Drug releasing device and method

Abstract

The present disclosure relates generally to bioactive releasing membranes utilized with implantable devices, such as devices for the detection of analyte concentrations in a biological sample. More particularly, the disclosure relates to drug releasing implantable devices and to methods for improved initial monitoring of analyte levels in a biological fluid sample using an implantable analyte detection device.

Description

Attorney Docket No.: 0934-PCT01_0239DRUG RELEASING DEVICE AND METHODTechnical Field

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

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

[0003] In examples, a device for measurement of a concentration of an analyte is provided, the device comprising: an analyte sensor configured for subcutaneous insertion; said sensor comprising (i) a sensing portion configured to generate a signal associated with a concentration of an analyte and (ii) a vasodilator-releasing portion comprising a vasodilator, said vasodilator-releasing portion being configured to release said at least one vasodilator upon subcutaneous insertion of the sensor.

[0004] In aspects, the vasodilator is a nitric oxide (NO) releasing molecule, polymer, or oligomer; minoxidil; hydralazine; nitroglycerin, or combinations thereof. In aspects, alone or in combination with any previous aspect, the vasodilator is a nitric oxide (NO) releasing molecule selected from N-diazeniumdiolates and S-nitrosothiols, and N-diazeniumdiolates. In aspects, alone or in combination with any previous aspect, the vasodilator isAttorney Docket No.: 0934-PCT01_0239phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, Hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L- arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, and combinations thereof.

[0005] In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a biocompatible hydrophilic polymer. In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a polymer chain having one or more zwitterionic compounds. In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a hydrolytically degradable biopolymer.

[0006] In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a polymer chain having hydrophilic regions. In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a hydrophilic hydrogel, wherein the hydrophilic hydrogel is at least partly crosslinked and dissolvable in biological fluid.

[0007] In aspects, alone or in combination with any previous aspect, the analyte is glucose, ketone, lactate, potassium, or combinations thereof.

[0008] In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a coating comprising a polymer chain having polyurethane and / or polyurea segments. In aspects, alone or in combination with any previous aspect, the analyte sensorfurther comprises a coating comprising a polymer chain having both hydrophilic and hydrophobic regions.

[0009] In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a coating comprising a polymer with a styrene group. In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a coating comprising a polymer with a heterocyclic group. In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a coating comprising a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly(2-vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers or quaternized forms thereof.

[0010] In aspects, alone or in combination with any previous aspect, the sensorfurther comprises (i) a tissue response modifier releasing portion which comprises a tissue responseAttorney Docket No.: 0934-PCT01_0239modifier, and is configured to release said tissue response modifier from the device upon subcutaneous insertion; or (ii) an anti-inflammatory agent releasing portion, which comprises an anti-inflammatory agent, and is configured to release said anti-inflammatory agent from the device upon subcutaneous insertion of the sensor.

[0011] In aspects, alone or in combination with any previous aspect, the antiinflammatory agent comprises pilocarpine, dexamethasone, a derivative form of dexamethasone, dexamethasone acetate, or a combination of a derivative form of dexamethasone or dexamethasone acetate with dexamethasone.

[0012] In aspects, alone or in combination with any previous aspect, the antiinflammatory agent or the tissue response modifier is coupled to a coating of the analyte sensor with a hydrolytically degradable linkergroup.

[0013] In aspects, alone or in combination with any previous aspect, the sensor further comprises at least one wound extrudate absorbing coating configured to absorb wound extrudate upon subcutaneous insertion.

[0014] In aspects, alone or in combination with any previous aspect, the sensor comprises a wire substrate or a planar substrate, wherein the sensing portion and the vasodilator-releasing portion are spatially separated along a longitudinal axis of said wire substrate or a planar substrate.

[0015] In aspects, alone or in combination with any previous aspect, the sensor comprises more than one wire substrates and / or planar substrates, wherein the sensing portion and the vasodilator-releasing portion are present on separate wire substrates and / or planar substrates.

[0016] In aspects, alone or in combination with any previous aspect, the sensing portion is present on a planar substrate. In aspects, alone or in combination with any previous aspect, the sensing portion is present on a wire substrate.

[0017] In aspects, alone or in combination with any previous aspect, the vasodilatorreleasing portion is present on a planar substrate. In aspects, alone or in combination with any previous aspect, the vasodilator-releasing portion is present on a wire substrate.

[0018] In aspects, alone or in combination with any previous aspect, the vasodilatorreleasing portion and the analyte sensing portion are spatially separated.

[0019] In aspects, alone or in combination with any previous aspect, the sensing portion comprises a working electrode, a reference, and / or a counter electrode configured toAttorney Docket No.: 0934-PCT01_0239generate a signal associated with the analyte. In aspects, alone or in combination with any previous aspect, the vasodilator-releasing portion comprises at least one vasodilatorreleasing electrode. In aspects, alone or in combination with any previous aspect, the vasodilator-releasing electrode is distal from the working electrode or reference electrode. In aspects, alone or in combination with any previous aspect, the working electrode and the vasodilator-releasing electrode share the counter electrode or the reference electrode. In aspects, alone or in combination with any previous aspect, the vasodilator-releasing electrode is positioned most distal relative to any other working electrode.

[0020] In aspects, alone or in combination with any previous aspect, the sensor further comprises an electrically conductive membrane in proximity to the vasodilator-releasing electrode, the electrically conductive membrane comprising a tissue response modifier which is releasable from said electrically conductive membrane. In aspects, alone or in combination with any previous aspect, the electrically conductive membrane comprises at least one electrically conductive polymer. In aspects, alone or in combination with any previous aspect, the at least one electrically conductive polymer is doped.

[0021] In aspects, alone or in combination with any previous aspect, the signal is measure potentiometrically, coulometrically, or amperometrically.

[0022] In aspects, alone or in combination with any previous aspect, the sensing portion comprises a first working electrode configured to generate a signal associated with a first analyte. In aspects, alone or in combination with any previous aspect, the sensing portion further comprises a second working electrode configured to generate a signal associated with a second analyte, the second analyte being chemically different from the first analyte.

[0023] In examples, use of a vasodilator to reduce time lag between (i) a change in concentration of an analyte in blood in response to a concentration of an analyte-changing event and (ii) a change in concentration of the same analyte in interstitial fluid in response to the same analyte concentration-changing event is provided.

[0024] In aspects, alone or in combination with any previous aspect, the vasodilator is provided on the vasodilator-releasing portion of a sensor comprised as part of the device as defined in any of the previous aspects.

[0025] In examples, use of a vasodilator to improve accuracy of a continuous glucose monitoring device, wherein the continuous glucose monitoring device comprises a subcutaneous sensor which comprises the vasodilator and optionally at least one of an antiAttorney Docket No.: 0934-PCT01_0239inflammatory agent and / or a tissue response modifier, said improvement in accuracy being relative to a corresponding sensor without the vasodilator is provided.

[0026] In aspects, alone or in combination with any previous aspect, accuracy is the degree of correspondence between (i) the glucose concentration measured in vivo within interstitial fluid by the continuous glucose monitoring device at at least one timepoint in between 0.5-24 hours after insertion of the sensor into the body and (ii) the glucose concentration measured by ex vivo blood within blood by a blood gas analyzer or blood analysis device.

[0027] In aspects, alone or in combination with any previous aspect, the vasodilator is provided on the vasodilator-releasing portion of a sensor comprised as part of the device as defined in any of previous aspects.

[0028] In examples, a method of assisting equilibrium of an analyte within interstitial fluid and / or venous blood volume in proximity to an implanted analyte sensor is provided, the method comprising: subcutaneously introducing an analyte sensor to an implant site, the analyte sensor configured for providing a signal corresponding to a concentration of an analyte in proximity to the implant site; releasing, in proximity to the implant site, an amount of at least one tissue response modifier, or an amount of anti-inflammatory agent that causes a delay in obtaining a signal corresponding to a concentration of an analyte; releasing an amount of at least one vasodilator in proximity to the implant site; and reducing or eliminating a difference between the concentration of the analyte in venous blood and in interstitial fluid (ISF) in proximity to the implant site.

[0029] In examples, a method of reducing or eliminating post-insertion delay or lag of a signal corresponding to a concentration of an analyte is provided, the method comprising: providing an analyte sensor configured for subcutaneous introduction to an implant site and for providing a signal corresponding to the concentration of the analyte in proximity to the implant site; releasing an amount of at least one vasodilator in proximity to the implant site; optionally releasing, in proximity to the implant site, an amount of at least one tissue response modifier and / or anti-inflammatory agent that causes a delay in obtaining the signal corresponding to the concentration of the analyte; and reducing or eliminating postinsertion delay or lag of the signal corresponding to the concentration of the analyte in proximity to the implant site.Attorney Docket No.: 0934-PCT01_0239

[0030] In aspects, the reducing or eliminating post-insertion delay of the signal comprises reducing a difference between the concentration of the analyte in blood and in interstitial fluid (ISF) in proximity to the implant site.

[0031] In aspects, alone or in combination with any previous aspect, the at least one vasodilator comprises a nitric oxide (NO) releasing molecule selected from N-diazeniumdiolates and S-nitrosothiols, or N-diazeniumdiolates. In aspects, alone or in combination with any previous aspect, the at least one vasodilator comprises phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, Hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L- arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, and combinations thereof.

[0032] In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a tissue response modifier or anti-inflammatory agent releasing portion configured to release at least one tissue response modifier or anti-inflammatory agent from the device upon subcutaneous insertion. In aspects, alone or in combination with any previous aspect, the anti-inflammatory agent comprises pilocarpine, dexamethasone, a derivative form of dexamethasone, dexamethasone acetate, or a combination thereof.

[0033] In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a biocompatible hydrophilic polymer. In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a polymer chain having one or more zwitterionic compounds. In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a hydrolytically degradable biopolymer. In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a polymer chain having hydrophilic regions. In aspects, alone or in combination with any previous aspect, the analyte sensor comprises a coating comprising a hydrophilic hydrogel, wherein the hydrophilic hydrogel is at least partly crosslinked and dissolvable in biological fluid.

[0034] In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a coating comprising a polymer chain having polyurethane and / or polyurea segments. In aspects, alone or in combination with any previous aspect, theAttorney Docket No.: 0934-PCT01_0239analyte sensorfurther comprises a coating comprising a polymer chain having both hydrophilic and hydrophobic regions.

[0035] In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a coating comprising a polymer with a styrene group. In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a coating comprising a polymer with a heterocyclic group. In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a coating comprising a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly(2-vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers or quaternized forms thereof.

[0036] In aspects, alone or in combination with any previous aspect, the antiinflammatory agent or the tissue response modifier, or the second anti-inflammatory agent or the second tissue response modifier is coupled to a coating of the analyte sensor with a hydrolytically degradable linker group.

[0037] In aspects, alone or in combination with any previous aspect, the analyte is glucose, ketone, lactate, potassium, or combination thereof.

[0038] In other examples, a method of assisting equilibrium of an analyte within interstitial fluid and / or venous blood volume in proximity to an implanted analyte sensor is provided, the method comprising: subcutaneously introducing an analyte sensor at an implant site, wherein the subcutaneously introducing causes an amount of exudate at the implant site; absorbing at least some of the exudate at the implant site; assisting equilibrium of an analyte within the interstitial fluid and / or the venous blood volume at the implant site, wherein the implanted analyte sensor comprises a biocompatible hydrophilic coating, the biocompatible hydrophilic coating configured to absorb exudates at the implant site; and absorbing at least some of the exudates at the implant site.

[0039] In aspects, the biocompatible hydrophilic coating comprises a polymer chain having one or more zwitterionic compounds.

[0040] In aspects, alone or in combination with any previous aspect, the analyte sensor further comprises a tissue response modifier or anti-inflammatory agent releasing portion configured to release at least one tissue response modifier or anti-inflammatory agent upon subcutaneous introduction.Attorney Docket No.: 0934-PCT01_0239

[0041] In aspects, alone or in combination with any previous aspect, the antiinflammatory agent comprises pilocarpine, dexamethasone, a derivative form of dexamethasone, dexamethasone acetate, or a combination thereof.

[0042] In aspects, alone or in combination with any previous aspect, the at least one vasodilator comprises a nitric oxide (NO) releasing molecule selected from N-diazeniumdiolates and S-nitrosothiols, or N-diazeniumdiolates. In aspects, alone or in combination with any previous aspect, the at least one vasodilator comprises phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, Hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L- arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, and combinations thereof.

[0043] In other examples, a device for measurement of a concentration of an analyte is provided, the device comprising: an analyte sensing portion configured to generate a signal associated with the concentration of the analyte; and a bioactive agent releasing portion configured to release a bioactive agent; wherein the bioactive agent-releasing portion and the analyte sensing portion are spatially separated along a longitudinal axis of a wire substrate or a planar substrate; or wherein the bioactive agent-releasing portion and the analyte sensing portion are present on separate wire substrates or separate planar substrates.

[0044] In aspects, the analyte sensing portion is present on the planar substrate. In aspects, alone or in combination with any previous aspect, the analyte sensing portion is present on the wire substrate. In aspects, alone or in combination with any previous aspect, the bioactive agent releasing portion is present on the planar substrate. In aspects, alone or in combination with any previous aspect, the bioactive agent releasing portion is present on the wire substrate. In aspects, alone or in combination with any previous aspect, the bioactive agent-releasing portion and the analyte sensing portion are spatially separated.

[0045] In aspects, alone or in combination with any previous aspect, the analyte sensing portion comprises a working electrode, a reference, and / or a counter electrode configured to generate a signal associated with the analyte.

[0046] In aspects, alone or in combination with any previous aspect, the bioactive agent-releasing portion comprises at least one bioactive agent-releasing electrode. InAttorney Docket No.: 0934-PCT01_0239aspects, alone or in combination with any previous aspect, the bioactive agent-releasing electrode is distal from the working electrode or reference electrode. In aspects, alone or in combination with any previous aspect, the working electrode and the bioactive agentreleasing electrode share the counter electrode or the reference electrode.

[0047] In aspects, alone or in combination with any previous aspect, the analyte sensing portion comprises a first WE configured to generate a signal associated with a first analyte. In aspects, alone or in combination with any previous aspect, the analyte sensing portion comprises a second working electrode configured to generate a signal associated with a second analyte, the second analyte being chemically different from the first analyte. In aspects, alone or in combination with any previous aspect, the bioactive agent-releasing electrode is positioned most distal relative to any other working electrode.

[0048] In aspects, alone or in combination with any previous aspect, the device further comprises an electrically conductive membrane in proximity to the bioactive agent-releasing electrode, the electrically conductive membrane comprising at least one bioactive agent, the at least one bioactive agent configured to be released from the electrically conductive membrane to modify a tissue response of a subject. In aspects, alone or in combination with any previous aspect, the electrically conductive membrane comprises at least one electrically conductive polymer. In aspects, alone or in combination with any previous aspect, the at least one electrically conductive polymer is doped.

[0049] In aspects, alone or in combination with any previous aspect, the signal is measured potentiometrically, coulometrically, or amperometrically.

[0050] In other examples, a method of making an analyte sensor as defined in of the previous aspects is provided, the method comprising: contacting (i) an implantable analyte sensor precursor and (ii) a first liquid composition comprising a vasodilator; and then removing the first liquid composition from the implantable analyte sensor precursor while allowing at least some of the vasodilator from said first liquid composition to remain on the sensor.

[0051] In aspects, the first liquid composition is a calibration composition which comprises the analyte at a first known concentration, wherein the method simultaneously makes the sensor and makes at least one calibration measurement by detecting the signal associated with said first known analyte concentration.Attorney Docket No.: 0934-PCT01_0239

[0052] In aspects, alone or in combination with any previous aspect, the method further comprises contacting the sensor or the sensor precursor with a second liquid composition comprising the analyte at a second known concentration, the first and second concentrations being different, and detecting the signal associated with said second known analyte concentration. In aspects, alone or in combination with any previous aspect, the implantable analyte sensor precursor comprises a coating configured to absorb the effective amount of the vasodilator during the method.

[0053] In other examples, a method of increasing perfusion of blood about an implantable portion of a medical device is provided, the method comprising: providing a medical device, the medical device comprising: a subcutaneous implantable portion configured for positioning between the epidermis and muscle tissue of a host; and at least one layer on the subcutaneous implantable portion comprising at least one vasodilator, wherein the subcutaneous implantable portion is configured for releasing the at least one vasodilator after implantation in a host thereby increasing perfusion of the blood about the subcutaneous implantable portion of the medical device.

[0054] In aspects, the method further comprises dilation of microvessels. In aspects, alone or in combination with any previous aspect, the microvessels are capillaries. In aspects, alone or in combination with any previous aspect, the subcutaneous implantable portion is configured for positioning in one or more of a hypodermis, an adipose tissue, or a capillary bed. In aspects, alone or in combination with any previous aspect, the subcutaneous implantable portion is configured to exclude muscle tissue. In aspects, alone or in combination with any previous aspect, the subcutaneous implantable portion is configured to exclude an epidermis layer.

[0055] In aspects, alone or in combination with any previous aspect, the releasing of the at least one vasodilator is to one or more of the hypodermis, the adipose tissue, or the capillary bed. In aspects, alone or in combination with any previous aspect, the releasing of the at least one vasodilator excludes an epidermis layer.

[0056] In other examples, a method of operating an analyte sensor for detecting a concentration of an analyte, is provided, the analyte sensor comprising: at least a first working electrode; an analyte sensing portion disposed on a surface of the first working electrode, the analyte sensing portion configured for introduction to a space between an epidermis and muscle tissue, the analyte sensing portion capable of at least facilitatingAttorney Docket No.: 0934-PCT01_0239detection of the analyte; a vasodilation layer adjacent the analyte sensing portion, the vasodilation layer comprising at least one vasodilation agent diffusible through the vasodilation layer, the at least one vasodilation agent dilating microvessels in the space; the method comprising: applying a potential to the first working electrode at or above an oxidation-reduction potential of the analyte sensing portion to generate a signal corresponding to the concentration in the space; and correlating the signal to a concentration of an analyte in the space.

[0057] In aspects, the method further comprises reducing or eliminating post-insertion delay of the signal generated upon introduction in the space, wherein reducing or eliminating post-insertion delay of the signal comprises reducing a difference between the analyte concentration in blood and in the space.

[0058] In aspects, alone or in combination with any previous aspect, the analyte sensing portion further comprises a drug releasing layer adjacent the analyte sensing portion comprising at least one anti-inflammatory agent or tissue response modifier; the at least one anti-inflammatory agent or tissue response modifier diffusible through the drug releasing layer into the space, the method further comprising reducing or eliminating postinsertion delay of the signal generated upon introduction in the space from the at least one anti-inflammatory agent or tissue response modifier.BRIEF DESCRIPTION OF THE DRAWINGS

[0059] FIG. 1A is a perspective view schematic illustrating the layer of an in vivo portion of a continuous analyte sensor, as shown and described herein.

[0060] FIG. IB is a side view schematic illustrating an in vivo portion of a continuous analyte sensor, as shown and described herein.

[0061] FIG. 1C is a side view schematic illustrating an in vivo portion of an exemplary continuous analyte sensor, as shown and described herein.

[0062] FIG. ID is a cross-sectional / side-view schematic illustrating an in vivo portion of an exemplary continuous analyte sensor, as shown and described herein.

[0063] FIG. IE is a perspective-view schematic illustrating an in vivo portion of an exemplary continuous analyte sensor as disclosed and described herein.

[0064] FIG. IF is a perspective-view schematic illustrating an in vivo portion of an exemplary continuous multi-electrode, multi-analyte sensor.Attorney Docket No.: 0934-PCT01_0239

[0065] FIG. 1G is an expanded view of section 1G the distal portion of the sensor example illustrated in FIG. IF.

[0066] FIGS. 2A-2C are cross-sectional views of a sensor illustrating various embodiments of an exemplary membrane system coated as shown and described herein.

[0067] FIG. 3A is a schematic illustrating an exemplary elongated analyte sensor body with a distal tip dual drug coating construct as disclosed and described herein.

[0068] FIG. 3B is experimental data showing burst / bolus release of vasodilation drug using one or more polymer layers as disclosed and described herein.

[0069] FIGS. 4A-4E are perspective-view schematics illustrating an in vivo portion of an exemplary continuous, multi-drug releasing sensor with drug coating constructs as disclosed and described herein.

[0070] FIG. 4F is a graphical representation of data comparing an analyte sensor with a drug releasing coating compared to controls as disclosed and described herein.

[0071] FIG. 4G is a graphical representation of data comparing an analyte sensor with a drug releasing coating compared to an analyte sensor with multi-drug releasing coatings verses controls as disclosed and described herein.

[0072] FIG. 5A is a schematic illustrating an exemplary analyte sensor with dual elongated bodies with drug releasing coating and / or anti-inflammatory coating as disclosed and described herein.

[0073] FIG. 5B is a schematic illustrating an exemplary conductive polymer and drug complex as disclosed and described herein.

[0074] FIG. 6 is a schematic illustrating an exemplary elongated body analyte sensor body with a drug releasing electrode configuration as disclosed and described herein.

[0075] FIG. 7 is a schematic illustrating another exemplary elongated body analyte sensor body with a drug releasing electrode configuration as disclosed and described herein.

[0076] FIG. 8 is a schematic illustrating another exemplary elongated body analyte sensor body with a drug releasing electrode configuration as disclosed and described herein.

[0077] FIG. 9 is a perspective view of an exemplary planar analyte sensor body with a drug releasing electrode configuration as disclosed and described herein.

[0078] FIG. 10 is a top view of another exemplary planar multi-analyte analyte sensor body with a drug releasing electrode configuration as disclosed and described herein.Attorney Docket No.: 0934-PCT01_0239

[0079] FIG. 11 is a front and back side view of the planar multi-analyte sensor body of FIG. 10 as disclosed and described herein.

[0080] FIG. 12 is an exploded perspective view of another exemplary planar multianalyte analyte sensor body with a drug releasing electrode configuration as disclosed and described herein.

[0081] FIG. 13 is an enlarged view of section 13 of the sensor of FIG. 12.

[0082] FIG. 14 is a top view of another exemplary planar multi-analyte analyte sensor body with a drug releasing configuration as disclosed and described herein.

[0083] FIG. 15 is cross-section view along section line 15-15 of the sensor of FIG. 14

[0084] FIG. 16 is cross-section view along section line 16-16 of the sensor of FIG. 14.

[0085] FIG. 17A is a top view of an exemplary planar sensor illustrating various embodiments of a membrane system as described herein.

[0086] FIGS. 17B and 17C are cross-sectional views of the planar sensor of FIG. 17A illustrating various embodiments of a membrane system as described herein.

[0087] FIG. 18 illustrates a wearable device having an analyte sensor with an ex-vivo vasodilator-releasing patch, as disclosed and described herein.

[0088] FIG. 19 is a diagram illustrating certain embodiments of an example continuous transcutaneous analyte sensor system communicating with at least one display device in accordance with various technologies described in the present disclosure.DETAILED DESCRIPTION

[0089] The present disclosure aims at making improvements in the field of analyte detection, in particular in connection with detection of analytes based on measurements carried out in interstitial fluid in a host. Existing devices, for example continuous glucose monitoring devices, work well but there is still a need for technical improvements and the provision of solutions to technical problems. The present inventors set out to solve at least the following problems:

[0090] A first problem to be addressed is the desire for devices which can measure analyte concentrations more accurately. For example, improved accuracy can mean that there is better correspondence between the measurements made by the device (e.g. based on measurements taken on interstitial fluid) and the concentration of the same analyte inAttorney Docket No.: 0934-PCT01_0239the same host at the same timepoint in the blood of that host, as measured by a recognized measurement method.

[0091] A sensor which is subcutaneously implanted will have a defined lifetime, defined as the period between insertion of the sensor and the time it is removed.

[0092] A second problem is how to prolong the lifetime of a sensor.

[0093] A third problem to be solved is to improve accuracy at the start of the sensor session. Some known devices often have relatively poor sensitivity at the start of the sensor session.

[0094] A fourth problem to be solved is to improve accuracy at the end of the sensor lifetime. Some known devices often have relatively poor sensitivity at the end of the sensor lifetime.

[0095] A fifth problem to be solved is to improve accuracy by eliminating or reducing lag time between (i) a change in concentration of an analyte in blood in response to a concentration of an analyte-changing event and (ii) a change in concentration of the same analyte in interstitial fluid in response to the same analyte concentration-changing event.

[0096] A sixth problem to be solved is the acceleration of establishing equilibrium of the analyte content in the region surrounding an inserted sensor, i.e. avoiding that the analyte concentration at the sensor surface differs too much from the analyte concentration in nearby tissue.

[0097] A seventh problem to be solved is the design of a sensor to allow the incorporation of a drug to be eluted during use.

[0098] An eighth problem to be solved is the provision of a method for making such improved devices, ideally in an efficient manner.

[0099] A ninth problem to be solved is how to conveniently calibrate sensors, without compromising on calibration convenience nor on sensor design optimization.The present disclosure, through the inventions defined in the appended claims, provide technical solutions to some orall of the above problems.

[0100] The present disclosure is also directed to eliminating or reducing the difference between a concentration of an analyte in blood and in interstitial fluid (ISF) in proximity to an implantable sensor (e.g. the sensor compartment). The present disclosure provides for eliminating or reducing the difference between a concentration of an analyte in blood and in interstitial fluid (ISF) in proximity to an implantable sensor using one or more vasodilatorAttorney Docket No.: 0934-PCT01_0239compounds. In examples, the one or more vasodilator compounds are configured to release from one or more membranes or layer about an implanted portion of the implanted sensor. In examples, the one or more vasodilator compounds are used alone or together with one or more anti-inflammatory agents, which are configured to release from one or more membranes or layer about an implanted portion of the implanted sensor. Thus, the present disclosure provides for improving analyte sensor response and / or accuracy by reducing the ISF-blood lag time of an implanted sensor.

[0101] While not being held to any particular theory, the present disclosure uses vasodilation to counteract lag time after insertion. Lag time can have several different causes. One cause is of lag is the inclusion of anti-inflammatories. Therefore, the present disclosure is particularly useful in the context of analyte-measuring devices which elute an anti-inflammatory. The present disclosure provides for one or more membranes or layers that release one or more vasodilator compounds alone or together with one or more antiinflammatory agents from an implanted portion of the implantable sensor.

[0102] The following description and examples illustrate a preferred example of the present disclosure in detail. Those of skill in the art will recognize that there are numerous variations and modifications of this disclosure that are encompassed by its scope.Accordingly, the description of an example should not be deemed to limit the scope of the present disclosure.Definitions

[0103] In order to facilitate an understanding of the disclosed examples, a number of terms are defined below.

[0104] The term "about" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not be limited to a special or customized meaning), and refers without limitation to allowing for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The phrase "substantially free of" as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that aboutAttorney Docket No.: 0934-PCT01_02390 wt.% to about 5 wt.% of the composition is the material, or about 0 wt.% to about 1 wt.%, or about 5 wt.% or less, or less than or equal to about 4.5 wt.%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt.% or less, or about 0 wt.%.

[0105] The term "accuracy," as used herein, is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the closeness of a measured value to a standard or known value, such as measured by a benchtop device such as YSI 2500 Glucose Analyzer or Radiometer ABL90 FLEX PLUS analyzer, which are both widely accepted in the field for providing highly accurate blood glucose values. One such measure of accuracy is known as MARD (Mean Absolute Relative Difference). MARD measures an average difference between a device measurement, e.g. an analyte measurement in interstitial fluid using a wearable device, and a reference measurement, e.g. an analyte measurement in blood using a benchtop device. For example, a MARD accuracy percentage can be calculated for glucose measurement(s) in interstitial fluid from a continuous glucose sensor (e.g. a Continuous Glucose Monitor (CGM), and reference measurement(s) of glucose in the blood made by a benchtop device.

[0106] The term "adhere" and "attach" as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not be limited to a special or customized meaning), and refer without limitation to hold, bind, or stick, for example, by gluing, bonding, grasping, interpenetrating, or fusing.

[0107] The term "agent" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to modulators, drugs, physiological stimulators, and other substances that brings about a chemical or physical effect or causes a chemical reaction.

[0108] The term "analyte" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a substance or chemical constituent in a biological fluid (e.g., blood, interstitial fluid, cerebral spinal fluid, lymph fluid, urine, sweat, saliva, etc.) that can be analyzed. Analytes can include naturally occurring substances, artificial substances, metabolites, and / or reaction products. In some examples, the analyte measured by the sensing regions, devices, and methods is glucose,Attorney Docket No.: 0934-PCT01_0239ketone, lactate, or potassium. However, other analytes are contemplated as well, including but not limited to troponin, brain natriuretic peptide (BNP), insulin, glucagon-like peptide-1 (GLP-1), dopamine, serotonin, and levodopa (L-DOPA).

[0109] The phrases "analyte-measuring device," "analyte-monitoring device," "analytesensing device," "continuous analyte sensing device," "continuous analyte sensor device," and / or "multi-analyte sensor device" as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to an apparatus and / or system responsible for the detection of, or transduction of a signal associated with, a particular analyte, or combination of analytes. For example, these phrases may refer without limitation to an instrument responsible for detection of a particular analyte or combination of analytes. In examples, the instrument includes a sensor coupled to circuitry disposed within a housing, and configure to process signals associated with analyte concentrations into information. In examples, such apparatuses and / or systems are capable of providing specific quantitative, semi-quantitative, qualitative, and / or semi qualitative analytical information using a biological recognition element combined with a transducing and / or detecting element.

[0110] The phrase and term "bioactive agent" and "bioactive" as used herein is a broad phrase and a broad term, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to any substance that has an effect on or elicits a response from living tissue, for example, drugs, biologies, reactive oxygen scavenger (ROS), and metal ions.

[0111] The phrases "biointerface membrane," "biointerface domain," and "biointerface layer" as used interchangeably herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a permeable membrane (which can include multiple domains) or layer that functions as a bioprotective interface between host tissue and an implantable device. The terms "biointerface" and "bioprotective" are used interchangeably herein.

[0112] The terms "biosensor" and / or "sensor" as used herein are broad terms and are to be given their ordinary and customary meaning to a person of ordinary skill in the artAttorney Docket No.: 0934-PCT01_0239(and are not to be limited to a special or customized meaning), and refer without limitation to a part of an analyte measuring device, analyte-monitoring device, analyte sensing device, continuous analyte sensing device, continuous analyte sensor device, and / or multi-analyte sensor device responsible for the detection of, or transduction of a signal associated with, a particular analyte or combination of analytes. In examples, the biosensor or sensor generally comprises a body, a working electrode, a reference electrode, and / or a counter electrode coupled to body and forming surfaces configured to provide signals during electrochemically reactions. One or more membranes can be affixed to the body and cover electrochemically reactive surfaces. In examples, such biosensors and / or sensors are capable of providing specific quantitative, semi-quantitative, qualitative, semi qualitative analytical signals using a biological recognition element combined with a detecting and / or transducing element.

[0113] The term "biostable" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to materials that are relatively resistant to degradation by processes that are encountered in vivo.

[0114] The term "co-adsorbate" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to materials that absorb, associate, or couple via covalent, ionic, or molecular interaction to a substrate surface (absorbent).

[0115] The term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0116] The term "continuous" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an uninterrupted or unbroken portion, domain, coating, or layer.

[0117] The phrase "continuous analyte sensing" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the period in which monitoring of a concentration of an analyte is continuously, continually, and / or intermittently (but regularly) performed, for example, from about every 5 seconds orAttorney Docket No.: 0934-PCT01_0239less to about 10 minutes or more. In further examples, continuous monitoring of analyte concentration is performed from about every 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 second to about 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, 4.00, 4.25, 4.50, 4.75, 5.00, 5.25, 5.50, 5.75, 6.00, 6.25, 6.50, 6.75, 7.00, 7.25, 7.50, 7.75, 8.00, 8.25, 8.50, 8.75, 9.00, 9.25, 9.50 or 9.75 minutes. In further examples, continuous monitoring of analyte concentration is performed daily and can be performed for weeks.

[0118] The term "coupled" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to two or more system elements or components that are configured to be at least one of electrically, mechanically, thermally, operably, chemically or otherwise attached. Similarly, the phrases "operably connected", "operably linked", and "operably coupled" as used herein may refer to one or more components linked to another component(s) in a manner that facilitates transmission of at least one signal between the components. In some examples, components are part of the same structure and / or integral with one another (i.e. "directly coupled"). In other examples, components are connected via remote means. For example, one or more electrodes can be used to detect an analyte in a sample and convert that information into a signal; the signal can then be transmitted to an electronic circuit. In this example, the electrode is "operably linked" to the electronic circuit. The phrase "removably coupled" as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached and detached without damaging any of the coupled elements or components. The phrase "permanently coupled" as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached but cannot be uncoupled without damaging at least one of the coupled elements or components.

[0119] The term "discontinuous" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to disconnected, interrupted, or separated portions, layers, coatings, or domains.

[0120] The term "distal" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to aAttorney Docket No.: 0934-PCT01_0239special or customized meaning), and refers without limitation to a region spaced relatively far from a point of reference, such as an origin or a point of attachment.

[0121] The term "domain" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region of the membrane system that can be a layer, a uniform or non-uniform gradient (for example, an anisotropic region of a membrane), or a portion of a membrane that is capable of sensing one, two, or more analytes. The domains discussed herein can be formed as a single layer, as two or more layers, as pairs of bi-layers, or as combinations thereof.

[0122] The term "drift" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a progressive increase or decrease in signal over time that is unrelated to changes in host systemic analyte concentrations. While not wishing to be bound by theory, it is believed that drift may be the result of a local decrease in analyte transport to the sensor, for example, due to a formation of a foreign body capsule (FBC). It is also believed that an insufficient amount of interstitial fluid surrounding the sensor may result in reduced transport to the sensor. In examples, an increase in local interstitial fluid may slow or reduce drift and thus improve sensor performance. Drift may also be the result of sensor electronics, or algorithmic models used to compensate for noise or other anomalies that can occur with electrical signals in ranges including the milliampere range, microampere range, picoampere range, nanoampere range, and femtoampere range, likewise with faradic, capacitance, and voltage measurements.

[0123] The phrases "bioactive releasing membrane" and "drug releasing layer" and "bioactive releasing domain" and "bioactive agent releasing membrane" are used interchangeably herein and are each a broad phrase, and each are to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane which is permeable to one or more bioactive agents. In examples, the "bioactive releasing membrane" and "drug releasing layer" and "bioactive releasing domain" and "bioactive agent releasing membrane" can be comprised of two or more domains and is typically of a few microns thickness or more. In examples the bioactiveAttorney Docket No.: 0934-PCT01_0239releasing membrane and / or bioactive releasing membrane and / or bioactive agent releasing membrane and / or and bioactive agent releasing membrane are substantially the same as the biointerface layer and / or biointerface membrane. In other examples, the bioactive releasing membrane and / or bioactive releasing membrane and / or bioactive agent releasing membrane and / or and bioactive agent releasing membrane are distinct from the biointerface layer and / or biointerface membrane.

[0124] The term "electrochemically reactive surface" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the surface of an electrode where an electrochemical reaction takes place. In other examples, electron transfer is provided using a redox moiety associated with an aptamer conjugate, where the redox moiety is capable of undergoing reduction-oxidation (redox) that is related to a reversible binding interaction of the aptamer and an analyte proportional to the analyte concentration.

[0125] The term "gain" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a differential measure between signal OFF state and signal ON state. For example, a typical range of gain is 1-200% of a signal percentage change produced by analyte of certain concentration as compared to zero analyte concentration. Analyte concentration is typically quantified in micromolar (uM), nanomolar (nM), nanograms / milliliter (ng / mL) or picograms / milliliter (pg / mL).

[0126] The phrase "hard segment" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an element of a copolymer, for example, a polyurethane, a polycarbonate polyurethane, or a polyurethane urea copolymer, which imparts resistance properties, e.g., resistance to bending or twisting. The term "hard segment" can be further characterized as a crystalline, semi-crystalline, or glassy material with a glass transition temperature (Tg) determined by dynamic scanning calorimetry (DSC) typically above ambient temperature, and is typically made of diisocyanate with or without chain extender.

[0127] The term "host" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to aAttorney Docket No.: 0934-PCT01_0239special or customized meaning), and refers without limitation to mammals, for example humans.

[0128] The terms "implanted" or "implantable" as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to objects (e.g., sensors) that are inserted subcutaneously (i.e. in the layer of fat between the skin and the muscle) or transcutaneously (i.e. penetrating, entering, or passing through intact skin), which may result in a sensor that has an in vivo portion and an ex vivo portion.

[0129] The terms "interfe rants" and "interfering species" as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to effects and / or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement. In examples of an electrochemical aptamer sensor, interfering species are compounds with a redox (reduction-oxidation) potential that overlaps with the analyte to be measured or one or more redox moieties associated with one or more aptamers.

[0130] The term "in vivo’’ as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of the portion of a device (for example, a sensor) adapted for insertion into and / or existence within a living body of a host.

[0131] The term "ex vivo" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of a portion of a device (for example, a sensor) adapted to remain and / or exist outside of a living body of a host.

[0132] The phrase "lag time" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is the delay between(i) a change in concentration of an analyte in blood in response to a concentration of an analytechanging event and (ii) a change in concentration of the same analyte in interstitial fluid in response to the same analyte concentration-changing event. In some examples, lag time is aAttorney Docket No.: 0934-PCT01_0239consequence of a physical event, e.g., hydration of one or more membranes and / or electrochemical equilibrium, a physiological event related to access of glucose transferring from capillary blood to interstitial fluid proximate the sensor, which may be impaired by vasoconstricting drugs such as anti-inflammatories, or due to processing lag time due to signal filtering and / or processing and combinations thereof. It can be appreciated that a time difference or delay between a change in a sensed value compared to the corresponding change in a blood-based value can be one factor that affects system accuracy, as the physiological analyte level in the blood may have changed or is changing rapidly during such lag time.

[0133] The term "lifetime" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation refers to the time period between insertion of a sensor and its removal from the host.

[0134] The term "linker" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of a chemical group or a molecule linking two molecules or moieties. In examples, the linker is positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond, thus connecting the two. In examples, the linker is an oligonucleotide, biotin, maleimide (NHS) esters, polyethylene glycol-NHS esters, or a "click" chemistry component.

[0135] The term "membrane" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a structure configured to perform functions including, but not limited to, protection of the exposed electrode surface from the biological environment, diffusion resistance (limitation) of the analyte, service as a matrix for a catalyst for enabling an enzymatic reaction, limitation or blocking of interfering species, provision of hydrophilicity at the electrochemically reactive surfaces of the sensor interface, service as an interface between host tissue and the implantable device, modulation of host tissue response via drug (or other substance) release, and combinations thereof. When used herein, the terms "membrane" and "matrix" are meant to be interchangeable.Attorney Docket No.: 0934-PCT01_0239

[0136] The phrase "membrane system" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can be comprised of two or more domains, layers, or layers within a domain, and is typically constructed of materials of a few microns thickness or more, which is permeable to analyte. In examples, the membrane system comprises an immobilized or encapsulated aptamer, which enables transduction to occur between the aptamer and analyte whereby a concentration of analyte can be measured.

[0137] The term "micro," as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a small object or scale of approximately 10-6 m that is not visible without magnification. The term "micro" is in contrast to the term "macro," which refers to a large object that may be visible without magnification. Similarly, the term "nano" refers to a small object or scale of approximately IO'9m.

[0138] The term "noise," as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a signal detected by the sensor or sensor electronics that is unrelated to analyte concentration and can result in reduced sensor performance. One type of noise has been observed during the few hours (e.g., about 2 to about 24 hours) after sensor insertion. Afterthe first 24 hours, the noise may disappear or diminish, but in some hosts, the noise may last for about three to four days. In some cases, noise can be reduced using predictive modeling, artificial intelligence, and / or algorithmic means. In other cases, noise can be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as using a bioactive releasing membrane with at least one bioactive agent. For example, noise of one or more exemplary biosensors as presently disclosed can be determined and then compared qualitatively or quantitatively. By way of example, by obtaining a raw signal timeseries with a fixed sampling interval (in units of picoampere (pA)), a smoothed version of the raw signal timeseries can be obtained, e.g., by applying a 3rd order lowpass digital Chebyshev Type II filter. Others smoothing algorithms can be used. At each sampling interval, an absolute difference, in units of pA, can be calculated to provide a smoothed timeseries. This smoothed timeseries can be converted into units (the unit of "noise"), using, for example, an analyte sensitivity timeseries, whereAttorney Docket No.: 0934-PCT01_0239the analyte sensitivity timeseries is derived by using a mathematical model between the raw signal and reference blood analyte measurements. Optionally, the timeseries can be aggregated as desired, e.g., by hour or day. Comparison of corresponding timeseries between different exemplary biosensors with the presently disclosed bioactive releasing membrane and one or more bioactive agents provides for qualitative or quantitative determination of improvement of noise.

[0139] The term "optional" or "optionally" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and, without limitation, means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0140] The phrase "polymerization group" used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a functional group that permits polymerization of the monomer with itself to form a homopolymer or together with different monomers to form a copolymer. Depending on the type of polymerization methods employed, the polymerization group can be selected from alkene, alkyne, epoxide, lactone, amine, hydroxyl, isocyanate, carboxylic acid, anhydride, silane, halide, aldehyde, and carbodiimide.

[0141] The term "polyzwitterions" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to polymers where a repeating unit of the polymer chain is a zwitterionic moiety. Polyzwitterions are also known as polybetaines. Since polyzwitterions have both cationic and anionic groups, they are a type of polyampholytic polymer. They are unique, however, because the cationic and anionic groups are both part of the same repeating unit, which means a polyzwitterion has the same number of cationic groups and anionic groups whereas other polyampholytic polymers can have more of one ionic group than the other. Also, polyzwitterions have the cationic group and anionic group as part of a repeating unit. Polyampholytic polymers need not have cationic groups connected to anionic groups; they can be on different repeating units and thus may be distributed apart from one another at random intervals, or one ionic group may outnumber the other.Attorney Docket No.: 0934-PCT01_0239

[0142] The term "proximal" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference. For example, some examples of a device include a membrane system having a biointerface layer and an enzyme layer. If the sensor is deemed to be the point of reference and the enzyme layer is positioned nearer to the sensor than the biointerface layer, then the enzyme layer is more proximal to the sensor than the biointerface layer.

[0143] The phrase and term "processor module" and "microprocessor" as used herein are each a broad phrase and term, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a computer system, state machine, processor, or the like designed to perform arithmetic or logic operations using logic circuitry that responds to and processes the basic instructions that drive a computer.

[0144] The term "semi-continuous" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a portion, coating, domain, or layer that includes one or more continuous and noncontinuous portions, coatings, domains, or layers. For example, a coating disposed around a sensing region but not about the sensing region is "semi-continuous."

[0145] The phrases "sensing portion," "sensing membrane," "sensing region," "sensing domain," and / or "sensing mechanism" as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to the part of a biosensor and / or a sensor responsible for the detection of, or transduction of a signal associated with, a particular analyte or combination of analytes. In examples, the sensing portion, sensing membrane, and / or sensing mechanism generally comprise an electrode configured to provide signals during electrochemically reactions with one or more membranes covering electrochemically reactive surface. In examples, such sensing portions, sensing membranes, and / or sensing mechanisms are capable of providing specific quantitative, semi-quantitative, qualitative, semi qualitative analytical signals using a biological recognition element combined with a detecting and / or transducing element.Attorney Docket No.: 0934-PCT01_0239

[0146] In examples, the sensing region or sensing portion can comprise at least a portion of a conductive substrate or at least a portion of a conductive surface, for example, a wire or conductive trace or a substantially planar substrate including substantially planar trace(s), and a membrane. In examples, the sensing region or sensing portion can comprise a non-conductive body, a working electrode, a reference electrode, and a counter electrode (optional), forming an electrochemically reactive surface at one location on the body and an electronic connection at another location on the body, and a sensing membrane affixed to the body and covering the electrochemically reactive surface.

[0147] In examples, multiple working electrodes can be employed. For example, a second working electrode comprising a plurality of different analyte (e.g., analyte 1, analyte2, etc.) aptamer conjugates on the second working electrode to correct for sensor drift and / or interference. Likewise, a second working electrode comprising a non-selective aptamer conjugate to a plurality of different analytes (e.g., analyte 1, analyte2, etc.) on the second working electrode can be used to correct for sensor drift and / or interference.

[0148] In other examples, the sensing region can comprise one or more periplasmic binding protein (PBP) or mutant or fusion protein thereof having one or more analyte binding regions, each region capable of specifically and reversibly binding to at least one analyte. Mutations of the PBP can contribute to or alter one or more of the binding constants, extended stability of the protein, including thermal stability, to bind the protein to a special encapsulation matrix, membrane or polymer, or to attach a detectable reporter group or "label" to indicate a change in the binding region. Specific examples of changes in the binding region include, but are not limited to, hydrophobic / hydrophilic environmental changes, three-dimensional conformational changes, changes in the orientation of amino acid side chains in the binding region of proteins, and redox states of the binding region. Such changes to the binding region provide for transduction of a detectable signal corresponding to the one or more analytes present in the biological fluid.

[0149] In examples, the sensing region determines the selectivity among one or more analytes, so that only the analyte which has to be measured leads to (transduces) a detectable signal. The selection may be based on any chemical or physical recognition of the analyte by the sensing region, where the chemical composition of the analyte is unchanged, or in which the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.Attorney Docket No.: 0934-PCT01_0239

[0150] The sensing region transduces the recognition of analytes into a semi-quantitative or quantitative signal. Thus, "transducing" or "transduction" and their grammatical equivalents as are used herein encompasses optical, electrochemical, acoustical / mechanical, or colorimetrical technologies and methods. Electrochemical properties include current and / or voltage, capacitance, and potential. Optical properties include absorbance, fluorescence / phosphorescence, wavelength shift, phase modulation, bio / chemiluminescence, reflectance, light scattering, and refractive index.

[0151] The term "sensitivity" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an amount of signal (e.g., in the form of electrical current and / or voltage) produced by a predetermined amount (unit) of the measured analyte. For example, an amperometric sensor has a sensitivity (or slope) of from about 1 to about 100 picoAmps of current for every 1 mg / dL of analyte.

[0152] The phrases and terms "small diameter sensor," "small structured sensor," and "micro-sensor" as used herein are broad phrases and terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to sensing mechanisms that are less than about 2 mm in at least one dimension. In further examples, the sensing mechanisms are less than about 1 mm in at least one dimension. In some examples, the sensing mechanism (sensor) is less than about 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm. In some examples, the maximum dimension of an independently measured length, width, diameter, thickness, or circumference of the sensing mechanism does not exceed about 2 mm. In some examples, the sensing mechanism is a needle-type sensor, wherein the diameter is less than about 1 mm, see, for example, U.S. Pat. No. 6,613,379 to Ward et al. and U.S. Pat. No. 7,497,827 to Brister et al., both of which are incorporated herein by reference in their entirety. In some alternate examples, the sensing mechanism includes electrodes deposited on a substantially planar substrate, wherein the thickness of the implantable portion is less than about 1 mm, see, for example U.S. Pat. No. 6,175,752 to Say et al. and U.S. Pat. No. 5,779,665 to Mastrototaro et. al., both of which are incorporated herein by reference in their entirety. Examples of methods of forming the sensors (sensor electrode layouts and membrane) and sensor systems discussedAttorney Docket No.: 0934-PCT01_0239herein may be found in currently pending U.S. Pat. Pub. No. 2019-0307371, which is incorporated by reference in its entirety herein.

[0153] The phrase "soft segment" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an element of a copolymer, for example, a polyurethane, a polycarbonate polyurethane, or a polyurethane urea copolymer, which imparts flexibility to the chain. The phrase "soft segment" can be further characterized as an amorphous material with a low Tg, e.g., a Tg not typically higher than ambient temperature or normal mammalian body temperature.

[0154] The phrase "solid portions" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to portions of a membrane's material having a mechanical structure that demarcates cavities, voids, or other non-solid portions.

[0155] The term "vasodilator" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to compounds that dilate blood vessels, including capillary vessels. Non-limiting examples of compounds useful as vasodilators include angiotensin-converting enzyme (ACE) inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril; angiotensin receptor blockers (ARBs), such as losartan, irbesartan, valsartan, and candesartan; calcium channel blockers (CCBs), such as diltiazem, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil. Other compounds useful as vasodilators include "direct vasodilators", such as nitrates, nitric oxides, hydralazine, minoxidil, nitroglycerin, diazoxide, N-diazeniumdiolates, S-nitrosothiols, N-diazeniumdiolates, nitroprusside, phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, Hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L- arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, and combinations thereof.

[0156] Combinations of one or more ACE inhibitors, ARBs, CCBs or direct vasodilators can be used in the devices and methods herein disclosed.Attorney Docket No.: 0934-PCT01_0239

[0157] The term "warm-up period" is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation refers to the amount of time between insertion of a sensor and making or being ready to make the first analyte measurement with said sensor.

[0158] The term and phrases "zwitterion" and "zwitterionic compound" as used herein are each a broad term and phrase, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to compounds in which a neutral molecule of the compound has a unit positive and unit negative electrical charge at different locations within the molecule. Such compounds are a type of dipolar compound, and are also sometimes referred to as "inner salts."

[0159] The phrases "zwitterion precursor" or "zwitterionic compound precursor" as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to any compound that is not itself a zwitterion, but can become a zwitterion in a final or transition state through chemical reaction. In some examples described herein, devices comprise zwitterion precursors that can be converted to zwitterions prior to in vivo implantation of the device. Alternately, in some examples described herein, devices comprise zwitterion precursors that can be converted to zwitterions by some chemical reaction that occurs after in vivo implantation of the device. Such reactions are known to a person of ordinary skill in the art and include ring opening reaction, addition reaction such as Michael addition. This method is especially useful when the polymerization of betaine containing monomer is difficult due to technical challenges such as solubility of betaine monomer to achieve desired physical properties such as molecular weight and mechanical strength. Post-polymerization modification or conversion of betaine precursor can be a practical way to achieve desired polymer structure and composition. Examples of such as precursors include tertiary amines, quaternary amines, pyridines, and others detailed herein.

[0160] The phrases "zwitterion derivative" or "zwitterionic compound derivative" as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customizedAttorney Docket No.: 0934-PCT01_0239meaning), and refer without limitation to any compound that is not itself a zwitterion, but rather is the product of a chemical reaction where a zwitterion is converted to a nonzwitterion. Such reactions can be reversible, such that under certain conditions zwitterion derivatives can act as zwitterion precursors. For example, hydrolysable betaine esters formed from zwitterionic betaines are cationic zwitterion derivatives that under the appropriate conditions are capable of undergoing hydrolysis to revert to zwitterionic betaines.

[0161] The phrases "zwitterionic repeating group" as used herein is a broad phrase, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to, independently, two or more zwitterionic compounds, zwitterion derivatives or zwitterionic compound derivatives in the same compound or polymer.

[0162] Coatings applied to a sensor or an elongated body are generally described herein after the coating has dried or cured on the sensor or an elongated body, unless noted otherwise. Coatings can improve the sensor function and mitigate degradation during in vivo use.

[0163] One reason for functional degradation of Continuous Glucose Monitors (CGM's) is the immunological response to the implanted portion thereof, which results in a progressive degeneration of the signal during operation. For implantable sensors with electrochemically active sites, a hydrophobic coating layer containing a releasable antiinflammatory agent, for example, proximal to an in vivo electrochemically active site of the implantable sensor has been shown to suppress / inhibit the immunological response and extend the end-of-life of the implantable sensor, however, close proximity of the hydrophobic coating layer containing a releasable anti-inflammatory agent to the active site may result in measurable drift and lag time response.

[0164] FIGS. 1A through ID illustrate an exemplary configurations of an in vivo portion of a continuous analyte sensor 99, which includes an elongated conductive body 101 configured to comprise an implantable portion 102. The elongated conductive body 101 includes a core 110 (see FIG. IB) and a first layer 112 at least partially surrounding the core. The first layer includes a working electrode (for example, located in window 106) and a sensing membrane 400 located over the working electrode. In some examples, the core and first layer can be of a single material (such as, for example, platinum). In some examples, theAttorney Docket No.: 0934-PCT01_0239elongated conductive body is a composite of at least two materials, such as a composite of two conductive materials, or a composite of at least one conductive material and at least one non-conductive material. In some examples, the elongated conductive body comprises a plurality of layers. In certain examples, there are at least two concentric or annular layers, such as a core formed of a first material and a first layer formed of a second material.However, additional layers can be included in some examples. In some examples, the layers are coaxial.

[0165] The elongated conductive body can be long and thin, yet flexible and strong. For example, in some examples, the smallest dimension of the elongated conductive body is less than about 0.1 inches (2.54 mm), 0.075 inches (1.90 mm), 0.05 inches (1.27 mm), 0.025 inches (0.635 mm), 0.01 inches (0.254 mm), 0.004 inches (0.1 mm), or 0.002 inches (0.05 mm). While the elongated conductive body is illustrated in FIGS. 1A through 1C as having a circular cross-section, in other examples the cross-section of the elongated conductive body can be planar, ovoid, rectangular, triangular, polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-Shaped, irregular, or the like. In examples, a conductive wire electrode is employed as a core. To such a clad electrode, two additional conducting layers can be added (e.g., with intervening insulating layers provided for electrical isolation). The conductive layers can be comprised of any suitable material. In certain examples, it can be desirable to employ a conductive layer comprising conductive particles (i.e., particles of a conductive material) in a polymer or other binder.

[0166] In examples, the implantable portion 102 has a length of about 1 mm to about 20 mm. In other examples, the implantable portion 102 has a length of about 2 mm to about 14 mm. In a further example, the implantable portion 102 has a length of about 4 mm to about 12 mm. For example, the implantable portion 102 has a length of at least about any of the following: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19 mm and / or at most about 20, 19, 18, 17, 16, 15, 4, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, and 2 mm (e.g., about 1-15 mm, about 5-18 mm, etc.).

[0167] The materials used to form the elongated conductive body (such as, for example, stainless steel, titanium, tantalum, platinum, platinum-iridium, iridium, nitinol, certain polymers, and / or combinations thereof) can be strong and hard, and therefore are resistant to breakage. In some examples, the sensor's small diameter provides flexibility to theseAttorney Docket No.: 0934-PCT01_0239materials, and therefore to the sensor as a whole. Thus, the sensor can withstand repeated forces applied to it by surrounding tissue.

[0168] In addition to providing structural support, resiliency and flexibility, in some examples, the core 110, or a component thereof, provides electrical conduction for an electrical signal from the working electrode to sensor electronics (not shown). In some examples, the core 110 comprises a conductive material, such as nitinol, stainless steel, titanium, tantalum, a conductive polymer, and / or the like. However, in other examples, the core is formed from a non-conductive material, such as a non-conductive polymer. In yet other examples, the core comprises a plurality of layers of materials. For example, in one example the core includes an inner core and an outer core. In a further example, the inner core is formed of a first conductive material and the outer core is formed of a second conductive material. For example, in some examples, the first conductive material is nitinol, stainless steel, titanium, tantalum, a conductive polymer, an alloy, and / orthe like, and the second conductive material is a conductive material selected to provide electrical conduction between the core and the first layer, and / or to attach the first layer to the core (that is, if the first layer is formed of a material that does not attach well to the core material). In other examples, the core is formed of a non-conductive material (such as, for example, a non-conductive metal and / or a non-conductive polymer) and the first layer is formed of a conductive material, such as nitinol, stainless steel, titanium, tantalum, a conductive polymer, and / or the like. The core and the first layer can be of a single (or same) material, such as platinum. One skilled in the art appreciates that additional configurations are possible.

[0169] F irst layer 112 can be formed of a conductive material and the working electrode can be an exposed portion of the surface of the first layer 112. Accordingly, the first layer 112 can be formed of a material configured to provide a suitable electroactive surface for the working electrode, a material such as, but not limited to, platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, an alloy and / orthe like.

[0170] As illustrated in FIG. IB and FIG. 1C, a second layer 104 surrounds at least a portion of the first layer 112, thereby defining the boundaries of the working electrode. In some examples, the second layer 104 serves as an insulator and is formed of an insulating material, such as polyimide, polyurethane, parylene, or any other known insulating materials. For example, in one example the second layer is disposed on the first layer andAttorney Docket No.: 0934-PCT01_0239configured such that the working electrode is exposed via window 106. In some examples, an elongated conductive body, including the core, the first layer and the second layer, is provided. A portion of the second layer can be removed to form a window 106, through which the electroactive surface of the working electrode (that is, the exposed surface of the first layer 112) is exposed. In some examples, a portion of the second and (optionally) third layers can be removed to form the window 106, thus exposing the working electrode.Removal of coating materials from one or more layers of the elongated conductive body (for example, to expose the electroactive surface of the working electrode) can be performed by hand, excimer lasing, chemical etching, laser ablation, grit-blasting, or the like.

[0171] The sensor can further comprise a third layer 114 comprising a conductive material. For example, the third layer 114 can comprise a reference electrode, which can be formed of a silver-containing material that is applied onto the second layer 104 (that is, the insulator).

[0172] The elongated conductive body 101 can further comprise one or more intermediate layers (not shown) located between the core 110 and the first layer 112. For example, the intermediate layer can be one or more of an insulator, a conductor, a polymer, and / or an adhesive. In some examples, the core 110 comprises a non-conductive polymer and the first layer 112 comprises a conductive material. Such a sensor configuration can advantageously provide reduced material costs, in that it replaces a typically expensive material with an inexpensive material. For example, the core 110 can be formed of a non-conductive polymer, such as, a nylon or polyester filament, string or cord, which can be coated and / or plated with a conductive material, such as platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, and allows or combinations thereof.

[0173] Referring to FIG. IB and FIG. 1C, the reference electrode 114 can comprise a silver-containing material (e.g., silver / silver chloride) applied over at least a portion of the second layer (e.g., insulating material) 104, as discussed in greater detail elsewhere herein. For example, the silver-containing material can be applied using the presently disclosed coating methods described herein. In examples, the silver-containing material can be applied using the presently disclosed coating methods in combination with thin film and / or thick film techniques, such as but not limited to the methods disclosed herein, dipping, spraying, printing, electro-depositing, vapor deposition, spin coating, and sputterAttorney Docket No.: 0934-PCT01_0239deposition. For example, a silver or silver chloride-containing paint (or similar formulation) can be applied to a reel of the insulated conductive core using the presently disclosed coating methods.

[0174] As illustrated in FIG. IB, 1C and FIG. ID, the sensor can also include a sensing membrane 400, such as those discussed elsewhere herein, for example, with reference to FIGS. 2A through 2C. The sensing membrane 400 can include an enzyme layer (not shown), as described elsewhere herein. For example, the sensing membrane 400 can include a catalyst or enzyme configured to interact / react with an analyte. For example, the sensing membrane 400 can be an immobilized enzyme-containing layer including glucose oxidase, glucose dehydrogenase, p-hydroxybutyrate dehydrogenase, or lactate dehydrogenase. In other examples, the sensing membrane 400 can be impregnated with other oxidases, including, for example, galactose oxidase, cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate oxidase, aspartate oxidase, or uricase. In examples, the sensing membrane 400 can include one or more of glucose dehydrogenase, lactate dehydrogenase, malate dehydrogenase, glycerol dehydrogenase, alcohol dehydrogenase, sorbitol dehydrogenase, and an amino acid dehydrogenase comprising L-amino acid dehydrogenase, asparaginase, or superoxide dismutase.

[0175] In examples, the enzyme layer can include p-hydroxybutyrate dehydrogenase (HBD) enzyme, a nicotinamide adenine dinucleotide (NAD+) and a metal or non-metal mediator. In examples, the sensing membrane 400 comprises P-hydroxybutyrate dehydrogenase (HBD) enzyme, a nicotinamide adenine dinucleotide (NAD+) and a metal or non-metal mediator in combination with glucose oxidase or glucose dehydrogenase.

[0176] In examples, the sensing membrane 400 comprises aspartate oxidase and / or asparaginase. In examples, the sensing membrane 400 comprises aspartate oxidase and / or asparaginase in combination with glucose oxidase or glucose dehydrogenase or P-hydroxy butyrate dehydrogenase (HBD) enzyme, a nicotinamide adenine dinucleotide (NAD+) and a metal or non-metal mediator.

[0177] Combinations of the above enzymes can be combined in the same layer or provided in separated layers vertically and / or horizontally separated about the elongated body are envisaged with the coating methods disclosed herein. Combinations of the above enzymes can be combined in the same layer or provided in separated layers verticallyAttorney Docket No.: 0934-PCT01_0239and / or horizontally separated with one or more intervening layers about the elongated body are envisaged with the coating methods disclosed herein.

[0178] FIG. IE is a perspective view of the in vivo portion of a multi-electrode, multianalyte sensor. In this example, the insulated elongated body comprises three conductive cores 210A, 210B, 210C located in (e.g., embedded in, coated with) the second layer, (e.g., insulator) 104. In this example, a plurality of windows is formed in and / or through the insulator, such that each window exposes a portion of a core. As a non-limiting example, window 206 is formed in the insulator such that a portion of core 210A is exposed. Similarly, window 208 is formed in the insulator such that a portion of core 210B is exposed. The windows can be staggered and / or non-staggered along the longitudinal length of the sensor. In a further example, each conductive core includes an inner core and an outer core, such as described elsewhere herein.

[0179] In examples, the first conductive core is formed of platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer and / or an alloy, and a first window 206 is configured and arranged to expose an electroactive portion of the first conductive core. The second conductive core is formed of a silver-containing material (e.g., a silver or silver / silver-chloride wire, or a silver-containing wire-shaped a silver-containing material body), and a second window 208 is configured and arranged to expose an electroactive portion of the second conductive core. In some examples, instead of a bulk metal wire, the first conductive core comprises an inner core and an outer core. For example, to reduce material costs, the inner core is formed of a material that is relatively less expensive than platinum, such as stainless steel, titanium, tantalum and / or a polymer, and the outer core is formed of a material that provides an appropriate electroactive surface, such as but not limited to platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer and / or an alloy. In some examples, the membrane covers the exposed electroactive portion of the first conductive core. In a further example, the membrane covers the in vivo portion of the sensor. In some examples, a third conductive core is embedded in the insulator. In some examples, the third conductive core is configured and arranged as a second working electrode, which can be configured as a redundant working electrode, a non-analyte signal-measuring working electrode (e.g., no transducing element as described below), as a counter working electrode, to detect a second analyte, and / or the like.Attorney Docket No.: 0934-PCT01_0239

[0180] FIG. IF is a perspective view of the in vivo portion of an example of a multielectrode sensor 300 comprising two working electrodes and at least one reference / counter electrode. The sensor 300 comprises first and second elongated bodies El, E2, each formed of a conductive core or of a core with a conductive layer deposited thereon. In this particular example, a wire-based sensor is shown, however, a planar arrangement is also envisaged. In this particular example, an insulating layer 310, a conductive layer 320 e.g., a reference electrode, and any one of the previously described membranes (not shown) are deposited on top of the elongated bodies El, E2. The insulating layer 310 separates the conductive layer 320 from the elongated body. The materials selected to form the insulating layer 310 may include any of the insulating materials described elsewhere herein, including polyurethane and polyimide. The materials selected to form the conductive layer 320 may include any of the conductive materials described elsewhere herein, including silver / silver chloride, platinum, gold, etc. Working electrodes 302, 303 are formed by removing portions of the conductive layer 320 and the insulating layer 310, thereby exposing electroactive surface of the elongated bodies El, E2, respectively. FIG. 1G provides a close perspective view of the distal portion of the elongated bodies El, E2.

[0181] In examples, the two elongated bodies illustrated in FIG. IF are fabricated to have substantially the same shape and dimensions. In examples, the two elongated bodies illustrated in FIG. IF are fabricated to have substantially the same shape and dimensions but with one elongated body having no enzyme or a deactivated enzyme and a drug releasing layer, whereas the other elongated body includes an active enzyme without a drug releasing layer.

[0182] In other examples, the two elongated bodies illustrated in FIG. IF, but with one elongated body having no window and a drug releasing layer, whereas the other elongated body includes a window 106 and sensing membrane with an active enzyme without a drug releasing layer.

[0183] In some examples, the working electrodes of FIG. IF are fabricated to have the same properties, thereby providing a sensor system capable of providing redundancy of signal measurements or providing unique signals representing two or more different analytes. In other examples, the working electrodes, associated with the elongated bodies El, E2, may each have one or more characteristics that distinguish each working electrode from the other. For example, In examples, each of the elongated bodies El, E2 may beAttorney Docket No.: 0934-PCT01_0239different conductive surfaces, so that each working electrode has a different electrochemical property than the other working electrode. In addition, In examples, each of the elongated bodies El, E2 may be covered with different membrane(s), so that each working electrode has a different membrane property than the other working electrode.

[0184] Although not shown in FIGS. 1F-1G, in certain examples, the exposed distal ends 331 of the core portions of the elongated bodies El, E2 may be covered with an insulating material (e.g., polyurethane or polyimide). In alternative examples, the exposed distal ends 331 of the core portions are covered with any of the previously described membrane system and / or serve as additional or "secondary" working electrode surface area.

[0185] Regarding fabrication of the sensor system illustrated in FIG. 1F-1G, In examples, the elongated bodies El, E2 may be formed as an elongated conductive core, or alternatively as a core (conductive or non-conductive) having at least one conductive material deposited thereon. Next, an insulating layer 310 is deposited onto each of the elongated bodies El, E2. Thereafter, a conductive layer 320 is deposited over the insulating layer 310. The conductive layer 320 may serve as a reference / counter electrode and may be formed of silver / silver chloride, or any other material that may be used for a reference electrode. In alternative examples, the conductive layer 320 may be formed of a different conductive material, and may be used another working electrode. After these steps, a layer removal process is performed to remove portions of the deposited layers (i.e., the conductive layer320 and / orthe insulating layer 310). Any of the techniques described elsewhere herein (e.g., laser ablation, chemical etching, grit blasting) may be used. In the example illustrated in FIGS. IF and 1G, layers of the conductive layer 320 and the insulating layer 310 are removed to form the working electrodes 302, 303. Although in the example shown, layer removal is performed across the entire cross-sectional perimeter (e.g., circumference) of the deposited layer, it is contemplated that in other examples, layer removal may be performed across a preselected section of the cross-sectional perimeter, instead of across the entire cross-sectional perimeter.

[0186] Contacts 304 are used to provide electrical connection between the working electrodes and other components of the sensor system may be formed in a similar manner. As shown, contacts 304 are separated from each other to prevent an electrical connection therebetween. Because the layer removal process is performed on each individual elongated body El, E2, instead of a single geometrically complicated elongated body, thisAttorney Docket No.: 0934-PCT01_0239particular sensor design (i.e., two elongated bodies placed side by side) may provide ease of manufacturing, as compared to the manufacturing processes involved with other multielectrode systems having other geometries.

[0187] After the conductive and insulating layers are deposited onto the elongated body, and after selected portions of the deposited layers have been removed, one or more membranes are applied onto at least a portion of the elongated bodies using the apparatuses and method disclosed herein, either alone or in combination with the apparatuses and method disclosed herein or with other coating apparatuses and methods. In certain examples, any of the aforementioned membrane systems are applied only to the working electrodes, but in other examples any of the aforementioned membrane systems are applied to the entire elongated body. In examples, any of the aforementioned membrane systems are deposited onto the two working electrodes simultaneously while they are placed together (e.g., by bundling), but in other examples, any of the aforementioned membrane systems are deposited onto each individual working electrode first, and the two working electrodes are then placed together.

[0188] FIG. 2A is a cross-sectional view through the exemplary sensor of FIG. 1A-1C, illustrating one example of sensing membrane 400. In this particular non-limiting example, the membrane system includes an electrode layer 420, an enzyme layer 440, a diffusion resistance layer 460, and a biointerface layer 480 and / or drug releasing layer 470, all of which are located around a working electrode of the sensor, and all of which are described in more detail elsewhere herein. In some examples, a unitary diffusion resistance domain and biointerface layer and / or drug releasing layer can be included in the membrane system (e.g., wherein the functionality of both layers is incorporated into one domain). In some examples, the sensor is configured for short-term implantation (e.g., from about 1 to 30 days). However, it is understood that the sensing membrane 400 can be modified and / or used in other devices, for example, by including only one or more of the domains, or including additional domains.

[0189] FIG. 2B is a cross-sectional view through examples of the sensor, illustrating another example of the sensing membrane 400. In this particular example, the membrane system includes an interference reduction or blocking layer 430, an enzyme layer 440, a diffusion resistance layer 460, and a biointerface layer 480 and / or drug releasing layer 470Attorney Docket No.: 0934-PCT01_0239located around the working electrode of the sensor, all of which are described in more detail elsewhere herein.

[0190] FIG. 2C is a cross-sectional view through examples of the sensor, illustrating still another example of the sensing membrane 400. In this particular example, the membrane system includes an interferent reduction or blocking layer 430, an enzyme layer 440, and a unitary diffusion resistance / biointerface layer 480 located around the working electrode of a sensor and drug releasing layer 470 (not shown), all of which are described in more detail elsewhere herein.

[0191] Sensing membrane 400 of some examples can also include a plurality of domains or layers including, for example, an optional electrode domain (e.g., as illustrated in the FIG.2A), an interference reduction or blocking domain (e.g., as illustrated in FIGS. 2B and 2C), enzyme domain 108, or a cell disruptive domain (not shown).

[0192] FIG. 3A is a schematic illustrating an exemplary elongated analyte sensor body of sensor 300 with a distal tip dual drug coating construct, where elongated body 101 includes window 106 having sensing membrane 400 and a distal tip 305 extending distally therefrom. Distal tip 305 includes one or more distally positioned layers 350 (from sensing membrane 400) introduced, for example, via dip coating, meniscus coating or electrofluidic coating methods. As illustrated, drug releasing layer 470 is most proximal to distal tip 305, delayed release layer 330 is positioned adjacent drug releasing layer 470. Vasodilation drug releasing layer 375 is positioned adjacent delayed release layer 330. In examples, delayed release layer 330 at least partially covers drug releasing layer 470. In examples, delayed release layer 330 completely covers drug releasing layer 470. In examples, delayed release layer 330 and / or vasodilation drug releasing layer 375 is a hydrophilic biodegradable material, for example a poly(lactic-co-glycolic) acid polymer (PLGA) or copolymer, cellulose-based polymer or copolymer, polyhydroxybutyrate, (PHB)poly 3-hydroxybutyrate - co-|3-hydroxy valerate (PHBV) and the like. The thickness of delayed release layer 330 can be adjusted so as to control the beginning of drug release and / or the rate of drug release from drug releasing layer 470 or to allow vasodilator drug to have a drug action, drug effect, e.g., a biochemical or physiological effect.

[0193] In examples, drug releasing layer 470 comprises a polyurethane or polyurethaneurea polymer or copolymer with desired hydrophobic / hydrophilic functionality to release an amount of one or more anti-inflammatory or tissue response modifier drug, as needed toAttorney Docket No.: 0934-PCT01_0239suppress one or more immune responses caused by the implanted sensor. Likewise, In examples, vasodilation drug releasing layer 375 comprises a polyurethane or polyurethaneurea polymer or copolymer with desired hydrophobic / hydrophilic functionality to release an amount of one or more vasodilation drugs, e.g., ACE inhibitors, CCBs, and direct vasodilators, as needed to suppress or delay the drug action or drug effect of the one or more immune responses.

[0194] In examples, drug releasing layer 470 comprises a polyurethane or polyurethaneurea polymer or copolymer with hydrophobic functionality for release of pilocarpine, or adrenal corticosteroids, such as dexamethasone, dexamethasone acetate or other derivatives or salts of dexamethasone.

[0195] In examples, vasodilation drug releasing layer 375 comprises a polyurethane or polyurethane-urea polymer or copolymer with hydrophilic functionality for rapid or bolus release of one or more vasodilation drugs, e.g., ACE inhibitors, CCBs, and direct vasodilators.

[0196] In examples, drug releasing layer 470 comprising a polyurethane or polyurethane-urea polymer or copolymer with hydrophobic functionality for release of pilocarpine, or adrenal corticosteroids, such as dexamethasone, dexamethasone acetate or other derivatives or salts of dexamethasone is positioned most proximal to distal end 305 of sensor 300 with a hydrophilic biodegradable delayed release layer 330 at least partially covering the drug releasing layer 470 and vasodilation drug releasing layer 375 comprises a polyurethane or polyurethane-urea polymer or copolymer with hydrophilic functionality for rapid or bolus release of one or more vasodilation drugs covering the hydrophilic biodegradable delayed release layer 330 as illustrated in FIG. 3A. In other examples the arrangement of the drug releasing layer 470, hydrophilic biodegradable delayed release layer 330, and vasodilation drug releasing layer 375 are arranged as previously described but are proximal from window 106 (not shown) of elongated sensor body 101. Other configurations and locations about the elongated sensor body 101 of the drug releasing layer 470, hydrophilic biodegradable delayed release layer 330, and vasodilation drug releasing layer 375 are envisaged.

[0197] In examples, a loading of about 5%, 10%, 20%, 25%, 30%, 35% weight percent per polymer matrix or more of vasodilator is used. In examples, 10-30% weight percent minoxidil is used.Attorney Docket No.: 0934-PCT01_0239

[0198] In aspects, the vasodilation drug releasing layer 375 is configured for burst or bolus release. For example, the vasodilation drug is contained in a water soluble or water swellable polymer. Examples of water soluble or water swellable polymer matrixes for the vasodilation drug include polyvinyl alcohol polymer and copolymers, polyvinyl pyrrolidone (PVP) and hydrophilic hydrogel matrixes. Such water soluble or water swellable polymer matrixes have faster release rates of the vasodilation drug than hydrophilic polyurethane or polyurethane urea polymers. Combinations of water soluble or water swellable polymer and hydrophilic polyurethane or polyurethane urea polymers can be used, each independently having different vasodilation drugs, different vasodilation drug concentrations of the same or different vasodilation drug, and / or different thickness. Underneath such combinations of water soluble or water swellable polymer and hydrophilic polyurethane or polyurethane urea polymers comprising vasodilation drug, drug releasing layer 470 having a hydrophobic polyurethane or polyurethane urea can be provided.

[0199] FIG. 3B is experimental data showing the above concept of burst / bolus release of vasodilation drug using one or more polymer layers with specific hydrophilic or hydrophobic polymers and water soluble or water swellable polymer. As shown in FIG. 3B, compared to hydrophobic polyurethane 366 or polyurethane urea matrix 368 or hydrophilic polyurethane or polyurethane urea matrix 364, water soluble or water swellable polymers 360 alone (e.g., polyvinylpyrrolidone (PVP)) or in combination with hydrophilic polyurethane 362 (poly(lactic-co-glycolic) acid (PLGA) or poly lactic acid (PLA) and polyurethane (PU) or polyurethane urea (PUU)) showed faster release kinetics, with almost 90 wt% of drug (Minoxidil) being released within 24 hours post implantation in ISF. As shown in FIG. 3B, PVP matrix loaded with vasodilation drug (e.g., minoxidil) showed immediate burst release. As a result of sensor coatings comprising the vasodilation drug coatings as described above, improved lag post implantation in ISF was observed, whether the vasodilation drug releasing layer 375 was proximal or distally located along the elongated body of the implantable portion of the sensor. Improvement of lag (reduction of time) as much as 1.5 minutes (~13-25% reduction in lag) was observed in median peak signal compared with controls without the vasodilation drug releasing layer and having a drug releasing layer 470.

[0200] FIGS. 4A-4C show perspective-view schematics illustrating various exemplary examples of an in vivo portion of an exemplary continuous, multi-drug releasing sensor with a dual drug coating construct. FIG. 4A depicts sensor 410 with elongated body 101, a layerAttorney Docket No.: 0934-PCT01_0239440 comprising one or more of both vasodilation drug and anti-inflammatory or tissue response modifier drug, where layer 440 is distally positioned along elongated body 101, e.g., distal from window 106, electroactive surface 103 and sensing membrane 400. FIG. 4B depicts sensor 410 with elongated body 101, and spatially separated drug releasing layer 470 comprising one or more anti-inflammatory or tissue response modifier drug and vasodilation drug releasing layer 375 comprising one or more of both vasodilation drug. As shown, vasodilation drug releasing layer 375 is distal from drug releasing layer 470, where layer 470 is proximally positioned along elongated body 101, e.g., away from window 106, electroactive surface 103 and sensing membrane 400. It is understood that vasodilation drug releasing layer 375 and drug releasing layer 470, positioning can be reversed (not shown). It is understood that delayed release layer 330 (not shown) can be employed as described above (to modulate release of one or more anti-inflammatory or tissue response modifier drug) in the configurations of FIGs. 4A and 4B.

[0201] Another configuration is depicted in FIG. 4C, without delayed release layer 330, where more proximal drug releasing layer 470 and vasodilation drug releasing layer 375 are arranged at distal tip 305. Similar materials or polymers as described above and herein are envisaged for containing the one or more anti-inflammatory or tissue response modifier drug and the one or more vasodilator drugs. In examples, drug releasing layer 470 and vasodilation drug releasing layer 375 are presented to elongated body using dip coating methods and or meniscus coating and / or microfluidic coating methods as disclosed in coassigned Attorney Docket No. 0931_US01PR_0212.

[0202] Another configuration is depicted in FIG. 4D, without delayed release layer 330, where drug releasing layer 470 is distally positioned and vasodilation drug releasing layer 375 is more proximal from distal tip 305 than drug releasing layer 470. Similar materials or polymers as described above and herein are envisaged for containing the one or more antiinflammatory or tissue response modifier drug and the one or more vasodilator drugs. In examples, drug releasing layer 470 and vasodilation drug releasing layer 375 are presented to elongated body using dip coating methods and or meniscus coating and / or microfluidic coating methods as disclosed in co-assigned Attorney Docket No. 0931_US01PR_0212.

[0203] Another configuration is depicted in FIG. 4E, where drug releasing layer 470 and vasodilation drug releasing layer 375 are arranged together at distal tip 305. Additional vasodilation drug releasing layer 375 is positioned more proximal from distal tip than theAttorney Docket No.: 0934-PCT01_0239combination of drug releasing layer 470 and vasodilation drug releasing layer 375 at distal tip.

[0204] In examples, drug releasing layer 470 and vasodilation drug releasing layer 375 are present in a first polymer matrix (or membrane) and more proximal vasodilation drug releasing layer 375 is present in a second polymer matrix (or membrane). In examples, first polymer matrix is configured for slow or medium and long acting release of the drug from drug releasing layer 470 and vasodilator from vasodilation drug releasing layer 375. In examples, first polymer matrix is configured for, independently, slow / medium and long acting release of both anti-inflammatory from drug releasing layer 470 and vasodilator from vasodilation drug releasing layer 375, respectively, and second polymer matrix (more proximal vasodilation drug releasing layer 375) is configured for bolus, short acting release of vasodilator. In examples, controlling release rate of anti-inflammatory and / or vasodilator is achieved by selecting a PU with appropriate soft segment and hydrophobic / hydrophilic structure, as further discussed herein. In examples, controlling duration of release of antiinflammatory and / or vasodilator is achieved by anti-inflammatory and / or vasodilator chemistry-polymer interaction, polymer coating thickness, and anti-inflammatory and / or vasodilator loading, among other parameters.

[0205] Similar or dissimilar materials or polymers as described above and herein are envisaged for containing the one or more anti-inflammatory or tissue response modifier drug and the one or more vasodilator drugs. In examples, drug releasing layer 470 and vasodilation drug releasing layer 375 are presented to elongated body using dip coating methods and or meniscus coating and / or microfluidic coating methods as disclosed in coassigned Attorney Docket No. 0931_US01PR_0212.

[0206] FIG. 4F is a collection of data from day / night reading as well as arm / abdomen locations overlayed with blood glucose values (circles) from a YSI and Radiometer instrument data (triangles) (collectively "the Controls 560"). Data trace 565 represents a continuous glucose sensor configured to release an anti-inflammatory upon implantation and shows both a signal suppression and a time lag of determined mg / dL glucose readings compared with the Controls 560. FIG. 4F demonstrates that when glucose concentration is increasing quickly the lag 575 is more pronounced. Likewise, when glucose concentration is decreasing quickly the lag 577 is again more pronounced. While not to be held to any particular theory, it is believed that anti-inflammatory release causes vasorestriction of theAttorney Docket No.: 0934-PCT01_0239capillary bed and / or adipose tissue about the implantable portion of the continuous glucose sensor.

[0207] FIG. 4G depicts experimental results of a continuous glucose sensor configured to release both an anti-inflammatory drug and a vasodilator drug from the implantable portion upon implantation verses a sensor configured with only anti-inflammatory drug and a Control sensor without an anti-inflammatory drug and without a vasodilator drug from the implantable portion. Blood glucose data 560 is from blood analyzers (YSI (circles) or Radiometer (triangles)) provides reference points along the time-concentration plot.

[0208] FIG. 4F depicts experimental results of sensors configured for: release of an antiinflammatory drug from an implantable portion of a continuous glucose sensor; sensors configured for release of an anti-inflammatory drug and vasodilators; and controls (blood glucose values and sensors without anti-inflammatory or vasodilation drug). Aggregate data 584 depicts sensors configured for release of only anti-inflammatory drug from an implantable portion. Aggregate data 582 depicts sensors configured for release of both an anti-inflammatory drug and vasodilator from the implantable portion of the sensor. Control senor data 581 is without anti-inflammatory drug and vasodilator. Blood glucose reference data 580 is from blood analyzers. The data of FIG. 4F demonstrates that the release of vasodilator decreases the lag observed when anti-inflammatory is released from the implantable portion of the sensor. As lag effects sensor accuracy, the combination of a releasable anti-inflammatory drug and vasodilator from the implantable portion of the sensor also improves accuracy by reducing lag and further extends end of life of the sensor.

[0209] FIG. 5A is a schematic illustrates an exemplary analyte sensor 500 with dual elongated bodies 101a, 101b, both of which include implantable portions 102 that may be same length or of different lengths. Elongated bodies 101a, 101b are shown separated, but can be abutted together or twisted about each other. In examples, one of the dual elongated bodies 101a, 101b comprises a drug releasing coating with configured with at least one anti-inflammatory, tissue modifying agent, or vasodilator releasable from the drug releasing coating while the other dual elongated bodies 101a, 101b does not. Each of the dual elongated bodies 101a, 101b can be independently configured to receive the same or different potential or current.

[0210] In examples, elongated body 101a is coated with drug releasing layer 470 configured with at least one anti-inflammatory, tissue modifying agent, or vasodilatorAttorney Docket No.: 0934-PCT01_0239releasable from the drug releasing coating and has no sensing membrane or active enzyme, whereas elongated body 101b has a sensing membrane and active enzyme. In other examples, elongated body 101a is coated with drug releasing layer 470 configured with at least one anti-inflammatory, tissue modifying agent releasable from the drug releasing coating and has no sensing membrane or active enzyme, whereas elongated body 101b has a vasodilator-releasing coating and a sensing membrane and active enzyme. In these configurations, minimization of interactions of the drug released from the drug releasing coating with the sensing membrane or signal from analyte detection is provided and delay of sensor signal during the time period of 0.1 to lhr is reduced or minimized.

[0211] In examples, still with reference to FIG. 5A, an electrode can be electrodeposited / electropolymerized with a drug-eluting layer (DE), such as PEDOT for example, which carries a net positive charge repeat unit having a negatively charged counter-ion. In examples, the electrodeposited / electropolymerized polymer is oxidized and a negative charged medicament, drug, active pharmaceutical ingredient, pharmacologic, or therapeutic agent is introduced to the oxidized polymer. In examples, the DE layer is a DE membrane.

[0212] In examples, the DE layer is controlled using potential or current to modulate the release of an amount of drug from the DE layer. For example, charge passing through the electrode can be controlled and measured to effectuate the release of a precisely-controlled amount of charged medicament, drug, active pharmaceutical ingredient, pharmacologic, or therapeutic agent per Faraday's relation:m = (Q* M) / (v * F);

[0213] where m refers to the amount of mass liberated (g), Q is the amount of charge passed (Coulombs), M is the molar mass of the substance (g / mol), v is the valency of the ionized form of the mass (e.g., +1, +2, -1, -2, etc), and F is Faraday's constant (96,485 Coulombs / mol). In the case of constant current control, this relation becomes m = (I * t * M) / (v * F) where I is the current flowing through the electrode (A) and t is the time of the constant current electrolysis (sec).

[0214] As shown in FIG. 5B, In examples, a suitable charged medicament, drug, active pharmaceutical ingredient, pharmacologic, or therapeutic agent 525 is electrostatically bound to the positive charge repeat unit of a conductive polymer 550, exemplified by a PEDOT backbone as shown. Upon application of a suitable current or potential at theAttorney Docket No.: 0934-PCT01_0239electrode, the charged medicament, drug, active pharmaceutical ingredient, pharmacologic, or therapeutic agent is driven out of the polymer matrix via charge repulsion and drifts thru the ISF under the applied electric field to the opposing electrode. In the example of Scheme I, the polymer and the drug can be any electrodeposited / electropolymerized polymer and any charged medicament, drug, active pharmaceutical ingredient, pharmacologic, or therapeutic agent.

[0215] Non-limiting examples of suitable polymers for doping include polyaniline, polypyrrole [PPy], poly(3,4-ethylenedioxythiphene) [PEDOT], polyphenylene, polyacetylene, polyphenylene vinylene, polythiophene, and combinations or copolymers thereof. Some exemplary conducting polymers suitable for doping with charged medicament, drug, active pharmaceutical ingredient, pharmacologic, or therapeutic agent include poly(pyrrole) [PPy] and poly(poly(3,4-ethylenedioxythiophene)) [PEDOT],

[0216] Some exemplary charged medicament, drug, active pharmaceutical ingredient, pharmacologic, or therapeutic agent suitable as dopants include one or more adrenal corticosteroids. Some exemplary therapeutic agents suitable as dopants include one or more ACE inhibitors, CCBs, and direct vasodilators. Some exemplary therapeutic agents suitable as dopants include one or more adrenal corticosteroids and salts thereof in combination with one or more ACE inhibitors, CCBs, and direct vasodilators and salts thereof.

[0217] Some exemplary therapeutic agents suitable as dopants include dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, pilocarpine, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, losartan, irbesartan, valsartan, candesartan, diltiazem, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, nitrates, nitric oxides, hydralazine, minoxidil, nitroglycerin, diazoxide, N-diazeniumdiolates, S-nitrosothiols, N-diazeniumdiolates, nitroprusside, and salts thereof. In examples, therapeutic agents suitable as dopants include dexamethasone sodium phosphate alone or in combination with nitric oxides, hydralazine, minoxidil, nitroglycerin, and salts thereof.

[0218] FIG. 6 is a schematic illustrating exemplary elongated body analyte sensor 600 having a drug releasing electrode 635 proximally located from working electrode 625 and distal tip 305. Elongated body analyte sensor 600 includes a DE layer on drug releasing electrode 635. The DE layer including electrodeposited / electropolymerized polymer and anyAttorney Docket No.: 0934-PCT01_0239charged medicament as discussed above is electrically isolated from working electrode 625 and reference electrode 675 by the second layer (e.g., insulating material) 104. As discussed above, DE layer can be a DE membrane. In examples, drug releasing electrode 635 and working electrode 625 share the same reference electrode 675 and / or (CEs) (not shown). In examples, drug releasing electrode 635 and working electrode 625 use separate reference electrodes and / or counter electrodes (CE) (not shown). Each of working electrode 625 and drug releasing electrode 635 can be independently configured to receive the same or different potential or current.

[0219] FIG. 7 is a schematic illustrating another exemplary elongated body multi-analyte sensor 700 having a drug releasing electrode 735 located proximal from dual working electrodes and distal tip 305. The dual working electrodes include a first working electrode 725 and a second working electrode 750. In examples, first working electrode 725 and a second working electrode 750 are configured for glucose and ketone analyte concentration measurement. In examples, first working electrode 725 and a second working electrode 750 are configured for glucose and lactate analyte concentration measurement. In examples, first working electrode 725 and second working electrode 750 are configured for ketone and lactate analyte concentration measurement. Elongated body multi-analyte sensor 700 includes a DE layer. The DE layer comprising electrodeposited / electropolymerized polymer and any charged medicament as discussed above is electrically isolated from first working electrode 725 and second working electrode 750 and reference electrode 775 by the second layer (e.g., insulating material) 104. In examples, drug releasing electrode 735 and first working electrode 725 and second working electrode 750 share the same reference electrode 775 and / or counter electrode (CE) (not shown). In examples, drug releasing electrode 735, first working electrode 725 and second working electrode 750 use separate REs and / or CEs (not shown). Each of drug releasing electrode 735, first working electrode 725, and second working electrode 750 can be independently configured to receive the same or different potential or current.

[0220] FIG. 8 is a schematic illustrating another exemplary elongated body analyte sensor 800 having a drug releasing electrode 835 located proximal from first working electrode 825 and distal from second working electrode 850 relative to distal tip 305. In examples, first working electrode 825 and second working electrode 850 of the elongated body analyte sensor 800 are configured for glucose and ketone analyte concentrationAttorney Docket No.: 0934-PCT01_0239measurement. In examples, first working electrode 825 and second working electrode 850 are configured for glucose and lactate analyte concentration measurement. In examples, first working electrode 825 and second working electrode 850 are configured for ketone and lactate analyte concentration measurement. Elongated body analyte sensor 800 includes a DE layer (not shown) on drug releasing electrode 835. The DE layer including electrodeposited / electropolymerized polymer and any charged medicament as discussed above is electrically isolated from first working electrode 825 and second working electrode 850 and reference electrode 875 by the second layer (e.g., insulating material) 104. In examples, drug releasing electrode 835 and first working electrode 825 and second working electrode 850 share the same reference electrode 875 and CE (not shown). In examples, drug releasing electrode 835 and first working electrode 825 and second working electrode 850 use separate RE's and counter electrodes (CE) (not shown). Each first working electrode 825 and second working electrode 850 and drug releasing electrode 835 can be independently configured to receive the same or different potential or current.

[0221] In examples, DE layer or precursor materials (monomers and / or drug) and other materials (sensing membrane components, RE, CE materials, etc.) are selectively presented to implantable portion 102 using one or more dip coating methods and or meniscus coating and / or microfluidic coating methods as disclosed in co-assigned Attorney Docket No.0931_US01PR_0212.Planar Substrate Sensor Constructs

[0222] The previously disclosed analyte sensors are configurable as planar analyte sensors, for example, as disclosed in U.S. Patent Application Publication No. 2023 / 0293060. FIG. 9 is a perspective view of an exemplary planar analyte sensor body 900 with a drug releasing electrode configuration as previously described. Sensor body 900 includes dielectric substrate 142 having implantable portion 102 comprising DE layer (e.g., membrane) configured to modulate the release of an amount of one or more drugs from the DE layer using potential or current as discussed above. As shown, DE layer is most proximal to distal tip 305, followed by CE, then WE and then RE along implantable portion 102.

[0223] In examples, DE layer or precursor materials (monomers and / or drug) and other materials (sensing membrane components, RE, CE materials, etc.) are selectively presented to implantable portion 102 using one or more dip coating methods and or meniscus coatingAttorney Docket No.: 0934-PCT01_0239and / or microfluidic coating methods as disclosed in co-assigned Attorney Docket No.0931 US01PR 0212.

[0224] In examples, DE layer in combination with CE are configured to modulate the release of an amount of one or more drugs from the DE layer using potential or current as discussed above. In examples, DE layer in combination with CE are configured to modulate the release of an amount of one or more drugs from the DE layer while WE in combination with RE are configured to monitor one or more analytes in the vicinity of the implantable portion 102.

[0225] It is understood that other configurations of the DE electrode, CE, WE, RE are envisaged as well as multiple WE for detecting multiple analytes, for example FIG. 10 illustrates an array 1000 of the DE electrode, CE, WE and RE's positioned about the implantable portion 102 for single or multi-analyte continuous monitoring.

[0226] With reference to FIG. 11, a front and back side view of an exemplary planar multi-analyte sensor body of FIG. 10 depicting an exemplary multi-electrode arrangement with conductive traces with first portion 1010 with WEI, WE2, RE1, and CE configured for single- or multi-analyte continuous monitoring and second portion 1020 with WE3 and RE2 configured for drug elution of an amount of one or more drugs from a DE layer on WE3.

[0227] With reference to FIGs. 12-16, an exploded perspective view of another exemplary planar multi-analyte analyte sensor 1200 with a drug eluting electrode configuration as disclosed above is provided, sensor 1200 having dielectric substrate 142 with contact pads 1215 for receiving conductive traces 1205 from WEI, RE1, DE electrode, and RE2. FIG. 13 is an enlarged view of section 13 of the sensor of FIG. 12 and 14 providing more detail to the exemplary configuration, including windows 1207 in dielectric substrate 142.

[0228] Such configurations as depicted in FIG. 12-16 are fabricated using conventional electrical plating, masking, and / or etching as known in circuit board and / or semiconducting manufacturing and processing.

[0229] FIG. 14 is a top view of planar multi-analyte analyte sensor 1200 with section lines 15-15, and 16-16. FIG. 15 depicts the cross-section view along section line 15-15 of the sensor of FIG. 14 showing the embedded conductive traces 1205 in dielectric 142. FIG. 16 is the cross-section view along section line 16-16 of the sensor of FIG. 14 along the implantable portion 102 showing WE.Attorney Docket No.: 0934-PCT01_0239

[0230] FIG. 17A is a top view of an exemplary planar sensor illustrating various embodiments of drug eluting electrode configurations on a planar substrate 144 with spatially separated WE, DE electrode, RE, and CE. The planar substrate 144 may be substantially planar, having a rectangular cross-section. FIGs. 17B and 17C are cross-sectional views of the planar sensor of FIG. 17A illustrating various embodiments of a drug eluting membrane system 475 as described above. As illustrated in FIG. 17B, exemplary membrane stack includes substrate 144 with most proximal DE electrode having drug eluting membrane system 475 as described above. FIG. 17C, another exemplary membrane stack includes substrate 144 with most proximal DE electrode having drug eluting membrane system 475 as described above with additional biointerface layer 480 at least partially covering the drug eluting membrane system 475. Other membranes and / or configurations are envisaged. Non-planar, elongated body configurations using the membrane stack of FIGs. 17B, 17C are envisaged.

[0231] FIG. 18 illustrates a wearable device having an analyte sensor with an ex-vivo vasodilator-releasing patch, as disclosed and described herein, we proposed design of a vasodilator loaded patch to deliver vasodilator. In examples, drug releasing layer 470 is provided on tip of implantable portion 102 in combination with anti-inflammatory or tissue response modifier. In this configuration, interactions of vasodilator with anti-inflammatory / tissue response modifier is minimized. A combined drug release platform allows for release two drugs with independent release kinetics. In examples, this configuration minimizes interactions of minoxidil with dexamethasone acetate. In examples, dexamethasone acetate is controlled slow release through drug layer coating on tip and vasodilator is configured for burst release through patch vasodilator loaded patch.

[0232] FIG. 18 illustrates an exemplary implementation of analyte sensor system implemented as a wearable device such as an on-skin sensor assembly 1800 with a vasodilation patch 129. In examples, drug releasing layer 470 with anti-inflammatory or tissue response modifier as previously disclosed is provided on tip of implantable portion 102 in combination with vasodilation patch 129 comprising vasodilation agents as previously described. As shown in FIG. 18, on-skin sensor assembly comprises a housing 125. An adhesive patch 127 can couple the housing 125 to the skin of the host. The adhesive patch 127 can be a pressure sensitive adhesive (e.g. acrylic, rubber based, or other suitable type) bonded to a carrier substrate (e.g., spun lace polyester, polyurethane film, or other suitableAttorney Docket No.: 0934-PCT01_0239type) for skin attachment. In examples, adhesive patch 127 comprises one or more vasodilation agents alone or in combination with one or more skin penetrating agents, e.g., dimethyl sulfoxide and the like used in conventional transdermal systems.

[0233] In examples, the present disclosure of providing a vasodilator on an implantable portion of a device, e.g., a continuous analyte monitoring device, provides for an increase in blood perfusion in the sublayers, e.g., hypodermis, dermis, and adipose tissues, between the epidermis and muscle tissues. In examples, the present disclosure of providing a vasodilator on an implantable portion of a device, e.g., a continuous analyte monitoring device, provides for an increase in blood perfusion in the capillary bed, for example, via dilation of capillaries. In examples, the present disclosure of providing a vasodilator on an implantable portion of a device, e.g., a continuous analyte monitoring device, so as to introduce a vasodilator to the hypodermis, dermis, and adipose tissues is distinguished from application of a vasodilator on the epidermis, e.g., via a topical administration. Introduction of a vasodilator to the hypodermis, dermis, and adipose tissues when an anti-inflammatory is also administered to the same implant site provides for improved signal response postinsertion (reduced lag-time). In examples, providing a vasodilator on an implantable portion of a device, e.g., a continuous analyte monitoring device, so as to introduce a vasodilator to the hypodermis, dermis, and adipose tissues is used together with the application of a vasodilator to the epidermis.

[0234] In other examples, the present disclosure provides a vasodilator on an implantable portion of a device in the sublayers, e.g., hypodermis, dermis, and adipose tissues, e.g., a continuous analyte monitoring device, the continuous analyte monitoring device configured for release of one or more anti-inflammatory or tissue response modifiers, where the release of the vasodilator provides for an increase in blood perfusion in the sublayers, e.g., hypodermis, dermis, and adipose tissues, between the epidermis and muscle tissues and reduces post-insertion delay of a signal corresponding to an analyte concentration.

[0235] The housing 125 may include a through-hole 180 that cooperates with a sensor inserter device (not shown) that is used for implanting the sensor 139 under the skin of a subject. Vasodilation patch 129 can be integral with or separate from adhesive patch 127. Distal tip 305 of implantable portion 102 comprises a drug releasing layer 470, with antiAttorney Docket No.: 0934-PCT01_0239inflammatory or tissue response modifier as described above, positioned distally from window 106.

[0236] The wearable sensor assembly 600 can include sensor electronics operable to measure and / or analyze analyte indicators sensed by sensor 139. Sensor electronics within sensor assembly 1800 can transmit information (e.g., measurements, analyte data, and glucose data) to a remotely located device.

[0237] FIG. 19 is a diagram depicting an example continuous transcutaneous analyte monitoring system 100 configured to measure one or more analytes and / or electrophysiological indicators (e.g., blood pressure, heart rate, core temperature, etc.). The monitoring system includes a continuous transcutaneous analyte sensor system 124 operatively connected to a host 120 and a plurality of display devices 134 a-e according to certain aspects of the present disclosure. It should be noted that display device 134e alternatively or in addition to being a display device, may be a medicament delivery device that can act cooperatively with the continuous transcutaneous analyte sensor system 124 to deliver medicaments to host 120. The continuous transcutaneous analyte sensor system 124 may include a sensor electronics module 126 and a continuous transcutaneous analyte sensor 122 associated with the sensor electronics module 126. The sensor electronics module 126 may be in direct wireless communication with one or more of the plurality of the display devices 134a-e via wireless communications signals. In one example, display devices 134a-e may also communicate amongst each other and / or through each other to continuous transcutaneous analyte sensor system 124. For ease of reference, wireless communications signals from analyte sensor system 124 to display devices 134a-e can be referred to as "uplink" signals 128. Wireless communications signals from, e.g., display devices 134a-e to continuous transcutaneous analyte sensor system 124 can be referred to as "downlink" signals 130. Wireless communication signals between two or more of display devices 134a-e may be referred to as "crosslink" signals 132. Additionally, wireless communication signals can include data transmitted by one or more of display devices 134a-d via "long-range" uplink signals 136 (e.g., cellular signals) to one or more remote servers 140 or network entities, such as cloud-based servers or databases, and receive long-range downlink signals 138 transmitted by remote servers 140.

[0238] The sensor electronics module 126 includes sensor electronics that are configured to process sensor information and generate transformed sensor information. InAttorney Docket No.: 0934-PCT01_0239certain examples, the sensor electronics module 126 includes electronic circuitry associated with measuring and processing data from continuous transcutaneous analyte sensor 122, including prospective algorithms associated with processing and calibration of the continuous transcutaneous analyte sensor data. The sensor electronics module 126 can be integral with (non-releasably attached to) or releasably attachable to the continuous transcutaneous analyte sensor 122 achieving a physical connection therebetween. The sensor electronics module 126 may include hardware, firmware, and / or software that enables analyte level measurement. For example, the sensor electronics module 126 can include a potentiostat, a power source for providing power to continuous transcutaneous analyte sensor 122, other components useful for signal processing and data storage, and a telemetry module for transmitting data from itself to one or more display devices 134a-e. Electronics can be affixed to a printed circuit board (PCB), or the like, and can take a variety of forms. For example, the electronics can take the form of an integrated circuit (IC), such as an Application-Specific Integrated Circuit (ASIC), a microcontroller, and / or a processor. Examples of systems and methods for processing sensor analyte data are described in more detail herein and in U.S. Pat. Nos. 7,310,544 and 6,931,327 and U.S. Patent Publication Nos.2005 / 0043598, 2007 / 0032706, 2007 / 0016381, 2008 / 0033254, 2005 / 0203360, 2005 / 0154271, 2005 / 0192557, 2006 / 0222566, 2007 / 0203966 and 2007 / 0208245, each of which are incorporated herein by reference in their entirety for all purposes.

[0239] Display devices 134a-e are configured for displaying, alarming, and / or basing medicament delivery on the sensor information that has been transmitted by the sensor electronics module 126 (e.g., in a customized data package that is transmitted to one or more of display devices 134a-e based on their respective preferences). Each of the display devices 134a-e can include a display such as a touchscreen display for displaying sensor information to a user (most often host 120 or a care taker / medical professional) and / or receiving inputs from the user. In some examples, the display devices 134a-e may include other types of user interfaces such as a voice user interface instead of or in addition to a touchscreen display for communicating sensor information to the user of the display device 134a-e and / or receiving user inputs. In some examples, one, some or all of the display devices 134a-e are configured to display or otherwise communicate the sensor information as it is communicated from the sensor electronics module 126 (e.g., in a data package that isAttorney Docket No.: 0934-PCT01_0239transmitted to respective display devices 134a-e), without any additional prospective processing required for calibration and real-time display of the sensor information.

[0240] In the example of FIG. 19, one of the plurality of display devices 134a-e may be a custom display device 134a specially designed for displaying certain types of displayable sensor information associated with analyte values received from the sensor electronics module 126 (e.g., a numerical value and an arrow, in some examples). In some examples, one of the plurality of display devices 134a-e may be a handheld device 134c, such as a mobile phone based on the Android, iOS operating system or other operating system, a palm-top computer and the like, where handheld device 134c may have a relatively larger display and be configured to display a graphical representation of the continuous sensor data (e.g., including current and historic data). Other display devices can include other handheld devices, such as a tablet 134d, a smart watch 134b, a medicament delivery device 134e, a blood glucose meter, and / or a desktop or laptop computers.

[0241] As alluded to above, because the different display devices 134a-e provide different user interfaces, content of the data packages (e.g., amount, format, and / or type of data to be displayed, alarms, and the like) can be customized (e.g., programmed differently by the manufacture and / or by an end user) for each particular display device and / or display device type. Accordingly, in the example of FIG. 19, one or more of display devices 134a-e can be in direct or indirect wireless communication with the sensor electronics module 126 to enable a plurality of different types and / or levels of display and / or functionality associated with the sensor information, which is described in more detail elsewhere herein. Calibration Solution Impregnation of Membrane with Drug

[0242] In aspects, a method of inducing one or more drugs into one or more layers of a sensing membrane 400 during a calibration procedure is provided. In examples, inducing one or more drugs into an analyte diffusion resistance layer 460 of the sensing membrane 400 during a calibration procedure is provided.

[0243] Thus, in examples, a non-drug layer of sensing membrane 400 is impregnated with one or more drugs added to a calibration buffer solution. In examples, a buffer solution is used as the calibration media for exploiting anti-inflammatory drugs that are weak hydrophiles but otherwise increases solubility in the presence of certain buffers. In other examples, a phosphate buffer solution is used as the calibration media for exploiting antiinflammatory drugs that can form more soluble complex phosphates with the drug. EitherAttorney Docket No.: 0934-PCT01_0239or both of these processes provide for transport / impregnation of drug into the one or more layers of the sensing membrane. After exposure to the calibration solution comprising the one or more drugs, removing, and drying, any weak associations of the drug, if any, created with the one or more layer of the sensing membrane are overcome when the implantable section is introduced to aqueous interstitial fluids, thus, facilitating release of the drug in-vivo fand extending the electrochemical activity of the sensor. This method avoids or eliminates additional coating layers for drug release. In one example an anti-inflammatory drug or tissue response modifier in combination with another class of drug, e.g., vasodilation agents are used to impregnate one or more layers of the sensing membrane for the reasons discussed above.

[0244] In examples, the sensing membrane also contains the anti-inflammatory compound or tissue response modifier and the calibration solution is configured so that the coating does not release any anti-inflammatory compound or tissue response modifier, i.e. the sensing membrane has a zero diffusion gradient of the drug. In other examples, the sensing membrane includes a drug releasing layer, where drug contained the drug releasing layer does not release drug into the calibration solution, and where the buffer solution is configured such that the same or a different drug is induced or impregnated into the sensing membrane.Experimental Data

[0245] Experiments to demonstrate the reduction of delay (lag) of sensor response upon insertion of an implantable portion of a continuous analyte sensor having a drug releasing layer with anti-inflammatory or tissue response modifier were performed. Control sensors with drug releasing layer with anti-inflammatory or tissue response modifier (dexamethasone acetate) without vasodilator-releasing layer were used (Control).Preclinical test sensors with vasodilation agent (minoxidil) arranged at distally positioned locations and proximally positioned locations about the implantable portion relative to the drug releasing layer with anti-inflammatory or tissue response modifier were prepared.

[0246] A vasodilator-releasing layer of minoxidil showed median lag time 19.5 min, which is a 7.5 min improvement compared to Control (27 min). Spatially separated vasodilator-releasing layers showed median lagtime 17.5 min, which is a 9.5 min improvement compared to control (27 min). Preclinical study results indicate both single and double vasodilator-releasing layers significantly improve lag time and peak signal overAttorney Docket No.: 0934-PCT01_0239Control. This data demonstrates both distally positioned vasodilator-releasing layer and a proximal vasodilator-releasing layer shows improvement in median lag over Control. In addition, a distally positioned vasodilator-releasing layer and a proximal vasodilatorreleasing layer show a ~13-25% increase in median peak signal over Control sensor. Thus, the use of a releasable vasodilation agent in combination with a releasable antiinflammatory or tissue response modifier improves lag within the first day ("day 1 lag") of insertion of the implantable section of a continuous analyte sensor compared to control group (without vasodilation agent).

[0247] Suitable dosage amounts of vasodilator and of anti-inflammatory, present about the implantable portion 102 was determined. For example, as shown in Table 1 suitable available dosage ranges of a number of vasodilators were determined based on an estimated target tissue mass about 0.2 mg (for about 3 mm thickness of tissue) around an implantable portion of about 0.1 to about 0.5 mm diameter or width. Suitable available antiinflammatory dosage present around an implantable portion of about 0.1 to about 0.5 mm diameter or width, In examples, is about 0.01 to about 2.0 ug / day. "Available dosage" is the amount actually released from the implantable portion after implantation until end-of-life, compared to the amount present about the implantable portion prior to implantation. Available dosage, In examples, is 50-100 wt. % In examples, the available dosage of vasodilator present around the implantable portion 102 is configured to temporarily inhibit or suppress the pharmacological action of anti-inflammatory released around the implantable portion 102. In examples, the available dosage of vasodilator present around the implantable portion 102 is configured to compliment delayed release layer 330 function and to temporarily inhibit or suppress the pharmacological action of anti-inflammatory released as disclosed herein.Attorney Docket No.: 0934-PCT01_0239Table 1. Target SubQ injection dose range (ug) for vasodilator (present on implantable portion of sensor).Sensing Membrane

[0248] In examples, a sensing membrane 400 is disposed over the electroactive surface 103 of the continuous analyte sensor 99 and includes one or more domains or layers. In general, the sensing domain functions to control the flux of a biological fluid there through and / or to protect sensitive regions of the sensor from contamination by the biological fluid, provide a matrix for one or more enzymes, and interface with the in vivo environment, for example. Some conventional electrochemical enzyme-based analyte sensors generally include a sensing domain that controls the flux of the analyte being measured, protects the electrodes from contamination of the biological fluid, and / or provides an enzyme that catalyzes the reaction of the analyte with a co-factor, for example. See, e.g., co-pending U.S.Attorney Docket No.: 0934-PCT01_0239Patent Publication No. 2005 / 0245799, filed May 3, 2004 entitled "IMPLANTABLE ANALYTE SENSOR" and U.S. Patent No. 7,497,827, filed Mar. 10, 2005 and entitled "TRANSCUTANEOUS ANALYTE SENSOR" which are incorporated herein by reference in their entirety.

[0249] The sensing domains of the present disclosure can include any membrane configuration suitable for use with any analyte sensor. In general, the sensing domains of the present disclosure include one or more domains, all or some of which can be adhered to or deposited on the analyte sensor as is appreciated by one skilled in the art. In examples, the sensing domain generally provides one or more of the following functions: 1) protection of the exposed electrode surface from the biological environment, 2) diffusion resistance (limitation) of the analyte, 3) a catalyst for enabling an enzymatic reaction, 4) limitation or blocking of interfering species, and 5) hydrophilicity at the electrochemically reactive surfaces of the sensor interface, such as described in the above-referenced co-pending U.S. patent applications.

[0250] Accordingly, In examples, the sensing membrane is designed with a sensitivity of from about 1 pA / mg / dL to about 100 pA / mg / dL, preferably from about 5 pA / mg / dL to 25 pA / mg / dL, and more preferably from about 4 to about 7 pA / mg / dL. While not wishing to be bound by any particular theory, it is believed that membrane systems designed with a sensitivity in the preferred ranges permit measurement of the analyte signal in low analyte and / or low oxygen situations. Namely, conventional analyte sensors have shown reduced measurement accuracy in low analyte ranges due to lower availability of the analyte to the sensor and / or have shown increased signal noise in high analyte ranges due to insufficient oxygen necessary to react with the amount of analyte being measured. While not wishing to be bound by theory, it is believed that the membrane systems of the present disclosure, in combination with the electronic circuitry design and exposed electrochemical reactive surface area design, support measurement of the analyte in the picoampere range or less, which enables an improved level of resolution and accuracy in both low and high analyte ranges not seen in the prior art.Electrode Domain

[0251] In some examples, the membrane system comprises an optional electrode domain. The electrode domain is provided to ensure that an electrochemical reaction occurs between the electroactive surface 103 of the working electrode and the referenceAttorney Docket No.: 0934-PCT01_0239electrode, and thus the electrode domain is preferably situated more proximal to the electroactive surface 103 than the enzyme domain. Preferably, the electrode domain includes a semipermeable coating that maintains a layer of water at the electrochemically reactive surfaces of the sensor, for example, a humectant in a binder material can be employed as an electrode domain; this allows for the full transport of ions in the aqueous environment. The electrode domain can also assist in stabilizing the operation of the sensor by overcoming electrode start-up and drifting problems caused by inadequate electrolyte. The material that forms the electrode domain can also protect against pH-mediated damage that can result from the formation of a large pH gradient due to the electrochemical activity of the electrodes.

[0252] In certain examples, the electrode domain is formed of a curable mixture of a urethane polymer and a hydrophilic polymer. Particularly preferred coatings are formed of a polyurethane polymer having carboxylate functional groups and non-ionic hydrophilic polyether segments, wherein the polyurethane polymer is crosslinked with a water soluble carbodiimide (e.g., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC))) in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

[0253] Although an independent electrode domain is described herein, in some examples, sufficient hydrophilicity can be provided in the interference domain and / or enzyme domain (the domain adjacent to the electroactive surface 103) so as to provide for the full transport of ions in the aqueous environment (e.g. without a distinct electrode domain).Interference Domain

[0254] In some examples, an optional interference domain is provided, which generally includes a polymer domain that restricts the flow of one or more interferants. In some examples, the interference domain functions as a molecular sieve that allows analytes and other substances that are to be measured by the electrodes to pass through, while preventing passage of other substances, including interferants such as ascorbate and urea (see U.S. Pat. No. 6,001,067 to Shults). Some known interferants for a glucose-oxidase based electrochemical sensor include acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid.Attorney Docket No.: 0934-PCT01_0239

[0255] Several polymer types that can be utilized as a base material for the interference domain include polyurethanes, polymers having pendant ionic groups, and polymers having controlled pore size, for example. In examples, the interference domain includes a thin, hydrophobic membrane that is non-swellable and restricts diffusion of low molecular weight species. The interference domain is permeable to relatively low molecular weight substances, such as hydrogen peroxide, but restricts the passage of higher molecular weight substances, including glucose and ascorbic acid. Other systems and methods for reducing or eliminating interference species that can be applied to the membrane system of the present disclosure are described in co-pending U.S. Patent No. 7,074,307, filed Jul. 21, 2004 and entitled "ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS," U.S. Publication No. 2005 / 0176136, filed Nov. 16, 2004 and entitled, "AFFINITY DOMAIN FOR AN ANALYTE SENSOR," U.S. Patent No. 7,081,195, filed Dec. 7, 2004 and entitled "SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS," and U.S. Patent No. 7,715,893, filed Dec. 3, 2004 and entitled, "CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR." In some alternative examples, a distinct interference domain is not included.Enzyme Domain

[0256] In examples, the membrane system further includes an enzyme domain disposed more distally from the electroactive surface 103 than the interference domain (or electrode domain when a distinct interference is not included). In some examples, the enzyme domain is directly deposited onto the electroactive surface 103 (when neither an electrode or interference domain is included). In examples, the enzyme domain provides an enzyme to catalyze the reaction of the analyte and its co-reactant, as described in more detail below. Preferably, the enzyme domain includes glucose oxidase; however other oxidases, for example, galactose oxidase or uricase oxidase, can also be used.

[0257] For an enzyme-based electrochemical glucose sensor to perform well, the sensor's response is preferably limited by neither enzyme activity nor co-reactant concentration. Because enzymes, including glucose oxidase, are subject to deactivation as a function of time even in ambient conditions, this behavior is compensated for in forming the enzyme domain. Preferably, the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme. However, in alternative examples the enzyme domain is constructed from an oxygen enhancing material, for example,Attorney Docket No.: 0934-PCT01_0239silicone, or fluorocarbon, in order to provide a supply of excess oxygen during transient ischemia. Preferably, the enzyme is immobilized within the domain. See U.S. Patent No. 7,379,765 filed on Jul. 21, 2004 and entitled "Oxygen Enhancing Membrane Systems for Implantable Device."Resistance Domain

[0258] In examples, the membrane system includes a resistance domain disposed more distal from the electroactive surface 103 than the enzyme domain. Although the following description is directed to a resistance domain fora glucose sensor, the resistance domain can be modified for other analytes and co-reactants as well.

[0259] There exists a molar excess of glucose relative to the amount of oxygen in blood; that is, for every free oxygen molecule in extracellular fluid, there are typically more than 100 glucose molecules present (see Updike et al., Diabetes Care 5:207-21(1982)). However, an immobilized enzyme-based glucose sensor employing oxygen as co-reactant is preferably supplied with oxygen in non-rate-limiting excess in order for the sensor to respond linearly to changes in glucose concentration, while not responding to changes in oxygen concentration. Specifically, when a glucose-monitoring reaction is oxygen limited, linearity is not achieved above minimal concentrations of glucose. Without a semipermeable membrane situated over the enzyme domain to control the flux of glucose and oxygen, a linear response to glucose levels can be obtained only for glucose concentrations of up to about 40 mg / dL. However, in a clinical setting, a linear response to glucose levels is desirable up to at least about 400 mg / dL.

[0260] The resistance domain includes a semi-permeable membrane that controls the flux of oxygen and glucose to the underlying enzyme domain, preferably rendering oxygen in a non-rate-limiting excess. As a result, the upper limit of linearity of glucose measurement is extended to a much higher value than that which is achieved without the resistance domain. In examples, the resistance domain exhibits an oxygen to glucose permeability ratio of from about 50:1 or less to about 400:1 or more, preferably about 200:1. As a result, onedimensional reactant diffusion is adequate to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (See Rhodes et al., Anal. Chem., 66:1520-1529 (1994)).

[0261] In an example, the resistance domain includes a polyurethane membrane with both hydrophilic and hydrophobic regions to control the diffusion of glucose and oxygen toAttorney Docket No.: 0934-PCT01_0239an analyte sensor, the membrane being fabricated easily and reproducibly from commercially available materials. A suitable hydrophobic polymer component is a polyurethane, or polyetherurethaneurea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxyl-containing material. A polyurethaneurea is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material. Preferred diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be useful in the preparation of the polymer and copolymer components of the membranes of the present disclosure. The material that forms the basis of the hydrophobic matrix of the resistance domain can be any of those known in the art as appropriate for use as membranes in sensor devices and as having sufficient permeability to allow relevant compounds to pass through it, for example, to allow an oxygen molecule to pass through the membrane from the sample under examination in order to reach the active enzyme or electrochemical electrodes. Examples of materials which can be used to make non-polyurethane type membranes include vinyl polymers, polyethers, polyesters, polyamides, inorganic polymers such as polysiloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein-based materials, and mixtures or combinations thereof.

[0262] In an example, the hydrophilic polymer component of the resistance domain is polyethylene oxide. For example, one useful hydrophobic-hydrophilic copolymer component is a polyurethane polymer that includes about 20% hydrophilic polyethylene oxide. The polyethylene oxide portions of the copolymer are thermodynamically driven to separate from the hydrophobic portions of the copolymer and the hydrophobic polymer component. The 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend affects the water pick-up and subsequent glucose permeability of the membrane.Interference-Free Membrane Systems

[0263] Although sensors of some examples described herein include an optional interference domain in order to block or reduce one or more interferants, sensors with the membrane system of the present disclosure, including an electrode domain, an enzyme domain, and a resistance domain, have been shown to inhibit ascorbate without an additional interference domain. Namely, the membrane system of the present disclosure,Attorney Docket No.: 0934-PCT01_0239including an electrode domain, an enzyme domain, and a resistance domain, has been shown to be substantially non-responsive to ascorbate in physiologically acceptable ranges. While not wishing to be bound by theory, it is believed that the process of depositing the resistance domain by spray coating, as described herein, results in a structural morphology that is substantially resistance resistant to ascorbate.

[0264] In general, it is believed that appropriate solvents and / or deposition methods can be chosen for one or more of the domains of the membrane system that form one or more transitional domains such that interferants do not substantially permeate there through. Thus, sensors can be built without distinct or deposited interference domains, which are non-responsive to interferants. While not wishing to be bound by theory, it is believed that a simplified multilayer membrane system, more robust multilayer manufacturing process, and reduced variability caused by the thickness and associated analyte sensitivity of the deposited micron-thin interference domain can be provided. Additionally, the optional polymer-based interference domain, which usually inhibits hydrogen peroxide diffusion, is eliminated, thereby enhancing the amount of hydrogen peroxide that passes through the membrane system.Sensing Membrane Compositions

[0265] In some examples, one or more domains of the sensing systems are formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinyl pyridine, polyvinyl pyridine-co-polystyrene, polyvinylidenefluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, polyethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers. Co-assigned U.S Publication. No. 2005 / 0245799, which is incorporated herein by reference in its entirety, describes biointerface and sensing domain configurations and materials that may be applied to the presently disclosed sensor.

[0266] In other examples, on or more membranes, domains, or layers of the sensing system is a block copolymer, e.g., a polyurethane block polymer with a hard segment and a soft segment, where the soft segment can comprise a hydrophobic portion, a hydrophilicAttorney Docket No.: 0934-PCT01_0239portion, or a combination of hydrophobic / hydrophilic portion. Each of the of hydrophobic / hydrophilic portions can independently be of a different average molecular weight or chain length. In other examples, the diffusion adjustment membrane is a segmented block copolymer of hydrophobic / hydrophilic portions and one or more independent hard segments, e.g. an aliphatic or aromatic diisocyanate such as norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene (TDI), 1,3-phenylene diisocyanate (MPDI), trans-l,3-bis(isocyanatomethyl) cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocyanate(HMDI), 4,4'-Diphenylmethane diisocyanate (MDI), trans-l,4-bis(isocyanatomethyl) cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3’-Dimethyl-4,4'-biphenyldiisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0267] In other examples, the diffusion adjustment membrane is a multi-block copolymer. In other examples, the diffusion adjustment membrane is annealed to provide stable separated phases and / or diffusion channels for release of bioactive agent. In examples, the diffusion adjustment membrane is continuously, semi-continuously, or segmentally (randomly or in a pattern) applied over the bioactive releasing membrane 470.

[0268] The sensing membrane can be deposited on the electroactive surface 103 of the electrode material using known thin or thick film techniques (for example, spraying, electrodepositing, dipping, or the like) or by meniscus coating or microfluidic coating method, for example, as disclosed in co-assigned Attorney Docket No. 0931_US01PR_0212. It is noted that the sensing membrane that surrounds the working electrode does not have to be the same structure as what surrounds a reference electrode, etc. For example, the enzyme domain deposited over the working electrode does not necessarily need to be deposited over the reference and / or counter electrodes.

[0269] In examples, the sensor is an enzyme-based electrochemical sensor, wherein the WE measures electronic current, e.g. detection of hydrogen peroxide H2O2 as a by-product, or via direct electron transfer of a redox system, e.g., a "wired enzyme" system. One or more potentiostats is employed to monitor the electrochemical reaction at the electroactive surface 103 of the working electrode(s). The potentiostat applies a constant potential to the working electrode and its associated reference electrode to determine the current produced at the working electrode. The current that is produced at the working electrode (and flows through the circuitry to the counter electrode) is substantially proportional to the amount ofAttorney Docket No.: 0934-PCT01_0239H2O2 that diffuses to the working electrode or analyte that facilitates electron transfer in the wired enzyme system. The output signal is typically a raw data stream that is used to provide a useful value of the measured analyte concentration in a host to the host or doctor, for example.

[0270] Some alternative analyte sensors that can benefit from the systems and methods of the present disclosure include U.S. Pat. No. 5,711,861 to Ward et al., U.S. Pat. No.6,642,015 to Vachon et al., U.S. Pat. No. 6,654,625 to Say et al., U.S. Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,514,718 to Heller, U.S. Pat. No. 6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,185 to Offenbacher et al., U.S. Pat. No. 5,310,469 to Cunningham et al., and U.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No. 6,579,690 to Bonnecaze et al., U.S. Pat. No. 6,484,046 to Say et al., U.S. Pat. No. 6,512,939 to Colvin et al., U.S. Pat. No. 6,424,847 to Mastrototaro et al., U.S. Pat. No. 6,424,847 to Mastrototaro et al., for example. All of the above patents are incorporated in their entirety herein by reference and are not inclusive of all applicable analyte sensors; in general, it should be understood that the disclosed examples are applicable to a variety of analyte sensor configurations.

[0271] The sensor of the present disclosure may be inserted into a variety of locations on the host's body, such as the abdomen, the thigh, the upper arm, and the neck or behind the ear. Although the present disclosure may suggest insertion through the abdominal region, the systems and methods described herein are limited neither to the abdominal nor to the subcutaneous insertions. One skilled in the art appreciates that these systems and methods may be implemented and / or modified for other insertion sites and may be dependent upon the type, configuration, and dimensions of the analyte sensor.

[0272] Transcutaneous / subcutaneous continuous analyte sensors can be used in vivo over various lengths of time. For example, the device includes a sensor, for measuring the analyte in the host, a porous, biocompatible matrix covering at least a portion of the sensor, and an applicator, for inserting the sensor through the host's skin. In some examples, the sensor has architecture with at least one dimension less than about 1 mm. However, one skilled in the art will recognize that alternative configurations are possible and may be desirable, depending upon factors such as intended location of insertion, for example. The sensor is inserted through the host's skin and into the underlying tissue, such as soft tissue or fatty tissue.Attorney Docket No.: 0934-PCT01_0239

[0273] After insertion, fluid moves into the spacer, e.g., a biocompatible matrix or membrane, such as the bioactive releasing membrane 470 and / or biointerface membrane 480, creating a fluid-filled pocket therein. This process may occur immediately or may take place over a period of time, such as several minutes or hours post insertion. A signal from the sensor is then detected, such as by the sensor electronics unit located in the mounting unit on the surface of the host's skin. In general, the sensor may be used continuously for a period of days, such as 1 to 7 days, 14 days, or 21 days. After use, the sensor is simply removed from the host's skin. In examples, the host may repeat the insertion and detection steps as many times as desired. In some implementations, the sensor may be removed after about 14 days or more, and then another sensor inserted, and so on. Similarly, in other implementations, the sensor is removed after about 3, 5, 7, 10 or 21 days, followed by insertion of a new sensor, and so on.

[0274] Some examples of transcutaneous analyte sensors are described in U.S. Pat. No.8,133,178 to Brauker et al., which is incorporated herein by reference in its entirety, as well as U.S. Pat. Nos. 8,828,201, Simpson, et al.; 9,131,885 Simpson, et al.; 9,237,864, Simpson, et al.; and 9,763, 608, Simpson, et al., each of which is incorporated by reference in its entirety herein. In general, transcutaneous analyte sensors comprise the sensor and a mounting unit with electronics associated therewith.

[0275] PCT Publication No. WO2024 / 144921 and U.S. Publication No. 2024 / 0090802, which are incorporated herein by reference in their entireties, describe drug releasing-, biointerface-, and sensing-membrane configurations and materials that are to be applied to elongated bodies. Suitable bioactive agents include those which are known to discourage or prevent bacterial growth and infection, for example, anti-inflammatory agents, antimicrobials, antibiotics, or the like.Biointerface Membrane / Layer

[0276] In examples, the sensor includes a porous material disposed over some portion thereof, which modifies the host's tissue response to the sensor. In some examples, the porous material surrounding the sensor advantageously enhances and extends sensor performance and lifetime by slowing or reducing cellular migration to the sensor and associated degradation that would otherwise be caused by cellular invasion if the sensor were directly exposed to the in vivo environment. Alternatively, the porous material can provide stabilization of the sensor via tissue ingrowth into the porous material in the longAttorney Docket No.: 0934-PCT01_0239term. Suitable porous materials include silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes, cellulosic polymers, polyethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers, as well as metals, ceramics, cellulose, hydrogel polymers, poly(2-hydroxyethyl methacrylate, pHEMA), hydroxyethyl methacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC), high density polyethylene, acrylic copolymers, nylon, polyvinyl difluoride, polyanhydrides, poly(l-lysine), poly( L-lactic acid), hydroxyethylmetharcrylate, hydroxyapeptite, alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium, titanium alloy, nintinol, stainless steel, and CoCr alloy, or the like, such as are described in co-pending U.S. U.S. Patent No. 7,875,293, filed May 10, 2004 and entitled, "BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVE AGENTS" and U.S. Patent No. 7,192,450, filed Aug. 22, 2003 and entitled "POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES."

[0277] When used herein, the terms "membrane" and "layer" are meant to be interchangeable. In these examples, the aforementioned porous material is a biointerface membrane comprising a first domain that includes an architecture, including cavity size, configuration, and / or overall thickness, that modifies the host's tissue response, for example, by creating a fluid pocket, encouraging vascularized tissue ingrowth, disrupting downward tissue contracture, resisting fibrous tissue growth adjacent to the device, and / or discouraging barrier cell formation. The biointerface membrane in one example covers at least the sensing mechanism of the sensor and can be of any shape or size, including uniform, asymmetrically, or axi-symmetrically covering or surrounding a sensing mechanism or sensor.

[0278] A second domain of the biointerface membrane is optionally provided that is impermeable to cells and / or cell processes. A bioactive agent is optionally provided that is incorporated into the at least one of the first domain, the second domain, the sensing domain, or other part of the implantable device, wherein the bioactive agent is configuredAttorney Docket No.: 0934-PCT01_0239to modify a host tissue response. In examples, the biointerface includes a bioactive agent, the bioactive agent being incorporated into at least one of the first and second domains of the biointerface membrane, or into the device and adapted to diffuse through the first and / or second domains, in order to modify the tissue response of the host to the membrane.

[0279] Due to the small dimension(s) of the sensor (sensing mechanism) of the present disclosure, some conventional methods of porous membrane formation and / or porous membrane adhesion are inappropriate for the formation of the biointerface membrane onto the sensor as described herein. Accordingly, the following examples exemplify systems and methods for forming and / or adhering a biointerface membrane onto a small structured sensor as defined herein. For example, the biointerface membrane or release membrane of the present disclosure can be formed onto the sensor using techniques such as electrospinning, molding, weaving, direct-writing, lyophilizing, wrapping, and the like.

[0280] In examples wherein the biointerface is directly-written onto the sensor, a dispenser dispenses a polymer solution using a meniscus coater, microfluidic coater, or nozzle with a valve, or the like, for example as described in U.S. Publication No.2004 / 0253365 Al and Attorney Docket No. 0931_US01PR_0212. In general, a variety of nozzles and / or dispensers can be used to dispense a polymeric material to form the biointerface membrane.Bioactive Agent / Bioactive Agent Releasing Layer

[0281] It is understood that "bioactive agent" is used herein to encompass antiinflammatory drugs or tissue response modifiers and vasodilation drugs as disclosed herein. It is understood that "bioactive agent releasing layer" is used herein to encompass the drug releasing layer 470 and / or vasodilation drug releasing layer 375.

[0282] In general, bioactive agents that are believed to modify tissue response include anti-inflammatory agents, anti-infective agents, anti-proliferative agents, anti-histamine agents, anesthetics, inflammatory agents, growth factors, angiogenic (growth) factors, adjuvants, immunosuppressive agents, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-barrier cell compounds, vascularization compounds, anti-sense molecules, vasodilation agents, and the like. In some examples, bioactive agents include SIP (Sphingosine-l-phosphate), Monobutyrin, Cyclosporin A, Anti-thrombospondin-2, Rapamycin (and its derivatives), NLRP3 inflammasome inhibitors such as MCC950, andAttorney Docket No.: 0934-PCT01_0239Dexamethasone (and its derivatives). However, other bioactive agents, biological materials (for example, proteins), or even non-bioactive substances can incorporated into the membranes of the present disclosure.

[0283] Bioactive agents suitable for use in the present disclosure are loosely organized into two groups: anti-barrier cell agents and vascularization agents. These designations reflect functions that are believed to provide short-term solute transport through the one or more membranes of the presently disclosed sensor, and additionally extend the life of a healthy vascular bed and hence solute transport through the one or more membranes long term in vivo. However, not all bioactive agents can be clearly categorized into one or other of the above groups; rather, bioactive agents generally comprise one or more varying mechanisms for modifying tissue response and can be generally categorized into one or both of the above-cited categories.

[0284] In examples, pilocarpine, dexamethasone, dexamethasone salts, or dexamethasone derivatives in particular, dexamethasone acetate, which, for example, abates the intensity of the FBC response at the device-tissue interface, is incorporated into the bioactive releasing membrane 470. In other examples, a combination of dexamethasone and dexamethasone acetate is incorporated into the bioactive releasing membrane 470. In other examples, dexamethasone and / or dexamethasone acetate combined with one or more other anti-inflammatory and / or immunosuppressive agents is incorporated into the bioactive releasing membrane 470. Alternatively, Rapamycin, which is a potent specific inhibitor of some macrophage inflammatory functions, can be incorporated into the release membrane alone or in combination with pilocarpine, dexamethasone, dexamethasone salts, dexamethasone derivatives in particular, dexamethasone acetate.

[0285] Other suitable medicaments, pharmaceutical compositions, therapeutic agents, or other desirable substances can be incorporated into the bioactive releasing membrane 470 of the present disclosure, including, but not limited to, anti-inflammatory agents, anti-infective agents, necrosing agents, and anesthetics.

[0286] Generally, anti-inflammatory agents reduce acute and / or chronic inflammation adjacent to the implant, in order to decrease the formation of a FBC capsule to reduce or prevent barrier cell layer formation. Suitable anti-inflammatory agents include but are not limited to, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetometaphen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate,Attorney Docket No.: 0934-PCT01_0239diclofenac, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-IO, IL-6 mutein, anti-IL-6 iNOS inhibitors (for example, L-NAME or L-NMDA), Interferon, ketoprofen, ketorolac, leflunomide, melenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, pilocarpine, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin; and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethesone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, NLRP3 inflammasome inhibitors such as MCC950, dexamethasone, and dexamethasone acetate.

[0287] Generally, immunosuppressive and / or immunomodulatory agents interfere directly with several key mechanisms necessary for involvement of different cellular elements in the inflammatory response. Suitable immunosuppressive and / or immunomodulatory agents include anti-proliferative, cell-cycle inhibitors, (for example, paclitaxol (e.g., Sirolimus), cytochalasin D, infiximab), taxol, actinomycin, mitomycin, thospromote VEGF, estradiols, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methothrexate, mycophenolic acid, angiopeptin, vincristing, mitomycine, statins, C MYC antisense, sirolimus (and analogs), RestenASE, 2-chloro-deoxyadenosine, PCNA Ribozyme, batimstat, prolyl hydroxylase inhibitors, PPARy ligands (for example troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catchins, glycating agents, endothelin inhibitors (for example, Ambrisentan, Tesosentan, Bosentan), Statins (for example, Cerivasttin), E. coli heat-labile enterotoxin, and advanced coatings.

[0288] Generally, anti-infective agents are substances capable of acting against infection by inhibiting the spread of an infectious agent or by killing the infectious agent outright, which can serve to reduce immuno-response without inflammatory response at the implant site. Anti-infective agents include, but are not limited to, anthelmintics (mebendazole), antibiotics including aminoclycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime,Attorney Docket No.: 0934-PCT01_0239ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcil lin), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; colistimethate sodium; polymyxin b sulfate; vancomycin; antivirals including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum; gatifloxacin; and sulfa methoxazole / trimethoprim.

[0289] Generally, necrosing agents are any drug that causes tissue necrosis or cell death. Necrosing agents include cisplatin, BCNU, taxol or taxol derivatives, and the like.Vascularization Agents

[0290] Generally, vascularization agents include substances with direct or indirect angiogenic properties. In some cases, vascularization agents may additionally affect formation of barrier cells in vivo. By indirect angiogenesis, it is meant that the angiogenesis can be mediated through inflammatory or immune stimulatory pathways. It is not fully known how agents that induce local vascularization indirectly inhibit barrier-cell formation; however it is believed that some barrier-cell effects can result indirectly from the effects of vascularization agents.

[0291] Vascularization agents include mechanisms that promote neovascularization around the membrane and / or minimize periods of ischemia by increasing vascularization close to the device-tissue interface. Sphingosine-l-Phosphate (SIP), which is a phospholipid possessing potent angiogenic activity, is incorporated into a biointerface membrane or release membrane of a preferred example. Monobutyrin, which is a potent vasodilator and angiogenic lipid product of adipocytes, is incorporated into a biointerface membrane or release membrane of a preferred example. In other examples, an anti-sense molecule (for example, thrombospondin-2 anti-sense), which increases vascularization, is incorporated into a biointerface membrane or release membrane.

[0292] Vascularization agents can include mechanisms that promote inflammation, which is believed to cause accelerated neovascularization in vivo. In examples, a xenogenic carrier, for example, bovine collagen, which by its foreign nature invokes an immuneAttorney Docket No.: 0934-PCT01_0239response, stimulates neovascularization, and is incorporated into a biointerface membrane or release membrane of the present disclosure. In other examples, Lipopolysaccharide, which is a potent immunostimulant, is incorporated into a biointerface membrane or release membrane. In other examples, a protein, for example, a bone morphogenetic protein (BMP), which is known to modulate bone healing in tissue, is incorporated into a biointerface membrane or release membrane of a preferred example.

[0293] Generally, angiogenic agents are substances capable of stimulating neovascularization, which can accelerate and sustain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include, but are not limited to, copper ions, iron ions, tridodecylmethylammonium chloride, Basic Fibroblast Growth Factor (bFGF), (also known as Heparin Binding Growth Factor-ll and Fibroblast Growth Factor II), Acidic Fibroblast Growth Factor (aFGF), (also known as Heparin Binding Growth Factor-1 and Fibroblast Growth Factor-1), Vascular Endothelial Growth Factor (VEGF), Platelet Derived Endothelial Cell Growth Factor BB (PDEGF-BB), Angiopoietin-1, Transforming Growth Factor Beta (TGF-Beta), Transforming Growth Factor Alpha (TGF-Alpha), Hepatocyte Growth Factor, Tumor Necrosis Factor-Alpha (TNF-Alpha), Placental Growth Factor (PLGF), Angiogenin, lnterleukin-8 (IL-8), Hypoxia Inducible Factor-1 (HIF-1), Angiotensin-Converting Enzyme (ACE) Inhibitor Quinaprilat, Angiotropin, Thrombospondin, Peptide KGHK, Low Oxygen Tension, Lactic Acid, Insulin, Copper Sulphate, Estradiol, prostaglandins, cox inhibitors, endothelial cell binding agents (for example, decorin or vimentin), glenipin, hydrogen peroxide, nicotine, and Growth Hormone.

[0294] Generally, pro-inflammatory agents are substances capable of stimulating an immune response in host tissue, which can accelerate or sustain formation of a mature vascularized tissue bed. For example, pro-inflammatory agents are generally irritants or other substances that induce chronic inflammation and chronic granular response at the implantation-site. While not wishing to be bound by theory, it is believed that formation of high tissue granulation induces blood vessels, which supply an adequate or rich supply of analytes to the device-tissue interface. Pro-inflammatory agents include, but are not limited to, xenogenic carriers, Lipopolysaccharides, S. aureus peptidoglycan, and proteins.

[0295] Other substances that can be incorporated into membranes of the present disclosure include various pharmacological agents, excipients, and other substances well known in the art of pharmaceutical formulations.Attorney Docket No.: 0934-PCT01_0239

[0296] Although the bioactive agent in some examples is incorporated into the biointerface membrane or release membrane and / or implantable device, in some examples the bioactive agent can be administered concurrently with, prior to, or after implantation of the device systemically, for example, by oral administration, or locally, for example, by subcutaneous injection near the implantation site. A combination of bioactive agent incorporated in the biointerface membrane and bioactive agent administration locally and / or systemically can be preferred in certain examples.

[0297] In examples, the drug releasing layer 470 and / or vasodilation drug releasing layer 375 functions as the biointerface layer 480. In other examples, the bioactive releasing layer 470 is chemically distinct from the biointerface layer 480, or no biointerface layer 480 is used. In such examples, one or more bioactive agents are incorporated into the bioactive releasing layer 470 or both the biointerface layer 480 and the bioactive releasing layer 470.

[0298] Generally, numerous variables can affect the pharmacokinetics of bioactive agent release. The bioactive agents of the present disclosure can be optimized for short- and / or extended release. In some examples, the bioactive agents of the present disclosure are designed to aid or overcome factors associated with short-term effects (for example, acute inflammation) of the foreign body response, which can begin as early as the time of implantation and extend up to about one month after implantation. In some examples, the bioactive agents of the present disclosure are designed to aid or overcome factors associated with extended effects, for example, chronic inflammation, barrier cell layer formation, or build-up of fibrotic tissue of the foreign body response, which can begin as early as about one week after implantation and extend for the life of the implant, for example, months to years. In some examples, the bioactive agents of the present disclosure combine short- and extended release to exploit the benefits of both. Published U.S.Publication No. 2005 / 0031689 Al to Shults et al. discloses a variety of systems and methods for release of the bioactive agents.

[0299] The amount of loading of the bioactive agent into the release membrane can depend upon several factors. For example, the bioactive agent dosage and duration can vary with the intended use of the release membrane, for example, cell transplantation, analyte measuring-device, and the like; differences among hosts in the effective dose of bioactive agent; location and methods of loading the bioactive agent; and release rates associated with bioactive agents and optionally their chemical composition and / or bioactive agentAttorney Docket No.: 0934-PCT01_0239loading. Therefore, one skilled in the art will appreciate the variability achieving a reproducible and controlled release of the one or more bioactive agents, at least for the reasons described above. U.S. Publication No. 2005 / 0031689 Al to Shults et al. that discloses a variety of systems and methods for loading of the bioactive agents.

[0300] In examples, multiple layers or discrete or semi-discrete rings or bands of the bioactive releasing membrane are employed to specifically tailor the drug release of the bioactive agent for the intended sense of life. Thus, In examples, two or more layers of the multilayer bioactive releasing membrane differs in one or more aspects, for example: of hydrophobicity / hydrophilicity content or ratio of the segments of a soft-hard segmented polymer or copolymer; compositional makeup or weight percent of two or more different polymers or copolymers or blends of different polymers and / or copolymers in each layer or their vertical or horizontal distribution in one or more layers; bioactive loading and / or distribution (vertically or longitudinally within the coated membrane) in each layer; membrane thickness of each layer; composition and loading amount of two or more distinct bioactive agents (e.g., a neutral, derivative and / or salt form or a primary form and derivative form of the bioactive agent); the solvent system used to cast or deposit or dip coat the individual bioactive releasing membrane layers; and the relative position(s) (continuous, semicontinuous, or noncontinuous positioning) of the bioactive releasing membrane layers along the length of the sensor.

[0301] Suitable bioactive releasing membranes are those membranes which provide a therapeutically effective amount and release rate of bioactive agent beginning with the insertion of the sensor and throughout the life of the sensor. In examples, the bioactive releasing membrane in combination with an amount of bioactive agent provides for extending the useful life of the sensor when compared to an equivalent sensor the bioactive releasing membrane without the bioactive agent (or compared to the absence of the bioactive releasing membrane and bioactive agent). As used herein a therapeutically effective amount of the bioactive agent is an amount capable of inducing an intended therapeutic effect. An intended therapeutic effect is one that can be readily determined using conventional diagnostic methods. For example, an intended therapeutic effect encompasses suppressing unwanted foreign body response to an implant (foreign body) including, but not limited to inflammation and / or fibrous capsule formation.Attorney Docket No.: 0934-PCT01_0239

[0302] In some examples, the wetting property of the membrane (and by extension the extent of sensor drift exhibited by the sensor) can be adjusted and / or controlled by creating covalent cross-links between surface-active group-containing polymers, functional-group containing polymers, polymers with zwitterionic groups (or precursors or derivatives thereof), and combinations thereof. Cross-linking can have a substantial effect on film structure, which in turn can affect the film's surface wetting properties. Crosslinking can also affect the film's tensile strength, mechanical strength, water absorption rate and other properties.

[0303] Cross-linked polymers can have different cross-linking densities. In certain examples, cross-linkers are used to promote cross-linking between layers. In other examples, in replacement of (or in addition to) the cross-linking techniques described above, heat is used to form cross-linking. For example, in some examples, imide and amide bonds can be formed between two polymers as a result of high temperature. In some examples, photo cross-linking is performed to form covalent bonds between the polycationic layers(s) and polyanionic layer(s). One major advantage to photo-cross-linking is that it offers the possibility of patterning. In certain examples, patterning using photocross linking is performed to modify the film structure and thus to adjust the wetting property of the membrane.

[0304] Polymers with domains or segments that are functionalized to permit crosslinking can be made by methods known in the art. For example, polyurethaneurea polymers with aromatic or aliphatic segments having electrophilic functional groups (e.g., carbonyl, aldehyde, anhydride, ester, amide, isocyano, epoxy, allyl, or halo groups) can be crosslinked with a crosslinking agent that has multiple nucleophilic groups (e.g., hydroxyl, amine, urea, urethane, or thio groups). In further examples, polyurethaneurea polymers having aromatic or aliphatic segments having nucleophilic functional groups can be crosslinked with a crosslinking agent that has multiple electrophilic groups. Still further, polyurethaneurea polymers having hydrophilic segments having nucleophilic or electrophilic functional groups can be crosslinked with a crosslinking agent that has multiple electrophilic or nucleophilic groups. Unsaturated functional groups on the polyurethane urea can also be used for crosslinking by reacting with multivalent free radical agents. Non-limiting examples of suitable cross-linking agents include isocyanate, carbodiimide, glutaraldehyde, aziridine, silane, or other aldehydes, epoxy, acrylates, free-radical based agents, ethylene glycolAttorney Docket No.: 0934-PCT01_0239diglycidyl ether (EGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). In examples, from about 0.1% to about 15% w / w of cross-linking agent is added relative to the total dry weights of cross-linking agent and polymers added when blending the ingredients (In examples, about 1% to about 10%). During the curing process, substantially all of the cross-linking agent is believed to react, leaving substantially no detectable unreacted cross-linking agent in the final film.

[0305] Polymers disclosed herein can be formulated into mixtures that can be drawn into a film or applied to a surface using any method known in the art (e.g., microfluidic spraying, painting, dip coating, vapor depositing, molding, 3-D printing, lithographic techniques (e.g., photolithograph), micro- and nano-pipetting printing techniques, silkscreen printing, etc.). The mixture can then be cured under high temperature (e.g., 50-150° C.). Other suitable curing methods can include ultraviolet or gamma radiation, for example.

[0306] In examples, the weight of bioactive agent associated with the sensor is 1-120 pL, 2-110 pL, 3-100 pL, 4-90 pL, 5-80 pL, 6-70 pL, 7-60 pL, 8-50 pL, 9-40 pL, or 10-30 pL. In other examples, the weight of two or more bioactive agents associated with the sensor, independently or collectively is 1-120 pL, 2-110 pL, 3-100 pL, 4-90 pL, 5-80 pL, 6-70 pL, 7-60 pL, 8-50 pL, 9-40 pL, or 10-30 pL.

[0307] In examples, the weight percent loading of bioactive agent in the bioactive releasing membrane 470 is about 10 weight percent to about 90 weight percent. In examples, the weight percent loading of bioactive agent in the bioactive releasing membrane 470 is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, of the total weight of the bioactive releasing membrane plus bioactive agent (as a deposited membrane on a sensor). In examples, the weight percent loading of bioactive agent in the bioactive releasing membrane 470 is 30%, 40%, 50%, or 60%, of the total weight of the bioactive releasing membrane plus bioactive agent (as a deposited membrane on a sensor).Depending on the nature of the bioactive releasing membrane, for example, the ratio of hydrophobic / hydrophilic soft segments, the weight percent of the bioactive agent is chosen based on solubility / miscibility / dispersion of the bioactive agent with the bioactive releasing membrane and any solvent or solvent system used to dispense the bioactive releasing membrane and bioactive agent onto the sensor. Too high a loading of bioactive agent in a particular bioactive releasing membrane can result in precipitation of the bioactive agent, and / or reduced coating quality. Too low a loading of bioactive agent in the bioactiveAttorney Docket No.: 0934-PCT01_0239releasing membrane can result in inefficient therapeutic effect over the intended lifetime of the sensor, which can manifest itself as undesirable signal-to-noise initially and / or prior to the designed end-of-life of the sensor, reduction or fluctuation of sensitivity of the sensor to the target analyte(s) shortly after insertion and / or prior to the designed end-of-life of the sensor, among other things.

[0308] In examples, the bioactive releasing membrane is configured to release, in weight percent, after insertion and up to the end of life of the sensor, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, up to and including 100% of the initial loading of the bioactive agent. In examples, the bioactive releasing membrane is configured to release, after insertion and up to the end of life of the sensor, between 60-90 weight percent of the bioactive agent. In other examples, the bioactive releasing membrane is configured to release, after insertion and up to the end of life of the sensor, between 75-85 weight percent of the bioactive agent.

[0309] In examples, the bioactive releasing membrane of the present disclosure provides for release of the bioactive agent from the bioactive releasing membrane commensurate with a bolus amount of the bioactive agent. In other examples, the bioactive releasing membrane of the present disclosure provides for release of the bioactive agent from the bioactive releasing membrane commensurate with a therapeutically effective amount of the bioactive agent. In examples, the bioactive releasing membrane of the present disclosure provides for release of the bioactive agent from the bioactive releasing membrane commensurate with a non-therapeutically effective amount where the non-therapeutically effective amount follows one or more of a release of a bolus amount or therapeutic amount of the bioactive agent.

[0310] In examples, the bioactive releasing membrane of the present disclosure provides for a bolus release of the bioactive agent essentially immediately upon insertion of the sensor for a first time period or range (for example, minutes, hours, days, weeks, etc.), the first time period or range initiated at a first time point (for example, a second or less) into the subject's soft tissue. In examples, the bioactive releasing membrane of the present disclosure provides for release of a bolus amount of the bioactive agent essentially immediately upon insertion of the sensor, for the first time period initiated at the first time point, into the subject's soft tissue followed by release of a therapeutically effective amount of the bioactive agent beginning at a second time point for a second time period, the secondAttorney Docket No.: 0934-PCT01_0239time period overlapping with or subsequent to the first time period. In examples, the second time point is subsequent to the first time point by at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes or more. In examples, the bioactive releasing membrane of the present disclosure provides for release of a bolus amount of the bioactive agent essentially immediately upon insertion of the sensor, forthe first time period initiated at the first time period, into the subject's soft tissue followed by release of a therapeutically effective amount of the bioactive agent beginning at a second time point for a second time period, the second time period overlapping with or subsequent to the first time period, followed by a release of a non-therapeutically effective amount of the bioactive agent beginning at a third time point for a third time period, the third time period overlapping with or subsequent to the second time period. In examples, the third time point is subsequent to the second time point by at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes or more.

[0311] Release rates of the bioactive agent in any of the aforementioned first, second or third time periods can be the same or different. Release rates of the bioactive agent in any of the aforementioned first, second or third time periods can be configured to occur at a substantially constant rate or a variable rate (intermittent, periodic, and / or random) by modifying one or more of membrane chemistry, structure, and / or morphology, bioactive agent loading, bioactive chemistry, for example. Release rates (the concentration or amount of bioactive released over time) of the bioactive agent in any of the aforementioned time periods can be configured to change after implantation overtime by modifying one or more of membrane chemistry, structure, and / or morphology, bioactive agent loading, bioactive chemistry, for example.

[0312] In examples, the release rate of the bioactive agent from the bioactive releasing membrane initially or during the first time period is greater than the release rate of the bioactive agent from the bioactive releasing membrane initially or during the second time period. In examples, the release rate of the bioactive agent from the bioactive releasing membrane initially or during the second time period is greater than the release rate of the bioactive agent from the bioactive releasing membrane initially or during the third time period. In examples, the release rate of the bioactive agent from the bioactive releasing membrane initially or during the first time period is greater than the release rate of the bioactive agent from the bioactive releasing membrane initially or during the second timeAttorney Docket No.: 0934-PCT01_0239period and the and release rate of the bioactive agent from the bioactive releasing membrane initially or during the second time period is greater than the release rate of the bioactive agent from the bioactive releasing membrane initially the third time period.

[0313] Suitable bioactive releasing membranes of the present disclosure capable of the aforementioned release rates and released amounts of the bioactive agents can be selected from silicone polymers, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polyureas, polyurethane ureas, polyethers, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes and copolymers and blends thereof, cellulosic polymers and copolymers and blends thereof, polyethylene oxide) and copolymers and blends thereof, polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers cellulose, hydrogel polymers, poly(2-hydroxyethyl methacrylate, pHEMA) and copolymers and blends thereof, hydroxyethyl methacrylate, (HEMA) and copolymers and blends thereof, polyacrylonitrile-polyvinyl chloride (PAN-PVC) and copolymers and blends thereof, acrylic copolymers and copolymers and blends thereof, nylon and copolymers and blends thereof, polyvinyl difluoride, polyanhydrides, poly(l-lysine), poly(L-lactic acid), hydroxyethylmetharcrylate and copolymers and blends thereof, and hydroxyapeptite and copolymers and blends thereof.

[0314] A suitable bioactive releasing membrane is a polyurethane, or polyetherurethaneurea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxyl-containing material. A polyurethaneurea is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material. Exemplary diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be useful in the preparation of the polymer and copolymer components of the bioactive releasing membranes of the present disclosure. The material that forms the basis of the hydrophobic matrix of the bioactive releasing membrane or its domains can be any of those known in the art as appropriate for use as membranes in sensor devices. In examples,Attorney Docket No.: 0934-PCT01_0239the bioactive releasing membrane is different from the other membranes of the sensor system in that the bioactive releasing membrane is less sufficient in its permeability to relevant compounds, for example, to allow an glucose molecule to pass through the membrane.

[0315] Examples of other materials which can be used to make non-polyurethane type bioactive releasing membranes include vinyl polymers, polyethers, polyesters, polyamides, polysilicones poly(dialkylsiloxanes), poly(alkylarylsiloxanes), poly(diarylsiloxanes), polycarbosiloxanes, polycarbonate, polyvinyl pyridine, polyvinyl pyridine-co-polystyrene, natural polymers such as cellulosic and protein-based materials, and mixtures, copolymers, or combinations thereof with or without the aforementioned polyurethane, or polyetherurethaneurea polymers.

[0316] In other examples, the bioactive agent is minoxidil, hydralazine, nitroglycerin alone or in combination with at least one of pilocarpine, dexamethasone, dexamethasone and a derivative or salt. Dexamethasone derivatives include dexamethasone acetate, or dexamethasone acetate salt.

[0317] In examples, suitable bioactive releasing membranes 470 are hard-soft segmented polymers, where hard segments include polymer segments providing crystallinity or crystalline like structure and a soft segments providing an amorphous or amorphous-like structure. In one example the bioactive releasing membrane 470 is a hard-soft segmented copolymer where the soft segment comprises a hydrophilic polymer or hydrophilic polymer segment. In one example the bioactive releasing membrane 470 of the present disclosure is a hard-soft segmented copolymer where the soft segment comprises a hydrophilic polymer or hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. Various confirmations and distributions of the hydrophobic domains and hydrophilic domains are envisioned depending on the relative concentrations of each domain and whether there are non-stoichiometric or stoichiometric amounts of each domain. In examples, the soft segment of the bioactive releasing membrane 470 comprises a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent.

[0318] In examples, the bioactive releasing membrane 470 comprises a hard-soft segmented polyurethane copolymer. In other examples, the bioactive releasing membrane 470 comprises a hard-soft segmented polyurethane urea copolymer. In one example theAttorney Docket No.: 0934-PCT01_0239bioactive releasing membrane 470 is a hard-soft segmented polyurethane or polyurethane urea copolymer where the soft segment comprises a hydrophilic polymer, or hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. In one example the bioactive releasing membrane 470 of the present disclosure is a hard-soft segmented polyurethane or polyurethane urea copolymer blend where at least one of the individual polymers of the polymer blend comprises a soft segment comprises a hydrophilic polymer or hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment. In one example the bioactive releasing membrane 470 of the present disclosure is a hard-soft segmented polyurethane or polyurethane urea copolymer blend, where at least one of the individual polymers of the polymer blend comprises a soft segment comprises a hydrophilic polymer segment only and at least one polymer of the polymer blend comprises a soft segment comprising hydrophilic polymer segment in combination with a hydrophobic polymer or hydrophobic polymer segment.

[0319] In some examples, the hard segment of the copolymer may have a molecular weight of from about 160 daltons to about 10,000 daltons, or from about 200 daltons to about 2,000 daltons. In some examples, the molecular weight of the soft segment may be from about 200 daltons to about 100,000 daltons, or from about 500 daltons to about 500,000 daltons, or from about 5,000 daltons to about 20,000 daltons.

[0320] In examples, aliphatic or aromatic diisocyanates are used to prepare the hard segment of bioactive releasing membrane 470. In examples, the aliphatic or aromatic diisocyanate used to provide the hard segment of bioactive releasing membrane 470 is norbornane diisocyanate (NBDI), isophorone diisocyanate (I PDI), tolylene diisocyanate (TDI), 1.3-phenylene diisocyanate (MPDI), trans-l,3-bis(isocynatomethyl) cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocyanate(HI\ / IDI), 4,4'-Diphenylmethane diisocyanate (MDI), trans-l,4-bis(isocynatomethyl) cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1.4-phenylene diisocyanate (PPDI), 3,3’-Dimethyl-4,4'-biphenyldiisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0321] In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises polysiloxane or copolymer thereof. In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises poly(dialkyl)siloxane, poly(diphenyl)siloxane, poly(alkylphenyl)siloxane orAttorney Docket No.: 0934-PCT01_0239copolymer thereof. In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises poly(a I ky I )oxy polymer, poly (alkylene)oxide, or copolymers thereof. In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises poly(alkyl)oxide, poly(ethylene)oxide, poly(propylene)oxide, poly(ethylene-propylene) oxide, poly(tetraalkylene)oxide, poly(tetramethylene)oxide polymer or copolymers or blends thereof. The soft segments can be comprised of hydrophilic and / or hydrophobic oligomers of, for example, polyalkylene glycols, polycarbonates, polyesters, polyethers, polyvinylalcohol, polyvinypyrrolidone, polyoxazoline, and the like.

[0322] In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises polysiloxane or copolymer thereof and poly(alkylene)oxy polymer or copolymers thereof. In examples, the soft segment of the hard-soft segmented polyurethane or polyurethane urea copolymer comprises poly(dialkyl)siloxane, poly(diphenyl)siloxane, poly(alkylphenyl)siloxane or copolymer and poly(alkyl)oxide, poly(ethylene) oxide, poly(propylene)oxide, poly(ethylene-propylene) oxide, poly(tetraalkylene)oxide, poly(tetramethylene)oxide polymer or copolymers or blends thereof.

[0323] In examples, the bioactive releasing membrane 470 has a hard segment weight percent content of between about 20-60%, 30-50%, or 35-45% so as to achieve a 70A-55D durometer. In other examples, the bioactive releasing membrane 470 has a hard segment weight percent content of between about 20-60%, 30-50%, or 35-45% so as to achieve a target modulus. In examples, the durometer and / or modulus of the bioactive releasing membrane 470 is provided in a single copolymer or blends of copolymers.

[0324] In examples, the bioactive releasing membrane 470 comprises a soft segment-hard segment copolymer comprising less than 70 weight percent of soft segment, not including zero weight percent. In examples, the releasing membrane comprises a soft segment-hard segment copolymer comprising a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising less than 70 weight percent of soft segment, not including zero weight percent.

[0325] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer comprising a hydrophilic segment weight percent that is greater than the hydrophobic segment weight percent thereof. In examples, the releasing membraneAttorney Docket No.: 0934-PCT01_0239comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment weight percent of a soft segment-hard segment that is greater than the hydrophobic segment weight percent thereof.

[0326] In examples, the hydrophilic segment weight percent of the soft segment-hard segment copolymer is less than the hydrophobic segment weight percent thereof. In examples, the hydrophilic segment weight percent of the soft segment-hard segment polyurethane or polyurethane urea copolymer is less than the hydrophobic segment weight percent thereof.

[0327] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer that is blends of different soft segment-hard segment copolymers. In examples, the bioactive releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer that is blends of different soft segment-hard segment copolymers.

[0328] In examples, the bioactive releasing membrane comprises a blend of different soft segment-hard segment copolymers that is a first soft segment-hard segment copolymer comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent, blended with another second soft segment-hard segment copolymer comprising a hydrophilic segment weight percent greater than a hydrophobic segment weight percent. In examples, the bioactive releasing membrane comprises a blend of different soft segment-hard segment polyurethane or polyurethane urea copolymers that comprise a first soft segment-hard segment copolymer comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent, blended with another soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment weight percent greater than a hydrophobic segment weight percent.

[0329] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent, blended with another soft segment-hard segment copolymer comprising a hydrophilic segment weight percent less than a hydrophobic segment weight percent. In examples, the bioactive releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment, not including zero weight percent, and aAttorney Docket No.: 0934-PCT01_0239hydrophobic segment, including zero weight percent, blended with another soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment weight percent less than a hydrophobic segment weight percent.

[0330] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer and a soft segment-hard segment copolymer, each comprising less than 70 weight percent of soft segment, not including zero weight percent, and each comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent. In examples, the bioactive releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer and another, different, soft segment-hard segment polyurethane or polyurethane urea copolymer, each comprising less than 70 weight percent of soft segment, not including zero weight percent, and each comprising a hydrophilic segment, not including zero weight percent, and a hydrophobic segment, including zero weight percent.

[0331] In examples, the bioactive releasing membrane comprises a soft segment-hard segment copolymer blended with a hydrophobic polymer and / or a hydrophilic polymer. In examples, the bioactive releasing membrane comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer blended with a hydrophobic polymer and / or a hydrophilic polymer.

[0332] In examples, the bioactive releasing membrane 470 is substantially impervious to analyte transport there through. In other examples, the bioactive releasing membrane 470 is less permeable to the analyte than an interference layer of the sensing membrane 400. In such examples, the bioactive releasing membrane 470 is deposited on portions of the sensor adjacent to but not covering the electroactive portion of the sensor.

[0333] In examples, the bioactive releasing membrane 470 is loaded with bioactive agent prior to depositing on the sensor 99 and / or sensing membrane 400. In examples, the bioactive agent is dissolved in one or more solvents that are miscible with the bioactive releasing membrane 470. Mild heating can be used to facilitate dissolution, distribution, or dispersing of the bioactive agent in the bioactive releasing membrane 470. Suitable solvents include THF, alcohols, ketones, ethers, acetates, NMP, methylene chloride, heptane, hexane, and combinations thereof.

[0334] In examples, the bioactive releasing membrane 470 is deposited onto at least a portion of the sensing membrane 400. In other examples, the bioactive releasing membraneAttorney Docket No.: 0934-PCT01_0239470 is deposited adjacent to but not directly on sensing membrane 400. In examples, the bioactive releasing membrane is deposited so as to provide a membrane thickness of from about 0.05 micron or more to about 50 microns or less. In other examples, the bioactive releasing membrane is deposited so as to provide a membrane thickness of from about 0.5 to 50 microns, 1 to 50 microns, 2 to 50 microns, 3 to 50 microns, 4 to 50 microns, 5 to 50 microns, 6 to 50 microns, 7 to 50 microns, 8 to 50 microns, 9 to 50 microns, 10 to 50 microns, 10 to 40 microns, 10 to 30 microns, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 microns.

[0335] In examples, the bioactive releasing membrane 470 is deposited onto the enzyme domain by spray coating, brush coating, pad printing, meniscus coating, microfluidic coating, or dip coating. In examples, the bioactive releasing membrane 470 is deposited on the sensing membrane 400 by meniscus-, microfluidic-, or spray-coating a solution of from about 1 wt. % to about 50 wt. % polymer and from about 50 wt. % to about 99 wt. % solvent. In spraying a solution of bioactive releasing membrane 470, including a solvent, onto the sensing domain, it is desirable to mitigate or substantially reduce any contact with enzyme of any solvent in the spray solution that can deactivate the underlying enzyme of the enzyme domain. Tetrahydrofuran (THF) is one solvent, alone or in combination with one or more alcohols, that minimally or negligibly affects the enzyme of the enzyme domain upon spraying. Other solvents can also be suitable for use, as is appreciated by one skilled in the art.

[0336] The at least one polymer layer of the bioactive releasing membrane 470 can include any suitable polymeric materials discussed previously herein. In examples, the at least one polymer layer of the bioactive releasing membrane 470 comprises one or more epoxides, polyolefins, polysiloxanes, polyamide, polystyrene, polyacrylate, polyethers, polyvinyl pyridines, polyvinyl pyridine-co-polystyrene, polyvinylimidazoles, polyesters, polycarbonates, polyurethane, polyurethaneurea, and copolymers thereof. In other examples, the at least one polymer layer of the bioactive releasing membrane 470 comprises one or more zwitterionic repeating units associated with the at least one bioactive agent, the at least one bioactive agent configured to be released from the one or more zwitterionic repeating units to modify tissue response of a subject.

[0337] The at least one bioactive agent includes any suitable bioactive agent discussed previously herein. In examples, the at least one bioactive agent comprises an antiAttorney Docket No.: 0934-PCT01_0239inflammatory compound or a tissue response modifier. In examples, the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier in combination with a vasodilator. For instance, In examples, the at least one bioactive agent comprises at least one of pilocarpine, dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or any combination thereof with at least one of minoxidil, hydralazine, and nitroglycerin.Sensor Electronics

[0338] The sensor electronics includes hardware, firmware, and / or software that enable measurement of levels of the analyte via the sensor. For example, the sensor electronics can comprise a potentiostat, a power source for providing power to the sensor, other components useful for signal processing, and preferably an RF module for transmitting data from the sensor electronics to a receiver. Electronics can be affixed to a printed circuit board (PCB), or the like, and can take a variety of forms. For example, the electronics can take the form of an integrated circuit (IC), such as an Application-Specific Integrated Circuit (ASIC), a microcontroller, ora processor. Preferably, sensor electronics comprise systems and methods for processing sensor analyte data. Examples of systems and methods for processing sensor analyte data are described in more detail below and in U.S. Patent No. 7,778,680, filed Aug. 1, 2003, and entitled, "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA."

[0339] In this example, after insertion of the sensor using the applicator, and subsequent release of the applicator from the mounting unit, the sensor electronics are configured to releasably mate with the mounting unit. In examples, the electronics are configured with programming, for example initialization, calibration reset, failure testing, or the like, each time it is initially inserted into the mounting unit and / or each time it initially communicates with the sensor.

[0340] In some embodiments, sensitivity loss may be indicative of end of life. Sensitivity loss may occur towards the sensor end of life due to physiological wound healing and foreign body mechanisms around the sensor or other mechanisms including reference electrode capacity, enzyme depletion, membrane changes, or the like.

[0341] In some embodiments, sensor sensitivity may be computed in using an analysis of uncalibrated sensor data (e.g., raw or filtered). In examples, a slow moving average or median of raw count starts showing negative trends, the sensor may be losing sensitivity.Attorney Docket No.: 0934-PCT01_0239Loss of sensitivity may be computed by calculating a short term (e.g. ~6-8 hours) average (or median) of the sensor output and normalizing it by the expected longer term (48 hours) average sensor sensitivity. If the ratio of short term to long term sensitivity is smaller than 70%, there may be a risk of sensor losing sensitivity. Loss of sensitivity may be translated into an end of life risk factor value, for example a value of about 1 until the ratio is about 70%, reducing to 0.5 at 50% and <0.1 at 25%.

[0342] In some embodiments, sensor sensitivity may be computed by comparing sensor data (e.g., calibrated sensor data) with reference blood glucose (BG). For example, calibration algorithms adjust the glucose estimates based on the systematic bias between sensor and a reference BG. End of life algorithms may use this bias, called error at calibration or downward drift, to quantify or qualify end of life symptoms. The error at calibration may be normalized to account for irregular calibration times and smoothed to give more weight to recent data (e.g., moving average or exponential smoothing). In some embodiments, end of life risk factor value is determined based on the resulting smoothed error at calibration. In such embodiments, end of life risk factor value is 1 for all values of error at calibration>-0.3, and reduces to 0.5 at error at calibration=-0.4, and to <0.1 for error at calibration=-0.6. In some examples, one more of a downward drift in sensor sensitivity over time, an amount of non-symmetrical, nonstationary noise, and a duration of noise can be employed, for example, as disclosed in co-assigned U.S. Patent Publication No.2021 / 0209497, which is incorporated herein by reference.

[0343] In some embodiments, sensor sensitivity may be computed in using an analysis of uncalibrated sensor data (e.g., raw or filtered). In examples, a slow moving average or median of raw count starts showing negative trends, the sensor may be losing sensitivity. Loss of sensitivity may be computed by calculating a short term (e.g. ~6-8 hours) average (or median) of the sensor output and normalizing it by the expected longer term (48 hours) average sensor sensitivity. If the ratio of short term to long term sensitivity is smaller than 70%, there may be a risk of sensor losing sensitivity. Loss of sensitivity may be translated into an end of life risk factor value, for example a value of about 1 until the ratio is about 70%, reducing to 0.5 at 50% and <0.1 at 25%.Preferred FeaturesAttorney Docket No.: 0934-PCT01_0239

[0344] The present invention is defined by the attached independent claims. Preferred features are defined in the dependent claims. A non-exhaustive list of preferred features are:

[0345] Device type: It is preferred that the device of the present invention is a continuous glucose monitor, whose sensor is configured to be in contact with interstitial fluid. The device is preferably to be used transcutaneously. Preferably, the sensor is placed transcutaneously during use, and the sensor is connected to at least one other part of the device which is places on the skin of the host during use.

[0346] Detection method: it is preferred that the device of the present invention measures analyte concentration by use of electrochemical detection of a species whose concentration is proportional to the concentration of the analyte. The device preferably makes use of enzymes.

[0347] Host: In examples, the host is a human. In other examples, the host is an animal. In a preferred example, the host is human.

[0348] Analyte: The preferred analyte is glucose. In practice, monitoring glucose is important - e.g. in human with diabetes.

[0349] Anti-inflammatory: The preferred anti-inflammatory is dexamethasone acetate. Inclusion of dexamethasone acetate is believed to result in sensors which have a longer sensor lifetime and / or improved accuracy towards the end of the sensor lifetime. This applies also to other anti-inflammatory agents.

[0350] Vasodilator: The preferred vasodilator is minoxidil. Minoxidil inclusion is believed to improve accuracy, particularly at the start of the sensor lifetime. It is also believed to be helpful in reducing lag time, which may in turn contribute to accuracy improvements. It is also believed that using a vasodilator such as minoxidil may reduce warm-up time. These advantages are also expected when using other vasodilators.

[0351] Combination of bioactive agents: It is preferred to use a vasodilator together with an anti-inflammatory. It is believed that this will result in a suitable blend of advantageous properties, including one or more of (i) extended sensor lifetime; (ii) improved or at least maintained accuracy over the entire sensor lifetime; (iii) improved or at least maintained accuracy at the start of the sensor lifetime; and / or (iv) decreased warm-up time.Attorney Docket No.: 0934-PCT01_0239

[0352] Calibration: The device of the present invention is preferably factory-calibrated. This means that the device can be used without prior user calibration, particularly without the need for finger-pricking by the host. It is preferred that no user calibration is necessary for the duration of the sensor lifetime.

[0353] Manufacturing methods: It is preferred that at least one bioactive agent, e.g. the vasodilator, is applies to a sensor at the same time as carrying out factory calibration. This is a particularly efficient way to make a factory calibrated sensor, and it avoids the risk of washing off the bioactive agent (e.g. the vasodilator and / or the anti-inflammatory agent) during factory calibration.

[0354] Cumulation of preferred features: The above preferred features can use used individually together with e.g. features of any independent claim. The above features are mutually compatible, and so they can also be used in various combinations of two or more of the above preferences together. All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

[0355] The term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0356] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0357] The above description discloses several methods and materials of the present disclosure. This disclosure is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications willAttorney Docket No.: 0934-PCT01_0239become apparent to those skilled in the art from a consideration of this disclosure or practice of the disclosure disclosed herein. Consequently, it is not intended that this disclosure be limited to the specific examples disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the disclosure.

[0358] While certain examples of the present disclosure have been illustrated with reference to specific combinations of elements, various other combinations may also be provided without departing from the teachings of the present disclosure. Thus, the present disclosure should not be construed as being limited to the particular exemplary examples described herein and illustrated in the Figures, but may also encompass combinations of elements of the various illustrated examples and aspects thereof.

Claims

1. Attorney Docket No.: 0934-PCT01_0239WE Claim:

1. A device for measurement of a concentration of an analyte, the device comprising:an analyte sensor configured for subcutaneous insertion;said sensor comprising (i) a sensing portion configured to generate a signal associated with a concentration of an analyte and (ii) a vasodilator-releasing portion comprising a vasodilator, said vasodilator-releasing portion being configured to release said at least one vasodilator upon subcutaneous insertion of the sensor.

2. The device of claim 1, wherein the vasodilator is a nitric oxide (NO) releasing molecule, polymer, or oligomer; minoxidil; hydralazine; nitroglycerin, or combinations thereof.

3. The device of claim 2, wherein the vasodilator is a nitric oxide (NO) releasing molecule selected from N-diazeniumdiolates and S-nitrosothiols, and N-diazeniumdiolates.

4. The device of claim 1, wherein the vasodilator is phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L- arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, or combinations thereof.

5. The device of any preceding claim, wherein the analyte sensor comprises a coating comprising a biocompatible hydrophilic polymer.

6. The device of any preceding claim, wherein the analyte sensor comprises a coating comprising a polymer chain having one or more zwitterionic compounds.

7. The device of any preceding claim, wherein the analyte sensor comprises a coating comprising a hydrolytically degradable biopolymer.

8. The device of any preceding claim, wherein the analyte sensor comprises a coating comprising a polymer chain having hydrophilic regions.Attorney Docket No.: 0934-PCT01_02399. The device of any preceding claim, wherein the analyte sensor comprises a coating comprising a hydrophilic hydrogel, wherein the hydrophilic hydrogel is at least partly crosslinked and dissolvable in biological fluid.

10. The device of any preceding claim, wherein the analyte is glucose, ketone, lactate, potassium, or combinations thereof.

11. The device of any preceding claim, wherein the analyte sensor further comprises a coating comprising a polymer chain having polyurethane and / or polyurea segments.

12. The device of any preceding claim, wherein the analyte sensor further comprises a coating comprising a polymer chain having both hydrophilic and hydrophobic regions.

13. The device of any preceding claim, wherein the analyte sensor further comprises a coating comprising a polymer with a styrene group.

14. The device of any preceding claim, wherein the analyte sensor further comprises a coating comprising a polymer with a heterocyclic group.

15. The device of any preceding claim, wherein the analyte sensor further comprises a coating comprising a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly (2-vi nyl pyridine), acrylonitrile, acrylamide, and / or copolymers or quaternized forms thereof.

16. The device of any preceding claim, wherein the sensor further comprises(i) a tissue response modifier releasing portion which comprises a tissue response modifier, and is configured to release said tissue response modifier from the device upon subcutaneous insertion; or(ii) an anti-inflammatory agent releasing portion, which comprises an antiinflammatory agent, and is configured to release said anti-inflammatory agent from the device upon subcutaneous insertion of the sensor.

17. The device of claim 16, wherein the anti-inflammatory agent comprises pilocarpine, dexamethasone, a derivative form of dexamethasone, dexamethasone acetate, or aAttorney Docket No.: 0934-PCT01_0239combination of a derivative form of dexamethasone or dexamethasone acetate with dexamethasone.

18. The device of any of claims 16 and 17, wherein the anti-inflammatory agent or the tissue response modifier is coupled to a coating of the analyte sensor with a hydrolytically degradable linkergroup.

19. The device of any preceding claim, wherein the sensor further comprises at least one wound extrudate absorbing coating configured to absorb wound extrudate upon subcutaneous insertion.

20. The device of any preceding claim, which is a continuous glucose monitoring device.

21. The device of any preceding claim, wherein the sensing portion is configured to generate a signal associated with a concentration of an analyte in interstitial fluid.

22. The device of any preceding claim, wherein the sensor comprises a wire substrate or a planar substrate, wherein the sensing portion and the vasodilator-releasing portion are spatially separated along a longitudinal axis of said wire substrate or a planar substrate.

23. The device of any of claims 1-21, wherein the sensor comprises more than one wire substrates and / or planar substrates, wherein the sensing portion and the vasodilatorreleasing portion are present on separate wire substrates and / or planar substrates.

24. The device of any preceding claim, wherein the sensing portion is present on a planar substrate.

25. The device of any of claims 1-23, wherein the sensing portion is present on a wire substrate.

26. The device of any preceding claim, wherein the vasodilator-releasing portion is present on a planar substrate.

27. The device of any of claims 1-25, wherein the vasodilator-releasing portion is present on a wire substrate.Attorney Docket No.: 0934-PCT01_023928. The device of any preceding claim, wherein the vasodilator-releasing portion and the analyte sensing portion are spatially separated.

29. The device of any preceding claim, wherein the sensing portion comprises a working electrode, a reference, and / or a counter electrode configured to generate a signal associated with the analyte.

30. The device of claim 29, wherein the vasodilator-releasing portion comprises at least one vasodilator-releasing electrode.

31. The device of claim 30, wherein the vasodilator-releasing electrode is distal from the working electrode or reference electrode.

32. The device of any one of claims 30-31, wherein the working electrode and the vasodilator-releasing electrode share the counter electrode or the reference electrode.

33. The device of any of claims 30-32, wherein the vasodilator-releasing electrode is positioned most distal relative to any other working electrode.

34. The device of any one of claims 30-33, wherein the sensor further comprises an electrically conductive membrane in proximity to the vasodilator-releasing electrode, the electrically conductive membrane comprising a tissue response modifier which is releasable from said electrically conductive membrane.

35. The device of claim 34, wherein the electrically conductive membrane comprises at least one electrically conductive polymer.

36. The device of claim 35, wherein the at least one electrically conductive polymer is doped.

37. The device of any preceding claim, wherein the signal is measure potentiometrically, coulometrically, or amperometrically.

38. The device of any preceding claim, wherein the sensing portion comprises a first working electrode configured to generate a signal associated with a first analyte.Attorney Docket No.: 0934-PCT01_023939. The device of claim 38, wherein the sensing portion further comprises a second working electrode configured to generate a signal associated with a second analyte, the second analyte being chemically different from the first analyte.

40. Use of a vasodilator to reduce time lag between (i) a change in concentration of an analyte in blood in response to a concentration of an analyte-changing event and (ii) a change in concentration of the same analyte in interstitial fluid in response to the same analyte concentration-changing event.

41. The use according to claim 40, wherein the vasodilator is provided on the vasodilator-releasing portion of a sensor comprised as part of the device as defined in any of claims 1-39.

42. Use of a vasodilator to improve accuracy of a continuous glucose monitoring device, wherein the continuous glucose monitoring device comprises a subcutaneous sensor which comprises the vasodilator and optionally at least one of an anti-inflammatory agent and / or a tissue response modifier, said improvement in accuracy being relative to a corresponding sensor without the vasodilator.

43. The use according to claim 42, wherein accuracy is the degree of correspondence between (i) the glucose concentration measured in vivo within interstitial fluid by the continuous glucose monitoring device at at least one timepoint in between 0.5-24 hours after insertion of the sensor into the body and (ii) the glucose concentration measured by ex vivo blood within blood by a blood gas analyzer or blood analysis device.

44. The use according to claim 42 or claim 43, wherein the vasodilator is provided on the vasodilator-releasing portion of a sensor comprised as part of the device as defined in any of claims 1-39.

45. A method of assisting equilibrium of an analyte within interstitial fluid and / or venous blood volume in proximity to an implanted analyte sensor, the method comprising:subcutaneously introducing an analyte sensor to an implant site, the analyte sensor configured for providing a signal corresponding to a concentration of an analyte in proximity to the implant site;Attorney Docket No.: 0934-PCT01_0239releasing, in proximity to the implant site, an amount of at least one tissue response modifier, or an amount of anti-inflammatory agent that causes a delay in obtaining a signal corresponding to a concentration of an analyte;releasing an amount of at least one vasodilator in proximity to the implant site; andreducing or eliminating a difference between the concentration of the analyte in venous blood and in interstitial fluid (ISF) in proximity to the implant site.

46. A method of reducing or eliminating post-insertion delay or lag of a signal corresponding to a concentration of an analyte, the method comprising:providing an analyte sensor configured for subcutaneous introduction to an implant site and for providing a signal corresponding to the concentration of the analyte in proximity to the implant site;releasing an amount of at least one vasodilator in proximity to the implant site; optionally releasing, in proximity to the implant site, an amount of at least one tissue response modifier and / or anti-inflammatory agent that causes a delay in obtaining the signal corresponding to the concentration of the analyte; andreducing or eliminating post-insertion delay of the signal corresponding to the concentration of the analyte in proximity to the implant site.

47. The method of claim 46, wherein the reducing or eliminating post-insertion delay of the signal comprises reducing a difference between the concentration of the analyte in blood and in interstitial fluid (ISF) in proximity to the implant site.

48. The method of any one of claims 46-47, wherein the at least one vasodilator comprises a nitric oxide (NO) releasing molecule selected from N-diazeniumdiolates and S-nitrosothiols, or N-diazeniumdiolates.

49. The method of any one of claims 46-48, wherein the at least one vasodilator comprises phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L- arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20),Attorney Docket No.: 0934-PCT01_0239S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, or combinations thereof.

50. The method of any one claims 46-49, wherein the analyte sensor further comprises a tissue response modifier or anti-inflammatory agent releasing portion configured to release at least one tissue response modifier or anti-inflammatory agent from the device upon subcutaneous insertion.

51. The method of any one claims 46-50, wherein the anti-inflammatory agent comprises pilocarpine, dexamethasone, a derivative form of dexamethasone, dexamethasone acetate, or a combination thereof.

52. The method of any one of claims 46-51, wherein the analyte sensor comprises a coating comprising a biocompatible hydrophilic polymer.

53. The method of any one of claims 46-52, wherein the analyte sensor comprises a coating comprising a polymer chain having one or more zwitterionic compounds.

54. The method of any one of claims 46-53, wherein the analyte sensor comprises a coating comprising a hydrolytically degradable biopolymer.

55. The method of any one of claims 46-54, wherein the analyte sensor comprises a coating comprising a polymer chain having hydrophilic regions.

56. The method of any one of claims 46-55, wherein the analyte sensor comprises a coating comprising a hydrophilic hydrogel, wherein the hydrophilic hydrogel is at least partly crosslinked and dissolvable in biological fluid.

57. The method of any one of claims 46-56, wherein the analyte sensor further comprises a coating comprising a polymer chain having polyurethane and / or polyurea segments.

58. The method of any one of claims 46-57, wherein the analyte sensor further comprises a coating comprising a polymer chain having both hydrophilic and hydrophobic regions.Attorney Docket No.: 0934-PCT01_023959. The method of any one of claims 46-58, wherein the analyte sensor further comprises a coating comprising a polymer with a styrene group.

60. The method of any one of claims 46-59, wherein the analyte sensor further comprises a coating comprising a polymer with a heterocyclic group.

61. The method of any one of claims 46-60, wherein the analyte sensor further comprises a coating comprising a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly(2-vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers or quaternized forms thereof.

62. The method of any one of claims 46-61, wherein the anti-inflammatory agent or the tissue response modifier, or the second anti-inflammatory agent or the second tissue response modifier is coupled to a coating of the analyte sensor with a hydrolytically degradable linkergroup.

63. The method of any one of claims 46-62, wherein the analyte is glucose, ketone, lactate, potassium, or combination thereof.

64. A method of assisting equilibrium of an analyte within interstitial fluid and / or venous blood volume in proximity to an implanted analyte sensor, the method comprising:subcutaneously introducing an analyte sensor at an implant site, wherein the subcutaneously introducing causes an amount of exudate at the implant site;absorbing at least some of the exudate at the implant site;assisting equilibrium of an analyte within the interstitial fluid and / or the venous blood volume at the implant site, wherein the implanted analyte sensor comprises a biocompatible hydrophilic coating, the biocompatible hydrophilic coating configured to absorb exudates at the implant site; andabsorbing at least some of the exudates at the implant site.

65. The method of claim 64, wherein the analyte is glucose, ketone, lactate, potassium, or combinations thereof.

66. The method of any one of claims 64-65, wherein the biocompatible hydrophilic coating comprises a polymer chain having one or more zwitterionic compounds.Attorney Docket No.: 0934-PCT01_023967. The method of any one of claims 64-66, wherein the analyte sensor further comprises a tissue response modifier or anti-inflammatory agent releasing portion configured to release at least one tissue response modifier or anti-inflammatory agent upon subcutaneous introduction.

68. The method of any one of claims 64-67, wherein the anti-inflammatory agent comprises pilocarpine, dexamethasone, a derivative form of dexamethasone, dexamethasone acetate, or a combination thereof.

69. The method of any one of claims 64-68, wherein the at least one vasodilator comprises a nitric oxide (NO) releasing molecule selected from N-diazeniumdiolates and S-nitrosothiols, or N-diazeniumdiolates.

70. The method of any one of claims 64-69, wherein the at least one vasodilator comprises phenoxybenzamine HCL, nicardapine, phentolamine, nitroglycerine, nitroprusside, hydralazine, diphenylhydramine, epinephrine, aspirin, minoxidil, celecoxib, nifedipine, verapamil, L- arginine HCL, nisoldipine, menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), everolimus, MCC950, empagliflozin, or combinations thereof.

71. A device for measurement of a concentration of an analyte, the device comprising:an analyte sensing portion configured to generate a signal associated with the concentration of the analyte; anda bioactive agent releasing portion configured to release a bioactive agent;wherein the bioactive agent-releasing portion and the analyte sensing portion are spatially separated along a longitudinal axis of a wire substrate or a planar substrate; orwherein the bioactive agent-releasing portion and the analyte sensing portion are present on separate wire substrates or separate planar substrates.

72. The device of claim 71, wherein the analyte sensing portion is present on the planar substrate.Attorney Docket No.: 0934-PCT01_023973. The device of any one of claims 71-72, wherein the analyte sensing portion is present on the wire substrate.

74. The device of any one of claims 71-73, wherein the bioactive agent releasing portion is present on the planar substrate.

75. The device of any one of claims 71-74, wherein the bioactive agent releasing portion is present on the wire substrate.

76. The device of any one of claims 71-75, wherein the bioactive agent-releasing portion and the analyte sensing portion are spatially separated.

77. The device of any one of claims 71-76, wherein the analyte sensing portion comprises a working electrode, a reference, and / or a counter electrode configured to generate a signal associated with the analyte.

78. The device of any one of claims 71-77, wherein the bioactive agent-releasing portion comprises at least one bioactive agent-releasing electrode.

79. The device of any one of claims 71-78, wherein the bioactive agent-releasing electrode is distal from the working electrode or reference electrode.

80. The device of any one of claims 71-79, wherein the working electrode and the bioactive agent-releasing electrode share the counter electrode or the reference electrode.

81. The device of any one of claims 71-80, wherein the analyte sensing portion comprises a first WE configured to generate a signal associated with a first analyte.

82. The device of any one of claims 71-81, wherein the analyte sensing portion comprises a second working electrode configured to generate a signal associated with a second analyte, the second analyte being chemically different from the first analyte.

83. The device of any one of claims 71-82, wherein the bioactive agent-releasing electrode is positioned most distal relative to any other working electrode.

84. The device of any one of claims 71-83, further comprising an electrically conductive membrane in proximity to the bioactive agent-releasing electrode, the electricallyAttorney Docket No.: 0934-PCT01_0239conductive membrane comprising at least one bioactive agent, the at least one bioactive agent configured to be released from the electrically conductive membrane to modify a tissue response of a subject.

85. The device of any one of claims 71-84, wherein the electrically conductive membrane comprises at least one electrically conductive polymer.

86. The device of any one of claims 71-85, wherein the at least one electrically conductive polymer is doped.

87. The device of any one of claims 71-86, wherein the signal is measured potentiometrically, coulometrically, or amperometrically.

88. A method of making an analyte sensor as defined in any of claims 71-86, the method comprising:contacting (i) an implantable analyte sensor precursor and (ii) a first liquid composition comprising a vasodilator; and thenremoving the first liquid composition from the implantable analyte sensor precursor while allowing at least some of the vasodilator from said first liquid composition to remain on the sensor.

89. The method of claim 88, wherein the first liquid composition is a calibration composition which comprises the analyte at a first known concentration, wherein the method simultaneously makes the sensor and makes at least one calibration measurement by detecting the signal associated with said first known analyte concentration.

90. The method of claim 88, wherein the method further comprises contacting the sensor or the sensor precursor with a second liquid composition comprising the analyte at a second known concentration, the first and second concentrations being different, and detecting the signal associated with said second known analyte concentration.

91. The method of any one of claims 88-90, wherein the implantable analyte sensor precursor comprises a coating configured to absorb the effective amount of the vasodilator during the method.Attorney Docket No.: 0934-PCT01_023992. A method of increasing perfusion of blood about an implantable portion of a medical device, the method comprising:providing a medical device, the medical device comprising:a subcutaneous implantable portion configured for positioning between the epidermis and muscle tissue of a host; andat least one layer on the subcutaneous implantable portion comprising at least one vasodilator, wherein the subcutaneous implantable portion is configured for releasing the at least one vasodilator after implantation in a host thereby increasing perfusion of the blood about the subcutaneous implantable portion of the medical device.

93. The method of claim 92, wherein the method further comprises dilation of microvessels.

94. The method of claim 93, wherein the microvessels are capillaries.

95. The method of any one of claims 92-94, wherein the subcutaneous implantable portion is configured for positioning in one or more of a hypodermis, an adipose tissue, or a capillary bed.

96. The method of any one of claims 92-95, wherein the subcutaneous implantable portion is configured to exclude muscle tissue.

97. The method of any one of claims 92-96, wherein the subcutaneous implantable portion is configured to exclude an epidermis layer.

98. The method of any one of claims 92-97, wherein the releasing of the at least one vasodilator is to one or more of the hypodermis, the adipose tissue, or the capillary bed.

99. The method of any one of claims 92-98, wherein the releasing of the at least one vasodilator excludes an epidermis layer.

100. A method of operating an analyte sensor for detecting a concentration of an analyte, the analyte sensor comprising:Attorney Docket No.: 0934-PCT01_0239at least a first working electrode;an analyte sensing portion disposed on a surface of the first working electrode, the analyte sensing portion configured for introduction to a space between an epidermis and muscle tissue, the analyte sensing portion capable of at least facilitating detection of the analyte;a vasodilation layer adjacent the analyte sensing portion, the vasodilation layer comprising at least one vasodilation agent diffusible through the vasodilation layer, the at least one vasodilation agent dilating microvessels in the space;the method comprising:applying a potential to the first working electrode at or above an oxidation-reduction potential of the analyte sensing portion to generate a signal corresponding to the concentration in the space; andcorrelating the signal to a concentration of an analyte in the space.

101. The method of claim 100, further comprising reducing or eliminating post-insertion delay of the signal generated upon introduction in the space, wherein reducing or eliminating post-insertion delay of the signal comprises reducing a difference between the analyte concentration in blood and in the space.

102. The method of any one of claims 100-101, wherein the analyte sensing portion further comprises a drug releasing layer adjacent the analyte sensing portion comprising at least one anti-inflammatory agent or tissue response modifier; the at least one antiinflammatory agent or tissue response modifier diffusible through the drug releasing layer into the space, the method further comprising reducing or eliminating post-insertion delay of the signal generated upon introduction in the space from the at least one antiinflammatory agent or tissue response modifier.

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