CN117597066A

CN117597066A - Drug release film for analyte sensor

Info

Publication number: CN117597066A
Application number: CN202280022448.6A
Authority: CN
Inventors: M·N·阿伍拉; C·德林; 李致胜; X·刘; S·R·帕内尔; 王尚儿; 邹炯
Original assignee: Dexcom Inc
Current assignee: Dexcom Inc
Priority date: 2021-03-19
Filing date: 2022-03-17
Publication date: 2024-02-23

Abstract

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

Description

Drug release film for analyte sensor

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application Ser. No. 63/163,651 filed on day 19 of 3 months 2021 and U.S. provisional application Ser. No. 63/244,644 filed on day 9 months 2021, each of which is incorporated herein by reference in its entirety.

Technical Field

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

Background

One of the most deeply studied analyte sensing devices is an implantable glucose device for detecting glucose levels in a subject suffering from diabetes (host). Despite the increasing number of individuals diagnosed with diabetes and recent advances in the field of implantable glucose monitoring devices, currently used devices are unable to safely and reliably provide data over a specific period of time due to local tissue reactions. For example, there are two common types of subcutaneously implantable glucose sensing devices. These types include those of percutaneous implantation and those of total implantation.

Disclosure of Invention

In a first example, there is provided a continuous percutaneous sensor comprising: a sensing portion configured to interact with at least one analyte and transduce a detectable signal corresponding to the at least one analyte or a characteristic of the at least one analyte; a drug release membrane in proximity to the sensing portion, the drug release membrane configured to provide an interface with an in vivo environment, the drug release membrane storing a bioactive agent, wherein the bioactive agent is configured to be released from the drug release membrane to alter a tissue response of the recipient, wherein the bioactive agent comprises an anti-inflammatory compound or a tissue response modifier.

In one aspect, the sensing portion includes at least one transduction element configured to interact with at least one analyte present in a biological fluid of a subject and provide a detectable signal corresponding to the at least one analyte.

In one aspect, alone or in combination with any of the preceding aspects, the at least one transduction element comprises an enzyme, a protein, DNA, RNA, a conjugate, or a combination thereof. In one aspect, the detectable signal is optical, electrochemical, or electrical, alone or in combination with any of the preceding aspects.

In one aspect, alone or in combination with any of the preceding aspects, the sensing portion includes a longitudinal length defined by a proximal end and a corresponding distal end, a transduction element positioned between the proximal end and the distal end, a drug release film positioned adjacent to the transduction element.

In one aspect, alone or in combination with any of the preceding aspects, the at least one transduction element comprises at least one electrode comprising at least one electroactive moiety; a sensing membrane deposited on at least a portion of the at least one electroactive moiety, the sensing membrane comprising an enzyme configured to catalyze a reaction with at least one analyte present in a biological fluid of a subject.

In one aspect, alone or in combination with any of the preceding aspects, the drug release film is substantially impermeable to transport of the at least one analyte when an interface with an in vivo environment is provided. In one aspect, alone or in combination with any of the preceding aspects, the transduction element is devoid of a drug release film. In one aspect, alone or in combination with any of the preceding aspects, the drug release layer is present only at the distal end and adjacent to the transduction element.

In one aspect, alone or in combination with any of the preceding aspects, the drug release layer is present only at the distal end of the sensor portion. In one aspect, alone or in combination with any of the preceding aspects, the drug release film is disposed continuously, semi-continuously or non-continuously along the longitudinal axis of the sensing portion, provided that the drug release film does not cover the transduction element.

In one aspect, alone or in combination with any of the preceding aspects, the drug release film is configured to release the at least one bioactive agent in a multiple release profile comprising at least a first release. In one aspect, alone or in combination with any of the preceding aspects, the first release corresponds to release of a bolus therapeutic amount of the bioactive agent at a time associated with sensor insertion. In one aspect, alone or in combination with any of the preceding aspects, the drug release film is further configured to release the at least one bioactive agent continuously or semi-continuously at a time after sensor insertion with a second release corresponding to a therapeutic amount of the at least one bioactive agent. In one aspect, alone or in combination with any of the preceding aspects, wherein the drug release film is further configured to release the at least one bioactive agent continuously or semi-continuously at a time after the second release, with a third release corresponding to a non-therapeutic amount of the at least one bioactive agent, until sensor lifetime is terminated.

In one aspect, alone or in combination with any of the preceding aspects, the drug release film comprises a soft segment-hard segment copolymer. In one aspect, alone or in combination with any of the preceding aspects, the release film comprises a soft segment-hard segment copolymer or a blend of different soft segment-hard segment copolymers. In one aspect, alone or in combination with any of the preceding aspects, the release film comprises less than 70% but not 0% by weight soft segments. In one aspect, alone or in combination with any of the preceding aspects, the soft segment of the drug release film comprises a hydrophilic segment in an amount other than 0% by weight and a hydrophobic segment in an amount including 0% by weight.

In one aspect, alone or in combination with any of the preceding aspects, the weight percent of hydrophilic segments is greater than the weight percent of hydrophobic segments. In one aspect, alone or in combination with any of the preceding aspects, the weight percent of hydrophilic segments is less than the weight percent of hydrophobic segments. In one aspect, alone or in combination with any of the preceding aspects, the weight percent of hydrophilic segments is less than the weight percent of hydrophobic segments.

In one aspect, alone or in combination with any of the preceding aspects, the blend of different soft segment-hard segment copolymers of the drug release film is selected from the group consisting of: a blend of a first soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percent other than 0% and a hydrophobic segment in a weight percent including 0% and a second soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percent greater than the weight percent of the hydrophobic segment;

A blend of a third soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percent other than 0% and a hydrophobic segment in a weight percent including 0% and a fourth soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percent less than the weight percent of the hydrophobic segment;

a blend of a fifth soft segment-hard segment copolymer and a sixth soft segment-hard segment copolymer, each comprising less than 70% but not 0% by weight of soft segments and each comprising not 0% by weight of hydrophilic segments and 0% by weight including 0% by weight of hydrophobic segments;

any one or more of the first soft segment-hard segment copolymer, the second soft segment-hard segment copolymer, the third soft segment-hard segment copolymer, the fourth soft segment-hard segment copolymer, the fifth soft segment-hard segment copolymer, or the sixth soft segment-hard segment copolymer, with a hydrophobic polymer and/or a hydrophilic polymer; and combinations thereof.

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

In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent is present in the drug release film in an amount between about 5 μg and 1000 μg. In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent is present in the drug release film in an amount between about 5 μg and 500 μg. In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent is present in the drug release film in an amount between about 5 μg and 200 μg. In one aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent is present in the drug release film in an amount between about 5 μg and 100 μg.

In another aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent is a Nitric Oxide (NO) releasing molecule, polymer, or oligomer. In another aspect, alone or in combination with any of the preceding aspects, the Nitric Oxide (NO) releasing molecule is selected from the group consisting of N-diazeniumdiolate and S-nitrosothiol or N-diazeniumdiolate.

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

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

In another aspect, alone or in combination with any of the preceding aspects, the bioactive agent is a conjugate comprising at least one linker cleavable by subcutaneous stimulation. In another aspect, alone or in combination with any of the preceding aspects, the subcutaneous stimulus is a matrix metallopeptidase or protease challenge.

In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises a hydrophilic hydrogel, wherein the hydrophilic hydrogel is at least partially crosslinked and soluble in biological fluids. In another aspect, alone or in combination with any of the preceding aspects, the hydrophilic hydrogel comprises Hyaluronic Acid (HA) crosslinked by divinyl sulfone or polyethylene glycol divinyl sulfone.

In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises silver nanoparticles. In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises polymeric nanoparticles comprising the at least one bioactive agent, the polymeric nanoparticles being selected from the group consisting of PLGA, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphates, PEO-b-polypeptides.

In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises an organogel carrier and/or an inorganic gel carrier. In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises a combination of the at least one bioactive agent encapsulated in the drug release film and the at least one bioactive agent covalently coupled to the drug release film. In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises a spatially distal drug reservoir of the at least one bioactive agent.

In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises a hydrolytically degradable biopolymer comprising the at least one bioactive agent. In another aspect, alone or in combination with any of the preceding aspects, the hydrolytically degradable biopolymer comprises a poly (anhydride salicylate).

In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises a polyurethane segment and/or a polyurea segment, wherein the polyurethane segment and/or polyurea segment comprises from about 15 wt% to about 75 wt% of the total weight of the polymer. In another aspect, alone or in combination with any of the preceding aspects, the drug release film comprises at least one polymer segment, wherein the at least one segment is selected from the group consisting of epoxides, polyolefins, polysiloxanes, polyamides, polystyrenes, polyacrylates, polyethers, polypyridines, polyesters, polycarbonates, and copolymers thereof.

In another aspect, alone or in combination with any of the preceding aspects, the drug release film has a molecular weight of about 10kDa to about 500,000 kDa. In another aspect, alone or in combination with any of the preceding aspects, the drug release film has a polydispersity index of 1 to about 10 as measured by light scattering, gel Permeation Chromatography (GPC), size Exclusion Chromatography (SEC), matrix assisted laser desorption/ionization time of flight (MALDI-TOF), rheology, or viscosity. In another aspect, alone or in combination with any of the preceding aspects, the biological interface/drug release layer has a measured advancing dynamic contact angle of about 90 ° to about 160 °, as measured, for example, by a tensiometer.

In another example, there is provided a method of extending the end of life of a continuous transcutaneous sensor at least partially implanted in a subject, the method comprising: releasing a bioactive agent from a drug release film associated with at least a portion of a transdermal sensor at least partially implanted in a subject, improving the signal-to-noise ratio immediately after a time associated with insertion of the transdermal sensor compared to the signal-to-noise ratio of a transdermal sensor without an anti-inflammatory agent and a release film that would be available after the time associated with insertion; and/or decreasing the sensitivity decay at a time associated with the end of a predetermined lifetime of the transdermal sensor compared to the sensitivity decay at a time associated with the end of a predetermined lifetime of a transdermal sensor without the anti-inflammatory agent and the release film.

In another example, a method of delivering a bioactive agent from a continuous transdermal sensor configured for insertion into soft tissue of a subject is provided, the method comprising: releasing at least one bioactive agent from the drug release film at a first release rate over a first period of time; the at least one bioactive agent is released from the drug release film at a second release rate for a second period of time, the second rate being different from the first release rate and the second period of time being subsequent to the first period of time.

In one aspect, the method further comprises releasing the at least one bioactive agent from the drug release film at a third release rate for a third time period, the third release rate being different from the first release rate and the second release rate, and the third time period being subsequent to the second time period. In another aspect, alone or in combination with any of the preceding aspects, the first release rate provides a therapeutic bolus amount of the at least one bioactive agent, and wherein the therapeutic bolus amount is provided at a time associated with sensor insertion.

In another aspect, alone or in combination with any of the preceding aspects, the second release rate provides for continuous or semi-continuous release of a therapeutic amount of the at least one bioactive agent, and wherein the therapeutic amount is provided after sensor insertion. In another aspect, alone or in combination with any of the preceding aspects, the third release rate corresponds to continuous or semi-continuous release of a non-therapeutic amount of the at least one bioactive agent, and wherein the non-therapeutic amount is provided until the end of life of the transdermal sensor. In another aspect, alone or in combination with any of the preceding aspects, the method further comprises improving sensor signal-to-noise performance between the first time and the third time. In another aspect, alone or in combination with any of the preceding aspects, the method further comprises reducing sensitivity decay performance between the first time and the third time.

In another example, a method of delivering a bioactive agent from a percutaneous sensor configured for insertion into soft tissue of a subject is provided, the method comprising: releasing at least one bioactive agent from the drug release film at a first time point; releasing the at least one bioactive agent from the drug release film at a second point in time, the second point in time being different from the first point in time.

In one aspect, the method further comprises releasing the at least one bioactive agent from the drug release film at a third time point, the third time point being different from the first time point and the second time point. In another aspect, alone or in combination with any of the preceding aspects, the first point in time is associated with sensor insertion.

In another aspect, alone or in combination with any of the preceding aspects, the at least one bioactive agent of the therapeutic bolus quantity begins at the first time point. In another aspect, alone or in combination with any of the preceding aspects, the second point in time is after sensor insertion.

In another aspect, alone or in combination with any of the preceding aspects, continuous or semi-continuous release of the therapeutic amount of the at least one bioactive agent begins at the second time point. In another aspect, alone or in combination with any of the preceding aspects, the third time point is after the second time point and before the end of life of the transcutaneous sensor. In another aspect, alone or in combination with any of the preceding aspects, continuous or semi-continuous release of a non-therapeutic amount of the at least one bioactive agent begins at the third point in time.

Drawings

FIG. 1A is an expanded view of an illustrative example of a continuous analyte sensor.

FIG. 1B is an expanded view of an illustrative example of a continuous analyte sensor.

FIG. 2A is an expanded view of an exemplary sensor as disclosed and described herein.

Fig. 2B is a cross-sectional view through the sensor of fig. 2A along section line B-B.

Fig. 2C is a cross-sectional view through the sensor of fig. 2A along section line B-B, showing the drug release layer.

Fig. 2D is a cross-sectional view through the sensor of fig. 2A along line D-D of an exemplary drug release film deposition as disclosed and described herein.

Fig. 2E is a cross-sectional view through the sensor of fig. 2A along line D-D of another exemplary drug release film deposition as disclosed and described herein.

Fig. 2F is a perspective schematic diagram showing an in-vivo portion of an exemplary sensor as disclosed and described herein.

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

FIG. 2H is a cross-sectional plan view of a continuous analyte sensing device in one example.

Fig. 3A is a schematic side view of a transdermal analyte sensor in one example.

Fig. 3B is a schematic side view of a transdermal analyte sensor in an alternative example.

Fig. 3C is a schematic side view of a fully implantable analyte sensor in one example.

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

Fig. 3E is a schematic side view of a fully implantable analyte sensor in another alternative example.

Fig. 3F is a side view of one example of an implanted sensor inductively coupled to an electronic unit over a functionally useful distance on the skin of a recipient.

Fig. 3G is a side view of one example of an implanted sensor inductively coupled to an electronic unit in implanted recipient tissue at a functionally useful distance.

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

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

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

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

Fig. 6 is a graphical representation of in vitro and in vivo release of a bioactive agent from a drug release film over time as disclosed and described herein.

Fig. 7 is a graphical representation of multiple release rates of a bioactive agent from a drug release film over time as disclosed and described herein.

Fig. 8 is a graphical representation of normalized sensitivity versus time for drug release films as disclosed and described herein versus controls.

Fig. 9 is a graphical representation of the average absolute noise versus time for a drug release film as disclosed and described herein versus a control.

Detailed Description

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

Definition of the definition

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

The terms and phrases "analyte measurement device," "analyte sensing device," "biosensor," "sensor," "sensing region," "sensing portion," and "sensing mechanism" as used herein are broad terms and phrases and will be given their ordinary and customary meaning (and are not limited to special or customized meanings) to those of ordinary skill in the art and refer to, but are not limited to, the field of analyte monitoring devices that are responsible for the detection of or the transduction of signals associated with a particular analyte or combination of analytes. For example, those terms may refer to, but are not limited to, the area of the monitoring device responsible for detecting a particular analyte. In one example, the sensing region generally includes a non-conductive body; a working electrode (anode), a reference electrode (optional), and/or a counter electrode (cathode) that pass through and are fixed within the body, thereby forming an electrochemically reactive surface on the body and an electronic connection means at another location on the body; and a multi-domain membrane affixed to the body and covering the electrochemically reactive surface. In one example, such devices are capable of providing specific quantitative, semi-quantitative, qualitative, semi-qualitative analytical information using a biological recognition element in combination with a transduction (detection) element.

The term "about" as used herein is a broad term and will give one of ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a degree of variability of a permitted value or range, e.g., within 10%, within 5% or within 1% of the value or range limit, and includes the exact value or range. As used herein, the term "substantially" refers to a majority or majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the phrase "substantially free" may mean free of or having a minor amount such that the amount of material present does not affect the material properties of the composition comprising the material, such that the material comprises from about 0 wt% to about 5 wt%, or from about 0 wt% to about 1 wt%, or about 5 wt% or less, 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% of the composition.

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

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

As used herein, the term "bioactive agent" is a broad term and will give the person of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, any substance that has an effect on or elicits a response from living tissue.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Additional examples of drug release layers and membranes can be found in pending U.S. provisional application No. 63/318901 entitled "drug release membrane for analyte sensor (DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR)" filed on 3-11 of 2022, which provisional application is incorporated herein by reference in its entirety.

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

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

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

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

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

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

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

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

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

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

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

As used herein, the term "noise" is a broad term and is used in its ordinary sense, including but not limited to signals detected by the sensor or sensor electronics that are independent of the concentration of the analyte and may result in reduced sensor performance. One type of noise has been observed during several hours (e.g., about 2 hours to about 24 hours) after sensor insertion. After the first 24 hours, the noise may disappear or decrease, but in some recipients the noise may last for about three to four days. In some cases, predictive modeling, artificial intelligence, and/or algorithmic means may be used to reduce noise. In other cases, noise may be reduced by addressing immune response factors associated with the presence of an implanted sensor, for example, by using a drug release layer having at least one bioactive agent. For example, the noise of one or more exemplary biosensors as disclosed herein may be determined and then compared qualitatively or quantitatively. For example, by obtaining an original signal time series with a fixed sampling interval (in picoamperes (pA)), a smoothed version of the original signal time series may be obtained, for example, by applying a 3 rd order chebyshev type II low pass digital filter. Other smoothing algorithms may be used. At each sampling interval, the absolute difference in pA can be calculated to provide a smooth time series. The smoothed time series may be converted to units of mg/dL ("units of noise") using glucose sensitivity time series in units of pA/mg/dL, where the glucose sensitivity time series is derived using a mathematical model between the raw signal and a reference blood glucose measurement (e.g., obtained from a blood glucose meter). Optionally, the time series may be aggregated as desired, for example, on an hourly or daily basis. Comparison of corresponding time series between different exemplary biosensors having the disclosed drug release layer and one or more bioactive agents provides a qualitative or quantitative determination of noise improvement.

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

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

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

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

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

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

As used herein, the term "semi-continuous" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a portion, coating, domain, or layer that includes one or more continuous and discontinuous portions, coatings, domains, or layers. For example, the coating disposed around the sensing region, but not with respect to the sensing region, is "semi-continuous".

As used herein, the phrase "sensing membrane" is a broad phrase and will give one of ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, a permeable or semi-permeable membrane that may include one or more domains, one or more layers within one or more domains, and be composed of a material having a thickness of a few microns or more, and that is permeable to reactants and/or co-reactants for determining an analyte of interest. For example, the sensing membrane may comprise an immobilized glucose oxidase that catalyzes an electrochemical reaction with glucose and oxygen to allow measurement of glucose concentration.

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

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

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

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

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

The phrases and terms "small diameter sensor," "small structure sensor," and "microsensor" as used herein are broad phrases and terms and will give one of ordinary and customary meaning (and are not limited to special or customized meanings) to such and refer to, but are not limited to, a sensing mechanism that is less than about 2mm in at least one dimension. In further examples, the sensing mechanism is less than about 1mm in at least one dimension. In some examples, the sensing mechanism (sensor) is less than about 0.95mm, 0.9mm, 0.85mm, 0.8mm, 0.75mm, 0.7mm, 0.65mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm, or 0.1mm. In some examples, the largest dimension of the independently measured length, width, diameter, thickness, or circumference of the sensing mechanism is no more than about 2mm. In some examples, the sensing mechanism is a needle sensor with a diameter of less than about 1mm, see, for example, U.S. Pat. No. 6,613,379 to Ward et al and U.S. Pat. No. 7,497,827 to Brister et al, both of which are incorporated herein by reference in their entirety. In some alternative examples, the sensing mechanism includes electrodes deposited on a substantially planar substrate, wherein the thickness of the implantable portion is less than about 1mm, see, for example, U.S. Pat. No. 6,175,752 to Say et al and U.S. Pat. No. 5,779,665 to Mastrootaro et al, both of which are incorporated herein by reference in their entirety. Examples of methods of forming sensors (sensor electrode layout and membranes) and sensor systems discussed herein can be found in currently pending U.S. patent application Ser. No. 16/452,364 (Block et al), which is incorporated herein by reference in its entirety.

As used herein, the term "sensitivity" is a broad term and will give one of ordinary and customary meaning to those skilled in the art (and is not limited to a particular or customized meaning) and refers to, but is not limited to, the amount of signal (e.g., in the form of current and/or voltage) generated by a predetermined amount (unit) of a measured analyte. For example, in one example, the sensor has a sensitivity (or slope) of about 1 picoamp to about 100 picoamps of current per 1mg/dL glucose analyte.

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

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

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

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

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

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

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

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

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

Referring now to the extended function of the sensor, these devices typically lose their function after several days to two or more weeks of implantation. In some applications, cell attack or migration of cells to the sensor may cause a decrease in the sensitivity and/or function of the device, particularly after the first day of implantation. See also, e.g., U.S. Pat. No. 5,791,344 and Gross et al and "Performance Evaluation of the MiniMed Continuous Monitoring System During Host home Use," Diabetes Technology and Therapeutics, (2000) 2 (1): 49-56, which reports that glucose oxidase-based devices approved by the food and drug administration (Food and Drug Administration) for use in humans perform well a few days after implantation, but rapidly lose function after a few days (e.g., a few days up to about 14 days).

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

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

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

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

Sensing mechanism

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

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

In some illustrative examples, each electrode is formed from a thin wire, e.g., having a diameter of about 0.001 inch or less to about 0.010 inch or more, and is formed from, e.g., a plated insulator, a plated wire, or a bulk conductive material. While the illustrated electrode configuration and associated text describe one preferred method of forming a transdermal sensor, a variety of known transdermal sensor configurations may be used with the transdermal analyte sensor systems of the present disclosure, such as described in U.S. Pat. No. 6,695,860 to Ward et al, U.S. Pat. No. 6,565,509 to Say et al, U.S. Pat. No. 6,248,067 to Causey III et al, and U.S. Pat. No. 6,514,718 to Heller et al.

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

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

Working electrode 38 is covered with an insulating material, such as a non-conductive polymer. Dip coating, spray coating, vapor deposition, or other coating or deposition techniques may be used to deposit the insulating material on the working electrode. In one example, the insulating material comprises parylene, which may be an advantageous polymer coating due to its strength, lubricity, and electrical insulation properties. Generally, parylene is produced by vapor deposition and polymerization of p-xylene (or substituted derivatives thereof). However, any suitable insulating material may be used, such as fluorinated polymers, polyethylene terephthalate, polyurethane, polyimide, other non-conductive polymers, and the like. Glass or ceramic materials may also be used. Other materials suitable for use include surface energy modified coating systems such as those sold under the trade names AMC18, AMC148, AMC141 and AMC321 by Advanced Materials Components Express (Bellafonte, pa.). However, in some alternative examples, the working electrode may not require an insulator coating.

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

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

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

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

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

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

In some alternative examples, additional electrodes may be included within the assembly, such as a three-electrode system (working, reference, and counter electrodes) and/or additional working electrodes (e.g., electrodes that may be used to generate oxygen, configured as baseline-subtracted electrodes, or configured to measure additional analytes). Co-pending U.S. patent application serial No. 11/007,635 entitled "system and method for improving electrochemical analyte sensors (SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS)" filed on month 12 and 7 of 2004 and U.S. patent application serial No. 11/004,561 entitled "calibration technique for continuous analyte sensors (CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR)" filed on month 12 describe some systems and methods for implementing and using additional working, counter and/or reference electrodes. In one embodiment, where the sensor includes two working electrodes, the two working electrodes are disposed side-by-side (e.g., extending parallel to each other) and the reference electrode is disposed (e.g., spiral wound) around them. In some examples in which two or more working electrodes are provided, the working electrodes may be formed in a double helix, triple helix, quad helix, etc. configuration along the length of the sensor (e.g., around a reference electrode, an insulating rod, or other support structure). The resulting electrode system may be configured with a suitable membrane system, wherein the first working electrode is configured to measure a first signal comprising glucose and a baseline, and the additional working electrode is configured to measure a baseline signal consisting only of the baseline (e.g., configured substantially similar to the first working electrode with no enzyme disposed thereon). In this way, the baseline signal may be subtracted from the first signal to produce a glucose-only signal that is substantially unaffected by baseline fluctuations and/or interfering substances on the signal. Thus, the above dimensions may be changed as desired. While the present disclosure discloses one electrode configuration including one bulk metal wire and another bulk metal wire helically wound therearound, other electrode configurations are also contemplated. In an alternative example, the working electrode comprises a tube with a reference electrode disposed or coiled therein, with an insulator therebetween. Alternatively, the reference electrode comprises a tube with a working electrode disposed or coiled inside, with an insulator between the two. In another alternative example, a polymer (e.g., insulating) rod is provided with an electrode deposited (e.g., electroplated) thereon. In yet another alternative example, a metal (e.g., steel) rod coated with an insulating material is provided, and the working electrode and the reference electrode are deposited onto the metal rod. In yet another alternative example, one or more working electrodes are helically wound around the reference electrode.

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

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

Sensing film

In one example, sensing film 32 is disposed on an electroactive surface of continuous analyte sensor 34 and includes one or more domains or layers. Generally, the function of the sensing membrane is to control the flow of biological fluid therethrough and/or to protect sensitive areas of the sensor from contamination by, for example, biological fluid. Some conventional electrochemical enzyme-based analyte sensors typically include a sensing membrane that controls the flow of the analyte being measured, protects the electrodes from contamination by biological fluids, and/or provides enzymes that catalyze the reaction of the analyte with cofactors, for example. See, for example, co-pending U.S. patent application Ser. No. 10/838,912 entitled "implantable analyte sensor (IMPLANTABLE ANALYTE SENSOR)" filed 5/3/2004 and U.S. patent application Ser. No. 11/077,715 entitled "transdermal analyte sensor (TRANSCUTANEOUS ANALYTE SENSOR)" filed 3/10/2005, which are incorporated herein by reference in their entirety.

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

Electrode domain

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

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

In certain examples, the electrode domains are formed from a curable mixture of a urethane polymer and a hydrophilic polymer. Particularly preferred coatings are formed from polyurethane polymers having carboxylate functionality and nonionic hydrophilic polyether segments, wherein the polyurethane polymer is crosslinked with a water-soluble carbodiimide (e.g., 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC)) in the presence of polyvinylpyrrolidone and cured at a suitable temperature of about 50 ℃.

Preferably, the electrode domains are deposited by spraying or dip coating the electroactive surface of the sensor. More preferably, the electrode domain is formed by: dip-coating the electroactive surface in the electrode solution and curing the domains at a temperature of about 40 ℃ to about 55 ℃ for a time of about 15 minutes to about 30 minutes (and may be accomplished under vacuum (e.g., 20mmHg to 30 mmHg)). In examples where dip coating is used to deposit the electrode domains, the functional coating is provided with a preferred insertion rate of about 1 inch/min to about 3 inches/min, a preferred residence time of about 0.5 minutes to about 2 minutes, and a preferred withdrawal rate of about 0.25 inches/min to about 2 inches/min. However, as will be appreciated by those skilled in the art, in some examples, values other than those listed above may be acceptable or even desirable, for example, depending on viscosity and surface tension. In one example, the electroactive surface of the electrode system is dip coated once (one layer) and then cured in vacuum at 50 ℃ for 20 minutes.

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

Interference domain

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

Several polymer types that can be used as a base material for the interfering domains include, for example, polyurethanes, polymers with ionic side groups, and polymers with controlled pore sizes. In one example, the interfering domain includes a hydrophobic membrane that is non-swellable and limits low molecular weight species diffusion. The interfering domain is permeable to relatively low molecular weight substances, such as hydrogen peroxide, but restricts the passage of higher molecular weight substances including glucose and ascorbic acid. Other systems and methods for reducing or eliminating interfering substances that may be applied to the membrane systems of the present disclosure are described in co-pending U.S. patent application Ser. No. 10/896,312, filed on 7/21/2004, entitled "electrode System for electrochemical SENSOR (ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS)", U.S. patent application Ser. No. 10/991,353, filed on 11/2004, entitled "affinity domain for analyte SENSOR (AFFINITY DOMAIN FOR AN ANALYTE SENSOR)", U.S. patent application Ser. No. 11/007,635, filed on 12/2004, entitled "System and method for improving electrochemical analyte SENSOR (SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS)", and U.S. patent application Ser. No. 11/004,561, filed on 12/2004, entitled "calibration technique for continuous analyte SENSOR (CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR)". In some alternative examples, no distinct interference domains are included.

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

Enzyme domain

In one example, the membrane system further comprises an enzyme domain disposed further from the electroactive surface than the interfering domain (or electrode domain when no distinct interfering domain is included). In some examples, the enzyme domains are deposited directly onto the electroactive surface (when neither the electrode nor the interfering domain is included). In one example, the enzyme domain provides an enzyme that catalyzes a reaction of an analyte and its co-reactant, as described in more detail below. Preferably, the enzyme domain comprises glucose oxidase; however, other oxidases, such as galactose oxidase or uricase oxidase, may also be used.

In order for an enzyme-based electrochemical glucose sensor to perform well, the response of the sensor is preferably not limited by either the enzyme activity or the co-reactant concentration. Since enzymes, including glucose oxidase, are deactivated over time even under ambient conditions, this behavior is compensated for when the enzyme domain is formed. Preferably, the enzyme domain consists of an aqueous dispersion of a colloidal polyurethane polymer comprising the enzyme. However, in alternative examples, the enzyme domain is composed of an oxygen enhancing material (e.g., a silicone or fluorocarbon) in order to provide an excess oxygen supply during transient ischemia. Preferably, the enzyme is immobilized within the enzyme domain. See U.S. patent application Ser. No. 10/896,639, entitled "oxygen enhanced Membrane System for implantable devices (Oxygen Enhancing Membrane Systems for Implantable Device)" filed on 7/21/2004.

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

Resist domain

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

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

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

In alternative examples, a lower oxygen to glucose ratio may be sufficient to provide excess oxygen by using high oxygen solubility domains (e.g., silicone or fluorocarbon based materials or domains) to enhance the supply/transport of oxygen to the enzyme domains. If more oxygen is supplied to the enzyme, more glucose can also be supplied to the enzyme without creating an oxygen rate limiting excess. In an alternative example, the resistant domain is formed from a silicone composition, such as described in co-pending U.S. patent serial No. 10/695,636 entitled silicone composition for biocompatible films (SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE), filed 10/28 in 2003.

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

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

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

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

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

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

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

Advantageously, a sensor having a membrane system of the present disclosure comprising an electrode domain and/or an interference domain, an enzyme domain, and an impedance domain provides a stable signal response to increased glucose levels from about 40mg/dL to about 400mg/dL, and sustained function (at least 90% signal strength) even at low oxygen levels (e.g., at about 0.6mg/L O2). While not wishing to be bound by theory, it is believed that the resistant domain provides sufficient resistance, or the enzyme domain provides sufficient enzyme, such that oxygen limitation is seen at much lower oxygen concentrations than prior art sensors.

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

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

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

Non-interfering membrane system

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

Oxygen catheter

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

Because there is a proportional change in the product H2O2 for each glucose molecule reacted there, the change in H2O2 can be monitored to determine the glucose concentration. For example, oxidation of H2O2 by the working electrode is balanced by reduction of ambient oxygen, enzymatically produced H2O2, and other reducible species at the counter electrode. See Fraser, d.m. "," An Introduction to In vivo Biosensing: progress and Problems "in" Biosensors and the Body, "d.m. Fraser edit, 1997, pages 1-56 John Wiley and Sons, new York))

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

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

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

Membrane system

In some examples, one or more domains of the sensing film are formed from the following materials: such as silicone; polytetrafluoroethylene; polyethylene-co-tetrafluoroethylene; a polyolefin; a polyester; a polycarbonate; biostable polytetrafluoroethylene; homopolymers, copolymers, terpolymers of polyurethane; polypropylene (PP); polyvinyl chloride (PVC); polyvinylidene fluoride (PVDF); polybutylene terephthalate (PBT); polymethyl methacrylate (PMMA); polyetheretherketone (PEEK); polyurethane; a cellulosic polymer; poly (ethylene oxide), poly (propylene oxide), and copolymers and blends thereof; polysulfones and block copolymers thereof, including, for example, diblock copolymers, triblock copolymers, alternating copolymers, random copolymers, and graft copolymers. Co-pending U.S. patent application serial No. 10/838,912, which is incorporated herein by reference in its entirety, describes biological interface and sensing membrane configurations and materials that can be applied to the disclosed sensors.

The sensing film may be deposited on the electroactive surface of the electrode material using known thin or thick film techniques (e.g., spraying, electrodeposition, dipping, etc.). Note that the sensing film surrounding the working electrode does not have to have the same structure as the sensing film surrounding the reference electrode or the like. For example, the enzyme domains deposited on top of the working electrode need not necessarily be deposited on top of the reference electrode and/or the counter electrode.

In the illustrated example, the sensor is an enzyme-based electrochemical sensor in which the working electrode 38 measures electron flow, for example, detecting glucose with glucose oxidase to produce hydrogen peroxide as a byproduct, H2O2 reacts with the surface of the working electrode to produce two protons (2h+), two electrons (2 e-) and one oxygen molecule (O2), which produce a detected electron flow, or direct electron transfer via a redox system (e.g., a "wire enzyme" system), such as described in more detail above and as understood by those of skill in the art. One or more potentiostats are employed to monitor the electrochemical reaction at the electroactive surface of the working electrode. The potentiostat applies a constant potential to the working electrode and its associated reference electrode to determine the current generated at the working electrode. The current generated at the working electrode (and flowing through the circuit to the counter electrode) is substantially proportional to the amount of H2O2 diffused to the working electrode or analyte that promotes electron transfer in the wired enzyme system. For example, the output signal is typically a raw data stream that is used to provide the recipient or physician with an available value of measured analyte concentration in the recipient.

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

Exemplary sensor configuration

FIG. 2C is a cross-sectional view through the sensor of FIG. 2A along line B-B, showing the unexposed electroactive surface of at least one working electrode 38 surrounded by a sensing film comprising multiple domains or layers, e.g., interference domain 44, enzyme domain 46, and anti-domain 48, and additional domains/films, such as electrode domains, cell impermeable domains (not shown), oxygen domains (not shown), drug release film 70, and/or biological interface film 68 (not shown), such as described in more detail below. As shown in fig. 2C, the drug release film 70 is positioned adjacent to the surface of the working electrode 38 and does not cover multiple domains or layers of the working electrode 38 or sensing film 32, such as the interference domain 44, the enzyme domain 46, and the rejection domain 48. In one example, the drug release film 70 is positioned at the distal end 37 of the sensor 34. In another example, the drug release film 70 spans the electroactive portion of the working electrode 38 and does not cover the sensing film 32 associated with the working electrode 38.

Fig. 2D is a cross-sectional view through the sensor of fig. 2A on line D-D of the exemplary drug release film deposition of the sensor 34, wherein the drug release film 70 is farther from the electrode 38 than the resistant layer 48 and/or the biological interface layer 68 and is adjacent to but does not cover the enzyme domains 46 or transduction elements and/or the interference domains 44, and/or the sensing region or electroactive surface of the sensing region. The drug release film 70 may be disposed on the sensor 34 using one or more of screen printing, spray coating, or dip coating methods, as shown in fig. 2D.

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

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

While some of the figures herein illustrate sensors that may have a coaxial core and a circular or oval cross-section, in other examples of sensor systems that include a biological interface/drug release layer, the sensor may be a substantially planar sensor, as shown in the cross-section for illustration purposes in fig. 2H. For example, as shown in fig. 2H, the continuous analyte sensing device 100 can include a substantially planar substrate 142, and an interference domain 144, an enzyme domain 146, an impedance domain 148, and a biological interface/biological protection domain 168 and/or a drug release domain 170 disposed in a substantially planar manner about the substantially planar substrate 142 with one or more working electrodes.

Fig. 3A is a schematic side view of a transdermal analyte sensor 50 in one example. The sensor 50 includes a mounting unit 52 adapted to be mounted on the skin of a subject, a small (diameter) structural sensor 34 (as defined herein) adapted to be inserted percutaneously through the skin of the subject, and an electrical connection configured to provide a secure electrical contact between the sensor and electronics preferably housed within the mounting unit 52. Generally, the mounting unit 52 is designed to maintain the integrity of the sensor in the subject in order to reduce or eliminate motion conversion between the mounting unit, the subject and/or the sensor. See co-pending U.S. patent application Ser. No. 11/077,715, entitled "transdermal analyte sensor (TRANSCUTANEOUS ANALYTE SENSOR)" filed on 3/10 of 2005, which is incorporated herein by reference in its entirety. In one example, a drug release film is formed on the sensing mechanism 36, as described in more detail below.

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

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

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

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

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

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

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

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

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

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

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

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

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

The sensor electronics include hardware, firmware, and/or software capable of measuring analyte levels by the sensor. For example, the sensor electronics may include a potentiostat, a power supply for providing power to the sensor, other components for signal processing, and preferably an RF module for transmitting data from the sensor electronics to the receiver. The electronic device may be fixed to a Printed Circuit Board (PCB) or the like, and may take various forms. For example, the electronic device may take the form of an Integrated Circuit (IC), such as an Application Specific Integrated Circuit (ASIC), a microcontroller, or a processor. Preferably, the sensor electronics include a system and method for processing sensor analyte data. Examples of systems and methods for processing sensor analyte data are described in more detail in co-pending U.S. application Ser. No. 10/633,367, entitled "processing analyte sensor data (SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA)", filed below and on 1/8/2003.

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

Sensor electronics

The following description of the electronics associated with the sensor applies to a variety of continuous analyte sensors, such as non-invasive, minimally invasive, and/or invasive (e.g., percutaneous and fully implantable) sensors. For example, the sensor electronics and data processing described below and the receiver electronics and data processing may be incorporated into fully implantable glucose sensors disclosed in the following documents: co-pending U.S. patent application Ser. No. 10/838,912, entitled "implantable analyte sensor (IMPLANTABLE ANALYTE SENSOR)" filed on month 5 and 3 of 2004, and U.S. patent application Ser. No. 10/885,476, entitled "System and method for manufacturing an analyte measurement device including a membrane system (SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM)", filed on month 7 and 6 of 2004.

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

The processor module includes a central control unit that controls the processing of the sensor electronics. In some examples, the processor module includes a microprocessor, however computer systems other than microprocessors may be used to process data as described herein, e.g., ASICs may be used for some or all of the sensor central processing. The processor typically provides semi-permanent storage of data, FOR example, storing data such as SENSOR Identifiers (IDs) and programming FOR processing the data stream (e.g., programming FOR data smoothing and/or replacement of signal artifacts such as the system and method titled "system and method FOR replacing signal artifacts in GLUCOSE SENSOR data streams" filed on 8/22 2003 (SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM) ", co-pending U.S. patent application serial No. 10/648,849). The processor may additionally be used for a cache memory of the system, for example for temporarily storing the most recent sensor data. In some examples, the processor module includes memory storage components such as ROM, RAM, dynamic RAM, static RAM, non-static RAM, EEPROM, rewritable ROM, flash memory, and the like.

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

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

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

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

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

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

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

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

In some examples, the output signal (from the sensor electronics) is sent to a receiver (e.g., a computer or other communication station). For example, the output signal is typically a raw data stream that is used to provide the patient or physician with available values of measured analyte concentration. In some examples, the raw data stream may be continuously or periodically algorithmically smoothed or otherwise modified to reduce deviation points that inaccurately represent analyte concentration, for example, due to signal noise or other signal artifacts, such as described in the following documents: the co-pending U.S. patent application Ser. No. 10/632,537, entitled "System and method FOR replacing Signal artifacts of GLUCOSE SENSOR data streams" (SYSTEMS AND METHOD FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM) "filed on 8/22/2003, which is incorporated herein by reference in its entirety.

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

Receiver with a receiver body

In some examples, the sensor electronics are wirelessly connected to the receiver via unidirectional or bidirectional RF transmission or the like. However, wired connections are also contemplated. The receiver provides for a number of processes and displays of sensor data and may be selectively worn and/or removed at the convenience of the recipient. Thus, the sensor system may be carefully worn, and the receiver providing many processes and displays of the sensor data may be selectively worn and/or removed at the convenience of the recipient. In particular, the receiver includes programming for retrospectively and/or prospective initiating calibration, converting sensor data, updating calibration, evaluating received reference and sensor data, and evaluating calibration of the analyte sensor, such as described in more detail in co-pending U.S. patent application Ser. No. 10/633,367, entitled "System and method for processing analyte sensor data (SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA)" filed on month 1 of 2003.

Fig. 3C is a schematic side view of a fully implantable analyte sensor 53 in one example. The sensor includes a sensor body 60 adapted for subcutaneous implantation and includes a sensor 34 having a small structure as defined herein. Published U.S. patent application 2004/0199059 to Brauker et al, which is incorporated herein by reference in its entirety, describes systems and methods suitable for use with the sensor body 60. In one example, a biological interface film 68 is formed onto the sensing mechanism 36, as described in more detail elsewhere herein. The sensor body 60 includes sensor electronics and preferably communicates with a receiver, as described in more detail above. As shown in fig. 3C, a drug release film 70 is disposed over at least a portion of the bio-interface film 68 and/or the sensing film 36.

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

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

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

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

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

After implantation, the tissue is allowed to grow inward within the biological interface for a period of time. The length of time required for tissue ingrowth varies from recipient to recipient, such as from about one week to about 3 weeks, although other time periods are possible. Once the mature bed of vascularized tissue has grown into the biological interface, a signal can be detected from the sensor as described elsewhere herein and in U.S. patent application Ser. No. 10/838,912 to Brauker et al, entitled "implantable analyte sensor (IMPLANTABLE ANALYTE SENSOR)", which is incorporated herein in its entirety. The long-term sensor may remain implanted and generate glucose signal information for months to years, as described in the above-mentioned patent applications.

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

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

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

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

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

In this example, the sensing mechanism may be, for example, a wire-based sensor, as described in more detail with reference to fig. 2A and 2B and as described in published U.S. patent application US2006-0020187, or a planar substrate-based sensor, such as described in U.S. patent No. 6,175,752 to Say et al and U.S. patent No. 5,779,665 to masmototaro et al, all of which are incorporated herein by reference in their entirety. The biological interface film 68 may be any suitable biological interface, such as a porous biological interface film material layer, a mesh cage, or the like, as described in more detail elsewhere herein. In one illustrative example, the biological interface membrane 68 is a single or multi-layer sheet (e.g., pouch) of porous membrane material (such as ePTFE) in which the sensing mechanism 36 is incorporated.

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

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

Biological interface film/layer

In one example, the sensor includes a porous material disposed on portions thereof that alters the response of the recipient tissue to the sensor. In some examples, the porous material surrounding the sensor advantageously enhances sensor performance and extends sensor life by slowing or reducing cell migration to the sensor and associated degradation that would otherwise be caused by cell invasion if the sensor were directly exposed to the in vivo environment. Alternatively, the porous material may provide stabilization of the sensor via tissue ingrowth into the porous material over a long period of time. Suitable porous materials include silicones; polytetrafluoroethylene; expanded polytetrafluoroethylene; polyethylene-co-tetrafluoroethylene; a polyolefin; a polyester; a polycarbonate; biostable polytetrafluoroethylene; homopolymers, copolymers, terpolymers of polyurethane; polypropylene (PP); polyvinyl chloride (PVC); polyvinylidene fluoride (PVDF); polyvinyl alcohol (PVA); polybutylene terephthalate (PBT); polymethyl methacrylate (PMMA); polyetheretherketone (PEEK); a polyamide; polyurethane; a cellulosic polymer; poly (ethylene oxide), poly (propylene oxide), and copolymers and blends thereof; polysulfones and block copolymers thereof, including, for example, diblock, triblock, alternating, random, and graft copolymers; and metals, ceramics, cellulose, hydrogel polymers, poly (2-hydroxyethyl methacrylate) (pHEMA), hydroxyethyl methacrylate (HEMA), polyacrylonitrile-polyvinylchloride (PAN-PVC), high density polyethylene, acrylic acid copolymers, nylon, polydifluoroethylene, polyanhydrides, poly (L-lysine), poly (L-lactic acid), hydroxyethyl methacrylate, hydroxyapatite (hydroxypepite), alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium alloys, nitinol, stainless steel, and CoCr alloys, and the like, such as those described in co-pending U.S. patent application serial No. 10/842,716 entitled "biointerface membrane incorporating bioactive agent (BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVE AGENTS)", filed on 5 month 10 and U.S. patent application serial No. 10/647,065 entitled "porous membrane for use with implantable devices (POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES)", filed on 8 month 22 of 2004.

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

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

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

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

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

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

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

In examples where the biological interface is written directly onto the sensor, the dispenser uses a nozzle with a valve to dispense the polymer solution, as described, for example, in U.S. publication No. 2004/0253365 A1. Generally, a variety of nozzles and/or dispensers can be used to dispense the polymeric material to form woven or nonwoven fibers of the biological interface film.

Drug release membrane/layer-inflammatory response control

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

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

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

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

Anti-barrier cell agents

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

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

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

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

Other suitable drugs, pharmaceutical compositions, therapeutic agents, or other desirable substances may be incorporated into the drug release film 70 of the present disclosure, including but not limited to anti-inflammatory agents, anti-infective agents, necrosis agents, and anesthetics.

Typically, anti-inflammatory agents reduce acute and/or chronic inflammation adjacent to the implant in order to reduce FBC capsule formation, thereby reducing or preventing barrier cell layer formation. Suitable anti-inflammatory agents include, but are not limited to, for example, non-steroidal anti-inflammatory drugs (NSAIDs), such as acetaminophen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, potassium diclofenac, sodium diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL) -10, IL-6 muteins, anti-IL-6 iNOS inhibitors (e.g., L-NAME or L-NMDA), interferons, ketoprofen, ketorolac, leflunomide, mefenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen sodium, oxaprozin, piroxicam, rofecoxib, bis-salicylates, sulindac, and tolmetin; and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone acetonide, betamethasone dipropionate, betamethasone valerate, dexamethasone, desoxymethasone, fluocinolone, triamcinolone acetonide, clobetasol propionate, NLRP3 inflammatory body inhibitors (such as MCC 950), dexamethasone and dexamethasone acetate.

In general, immunosuppressants and/or immunomodulators directly interfere with several key mechanisms necessary to involve different cellular elements in the inflammatory response. Suitable immunosuppressants and/or immunomodulators include antiproliferative cell cycle inhibitors (e.g., paclitaxel (e.g., sirolimus), cytochalasin D, infliximab), paclitaxel, actinomycin, mitomycin, thosprote VEGF, estradiol, NO donor, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopepsin, vincristine, mitomycin, statins, C MYC antisense, sirolimus (and analogs), restenose, 2-chloro-deoxyadenosine, PCNA ribozymes, palmita, prolyl hydroxylase inhibitors, pparγ ligands (e.g., traglione, rosiglitazone, pioglitazone), halozone, C-proteinase inhibitors, probucol, BCP671, antibodies, catechins, saccharification agents, endothelin inhibitors (e.g., ambrisen, telogen), tenascin (tersotan), statins (e.g., tacroline), statins (e.g., colistin), and tacroline (e).

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

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

Angiogenesis agent

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

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

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

Typically, an angiogenic agent is a substance capable of stimulating neovascularization, which can accelerate and maintain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include, but are not limited to, copper ion, iron ion triacontylammonium methyl chloride, basic fibroblast growth factor (bFGF) (also known as heparin binding growth factor II and fibroblast growth factor II), acidic fibroblast growth factor (aFGF) (also known as heparin binding growth factor I and fibroblast growth factor I), vascular Endothelial Growth Factor (VEGF), platelet-derived endothelial growth factor BB (pdgf-BB), angiopoietin-1, transforming growth factor beta (TGF-beta), transforming growth factor alpha (TGF-alpha), hepatocyte growth factor, tumor necrosis factor-alpha (TNF-alpha), placenta growth factor (PLGF), angiopoietin, interleukin-8 (IL-8), hypoxia inducible factor-I (HIF-1), angiotensin Converting Enzyme (ACE) inhibitor quinaprilla, angiotrepin (anginopin), thrombospondin, peptide kg, hypoxia tension, lactic acid, insulin, copper sulfate, estradiol, prostate, cox inhibitors, cell-binding agents (e.g., core protein, proteoglycans or genipin), nicotine, and tenpin.

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

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

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

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

In general, many variables can affect the pharmacokinetics of release of a bioactive agent. The bioactive agents of the present disclosure can be optimized for short-term release and/or extended release. In some examples, the bioactive agents of the present disclosure are designed to help or overcome factors related to short term effects of foreign body response (e.g., acute inflammation) that may begin as early as implantation and extend up to about one month after implantation. In some examples, the bioactive agents of the present disclosure are designed to aid or overcome factors associated with an extension effect, such as chronic inflammation, barrier cell layer formation, or accumulation of fibrotic tissue of a foreign body response, which may begin about one week as early as after implantation and extend the lifetime of the implant, such as months to years. In some examples, the bioactive agents of the present disclosure combine the benefits of both short-term release and extended release to take advantage of both. U.S. publication No. 2005/0031689 A1 to Shults et al discloses various systems and methods for releasing bioactive agents.

The amount of bioactive agent loaded into the release film may depend on several factors. For example, the amount and duration of the bioactive agent may vary with the intended use of the release film (e.g., cell transplantation, analyte measurement device, etc.). Differences in effective dosages of bioactive agents between recipients; -location and method of loading bioactive agent; and release rates associated with the bioactive agents and optionally their chemical composition and/or bioactive agent loading. Thus, those skilled in the art will appreciate the variability in achieving reproducible and controlled release of one or more bioactive agents, at least for the reasons described above. U.S. publication No. 2005/0031689A1 to Shults et al discloses various systems and methods for loading bioactive agents.

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

Forming drug releasing films/layers on sensors

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

Although some of the following description relates to glucose measurement devices, including the described membrane systems and methods of use thereof, these membrane systems are not limited to devices for measuring or monitoring glucose. These membrane systems are suitable for use in any of a variety of devices, including, for example, devices that detect and quantify other analytes present in biological fluids (e.g., cholesterol, amino acids, alcohols, galactose, and lactate), cell transplantation devices (see, for example, U.S. Pat. No. 6,015,572, U.S. Pat. No. 5,964,745, and U.S. Pat. No. 6,083,523), drug delivery devices (see, for example, U.S. Pat. No. 5,458,631, U.S. Pat. No. 5,820,589, and U.S. Pat. No. 5,972,369), and the like, which are incorporated herein by reference in their entirety for their teachings of the membrane systems.

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

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

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

Polymers having domains or segments functionalized to allow crosslinking may be prepared by methods known in the art. For example, polyurethaneurea polymers having aromatic or aliphatic segments containing electrophilic functional groups (e.g., carbonyl, aldehyde, anhydride, ester, amide, isocyano, epoxy, allyl, or halo groups) can be crosslinked with a crosslinking agent having multiple nucleophilic groups (e.g., hydroxyl, amine, urea, urethane, or thio groups). In further examples, polyurethaneurea polymers having aromatic or aliphatic segments containing nucleophilic functional groups may be crosslinked with a crosslinking agent having multiple electrophilic groups. Still further, the polyurethaneurea polymer having a hydrophilic segment containing a nucleophilic functional group or an electrophilic functional group may be crosslinked with a crosslinking agent having a plurality of electrophilic functional groups or nucleophilic groups. Unsaturated functional groups on polyurethaneurea can also be used for crosslinking by reaction with polyvalent radical agents. Non-limiting examples of suitable cross-linking agents include isocyanate, carbodiimide, glutaraldehyde, aziridine, silane or other aldehydes, epoxy, acrylate, radical-based agents, ethylene Glycol Diglycidyl Ether (EGDE), poly (ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). In one example, about 0.1 wt% to about 15 wt% of the crosslinking agent (in one example, about 1 wt% to about 10 wt%) is added relative to the total dry weight of these ingredients added when blending the crosslinking agent and polymer. During the curing process, it is believed that substantially all of the crosslinker reacts leaving substantially no detectable unreacted crosslinker in the final film.

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

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

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

In one example, the drug release film is configured to release 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 weight% after insertion and until the end of life of the sensor. In one example, the drug release film is configured to release between 60 wt% and 90 wt% of the bioactive agent after insertion and until the end of sensor life. In another example, the drug release film is configured to release between 75 wt.% and 85 wt.% of the bioactive agent after insertion and until the end of sensor life.

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

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

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

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

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

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

Examples of other materials that may be used to prepare the non-polyurethane drug release film include vinyl polymers, polyethers, polyesters, polyamides, polysilicone poly (dialkylsiloxanes), poly (alkylaryl siloxanes), poly (diaryl siloxanes), polycarbosiloxanes, polycarbonates, natural polymers such as cellulose and protein based materials, and mixtures, copolymers or combinations thereof with or without the aforementioned polyurethanes, or polyether polyurethaneurea polymers.

In another example, the drug release film further comprises one or more zwitterionic repeat units selected from the group consisting of: cocoamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, decyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly (carboxybetaine), poly (sulfobetaine) and derivatives thereof. In another aspect, alone or in combination with any of the preceding aspects, the drug release film does not comprise zwitterionic groups only at the ends of the polymer chains.

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

wherein Z is branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; r1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R2, R3 and R4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and wherein R is ¹ 、R ² 、R ³ 、R ⁴ And one or more of Z is substituted with a polymeric group for use as at least a portion of a drug release film.

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

In one example, the at least one bioactive agent is covalently associated with the drug release film. In another example, the at least one bioactive agent is ionically associated with the drug release film. In another example, the bioactive agent is a conjugate. As used herein, "conjugate" is a broad term and will give the person of ordinary and customary meaning to (and is not limited to) and refers to (but is not limited to) a bioactive agent covalently attached to a carrier or nanocarrier such as a polymer (e.g., drug release layer or biological interface layer) through a linker that is biologically active in that it is capable of allowing the drug to separate from the carrier when exposed to or present in a biological environment such as a subcutaneous or transdermal environment. As used herein, conjugates include drug release layer-bioactive agent conjugates and nanoparticle polymer-bioactive agent conjugates. Suitable carriers/nanocarriers include PEG and N- (2-hydroxypropyl) methacrylamide (HPMA), polyglutamic acid (PGA) and copolymers thereof. As used herein, conjugates include drug release layer-bioactive agent conjugates and nanoparticle polymer-bioactive agent conjugates present in the drug release layer. In one example, the drug release layer comprises domains with drug release-bioactive agent conjugates and domains with bioactive agent reservoirs, wherein the domains may be spatially arranged vertically or horizontally.

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

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

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

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

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

In another aspect, the drug release film comprises silver nanoparticles or nanogels as bioactive agents alone or in combination with dexamethasone, a salt of dexamethasone, or a derivative of dexamethasone or a mixture thereof (in particular dexamethasone acetate or a salt of dexamethasone acetate). In one example, the nanoparticle is biodegradable. In one example, the drug release film comprises copper and/or zinc nanoparticles or nanogels as bioactive agents. The silver, copper or zinc nanoparticles/nanogels may be spatially distributed or dispersed throughout the drug release film, wherein the spatial distribution or dispersion may be uniform or non-uniform and/or vary vertically and/or horizontally with some gradient.

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

In one example, the drug release film comprises polymeric nanoparticles selected from the group consisting of: PLGA, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphates, PEO-b-polypeptides, wherein the polymeric nanoparticle/nanogel comprises dexamethasone, dexamethasone salts or dexamethasone derivatives (in particular dexamethasone acetate or dexamethasone acetate salts) associated covalently or non-covalently.

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

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

In another example, the drug release film comprises a hydrolytically degradable biopolymer comprising the at least one bioactive agent. In one example, the hydrolytically degradable biopolymer comprises a salicylic acid polyanhydride ester (structure I) capable of hydrolyzing to salicylic acid and adipic acid.

In one example, a suitable drug release film 70 is a hard segment-soft segment polymer. Referring to fig. 4A, an exemplary hard segment-soft segment copolymer 71 is depicted having a hard segment 72 in which there is a close association of polymer segments that provide a crystalline or crystal-like structure and a soft segment 74 that provide an amorphous or amorphous-like structure. In one example, the drug release film 70 of the present disclosure is a hard segment-soft segment copolymer 71, wherein the soft segment 74 comprises a hydrophilic polymer or hydrophilic polymer segment. In one example, the drug release film 70 of the present disclosure is a hard segment-soft segment copolymer 71, wherein the soft segment 74 comprises a hydrophilic polymer or a combination of hydrophilic polymer segments and hydrophobic polymer or hydrophobic polymer segments. Referring to fig. 4B, 4C, a hard segment-soft segment copolymer 71 (wherein the soft segment 74 comprises a hydrophilic polymer or a combination of hydrophilic polymer segments and hydrophobic polymer or hydrophobic polymer segments) is schematically shown as a three-dimensional volume 4C of the drug release film 70 of the sensing film 32 depicting an arrangement of hydrophobic domains 76 and hydrophilic domains 78. Depending on the relative concentration of each domain and whether a non-stoichiometric or stoichiometric amount of each domain is present, various confirmations and distributions of hydrophobic and hydrophilic domains are contemplated. In one example, the soft segment of the drug release film 70 includes a hydrophilic segment in an amount other than 0% by weight and a hydrophobic segment in an amount including 0% by weight.

In one example, the drug release film 70 comprises a hard segment-soft segment polyurethane copolymer. In another example, the drug release film 70 comprises a hard segment-soft segment polyurethaneurea copolymer. In one example, the drug release film 70 of the present disclosure is a hard segment-soft segment polyurethane or polyurethane urea copolymer, wherein the soft segment 74 comprises a hydrophilic polymer or a combination of hydrophilic polymer segments and hydrophobic polymer or hydrophobic polymer segments. In one example, the drug release film 70 of the present disclosure is a hard segment-soft segment polyurethane or polyurethane urea copolymer blend, wherein at least one of the individual polymers of the polymer blend comprises a soft segment 74 comprising a hydrophilic polymer or a combination of hydrophilic polymer segments and hydrophobic polymer or hydrophobic polymer segments. In one example, the drug release film 70 of the present disclosure is a hard segment-soft segment polyurethane or polyurethane urea copolymer blend, wherein at least one polymer of the individual polymers of the polymer blend comprises soft segments 74 comprising only hydrophilic polymer segments, and at least one polymer of the polymer blend comprises soft segments comprising a combination of hydrophilic polymer segments and hydrophobic polymers or hydrophobic polymer segments.

In some examples, the hard segment of the copolymer may have a molecular weight of about 160 daltons to about 10,000 daltons, or about 200 daltons to about 2,000 daltons. In some examples, the molecular weight of the soft segment can 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.

In one example, the hard segment 72 of the drug release layer 70 is prepared using an aliphatic or aromatic diisocyanate. In one example, the aliphatic or aromatic diisocyanate used to provide the hard segment 72 of the drug release layer 70 is norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene Diisocyanate (TDI), 1, 3-phenylene diisocyanate (MPDI), trans-1, 3-bis (isocyanatomethyl) cyclohexane (1, 3-H6 XDI), dicyclohexylmethane-4, 4 '-diisocyanate (HMDI), 4' -diphenylmethane diisocyanate (MDI), trans-1, 4-bis (isocyanatomethyl) cyclohexane (1, 4-H6 XDI), 1, 4-cyclohexyl diisocyanate (CHDI), 1, 4-phenylene diisocyanate (PPDI), 3 '-dimethyl-4, 4' -diphenyl diisocyanate (TODI), 1, 6-Hexamethylene Diisocyanate (HDI), or a combination thereof.

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

In one example, the soft segment 74 of the hard segment-soft segment polyurethane or polyurethane urea copolymer comprises a polysiloxane or copolymer thereof and a poly (alkylene) oxy polymer or copolymer thereof. In one example, the soft segment 74 of the hard segment-soft segment polyurethane or polyurethaneurea copolymer comprises a poly (dialkyl) siloxane, a poly (diphenyl) siloxane, a poly (alkylphenyl) siloxane or copolymer, and a poly (alkyl) oxide, a poly (ethylene oxide), a poly (propylene oxide), a poly (ethylene oxide-propylene oxide), a poly (tetramethylene) oxide polymer, or copolymers or blends thereof.

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

At least a portion of the surface of the biological interface layer/drug release layer may be hydrophobic as measured by contact angle. For example, the biological interface layer/drug release layer may have a contact angle of about 90 ° to about 160 °, about 95 ° to about 155 °, about 100 ° to about 150 °, about 105 ° to about 145 °, about 110 ° to about 140 °, at least about 100 °, at least about 110 °, or at least about 120 °. In one example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface layer/drug release layer, has an advancing contact angle of about 100 ° to about 150 °. In another example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface layer/drug release layer, has an advancing contact angle of about 105 ° to about 130 °, or 110 ° to about 120 °. In yet another example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface layer/drug release layer, has a receding contact angle of about 40 ° to about 80 °. In another example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface layer/drug release layer, has a receding contact angle of about 45 ° to about 75 °. In yet another example, the dynamic contact angle, i.e. the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface layer/drug release layer, has a receding contact angle of about 50 ° to about 70 °. In some examples, dynamic contact angle measurements and surface roughness (associated with contact angle hysteresis caused by chemical and morphological heterogeneity of the surface, solution impurities adsorbed on the surface, or swelling, rearrangement, or change of the surface by solvent) on the drug release layer after placement on the analyte sensor and after sterilization can be performed using a Sigma 701 force tensiometer and performing one or more of an advancing contact angle measurement, a receding contact angle measurement, a hysteresis measurement, and combinations thereof. In some examples, the solid sample is contacted with the test liquid using an immersion speed of about 30 inches per minute and a retraction speed of about 10 inches per minute. The force tensiometer measures the mass affecting the balance and calculates and automatically subtracts the effects of buoyancy and probe weight so that the only remaining force measured by the balance is the wetting force.

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

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

In one example, the drug release film comprises a soft segment-hard segment copolymer comprising a weight percent of hydrophilic segments that is greater than a weight percent of hydrophobic segments thereof. In one example, the release film comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a weight percent of soft segment-hard segment hydrophilic segments that is greater than a weight percent of its hydrophobic segments.

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

In one example, the drug release film comprises a soft segment-hard segment copolymer that is a blend of different soft segment-hard segment copolymers. In one example, the drug release film comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer that is a blend of different soft segment-hard segment copolymers.

In one example, the drug release film comprises a blend of different soft segment-hard segment copolymers, the blend being a blend of a first soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percentage other than 0% and a hydrophobic segment in a weight percentage including 0% with another second soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percentage greater than the weight percentage of the hydrophobic segment. In one example, the drug release film comprises a blend of different soft segment-hard segment polyurethane or polyurethane urea copolymers comprising a blend of a first soft segment-hard segment copolymer comprising a weight percent hydrophilic segment other than 0% and a weight percent hydrophobic segment including 0% with another soft segment-hard segment copolymer comprising a weight percent hydrophilic segment greater than the weight percent hydrophobic segment.

In one example, the drug release film comprises a blend of a soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percent other than 0% and a hydrophobic segment in a weight percent including 0% with another soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percent less than the weight percent of the hydrophobic segment. In one example, the drug release film comprises a blend of a soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment in a weight percent other than 0% and a hydrophobic segment in a weight percent including 0% with another soft segment-hard segment polyurethane or polyurethane urea copolymer comprising a hydrophilic segment in a weight percent less than the weight percent of the hydrophobic segment.

In one example, the drug release film comprises a soft segment-hard segment copolymer and a soft segment-hard segment copolymer, each of which comprises less than 70% by weight but not 0% by weight of soft segments and each of which comprises not 0% by weight of hydrophilic segments and 0% by weight including hydrophobic segments. In one example, the drug release film comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer and a different soft segment-hard segment polyurethane or polyurethane urea copolymer, each comprising less than 70% but not 0% by weight soft segments and each comprising not 0% by weight hydrophilic segments and hydrophobic segments comprising 0% by weight.

In one example, the drug release film comprises a soft segment-hard segment copolymer blended with a hydrophobic polymer and/or a hydrophilic polymer. In one example, the drug release film comprises a soft segment-hard segment polyurethane or polyurethane urea copolymer blended with a hydrophobic polymer and/or a hydrophilic polymer.

In one example, the drug release film 70 is substantially impermeable to transport of analytes therethrough. In another example, the drug release film 70 has a lower permeability to the analyte than the interfering layer 44 of the sensing film 32. In such examples, the drug release film 70 is deposited on the portion of the sensor adjacent to but not covering the electroactive portion of the sensor.

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

In one example, the drug release film 70 is deposited onto at least a portion of the sensing film 32. In another example, the drug release film 70 is deposited adjacent to but not directly onto the sensing film 32. In one example, the drug release film is deposited so as to provide a film thickness of about 0.05 microns or more to about 50 microns or less. In another example, the drug release film is deposited so as to provide a film thickness of about 0.5 to 50 microns, 1 to 50 microns, 2 to 50 microns, 3 to 50 microns, 4 to 50 microns, 5 to 50 microns, 6 to 50 microns, 7 to 50 microns, 8 to 50 microns, 9 to 50 microns, 10 to 40 microns, 10 to 30 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns, 20 microns, 21 microns, 22 microns, 23 microns, 24 microns, 25 microns, 26 microns, 27 microns, 28 microns, 29 microns, or 30 microns.

In one example, the drug release film 70 is deposited onto the enzyme domains by spraying, brushing, pad printing, or dipping. In some examples, the drug release film 70 is deposited using spray coating and/or dip coating. In one example, drug release film 70 is deposited onto sensing film 32 by pad printing a mixture of about 1 wt% to about 80 wt% polymer/drug combination and about 20 wt% to about 99 wt% solvent.

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

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

Release film/layer composition-bioactive agent release profile

The present disclosure provides for control of the release of a bioactive agent from a drug release film or for a release profile of a bioactive agent from a drug release film. For example, using an exemplary bioactive agent/drug release film system, e.g., dexamethasone and/or dexamethasone acetate/soft segment-hard segment polyurethane urea copolymer or blend, other combinations of bioactive agent and drug release film are contemplated.

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

Fig. 6 shows the correlation between in vitro release 77 and in vivo release 79 of dexamethasone acetate in the disclosed drug release membrane 70 over a 15 day period, demonstrating the ability of the in vitro data of the disclosed system to approximate in vivo data.

Referring to fig. 7, experimental data showing that the release rate of the bioactive agent (dexamethasone acetate) from the drug release film is greater than the release rate of the bioactive agent from the drug release film initially or during the first period of time than the release rate of the bioactive agent from the drug release film initially or during the second period of time, and the release rate of the bioactive agent from the drug release film is greater than the release rate of the bioactive agent from the drug release film initially or during the third period of time are shown. Thus, fig. 7 depicts the exemplary in vitro drug release profile of fig. 6, showing a first release rate (e.g., bolus) indicated as corresponding to a time period associated with sensor insertion and extended by about 2 days or more, followed by a second release rate (e.g., amount within a therapeutic range) indicated as corresponding to a second time period associated with a time period beginning at about 2 days and extending forward by 15 days after sensor insertion. An amount less than the therapeutic amount, e.g., a non-therapeutic amount, is released during a period of about 18 days or more after sensor insertion and lasting until the end of sensor life is reached (data not shown). As can be seen from the graph data of fig. 7, the first release rate corresponds to a bolus release of about 50% of the dexamethasone acetate initial load over a period of about two days, followed by a second release rate corresponding to a release of about 40% of the dexamethasone acetate initial load over a time span of about 13 days. The subsequent third release rate corresponds to the release of the remaining amount of dexamethasone acetate (about 10%) over a time span of 16-35 days.

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

Referring to fig. 8, study sensitivity data of an animal model (pig) of an exemplary experimental sensor 82 comprising the disclosed drug release film 70 (e.g., about 40-50 wt% load: drug release film) with an effective amount of DexAc over 15 days is presented as compared to a control sensor 84 without dexamethasone acetate (DexAc). As shown, the experimental sensor 82 provided consistent normalized sensitivity sustainability over 15 days post-insertion, while the control sensor 84 showed a decrease in normalized sensitivity after approximately 10 days post-insertion.

Referring to fig. 9, a study of an animal model (pig) of average absolute noise data of an exemplary experimental sensor 86 comprising the disclosed drug release film 70 (e.g., about 40-50 wt% load: drug release film) with an effective amount of DexAc over 15 days is presented as compared to a control sensor 84 without dexamethasone acetate (DexAc). As shown, the experimental sensor 86 provided a relatively consistent average absolute noise sustainability over 15 days post-insertion, while the control sensor 88 showed an increase in average absolute noise after about 8-10 days post-insertion. This data exemplifies the ability of the disclosed drug release film/bioactive agent combination to minimize increases in implantable sensor noise over an extended period of time.

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

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

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

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

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

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

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

Claims

1. A continuous percutaneous sensor, the continuous percutaneous sensor comprising:

a sensing portion configured to interact with at least one analyte and transduce a detectable signal corresponding to the at least one analyte or a characteristic of the at least one analyte;

a drug release membrane in proximity to the sensing portion, the drug release membrane configured to provide an interface with an in vivo environment, the drug release membrane storing at least one bioactive agent, wherein the at least one bioactive agent is configured to be released from the drug release membrane to alter a tissue response of a subject, wherein the at least one bioactive agent comprises an anti-inflammatory compound or a tissue response modifier.

2. The continuous transdermal sensor of claim 1, wherein the sensing portion comprises a transduction element configured to interact with at least one analyte present in a biological fluid of a subject and provide a detectable signal corresponding to the at least one analyte.

3. The continuous transdermal sensor of any one of the preceding claims, further comprising a transduction element that transduces the detectable signal, the transduction element comprising an enzyme, protein, DNA, RNA, conjugate, or combination thereof.

4. The continuous transdermal sensor of claim 3, wherein the detectable signal is optical, electrochemical or electrical.

5. The continuous transdermal sensor of claim 3, wherein the sensing portion comprises a longitudinal length defined by a proximal end and a distal end, the transduction element positioned between the proximal end and the distal end, the drug release film positioned adjacent the transduction element.

6. The continuous transdermal sensor of claim 3, wherein the transduction element comprises at least one electrode comprising at least one electroactive moiety; a sensing membrane deposited on at least a portion of the at least one electroactive moiety, the sensing membrane comprising an enzyme configured to catalyze a reaction with at least one analyte present in a biological fluid of a subject.

7. The continuous transdermal sensor of any one of the preceding claims, wherein the drug release membrane is substantially impermeable to transport of the at least one analyte when the interface with the in vivo environment is provided.

8. The continuous transdermal sensor of claim 3, wherein the transduction element is devoid of the drug release film.

9. The continuous transdermal sensor of claim 3, wherein the drug release membrane is present only at the distal end and adjacent to the transduction element.

10. The continuous transdermal sensor of claim 3, wherein the drug release membrane is continuously, semi-continuously or non-continuously disposed along the longitudinal axis of the sensing portion, provided that the drug release membrane does not cover the transduction element.

11. The continuous transdermal sensor of any one of the preceding claims, wherein the drug release film is configured to release the at least one bioactive agent in a release profile comprising at least a first release.

12. The continuous transdermal sensor of claim 11, wherein the first release corresponds to release of a bolus therapeutic amount of the at least one bioactive agent at a time associated with sensor insertion.

13. The continuous transdermal sensor of any one of claims 11-12, wherein the drug release film is further configured to continuously or semi-continuously release the at least one bioactive agent at a time after sensor insertion with a second release corresponding to a therapeutic amount of the at least one bioactive agent.

14. The continuous transdermal sensor of claim 13, wherein the drug release film is further configured to continuously or semi-continuously release the at least one bioactive agent at a time after the second release at a third release corresponding to a non-therapeutic amount of the at least one bioactive agent until sensor life is terminated.

15. The continuous transdermal sensor of any one of claims 11-14, wherein the drug release film comprises a soft segment-hard segment copolymer or a blend of different soft segment-hard segment copolymers.

16. The continuous transdermal sensor of claim 15, wherein the soft segment-hard segment copolymer comprises less than 70% but not 0% soft segments by weight.

17. The continuous transdermal sensor of claim 15, wherein the soft segment of the drug release film comprises a hydrophilic segment in an amount other than 0% by weight and a hydrophobic segment in an amount including 0% by weight.

18. The continuous transdermal sensor of claim 17, wherein the weight percent of the hydrophilic segment is greater than the weight percent of the hydrophobic segment.

19. The continuous transdermal sensor of claim 17, wherein the weight percent of the hydrophilic segment is less than the weight percent of the hydrophobic segment.

20. The continuous transdermal sensor of claim 17, wherein the weight percent of the hydrophilic segment is the same as the weight percent of the hydrophobic segment.

21. The continuous transdermal sensor of any one of claims 15-20, wherein the blend of different soft segment-hard segment copolymers is selected from the group consisting of:

a blend of a first soft segment-hard segment copolymer comprising a hydrophilic segment in a weight percent other than 0% and a hydrophobic segment in a weight percent including 0% and a second soft segment-hard segment copolymer comprising a weight percent of hydrophilic segment greater than the weight percent of hydrophobic segment;

a blend of a fifth soft segment-hard segment copolymer and a sixth soft segment-hard segment copolymer, each comprising less than 70% but not 0% by weight of soft segments, and each comprising not 0% by weight of hydrophilic segments and comprising 0% by weight of hydrophobic segments;

A blend of any one or more of the first soft segment-hard segment copolymer, the second soft segment-hard segment copolymer, the third soft segment-hard segment copolymer, the fourth soft segment-hard segment copolymer, the fifth soft segment-hard segment copolymer, or the sixth soft segment-hard segment copolymer with a hydrophobic polymer and/or a hydrophilic polymer; and

a combination thereof.

22. The continuous transdermal sensor of claim 21, wherein the at least one bioactive agent is present in the drug release film in an amount of between about 5 μg to 1000 μg.

23. The continuous transdermal sensor of claim 21, wherein the at least one bioactive agent is present in the drug release film in an amount of between about 5 μg to 500 μg.

24. The continuous transdermal sensor of claim 21, wherein the at least one bioactive agent is present in the drug release film in an amount of between about 5 μg to 200 μg.

25. The continuous transdermal sensor of claim 21, wherein the at least one bioactive agent is present in the drug release film in an amount of between about 5 μg to 100 μg.

26. The continuous transdermal sensor of claim 21, wherein the at least one bioactive agent is a dexamethasone derivative.

27. The continuous transdermal sensor of claim 26, wherein the at least one bioactive agent is dexamethasone acetate.

28. The continuous transdermal sensor of claim 26, wherein the at least one bioactive agent is a mixture of dexamethasone and dexamethasone acetate.

29. A method of extending the end of life of a continuous percutaneous sensor at least partially implanted in a subject, the method comprising:

releasing at least one bioactive agent from a drug release film associated with at least a portion of a transdermal sensor at least partially implanted in a subject,

improving the signal-to-noise ratio immediately after the time associated with the insertion of the continuous transdermal sensor compared to the signal-to-noise ratio of a transdermal sensor without an anti-inflammatory agent and a drug release film immediately after the time associated with the insertion; and/or

The sensitivity decay at a time associated with the end of a predetermined lifetime of the continuous transdermal sensor is reduced as compared to the sensitivity decay at a time associated with the end of a predetermined lifetime of a transdermal sensor without an anti-inflammatory agent and a drug release film.

30. A method of delivering a bioactive agent from a continuous transdermal sensor configured for insertion into soft tissue of a subject, the method comprising:

releasing at least one bioactive agent from the drug release film at a first release rate over a first period of time;

releasing the at least one bioactive agent from the drug release film at a second release rate for a second period of time, the second rate being different from the first release rate and the second period of time being subsequent to the first period of time.

31. The method of claim 30, further comprising releasing the at least one bioactive agent from the drug release film at a third release rate for a third period of time, the third release rate being different from the first release rate and the second release rate, and the third period of time being subsequent to the second period of time.

32. The method of any one of claims 30-31, wherein the first release rate provides a therapeutic bolus amount of the at least one bioactive agent, and wherein the therapeutic bolus amount is provided at a time associated with sensor insertion.

33. The method of any one of claims 30-32, wherein the second release rate provides for continuous or semi-continuous release of a therapeutic amount of the at least one bioactive agent, and wherein the therapeutic amount is provided after sensor insertion.

34. The method of any one of claims 30-33, wherein a third release rate corresponds to continuous or semi-continuous release of a non-therapeutic amount of the at least one bioactive agent, and wherein the non-therapeutic amount is provided until the end of life of the transdermal sensor.

35. The method of any of claims 30-34, further comprising improving signal to noise performance of the sensor during a period of time between the first time and the third time.

36. The method of any of claims 30-35, further comprising reducing sensitivity decay performance of the sensor during a period of time between the first time and the third time.

37. A method of delivering a bioactive agent from a continuous transdermal sensor configured for insertion into soft tissue of a subject, the method comprising:

releasing at least one bioactive agent from the drug release film at a first time point;

Releasing the at least one bioactive agent from the drug release film at a second point in time, the second point in time being different from the first point in time.

38. The method of claim 37, further comprising releasing the at least one bioactive agent from the drug release film at a third point in time, the third point in time being different from the first point in time and the second point in time.

39. The method of any one of claims 37-38, wherein the first point in time is associated with a sensor insertion.

40. The method of any one of claims 37-39, wherein the at least one bioactive agent of a therapeutic bolus quantity begins at the first point in time.

41. The method of any one of claims 37-40, wherein the second point in time is after sensor insertion.

42. The method of any one of claims 37-41, wherein continuous or semi-continuous release of the therapeutic amount of the at least one bioactive agent begins at the second point in time.

43. The method of any one of claims 37-42, wherein a third point in time is after the second point in time and before the end of life of the transcutaneous sensor.

44. The method of any one of claims 37-43, wherein continuous or semi-continuous release of a non-therapeutic amount of the at least one bioactive agent begins at the third point in time.

45. The method according to any one of claims 29-44, wherein the drug release layer is as defined in any one of claims 11-25.

46. The method of any one of claims 29-44, wherein the at least one bioactive agent is as defined in any one of claims 26-28.

47. The method of any one of claims 29-44, wherein the drug release layer is as defined in any one of claims 11-25, and wherein the at least one bioactive agent is as defined in any one of claims 26-28.