenobarbital; phenytoin; phytanic acid/pristanic acid; potassium, sodium, and/or other blood electrolytes; progesterone; prolactin; a proline enzyme; purine nucleoside phosphorylase; quinine; reverse triiodothyronine (rT 3); selenium; serum pancreatic lipase; sisomicin; growth regulator C; specific antibodies (adenovirus, antinuclear antibody, anti-zeta antibody, arbovirus, ojernsidisease virus, dengue virus, mic, echinococcosis granulosa, amebiasis, enterovirus, giardia, helicobacter pylori, hepatitis b virus, herpes virus, HIV-1, igE (atopic disease), influenza virus, leishmania donovani, leptospira, measles/mumps/rubella, mycobacterium leprae, mycoplasma pneumoniae, myoglobin, filarial, parainfluenza virus, plasmodium falciparum, poliovirus, pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (tsiosis), schistosoma, toxoplasma gondii, pallidum, trypanosoma cruzi/blue trypanosoma, vesicular stomatitis virus, banjo's nematodes, yellow fever virus); specific antigen (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uric acid; uroporphyrinogen I synthase; vitamin A; white blood cells; zinc protoporphyrin. In certain examples, naturally occurring salts, sugars, proteins, fats, vitamins, and hormones in the blood or interstitial fluid may also constitute the analyte. The analyte may be naturally occurring in the biological fluid or endogenous, such as a metabolite, hormone, antigen, antibody, or the like. Alternatively, the analyte may be introduced into the body or exogenous, such as a contrast agent for imaging, a radioisotope, a chemical agent, fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin; ethanol; cannabis (cannabis, tetrahydrocannabinol, cannabis indiana); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorinated hydrocarbons, hydrocarbons); cocaine (cleaved cocaine); stimulants (amphetamine, methamphetamine, and the like), ) ; Sedatives (barbiturates, mequinones, neuroleptics such as ) ; Hallucinogens (phencyclidine, lysergic acid, mo Sika, pinabout, nuda, etc.); anesthetic (heroin, codeine, morphine, opium, pethidine,/> Fentanyl,/>TALWIN、/>) ; Specially-produced drugs (analogues of fentanyl, pethidine, amphetamine, methamphetamine, and phencyclidine, e.g., headshaking); anabolic steroids; and nicotine. Metabolites of drugs and pharmaceutical compositions are also contemplated analytes. Analytes produced in vivo such as neurochemicals and other chemicals, for example, ascorbic acid, uric acid, dopamine, norepinephrine, 3-methoxytyramine (3 MT), 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5 HT) and 5-hydroxyindoleacetic acid (FHIAA), and histamine can also be analyzed.

As used herein, the phrases "analyte measurement device," "analyte monitoring device," "analyte sensing device," "continuous analyte sensor device," and/or "multi-analyte sensor device" are broad phrases and will give one of ordinary and customary meaning (and are not limited to special or customized meanings) to them, and refer to, but are not limited to, devices and/or systems responsible for detecting or transducing signals associated with a particular analyte or combination of analytes. For example, these phrases may refer, but are not limited to, an instrument responsible for detecting a particular analyte or combination of analytes. In one example, the instrument includes a sensor coupled to circuitry disposed within the housing and configured to process a signal associated with the analyte concentration into information. In one example, such devices and/or systems can use a biological recognition element in combination with a transduction and/or detection element to provide specific quantitative, semi-quantitative, qualitative, and/or semi-qualitative analysis information.

As used herein, the phrase "barrier cell layer" is a broad phrase and will give one of ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a portion of a foreign body response that forms an adherent monolayer of cells (e.g., macrophages and foreign body giant cells) that substantially blocks the transport of molecules and other substances to an implantable device.

As used herein, the phrases and terms "bioactive agent" and "bioactive substance" are broad terms and will give one of ordinary skill in the art their ordinary and customary meaning (and are not limited to special or customized meanings) and refer to, but are not limited to, any substance that has an effect on or elicits a response from living tissue, such as drugs, biologicals, reactive Oxygen Species (ROS), and metal ions.

As used interchangeably herein, the phrases "biological interface membrane," "biological interface domain," and "biological interface layer" are broad phrases and will give one of ordinary and customary meaning (and are not limited to special or customized meanings) to them, and refer to (but are not limited to) a permeable membrane (which may include multiple domains) or layer that serves as a biological protective interface between the recipient tissue and the implantable device. The terms "biological interface" and "bioprotective" are used interchangeably herein.

As used herein, the terms "biosensor" and/or "sensor" are broad terms and will be given their ordinary and customary meaning to those of ordinary skill in the art (and are not limited to a particular or customized meaning) and refer to, but are not limited to, an analyte measurement device, an analyte monitoring device, an analyte sensing device, a continuous analyte sensor device, and/or a portion of a multi-analyte sensor device that is responsible for detecting or transducing a signal associated with a particular analyte or combination of analytes. In an example, a biosensor or sensor generally includes a body, a working electrode, a reference electrode, and/or a counter electrode coupled to the body and forming a surface configured to provide a signal during an electrochemical reaction. One or more membranes may be secured to the body and cover the electrochemical reaction surface. In examples, such biosensors and/or sensors can use a biological recognition element in combination with a detection and/or transduction element to provide a specific quantitative, semi-quantitative, qualitative, semi-qualitative analysis signal.

As used herein, the term "biostable" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a material that is relatively resistant to degradation by processes encountered in the body.

As used herein, the phrase "cellular process" is a broad term and will give one of ordinary and customary meaning (and is not limited to a special or customized meaning) to it and refers to (but is not limited to) cellular pseudopodia.

As used herein, the phrase "cell attachment" is a broad phrase and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, adhesion of cells and/or cellular processes to a material at the molecular level, and/or attachment of cells and/or cellular processes to a microporous material surface or a macroporous material surface. One example of a material used in the prior art to promote cell attachment to its porous surface is BIOPORE ^TM cell culture support sold by Millipore (Bedford, mass.) and described in us patent No. 5,741,330 to Brauker et al.

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.

As used herein, the term "conjugate" is a broad term and will give the person of ordinary and customary meaning to (and is not limited to) and refers to, but is not limited to, a bioactive agent covalently attached to a carrier or nanocarrier such as a polymer (e.g., a bioactive substance releasing film or a biological interface layer) through a linker that is bioactive in that it is capable of allowing the drug to separate from the carrier when exposed to or present in a biological environment such as a subcutaneous or transdermal environment. As used herein, conjugates include drug release 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 copolymers thereof. As used herein, conjugates include drug release layer-bioactive agent conjugates and nanoparticle polymer-bioactive agent conjugates present in the drug release layer. In an example, the bioactive substance releasing membrane includes a domain having a drug release-bioactive agent conjugate and a domain having a bioactive agent reservoir, wherein the domains may be spatially arranged vertically or horizontally.

As used herein, the term "continuous" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, an uninterrupted or continuous portion, domain, coating or layer.

As used herein, the phrase "continuous analyte sensing" is a broad term and will give one of ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a particular or customized meaning) and refers to (but is not limited to) a period of time during which monitoring of the analyte concentration is performed continuously, or intermittently (but periodically) (e.g., about once every 5 seconds or less to about 10 minutes or more). In further examples, the monitoring of the analyte concentration is performed once every about 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, or 60 seconds to about 1.25 minutes, 1.50 minutes, 1.75 minutes, 2.00 minutes, 2.25 minutes, 2.50 minutes, 2.75 minutes, 3.00 minutes, 3.25 minutes, 3.50 minutes, 3.75 minutes, 4.00 minutes, 4.25 minutes, 4.50 minutes, 4.75 minutes, 5.00 minutes, 5.25 minutes, 5.50 minutes, 5.75 minutes, 6.00 minutes, 6.25 minutes, 6.50 minutes, 6.75 minutes, 7.00 minutes, 7.50 minutes, 7.75 minutes, 8.00 minutes, 8.25 minutes, 8.50 minutes, 8.75 minutes, 9.00 minutes, 9.25 minutes, 9.50 minutes, or 9.75 minutes.

As used herein, the term "coupled" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, two or more system elements or components configured to be at least one of electronically attached, mechanically attached, thermally attached, operatively attached, chemically attached, or otherwise attached. Similarly, the phrases "operatively connected," "operatively linked," and "operatively coupled," as used herein, may refer to one or more components being coupled to another component in a manner that facilitates 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 a remote device. For example, one or more electrodes may be used to detect an analyte in a sample and convert this information into a signal; the signal may then be transmitted to a circuit. In this example, the electrodes are "operably linked" to the electronic circuitry. The phrase "removably coupled" as used herein may refer to two or more system elements or components being configured or configured to have been electronically, mechanically, thermally, operatively, chemically, or otherwise attached and separated without damaging any of the coupled elements or components. The phrase "permanently coupled" as used herein may refer to two or more system elements or components being configured or configured to have been electronically, mechanically, thermally, operatively, chemically, or otherwise attached, but not decoupled without damaging at least one of the coupled elements or components.

As used herein, the term "defined edge" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, a distinct edge or boundary that is split between layers, domains, coatings or portions. "defined edges" are in contrast to gradual transitions between layers, domains, coatings, or portions.

As used herein, the term "discontinuous" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, discrete, intermittent or separate parts, layers, coatings or domains.

As used herein, the term "distal" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, a region that is relatively distant from a point of reference, such as a starting point or attachment point.

As used herein, the term "domain" is a broad term and will give the person of ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a region of a membrane system, which may be a layer, a uniform or non-uniform gradient (e.g., anisotropic region of a membrane), or a portion of a membrane capable of sensing one, two, or more analytes. The domains discussed herein may be formed as a single layer, two or more layers, a bilayer pair, or a combination thereof.

As used herein, the term "drift" is a broad term and will give one of ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a progressive increase or decrease in signal over time independent of changes in the concentration of a subject system analyte (e.g., the subject postprandial glucose concentration). While not wishing to be bound by theory, it is believed that the drift may be a result of a localized reduction in glucose transport to the sensor, for example, due to the formation of foreign body pockets (FBCs). It is also believed that insufficient amounts of interstitial fluid around the sensor may result in reduced oxygen and/or glucose transport to the sensor. In one example, the increase in local interstitial fluid can slow down or reduce drift and thus improve sensor performance. Drift may also be the result of sensor electronics or an algorithmic model to compensate for noise or other anomalies that may occur with electrical signals in a range including microampere range, nanoamp range, and femto amp range.

The phrases "bioactive substance releasing membrane" and "drug releasing layer" and "bioactive substance releasing domain" and "bioactive agent releasing membrane" are used interchangeably herein and are each broad phrases and will each give one of ordinary skill in the art their ordinary and customary meaning (and are not limited to special or customized meanings) and refer to, but are not limited to, a permeable membrane or semi-permeable membrane that is permeable to one or more bioactive agents. In examples, the "bioactive substance releasing membrane" and "drug releasing layer" and the "bioactive substance releasing domain" and "bioactive agent releasing membrane" may be composed of two or more domains, and typically have a thickness of a few microns or more. In an example, the bioactive substance releasing membrane and/or the bioactive agent releasing membrane are substantially the same as the biological interface layer and/or the biological interface membrane. In another example, the bioactive substance releasing film and/or the bioactive agent releasing film is different from the biological interface layer and/or the biological interface film.

As used herein, the term "electrochemically reactive surface" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, the surface of an electrode that is electrochemically reactive. In an example, a hydrogen peroxide reaction generated by an enzyme-catalyzed reaction of the analyte being detected may produce a measurable electron flow. For example, in the detection of glucose, glucose oxidase produces hydrogen peroxide (H ₂O₂) as a byproduct. H ₂O₂ reacts with the surface of the working electrode to produce two protons (2H ⁺), two electrons (2 e ^-) and one oxygen molecule (O ₂), thereby producing a detected electron flow. In the counter electrode, a reducible substance (e.g., O ₂) is reduced at the electrode surface to balance the current generated by the working electrode. In another example, a mediator or "wired enzyme" is used to provide electron transfer during the reduction-oxidation (redox) of the transduction element and analyte.

As used herein, the phrase "hard segment" is a broad phrase and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, elements of a copolymer, such as polyurethane, polycarbonate polyurethane, or polyurethane urea copolymer, that imparts resistance properties, such as resistance to bending or torsion. The term "hard segment" may also be characterized as a crystalline, semi-crystalline, or glassy material having a glass transition temperature ("Tg") that is typically above ambient temperature as determined by dynamic scanning calorimetry, and is typically made from a diisocyanate with or without a chain extender.

As used herein, the term "subject" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, mammals, such as humans.

As used herein, the term "implanted" or "implantable" is a broad term and will give one of ordinary skill in the art their ordinary and customary meaning (and is not limited to a special or customized meaning) and refers to (but is not limited to) an object (e.g., a sensor) inserted subcutaneously (i.e., in a fat layer between skin and muscle) or transdermally (i.e., penetrating, entering or passing through intact skin), which may result in a sensor having an in vivo portion and an ex vivo portion.

As used herein, the phrase "insertable surface area" is a broad phrase and will give one of ordinary and customary meaning to those of ordinary skill in the art (and is not limited to special or customized meanings) and refers to, but is not limited to, the surface area of the insertable portion of an analyte sensor, including but not limited to the surface area of a flat (substantially planar) and/or wire substrate used in an analyte sensor as described herein.

As used herein, the phrase "insertable volume" is a broad phrase and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, the volume that is in front of and beside the insertion path of the insertable portion of the analyte sensor as described herein, as well as the incision made in the skin for insertion of the insertable portion of the analyte sensor. The insertable volume further comprises at most 5mm radially or perpendicular to the volume in front of and beside the insertion path.

As used herein, the terms "interferents" and "interfering substances" are broad terms and will give one of ordinary skill in the art their ordinary and customary meaning (and are not limited to special or customized meanings) and refer to, but are not limited to, effects and/or substances that interfere with the measurement of an analyte of interest in a sensor to produce a signal that is inaccurately indicative of the analyte measurement. In the example of an electrochemical sensor, the interfering substance is a compound having an oxidation potential that overlaps with the analyte or one or more mediators to be measured.

As used herein, the term "in vivo" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and includes, but is not limited to, portions of a device (e.g., a sensor) adapted to be inserted into and/or present within a subject's living body.

As used herein, the term "ex vivo" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and includes, but is not limited to, portions of a device (e.g., a sensor) adapted to remain and/or reside outside of a subject's living body.

As used herein, the term "film" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, a structure configured to perform the following functions, including, but not limited to: protection of the exposed electrode surface from biological environmental influences, diffusion resistance (limitation) of the analyte, acting as a matrix for a catalyst for enabling enzymatic reactions, limiting or blocking interfering substances, providing hydrophilicity at the electrochemically reactive surface of the sensor interface, acting as an interface between the recipient tissue and the implantable device, modulating recipient tissue reactions via drug (or other substance) release, and combinations thereof. As used herein, the terms "membrane" and "matrix" are intended to be used interchangeably.

As used herein, the phrase "membrane system" is a broad phrase and will give the person of ordinary and customary meaning to those skilled in the art (and is not limited to special or customized meanings) and refers to (but is not limited to) a permeable or semi-permeable membrane that may be composed of two or more domains, two or more layers or two or more layers within a domain and is typically composed of a material of a thickness of a few microns or more, which is permeable to oxygen and optionally permeable to, for example, glucose or another analyte. In an example, the membrane system includes an immobilized glucose oxidase that enables a reaction between glucose and oxygen, whereby glucose concentration can be measured.

As used herein, the term "tiny" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or custom meaning) and refers to (but is not limited to) a small object or dimension of about 10 ^-6 m that is not visible without magnification. The term "tiny" is contrary to the term "large" which refers to large objects that are visible without magnification. Similarly, the term "nano" refers to small objects or dimensions of about 10 ^-9 m.

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 the concentration of the analyte and may result in reduced sensor performance. One type of noise has been observed during 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 recipients the noise may last for about three to four days. In some cases, predictive modeling, artificial intelligence, and/or algorithmic means may be used to reduce noise. In other cases, noise may be reduced by addressing immune response factors associated with the presence of an implanted sensor, such as by using a bioactive substance release film having at least one bioactive agent. For example, the noise of one or more exemplary biosensors as disclosed herein may be determined and then compared qualitatively or quantitatively. For example, by obtaining an original signal time series with a fixed sampling interval (in picoamperes (pA)), a smoothed version of the original signal time series may be obtained, for example, by applying a 3 rd order chebyshev type II low pass digital filter. Other smoothing algorithms may be used. At each sampling interval, the absolute difference in pA can be calculated to provide a smooth time series. The smoothed time series may be converted to units of mg/dL ("units of noise") using glucose sensitivity time series in units of pA/mg/dL, where the glucose sensitivity time series is derived using a mathematical model between the raw signal and a reference blood glucose measurement (e.g., obtained from a blood glucose meter). Optionally, the time series may be aggregated as desired, for example, on an hourly or daily basis. Comparison of corresponding time series between different exemplary biosensors having the disclosed bioactive substance releasing membrane and one or more bioactive agents provides a qualitative or quantitative determination of noise improvement.

As used herein, the terms "optional" or "optionally" are broad terms and will be given their ordinary and accustomed meaning to those of ordinary skill in the art (and are not limited to a special or custom meaning), and refer to (but are not limited to) the event or circumstance described subsequently, which may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not.

As used herein, the term "polyampholyte polymer" is a broad term and will give one of ordinary skill in the art its ordinary and customary meaning (and is not limited to a special or custom meaning) and refers to, but is not limited to, polymers comprising cationic and anionic groups. Such polymers may be prepared to have approximately equal numbers of positive and negative charges, and thus the surface of such polymers may be approximately net charge neutral. Alternatively, such polymers may be prepared with an excess of positive or negative charges, and thus the surface of such polymers may be net positive or net negative, respectively. "polyampholyte polymer" includes polyampholyte polymers.

As used herein, the phrase "polymeric group" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a functional group that allows a monomer to polymerize with itself to form a homopolymer or with a different monomer to form a copolymer. Depending on the type of polymerization process employed, the polymeric groups may be selected from the group consisting of alkenes, alkynes, epoxides, lactones, amines, hydroxyl groups, isocyanates, carboxylic acids, anhydrides, silanes, halides, aldehydes, and carbodiimides.

As used herein, the term "polyamphoterion" is a broad term and will give one of ordinary skill in the art its ordinary and customary meaning (and is not limited to a special or custom meaning) and refers to, but is not limited to, a polymer in which the repeating units of the polymer chain are zwitterionic moieties. The polyamphogen is also known as polybetaine (polybetaine). Polyampholytes are a class of polymers for polyampholytes because they have both cationic and anionic groups. However, they are unique in that both cationic and anionic groups are part of the same repeating unit, which means that the polyampholytes have the same number of cationic and anionic groups, whereas polymers of other polyampholytes may have more one ionic group than another. Also, polyamphoons have cationic groups and anionic groups as part of the repeating units. The polymer of the polyampholyte need not have cationic groups attached to anionic groups; they may be on different repeating units and thus may be distributed separately from each other at random intervals, or the number of one ionic group may exceed the number of another ionic group.

As used herein, the term "proximal" is a broad term and will give one of ordinary skill in the art its ordinary and customary meaning (and is not limited to a special or customized meaning) and refers to, but is not limited to, the spatial relationship between the various elements as compared to a specific reference point. For example, some examples of devices include a membrane system having a biological interface layer and an enzyme layer. If the sensor is considered a reference point and the enzyme layer is positioned closer to the sensor than the biological interface layer, the enzyme layer is closer to the sensor than the biological interface layer.

As used herein, the phrase and the terms "processor module" and "microprocessor" are each broad phrases and terms and will give rise to their ordinary and customary meaning to those skilled in the art (and are not limited to special or custom meanings), and refer to, but are not limited to, computer systems, state machines, processors, etc. that are designed to perform arithmetic or logical operations using logic circuits that respond to and process basic instructions that drive a computer.

As used herein, the term "semi-continuous" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular 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, the coating disposed around the sensing region, but not with respect to the sensing region, is "semi-continuous".

As used herein, the phrases "sensing portion," "sensing membrane," "sensing region," "sensing domain," and/or "sensing mechanism" are broad phrases and will give one of ordinary and customary meaning (and are not limited to special or customized meanings) to them and refer to (but are not limited to) a biosensor and/or a portion of a sensor that is responsible for detecting or transducing a signal associated with a particular analyte or combination of analytes. In an example, the sensing portion, sensing membrane, and/or sensing mechanism generally include an electrode configured to provide a signal during an electrochemical reaction with one or more membranes covering the electrochemically reactive surface. In examples, such sensing portions, sensing films, and/or sensing mechanisms can provide specific quantitative, semi-quantitative, qualitative, semi-qualitative analytical signals using a biological recognition element in combination with a detection and/or transduction element.

During general operation of the analyte measurement device, biosensor, sensor, sensing region, sensing portion, or sensing mechanism, a biological sample (e.g., blood or interstitial fluid) or component thereof is contacted with an enzyme (e.g., glucose oxidase) or protein (e.g., one or more Periplasmic Binding Proteins (PBPs) or mutants or fusion proteins thereof having one or more analyte binding regions), either directly or after passing through one or more membranes, each region capable of specifically and reversibly binding at least one analyte. Interaction of the biological sample or a component thereof with the analyte measurement device, biosensor, sensor, sensing area, sensing portion, or sensing mechanism results in signal transduction that allows for qualitative, semi-qualitative, quantitative, or semi-quantitative determination of the analyte level, e.g., glucose, in the biological sample.

In an example, the sensing region or sensing portion may include at least a portion of a conductive substrate or at least a portion of a conductive surface (e.g., a wire or conductive trace or a substantially planar substrate including a substantially planar trace) and a film. In an example, the sensing region or sensing portion may include a non-conductive body; forming an electrochemically reactive surface at one location on the body and forming electronically connected working, reference and counter electrodes (optional) at another location on the body; and a sensing film attached 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 comprising an electrolyte-containing fluid, described further below). These terms are broad enough to include the entire device or only a sensing portion thereof (or something in between).

In another example, the sensing region may comprise one or more Periplasmic Binding Proteins (PBPs) or mutants or fusion proteins thereof having one or more analyte binding regions, each region being capable of specifically and reversibly binding to at least one analyte. Mutations in the PBP may cause or alter one or more binding constants, prolonged protein stability (including thermostability), to bind the protein to a particular encapsulation matrix, membrane or polymer, or to attach a detectable reporter group or "tag" to indicate a change in binding region. Specific examples of binding region changes include, but are not limited to, hydrophobic/hydrophilic environmental changes, three-dimensional conformational changes, changes in amino acid side chain orientation in the protein binding region, and redox state of the binding region. Such changes in the binding region provide for transduction of a detectable signal corresponding to one or more analytes present in the biological fluid.

In an example, the sensing region determines the selectivity between one or more analytes such that only the analyte that must be measured produces (transduces) a detectable signal. The selection may be based on any chemical or physical recognition of the analyte by the sensing region, wherein the chemical composition of the analyte is unchanged, or wherein the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.

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

As used herein, the term "sensitivity" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular 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 predetermined amount (unit) of a measured analyte. For example, the sensor has a sensitivity (or slope) of about 1 picoamp to about 100 picoamps of current for every 1mg/dL of glucose analyte.

The phrases and terms "small diameter sensor," "small structure sensor," and "microsensor" as used herein are broad phrases and terms and will give one of ordinary and customary meaning (and are not limited to special or customized meanings) to such and refer to, but are not limited to, a sensing mechanism that is less than about 2mm in at least one dimension. In further examples, the sensing mechanism is less than about 1mm in at least one dimension. In some examples, the sensing mechanism (sensor) is less than about 0.95mm, 0.9mm, 0.85mm, 0.8mm, 0.75mm, 0.7mm, 0.65mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm, or 0.1mm. In some examples, the largest dimension of the independently measured length, width, diameter, thickness, or circumference of the sensing mechanism is no more than about 2mm. In some examples, the sensing mechanism is a needle sensor with a diameter of less than about 1mm, see, for example, U.S. Pat. No. 6,613,379 to Ward et al and U.S. Pat. No. 7,497,827 to Brister et al, both of which are incorporated herein by reference in their entirety. In some alternative examples, the sensing mechanism includes electrodes deposited on a substantially planar substrate, wherein the thickness of the implantable portion is less than about 1mm, see, for example, U.S. Pat. No. 6,175,752 to Say et al and U.S. Pat. No. 5,779,665 to Mastrootaro et al, both of which are incorporated herein by reference in their entirety. Examples of methods of forming sensors (sensor electrode layouts and membranes) and sensor systems discussed herein can be found in currently pending U.S. patent publication No. 2019-0307371 (Boock et al), which is incorporated herein by reference in its entirety.

As used herein, the phrase "soft segment" is a broad phrase and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, elements of a copolymer, such as polyurethane, polycarbonate polyurethane, or polyurethane urea copolymer, which imparts flexibility to the chain. The phrase "soft segment" may also be characterized as an amorphous material having a low Tg (e.g., a Tg typically no higher than ambient temperature or normal mammalian body temperature).

As used herein, the phrase "solid portion" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a portion of a film material having a mechanical structure that defines cavities, voids, or other non-solid portions.

As used herein, the terms and phrases "zwitterionic" and "zwitterionic compound" are each broad terms and phrases and will give one of ordinary skill in the art their ordinary and customary meaning (and are not limited to special or customized meanings) and refer to, but are not limited to, compounds in which the neutral molecule of the compound has a unit positive charge and a unit negative charge at different positions within the molecule. Such compounds are a class of dipole compounds, and are sometimes also referred to as "inner salts".

As used herein, the phrase "zwitterionic precursor" or "zwitterionic compound precursor" is a broad phrase and will give one of ordinary and customary meaning (and is not limited to a special or customized meaning) to any compound that is not zwitterionic per se, but can become zwitterionic in the final or transitional state by chemical reaction. In some examples described herein, the device comprises a zwitterionic precursor that can be converted to a zwitterionic prior to implantation of the device in vivo. Alternatively, in some examples described herein, the device comprises a zwitterionic precursor that can be converted to a zwitterionic by some chemical reaction that occurs after implantation within the device body. Such reactions are known to those of ordinary skill in the art and include ring opening reactions, addition reactions such as Michael addition (Michael addition). This method is particularly useful when the polymerization of betaine-containing monomers is difficult to achieve desired physical properties such as molecular weight and mechanical strength due to technical challenges such as solubility of betaine monomers. Post-polymerization modification or conversion of betaine precursors can be a practical way to achieve the desired polymer structure and composition. Examples of such precursors include tertiary amines, quaternary amines, pyridines, and other materials detailed herein.

As used herein, the phrase "zwitterionic derivative" or "zwitterionic compound derivative" is a broad phrase and will give one of ordinary and customary meaning to them (and is not limited to a special or customized meaning) and refers to, but is not limited to, any compound that is not itself a zwitterionic but is the product of a chemical reaction in which a zwitterionic is converted to a non-zwitterionic. Such reactions may be reversible such that under certain conditions the zwitterionic derivative may act as a zwitterionic precursor. For example, the hydrolyzable betaine ester formed from zwitterionic betaines is a cationic zwitterionic derivative that is capable of undergoing hydrolysis under appropriate conditions to revert to zwitterionic betaines.

Devices and probes inserted or implanted percutaneously into the subcutaneous tissue typically elicit a Foreign Body Response (FBR) that includes the invasion of inflammatory cells that ultimately form a Foreign Body Capsule (FBC) as part of the body's response to the introduction of the foreign body. The continuous monitoring systems discussed herein include continuous analyte monitoring systems configured to monitor one, two, or more analytes (which include events that may occur independently in picoseconds, nanoseconds, milliseconds, seconds, or minutes) simultaneously, sequentially, and/or randomly to predict health-related events and health system performance (e.g., current and future performance of a human system such as the circulatory system, respiratory system, digestive system, or other system or combination of organs or systems). In an example, insertion or implantation of a device (e.g., a glucose sensing device) may result in an acute inflammatory response that subsides to chronic inflammation while fibrotic tissue is established, such as described in detail above. Eventually, over time, mature FBCs are formed around the device, including predominantly contracted fibrous tissue. See Shanker and Greisler, inflammation and Biomaterials: greco RS, editions, "Implantation Biology: the Host Response and Biomedical Devices", pages 68-80, CRC Press (1994). FBCs surrounding conventional implant devices have been shown to block or block analyte transport across the device-tissue interface. Thus, in vivo continuous prolonged life analyte transport (e.g., over the first few days) is generally considered unreliable or impossible.

In some examples, certain aspects of the FBR may play a role in noise over the first few days. It has been observed that some sensors function worse than they function later during the first few hours after insertion. This is illustrated by noise and/or suppression of the signal during the first few hours (e.g., about 2 hours to about 24 hours) after insertion. These anomalies typically subside spontaneously, after which the sensor becomes less noisy, has improved sensitivity, and is more accurate than during the initial period. It has been observed that some percutaneous sensors and fully implantable sensors experience noise for some time after application to a subject (i.e., percutaneous insertion or fully implantation under the skin).

When the sensor is first inserted or implanted into subcutaneous tissue, it comes into contact with a variety of possible tissue conformations. Subcutaneous tissue in different recipients may be relatively fat free in the case of very robust people, or may consist primarily of fat in most people. Fat appears in a range of textures from very white, fluffy fat to very dense, fibrous fat. Some fats have a very yellow and dense appearance; some have a very clear, fluffy and white appearance, while in other cases they have a reddish or brown appearance. The fat may be a few inches thick or only 1cm thick. Which may be very vascular or relatively avascular. Many diabetic subjects have some subcutaneous scar tissue due to years of insulin pump use or insulin injection. Sometimes, during insertion, the sensor may stay in such scar areas. In the abdomen of a given recipient, subcutaneous tissue may even vary greatly from one location to another. Furthermore, occasionally, the sensor may reside near a more densely vascularized region or in a less vascularized region of a given recipient. While not wishing to be bound by theory, it is believed that creating a space between the sensor surface and surrounding cells (including forming a fluid pocket around the sensor) may enhance sensor performance. Thus, the continuous analyte monitoring systems discussed herein provide for extended life without compromising accuracy, which may also improve the experience of the recipient.

Fig. 1A is a schematic side view of adipocytes in contact with an inserted percutaneous sensor or implanted sensor 34. In this case, the sensor 34 is firmly inserted into a small space, and the adipocytes are closely attached to the surface. Tight binding of adipocytes to the sensor may also occur, for example, where the surface of the sensor is hydrophobic. For example, adipocytes 200 and/or inflammatory cells and/or other tissue types (such as dermis, myolayer, and/or connective tissue) may create an active metabolic interface that may physically block the surface of the sensor and/or access to working electrode 38.

Typically, the adipocytes can be about 120 microns in diameter and are typically fed nutrients by tiny capillaries 205. When the sensor is pressed against adipose tissue, very few capillaries may actually be close to the surface of the sensor. This may be similar to covering the surface of the sensor with an impermeable material, such as cellophane. Even with a few small holes in the cellophane, the function of the sensor may be compromised. In addition, the surrounding tissue has a low metabolic rate, and thus a large amount of glucose and oxygen is not required. While not wishing to be bound by theory, it is believed that during this initial period, the signal of the sensor may be noisy and may be suppressed due to the close binding of the sensor surface to the adipocytes and due to reduced availability of oxygen and glucose due to physical-mechanical and physiological reasons.

Referring now to the extended function of the sensor, these devices typically lose their function after a few days or weeks of implantation. In some applications, cell attack or migration of cells to the sensor may cause a decrease in the sensitivity and/or function of the device, particularly after the first day of implantation. See also, e.g., U.S. patent nos. 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 that glucose oxidase-based devices approved by the food and drug administration (Food and Drug Administration) for use in humans function well a few days after implantation, but are rapidly disabled a few days later (e.g., a few days up to about 14 days).

Without being bound by any theory, it is believed that this reduced performance of device function is most likely due to cells, such as polymorphonuclear cells and monocytes migrating to the sensor site during the first few days after implantation. These cells consume local glucose and oxygen, etc. If an excess of such cells are present, 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 nonfunctional. Further inhibition of device function may be due to inflammatory cells (e.g., macrophages) that associate with the implantable device and adjacent tissue, e.g., at the interface, and physically block and/or attenuate glucose transport/flow into the device, e.g., by forming a barrier cell layer. In addition, these inflammatory cells can biodegrade many artificial biomaterials (some of which have not been considered biodegradable until recently). When activated by foreign matter, tissue macrophages degranulate, releasing hypochlorite (bleach) and other oxidative species, enzymes, superoxide anions, hydroxyl ion/radical generating moieties known to decompose a variety of polymers.

FIG. 1B is a schematic side view of a biological interface membrane of a percutaneous sensor or an implanted sensor inserted in one illustrative example. In this illustration, a biological interface film 68 surrounds the sensor 34, covering the working electrode 38. In one example, the biological interface film 68 is used in combination with a bioactive substance release film 70, wherein the bioactive substance release film is adjacent to or at least partially covers a portion of the biological interface film 68. In another example, the bioactive substance releasing film 70 is at least partially covered by the biological interface film 68. In another example, the bioactive substance releasing film 70 is used without the biological interface film 68.

Thus, sensors comprising biological interfaces (including but not limited to, for example, porous biological interface materials, nettings, etc., all of which are described in more detail elsewhere herein) may be used to improve sensor function (e.g., the first hours to days).

In some cases, such as in an extended sensor, it is believed that the foreign body response is the primary event of an extended implant around the implanted device and may be managed or manipulated to support, rather than block or block analyte transport. In another aspect, to extend the life of the sensor, one example employs a material that promotes vascularized tissue ingrowth, for example, within a porous biological interface membrane. For example, tissue ingrowth into a porous biological interface material surrounding an extended sensor may promote sensor function over an extended period of time (e.g., weeks, months, or years). It has been observed that tissue bed ingrowth and formation can take up to 3 weeks. Tissue ingrowth and tissue bed formation are considered to be part of the foreign body response. As will be discussed herein, the foreign body reaction may be manipulated by using a porous biological interface material that surrounds the sensor and promotes tissue and microvasculature ingrowth over time.

Sensing mechanism

Generally, the analyte sensors of the present disclosure include a sensing mechanism 36 having a small structure (e.g., a micro-diameter or small-diameter sensor having a small structure) in at least a portion thereof, such as a needle sensor. As used herein, "small structure" preferably refers to a configuration having at least one dimension less than about 1 mm. The sensing mechanism with small structures may be a wire-based substrate, a substrate-based, or any other configuration. In some alternative examples, the term "small structure" may also refer to slightly larger structures, such as those having a smallest dimension greater than about 1mm, however, the configuration (e.g., mass or size) is designed to minimize foreign body reactions due to size and/or mass. In one example, a biological interface film is formed onto the sensing mechanism 36, as described in more detail below. In another example, a bioactive substance releasing film 70 is formed on the sensing mechanism 36 adjacent to the working electrode 38. In another example, the bioactive substance releasing membrane 70 is used in combination with the biological interface layer 68. In another example, the bioactive substance releasing membrane 70 is used without the biological interface layer 68.

Fig. 2A is an expanded view of one illustrative example of a continuous analyte sensor 34 (also referred to as a percutaneous analyte sensor or needle sensor), which specifically illustrates a sensing mechanism 36. Preferably, the sensing mechanism comprises a small structure as defined herein, and is adapted to be inserted under the skin of the subject, the remaining body of the sensor (e.g., electronics, etc.) may reside outside the body. In the illustrated example, continuous analyte sensor 34 includes two electrodes, namely a working electrode 38 and at least one additional electrode that can serve as a counter electrode and/or reference electrode 30, hereinafter referred to as reference electrode 30.

In some illustrative examples, each electrode is formed from a thin wire, e.g., having a diameter of about 0.001 inch or less to about 0.010 inch or more, and is formed from, e.g., a plated insulator, a plated wire, or a bulk conductive material. While the illustrated electrode configuration and associated text describe one preferred method of forming a transdermal sensor, a variety of known transdermal sensor configurations may be used with the transdermal analyte sensor systems of the present disclosure, such as 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.

In an example, the working electrode includes a wire formed of a conductive material (such as platinum, platinum-iridium, palladium, graphite, gold, carbon, a conductive polymer, an alloy, and the like). Although the electrodes may be formed by a variety of manufacturing techniques (bulk metal processing, deposition of metal onto a substrate, etc.), it may be advantageous to form the electrodes from plated wire (e.g., platinum plated on the wire) or bulk metal (e.g., platinum wire). It is believed that electrodes formed from bulk metal wires provide excellent performance (e.g., compared to deposited electrodes) including improved assay stability, simplified manufacturability, resistance to contamination (e.g., contamination may be introduced during deposition), and improved surface reactions (e.g., due to purity of the material) without delamination or delamination.

Working electrode 38 is configured to measure the concentration of one or more analytes. For example, in an enzymatic electrochemical sensor for detecting glucose, for example, a working electrode measures hydrogen peroxide generated by an enzyme-catalyzed reaction of an analyte being detected and forms a measurable electron current. For example, in glucose assays where glucose oxidase produces hydrogen peroxide as a byproduct, the hydrogen peroxide reacts with the surface of the working electrode, producing two protons (2h+), two electrons (2 e-) and one oxygen molecule (O2), thereby producing a stream of electrons that are being detected.

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 may be used to deposit the insulating material on the working electrode. In one example, the insulating material comprises parylene, which may be an advantageous polymer coating due to its strength, lubricity, and electrical insulation properties. Generally, parylene is produced by vapor deposition and polymerization of p-xylene (or substituted derivatives thereof). However, any suitable insulating material may be used, such as fluorinated polymers, polyethylene terephthalate, polyurethane, polyimide, other non-conductive polymers, and the like. Glass or ceramic materials may also be used. Other materials suitable for use include surface energy modified coating systems such as those sold under the trade names AMC18, AMC148, AMC141 and AMC321 by ADVANCED MATERIALS Components Express (Bellafonte, pa.). However, in some alternative examples, the working electrode may not require an insulator coating.

Preferably, the reference electrode 30 is formed of silver, silver/silver chloride, or the like, which may be used as a reference electrode alone or as dual reference and counter electrodes. Preferably, the electrodes are arranged side by side and/or are wound or twisted around each other; however, other configurations are also possible. In one example, reference electrode 30 is spiral wound around working electrode 38, as illustrated in fig. 1B. The wire assembly may then optionally be coated together with an insulating material, similar to that described above, to provide an insulating attachment (e.g., to secure the working and reference electrodes together).

In examples in which the outer insulator 35 is disposed, a portion of the coated component structure may be stripped or otherwise removed, for example, by hand, excimer laser, chemical etching, laser ablation, sand blasting (e.g., with sodium bicarbonate, solid carbon dioxide, or other suitable grit), etc., to expose the electrochemically active surface. Alternatively, a portion of the electrode may be masked prior to depositing the insulator in order to maintain the exposed electrochemically active surface area. In one illustrative example, a grit blasting process is performed to expose the electrochemically active surface, preferably with a grit material that is hard enough to abrade the polymeric material while being soft enough to minimize or avoid damage to the underlying metal electrode (e.g., platinum electrode). Although a variety of "sand" materials (e.g., sand, talc, walnut shells, ground plastic, sea salt, solid carbon dioxide, etc.) may be used, in some examples sodium bicarbonate is an advantageous sand material because it is hard enough to abrade, for example, a parylene coating without damaging underlying platinum conductors. An additional advantage of sodium bicarbonate blasting includes a polishing action on the metal as it peels off the polymer layer, eliminating a cleaning step that might otherwise be necessary.

In some examples, radial windows are formed through the insulating material to expose the circumferential electrochemically active surface of the working electrode. Additionally, multiple sections of the electrochemically active surface of the reference electrode are exposed. For example, multiple sections of the electrochemically active surface may be masked during deposition of the outer insulating layer or etched after deposition of the outer insulating layer.

In some applications, cell attack or migration of cells to the sensor may cause a decrease in the sensitivity and/or function of the device, particularly after the first day of implantation. However, when the exposed electroactive surface is distributed circumferentially around the sensor (e.g., as in a radial window), the available surface area for reaction may be distributed sufficiently to minimize the effect of localized cell invasion of the sensor on the sensor signal. Alternatively, the tangentially exposed electrochemically active window may be formed, for example, by peeling off only one side of the coated component structure. In other alternative examples, a window may be provided at the top end of the coated component structure such that the electrochemically active surface is exposed at the top end of the sensor. Other methods and configurations may also be employed to expose the electrochemically active surface.

Preferably, the overall diameter of the above-exemplified sensor is no more than about 0.020 inches (about 0.51 mm), more preferably no more than about 0.018 inches (about 0.46 mm), and most preferably no more than about 0.016 inches (0.41 mm). In some examples, the working electrode has a diameter of about 0.001 inch or less to about 0.010 inch or greater, preferably about 0.002 inch to about 0.008 inch, and more preferably about 0.004 inch to about 0.005 inch, including all ranges and subranges therebetween. The length of the window may be about 0.1mm (about 0.004 inch) or less to about 2mm (about 0.078 inch) or more, and preferably about 0.5mm (about 0.02 inch) to about 0.75mm (0.03 inch), including all ranges and subranges therebetween. In such examples, the exposed surface area of the working electrode is preferably about 0.000013 square inches (0.0000839 cm 2) or less to about 0.0025 square inches (0.016129 cm 2) or more (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 produce an analyte signal having a current in the femtoa range, picoamp range, nanoamp range, or microampere range, as described in more detail elsewhere herein. However, currents in the picoampere or less range may depend on a variety of factors, such as electronic circuit design (e.g., sample rate, current consumption, a/D converter bit resolution, etc.), membrane system (e.g., permeability of analyte through the membrane system), and exposed surface area of the working electrode. Thus, the exposed electrochemically active surface area of the working electrode may be selected to have a value greater or less than the above-described range, taking into account variations in the membrane system and/or electronic circuitry. In the example 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 over both high and low glucose concentration ranges.

In some alternative examples, the exposed surface area of the working (and/or other) electrode may be increased by changing the cross-section of the electrode itself. For example, in some examples, the cross-section of the working electrode may be defined by a cross, star, clover, rib, dimple, ridge, irregular, or other non-circular configuration; thus, for any predetermined length of electrode, an increase in specific surface area (compared to the area achieved by a circular cross section) can be achieved. For example, increasing the surface area of the working electrode may advantageously provide an increased signal in response to the analyte concentration, which in turn may help improve the signal-to-noise ratio.

In some alternative examples, additional electrodes may be included within the assembly, such as a three-electrode system (working, reference, and counter electrodes) and/or additional working electrodes (e.g., electrodes that may be used to generate oxygen, configured as baseline-subtracted electrodes, or configured to measure additional analytes). U.S. patent No. 7,081,195, entitled "SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS," filed on 7 th 12 th 2004, and U.S. patent No. 7,715,893, entitled "CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR," filed on 3 th 12 th 2004, describe some systems and methods for implementing and using additional working, counter, and/or reference electrodes. In one embodiment, where the sensor includes two working electrodes, the two working electrodes are disposed side-by-side (e.g., extending parallel to each other) and the reference electrode is disposed (e.g., spiral wound) around them. In some examples in which two or more working electrodes are provided, the working electrodes may be formed in a double helix, triple helix, quad helix, etc. configuration along the length of the sensor (e.g., around a reference electrode, an insulating rod, or other support structure). The resulting electrode system may be configured with a suitable membrane system, wherein the first working electrode is configured to measure a first signal comprising glucose and a baseline, and the additional working electrode is configured to measure a baseline signal consisting only of the baseline (e.g., configured substantially similar to the first working electrode with no enzyme disposed thereon). In this way, the baseline signal may be subtracted from the first signal to produce a glucose-only signal that is substantially unaffected by baseline fluctuations and/or interfering substances on the signal. Thus, the above dimensions may be changed as desired. While the present disclosure discloses one electrode configuration including one bulk metal wire and another bulk metal wire helically wound therearound, other electrode configurations are also contemplated. In an alternative example, the working electrode comprises a tube with a reference electrode disposed or coiled therein, with an insulator therebetween. Alternatively, the reference electrode comprises a tube with a working electrode disposed or coiled inside, with an insulator between the two. In another alternative example, a polymer (e.g., insulating) rod is provided with an electrode deposited (e.g., electroplated) thereon. In yet another alternative example, a metal (e.g., steel) rod coated with an insulating material is provided, and the working electrode and the reference electrode are deposited onto the metal rod. In yet another alternative example, one or more working electrodes are helically wound around the reference electrode.

While the methods of the present disclosure are particularly applicable to small-structure, micro-diameter or small-diameter sensors, the methods may also be applicable to larger diameter sensors, for example, sensors having diameters of 1mm to about 2mm or more.

In some alternative examples, the sensing mechanism includes electrodes deposited on a planar substrate, wherein the thickness of the implantable portion is less than about 1mm, see, for example, U.S. Pat. No. 6,175,752 to Say et al and U.S. Pat. No. 5,779,665 to Mastrootaro et al, both of which are incorporated herein by reference in their entirety.

Sensing film

In an example, the sensing membrane 32 is disposed on an electrochemically active surface of the continuous analyte sensor 34 and includes one or more domains or layers. Generally, the function of the sensing membrane is to control the flow of biological fluid therethrough and/or to protect sensitive areas of the sensor from contamination by, for example, biological fluid. Some conventional electrochemical enzyme-based analyte sensors typically include a sensing membrane that controls the flow of the analyte being measured, protects the electrodes from contamination by biological fluids, and/or provides enzymes that catalyze the reaction of the analyte with cofactors, for example. See, for example, U.S. patent publication No. 2005/0245599, filed on 3 months of 2004, entitled "IMPLANTABLE ANALYTE SENSOR", and U.S. patent No. 7,497,827, filed on 10 months of 2005, entitled "TRANSCUTANEOUS ANALYTE SENSOR", each of which is incorporated herein by reference in its entirety.

The sensing membrane of the present disclosure may include any membrane configuration suitable for use with any analyte sensor (such as described in more detail above). Generally, the sensing films of the present disclosure include one or more domains, all or some of which may be adhered or deposited on an analyte sensor, as understood by those of skill in the art. In an example, the sensing film generally provides one or more of the following functions: 1) protecting the exposed electrode surface from the biological environment, 2) diffusion resistance (limitation) of the analyte, 3) a catalyst for effecting the enzymatic reaction, 4) limiting or blocking interfering substances, and 5) hydrophilicity at the electrochemically reactive surface of the sensor interface, such as described in the above-referenced U.S. patent application.

Electrode domain

In some examples, the membrane system includes an optional electrode membrane including an electrode domain. The electrode fields are provided to ensure that an electrochemical reaction occurs between the electrochemically active surfaces of the working electrode and the reference electrode, and thus the electrode fields are preferably located closer to these electrochemically active surfaces than the enzyme fields. Preferably, the electrode field comprises a semipermeable coating that maintains an aqueous layer at the electrochemically reactive surface of the sensor, e.g., a wetting agent in the binder material may be used as the electrode field; this allows for complete transport of ions in an aqueous environment. The electrode domains may also help stabilize the operation of the sensor by overcoming electrode actuation and drift problems caused by insufficient electrolyte. The material forming the electrode domains may also protect the sensor from pH-mediated damage, which may be caused by a large pH gradient formed due to the electrochemical activity of the electrode.

In examples, the electrode domain includes 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 microns, 0.1 microns, 0.15 microns, 0.2 microns, 0.25 microns, 0.3 microns, 0.35 microns, 0.4 microns, 0.45 microns, 0.5 microns, 1 micron, 1.5 microns, 2 microns, 2.5 microns, 3 microns or 3.5 microns to about 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns or 19.5 microns, and more preferably about 2 microns, 2.5 microns or 3 microns to about 3.5 microns, 4 microns, 4.5 microns or 5 microns, including all ranges and subranges therebetween. "Dry film" thickness refers to the thickness of the cured film cast from the coating formulation by standard coating techniques.

In certain examples, the electrode domains are formed from a curable mixture of a urethane polymer and a hydrophilic polymer. Particularly preferred coatings are formed from polyurethane polymers having carboxylate functionality and nonionic hydrophilic polyether segments, wherein 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 suitable temperature of about 50 ℃.

Preferably, the electrode domains are 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 the electrode solution and curing the domain at a temperature of about 40 ℃ to about 55 ℃ for a time of about 15 minutes to about 30 minutes (and may be accomplished under vacuum (e.g., 20mmHg to 30 mmHg)), including all ranges and subranges therebetween. In examples where dip coating is used to deposit the electrode domains, the functional coating is provided with a preferred insertion rate 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 rate of about 0.25 inches/min to about 2 inches/min, including all ranges and subranges therebetween. However, as will be appreciated by those skilled in the art, in some examples, values other than those listed above may be acceptable or even desirable, for example, depending on viscosity and surface tension. In one example, the electrochemically active surface of the electrode system is dip-coated once (one layer) and then cured under vacuum at 50 ℃ for 20 minutes.

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

Interference domain

In some examples, an optional interfering domain is provided that generally includes a polymer domain that restricts the flow of one or more interferents. In some examples, the interfering domains act as molecular sieves that allow the passage of analytes and other substances to be measured by the electrode while preventing the passage of other substances (including interferents such as ascorbate and urea) (see U.S. patent No. 6,001,067 to Shults). Some known interferents of glucose oxidase-based electrochemical sensors include acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, levodopa, methyldopa, salicylates, tetracyclines, tolassulfuron, tolbutamide, triglycerides and uric acid.

Several polymer types that can be used as a base material for the interfering domains include, for example, polyurethanes, polymers with ionic side groups, and polymers with controlled pore sizes. In one example, the interfering domain includes a hydrophobic membrane that is non-swellable and limits low molecular weight species diffusion. The interfering 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 substances that may be applied to the membrane systems of the present disclosure are described in U.S. patent No. 7,074,307, filed on 7.21 2004, entitled "ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS", U.S. patent publication No. 2005/0176136, filed on 11.16 2004, entitled "AFFINITY DOMAIN FOR AN ANALYTE SENSOR", U.S. patent No. 7,081,195, filed on 12.7 2004, entitled "SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS", and U.S. patent No. 7,715,893, entitled "CALIBRATION TECHNIQUES FOR ACONTINUOUS ANALYTE SENSOR", filed on 12.3.2004. In some alternative examples, no distinct interference domains are included.

In an example, the interference domains are deposited onto the electrode domains (or directly onto the electrochemically active surface when no distinct electrode domains are included) to obtain a domain thickness of about 0.05 microns or less to about 20 microns or more, more preferably about 0.05 microns, 0.1 microns, 0.15 microns, 0.2 microns, 0.25 microns, 0.3 microns, 0.35 microns, 0.4 microns, 0.45 microns, 0.5 microns, 1 micron, 1.5 microns, 2 microns, 2.5 microns, 3 microns or 3.5 microns to about 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns or 19.5 microns, and more preferably about 2 microns, 2.5 microns or 3 microns to about 3.5 microns, 4 microns, 4.5 microns or5 microns, including all ranges and subranges therebetween. Thicker films may also be useful, but thinner films are generally preferred because they have only a low effect on the diffusion rate of hydrogen peroxide from the enzyme film to the electrode. Unfortunately, the thin thickness of the interference domains conventionally used can introduce variability in membrane system processing. For example, if too many or too few interfering domains are incorporated into a membrane system, the performance of the membrane may be adversely affected.

Enzyme domain

In one example, the membrane system further comprises an enzyme domain disposed further from the electrochemically active surface than the interfering domain (or electrode domain when no distinct interfering domain is included). In some examples, the enzyme domains are deposited directly onto the electrochemically active surface (when neither the electrode nor the interfering domain is included). In one example, the enzyme domain provides an enzyme that catalyzes a reaction of an 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.

In order for an enzyme-based electrochemical glucose sensor to perform well, the response of the sensor is preferably not limited by either the enzyme activity or the co-reactant concentration. Since enzymes, including glucose oxidase, are deactivated over time even under ambient conditions, this behavior is compensated for when the enzyme domain is formed. Preferably, the enzyme domain consists of an aqueous dispersion of a colloidal polyurethane polymer comprising the enzyme. However, in alternative examples, the enzyme domain is composed of an oxygen enhancing material (e.g., a silicone or fluorocarbon) in order to provide an excess oxygen supply during transient ischemia. Preferably, the enzyme is immobilized within the enzyme domain. See U.S. patent No. 7,379,765, entitled "Oxygen Enhancing Membrane Systems for Implantable Device," filed on 7/21/2004.

In an example, the enzyme domains are deposited onto the interfering domains to obtain a domain thickness of about 0.05 microns or less to about 20 microns or more, more preferably about 0.05 microns, 0.1 microns, 0.15 microns, 0.2 microns, 0.25 microns, 0.3 microns, 0.35 microns, 0.4 microns, 0.45 microns, 0.5 microns, 1 micron, 1.5 microns, 2 microns, 2.5 microns, 3 microns or 3.5 microns to about 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns or 19.5 microns, and more preferably about 2 microns, 2.5 microns or 3 microns to about 3.5 microns, 4 microns, 4.5 microns or 5 microns, including all ranges and subranges therebetween. However, in some examples, the enzyme domains are deposited onto the electrode domains or directly onto the electrochemically active surface. Preferably, the enzyme domains are deposited by spray coating or dip coating. More preferably, the enzyme domain is formed by: dip-coating the electrode domains in an enzyme domain solution and curing the domains at a temperature of about 40 ℃ to about 55 ℃ for about 15 minutes to about 30 minutes (and may be accomplished under vacuum (e.g., 20mmHg to 30 mmHg)), including all ranges and subranges therebetween. In examples where dip coating is used to deposit the enzyme domains at room temperature, the functional coating is provided with a preferred insertion rate 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 rate of about 0.25 inches/min to about 2 inches/min, including all ranges and subranges therebetween. However, as will be appreciated by those skilled in the art, in some examples, values other than those listed above may be acceptable or even desirable, for example, depending on viscosity and surface tension. In one example, the enzyme domains are formed by dip-coating twice (i.e., forming two layers) in a coating solution and curing under vacuum at 50 ℃ for 20 minutes. However, in some examples, the enzyme domains may be formed by dip-coating and/or spray-coating one or more layers at predetermined coating solution concentrations, insertion rates, residence times, withdrawal rates, and/or desired thicknesses.

Resist domain

In one example, the membrane system includes an anti-domain disposed farther from the electrochemically active surface than the enzyme domain. Although the following description refers to the resistant domain of a glucose sensor, the resistant domain may also be adapted for other analytes and co-reactants.

There is a molar excess of glucose relative to the amount of oxygen in the blood; that is, there are typically more than 100 glucose molecules per free oxygen molecule in the extracellular fluid (see Updike et al, diabetes Care 5:207-21 (1982)). However, immobilized enzyme based glucose sensors employing oxygen as a co-reactant preferably derive the oxygen supply in a non-rate limiting excess such that the sensor responds linearly to changes in glucose concentration, but not to changes in oxygen concentration. In particular, when the glucose monitoring reaction is an oxygen limited reaction, linearity cannot be achieved above the minimum concentration of glucose. Without a semipermeable membrane located over the enzyme domain to control the glucose and oxygen flux, a linear response to glucose levels can be obtained only for glucose concentrations up to about 40 mg/dL. However, in a clinical setting, it is desirable that a linear response to glucose levels be obtained at up to at least about 400 mg/dL.

The resistant domain comprises a semipermeable membrane that controls the flux of oxygen and glucose to the underlying enzyme domain, preferably such that the oxygen flows in a non-rate limiting excess. Thus, the upper linear limit of the glucose measurement is extended to a much higher value than would be achieved without the anti-domain. In examples, the neutralizing domain exhibits an oxygen to glucose permeability ratio of about 50:1 or less to about 400:1 or greater, preferably about 200:1, including all ranges and subranges therebetween. As a result, one-dimensional reactant diffusion is sufficient to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (see Rhodes et al, anal. Chem.,66:1520-1529 (1994)).

In alternative examples, a lower oxygen to glucose ratio may be sufficient to provide excess oxygen by using high oxygen solubility domains (e.g., silicone or fluorocarbon based materials or domains) to enhance the supply/transport of oxygen to the enzyme domains. If more oxygen is supplied to the enzyme, more glucose can also be supplied to the enzyme without creating an oxygen rate limiting excess. In an alternative example, the resistant 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 10/28 a 2003.

In a preferred example, the resistant domain comprises a polyurethane membrane having both hydrophilic and hydrophobic regions for controlling diffusion of glucose and oxygen to the analyte sensor, the membrane being readily and reproducibly manufactured from commercially available materials. Suitable hydrophobic polymer components are polyurethanes or polyether polyurethaneureas. Polyurethanes are polymers prepared by the condensation reaction of diisocyanates and difunctional hydroxyl-containing materials. Polyurethaneureas are polymers prepared by the condensation reaction of diisocyanates and difunctional amine-containing materials. In some examples, the diisocyanate includes an aliphatic diisocyanate containing from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be used in the preparation of the polymer and copolymer components of the films of the present disclosure. The material forming the basis of the hydrophobic matrix of the resistant domains may be any of those materials known in the art that are suitable for use as a membrane in a continuous analyte sensor apparatus and that have a permeability large enough to allow the relevant compounds to pass therethrough (e.g., to allow oxygen molecules to pass through the membrane from the sample being examined in order to reach the active enzyme electrode or electrochemical electrode). Examples of materials that may be used to prepare the non-polyurethane films include vinyl polymers, polyethylene vinyl acetate copolymers, polyethers, polyalkylcarbonates, polycarbonates, polyalkyl esters, polyesters, polyamides, inorganic polymers such as polysiloxanes and polycarbosiloxanes, natural polymers such as cellulose-based materials and protein-based materials, and mixtures or combinations thereof.

In a preferred example, the hydrophilic polymer component of the resistant domain is polyethylene oxide. For example, one useful hydrophobic-hydrophilic copolymer component is a polyurethane polymer that includes about 20% hydrophilic polyethylene oxide. The polyethylene oxide portion of the copolymer is thermodynamically driven to separate from the hydrophobic portion and the hydrophobic polymer component of the copolymer. The 20% polyethylene oxide based soft segment portion of the copolymer used to form the final blend affects the absorption of water by the membrane and the subsequent permeability of the membrane to glucose.

In an example, the resistant domains are deposited onto the enzyme domains to produce a domain thickness of about 0.05 microns or less to about 20 microns or more, more preferably about 0.05 microns, 0.1 microns, 0.15 microns, 0.2 microns, 0.25 microns, 0.3 microns, 0.35 microns, 0.4 microns, 0.45 microns, 0.5 microns, 1 micron, 1.5 microns, 2 microns, 2.5 microns, 3 microns or 3.5 microns to about 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns or 19.5 microns, and more preferably about 2 microns, 2.5 microns or 3 microns to about 3.5 microns, 4 microns, 4.5 microns or 5 microns, including all ranges and subranges therebetween. Preferably, the resistant domain is deposited onto the enzyme domain by spraying or dip coating. In some examples, spraying is a preferred deposition technique. The spraying process atomizes the solution and forms a mist, so that most or all of the solvent evaporates before the coating material settles onto the underlying area, thereby minimizing solvent contact with the enzyme. One additional advantage of the spray-on-resistant domains as described in the present disclosure includes forming a membrane system that substantially blocks or resists ascorbate (a known electrochemical interferent in glucose sensors that measure hydrogen peroxide). While not wishing to be bound by theory, it is believed that during the process of depositing the resist domains as described in the present disclosure, a structural morphology is formed, characterized by ascorbate being substantially impermeable therethrough.

In an example, the resist domain is deposited onto the enzyme domain by spraying a solution of about 1 wt% to about 5 wt% polymer and about 95 wt% to about 99 wt% solvent (including all ranges and subranges therebetween). When spraying a solution of the resistant domain material (including a solvent) onto the enzyme domain, it is desirable to reduce or significantly reduce any contact with the enzyme of any solvent in the spray solution that may inactivate the underlying enzyme of the enzyme domain. Tetrahydrofuran (THF) is a solvent that has minimal or negligible effect on enzymes in the enzyme domain when sprayed. Other solvents may also be suitable as will be appreciated by those skilled in the art.

While a variety of spray or deposition techniques may be used, spraying the resist field material and rotating the sensor at least 180 ° once may provide adequate coverage of the resist field. Spraying the resist field material and rotating the sensor at least 120 degrees at least twice provides an even greater coverage (one layer of 360 ° coverage) to ensure resistance to glucose, such as described in more detail above.

In an example, the resist field is sprayed and then cured at a temperature of about 40 ℃ to about 60 ℃ for a time of about 15 minutes to about 90 minutes (and may be accomplished under vacuum (e.g., 20mmHg to 30 mmHg)), including all ranges and subranges therebetween. Curing times as long as about 90 minutes or more may be advantageous to ensure complete drying of the resist domains. While not wishing to be bound by theory, it is believed that complete drying of the resist domain helps stabilize the sensitivity of the glucose sensor signal. It reduces drift in signal sensitivity over time and is believed to fully dry stabilizing the performance of the glucose sensor signal in a low oxygen environment.

In an example, the resist domains are formed by spraying at least six layers (i.e., rotating the sensor seventeen times 120 ° for at least six layers of 360 ° coverage) and curing under vacuum at 50 ℃ for 60 minutes. However, depending on the concentration of the solution, the insertion rate, residence time, withdrawal rate, and/or desired thickness of the resulting film, the resist domains may be formed by dip coating or spray coating any one or more layers.

Advantageously, a sensor having a membrane system of the present disclosure comprising an electrode domain and/or an interference domain, an enzyme domain, and an impedance domain provides a stable signal response to increased glucose levels of about 40mg/dL to about 400mg/dL (including all ranges and subranges therebetween), and provides sustained function (at least 90% signal strength) even at low oxygen levels (e.g., at about 0.6mg/L O ₂). While not wishing to be bound by theory, it is believed that the resistant domain provides sufficient resistance, or the enzyme domain provides sufficient enzyme, such that oxygen limitation is seen at much lower oxygen concentrations than prior art sensors.

In an example, a sensor signal having a current in the picoampere or less range is provided, which is described in more detail elsewhere herein. However, the ability to generate a signal having a current in the picoamp range may depend on a combination of factors, including electronic circuit design (e.g., a/D converter, bit resolution, etc.), membrane system (e.g., analyte permeability through the resist domain, enzyme concentration, and/or electrolyte availability for electrochemical reactions at the electrode), and exposed surface area of the working electrode. For example, depending on the design of the electronic circuit, membrane system, and/or exposed electrochemically active surface area of the working electrode, the resistant domains may be designed to more or less confine the analyte.

Thus, in an example, the membrane system is designed to have a sensitivity of about 1pA/mg/dL to about 100pA/mg/dL, preferably about 5pA/mg/dL to 25pA/mg/dL, and more preferably about 4pA/mg/dL to about 7pA/mg/dL, including all ranges and subranges therebetween. While not wishing to be bound by any particular theory, it is believed that a membrane system designed to have a sensitivity within a preferred range allows for measurement of analyte signals in low analyte and/or low oxygen conditions. That is, conventional analyte sensors exhibit reduced measurement accuracy in the low analyte range due to the lower availability of analyte to the sensor and/or increased signal noise in the high analyte range due to the lack of oxygen necessary to react with the amount of analyte being measured. While not wishing to be bound by theory, it is believed that the membrane system of the present disclosure in combination with an electronic circuit design and an exposed electrochemically reactive surface area design supports analyte measurements in the picoamp range or less, which enables improved levels of resolution and accuracy to be achieved in both the low and high analyte ranges, which are not visible in the prior art.

Although some of the example sensors described herein include an optional interference domain to block or reduce one or more interferents, sensors having the membrane systems of the present disclosure (including electrode, enzyme, and rejection domains) have been shown to inhibit ascorbate without additional interference domains. That is, the membrane systems of the present disclosure, including the electrode domain, the enzyme domain, and the neutralizing domain, have been shown to be substantially nonresponsive to neutralizing the bad-blood acid salts within a physiologically acceptable range. While not wishing to be bound by theory, it is believed that the method of depositing the resistant domains by spray deposition results in a structural morphology that is substantially resistant to the anti-ischemic salts, as described herein.

Membrane system without interference domain

In general, it is believed that the appropriate solvent and/or deposition method may be selected for one or more domains of the membrane system forming one or more transition domains such that the interferents are substantially impermeable therethrough. Thus, a sensor can be constructed that has no distinct or deposited interference domains, which is non-responsive to the interferents. While not wishing to be bound by theory, it is believed that a simplified multilayer film system, a more robust multilayer fabrication process, and reduced variability caused by the thickness of deposited micron thin interference domains and associated oxygen and glucose sensitivity may be provided. In addition, the optional polymer-based interference domains that normally inhibit hydrogen peroxide diffusion are eliminated, thereby increasing the amount of hydrogen peroxide that passes through the membrane system.

Oxygen catheter

As described above, certain sensors rely on enzymes within a membrane system through which a subject's bodily fluid passes, and in which an analyte (e.g., glucose) in the bodily fluid reacts in the presence of a co-reactant (e.g., oxygen) to produce a product. The product is then measured using electrochemical methods, so the output of the electrode system is used as a measure of the analyte. For example, when the sensor is a glucose sensor based on glucose oxidase, the substance measured at the working electrode is H ₂O₂. Enzymes (glucose oxidase) catalyze the conversion of oxygen and glucose to hydrogen peroxide and gluconate according to the following reactions: glucose +O2→gluconate +H2O2

Because there is a proportional change in product H ₂O₂ for each glucose molecule reacted there, the change in H ₂O₂ can be monitored to determine glucose concentration. Oxidation of H ₂O₂ by the working electrode is balanced by, for example, reduction of ambient oxygen, enzyme-generated H ₂O₂, and other reducible species at the counter electrode. See Fraser, d.m. "An Introduction to In vivo Biosensing: progress and Problems". In "Biosensors and the Body," D.M. Fraser, eds., 1997, pages 1-56, john Wiley and Sons, new York))

In vivo, glucose concentration is typically about 100 times or more the oxygen concentration. Thus, oxygen is a limiting reactant in electrochemical reactions, and when insufficient oxygen is provided to the sensor, the sensor cannot accurately measure glucose concentration. Thus, inhibited sensor function or inaccuracy is considered to be the result of oxygen availability issues to enzymes and/or electrochemically active surfaces.

Thus, in an alternative example, an oxygen conduit (e.g., a high oxygen solubility domain formed of a silicone or fluorine-containing compound) extending from an ex vivo portion of the sensor to an in vivo portion of the sensor is provided to increase availability of oxygen to the enzyme. The oxygen conduit may be formed as part of the coating (insulating) material or may be a separate conduit associated with the wire assembly forming the sensor.

FIG. 2B is a cross-sectional view through the sensor of FIG. 2A along line B-B, showing a core 39 having an exposed electrochemically active surface of at least one working electrode 38 surrounded by a sensing film 32. The core 39 is configured for multi-axis bending and may be stainless steel, titanium, tantalum, or a polymer. Generally, the sensing membrane of the present disclosure includes multiple domains or layers, e.g., interference domain 44, enzyme domain 46, and resistance domain 48, and may include additional domains, such as electrode domains, cell impermeable domains (not shown), oxygen domains (not shown), bioactive substance releasing membrane 70, and/or biological interface membrane 68 (not shown), such as described in more detail below and/or in the above-referenced U.S. patent applications. However, it should be understood that it is within the scope of the present disclosure to modify the sensing film for other sensors, for example by including fewer domains or additional domains.

Membrane system

In some examples, one or more domains of the sensing film are formed from the following materials: such as silicone; polytetrafluoroethylene; polyethylene-co-tetrafluoroethylene; a polyolefin; a polyester; a polyalkyl ester; a polyalkylcarbonate; a polycarbonate; biostable polytetrafluoroethylene; homopolymers, copolymers, terpolymers or polyurethaneurea copolymers of polyurethane; polypropylene (PP); polyvinyl chloride (PVC); polyvinylidene fluoride (PVDF); polybutylene terephthalate (PBT); polymethyl methacrylate (PMMA); polyethylene vinyl acetate; polyetheretherketone (PEEK); polyurethane; a cellulosic polymer; poly (ethylene oxide), poly (propylene oxide), and copolymers and blends thereof; polysulfones and block copolymers thereof, including, for example, diblock copolymers, triblock copolymers, alternating copolymers, random copolymers, and graft copolymers. U.S. patent publication 2005/0245999, which is incorporated herein by reference in its entirety, describes a bio-interface and sensing membrane configuration and materials that can be applied to the disclosed sensors.

The sensing film may 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 film surrounding the working electrode does not have to have the same structure as the sensing film surrounding the reference electrode or the like. For example, the enzyme domains deposited on top of the working electrode need not necessarily be deposited on top of the reference electrode and/or the counter electrode.

In the illustrated example, the sensor is an enzyme-based electrochemical sensor in which the working electrode 38 measures electron flow, for example, detecting glucose with glucose oxidase to produce hydrogen peroxide as a byproduct, and H ₂O₂ reacts with the surface of the working electrode to produce two protons (2h+), two electrons (2 e-) and one oxygen molecule (O2), which produce a detected electron flow, or direct electron transfer via a redox system (e.g., a "wired enzyme" system), such as described in more detail above and as understood by those of skill in the art. One or more potentiostats are employed 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 generated at the working electrode. The current generated at the working electrode (and flowing through the circuit to the counter electrode) is substantially proportional to the amount of H ₂O₂ that diffuses to the working electrode or analyte that promotes electron transfer in the wired enzyme system. For example, the output signal is typically a raw data stream that is used to provide the recipient or physician with an available value of measured analyte concentration in the recipient.

Some alternative analyte sensors that may benefit from the systems and methods of the present disclosure include, for example, U.S. patent No. 5,711,861 to Ward et al, U.S. patent No. 6,642,015 to Vachon et al, U.S. patent No. 6,654,625 to Say et al, U.S. patent No. 6,565,509 to Say et al, U.S. patent No. 6,514,718 to Heller, U.S. patent No. 6,465,066 to ESSENPREIS et al, U.S. patent No. 6,214,185 to Offenbacher et al, U.S. patent No. 5,310,469 to Cunningham et al and 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 mastrotaro et al, and U.S. patent No. 6,424,847 to mastrotaro et al. All of the above patents are incorporated by reference herein in their entirety and do not include all applicable analyte sensors; in general, it should be understood that the disclosed examples are applicable to a variety of analyte sensor configurations. Exemplary sensor configuration

FIG. 2C is a cross-sectional view through the sensor of FIG. 2A along line B-B, showing the unexposed electrochemically active surface of at least one working electrode 38 surrounded by a sensing membrane that includes multiple domains or layers, e.g., interference domain 44, enzyme domain 46, and counter domain 48, and that includes additional domains/membranes, such as electrode domains, cell impermeable domains (not shown), oxygen domains (not shown), bioactive substance releasing membrane 70, and/or biological interface membrane 68 (not shown), such as described in more detail below. The bioactive substance releasing membrane 70 is positioned adjacent to the working electrode 38 surface and does not cover multiple domains or layers of the working electrode 38 or the sensing membrane 32 adjacent to the working electrode surface, such as the interference domain 44, the enzyme domain 46, and the rejection domain 48. In one example, the bioactive substance releasing membrane 70 is positioned at the distal end 37 of the sensor 34. In another example, the bioactive substance releasing 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.

Fig. 2D is a cross-sectional view through the sensor of fig. 2A on line D-D of the exemplary bioactive substance releasing film deposition of the sensor 34, wherein the bioactive substance releasing film 70 is farther from the electrode 38 than the anti-domain 48 and/or the bio-interface domain 68 and is adjacent to but does not cover the enzyme domain 46 or the transduction element and/or the interference domain 44 and/or the electrochemically active surface of the sensing region or area. The bioactive substance release film 70 may be disposed on the sensor 34 using one or more of screen printing, spray coating, or dip coating methods, as shown in fig. 2D.

Fig. 2E is a cross-sectional view through the sensor of fig. 2A on line B-B of another exemplary bioactive substance releasing film deposition, wherein the bioactive substance releasing film 70 is farther from the electrode 38 than the anti-domain 48 and/or the bio-interface layer 68 and is adjacent to and generally covers only the tip or distal end 37 of the sensor 34 until and adjacent to and does not cover the electrochemically active surface of the enzyme domain 46 or transduction element and/or the interference domain 44 and/or the sensing region or sensing region. The bioactive substance release film 70 may be disposed on the sensor 34 using one or more of screen printing, spray coating, or dip coating methods, as shown in fig. 2E.

Fig. 2F may be considered to be built upon a general structure as depicted in fig. 2A, with the addition of two or more additional layers to create one or more additional electrodes. Methods for selectively removing two or more windows to create two or more electrodes may also be employed. For example, by adding another conductive layer 38b and insulating layer 35b under the reference electrode layer 30, two electrodes (a first working electrode and (optionally) a second working electrode, etc.) can then be formed, resulting in a dual-electrode sensor or a multi-electrode sensor. For example, the same concepts may be applied to electrodes that generate counter electrodes, measure additional analytes (e.g., oxygen), and the like. Fig. 2G shows a sensor with an additional electrode 38b, where the window is selectively removed to expose working electrodes 38a, 38b between reference electrodes (comprising multiple segments) 30, with a small amount of insulators 35a, 35b exposed therebetween.

While some of the figures herein illustrate sensors that may have a coaxial core and a circular or oval cross-section, in other examples of sensor systems that include a bioactive substance releasing membrane, the sensor may be a substantially planar sensor, as shown in the cross-section for illustration purposes in fig. 2H. For example, as shown in fig. 2H, the continuous analyte sensing device 100 can include a substantially planar substrate 142, and an interference domain 144, an enzyme domain 146, an impedance domain 148, and a biological interface/bioprotective domain 168 and/or a bioactive substance release domain 170 disposed in a substantially planar manner about the substantially planar substrate 142 with one or more working electrodes. Referring to fig. 2G-2H, in some examples, reference electrode 30 includes a silver-containing material applied to at least a portion of insulating material 35. In some examples, silver-containing materials are 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, in an example, a silver-containing or silver chloride-containing coating (or similar formulation) is applied to a reel of insulated conductive cores. In another example, a reel of insulating elongated body (or core) is cut into individual die (e.g., "singulated") and silver-containing ink is pad printed onto it. In still other examples, the silver-containing material is applied as a silver foil. For example, an adhesive may be applied to an insulating elongated body, and then a silver foil wrapped around the elongated body. Alternatively, the sensor may be rolled in Ag/AgC1 particles such that a sufficient amount of silver sticks to and/or embeds and/or otherwise adheres to the binder to allow the particles to function as a reference electrode. In some examples, the reference electrode of the sensor includes a sufficient amount of silver chloride such that the sensor measures and/or detects the analyte for at least three days.

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

Fig. 2G is a diagram showing the layers cut away, but during the manufacturing process, the material typically obtained has all layers ending at the top end. The step of removing layers 30 and 30 may be performed to form a window. Fig. 2I illustrates the result of this removal/excision process in side view/cross section. The removal process may be accomplished by methods already described or other methods known in the art. In one example, the removing step is performed, for example, by laser scraping, and may be performed in a reel-to-reel process on a continuous string. For example, by removing different layers at different lengths, the removed areas may be stepped (fig. 2I). In such manufacturing methods involving continuous strings, the sensor may be singulated after the removal step, resulting in singulation 29 (fig. 7A-7C). In some examples, if the core is metal, an end cap may be employed, such as by dipping, spraying, heat shrinking tubing, crimping onto the top end, or the like, with an insulating or other insulating material. If the core is a polymer (e.g., a hydrophobic material), the end cap may not be necessary. For example, in the sensor depicted in fig. 2I, an end cap 40 (e.g., made of a polymer or insulating material) or other structure may be provided on the core (e.g., if the core 39 is not insulating).

Fig. 2J may be considered to be built upon a generic structure as depicted in fig. 2G, with the addition of two or more additional layers to create one or more additional electrodes. Methods for selectively removing two or more windows to create two or more electrodes may also be employed. For example, by adding another conductive layer 38b and an insulating layer 35b under the reference electrode layer 30, two electrodes (a first working electrode and a second working electrode) can then be formed, resulting in a dual electrode sensor. For example, the same concepts may be applied to electrodes that generate counter electrodes, measure additional analytes (e.g., oxygen), and the like.

Fig. 2K shows a sensor with an additional electrode 38b (as compared to fig. 2G-2I), where the window is selectively removed to expose working electrodes 38a, 38b between reference electrodes (including various segments) 30, with a small amount of insulator 35a, 35b exposed therebetween. Fig. 2L illustrates another example in which selective removal of layers is performed stepwise to expose electrodes 38a, 38b and insulators 35a, 35b along the length of the elongate body.

FIG. 2J is a cross-sectional view of an alternative sensor configuration showing an unexposed electrochemically active surface of at least one working electrode 38 surrounded by a sensing membrane 32 that includes multiple domains or layers, e.g., interference domain 44, enzyme domain 46, and rejection domain 48, and additional domains/membranes, such as electrode domains, cell impermeable domains (not shown), oxygen domains (not shown), bioactive substance releasing membrane 70, and/or biological interface membrane 68 (not shown), such as described in more detail below. The bioactive substance releasing membrane 70 is positioned adjacent to the surface of the working electrode 38 and does not cover multiple domains or layers of the working electrode 38 or the sensing membrane 32 associated with the working electrode, such as the interference domain 44, the enzyme domain 46, and the rejection domain 48. As shown in fig. 2J, a bioactive diffusion regulating membrane 73 is provided adjacent to the bioactive substance releasing membrane 70. In one example, the diffusion regulating membrane 73 is directly adjacent to the bioactive substance releasing membrane 70. In another example, the diffusion regulating membrane 73 is chemically, structurally, or functionally different from the bioactive substance releasing membrane 70. In another example, the diffusion regulating membrane 73 is a block copolymer, such as a polyurethane block polymer having a hard segment and a soft segment, wherein the soft segment may include a hydrophobic portion, a hydrophilic portion, or a combination of hydrophobic/hydrophilic portions. Each of the hydrophobic/hydrophilic moieties may independently have a different average molecular weight or chain length. In another example, the diffusion regulating membrane 73 is a segmented block copolymer of a soft segment comprising a combination of hydrophobic/hydrophilic moieties such as a polyol (polyethylene oxide, polyethylene propylene oxide, polytetrahydrofuran or polytetramethylene oxide), polyether, polysiloxane, polyamine, polysiloxane amine, polyester, polyalkyl ester, polyalkylcarbonate, polycarbonate and one or more separate hard segments such as aliphatic or aromatic diisocyanates such as norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene Diisocyanate (TDI), 1, 3-phenylene diisocyanate (MPDI), trans-1, 3-bis (isocyanatomethyl) cyclohexane (1, 3-H6 XDI), dicyclohexylmethane-4, 4' -diisocyanate (HMDI), 4' -diphenylmethane diisocyanate (MDI), trans-1, 4-bis (isocyanatomethyl) cyclohexane (1, 4-H6 XDI), 1, 4-Cyclohexyldiisocyanate (CHDI), 1, 4-phenylene diisocyanate (3, 3' -bis (isocyanatomethyl) cyclohexane (1, 4-H6 XDI), hexamethylene diisocyanate (PPDI), or a combination thereof.

In another example, the diffusion regulating membrane 73 is a multi-block copolymer. In another example, the diffusion regulating membrane is annealed to provide a stable separate phase and/or to provide a diffusion path for release of the bioactive agent. In an example, the diffusion regulating membrane 73 is applied continuously, semi-continuously or stepwise (randomly or in a pattern) to the bioactive substance releasing membrane 70.

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

Fig. 3A is a schematic side view of a transdermal analyte sensor 50 in one example. The sensor 50 includes a mounting unit 52 adapted to be mounted on the skin of a subject, a small (diameter) structural sensor 34 (as defined herein) adapted to be inserted percutaneously through the skin of the subject, and an electrical connection configured to provide a secure electrical contact between the sensor and electronics preferably housed within the mounting unit 52. Generally, the mounting unit 52 is designed to maintain the integrity of the sensor in the subject in order to reduce or eliminate motion conversion between the mounting unit, the subject and/or the sensor. See U.S. patent publication No. 2006/0020187, entitled "TRANSCUTANEOUS ANALYTE SENSOR," filed 3/10/2005, which is incorporated herein by reference in its entirety. In one example, a bioactive substance releasing film is formed on the sensing mechanism 36, as described in more detail below.

Fig. 3B is a schematic side view of transdermal analyte sensor 54 in an alternative example. The transcutaneous analyte sensor 54 comprises a mounting unit 52, wherein the sensing mechanism 36 comprises a small structure as defined herein, and is tethered to the mounting unit 52 via a cable 56 (alternatively a wireless connection may be utilized). The mounting unit is adapted to be mounted on the skin of a subject and is operatively connected via a tether or the like to a small-structure sensor 34 adapted to be inserted percutaneously through the skin of the subject and to measure an analyte therein; see, for example, U.S. patent No. 6,558,330 to Causey III et al, which is incorporated herein by reference in its entirety. In one example, a bioactive substance release film 70 is formed on at least a portion of the sensing mechanism 36, as described in more detail below.

The sensors of the present disclosure may be inserted into various locations on the subject's body, such as the abdomen, thigh, upper arm, and neck or behind the ear. Although the present disclosure may suggest insertion through the abdominal region, the systems and methods described herein are not limited to either abdominal insertion or subcutaneous insertion. Those skilled in the art will appreciate 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.

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

After insertion, the fluid moves into the spacer region, e.g., a biocompatible matrix or membrane, such as a bioactive substance releasing membrane 70 and/or a biological interface membrane 68, creating a fluid-filled bag therein. This process may occur immediately or may occur over a period of time, such as minutes or hours after insertion. The signal from the sensor is then detected, such as by sensor electronics in a mounting unit located on the skin surface of the recipient. Generally, the sensor may be used continuously for a period of days, such as 1 to 7 days, 14 days, or 21 days. After use, the sensor is simply removed from the skin of the recipient. In one example, the recipient may repeat the inserting and detecting steps as many times as desired. In some embodiments, the sensor may be removed after about 3 days, then another sensor inserted, and so on. Similarly, in other embodiments, the sensor is removed after about 3, 5, 7, 10, or 14 days, followed by insertion of a new sensor, and so forth.

Some examples of transdermal analyte sensors are described in the following documents: U.S. patent No. 8,133,178 to Brauker et al (incorporated herein by reference in its entirety) and U.S. patent nos. 8,828,201, simpson et al; 9,131,885, simpson et al; 9,237,864 to simpson et al; and 9,763,608, simpson et al, each of which is incorporated herein by reference in its entirety. Generally, a transdermal analyte sensor includes a sensor and a mounting unit having electronics associated therewith.

Generally, the mounting unit includes a base adapted to be mounted on the skin of a subject, a sensor adapted to be inserted percutaneously through the skin of the subject, and one or more contact points configured to provide secure electrical contact between the sensor and the sensor electronics. The mounting unit is designed to maintain the integrity of the sensor in the subject so as to reduce or eliminate motion conversion between the mounting unit, the subject and/or the sensor. The base may be formed of a variety of hard or soft materials and preferably includes a low profile to minimize protrusion of the device from the recipient during use. In some examples, the base is formed at least in part from a flexible material that is believed to provide a number of advantages over conventional percutaneous sensors that, unfortunately, may suffer from motion-related artifacts associated with the movement of the recipient when the recipient uses the device. For example, when a transdermal analyte sensor is inserted into a subject, 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 subject (dermal or subcutaneous)) create stresses on the device and may create noise in the sensor signal. It is believed that even small movements of the skin may translate into discomfort and/or movement related artifacts, which may be reduced or eliminated by the flexible or hinged base. Thus, by providing flexibility and/or articulation of the device to the skin of the subject, a better consistency of the regular use and movement of the sensor system to the subject may be achieved. The flexibility or articulation is believed to increase the adhesion of the mounting unit to the skin (through the use of an adhesive pad) thereby reducing motion-related artifacts that could otherwise be translated by the motion of the recipient and reduce sensor performance.

In some examples, the mounting unit may be provided with an adhesive pad, preferably provided on a rear surface of the mounting unit and preferably comprising a releasable backing layer. Thus, removing the backing layer and pressing the base portion of the mounting unit against the skin of the recipient adheres the mounting unit to the skin of the recipient. Additionally or alternatively, after sensor insertion is completed, an adhesive pad may be placed over some or all of the sensor system to ensure adhesion, and optionally, an airtight or watertight seal around the wound outlet site (or sensor insertion site). An appropriate adhesive pad may be selected and designed to stretch, elongate, conform to, and/or vent the area (e.g., the skin of the recipient).

In examples, the adhesive pad is formed from spunlaced, open or closed cell foam, and/or nonwoven fibers and includes an adhesive disposed thereon, however, as will be appreciated by those skilled in the medical adhesive pad arts, a variety of adhesive pads suitable for adhering to the skin of a recipient may be used. In some examples, a double-sided adhesive pad is used to adhere the mounting unit to the skin of the recipient. In other examples, the adhesive pad includes a foam layer, such as a layer in which foam is disposed between the side edges of the adhesive pad and acts as a shock absorber.

In some examples, the surface area of the adhesive pad is greater than the surface area of the rear surface of the mounting unit. Alternatively, the adhesive pad may be sized to have substantially the same surface area as the rear surface of the base portion. Preferably, the surface area of the adhesive pad on the side to be mounted on the skin of the recipient is about 1, 1.25, 1.5, 1.75, 2, 2.25 or 2.5 times greater than the surface area of the rear surface of the mounting unit substrate. Such a greater surface area may increase adhesion between the mounting unit and the recipient's skin, minimize movement between the mounting unit and the recipient's skin, and/or protect the wound outlet site (sensor insertion site) from environmental and/or biological contamination. However, in some alternative examples, the surface area of the adhesive pad may be less than the rear surface, provided that adequate adhesion can be achieved.

In some examples, the adhesive pad has substantially the same shape as the back surface of the base, but other shapes, such as butterfly, circular, positive, or rectangular, may also be advantageously employed. The adhesive pad backing may be designed for two-step release, such as a primary release (where only a portion of the adhesive pad is initially exposed to allow adjustable positioning of the device) and a secondary release (where the remaining adhesive pad is later exposed to securely and safely adhere the device to the recipient's skin after proper positioning). The adhesive pad is preferably waterproof. Preferably, a stretch releasing adhesive pad is provided on the rear surface of the base portion to enable easy release from the skin of the recipient at the end of the usable life of the sensor.

In some cases, it has been found that conventional bonding between the adhesive pad and the mounting unit may be inadequate, for example, due to humidity that may cause the adhesive pad to peel away from the mounting unit. Thus, in some examples, an adhesive activated or accelerated by ultraviolet, sonic, radio frequency, or moisture curing may be used to bond the adhesive pads. In some examples, the eutectic bonding of the first composite and the second composite may form a strong adhesion. In some examples, the surface of the mounting unit may be pretreated with ozone, plasma, chemicals, or the like, in order to enhance the adhesion of the surface.

The bioactive agent is preferably topically applied to the insertion site prior to or during sensor insertion. Suitable bioactive agents include those known to hinder or prevent bacterial growth and infection, e.g., anti-inflammatory agents, antimicrobial agents, antibiotics, and the like. It is believed that the diffusion or presence of the bioactive agent may help prevent or eliminate bacteria adjacent to the exit site. Additionally or alternatively, the bioactive agent may be integrated with or coated on the adhesive pad, or no bioactive agent may be employed at all.

In some examples, an applicator is provided for inserting the sensor through the skin of the recipient with the aid of a needle at an appropriate insertion angle, and for subsequently removing the needle using a continuous push-pull action. Preferably, the applicator comprises an applicator body guiding the applicator and comprising an applicator body base configured to cooperate with the mounting unit during insertion of the sensor into the recipient. The fit between the applicator body base and the mounting unit may use any known fit arrangement, such as a snap fit, press fit, interference fit, etc., to resist separation during use. The one or more release spring keys enable release of the applicator body base, for example, when the applicator body base is snap-fitted into the mounting unit.

The sensor electronics include hardware, firmware, and/or software capable of measuring analyte levels by the sensor. For example, the sensor electronics may include a potentiostat, a power supply for providing power to the sensor, other components for signal processing, and preferably an RF module for transmitting data from the sensor electronics to the receiver. The electronic device may be fixed to a Printed Circuit Board (PCB) or the like, and may take various forms. For example, the electronic device may take the form of an Integrated Circuit (IC), such as an Application Specific Integrated Circuit (ASIC), a microcontroller, or a processor. Preferably, the sensor electronics include a system and method 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 entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA" filed 8/1/2003.

In this example, the sensor electronics are configured to releasably mate with the mounting unit after insertion of the sensor using the applicator and subsequent release of the applicator from the mounting unit. In an example, the electronic device is configured with programming, such as initialization, calibration reset, fault test, etc., each time the electronic device is initially inserted into the mounting unit and/or each time the electronic device is initially in communication with the sensor.

Sensor electronics

The following description of the electronics associated with the sensor applies to a variety of continuous analyte sensors, such as non-invasive, minimally invasive, and/or invasive (e.g., percutaneous and fully implantable) sensors. For example, the sensor electronics and data processing described below, as well as the receiver electronics and data processing, may be incorporated into fully implantable glucose sensors disclosed in U.S. patent publication 2005/0245499, entitled "IMPLANTABLE ANALYTE SENSOR", filed on day 5, 3, 2004, and U.S. patent publication 2006/0015020, entitled "SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM", filed on day 7, 2004.

In one example, a potentiostat operatively connected to an electrode system (such as described above) provides a voltage to the electrodes that biases the sensor to be able to measure a current signal (also referred to as an analog portion) indicative of the concentration of the analyte in the subject. In some examples, the potentiostat includes a resistor that converts current into voltage. In some alternative examples, a current to frequency converter is provided that is configured to continuously integrate a measured current, for example, using a charge counting device. The a/D converter digitizes the analog signal into a digital signal (also referred to as a "count") for processing. Thus, the raw data stream (also referred to as raw sensor data) obtained in the count is directly related to the current measured by the potentiostat.

The processor module includes a central control unit that controls the processing of the sensor electronics. In some examples, the processor module includes a microprocessor, however computer systems other than microprocessors may be used to process data as described herein, e.g., ASICs may be used for some or all of the sensor central processing. The processor typically provides semi-permanent storage of data, e.g., storing data such as SENSOR Identifiers (IDs) and programming FOR processing the data stream (e.g., programming FOR data smoothing and/or replacement signal artifacts, such as described in U.S. patent No. 8,010,174, filed on 8/22/2003, entitled "SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM"). The processor may additionally be used for a cache memory of the system, for example for temporarily storing the most recent sensor data. In some examples, the processor module includes memory storage components such as ROM, RAM, dynamic RAM, static RAM, non-static RAM, EEPROM, rewritable ROM, flash memory, and the like.

In some examples, the processor module includes a digital filter (e.g., IIR or FIR filter) configured to smooth the raw data stream from the a/D converter. Typically, a digital filter is programmed to filter data sampled at predetermined time intervals (also referred to as a sampling rate). In some examples, wherein the potentiostat is configured to measure the analyte at discrete time intervals, the time intervals determine the sampling rate of the digital filter. In some alternative examples, where the potentiostat is configured to continuously measure the analyte, for example using a current and frequency converter as described above, the processor module may be programmed to request digital values from the a/D converter at predetermined time intervals (also referred to as acquisition times). In these alternative examples, the values obtained by the processor are advantageously averaged over the acquisition time due to the continuity of the current measurements. Thus, the acquisition time determines the sampling rate of the digital filter. In one example, the processor module is configured with a programmable acquisition time, i.e., the predetermined time interval for requesting a digital value from the a/D converter is programmable by a user within the digital circuitry of the processor module. Acquisition times of about 2 seconds to about 512 seconds are preferred; however, any acquisition time may be programmed into the processor module. The programmable acquisition time is advantageous in optimizing noise filtering, time lags, and processing/battery power.

Preferably, the processor module is configured to construct data packets for transmission to an external source, e.g., RF, to a receiver, as described in more detail below. Typically, the data packet includes a plurality of bits, which may include a sensor ID code, raw data, filtered data, and/or error detection or correction. The processor module may be configured to transmit any combination of raw data and/or filtered data.

In some examples, the processor module further includes a transmitter portion or the like that determines a transmission interval of the sensor data to the receiver. In some examples, the transmitter portion that determines the transmission interval is configured to be programmable. In one such example, a coefficient (e.g., a number from about 1 to about 100 or more) may be selected, where the coefficient is multiplied by the acquisition time (or sampling rate) (such as described above) to define the transmission interval of the data packet. Thus, in some examples, the transmission interval is programmable between about 2 seconds and about 850 minutes, more preferably between about 30 seconds and 5 minutes. However, any transmission interval may be programmable or programmed into the processor module. However, various alternative systems and methods for providing programmable transmission intervals may also be employed. By providing programmable transmission intervals, data transmission can be customized to meet a variety of design criteria (e.g., reduced battery consumption, timeliness of reporting sensor values, etc.).

Conventional glucose sensors measure currents in the nanoamp range. In contrast to conventional glucose sensors, the disclosed sensors are configured to measure current in the picoamp range (and in some examples, in femto amps). That is, for each unit (mg/dL) of glucose measured, a current of at least 1 picoamp is measured. Preferably, the analog portion of the a/D converter is configured to continuously measure the current flowing at the working electrode and to convert the current measurement result into a digital value representing the current. In an example, the current is measured by a charge counting device (e.g., a capacitor). Thus, a signal is provided whereby high sensitivity maximizes the signal received by a minimum amount of measured hydrogen peroxide (e.g., minimum glucose requirement that does not sacrifice accuracy even in low glucose ranges), thereby reducing sensitivity to in vivo oxygen limitations (e.g., in oxygen-dependent glucose sensors).

The battery is operatively connected to the sensor electronics and provides power to the sensor. In an example, the battery is a lithium manganese dioxide battery; however, any suitable size and power battery may be used (e.g., a No. seven battery (AAA), a nickel cadmium battery, a zinc carbon battery, an alkaline battery, a lithium battery, a nickel metal hydride battery, a lithium ion battery, a zinc air battery, a zinc mercury oxide battery, a silver zinc battery, and/or a fully sealed battery). In some examples, the battery is rechargeable and/or multiple batteries may be used to power the system. For example, the sensor may be powered transdermally via inductive coupling. In some examples, the quartz crystal is operably connected to the processor and maintains system time for the computer system as a whole, such as for programmable acquisition time within the processor module.

An optional temperature probe may be provided, wherein the temperature probe is located on the electronics or the glucose sensor itself. The temperature probe may be used to measure the ambient temperature in the vicinity of the glucose sensor. The temperature measurement may be used to add temperature compensation to the calculated glucose value.

The RF module is operatively connected to the processor and transmits sensor data from the sensor to the receiver within a wireless transmission via the antenna. In some examples, the second quartz crystal provides a time base for an RF carrier frequency used for data transmission from the RF transceiver. However, in some alternative examples, other mechanisms such as optics, infrared Radiation (IR), ultrasound, etc. may be used to transmit and/or receive data.

In the RF telemetry module of the present disclosure, the hardware and software are designed for low power requirements to increase the lifetime of the device (e.g., to enable a lifetime of about 3 months to about 24 months or more), with maximum RF transmission from an in vivo environment to an ex vivo environment (e.g., a distance of about 1 meter to 10 meters or more) for a fully implantable sensor. Preferably, a high frequency carrier signal of about 402MHz to about 433MHz is employed in order to maintain a low power requirement. Additionally, in a fully implantable device, the carrier frequency is adapted to the physiological attenuation level by tuning the RF module in an analog in-vivo environment to ensure post-implantation RF functionality; thus, a preferred glucose sensor can maintain sensor function for 3 months, 6 months, 12 months, or 24 months or longer.

In some examples, the output signal (from the sensor electronics) is sent to a receiver (e.g., a computer or other communication station). For example, the output signal is typically a raw data stream that is used to provide the patient or physician with available values of measured analyte concentration. In some examples, the raw data stream may be continuously or periodically algorithmically smoothed or otherwise modified to reduce deviation points that inaccurately represent analyte concentration due to, FOR example, signal noise or other signal artifacts, such as described in U.S. patent No. 6,931,327, filed on 8/1/2003, entitled "SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM," which is incorporated herein by reference in its entirety.

When the sensor is first implanted in the recipient tissue, the sensor and receiver are initialized. This may be referred to as a start-up mode and includes optionally resetting the sensor data and calibrating the sensor. In selected examples, mating the electronic unit to the mounting unit triggers a start-up mode. In other examples, the start-up mode is triggered by the receiver.

Receiver with a receiver body

In some examples, the sensor electronics are wirelessly connected to the receiver via unidirectional or bidirectional RF transmission or the like. However, wired connections are also contemplated. The receiver provides for a number of processes and displays of sensor data and may be selectively worn and/or removed at the convenience of the recipient. Thus, the sensor system may be carefully worn, and the receiver providing many processes and displays of the sensor data may be selectively worn and/or removed at the convenience of the recipient. In particular, the receiver includes programming for retrospectively and/or prospectively initiating calibration, converting sensor data, updating calibration, evaluating received reference and sensor data, and evaluating calibration of the analyte sensor, such as described in more detail in U.S. patent No. 7,778,680, entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA," filed on 8-1-2003.

Fig. 3C is a schematic side view of a fully implantable analyte sensor 53 in one example. The sensor includes a sensor body 60 adapted for subcutaneous implantation and includes a sensor 34 having a small structure as defined herein. U.S. patent publication No. 2004/0199059 to Brauker et al, which is incorporated herein by reference in its entirety, describes a system and method suitable for use with the sensor body 60. In one example, a biological interface film 68 is formed onto the sensing mechanism 36, as described in more detail elsewhere herein. The sensor body 60 includes sensor electronics and preferably communicates with a receiver, as described in more detail above. As shown in fig. 3C, a bioactive substance releasing film 70 is disposed on at least a portion of the bio-interface film 68 and/or the sensing film 32.

Fig. 3D is a schematic side view of a fully implantable analyte sensor 62 in an alternative example. The fully implantable analyte sensor 62 includes a sensor body 60 and a sensor 34 having a small structure as defined herein. The sensor body 60 includes sensor electronics and preferably communicates with a receiver, as described in more detail above.

In one example, a biological interface film 68 is formed onto the sensing mechanism 36, as described in more detail elsewhere herein. In another example, a bioactive substance release film 70 is formed on at least a portion of the sensing mechanism 36. In another example, the bioactive substance releasing membrane 70 is formed on discrete, separated portions of the sensing mechanism 36. In yet another example, the biological interface film 68 is formed on at least a portion of the bioactive substance releasing film 70. In yet another example, a bioactive substance releasing film 70 is formed on at least a portion of the biological interface film 68. In one example, a matrix or frame 64 surrounds the sensing mechanism 36 for protecting the sensor from some foreign object processes, such as by pressing tissue against or around the frame 64 instead of the sensing mechanism 36.

Generally, the optional protective frame 64 is formed of a two-or three-dimensional flexible, semi-rigid, or rigid matrix (e.g., mesh) and includes spaces or pores through which the analyte may pass. In some examples, the frame is incorporated as part of the biological interface film, however to provide a separate frame. While not wishing to be bound by theory, it is believed that the frame 64 protects the sensing mechanism, which has a small structure, from mechanical forces generated in the body.

Fig. 3E is a schematic side view of a fully implantable analyte sensor 66 in another alternative example. The sensor 66 includes a sensor body 60 and a sensor 34 having a small structure, as defined herein, having a biological interface film 68 and/or a bioactive substance releasing film 70, such as described in more detail elsewhere herein. Preferably, the frame 64 protects the sensing mechanism 36, such as described in more detail above. The sensor body 60 includes sensor electronics and preferably communicates with a receiver, as described in more detail above.

In some examples, a sensing device adapted to be implanted entirely within a subject (such as in soft tissue beneath the skin) is implanted subcutaneously, such as, for example, in the abdomen of the subject. Due to the small size of the sensor, one skilled in the art will appreciate that a variety of suitable implantation sites are available. In some examples, the sensor configuration is less than about 0.5mm in at least one dimension, such as a wire-based sensor having a diameter of less than about 0.5 mm. In another illustrative example, the sensor may be 0.5mm thick, 3mm long, and 2cm wide, such as a substrate, needle, wire, rod, sheet, or pouch, which may be narrow, for example. In another illustrative example, a plurality of wires about 1mm wide and about 5mm long may be connected at their first ends, creating a fork-like sensor structure. In yet another example, a 1mm wide sensor may be coiled to create a planar spiral sensor structure. Although a few examples are cited above, the present disclosure contemplates many other useful examples, as will be appreciated by those skilled in the art.

After implantation, the tissue is allowed to grow inward within the biological interface for a period of time. The length of time required for tissue ingrowth varies from recipient to recipient, such as from about one week to about 3 weeks, although other time periods are possible. Once the mature bed of vascularized tissue has grown into the biological interface, signals can be detected from the sensor as described elsewhere herein and in U.S. patent publication 2005/0245999 entitled "IMPLANTABLE ANALYTE SENSOR" to Brauker et al, which is incorporated herein in its entirety. The long-term sensor may remain implanted and generate glucose signal information for months to years, as described in the above-mentioned patent applications.

In some examples, the device is configured such that the sensing unit is separated from the electronics unit by a tether or cable or similar structure (similar to the structure shown in fig. 3B). Those skilled in the art will recognize that various known and useful means may be used to tether the sensor to the electronics. While not wishing to be bound by theory, it is believed that the FBR for an individual electronics unit may be greater than the FBR for an individual sensing unit, for example, due to the greater mass of the electronics unit. Thus, the separation of the sensing unit and the electronics unit effectively reduces the FBR to the sensing unit and results in improved device functionality. As described elsewhere herein, the construction and/or composition of the sensing unit (e.g., including a bioactive substance release film having certain bioactive agents) can be implemented to further reduce foreign body reactions to tethered sensing units.

In another example, the analyte sensor is designed with separate electronics and sensing units, where the sensing units are inductively coupled to the electronics units. In this example, the electronics unit provides power to the sensing unit and/or enables data communication therebetween. Fig. 3F and 3G illustrate exemplary systems employing inductive coupling between electronics unit 52 and sensing unit 58.

Fig. 3F is a side view of one example of an implanted sensor inductively coupled to an electronic unit over a functionally useful distance on the skin of a recipient. Fig. 3F shows the sensing unit 58 (including the sensing mechanism 36), the biological interface film 68 and the bioactive substance releasing film 70 at the distal end 37 of the sensor 34, and the chiplet 216 implanted under the subject's skin 212 within the subject's tissue 210. In this example, most of the electronics associated with the sensor are housed in an electronics unit 52 (also referred to as a mounting unit) that is located in close proximity on the recipient's skin. The electronics unit 52 is inductively coupled to the small electronic chip 216 on the sensing unit 58 and thereby transmits power to the sensor and/or collects data, for example. The small electronic chip 216 coupled to the sensing unit 58 provides the necessary electronics to provide bias potentials to the sensor, measure signal output, and/or other necessary requirements to allow the mechanism of the sensing unit 58 to function (e.g., the chip 216 may include an ASIC (application specific integrated circuit), antenna, and other necessary components as understood by those skilled in the art).

In yet another example, the implanted sensor additionally comprises a capacitor to provide the necessary power for the function of the device. A portable scanner (e.g., a stick-like device) is used to collect data stored on the circuit and/or recharge the device.

Generally, inductive coupling enables power to be transmitted to the sensor for continuous power supply, recharging, and the like, as described herein. In addition, inductive coupling utilizes appropriately spaced and oriented antennas (e.g., coils) on the sensing unit and the electronics unit in order to efficiently transmit/receive power (e.g., current) and/or data communications therebetween. One or more coils in each sensing and electronics unit may provide the necessary power induction and/or data transmission.

In this example, the sensing mechanism may be, for example, a wire-based sensor, as described in more detail with reference to fig. 2A and 2B and as described in U.S. patent publication No. 2006/0020187, or a planar substrate-based sensor, such as described in U.S. patent No. 6,175,752 to Say et al and U.S. patent No. 5,779,665 to masmototaro et al, all of which are incorporated herein by reference in their entirety. The biological interface film 68 may be any suitable biological interface, such as a porous biological interface film material layer, a mesh cage, or the like, as described in more detail elsewhere herein. In one illustrative example, the biological interface membrane 68 is a single or multi-layer sheet (e.g., pouch) of porous membrane material (such as ePTFE) in which the sensing mechanism 36 is incorporated.

Fig. 3G is a side view of one example of an implanted sensor inductively coupled to an electronic unit in implanted recipient tissue at a functionally useful distance. Fig. 3G shows a sensing unit 58 and electronics unit 52 similar to those described above with reference to fig. 3F, however both are implanted in reasonably close proximity under the skin of the recipient.

In general, it is believed that when the electronics unit 52 carrying the majority of the mass of the implantable device is separated from the sensing unit 58, less foreign body reaction will occur around the sensing unit (e.g., as compared to a device of greater mass (e.g., a device including certain electronics and/or a power source)). Thus, the configuration of the sensing unit including the biological interface membrane and/or the bioactive substance releasing membrane may be optimized to minimize and/or alter tissue reactions of the recipient, e.g., with minimal mass as described in more detail elsewhere.

Biological interface film/layer

In one example, the sensor includes a porous material disposed on portions thereof that alters the response of the recipient tissue to the sensor. In some examples, the porous material surrounding the sensor advantageously enhances sensor performance and extends sensor life by slowing or reducing cell migration to the sensor and associated degradation that would otherwise be caused by cell invasion if the sensor were directly exposed to the in vivo environment. Alternatively, the porous material may provide stabilization of the sensor via tissue ingrowth into the porous material over a long period of time. Suitable porous materials include silicones; polytetrafluoroethylene; expanded polytetrafluoroethylene; polyethylene-co-tetrafluoroethylene; a polyolefin; a polyester; a polyalkylcarbonate; a polycarbonate; biostable polytetrafluoroethylene; homopolymers, copolymers, terpolymers of polyurethane; polypropylene (PP); polyvinyl chloride (PVC); polyvinylidene fluoride (PVDF); polyvinyl alcohol (PVA); polybutylene terephthalate (PBT); polymethyl methacrylate (PMMA); polyetheretherketone (PEEK); a polyamide; polyurethane; a polyurethaneurea copolymer; a cellulosic polymer; 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; and metals, ceramics, cellulose, hydrogel polymers, polyethylene vinyl acetate (EVA), poly (2-hydroxyethyl methacrylate) (pHEMA), hydroxyethyl methacrylate (HEMA), polyacrylonitrile-polyvinylchloride (PAN-PVC), high density polyethylene, acrylic acid copolymers, nylon, polydifluoroethylene, polyanhydrides, poly (L-lysine), poly (L-lactic acid), hydroxyethyl methacrylate, hydroxyapatite (hydroxyapeptite), alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium alloys, nitinol, stainless steel, and CoCr alloys, and the like, such as described in U.S. patent No. 7,875,293 to date 5 and 22 to date 8 of 2003 entitled "POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES".

In some examples, the porous material surrounding the sensor provides unique advantages in vivo (e.g., 1 day to 14 days) that can be used to enhance sensor performance and extend sensor life. However, such materials may also provide long term (e.g., greater than 14 days) advantages. In particular, the in vivo portion of the sensor (the portion of the sensor that is implanted in the recipient tissue) is encased (partially or completely) in a porous material. The porous material may 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 may be deposited on the sensor (e.g., by directly electrospinning the polymer thereon). In yet other alternative examples, the sensor is inserted into a selected section of porous biological material. Other methods of surrounding the in vivo portion of the sensor with a porous material may also be used, as will be appreciated by those skilled in the art.

The porous material surrounding the sensor advantageously slows or reduces migration of cells to the sensor and associated degradation that would otherwise 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 migration of cells to the sensor more tortuous and thus slower. This is believed to reduce or slow down the sensitivity loss typically observed over time.

In examples where the porous material is a high oxygen solubility material (such as a porous silicone), the high oxygen solubility porous material surrounds a portion or all of the sensor body interior portion. In some examples, a lower oxygen-to-glucose ratio may be sufficient to provide excess oxygen by using high oxygen-soluble domains (e.g., silicone or fluorocarbon based materials) to enhance the supply/transport of oxygen to the enzyme membrane and/or electroactive surface. It is believed that some of the signal noise typically encountered by conventional sensors may be due to hypoxia. The silicone has high oxygen permeability, thus facilitating oxygen transport to the enzyme layer. For example, by using a silicone composition to enhance oxygen supply, glucose concentration may no longer be a limiting factor. In other words, if more oxygen is supplied to the enzyme and/or electrochemically active surface, more glucose may also be supplied to the enzyme without creating an oxygen rate limiting excess. While not being bound by any particular theory, it is believed that the silicone material provides enhanced biostability when compared to other polymeric materials, such as polyurethane.

In another example, the porous material further comprises a bioactive agent that is released upon insertion. In an example, the porous structure provides a pathway for glucose permeation while allowing release/elution of the bioactive agent. In an example, glucose transport may be increased when the bioactive agent is released/eluted from the porous structure, e.g., to offset any decay in glucose transport from the aforementioned immune response factors.

As used herein, the terms "membrane" and "matrix" are intended to be used interchangeably. In these examples, the aforementioned porous material is a biological interface membrane comprising a first domain comprising a configuration that alters the tissue response of the recipient, the configuration comprising cavity size, configuration, and/or overall thickness, for example, by creating a fluid pocket, promoting vascularized tissue ingrowth, disrupting tissue downcontracture, resisting fibrous tissue growth of adjacent devices, and/or impeding barrier cell formation. In an example, the biological interface film covers at least the sensing mechanism of the sensor, and can have any shape or size, including uniformly, asymmetrically, or axisymmetrically covering or surrounding the sensing mechanism or sensor.

Optionally providing a second domain of the biological interface membrane that is impermeable to cells and/or cellular processes. Optionally providing a bioactive agent incorporated into at least one of the first domain, the second domain, the sensing membrane, or other portion of the implantable device, wherein the bioactive agent is configured to alter a tissue response of the recipient. In an example, the biological interface includes a bioactive agent incorporated into at least one of the first domain and the second domain of the biological interface membrane, or into the device and adapted to diffuse through the first domain and/or the second domain so as to alter the tissue response of the recipient to the membrane.

Due to the small size of the sensor (sensing mechanism) of the present disclosure, some conventional methods of porous film formation and/or porous film adhesion are not suitable for forming a biological interface film on a sensor as described herein. Thus, the following examples illustrate systems and methods for forming and/or adhering a biological interface film on a sensor having a small structure as defined herein. For example, the biological interface film or release film of the present disclosure can be formed on the sensor using techniques such as electrospinning, molding, braiding, direct writing, lyophilization, encapsulation, and the like.

In examples where the biological interface is written directly onto the sensor, the dispenser uses a nozzle with a valve to dispense the polymer solution, as described in, for example, U.S. patent publication 2004/0253365. Generally, a variety of nozzles and/or dispensers can be used to dispense the polymeric material to form woven or nonwoven fibers of the biological interface film.

Bioactive substance releasing membrane/layer-inflammatory response control

Generally, the inflammatory response to a biomaterial implant can be divided into two phases. The first phase consists of mobilization of mast cells and subsequent infiltration of the major Polymorphonuclear (PMN) cells. This phase is called the acute inflammatory phase. Chronic cell types containing second-stage inflammation replace PMNs during days to weeks. Macrophages and lymphocytes predominate during this phase. While not 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 scarring or barrier cell layer formation provides protection against scar tissue formation and/or reduces acute inflammation, thereby providing a stable platform for, for example, sustained maintenance of altered foreign body responses.

Thus, bioactive interventions can alter foreign body responses within the early weeks of foreign body capsule formation and alter the prolongation of foreign body capsule behavior. Additionally, it is believed that in some cases, the biological interface membranes of the present disclosure may benefit from bioactive intervention to overcome the sensitivity of the membrane to the implant procedure, movement of the implant, or other factors known to otherwise cause inflammation, scarring, and impeding the function within the device.

Generally, bioactive agents that are believed to alter tissue response include anti-inflammatory agents, anti-infective agents, antiproliferative 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, and the like. In some examples, preferred bioactive agents include S1P (sphingosine-1-phosphate), glycerol monobutyrate, cyclosporin a, antithrombin-sensitive protein 2, rapamycin (and derivatives thereof), NLRP3 inflammasome inhibitors (such as MCC 950), and dexamethasone. However, other bioactive agents, biological materials (e.g., proteins), or even non-bioactive substances may be incorporated into the films of the present disclosure.

Bioactive agents suitable for use in the present disclosure are loosely organized into two groups: anti-barrier cell agents and angiogenic agents. These designations reflect functions believed to provide short-term solute transport through one or more membranes of the disclosed sensor and additionally extend the life of a healthy vascular bed and thus extend in vivo long-term solute transport through the one or more membranes. However, not all bioactive agents can be clearly classified as one or the other of the above groups. In contrast, bioactive agents typically comprise one or more mechanisms of change for altering tissue response, and may generally be categorized into one or both of the above categories.

Anti-barrier cell agents

Generally, anti-barrier cell agents include compounds that exhibit an effect on macrophages and Foreign Body Giant Cells (FBGC). It is believed that the anti-barrier cell agent prevents closure of the barrier to solute transport provided by macrophages and FBGC at the device-tissue interface during FBC maturation.

Anti-barrier cellular agents typically include mechanisms to inhibit foreign giant cells and/or occlusive cell layers. For example, superoxide dismutase (SOD) mimics are incorporated into the biological interface or release films of the preferred examples, which mimic native SOD using manganese catalytic centers within porphyrin-like molecules and effectively remove superoxide for long periods of time, thereby inhibiting FBGC formation on the surface of biological materials in vivo.

The anti-barrier cell agent may include anti-inflammatory and/or immunosuppressive mechanisms that affect early FBC formation. Cyclosporine, which stimulates the formation of very high levels of new blood vessels around biological materials, can be incorporated into the biological interface film (see U.S. patent No. 5,569,462 to Martinson et al) or the release film of the preferred examples.

In an example, dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone (in particular dexamethasone acetate), for example to attenuate the intensity of the FBC reaction at the device-tissue interface, is incorporated into the bioactive substance release membrane 70. In another example, a combination of dexamethasone and dexamethasone acetate is incorporated into the bioactive substance release membrane 70. In another example, dexamethasone and/or dexamethasone acetate in combination with one or more other anti-inflammatory agents and/or immunosuppressants are incorporated into the bioactive substance release film 70. Alternatively, rapamycin as a potent specific inhibitor of some macrophage inflammatory functions may be incorporated into the release film alone or in combination with dexamethasone, dexamethasone salts, dexamethasone derivatives (in particular dexamethasone acetate).

Other suitable drugs, pharmaceutical compositions, therapeutic agents, or other desired substances may be incorporated into the bioactive substance release film 70 of the present disclosure, including but not limited to anti-inflammatory agents, anti-infective agents, necrotic agents (necrosing agent), and anesthetics.

Typically, anti-inflammatory agents reduce acute and/or chronic inflammation adjacent to the implant in order to reduce FBC capsule formation, thereby reducing or preventing barrier cell layer formation. Suitable anti-inflammatory agents include, but are not limited to, for example, non-steroidal anti-inflammatory drugs (NSAIDs), such as acetaminophen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, potassium diclofenac, sodium diclofenac, 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, mefenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen sodium, oxaprozin, piroxicam, rofecoxib, bis-salicylates, sulindac, and tolmetin; and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone acetonide, betamethasone dipropionate, betamethasone valerate, dexamethasone, desoxymethasone, fluocinolone, triamcinolone acetonide, clobetasol propionate, NLRP3 inflammatory body inhibitors (such as MCC 950), dexamethasone and dexamethasone acetate.

In general, immunosuppressants and/or immunomodulators directly interfere with several key mechanisms necessary to involve different cellular elements in the inflammatory response. Suitable immunosuppressants and/or immunomodulators include antiproliferative cell cycle inhibitors (e.g., paclitaxel (e.g., sirolimus), cytochalasin D, infliximab), paclitaxel, actinomycin, mitomycin, thospromote VEGF, estradiol, NO donor, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopepsin, vincristine, mitomycin, statins, C MYC antisense, sirolimus (and analogs), RESTENASE, 2-chloro-deoxyadenosine, PCNA ribozymes, pamarcetate, prolyl hydroxylase inhibitors, pparγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, 671, EPC antibodies, catechins, saccharification agents, endothelin inhibitors (e.g., ambrisen, tembusin (Tesosentan), raw), statins (e.g., colistin), colistin, e.g., colistin, and E.E.coli and high-grade heat stable coatings.

In general, anti-infective agents are substances that can act as anti-infective agents by inhibiting the spread of an infectious agent or by killing the infectious agent thoroughly, which can be used to reduce the immune response without an inflammatory response at the implantation site. Anti-infective sources include, but are not limited to, anthelmintics (mebendazole); antibiotics, including aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin B, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, miconazole, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, ceftazidime), β -lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, bischlorocilin, nafcillin, piperacillin, ticarcillin), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; sodium polymyxin E mesylate; polymyxin B sulfate; vancomycin; antiviral agents including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamide (sulfadiazine, sulfaisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sterilizing and crystallizing sulfanilamide; gatifloxacin; and sulfamethoxazole/trimethoprim.

In general, a necrotic agent is any drug that causes necrosis of tissue or cell death. The necrosis agent comprises cisplatin, BCNU, paclitaxel or paclitaxel derivatives, etc.

Angiogenesis agent

Typically, angiogenic agents include substances having direct or indirect angiogenic properties. In some cases, the angiogenic agent may additionally affect the formation of barrier cells in vivo. Indirect angiogenesis means that angiogenesis can be mediated by inflammatory or immunostimulatory pathways. It is not fully known how agents that induce local angiogenesis indirectly inhibit barrier cell formation; however, it is believed that some barrier-cell effects may be caused indirectly by the effects of the angiogenic agent.

Angiogenic agents include mechanisms that promote neovascularization around the membrane and/or minimize the ischemic cycle by increasing angiogenesis near the device-tissue interface. Sphingosine-1-phosphate (S1P) is incorporated as a phospholipid having potent angiogenic activity into a biological interface membrane or release membrane of a preferred example. The glycerol monobutylate is incorporated into a biological interface film or release film of a preferred embodiment as an effective vasodilator for adipocytes and angiogenic lipid products. In another example, an antisense molecule that increases angiogenesis (e.g., thrombin sensitive protein 2 antisense) is incorporated into a biological interface membrane or release membrane.

Angiogenic agents may include mechanisms that promote inflammation, which is believed to cause accelerated neovascularization in the body. In one example, a heterologous carrier (e.g., bovine collagen) that elicits an immune response by its exogenous nature stimulates neovascularization and is incorporated into the biological interface or release film of the present disclosure. In another example, lipopolysaccharide is incorporated into a biological interface or release film as an effective immunostimulant. In another example, a protein known to regulate bone healing in tissue, such as Bone Morphogenic Protein (BMP), is incorporated into the biological interface or release film of the preferred example.

Typically, an angiogenic agent is a substance capable of stimulating neovascularization, which can accelerate and maintain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include, but are not limited to, copper ion, iron ion triacontyl methyl ammonium 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 growth factor BB (PDEGF-BB), angiopoietin-1, transforming growth factor β (TGF- β), transforming growth factor α (TGF- α), hepatocyte growth factor, tumor necrosis factor- α (TNF- α), placenta growth factor (PLGF), angiopoietin, interleukin-8 (IL-8), hypoxia inducible factor-I (HIF-1), angiotensin Converting Enzyme (ACE) inhibitor quinaprilla, angiostatin (Angiotropin), thrombospondin, peptide KGHK, hypoxia tension, lactic acid, insulin, copper sulfate, estradiol, prostaglandins, cox inhibitors, endothelial cell binding agents (e.g., proteoglycans or proteins), panin glenipin, nicotine, and hydrogen peroxide.

In general, a proinflammatory agent is a substance capable of stimulating an immune response in recipient tissue that can accelerate or maintain the formation of mature vascularized tissue beds. For example, pro-inflammatory agents are generally irritants or other substances that induce chronic inflammation and chronic particulate reactions at the implantation site. While not wishing to be bound by theory, it is believed that the formation of high tissue granulation induces blood vessels to provide a sufficient or abundant supply of analyte to the device-tissue interface. Pro-inflammatory agents include, but are not limited to, xenogenic carriers, lipopolysaccharide, staphylococcus aureus (s.aureus) peptidoglycan and proteins.

Other materials that may be incorporated into the films of the present disclosure include various pharmacological agents, excipients, and other materials well known in the art of pharmaceutical formulation.

While in some examples the bioactive agent is incorporated into the biointerface film or release film and/or the implantable device, in some examples the bioactive agent may be administered systemically (e.g., by oral administration) or topically (e.g., by subcutaneous injection near the implantation site) simultaneously with, before, or after implantation of the device. In certain examples, a combination of a bioactive agent incorporated into the biological interface film with a bioactive agent that is administered topically and/or systemically may be preferred.

In one example, the bioactive substance releasing membrane 70 serves as a biological interface membrane. In another example, the bioactive substance releasing film 70 is chemically different from the biological interface film 68 or the biological interface film 68 is not used. In such examples, one or more bioactive agents are incorporated into the bioactive substance releasing film 70 or both the biological interface film 68 and the bioactive substance releasing film 70.

In general, many variables can affect the pharmacokinetics of release of a bioactive agent. The bioactive agents of the present disclosure can be optimized for short-term release and/or extended release. In some examples, the bioactive agents of the present disclosure are designed to help or overcome factors related to short term effects of foreign body response (e.g., acute inflammation) that may begin as early as implantation and extend up to about one month after implantation. In some examples, the bioactive agents of the present disclosure are designed to aid or overcome factors associated with an extension effect, such as chronic inflammation, barrier cell layer formation, or accumulation of fibrotic tissue of a foreign body response, which may begin about one week as early as after implantation and extend the lifetime of the implant, such as months to years. In some examples, the bioactive agents of the present disclosure combine the benefits of both short-term release and extended release to take advantage of both. U.S. patent publication 2005/0031689 to Shults et al discloses various systems and methods for releasing bioactive agents.

The amount of bioactive agent loaded into the release film may depend on several factors. For example, the amount and duration of the bioactive agent may vary with the intended use of the release film (e.g., cell transplantation, analyte measurement device, etc.). Differences in effective dosages of bioactive agents between recipients; -location and method of loading bioactive agent; and release rates associated with the bioactive agents and optionally their chemical composition and/or bioactive agent loading. Thus, those skilled in the art will appreciate the variability in achieving reproducible and controlled release of one or more bioactive agents, at least for the reasons described above. U.S. patent publication 2005/0031689 to Shults et al discloses various systems and methods for loading bioactive agents.

In an example, multiple layers or discrete or semi-discrete rings or bands of bioactive substance releasing membrane are employed to specifically tailor the release of bioactive agent for the intended life sensation. Thus, in examples, two or more layers of a multi-layer bioactive substance releasing film differ in one or more aspects, such as: the hydrophobic/hydrophilic content or ratio of the segments of the soft-segmented-hard segmented polymer or copolymer; composition or weight percent of a blend of two or more different polymers or copolymers or different polymers and/or copolymers in each layer, or their vertical or horizontal distribution in one or more layers; the bioactive loading and/or distribution (vertical or longitudinal within the coated film) in each layer; film thickness of each layer; composition and loading of two or more different bioactive agents (e.g., neutral, derivative and/or salt forms or primary and derivative forms of the bioactive agents); a solvent system for casting or depositing or dip-coating the individual bioactive substance releasing film layers; and the relative position (continuous, semi-continuous or discontinuous positioning) of the bioactive substance releasing membrane layer along the length of the sensor.

Forming bioactive substance releasing films/layers on sensors

The membrane systems disclosed herein are suitable for use in implantable devices that are in contact with biological fluids. For example, the membrane system may be used with implantable devices, such as devices for monitoring and determining analyte levels in biological fluids, e.g., devices for monitoring glucose levels in individuals with diabetes. In some examples, the analyte measurement device is a continuous device. The analyte measurement device may employ any suitable sensing element to provide the primary signal, including but not limited to those involving enzymatic, chemical, physical, electrochemical, spectrophotometric, polarizing, potentiometric, colorimetric, radiative, immunochemical or the like.

Although some of the following description relates to glucose measurement devices, including the described membrane systems and methods of use thereof, these membrane systems are not limited to devices for measuring or monitoring 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, alcohols, galactose, and lactate), cell transplantation devices (see, for example, U.S. Pat. No. 6,015,572, U.S. Pat. No. 5,964,745, and U.S. Pat. No. 6,083,523), drug delivery devices (see, for example, U.S. Pat. No. 5,458,631, U.S. Pat. No. 5,820,589, and U.S. Pat. No. 5,972,369), and the like, which are incorporated herein by reference in their entirety for their teachings of the membrane systems.

Suitable bioactive substance releasing membranes are those that begin with insertion of the sensor and provide a therapeutically effective amount and release rate of bioactive agent throughout the life of the sensor. In one example, the bioactive substance releasing membrane in combination with an amount of bioactive agent provides for an extended sensor service life when compared to an equivalent sensor that includes the bioactive substance releasing membrane without the bioactive agent (or compared to no bioactive substance releasing membrane and bioactive agent). As used herein, a therapeutically effective amount of a bioactive agent is an amount capable of inducing a desired therapeutic effect. The expected therapeutic effect is a therapeutic effect that can be readily determined using conventional diagnostic methods. For example, the intended therapeutic effect encompasses inhibition of unwanted foreign body reactions to the implant (foreign body), including but not limited to inflammation and/or fibrocystic formation.

In some examples, the wetting characteristics of the membrane (and the extent of sensor drift exhibited by the extension sensor) may be modulated and/or controlled by creating covalent crosslinks between the surface-active group-containing polymer, the functional group-containing polymer, the polymer with zwitterionic groups (or precursors or derivatives thereof), and combinations thereof. Crosslinking can have a significant impact on the film structure, which in turn can affect the surface wetting characteristics of the film. Crosslinking can also affect the tensile strength, mechanical strength, water absorption rate, and other properties of the film.

The crosslinked polymers may have different crosslink densities. In some examples, a cross-linking agent is used to facilitate cross-linking between the layers. In other examples, heat is used to form the crosslinks instead of (or in addition to) the crosslinking techniques described above. For example, in some examples, imide and amide linkages may be formed between two polymers due to the high temperature. In some examples, photocrosslinking is performed to form covalent bonds between the polycationic layer and the polyanionic layer. One of the main advantages of photocrosslinking is that it provides the possibility of patterning. In some examples, the patterning is performed using photocrosslinking to alter the film structure and thus adjust the wetting characteristics of the film.

Polymers having domains or segments functionalized to allow crosslinking may be prepared by methods known in the art. For example, polyurethaneurea polymers having aromatic or aliphatic segments containing electrophilic functional groups (e.g., carbonyl, aldehyde, anhydride, ester, amide, isocyano, epoxy, allyl, or halo groups) can be crosslinked with a crosslinking agent having multiple nucleophilic groups (e.g., hydroxyl, amine, urea, urethane, or thio groups). In further examples, polyurethaneurea polymers having aromatic or aliphatic segments containing nucleophilic functional groups may be crosslinked with a crosslinking agent having multiple electrophilic groups. Still further, the polyurethaneurea polymer having a hydrophilic segment containing a nucleophilic functional group or an electrophilic functional group may be crosslinked with a crosslinking agent having a plurality of electrophilic functional groups or nucleophilic groups. Unsaturated functional groups on polyurethaneurea can also be used for crosslinking by reaction with polyvalent radical agents. Non-limiting examples of suitable cross-linking agents include isocyanate, carbodiimide, glutaraldehyde, aziridine, silane or other aldehydes, epoxy, acrylate, radical-based agents, ethylene Glycol Diglycidyl Ether (EGDE), poly (ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). In an example, about 0.1 wt.% to about 15 wt.% of the crosslinking agent (in an example, about 1 wt.% to about 10 wt.%) is added relative to the total dry weight of these components added when blending the crosslinking agent and polymer, 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.

The polymers disclosed herein can be formulated as a mixture that can be stretched into a film or applied to a surface using any method known in the art (e.g., spray, spread, dip, vapor deposition, molding, 3-D printing, lithographic techniques (e.g., photolithography), micro-and nano-pipetting techniques, screen printing, etc.). The mixture may then be cured at an elevated temperature (e.g., 50 ℃ -150 ℃). Other suitable curing methods may include, for example, ultraviolet radiation or gamma radiation.

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

In one example, the weight percent loading of bioactive agent in the bioactive substance releasing membrane 70 is about 10% to about 90% by weight. In examples, the weight percent loading of bioactive agent in the bioactive material releasing film 70 is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total weight of the bioactive material releasing film plus bioactive agent (as deposited film on the sensor). In an example, the weight percent loading of bioactive agent in the bioactive material releasing film 70 is 30%, 40%, 50% or 60% of the total weight of the bioactive material releasing film plus bioactive agent (as deposited film on the sensor). The weight percent of the bioactive agent is selected based on the solubility/miscibility/dispersion of the bioactive agent with the bioactive agent releasing film and any solvent or solvent system used to partition the bioactive agent and the bioactive agent onto the sensor, depending on the nature of the bioactive agent releasing film, such as the ratio of hydrophobic/hydrophilic soft segments. Too high a loading of the bioactive agent in a particular bioactive substance releasing membrane can result in precipitation of the bioactive agent and/or poor coating quality. Too low a loading of the bioactive agent in the bioactive substance releasing membrane may result in an ineffective therapeutic effect over the expected lifetime of the sensor, which may manifest itself as a poor signal-to-noise ratio initially and/or before the end of the sensor's designed lifetime, a decrease or fluctuation in the sensitivity of the sensor to the target analyte shortly after insertion and/or before the end of the sensor's designed lifetime, etc.

In an example, the bioactive substance releasing membrane is configured to release at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, up to and including 100%, of the initial load of bioactive agent in weight percent after insertion and until the end of life of the sensor. In an example, the bioactive substance releasing membrane is configured to release 60 wt% to 90 wt% of the bioactive agent after insertion and until the end of sensor life. In another example, the bioactive substance releasing membrane is configured to release 75 wt% to 85 wt% of the bioactive agent after insertion and until the end of sensor life.

In one example, the bioactive substance release film of the present disclosure provides a release of the bioactive agent from the bioactive substance release film commensurate with the bolus amount of the bioactive agent. In another example, the bioactive substance releasing membrane of the present disclosure provides a bioactive agent release from the bioactive substance releasing membrane commensurate with a therapeutically effective amount of the bioactive agent. In an example, the bioactive substance release film of the present disclosure provides for release of a bioactive agent from the bioactive substance release film commensurate with a non-therapeutically effective amount, wherein the non-therapeutically effective amount is after release of one or more of the bolus amount or the therapeutic amount of the bioactive agent.

In an example, the bioactive substance releasing membrane of the present disclosure provides bolus release of the bioactive agent substantially immediately after insertion of the sensor into the soft tissue of the subject for a first period or range (e.g., minutes, hours, days, weeks, etc.), which begins at a first point in time (e.g., one second or less). In an example, the bioactive substance releasing membrane of the present disclosure provides for substantially immediate release of a bolus amount of bioactive agent upon insertion of the sensor into soft tissue of a subject for a first period of time beginning at a first time point followed by release of a therapeutically effective amount of bioactive agent beginning at a second time point for a second period of time that overlaps with or follows the first period of time. 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 example, the bioactive substance releasing membrane of the present disclosure provides for substantially immediate release of a bolus amount of bioactive agent upon insertion of the sensor into soft tissue of a subject for a first time period beginning at a first time point followed by release of a therapeutically effective amount of bioactive agent beginning at a second time point for a second time period overlapping or after the first time period followed by release of a non-therapeutically effective amount of bioactive agent beginning at a third time point for a third time period overlapping or after the second time period. In examples, the third time point is at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, or more after the second time point.

In an example, bolus release of bioactive substances is combined with release of inactive pharmaceutical ingredients (non-API) such as hydrophilic substances (zwitterionic substances, hydrogel particles or spheres) in order to change the environment created in the tissue due to the presence of the sensor volume. While not wishing to be bound by theory, it is believed that the hydrophilic agent attracts the fluid to the environment, which may reduce biofouling, slow metabolic breakdown of the bioactive agent, and/or increase uptake of the bioactive agent into the cells. Such release of non-APIs may promote a delay in foreign body response and/or promote release of the bioactive substance from the bioactive substance release film, among other benefits.

The release rate of the bioactive agent may be the same or different in any of the first, second, or third time periods described above. For example, the release rate of the bioactive agent in any of the first, second, or third time periods described above may be configured to occur at a substantially constant rate or a variable rate (intermittent, periodic, and/or random) by altering one or more of the chemical nature, structure, and/or morphology of the membrane, loading of the bioactive agent, and the bioactive agent chemistry. For example, the release rate of the bioactive agent (concentration or amount of bioactive agent released over time) during any of the foregoing time periods may be configured to change over time after implantation by altering one or more of the chemical nature, structure and/or morphology of the membrane, bioactive agent loading, bioactive agent chemistry.

In one example, the release rate of the bioactive agent from the bioactive substance release film is greater initially or during the first time period than the release rate of the bioactive agent from the bioactive substance release film during the first time period. In one example, the release rate of the bioactive agent from the bioactive substance release film is greater initially or during the second time period than the release rate of the bioactive agent from the bioactive substance release film during the first or third time period. In one example, the rate of release of the bioactive agent from the bioactive substance releasing membrane is greater than the rate of release of the bioactive agent from the bioactive substance releasing membrane initially or during the first time period than the rate of release of the bioactive agent from the bioactive substance releasing membrane initially or during the second time period, and the rate of release of the bioactive agent from the bioactive substance releasing membrane is greater than the rate of release of the bioactive agent from the bioactive substance releasing membrane initially or during the third time period.

Suitable bioactive substance releasing films of the present disclosure capable of having the foregoing release rates and amounts of bioactive agents can be selected from silicone polymers; polytetrafluoroethylene; expanded polytetrafluoroethylene; polyethylene-co-tetrafluoroethylene; a polyolefin; a polyester; a polyalkyl ester; a polyalkylcarbonate; a polycarbonate; biostable polytetrafluoroethylene; homopolymers, copolymers, terpolymers of polyurethane; polypropylene (PP); polyvinyl chloride (PVC); polyvinylidene fluoride (PVDF); polyvinyl alcohol (PVA); polyethylene vinyl acetate (EVA); polybutylene terephthalate (PBT); polymethyl methacrylate (PMMA); polyetheretherketone (PEEK); a polyamide; polyurethanes and copolymers and blends thereof; polyurethaneurea polymers and copolymers and blends thereof; cellulosic polymers and copolymers and blends thereof; poly (ethylene oxide) and copolymers and blends thereof; poly (propylene oxide) and copolymers and blends thereof; polysulfones and block copolymers thereof, including, for example, diblock, triblock, alternating, random, and graft copolymers; cellulose; a hydrogel polymer; poly (2-hydroxyethyl methacrylate) (pHEMA) and copolymers and blends thereof; hydroxyethyl methacrylate (HEMA) and copolymers and blends thereof; polyacrylonitrile-polyvinylchloride (PAN-PVC) and copolymers and blends thereof; acrylic copolymers and blends thereof; nylon and copolymers and blends thereof; a polydifluoroethylene; polyanhydrides; poly (l-lysine); poly (L-lactic acid); hydroxyethyl methacrylate and copolymers and blends thereof; and hydroxyapatite and copolymers and blends thereof.

Suitable bioactive substance releasing membranes are polyurethane or polyether polyurethaneurea. Polyurethanes are polymers prepared by the condensation reaction of diisocyanates and difunctional hydroxyl-containing materials. Polyurethaneureas are polymers prepared by the condensation reaction of diisocyanates and difunctional amine-containing materials. Exemplary diisocyanates include aliphatic diisocyanates having from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be used in the preparation of the polymer and copolymer components of the bioactive substance releasing membranes of the present disclosure. The material forming the basis of the hydrophobic matrix of the bioactive substance releasing membrane or domains thereof may be any of those materials known in the art as suitable for use as membranes in continuous analyte sensor apparatus. In one example, the bioactive substance releasing membrane differs from other membranes of the sensor system in that the bioactive substance releasing membrane is not sufficiently permeable to the relevant compound to, for example, allow glucose molecules to pass through the membrane.

Examples of other materials that may be used to prepare the non-polyurethane bioactive material releasing film include vinyl polymers, polyethylene vinyl acetate copolymers, polyethers, polyesters, polyalkyl esters, polyamides, polysilicones, poly (dialkylsiloxanes), poly (alkylaryl siloxanes), poly (diaryl siloxanes), polycarbosiloxanes, polyalkylcarbonates, polycarbonates, natural polymers (such as cellulose and protein based materials), and mixtures, copolymers or combinations thereof with or without the aforementioned polyurethane or polyether polyurethane urea polymers.

In an example, the bioactive substance releasing membrane 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 may be two or more different polymer segments. The soft segment may include a hydrophobic block and a hydrophilic block. The soft segment may comprise a polysiloxane, a polyalkylether, a polyalkylester, a polyalkylcarbonate, a polycarbonate, or a polysiloxane-polyalkylether segmented block.

In examples, the soft segments independently include 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, polyalkyl carbonates, polycarbonates), and the one or more independent hard segments are, for example, aliphatic or aromatic diisocyanates such as norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene Diisocyanate (TDI), 1, 3-phenylene diisocyanate (MPDI), trans-1, 3-bis (isocyanatomethyl) cyclohexane (1, 3-H6 XDI), dicyclohexylmethane-4, 4 '-diisocyanate (HMDI), 4' -diphenylmethane diisocyanate (MDI), trans-1, 4-bis (isocyanatomethyl) cyclohexane (1, 4-H6 XDI), 1, 4-phenylene diisocyanate (i), 3 '-dimethyl-4, 4' -biphenyl diisocyanate (PPDI), 1, 6-hexamethylene diisocyanate (PPDI), or a combination thereof.

In an example, the bioactive substance releasing membrane may further include a chain extender. The chain extender may be, for example, a diol, diamine, silicon-hydride or a multifunctional epoxide. Exemplary diols include aliphatic or aromatic low molecular weight diols such as diol, propylene glycol, diethylene glycol, and 1, 4-butanediol, and other exemplary chain extenders include dialkylamines such as ethylenediamine, 1, 6-hexamethylenediamine, 4' -diaminodiphenylmethane, triethylenediamine, putrescine, and diaminopropane or hydroxylamine.

In other examples, the bioactive substance releasing membrane further comprises one or more zwitterionic repeat units selected from the group consisting of: cocoamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, decyl 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 aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane does not include zwitterionic groups only at the ends of the polymer chains.

In an example, the one or more zwitterionic repeat units are derived from monomers selected from the group consisting of:

And

Wherein Z is branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; r1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R2, R3 and R4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and wherein one or more of R ¹、R²、R³、R⁴ and Z is substituted with a polymeric group for use as at least a portion of the bioactive substance releasing membrane.

In examples, the polymeric group is selected from the group consisting of alkene, alkyne, epoxide, lactone, amine, hydroxyl, isocyanate, carboxylic acid, anhydride, silane, halide, aldehyde, and carbodiimide. In another example, the one or more zwitterionic repeat units are at least about 1 wt%, based on the total weight of the polymer.

In one example, at least one bioactive agent is covalently associated with the bioactive substance releasing membrane. In another example, at least one bioactive agent is ionically associated with the bioactive substance releasing membrane. In another example, the bioactive agent is a conjugate.

In another example, the at least one bioactive agent is a Nitric Oxide (NO) releasing molecule, polymer, or oligomer. In another aspect, the nitric oxide releasing molecule is selected from the group consisting of N-diazeniumdiolate and S-nitrosothiols, alone or in combination with any of the preceding aspects. In an example, the nitric oxide releasing molecule is coupled covalently or non-covalently to a polymer or oligomer. In an example, the N-diazeniumdiolate has the following structure: RR 'N-N2O2, wherein R and R' are independently alkyl, aryl, phenyl, alkylaryl, alkylphenyl, or functionalized N-alkylaminotrialkoxysilane. In an example, at least one of the R and R 'groups of the N-diazeniumdiolate having the structure RR' N-N2O2 has sufficient lipophilicity to remain in the hydrophobic region of the bioactive substance releasing membrane while providing a source of nitric oxide to the insertion site. In an example, at least one of R and R' is sufficiently functionalized to couple with a bioactive substance releasing membrane while providing a source of nitric oxide to the insertion site. In an example, the S-nitrosothiol is S-nitroso-Glutathione (GSNO) or an S-nitrosothiol derivative of penicillamine.

In another example, the bioactive agent is a borate or borate. In one example, the bioactive agent, borate or borate, is covalently coupled to the bioactive substance release film. In another example, the bioactive agent-borate or borate is non-covalently coupled to the bioactive substance release film. In one example, the bioactive agent-borate or borate is covalently coupled to the bioactive agent and to the bioactive substance release film. In another example, the bioactive agent-borate or borate is covalently coupled to the bioactive agent and non-covalently coupled to the bioactive substance release film. In another example, the bioactive agent is a borate or borate salt of dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone (particularly dexamethasone acetate or a salt of dexamethasone acetate).

In another example, the bioactive agent is a conjugate comprising at least one linker cleavable by subcutaneous stimulation. In another example, the bioactive agent is a conjugate of dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone (particularly dexamethasone acetate or a salt of dexamethasone acetate), comprising at least one linker cleavable by subcutaneous stimulation. For example, after insertion of the analyte sensor into the subcutaneous domain of the subject, the bioactive agent conjugate comprising at least one cleavable linker is cleaved by subcutaneous stimulation. In one example, the subcutaneous stimulus is a chemical attack by one or more members of the zinc endopeptidase (metazincin) superfamily, matrix Metalloproteinases (MMPs), or matrix metalloproteinases or matrix proteases (matrixin) or any other protease. In examples, the MMP is a calcium or zinc dependent endopeptidase, a snake venom protease (adamalysin), astaxanthin, or serratia marcescens enzyme (serralysin).

In another example, a bioactive agent releasing membrane comprising a bioactive agent (alone or as a conjugate or associated with a bioactive agent releasing membrane) comprises a hydrophilic hydrogel, wherein the hydrophilic hydrogel is at least partially crosslinked and is capable of dissolving in a biological fluid. In another example, a bioactive substance release membrane comprising a bioactive agent (alone or as a conjugate) comprises a hydrophilic hydrogel associated with or coupled to dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone (particularly dexamethasone acetate or a salt of dexamethasone acetate), wherein the hydrophilic hydrogel is at least partially crosslinked and is capable of dissolving in a biological fluid, and provides release of dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone (particularly dexamethasone acetate or a salt of dexamethasone acetate).

In examples, the hydrophilic hydrogel at least partially dissolves in the biological fluid over 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more, and provides a continuous, semi-continuous, or bolus release of dexamethasone, a dexamethasone salt, or a dexamethasone derivative (particularly dexamethasone acetate or a dexamethasone acetate salt). In an example, the hydrophilic hydrogel includes Hyaluronic Acid (HA) crosslinked by divinyl sulfone or polyethylene glycol divinyl sulfone. In examples, the hydrophilic hydrogel includes a hydrogel conjugate of dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone (particularly dexamethasone acetate or a salt of dexamethasone acetate).

In another aspect, the bioactive substance releasing membrane comprises silver nanoparticles or nanogels as bioactive agents alone or in combination with dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone or a mixture thereof (in particular dexamethasone acetate or a salt of dexamethasone acetate). In one example, the nanoparticle is biodegradable. For example, the biodegradable polymer nanoparticle includes PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymer, polyphosphate, or PEO-b-polypeptide containing at least one bioactive agent. In an example, the bioactive substance releasing membrane includes copper and/or zinc nanoparticles or nanogels as bioactive agents. The silver, copper or zinc nanoparticles/nanogels may be spatially distributed or dispersed throughout the bioactive substance releasing membrane, wherein the spatial distribution or dispersion may be uniform or non-uniform and/or vary vertically and/or horizontally with a certain gradient.

In an example, bacterial cellulose with self-assembled nanoparticles/nanogels of silver, zinc or copper is used as a bioactive substance release film and provides release of dexamethasone, dexamethasone salts or dexamethasone derivatives (in particular dexamethasone acetate or dexamethasone acetate salts) alone or together with any of the polyurethane/polyurethaneurea films disclosed herein. In another example, chitosan oligosaccharide/poly (vinyl alcohol) nanoparticle/nanogel or silver, zinc or copper nanofibers are used as bioactive substance releasing films and provide for the release of dexamethasone, dexamethasone salts or dexamethasone derivatives (in particular dexamethasone acetate or dexamethasone acetate salts).

In an example, the bioactive substance releasing membrane includes biodegradable polymer nanoparticles selected from the group consisting of: PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphates, PEO-b-polypeptides, wherein the polymeric nanoparticle/nanogel comprises dexamethasone, dexamethasone salts or dexamethasone derivatives (in particular dexamethasone acetate or dexamethasone acetate salts) associated covalently or non-covalently.

In another example, the bioactive substance releasing membrane comprises an organic and/or inorganic sol-gel or organic-inorganic composite sol-gel or poloxamer-based carrier that provides release of dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone (in particular dexamethasone acetate or a salt of dexamethasone acetate). In another example, the bioactive substance releasing membrane comprises a thermosensitive controlled release hydrogel or poloxamer, such as a poly (epsilon-caprolactone) -poly (ethylene glycol) -poly (epsilon-caprolactone) hydrogel.

In one example, the aforementioned bioactive substance release film includes a combination of at least one bioactive agent encapsulated in the bioactive substance release film and at least one bioactive agent covalently coupled to the bioactive substance release film. In another example, as disclosed herein, a bioactive substance release membrane includes a spatially distal drug reservoir of at least one bioactive agent as a conjugate or associated with the bioactive substance release membrane.

In another example, the bioactive substance releasing membrane includes a hydrolytically degradable biopolymer containing at least one bioactive agent. In one example, the hydrolytically degradable biopolymer comprises a salicylic acid polyanhydride ester (structure I) capable of hydrolyzing to salicylic acid and adipic acid.

In one example, a suitable bioactive substance releasing film 70 is a hard segmented-soft segmented polymer. Referring to fig. 4A, an exemplary hard-segmented-soft segmented copolymer is depicted having a tightly-associated hard segment 72 in which there is a polymer segment providing a crystalline or crystal-like structure and a soft segment 74 providing an amorphous or amorphous-like structure. In one example, the bioactive substance release film 70 of the present disclosure is a hard segmented-soft segmented copolymer 71, wherein the soft segments 74 comprise hydrophilic polymers or hydrophilic polymer segments. In one example, the bioactive substance release film 70 of the present disclosure is a hard segmented-soft segmented copolymer 71, wherein the soft segments 74 comprise a hydrophilic polymer or a combination of hydrophilic polymer segments and hydrophobic polymers or hydrophobic polymer segments. Referring to fig. 4B, 4C, a hard-segmented-soft segmented copolymer (wherein the soft segment 74 comprises a hydrophilic polymer or a combination of hydrophilic polymer segments and hydrophobic polymer or hydrophobic polymer segments) is schematically illustrated as a three-dimensional volume 4C of the bioactive substance releasing membrane 70 of the sensing membrane 32 depicting an arrangement of hydrophobic domains 76 and hydrophilic domains 78. Depending on the relative concentration of each domain and whether a non-stoichiometric or stoichiometric amount of each domain is present, various confirmations and distributions of hydrophobic and hydrophilic domains are contemplated. In an example, the soft segment of the bioactive substance release film 70 includes a hydrophilic segment in an amount of not 0% by weight and a hydrophobic segment in an amount of 0% by weight.

In one example, the bioactive substance release film 70 includes a hard segmented-soft segmented polyurethane copolymer. In another example, the bioactive substance release film 70 includes a hard segmented-soft segmented polyurethaneurea copolymer. In an example, the bioactive substance release film 70 of the present disclosure is a hard segmented-soft segmented polyurethane or polyurethane urea copolymer, wherein the soft segments 74 comprise a hydrophilic polymer or a combination of hydrophilic polymer segments and hydrophobic polymers or hydrophobic polymer segments. In an example, the bioactive substance release film 70 of the present disclosure is a hard-segmented-soft segmented polyurethane or polyurethane urea copolymer blend, wherein at least one of the individual polymers of the polymer blend includes a soft segment 74 that includes a hydrophilic polymer or a combination of hydrophilic polymer segments and hydrophobic polymer or hydrophobic polymer segments. In an example, the bioactive substance release film 70 of the present disclosure is a hard segmented-soft segmented polyurethane or polyurethane urea copolymer blend, wherein at least one polymer of the individual polymers of the polymer blend includes a soft segment 74 that contains only hydrophilic polymer segments, and at least one polymer of the polymer blend includes a soft segment that contains a combination of hydrophilic polymer segments and hydrophobic polymer or hydrophobic polymer segments.

In an example, the bioactive substance release film 70 includes a hard segmented-soft segmented polyurethane copolymer or polyurethane urea copolymer that includes a drug amount of bioactive substance and provides release of the bioactive substance with a release profile (bolus, bolus followed by controlled release, etc.). The bioactive substance may be dexamethasone ((11 beta, 16 alpha) -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 analogue), in particular dexamethasone acetate; dexamethasone acetate salt; dexamethasone 17-propionate; dexamethasone enol-methylglyoxal; (Z) -2- ((8 s,9r,10s,11s,13s,14s,16 r) -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- ((10 r,13s,16s,17 r) -11, 17-dihydroxy-10, 13, 16-trimethyl-4,9,10,11,12,13,14,15,16,17-decahydro-spiro [ cyclopenta [ a ] phenanthrene-3, 2' - [1,3] dioxolan ] -17-yl) -2-oxoacetic acid ethyl ester; (8 s,9r,10r,11s,13s,14s,16r,17 r) -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-decatetrahydro-3H-cyclopenta [ a ] phenanthren-3-one; a plug Mi Songyi dialdehyde; or 2- ((8 s,9r,10s,11s,13s,14s,16r,17 r) -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.

In some examples, the hard segments of the copolymer may have an average molecular weight or number average molecular weight of about 160 Daltons (DA) to about 10,000DA or about 200DA to about 2,000DA, including all ranges and subranges therebetween. In some examples, the average molecular weight or number average molecular weight of the soft segment can be about 200DA to about 100,000DA, or about 500DA to about 500,000DA, or about 5,000DA to about 20,000DA, including all ranges and subranges therebetween.

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

In an example, aliphatic or aromatic diisocyanates are used to prepare the hard segments 72 of the bioactive substance releasing film 70. In an example, the aliphatic or aromatic diisocyanate used to provide the hard segment 72 of the bioactive substance releasing film 70 is norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene Diisocyanate (TDI), 1, 3-phenylene diisocyanate (MPDI), trans-1, 3-bis (isocyanatomethyl) cyclohexane (1, 3-H6 XDI), dicyclohexylmethane-4, 4 '-diisocyanate (HMDI), 4' -diphenylmethane diisocyanate (MDI), trans-1, 4-bis (isocyanatomethyl) cyclohexane (1, 4-H6 XDI), 1, 4-cyclohexyl diisocyanate (CHDI), 1, 4-phenylene diisocyanate (PPDI), 3 '-dimethyl-4, 4' -biphenyl diisocyanate (TODI), 1, 6-Hexamethylene Diisocyanate (HDI), or a combination thereof.

In an example, the soft segment 74 of the hard-segmented-soft-segmented polyurethane or polyurethane urea copolymer comprises a polysiloxane or copolymer thereof. In an example, the soft segment 74 of the hard-segmented-soft-segmented polyurethane or polyurethane urea copolymer includes a poly (dialkyl) siloxane, a poly (diphenyl) siloxane, a poly (alkylphenyl) siloxane, or a copolymer thereof. In an example, the soft segment 74 of the hard-segmented-soft-segmented polyurethane or polyurethaneurea copolymer comprises a poly (alkyl) oxy polymer, a poly (alkylene) oxide, or a copolymer thereof. In an example, the soft segment 74 of the hard-segmented-soft-segmented polyurethane or polyurethane urea copolymer includes a poly (alkyl) oxide, a poly (ethylene oxide), a poly (propylene oxide), a poly (ethylene oxide-propylene oxide), a poly (tetra-alkylene) oxide, a poly (tetra-methylene) oxide polymer, or a copolymer or blend thereof. The soft segment may include hydrophilic and/or hydrophobic oligomers such as polyalkylene glycols, polyalkylcarbonates, polycarbonates, polyesters, polyethers, polyvinyl alcohols, polyvinylpyrrolidone, polyoxazolines, and the like.

In an example, the soft segment 74 of the hard-segmented-soft-segmented polyurethane or polyurethane urea copolymer includes a polysiloxane or copolymer thereof and a poly (alkylene) oxy polymer or copolymer thereof. In an example, the soft segment 74 of the hard-segmented-soft-segmented polyurethane or polyurethaneurea copolymer includes a poly (dialkyl) siloxane, a poly (diphenyl) siloxane, a poly (alkylphenyl) siloxane or copolymer, and a poly (alkyl) oxide, a poly (ethylene oxide), a poly (propylene oxide), a poly (ethylene oxide-propylene oxide), a poly (tetra-alkylene) oxide, a poly (tetra-methylene) oxide polymer, or a copolymer or blend thereof.

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

At least a portion of the surface of the biological interface/bioactive substance releasing membrane may be hydrophobic, as measured by contact angle. For example, the bio-interface/bioactive substance releasing film 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 example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the bio-interface/bioactive substance releasing film, has an advancing contact angle of about 100 ° to about 150 °. In another example, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance releasing film, 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 example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the bio-interface/bioactive substance releasing film, has a receding contact angle of about 40 ° to about 80 °. In another example, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the bio-interface/bioactive substance releasing film, has a receding contact angle of about 45 ° to about 75 °. In yet another example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the bio-interface/bioactive substance releasing film, has a receding contact angle of about 50 ° to about 70 °. In some examples, dynamic contact angle measurements and surface roughness (associated with contact angle hysteresis, which is caused by chemical and morphological heterogeneity of the surface, swelling, rearrangement, or change of the surface by solution impurities or solvents adsorbed on the surface) on the bioactive substance 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 an advancing contact angle measurement, a receding contact angle measurement, a hysteresis measurement, and combinations thereof. The force tensiometer measures the mass affecting the balance and calculates and automatically subtracts the effects of buoyancy and probe weight so that the only remaining force measured by the balance is the wetting force.

In an example, the bioactive substance releasing film 70 has a weight percent content of hard segments of about 20% to 60%, 30% to 50%, or 35% to 45% in order to achieve 70A-55D durometer hardness. In another example, the bioactive substance releasing film 70 has a weight percent content of hard segments of about 20% to 60%, 30% to 50%, or 35% to 45% in order to achieve a target modulus. In one example, the durometer hardness and/or modulus of the bioactive substance release film 70 is provided by a single copolymer or blend of copolymers.

In one example, the bioactive substance releasing membrane 70 includes a soft segment-hard segment copolymer that includes less than 70% but not 0% soft segments by weight. In one example, the release film comprises a soft segment-hard segment copolymer comprising a soft segment-hard segment polyurethane or polyurethaneurea copolymer comprising less than 70% but not 0% soft segments by weight.

In one example, the bioactive substance releasing membrane includes a soft segment-hard segment copolymer that includes a greater weight percentage of hydrophilic segments than the weight percentage of hydrophobic segments. In an example, the release film includes a soft segment-hard segment polyurethane or polyurethane urea copolymer that includes a weight percent of a soft segment-hard segment hydrophilic segment that is greater than a weight percent of a hydrophobic segment thereof.

In one example, the weight percent of hydrophilic segments of the soft segment-hard segment copolymer is less than the weight percent of hydrophobic segments thereof. In one example, the weight percent of hydrophilic segments of the soft segment-hard segment polyurethane or polyurethane urea copolymer is less than the weight percent of hydrophobic segments thereof.

In one example, the bioactive substance releasing membrane includes a soft segment-hard segment copolymer that is a blend of different soft segment-hard segment copolymers. In one example, the bioactive substance releasing membrane includes a soft segment-hard segment polyurethane or polyurethane urea copolymer that is a blend of different soft segment-hard segment copolymers.

In one example, the bioactive substance releasing membrane includes a blend of different soft segment-hard segment copolymers, the blend being a blend of a first soft segment-hard segment copolymer including a hydrophilic segment in a weight percentage other than 0% and a hydrophobic segment in a weight percentage including 0% with another second soft segment-hard segment copolymer including a hydrophilic segment in a weight percentage greater than the weight percentage of the hydrophobic segment. In one example, the bioactive substance releasing membrane includes a blend of different soft segment-hard segment polyurethane or polyurethane urea copolymers including a blend of a first soft segment-hard segment copolymer including not 0% by weight hydrophilic segments and hydrophobic segments including 0% by weight with another soft segment-hard segment polyurethane or polyurethane urea copolymer including greater weight percent hydrophilic segments.

In one example, the bioactive substance releasing membrane includes a blend of a soft segment-hard segment copolymer including not 0% by weight of a hydrophilic segment and 0% by weight of a hydrophobic segment, and another soft segment-hard segment copolymer including less than 0% by weight of a hydrophobic segment. In one example, the bioactive substance releasing membrane includes a blend of a soft segment-hard segment polyurethane or polyurethane urea copolymer that includes not 0% by weight of hydrophilic segments and 0% by weight of hydrophobic segments, inclusive, with another soft segment-hard segment polyurethane or polyurethane urea copolymer that includes less than the weight percent of hydrophobic segments.

In one example, the bioactive substance releasing membrane includes a soft segment-hard segment copolymer and a soft segment-hard segment copolymer, each of which includes less than 70% but not 0% by weight of the soft segment and each of which includes not 0% by weight of the hydrophilic segment and 0% by weight of the hydrophobic segment including 0%. In one example, the bioactive substance releasing membrane includes a soft segment-hard segment polyurethane or polyurethane urea copolymer and a different soft segment-hard segment polyurethane or polyurethane urea copolymer, each including less than 70% but not 0% by weight soft segments and each including not 0% by weight hydrophilic segments and including 0% by weight hydrophobic segments.

In one example, the bioactive substance releasing membrane includes a soft segment-hard segment copolymer blended with a hydrophobic polymer and/or a hydrophilic polymer. In one example, the bioactive substance releasing membrane includes a soft segment-hard segment polyurethane or polyurethane urea copolymer blended with a hydrophobic polymer and/or a hydrophilic polymer.

In one example, the bioactive substance releasing membrane 70 is substantially impermeable to transport of analytes therethrough. In another example, the biologically active substance release membrane 70 has a lower permeability to the analyte than the interfering membrane 44 of the sensing membrane 32. In such examples, the bioactive substance releasing film 70 is deposited on the sensor portion adjacent to but not covering the electrochemically active portion of the sensor.

In one example, the bioactive substance release film 70 is loaded with a bioactive agent prior to deposition onto the sensor 34 and/or sensing film 32. In one example, the bioactive agent is dissolved in one or more solvents that are miscible with the bioactive substance release film 70. Gentle heating may be used to promote dissolution, distribution or dispersion of the bioactive agent in the bioactive substance releasing membrane 70. Suitable solvents include THF, alcohols, ketones, ethers, acetates, NMP, methylene chloride, heptane, hexane, and combinations thereof.

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

In an example, the bioactive substance releasing film 70 is deposited onto the enzyme domains by spraying, brushing, pad printing, or dipping. In certain examples, the bioactive substance releasing film 70 is deposited using spray coating and/or dip coating. In an example, the bioactive substance release film 70 is deposited onto the sensing film 32 by pad printing a mixture of about 1 wt.% to about 80 wt.% polymer/drug combination and about 20 wt.% to about 99 wt.% solvent (including all ranges and subranges therebetween).

Upon contacting the solution of the bioactive substance releasing membrane 72 (including the solvent) onto the sensing membrane, it is desirable to reduce or significantly reduce any contact of any solvent in the pad printing mixture with the enzyme that may inactivate the underlying enzyme of the enzyme domain. Tetrahydrofuran (THF) is a solvent that has minimal or negligible effect on enzymes in the enzyme domain when sprayed alone or in combination with one or more alcohols. Other solvents may also be suitable as will be appreciated by those skilled in the art.

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

Bioactive substance release film/layer composition-bioactive agent release profile

The present disclosure provides for control of the release of a bioactive agent from a bioactive substance release film or for a release profile of a bioactive agent from a bioactive substance release film. For example, an exemplary bioactive agent/bioactive substance release film system is used, such as dexamethasone and/or dexamethasone acetate/soft segment-hard segment polyurethaneurea copolymer or blend, however, other combinations of bioactive agent and bioactive substance release film are contemplated.

Referring to fig. 5A, an exemplary in vitro bioactive substance release profile of dexamethasone acetate is shown using an exemplary bioactive substance release membrane 70. The cumulative percent release of dexamethasone acetate can be determined using HPLC, e.g., using Phenomenex Kinetex. Mu. EVO C18(50X 3.0 mm) column, kept at 25 ℃, with 254nm UV detector, elution gradient A: water/B containing 0.1% formic acid: acetonitrile (v/v) containing 0.1% formic acid, wherein the gradient from time 0 to 2 minutes is 90% a/10% b; a gradient from 2 minutes to 5 minutes of 10% a/90% b; and a gradient of 90% A/10% B from 5 minutes. Dexamethasone acetate and dexamethasone HPLC standards were prepared at a concentration of about 0.1-20 ug/mL.

Fig. 5A shows the correlation between in vitro release 77 and in vivo release 79 of dexamethasone acetate in the disclosed bioactive substance release film 70 over a15 day period, demonstrating the ability of the in vitro data of the disclosed system to approximate in vivo data.

Referring to fig. 5B, experimental data showing that the release rate of the bioactive agent (dexamethasone acetate) from the bioactive substance release film 70 is greater than the release rate of the bioactive agent from the bioactive substance release film initially or during the first period of time, and the release rate of the bioactive agent from the bioactive substance release film initially or during the second period of time is greater than the release rate of the bioactive agent from the bioactive substance release film initially or during the third period of time are shown.

Thus, fig. 5B depicts the exemplary in vitro bioactive substance release profile of fig. 5A, showing a first release rate (e.g., bolus) indicated as corresponding to a time period associated with sensor insertion and extended by about 2 days or more, followed by a second release rate (e.g., an amount within a therapeutic range, or "sustained therapeutic amount") indicated as corresponding to a second time period associated with a time period beginning at about 2 days and extending forward by 15 days after sensor insertion. An amount less than the therapeutic amount, e.g., a non-therapeutic amount, is released during a period of about 18 days or more after sensor insertion and lasting until the end of sensor life is reached (data not shown). As can be seen from the graph data of fig. 5B, the first release rate corresponds to a bolus release of about 50% of the dexamethasone acetate initial load over a period of about two days, followed by a second release rate corresponding to a release of about 40% of the dexamethasone acetate initial load over a time span of about 13 days. The subsequent third release rate corresponds to the release of the remaining amount of dexamethasone acetate (about 10%) over a time span of 16-35 days.

Thus, with an initial loading of 50 μg to 100 μg dexamethasone acetate (DexAc)/sensor, for example, where a therapeutically effective amount per day or more of release is targeted, the disclosed bioactive substance release film 70 can provide release of a bolus therapeutic amount of DexAc immediately after insertion (about 3 μg to 20 μg/sensor/day, 4 μg to 18 μg/sensor/day, 5 μg to 16 μg/sensor/day, 6 μg to 14 μg/sensor/day) and for a period of time thereafter followed by release of an extended therapeutic amount of DexAc (about 0.5 μg to 10 μg/sensor/day, 0.6 μg to 9 μg/sensor/day, 0.4 μg to 7 μg/sensor/day, 0.5 μg to 8 μg/sensor/day), followed by an extended non-therapeutic amount release of DexAc (about less than 0.5 μg/sensor/day) until the lifetime of the sensor is terminated.

Referring to fig. 5C, the initial and sustained bioactive substance release rates of the different bioactive substance release films are presented. As shown, polyurethane polymer film examples having varying amounts of polysiloxane component in the soft segment ranging from about 10 wt% to about 40 wt% (each of the examples having a hard segment of 40 wt% to 55 wt%) demonstrate unique release rates of dexamethasone acetate over the initial 10to 48 hour period and varying total release amounts over an extended period of up to 15 days, summarized below: sample 120-10 wt% polysiloxane: 50 wt% hard segment; sample 121-22 wt% 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, a film containing 10% by weight of polysiloxane provides a fast initial release rate and a sustained high overall release rate, as compared to a film containing 35% by weight of polysiloxane provides a more linear-like release rate and a sustained low overall release rate. The data of fig. 5C further demonstrates the effect of the combination of hard segment weight percent and polysiloxane-containing film on tailoring the release rate of the bioactive substance during the initial and duration times. Thus, by varying the chemical composition of the bioactive substance release film 70, a desired or target bioactive substance release profile commensurate with a bioactive therapeutic regimen can be obtained.

Referring to fig. 6A, the effect of the bioactive substance releasing membrane 70 chemistry on bioactive substance release is related to the water absorption of the membrane. In one example, at least a portion (e.g., hard segment) of the bioactive substance releasing membrane 70 has a Hildebrand solubility parameter that is closer to that of the releasable bioactive agent than another portion (e.g., soft segment) of the bioactive substance releasing membrane. For example, the bioactive substance release film 70 can include a hydrophobic soft segment, at least one hydrophilic soft segment, and a hard segment including a urethane group, a urea group, or a combination of urethane and urea groups, wherein the hard segment has a Hildebrand solubility parameter that is closer to that of the releasable bioactive agent than either soft segment portion. Fig. 6A shows various samples of bioactive substance release film 70 having different hard segment portions (and different weight% ranges) and having different weight% ranges of hydrophobic soft segments and hydrophilic soft segment portions. Thus, samples 130, 136 and 137 comprising polyurethane block polymers having 40 to 60 wt.% hard segments (e.g., cyclic isophorone diisocyanate (IPDI)), 10 to 30 wt.% hydrophobic soft segment portions (e.g., polysiloxanes), and 20 to 50 wt.% hydrophilic soft segment portions (e.g., polyalkylethers) exhibited a desired release rate for a selected bioactive substance (e.g., dexamethasone acetate). In contrast, samples 131, 132, 133, 134, and 135 comprising polyurethane block polymers having 40 to 60 wt.% hard segments (e.g., linear 1, 6-Hexamethylene Diisocyanate (HDI)), 10 to 30 wt.% hydrophobic soft segment portions (e.g., polysiloxanes), and 0 to 50 wt.% hydrophilic soft segment portions (e.g., polyalkyl ethers) showed rapid release of selected bioactive substances (e.g., dexamethasone acetate). This data demonstrates that the correlation of the water absorption of the bioactive substance release layer (e.g., hard segment solubility similar to that of the releasable bioactive substance) to the water absorption of the bioactive substance can be used to tailor the release rate/profile of the bioactive substance.

In an example, the bioactive substance releasing film 70 chemistry includes a soft segment and a hard segment that includes urethane groups, urea groups, or a combination of urethane and urea groups. The soft segment is two or more different polymer segments. The soft segment includes a hydrophobic block and a hydrophilic block. The soft segment comprises a polysiloxane, a polyalkylether, a polyalkylester, a polyalkylcarbonate, a polycarbonate, or a polysiloxane-polyalkylether segmented block.

In an example, the bioactive substance releasing membrane 70 chemistry further includes a chain extender. Chain extenders include diols, diamines, silicon-hydrides or multifunctional epoxides.

In an example, the bioactive substance releasing membrane 70 chemical is polyurethaneurea.

In an example, the bioactive substance releasing film 70 chemistry includes about 10 wt% to 30 wt% polysiloxane and about 10 wt% to 30 wt% polyalkylether, 40 wt% to 60 wt% hard segment, and any remaining wt% is a chain extender, the hard segment including urethane groups, urea groups, or a combination of urethane groups and urea groups, based on the total weight of the bioactive substance releasing film.

In an example, the bioactive substance releasing film 70 chemistry includes about 20 to 30 wt.% polysiloxane, about 20 to 30 wt.% polyalkylether, and about 40to 60 wt.% hard segment, based on the total weight of the bioactive substance releasing film, and any remaining wt.% is a chain extender.

In an example, the bioactive substance releasing film 70 chemistry includes a soft segment comprising about 10 wt% to 30 wt% polysiloxane, about 10 wt% to 30 wt% polyalkylether, and about 0 wt% to 10 wt% chain extender, based on the total weight of the bioactive substance releasing film.

In an example, the polyalkyl ether is represented by a repeating unit of formula (I): - (R5-O) -; wherein R5 is a linear or branched alkyl group of 2 to 6 carbons.

Referring to fig. 6B, a sensitivity data study of living subjects of an exemplary experimental sensor 82 comprising a bioactive substance releasing membrane 70 of the present disclosure with an effective amount of DexAc (e.g., about 40 to 50 weight percent load: bioactive substance releasing membrane) is presented over 15 days as compared to a control sensor 84 having a membrane 70 without dexamethasone acetate (DexAc). As shown, the experimental sensor 82 provided consistent normalized sensitivity sustainability over 15 days post-insertion, while the control sensor 84 showed a decrease in normalized sensitivity after approximately 10 days post-insertion.

Referring to fig. 6C, a study of in vivo subject sensitivity data for an exemplary experimental sensor 83 comprising a bioactive substance releasing membrane 70 of the present disclosure having an effective amount DexAc (e.g., about 40 to 50 weight percent load: bioactive substance releasing membrane) over 30 days is presented as compared to a control sensor 85 without dexamethasone acetate (DexAc). As shown, the experimental sensor 83 provided improved normalized sensitivity sustainability of over 60% over 30 days post-insertion, while the control sensor 84 showed a normalized sensitivity drop below 60% about 20 days post-insertion.

In some implementations, a loss of sensitivity may indicate end of life. Sensitivity loss may occur at the end of sensor life due to physiological wound healing and foreign body mechanisms around the sensor or other mechanisms (including reference electrode capacity, enzyme consumption, membrane changes, etc.).

In some embodiments, analysis of uncalibrated sensor data (e.g., raw or filtered data) may be used to calculate sensor sensitivity. In an example, the slow moving average or median of the raw counts starts to show a negative trend, and the sensor may lose sensitivity. The loss of sensitivity may be calculated by calculating a short term (e.g., about 6 to 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%, there may be a risk of loss of sensitivity of the sensor. The loss of sensitivity may be translated into an end-of-life risk factor value, e.g., a value of about 1 until the ratio is about 70%, decreasing to 0.5 at 50% and <0.1 at 25%.

In some embodiments, sensor sensitivity may be calculated by comparing sensor data (e.g., calibrated sensor data) to a reference blood glucose. For example, a calibration algorithm adjusts glucose estimates based on a systematic deviation between the sensor and a reference blood glucose. The end-of-life algorithm may use this deviation (referred to as a calibration error or downward drift) to quantify or define end-of-life symptoms. Errors in calibration may be normalized to account for irregular calibration times and smoothed to give more weight to recent data (e.g., moving average or exponential smoothing). In some embodiments, the end-of-life risk factor value is determined based on a smoothed error resulting from calibration. In such an embodiment, the end-of-life risk factor value is 1 for all error values at calibration > -0.3, and the error at calibration= -0.4 is reduced to 0.5, and the error at calibration= -0.6 is reduced to <0.1. In some examples, one or more of a downward drift in sensor sensitivity over time, an amount of asymmetric, non-stationary noise, and a duration of noise may be employed, e.g., as disclosed in commonly assigned U.S. patent publication No. 2021/0209497, which is incorporated herein by reference.

In some embodiments, analysis of uncalibrated sensor data (e.g., raw or filtered data) may be used to calculate sensor sensitivity. In an example, the slow moving average or median of the raw counts starts to show a negative trend, and the sensor may lose sensitivity. The loss of sensitivity may be calculated by calculating a short term (e.g., about 6 to 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%, there may be a risk of loss of sensitivity of the sensor. The loss of sensitivity may be translated into an end-of-life risk factor value, e.g., a value of about 1 until the ratio is about 70%, decreasing to 0.5% at 50% and <0.1% at 25%.

Referring to fig. 6C, a survival plot of a continuous analyte sensor 90 (with a bioactive substance releasing membrane 70) versus a control 91 (without a membrane) and a sensor 92 (with a membrane but no bioactive substance present). As shown, the sensor with the bioactive substance releasing membrane 70 performed better than the control and sensor with the membrane alone for at least 5 days, with a sensitivity of less than 80% indicating significant end of life (EOL).

Referring to the survival diagram of fig. 6D, improvement in sensitivity retention is demonstrated by altering the bioactive substance releasing membrane chemistry, e.g., adjusting the weight percentage of the hard segment, soft segment, the weight percentage of the hydrophobic portion of the soft segment, etc., so as to alter the release rate of the bioactive substance from the bioactive substance releasing membrane 70 (typically characterized as a rapid, medium, or slow release of the bioactive substance, including any bolus release or absence of a bolus release). Thus, fig. 6D shows that the slow release rate film 93 of the bioactive substance (as exemplified by dexamethasone acetate) has a sensitivity retention of less than 80% after 14 days, the control 94 (no film) has a sensitivity retention of less than 80% after 18 days, the medium release rate film 95 has a sensitivity retention of less than 80% after 19 days, and the fast release rate film 96 has a sensitivity retention of less than 80% after 20 days.

Referring to fig. 7A, a study of the average absolute noise data of living subjects of an exemplary experimental sensor 86 comprising a bioactive substance release film 70 of the present disclosure with an effective amount DexAc (e.g., about 40 to 50 weight percent load: bioactive substance release film) is presented as compared to a control sensor 84 without dexamethasone acetate (DexAc) and a control sensor 87 with bioactive substance release film 70 without dexamethasone acetate over 22 days. As shown, the experimental sensor 86 provided relatively consistent average absolute noise sustainability over 22 days post-insertion, while the control sensor 88 and the control sensor 87 showed an increase in average absolute noise after about 8 to 10 days post-insertion. This data exemplifies the ability of the disclosed bioactive substance releasing membrane in combination with bioactive agents to minimize increases in implantable sensor noise over extended periods of time.

Referring to fig. 7B, a survival diagram of a continuous analyte sensor 90 (with a bioactive substance releasing membrane 70) versus a control 91 (without a membrane) and a sensor 92 (with a membrane but no bioactive substance present) is presented. As shown, the sensor with the bioactive substance releasing membrane 70 performed better than the control and sensor with the membrane alone for at least 10 days, with less than 80% noise indicating significant end of life (EOL).

Referring to fig. 7C, the improvement in minimizing noise increase is demonstrated by altering the bioactive substance releasing membrane chemistry, e.g., adjusting the weight percentage of the hard segment, soft segment, the weight percentage of the hydrophobic portion of the soft segment, etc., so as to alter the release rate of the bioactive substance from the bioactive substance releasing membrane 70 (typically characterized by a rapid, moderate, or slow release of the bioactive substance, including any bolus release or absence of a bolus release, as previously described in fig. 6D). Thus, fig. 7C shows that the slow release rate film 93 of the bioactive substance (dexamethasone acetate for example) has an increase in noise of more than 80% after 5 days, the control 94 (no film) has an increase in noise of more than 80% after 4 days, the medium release rate film 95 has an increase in noise of more than 80% after 8 days, and the fast release rate film 96 has an increase in noise of more than 80% after 8 days. This data exemplifies the ability of the disclosed bioactive substance releasing membrane in combination with bioactive agents to minimize increases in implantable sensor noise over an extended period of time relative to control membranes or non-bioactive substance membranes.

Additional experiments were performed using dexamethasone salts in different combinations of bioactive substance releasing membranes. For example, dexamethasone sodium phosphate in a water-soluble cellulose-based polymer provides a bolus release profile. Dexamethasone phosphate incorporated into a biointerfacial polymer membrane as disclosed herein provides sustained release for about 2 days. Dexamethasone acetate in a hard segment-soft segment polyurethaneurea copolymer having 0 wt.% hydrophobic soft segment provides sustained release for about 5 days. Dexamethasone acetate in a hard segment-soft segment polyurethaneurea copolymer having about equal weight percent hydrophobic segment/hydrophilic segment provides sustained release for about 15 days. Dexamethasone acetate in the hard segment-soft segment polyurethaneurea copolymer, having a weight percent of hydrophobic soft segment greater than a weight percent of hydrophilic soft segment, provides slow sustained release for more than 15 days. Dexamethasone acetate in the cellulose polymer provided a slow sustained (continuous or semi-continuous) release over 15 days. Using a combination of the foregoing bioactive substance releasing films, the release rate and/or release profile of the bioactive agent can be specifically tailored for a particular sensor and its expected end of life while providing sustained sensitivity and low noise performance.

This data exemplifies the ability of the disclosed bioactive substance releasing membrane/bioactive agent combinations to minimize the decay/decrease in sensitivity of implantable sensors over extended periods of time. The bioactive substance release film/bioactive agent combinations disclosed herein can be configured for use with other sensor platforms other than electrochemical-based sensor systems, such as optical-based sensor systems, as well as other medical devices intended for prolonged implantation that require subsequent removal from a subject.

As shown in fig. 3H, the continuous analyte sensing device 100 includes an analyte sensor having an insertable portion 102 operably coupled to a non-insertable portion 104, the continuous analyte sensing device 100 being 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 around the insertable portion 102 (and thus around the insertable surface area and/or the insertable volume). The insertable portion 102 also includes a bioactive substance releasing membrane 70 formed on the insertable portion 102.

In an example, the insertable portion 102 has a length of about 1mm to about 20mm, including all ranges and subranges therebetween. In another example, the insertable portion 102 has a length of about 2mm to about 14 mm. In further examples, the insertable portion 102 has a length of about 4mm to about 12 mm. For example, the insertable portion 102 has a length of at least about any of: 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm and 19mm and/or up to about 20mm, 19mm, 18mm, 17mm, 16mm, 15mm, 4mm, 13mm, 12mm, 11mm, 10mm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm and 2mm (e.g., about 1mm to 15mm, about 5mm to 18mm, etc.).

As shown in fig. 3I, the insertable portion includes a bioactive substance releasing membrane 70. In one example, the bioactive substance release film 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 insertable volume). The bioactive substance release film 70 includes at least one bioactive agent 110 dispersed in the bioactive substance release film. In one example, the bioactive substance release film 70 is configured to associate with and/or release at least one bioactive agent 110. The at least one bioactive agent 110 can be configured to be non-releasable from the bioactive substance releasing membrane and alter the tissue response of the subject. The at least one bioactive agent 110 can be independently configured to be non-releasable in some form and can be released from the bioactive substance releasing membrane and alter the tissue response of the subject.

The at least one polymer layer of the bioactive substance release film 70 can include any suitable polymer material previously discussed herein. In an example, at least one polymer layer of the bioactive substance releasing film 70 includes one or more epoxides, polyolefins, polysiloxanes, polyamides, polystyrenes, polyacrylates, polyethers, polyvinylpyridines, polyethylene-co-polystyrenes, polyvinylimidazoles, polyesters, polyalkylesters, polyalkylcarbonates, polycarbonates, polyurethanes, polyurethaneureas, polyvinylvinylacetate (EVA), polyvinylalcohol, and copolymers or blends thereof. In another example, at least one polymer layer of the bioactive substance releasing membrane 70 includes one or more zwitterionic repeat units associated with at least one bioactive agent configured to be released from the one or more zwitterionic repeat units to alter the tissue response of the subject.

In one aspect, alone or in combination with any of the preceding aspects, the polyethylene oxide segment is from about 5wt% to about 60 wt%, including all ranges and subranges therebetween, based on the total weight of the bioactive substance releasing film.

The at least one bioactive agent 110 includes any suitable bioactive agent previously discussed herein. In an example, the at least one bioactive agent 110 includes an anti-inflammatory compound or a tissue response modifier. For example, in an example, the at least one bioactive agent 110 includes at least one of dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or any combination thereof.

In an example, the at least one bioactive agent 110 is dispersed in at least one polymer layer (and thus in the volume of the polymer layer) of the bioactive agent release film 70 at a drug/polymer weight/weight ratio of about 0.1 to about 2 (including all ranges and subranges therebetween). In another example, the at least one bioactive agent 110 is dispersed in at least one polymer layer (and thus dispersed in the volume of the polymer layer) of the bioactive agent release film 70 at a drug/polymer weight/weight ratio of about 0.1 to about 0.3. In further examples, the at least one bioactive agent 110 is dispersed in the at least one polymer layer (and thus dispersed in the volume of the polymer layer) of the bioactive agent release film 70 at a drug/polymer weight/weight ratio of about 0.3 to about 0.5. For example, the at least one bioactive agent 110 is dispersed in the at least one polymer layer of the bioactive agent release film 70 at a drug/polymer weight/weight ratio of ：0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.2、0.21、0.22、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.3、0.31、0.32、0.33、0.34、0.35、0.36、0.37、0.38、0.39、0.4、0.41、0.42、0.43、0.44、0.45、0.46、0.47、0.48 and 0.49 and/or up to about 0.5、0.49、0.48、0.47、0.46、0.45、0.44、0.43、0.42、0.41、0.4、0.39、0.38、0.37、0.36、0.35、0.34、0.33、0.32、0.31、0.3、0.29、0.28、0.27、0.26、0.25、0.24、0.23、0.22、0.21、0.2、0.19、0.18、0.17、0.16、0.15、0.14、0.13、0.12、0.11、0.1、0.09、0.08、0.07、0.06、0.05、0.04、0.03 and 0.02 (e.g., about 0.19 to 0.49, about 0.01 to 0.3, etc.) starting from at least about any of the following. In further examples, the at least one bioactive agent is dispersed in the polymer layer volume at a drug/polymer weight/volume ratio (including all ranges and subranges therebetween) of about 0.1:2 μg/mm ³ to about 0.2:1 μg/mm ³.

In another example, the at least one bioactive agent is dispersed in the volume of the bioactive agent delivery film 70 at a drug/polymer weight/volume ratio of about 0.2 μg/mm ³ to about 1 μg/mm ³ (including all ranges and subranges therebetween). In another example, the at least one bioactive agent is dispersed in the polymer layer volume at a drug/polymer weight/volume ratio of about 1:10 μg/mm ³ to about 2:1 μg/mm ³. For example, at least one bioactive agent is dispersed in the polymer layer volume at a drug/polymer weight/volume ratio that begins with at least about any of: 1:10, 2:10 (i.e., 1:5), 3:10, 4:10 (i.e., 2:5), 5:10 (i.e., 1:2), 6:10 (i.e., 3:5), 7:10, 8:10 (i.e., 4:5), 9:10, 10:10 (i.e., 1:1), 11:10, 12:10 (i.e., 6:5), 13:10, 14:10 (i.e., 7:5), 15:10 (i.e., 3:2), 16:10 (i.e., 8:5), 17:10, 18:10 (i.e., 9:5), and 19:10 μg/mm ³ and/or up to about 20:10 (i.e., 2:1), 19:10, 18:10 (i.e.g., 9:5), 17:10, 16:10 (i.e., 8:5), 15:10 (i.e., 3:2), 14:10 (i.e., 7:5), 13:10, 12:10 (i.e., 6:5), 11:10, 10:10 (i.e., 1:1), 9:10, 8:10 (i.e., 4:5), 7:10, 6:10 (i.e., 1:5), 19:10, 18:10 (i.e., 1:10:10) and/or up to about 20:10 (i.e., 1:5), 19:10:10 (i.e., 1:10:10, 9:10 (i.g., 9:5), 17:10:10:10:10 (i.g., 7:5), 7:5:10:1:5, 7:10:1:5, 7:10:5, 7:5, and/10:5). The loading of the at least one bioactive agent 110 has been previously discussed in more detail herein.

In another example, and as shown in fig. 3J, the insertable portion coating is a bioactive substance releasing membrane 70 that may include at least one polymer layer, and at least one bioactive agent 110 is included in the membrane 70. In this example, the bioactive substance releasing membrane 70 may be adjacent to the sensing membrane 32 and include adjacent to any of the interferent membrane/domains, the resist membrane/domain, the biological interface membrane/domain, and the electrode membrane/domain. The various chemicals of the bioactive substance releasing membrane 70, their structures, bioactive loads, and other features contemplated by the present disclosure have been previously discussed herein.

As previously discussed herein, while some of the figures herein (e.g., fig. 3I and 3J) illustrate sensors that may have a coaxial core and a circular or oval cross-section, in other examples of sensor systems that include a bio-interface/bioactive substance release layer, the sensor may be a substantially planar sensor, as illustrated in the cross-section for illustration purposes in fig. 2H. For example, as shown in fig. 2H, the continuous analyte sensing device may include a substantially planar substrate 142, as well as interfering domains 144, enzyme domains 146, anti-domains 148, and bio-interface/bio-protective domains 168 and/or bioactive substance releasing domains 170 disposed about the planar or substantially planar substrate 142 in a substantially planar manner.

As shown in fig. 3K and 3L, in some examples, the bioactive substance releasing membrane 70 is spatially separated from the at least one sensing domain 112 by a distance such that the bioactive substance releasing membrane 70 does not overlap with the at least one sensing domain 112 or otherwise interfere with the diffusion path of one or more analytes or other substances associated with the generation of a measurable signal corresponding to the amount or presence of the one or more analytes. In this way, the bioactive substance releasing membrane 70 does not interfere with the sensing capabilities of the at least one sensing domain 112. In an example, the distance is about 1 μm or less to about 250 μm, including all ranges and subranges therebetween. In another example, the distance is about 1 μm or less to about 50 μm. In yet another example, the distance is about 15 μm to about 200 μm. In yet another example, the distance is about 50 μm to about 100 μm. For example, the distance is ：1μm、5μm、10μm、15μm、20μm、25μm、30μm、35μm、40μm、45μm、50μm、55μm、60μm、65μm、70μm、75μm、80μm、85μm、90μm、95μm、100μm、105μm、110μm、115μm、120μm、125μm、130μm、135μm、140μm、145μm、150μm、155μm、160μm、165μm、170μm、175μm、180μm、185μm、190μm、195μm、200μm、205μm、210μm、215μm、220μm、225μm、230μm、235μm、240μm and 245 μm from at least about any of and/or up to about 250μm、245μm、240μm、235μm、230μm、225μm、220μm、215μm、210μm、205μm、200μm、195μm、190μm、185μm、180μm、175μm、170μm、165μm、160μm、155μm、150μm、145μm、140μm、135μm、130μm、125μm、120μm、115μm、110μm、105μm、100μm、95μm、90μm、85μm、80μm、75μm、70μm、65μm、60μm、55μm、50μm、45μm、40μm、35μm、30μm、25μm、20μm、15μm、10μm and 5 μm (e.g., about 5 μm to 220 μm, about 45 μm to 250 μm, etc.).

In an example, and as illustrated in fig. 3K, the bioactive substance releasing membrane 70 is disposed on (and thus on) the insertable portion surface and is not in contact with the at least one sensing domain 112. In some examples, the bioactive substance releasing membrane 70 extends the entire length of the insertable portion 102 except for the area in contact with the at least one sensing domain 112. In another example, as illustrated in fig. 3L, the bioactive substance releasing film 70 is disposed only at the distal end 109 of the insertable portion 102 (e.g., the insertable portion 102 is not disposed on or in contact with the at least one sensing region 112, the proximal end 107 of the insertable portion 102, the remainder of the insertable portion 102, etc.). As further shown in fig. 3L, the insertable portion 102 has a distal end 109, and in one example as shown, the distal end 109 is spatially separated from the at least one sensing domain 112.

As also shown in fig. 3K, in one example, the insertable portion 102 is discontinuous or segmented, such as across the sensing domain 112. In another example, and as also illustrated in fig. 3L, the insertable portion 102 is continuous. As will be appreciated by those of ordinary skill in the art, any shape suitable for coating the insertable portion may be used continuously and/or discontinuously (e.g., the insertable portion coating may be continuous, discontinuous, or semi-continuous). Exemplary coating shapes include, but are not limited to, one or more cylinders, circles, ovals, squares, rectangles, triangles, diamonds, teardrop shapes, spirals, convolutions, leaf shapes (e.g., clover, flower shapes, butterfly shapes, heart shapes, etc.), and the like.

The insertable portion 102 has an insertable surface area and/or insertable volume and the bioactive substance releasing membrane 70 has a surface area and/or volume. In one example, the bioactive substance releasing membrane 70 has a surface area less than or equal to the insertable surface area. In further examples, the bioactive substance releasing membrane 70 has a volume that is the same as or different from (e.g., less than or equal to) the insertable volume.

Referring to fig. 3M, 3N and 3O, sensors similar to those depicted in fig. 3K, 3L are presented that illustrate the relationship of the bioactive substance releasing film 70 being near the distal tip of the sensor substrate without the sensing film 32 (e.g., including electrodes, interference, resistance, biointerface film/domain) covering the sensing domain 112. Fig. 3M shows the bioactive substance release film 70 surrounding the distal tip without the cut out 29 covering the lead or planar or substantially planar substrate. Fig. 3N shows an alternative configuration in which the bioactive substance releasing membrane 70 covers the end cap 40 immediately adjacent to the singulation section 29. Fig. 3O depicts another configuration in which the end cap 40 is directly adjacent to the singulation section 29 and the bioactive substance releasing film 70 is positioned around the distal tip of the insertable portion 102 without covering the end cap 40.

Referring to fig. 3P and 3Q, the bioactive substance release of a sensor having a bioactive substance release film 70 at the distal tip (e.g., a "tip coated" bioactive substance release film sensor) provides a bioactive substance release profile and improvements in sensitivity retention and noise reduction equivalent to other disclosed constructs described herein during long term use (e.g., 14 days, 21 days, 30 days, or longer). Among other advantages, a sensor with a tip coated bioactive substance-releasing membrane with a bioactive substance provides advantages of ease of manufacture, reduced overall bioactive substance required, and targeted delivery of the bioactive substance at the wound site, e.g., substantially immediate presentation of the bioactive substance upon insertion of the sensor at the initial insertion site, delivery of the API to the nearest desired location (i.e., sensing region), further physical protection from tip damage, and/or delivery of the API to the nearest wound volume created by the space between the needle tip and the sensor tip. The natural surface tension of the top coat forms a rounded surface, protecting tissue from penetration damage, and the overall curved geometry is believed to contribute to biocompatibility. The top coated bioactive substance releasing film can be added to the sensor without greatly altering the mechanical properties of the overall sensor. Manufacturing a sensor with a top coated bioactive substance releasing film can be accomplished by dip coating, which can be a fast and inexpensive manufacturing step. An example of a histological photograph of the insertable portion 102 of the sensor is shown in fig. 8A and 8B, wherein in fig. 8A, a microtome slice of a stained tissue image depicts a subcutaneous slice of recipient tissue after the insertable portion 102 of the sensor has caused a foreign body response of the immune system after an extended duration. Adipose tissue 150 and fibrous tissue 152 are depicted along with fibrotic envelope 154 and possibly cell portal 156. In contrast, fig. 8B depicts a microtome slice of a stained tissue image of an insertable portion 102 of a sensor having been inserted in a recipient tissue for an extended duration, the insertable portion having a bioactive substance release layer of the bioactive substance of the present disclosure. Adipose tissue 150 and fibrous tissue 152 are depicted without similar observable signs of fibrotic encapsulation or cellular entry.

While not wishing to be bound by theory, it is believed that the tissue at the end of the sensor is subject to the greatest degree of tissue trauma due to sensor insertion. By providing the bioactive agent at the tip of the sensor, foreign body reactions in the tissue near the tip of the sensor are reduced, as the local concentration of the bioactive agent is greatest in this surrounding environment. This also allows for less bioactive agent to be used within the bioactive substance releasing membrane 70. If the bioactive substance releasing membrane is placed near the tip, any time delay due to transport of the bioactive agent through the tissue is minimized. Moreover, by coating the tip of the sensor with the bioactive substance releasing film 70, the overall depth of insertion of the sensor and bioactive agent is reduced as compared to placing a large amount of bioactive agent near the tip of the sensor. A large amount of bioactive agent near the sensor tip may inadvertently separate from the sensor tip before or after insertion, resulting in a loss of therapeutic effect. In one example, the bioactive substance releasing membrane 70 having bioactive substances directly contacts and coats the sensing membrane present on the outer surface of the insertable tip portion of the sensor device. In one example, the bioactive substance release film 70 with bioactive agent is present only on the outer surface of the sensor of the insertable portion. The outer surface may include any and all of the previously disclosed electrode domains, interfering membranes, resistant membranes, and enzyme membranes, and the bioactive substance releasing membrane 70 with bioactive agent may be further from the electrode surface than any of these domains or membranes. In one example, the bioactive substance releasing membrane 70 with bioactive agent is furthest from the electrode surface than the electrode domain, interfering membrane, resistive membrane, and enzyme membrane. In one example, the diffusion regulating membrane 73 is further from the diffusion bioactive substance releasing membrane 70 having bioactive agents. In one example, the bioactive substance releasing membrane 70 with bioactive agent is present only on the outer surface of the sensor (e.g., a tip coated sensor, as shown in fig. 2E, 3H-3O) immediately adjacent to the insertable portion of the distal end 109 of the insertable portion 102.

In an example, the insertable surface area is from about 2mm ² to about 200mm ², including all ranges and subranges therebetween. In another example, the insertable surface area is from about 5mm ² to about 150mm ². In further examples, the insertable surface area is from about 25mm ² to about 100mm ². For example, the insertable surface area is ：2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54、56、58、60、62、64、66、68、70、72、74、76、78、80、82、84、86、88、90、92、94、96、98、100、102、104、106、108、110、112、114、116、118、120、122、124、126、128、130、132、134、136、138、140、142、144、146、148、150、152、154、156、158、160、162、164、166、168、170、172、174、176、178、180、182、184、186、188、190、192、194、196 and 198mm ² from at least about any of and/or up to about 200、198、196、194、192、190、188、186、184、182、180、178、176、174、172、170、168、166、164、162、160、158、156、154、152、150、148、146、144、142、140、138、136、134、132、130、128、126、124、122、120、118、116、114、112、110、108、106、104、102、100、98、96、94、92、90、88、86、84、82、80、78、76、74、72、70、68、66、64、62、60、58、56、54、52、50、48、46、44、42、40、38、36、34、32、30、28、26、24、22、20、18、16、14、12、10、8、6 and 4mm ² (e.g., about 30mm ² to 172mm ², about 2mm ² to 198mm ², etc.).

In an example, the insertable volume is from about 5mm ³ to about 500mm ³, including all ranges and subranges therebetween. In another example, the insertable volume is from about 10mm ³ to about 250mm ³. In further examples, the insertable volume is from about 25mm ³ to about 150mm ³. For example, the insertable volumes are ：5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、215、220、225、230、235、240、245、250、255、260、265、270、275、280、285、290、295、300、305、310、315、320、325、330、335、340、345、350、355、360、365、370、375、380、385、390、395、400、405、410、415、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490 and 495mm ³ from at least about any of the following and/or up to about 500、495、490、485、480、475、470、465、460、455、450、445、440、435、430、425、420、415、410、405、400、395、390、385、380、375、370、365、360、355、350、345、340、335、330、325、320、315、310、305、300、295、290、285、280、275、270、265、260、255、250、245、240、235、230、225、220、215、210、205、200、195、190、185、180、175、170、165、160、155、150、145、140、135、130、125、120、115、110、105、100、95、90、85、80、75、70、65、60、55、50、45、40、35、30、25、20、15 and 10mm ³ (e.g., about 20mm ³ to 420mm ³, about 10mm ³ to 500mm ³, etc.). The above range assumes a maximum insertable portion coating thickness of about 5mm.

In an example, the ratio of the polymer layer surface area to the insertable surface area is from about 0.1 to about 1, including all ranges and subranges therebetween. In another example, the ratio of the polymer layer surface area to the insertable surface area is from about 0.2 to about 0.8. In further examples, the ratio of the polymer layer surface area to the insertable surface area is from about 0.3 to about 0.7. For example, the ratio of polymer layer surface area to insertable surface area is from at least about any of: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9 and/or up to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, and 0.2 (e.g., about 0.2 to 0.9, about 0.5 to 0.8, etc.). The above ranges assume that the effective area of the sensor is at least 10% of the insertable portion.

In an example, the ratio of polymer layer volume to insertable volume of the bioactive substance releasing membrane 70 is about 1:100 to about 20:100 (i.e., 1:5), including all ranges and subranges therebetween. In another example, the ratio of the polymer layer volume to the insertable volume of the bioactive substance releasing membrane 70 is about 1:50 to about 15:75 (i.e., 1:5). In further examples, the ratio of polymer layer volume to insertable volume is from about 5:50 (i.e., 1:10) to about 10:80 (i.e., 1:8). For example, the ratio of polymer layer volume to insertable volume is from at least about any of: 1:100, 2:100 (i.e., 1:50), 3:100, 4:100 (i.e., 1:25), 5:100 (i.e., 1:20), 6:100 (i.e., 3:50), 7:100, 8:100 (i.e., 2:25), 9:100, 10:100 (i.e., 1:10), 11:100, 12:100 (i.e., 3:25), 13:100, 14:100 (i.e., 7:50), 15:100 (i.e., 3:20), 16:100 (i.e., 4:25), 17:100, 18:100 (i.e., 9:50), 17:100, 16:100 (i.e., 4:25), 15:100 (i.e., 3:20), 14:100 (i.e., 7:50), 13:100, 12:100 (i.e., 3:25), 11:100 (i.e., 1:10), 9:100, 8:100 (i.e., 2:25), 7:100), 6:100 (i.e., 1:5), 19:100, 18:100 (i.e., 1:50), and/or at most about 20:100 (i.e., 1:5:100) (i.e., 1:5:20:20:20), 19:100 (i.g., 1:50), 17:100:100 (i.1:50).

Providing a continuous analyte sensing device and applying an insertable portion coating composition comprising at least one polymer and at least one bioactive agent to the insertable portion to provide an insertable portion coating as described herein, thereby forming the continuous analyte sensing device described above. In an example, the insertable portion coating composition applied to the insertable portion has a viscosity of about 10cP to about 350cP, with or without a bioactive load. In another example, the insertable portion coating composition applied to the insertable portion has a viscosity of about 20cP to about 200cP, with or without a bioactive load. In yet another example, the insertable portion coating composition applied to the insertable portion has a viscosity of about 30cP to about 300cP, with or without a bioactive load.

As previously discussed herein, in examples, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance releasing film 70, has an advancing contact angle of about 105 ° to about 130 ° or 110 ° to about 120 °. In yet another example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the bio-interface/bioactive substance releasing film, has a receding contact angle of about 40 ° to about 80 °. In another example, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the bio-interface/bioactive substance releasing film 70, has a receding contact angle of about 45 ° to about 75 °. In yet another example, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the bio-interface/bioactive substance releasing film 70, has a receding contact angle of about 50 ° to about 70 °. In some examples, dynamic contact angle measurements and surface roughness on the bioactive substance releasing film 70 after placement on the analyte sensor and after sterilization may be performed using a Sigma 701 force tensiometer and performing one or more of an advancing contact angle measurement, a receding contact angle measurement, a hysteresis measurement, and combinations thereof.

Further, in the example, the resulting bioactive substance releasing film 70 has a film thickness of about 20 μm to about 40 μm, including all ranges and subranges therebetween. In certain examples, the thickness of the insertable portion coating of the bioactive substance releasing membrane 70 can be about 0.1 μm, about 0.5 μm, about 1 μm, about 2 μm, about 4 μm, about 6 μm, about 8 μm or less to about 10 μm, about 15 μm, about 20 μm, about 30 μm, about 40 μm, about 50 μm, about 75 μm, about 100 μm, about 125 μm, about 150 μm, about 175 μm, about 200 μm or about 250 μm or more. In some of these examples, the thickness of the insertable partial coating may sometimes be about 1 μm to about 5 μm, and may sometimes be about 2 μm to about 7 μm. In other examples, the insertable portion coating may be about 20 μm or about 25 μm to about 50 μm, about 55 μm or about 60 μm thick.

In another example, the resulting insertable portion coating of the bioactive substance releasing membrane 70 has a length of about 1mm to about 20mm, including all ranges and subranges therebetween. In another example, the insertable portion coating has a length of about 2mm to about 14 mm. In further examples, the insertable portion coating has a length of about 4mm to about 12 mm. For example, the insertable portion coating has a length of at least about any of: 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm and 19mm and/or up to about 20mm, 19mm, 18mm, 17mm, 16mm, 15mm, 4mm, 13mm, 12mm, 11mm, 10mm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm and 2mm (e.g., about 1mm to 15mm, about 5mm to 18mm, etc.).

The bioactive substance release film 70 is applied using at least one of spray coating, pad printing, spray coating, bubble film coating, drop coating, dip-wash, inverted dip-wash, or any combination thereof. For example, when dip coating is used in combination with washing, the resulting cross-section of the insertable portion and the insertable portion coating includes a plurality of concentric circles with defined edges or boundaries, as illustrated in fig. 2C, 3I and 3J. In contrast, when the resulting device is not impregnated, the cross-section does not include distinct, defined edges or boundaries, but rather shows a gradual transition between the layers.

The bioactive substance releasing membrane 70 provides therapeutic benefits including reducing or delaying an immune response (e.g., a local tissue response) in a subject in tissue into which the insertable portion is inserted.

Similarly, reducing or delaying the immune response increases the sensitivity of the continuous analyte sensing devices disclosed herein. For example, as shown in fig. 6B-6E, the control sensor exhibited a significantly greater decrease in sensitivity than the bioactive-loaded sensor, and the sensor described herein including the insertable portion coating on the distal end of the insertable portion exhibited the latest occurrence of the decrease in sensitivity. In fact, in the test results shown in fig. 6D, the control sensor had a sensitivity survival of 53% and the bioactive-loaded sensor had a sensitivity survival of 78% at 15 days post-insertion, and the bioactive-loaded sensor including only the insertable portion coating on the distal end of the insertable portion had a sensitivity survival of 94%.

Methods for reducing or delaying an immune response include: (i) Providing the continuous analyte sensing device 100 described above, the device configured to deploy the insertable portion 102; (ii) Upon deployment of the insertable portion 102, formation (e.g., development or production) of a tissue insertion volume is induced in the subject; (iii) Releasing at least one bioactive agent 110 from the bioactive substance release film 70 into the tissue insertion volume; and (iv) reducing or delaying an immune response with respect to the tissue insertion volume in response to (iii) releasing the at least one bioactive agent. As previously discussed herein, the tissue insertion volume comprises subcutaneous or intradermal adipose or muscle tissue, and the composition of the tissue insertion volume varies based on the insertion site. In an example, the tissue insertion volume is greater than or equal to the insertable volume. In further examples, the at least one bioactive agent 110 is released from the bioactive agent release film 70 at an average release rate of about 0.1 μg to about 5 μg per day (including all ranges and subranges therebetween).

As a result of the methods described herein, in examples, the immune response is reduced or delayed for at least 7 days. In another example, the immune response is reduced or delayed for at least 10 days. In further examples, the immune response is reduced or delayed for at least 14 days. In yet another example, the immune response is reduced or delayed for at least 21 days. Thus, the methods described herein reduce the immune response for at least 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, or 21 days (even longer). Thus, the continuous analyte sensing devices disclosed herein are capable of releasing a bioactive substance for at least 15 days after insertion.

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

All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. In any application where priority is claimed, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques and is not intended to limit the application of the doctrine of equivalents to the scope of any claim.

The foregoing description discloses several methods and materials of the present disclosure. The present disclosure is susceptible to modification of methods and materials, and changes in manufacturing methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the disclosure disclosed herein. Therefore, it is intended that the disclosure not be limited to the particular examples disclosed herein, but rather to cover all modifications and alternatives falling within the true scope and spirit of the disclosure.

While certain examples of the present disclosure have been described with reference to particular combinations of elements, various other combinations may be provided without departing from the teachings of the present disclosure. Accordingly, the present disclosure should not be construed as limited to the particular exemplary examples described herein and illustrated in the drawings, but may also cover various illustrated examples and combinations of elements of aspects thereof.

Claims

1. An apparatus for measuring a concentration of an analyte, the apparatus comprising:

a sensor substrate comprising a distal end separate 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 substance release film adjacent to the sensor substrate, the bioactive substance release film comprising at least one releasable bioactive agent capable of altering a tissue response of a subject.

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

3. The device of any one of the preceding claims, wherein the bioactive substance releasing membrane is positioned only at the distal end.

4. The device of any one of the preceding claims, wherein the bioactive substance releasing membrane is directly adjacent to a resistant membrane, wherein the bioactive substance releasing membrane is directly adjacent to an electrode membrane, or wherein the bioactive substance releasing membrane is directly adjacent to an interfering membrane.

5. The device of any one of the preceding claims, further comprising a dissolvable coating adjacent the bioactive substance releasing film.

6. The apparatus of any one of the preceding claims, wherein the dissolvable coating further comprises a releasable bioactive agent.

7. The device of any one of the preceding claims, 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, wherein the first releasable bioactive agent is the same as or different from the second releasable bioactive agent.

8. The device of any one of the preceding claims, wherein the dissolvable coating comprises the second releasable bioactive agent in combination with nanoparticles comprising one or more anti-inflammatory agents.

9. The apparatus of any one of the preceding claims, wherein the dissolvable coating provides bolus release of both the second releasable bioactive agent and the nanoparticles.

10. The apparatus of any one of the preceding claims, wherein the dissolvable coating is hydrophilic.

11. The device of any one of the preceding claims, wherein the dissolvable coating is analyte-diffusing.

12. The device of any one of the preceding claims, further comprising a diffusion modulating membrane adjacent to the bioactive substance releasing membrane, wherein the diffusion modulating membrane is different from the bioactive substance releasing membrane.

13. The device of any one of the preceding claims, wherein the diffusion regulating membrane is directly adjacent to the bioactive substance releasing membrane.

14. The apparatus of any one of the preceding claims, wherein the diffusion regulating membrane is a block copolymer.

15. The apparatus of any one of the preceding claims, wherein the diffusion regulating membrane is a segmented block copolymer.

16. The apparatus of any one of the preceding claims, wherein the diffusion regulating membrane is a multiblock copolymer.

17. The apparatus of any one of the preceding claims, wherein the diffusion regulating membrane is annealed.

18. The apparatus of any one of the preceding claims, wherein the annealed diffusion regulating membrane comprises a stable separate phase.

19. The device of any one of the preceding claims, wherein the stable separate phase provides a diffusion channel for the at least one releasable bioactive agent.

20. The device of any one of the preceding claims, wherein the bioactive substance releasing 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.

21. The apparatus of any one of the preceding claims, wherein the bioactive substance releasing membrane comprises a multicomponent soft segment comprising two or more different polymer segments.

22. The apparatus of any of the preceding claims, wherein the multicomponent soft segment comprises a hydrophobic block and a hydrophilic block of at least one of a polysiloxane, a polyalkylcarbonate, and a polycarbonate in combination with a polyalkylether, a polyalkylester.

23. The apparatus of any of the preceding claims, wherein the soft segment comprises a combination of one or more of polysiloxane, polyalkylether, polyalkyl ester, polyalkylcarbonate, polycarbonate, and polysiloxane-polyalkyl ether segmented blocks, and wherein the hard segment comprises at least one of norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene Diisocyanate (TDI), 1, 3-phenylene diisocyanate (MPDI), trans-1, 3-bis (isocyanatomethyl) cyclohexane (1, 3-H6 XDI), dicyclohexylmethane-4, 4 '-diisocyanate (HMDI), 4' -diphenylmethane diisocyanate (MDI), trans-1, 4-bis (isocyanatomethyl) cyclohexane (1, 4-H6 XDI), 1, 4-cyclohexyl diisocyanate (CHDI), 1, 4-phenylene diisocyanate (PPDI), 3 '-dimethyl-4, 4' -biphenyl diisocyanate (TODI), and 1, 6-Hexamethylene Diisocyanate (HDI).

24. The device of any one of the preceding claims, wherein the bioactive substance releasing membrane further comprises a chain extender.

25. The device of any one of the preceding claims, wherein the bioactive substance releasing membrane is polyurethaneurea.

26. The apparatus of any one of the preceding claims, wherein the bioactive substance releasing film comprises about 10 to 30 wt% polysiloxane and about 10 to 30 wt% polyalkylether, 40 to 60 wt% hard segment, and any remaining wt% is a chain extender, the hard segment comprising urethane groups, urea groups, or a combination of urethane groups and urea groups, based on the total weight of the bioactive substance releasing film.

27. The apparatus of any of the preceding claims, wherein the polyalkyl ether is represented by a repeating unit of formula (I): - (R ⁵ -O) -; wherein R ⁵ is a straight or branched alkyl of 2 to 6 carbons.

28. The apparatus of any one of the preceding claims, wherein the bioactive substance releasing film comprises about 20 to 30 wt% polysiloxane, about 20 to 30 wt% polyalkylether, and about 40 to 60 wt% hard segment, based on the total weight of the bioactive substance releasing film, and any remaining wt% is chain extender.

29. The apparatus of any one of the preceding claims, wherein the bioactive substance releasing membrane comprises a soft segment comprising about 10 wt% to 30 wt% polysiloxane, about 10 wt% to 30 wt% polyalkylether, and about 0wt% to 10 wt% chain extender, based on the total weight of the bioactive substance releasing membrane.

30. The device of any one of the preceding claims, wherein the bioactive substance releasing membrane has an equilibrium water absorption of 1 to 4 wt%.

31. The device of any one of the preceding claims, wherein the bioactive substance releasing membrane has an equilibrium water absorption of less than 3 wt%.

32. The device according to any one of the preceding claims, wherein the bioactive substance releasing membrane is an excipient of the at least one releasable bioactive agent.

33. The device of any one of the preceding claims, wherein the bioactive substance releasing membrane comprises a hydrophobic soft segment, at least one hydrophilic soft segment, and a hard segment comprising urethane groups, urea groups, or a combination of urethane and urea groups.

34. The device of any one of the preceding claims, wherein the bioactive substance releasing membrane comprises a hard segment and a soft segment, the hard segment having a hildebrand solubility parameter that is closer to the at least one releasable bioactive agent than the soft segment.

35. The apparatus of any of the preceding claims, wherein the distal end of the substrate comprises a wire singulation, a planar singulation, or a substantially planar singulation.

36. The apparatus of any one of the preceding claims, further comprising an electrically insulating end cap adjacent the distal end.

37. The apparatus of any one of the preceding claims, wherein the electrically insulating end cap is a hydrophobic coating.

38. The apparatus of any one of the preceding claims, wherein the electrically insulating end cap is impermeable to electrochemically active material.

39. The apparatus of any one of the preceding claims, wherein the electrically insulating end cap is impermeable to the analyte.

40. The apparatus of any one of the preceding claims, wherein the electrically insulating end cap extends longitudinally from the distal end.

41. The apparatus of any one of the preceding claims, wherein the electrically insulating end cap extends from the distal end up to the sensor portion.

42. The apparatus of any of the preceding claims, wherein the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, polyurethane acrylate, polybutadiene modified polyurethane, or a combination thereof.

43. A method of reducing or delaying an immune response in a tissue of a subject, the method comprising:

(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 the tissue, the insertable portion having an insertable surface area and an insertable volume;

At least one bioactive substance releasing membrane disposed on a portion of the insertable surface area, the bioactive substance releasing membrane being spatially separated from the sensing portion, the at least one bioactive substance releasing membrane comprising at least one bioactive agent;

(ii) Forming a tissue insertion volume in the tissue by inserting the insertable portion, the tissue insertion volume being greater than or equal to the insertable volume;

(iii) Releasing the at least one bioactive agent from the at least one bioactive agent release film into the tissue insertion 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.

44. The method of claim 43, wherein the bioactive material releasing membrane is spatially separated from the sensing portion.

45. The method of any one of claims 43 to 44, wherein the bioactive substance releasing membrane active further comprises a non-releasable bioactive agent.

46. The method of any one of claims 43-45, wherein the bioactive substance releasing membrane comprises a polymer and the weight/weight ratio of the at least one bioactive agent to the polymer is about 0.1 to about 2.

47. The method of any one of claims 43-46, wherein the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier.

48. The method of any one of claims 43-47, wherein the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.

49. A method of reducing signal noise caused by foreign body reactions in a continuous analyte sensor apparatus, the method comprising:

providing a continuous analyte sensing device, the continuous analyte sensing device comprising:

a substrate comprising an insertable portion operably coupled to a non-insertable portion, the insertable portion having a distal end;

at least one sensing portion positioned proximal to the distal end;

At least one bioactive substance releasing membrane disposed on at least a portion of the distal end, the bioactive substance releasing membrane comprising at least one bioactive agent capable of attenuating a foreign body response; and

Reducing the signal noise during use of the continuous analyte sensing device.

50. The method of claim 49, further comprising releasing or exposing the at least one bioactive agent to the tissue.

51. The method of any one of claims 49-50, further comprising attenuating the foreign body response near the distal end.

52. The method of any one of claims 49-51, wherein the analyte is glucose and the signal noise is maintained at less than 4mg/dL for at least 10 days.

53. The method of any one of claims 49-52, wherein the analyte is glucose and the signal noise is maintained at less than 4mg/dL for at least 15 days.

54. The method of any one of claims 49-53, wherein the analyte is glucose and the signal noise is maintained at less than 4mg/dL for at least 21 days.

55. The method of any one of claims 49 to 54, wherein the insertable portion comprises an insertable surface area and an insertable volume.

56. The method of any one of claims 49-55, wherein the at least one bioactive substance releasing membrane is disposed on a portion of the insertable surface area, the at least one bioactive substance releasing membrane having at least one of a bioactive substance releasing membrane surface area that is less than or equal to the insertable surface area.

57. The method of any one of claims 49 to 56, wherein the at least one bioactive substance releasing membrane comprises a polymer and the weight ratio of the polymer to the total amount of at least one bioactive agent is about 0.1 to about 2.

58. The method of any one of claims 49-57, wherein the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier.

59. The method of any one of claims 49-58, wherein the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.

60. The method of any one of claims 49-59, wherein the insertable portion and the non-insertable portion are disposed on the substrate, wherein the substrate is a wire, a planar substrate, or a substantially planar substrate, and the distal end further comprises a singulation.

61. The method of any one of claims 49-60, further comprising an electrically insulating end cap adjacent the distal end.

62. The method of any one of claims 49 to 61, wherein the electrically insulating end cap is a hydrophobic coating.

63. The method of any one of claims 49-62, wherein the electrically insulating end cap extends longitudinally from the distal end.

64. The method of any one of claims 49 to 63, wherein the electrically insulating end cap is impermeable to electrochemically active material.

65. The method of any one of claims 49 to 64, wherein the electrically insulating end cap is impermeable to the analyte.

66. The method of any one of claims 49-65, wherein the electrically insulating end cap extends from the distal end up to the sensor portion.

67. The method of any one of claims 49 to 66, wherein the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, polyurethane acrylate, polybutadiene modified polyurethane, polyethylene vinyl acetate, silicone, or a combination thereof.

68. A method of reducing the occurrence of sensitivity loss of a continuous analyte sensor apparatus caused by foreign body reactions in tissue during use, the method comprising:

providing the continuous analyte sensing device, the continuous analyte sensing device comprising:

A substrate comprising an insertable portion having a distal end operably coupled to a non-insertable portion;

at least one sensing portion positioned proximal of the distal end and distal of the non-insertable portion;

At least one bioactive substance releasing membrane disposed on a portion of the distal end, the at least one bioactive substance releasing membrane comprising at least one bioactive agent capable of attenuating a foreign body response; and

Reducing the occurrence of sensitivity loss of the continuous analyte sensing device during use.

69. The method of claim 68, further comprising releasing or exposing the at least one bioactive agent to the tissue.

70. The method of any one of claims 68-69, wherein the occurrence of the loss of sensitivity is reduced for at least 14 days.

71. The method of any one of claims 68-70, wherein the occurrence of the loss of sensitivity is reduced for at least 20 days.

72. The method of any one of claims 68-71, wherein the occurrence of the loss of sensitivity is reduced for at least 30 days.

73. The method of any one of claims 68-72, wherein the substrate is a wire, a planar substrate, or a substantially planar substrate, and the distal end further comprises a singulation.

74. The method of any one of claims 68-73, further comprising an electrically insulating end cap adjacent the distal end.

75. The method of any one of claims 68 to 74, wherein the electrically insulating end cap is different from the bioactive substance releasing membrane.

76. The method of any one of claims 68 to 75, wherein the electrically insulating end cap is a hydrophobic coating.

77. The method of any one of claims 68-77, wherein the electrically insulating end cap extends longitudinally from the distal end.

78. The method of any one of claims 68 to 77, wherein the electrically insulating end cap is impermeable to electrochemically active material.

79. The method of any one of claims 68-79, wherein the electrically insulating end cap is impermeable to the analyte.

80. The method of any one of claims 68-79, wherein the electrically insulating end cap extends longitudinally from the distal end up to the sensor portion.

81. The method of any of claims 68-80, wherein the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, polyurethane acrylate, polybutadiene modified polyurethane, polyethylene vinyl acetate, silicone, or a combination thereof.

82. The method of any one of claims 68-81, wherein the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier.

83. The method of any one of claims 68-82, wherein the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.

84. An apparatus for measuring a concentration of an analyte, the apparatus comprising:

a sensor portion configured to generate a signal associated with the concentration of the analyte; and

A bioactive substance release membrane proximate the sensor portion, the bioactive substance release membrane configured to form a complex with at least one bioactive agent configured to be released from the bioactive substance release membrane to alter a tissue response of a subject.

85. The device of claim 84, wherein the complex with the at least one bioactive agent is covalent or non-covalent.

86. The device of any one of claims 84-85 wherein said complex with said at least one bioactive agent is ionic.

87. The device of any one of claims 84-86, wherein said complex with said at least one bioactive agent provides a bioactive agent conjugate.

88. The device of any one of claims 84-87, wherein the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier.

89. The device of any one of claims 84-88, wherein said at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.

90. The device of any one of claims 84-89, wherein the at least one bioactive agent is a nitric oxide releasing molecule, polymer, or oligomer.

91. The device of any one of claims 84 to 90, wherein the nitric oxide releasing molecule is selected from the group consisting of N-diazeniumdiolate and S-nitrosothiols.

92. The device of any one of claims 84-91, wherein the at least one bioactive agent is covalently coupled factor H.

93. The device of any one of claims 84-92 wherein the complex is a bioactive agent conjugate comprising a borate or borate.

94. The device of any one of claims 84-93, wherein the complex is a bioactive agent conjugate comprising at least one cleavable linker capable of cleavage by subcutaneous stimulation.

95. The device of any one of claims 84-94, wherein the subcutaneous stimulus is a matrix metallopeptidase or protease challenge.

96. The device of any one of claims 84-95 wherein said bioactive substance releasing membrane comprises a hydrophilic hydrogel, wherein said hydrophilic hydrogel is at least partially crosslinked and is dissolvable in a biological fluid.

97. The device of any one of claims 84-96 wherein the hydrophilic hydrogel comprises hyaluronic acid crosslinked by divinyl sulfone or polyethylene glycol divinyl sulfone.

98. The device of any one of claims 84-97 wherein the bioactive substance release film comprises silver nanoparticles.

99. The device of any one of claims 84-98 wherein the bioactive substance release film comprises polymeric nanoparticles selected from the group consisting of PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphates, or PEO-b-polypeptides containing the at least one bioactive agent.

100. The device of any one of claims 84-99 wherein the bioactive substance release film comprises an organogel carrier and/or an inorganic gel carrier.

101. The device of any one of claims 84-100, wherein the bioactive substance release membrane configured to form the complex with the at least one bioactive agent comprises a combination of the at least one bioactive agent encapsulated in the bioactive substance release membrane and the at least one bioactive agent covalently coupled to the bioactive substance release membrane.

102. The device of any one of claims 84-101, wherein the bioactive substance release membrane configured to form the complex with the at least one bioactive agent comprises a spatially distal drug reservoir of the at least one bioactive agent.

103. The device of any one of claims 84-102, wherein the bioactive substance release film configured to form the complex with the at least one bioactive agent comprises a hydrolytically degradable biopolymer, the hydrolytically degradable biopolymer comprising the at least one bioactive agent.

104. The device of any one of claims 84 to 103 wherein the hydrolytically degradable biopolymer comprises a poly anhydride salicylate.

105. The device of any one of claims 84-104 wherein the bioactive substance releasing membrane comprises a polyurethane segment and/or a polyurea segment, wherein the polyurethane segment and/or the polyurea segment is about 15% to about 75% by weight, based on the total weight of the bioactive substance releasing membrane.

106. The device of any one of claims 84-105 wherein the bioactive substance releasing membrane comprises at least one polymer segment, wherein the at least one polymer segment is selected from the group consisting of an epoxide, polyolefin, polysiloxane, polyamide, polystyrene, polyacrylate, polyether, polypyridine, polyester, polyalkyl ester, polyalkylcarbonate, polycarbonate, polyethylene vinyl acetate, polyvinyl alcohol, and copolymers thereof.

107. The device of any one of claims 84-106 wherein the bioactive substance releasing membrane comprises polyethylene oxide segments.

108. The device of any one of claims 84 to 107 wherein the polyethylene oxide segment is about 5% to about 60% by weight, based on the total weight of the bioactive substance releasing membrane.

109. The device of any one of claims 84-108 wherein the base polymer of the bioactive substance releasing membrane has an average molecular weight of about 10kDa to about 500 kDa.

110. The device of any one of claims 84-109 wherein the base polymer of the bioactive substance release film has a polydispersity index of 1 to about 10.

111. The device of any one of claims 84-110 wherein the base polymer of the bioactive substance release film has a contact angle of about 90 ° to about 160 °.

112. An apparatus for measuring a concentration of an analyte, the apparatus comprising:

A bioactive substance releasing membrane proximate the sensor portion, the bioactive substance releasing membrane comprising one or more zwitterionic repeat units complexed with at least one bioactive agent configured to be released from the one or more zwitterionic repeat units to alter tissue response in a subject.

113. The apparatus of claim 112, wherein the one or more zwitterionic repeat units comprise a betaine compound or derivative thereof.

114. The apparatus of any one of claims 112-113, wherein the one or more zwitterionic repeat units comprise a betaine compound or precursor thereof.

115. The apparatus of any one of claims 112-114, wherein the one or more zwitterionic repeat units comprise at least one moiety selected from the group consisting of carboxybetaines, sulfobetaines, phosphobetaines, and derivatives thereof.

116. The device of any one of claims 112-115, wherein the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier.

117. The device of any one of claims 112-116, wherein the at least one bioactive agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.

118. The apparatus of any one of claims 112-117, wherein the one or more zwitterionic repeat units are derived from monomers selected from the group consisting of:

And

Wherein Z is branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; r1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R2, R3 and R4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and wherein one or more of R ¹、R²、R³、R⁴ and Z are substituted with a polymeric group.

119. The apparatus of any one of claims 112 to 118, wherein the polymeric group is selected from an alkene, alkyne, epoxide, lactone, amine, hydroxyl, isocyanate, carboxylic acid, anhydride, silane, halide, aldehyde, carbodiimide, or combinations thereof.

120. The device of any one of claims 112-119, wherein the one or more zwitterionic repeat units are at least about 1wt% based on the total weight of the bioactive substance releasing membrane.

121. The device of any one of claims 112-120, wherein the bioactive substance release film further comprises one or more zwitterions selected from the group consisting of: cocoamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, decyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly (carboxybetaine), poly (sulfobetaine) and derivatives thereof.

122. The device of any one of claims 112-121, wherein the bioactive substance releasing membrane comprises a polymer chain having zwitterionic groups at the ends of and along the polymer chain.

123. The device of any one of claims 112-122, wherein the bioactive substance releasing membrane comprises a polymer chain having both hydrophilic and hydrophobic regions, and wherein one or more zwitterionic compounds are present at the ends of the polymer chain; the bioactive substance releasing membrane comprises a base polymer selected from the group consisting of polyolefin, polystyrene, polyoxymethylene, polysiloxane, polyether, polyacrylic acid, polymethacrylic acid, polyester, polyalkyl ester, polyalkyl carbonate, polycarbonate, polyamide, polypyridine, poly (ether ketone), poly (ether imide), polyurethane, polyurethaneurea, polyvinyl acetate, polyvinyl alcohol, or copolymers or blends thereof.

124. The device of any one of claims 112-123, wherein the base polymer of the bioactive substance release membrane has an average molecular weight of about 10kDa to about 500 kDa.

125. The device of any one of claims 112-124, wherein the base polymer of the bioactive substance release film has a polydispersity index of about 1 to about 10.

126. The device of any one of claims 112-125, wherein the base polymer of the bioactive substance release film has a dynamic contact angle of about 90 ° to about 160 °.