Temperature insensitive membrane materials and analyte sensors containing same

Abstract

An analyte permeable membrane may cover an active sensing region of a sensor to limit flux of the analyte and improve response linearity of the sensor. Temperature changes in analyte permeability may be problematic in some cases. Polymer membrane compositions with limited analyte permeability over temperature can include a polymer backbone comprising one or more side chains comprising a heterocyclic ring, and amine-free polyether arms, the amine-free polyether arm is attached to at least a portion of the heterocyclic rings of the one or more side chains via an alkyl spacer or a hydroxyl-functionalized alkyl spacer.

Description

[0001] This application is a divisional application of a Chinese patent application (PCT / US2019 / 036469) with an application date of June 11, 2019, application number 201980039279.5, and invention name “Temperature-insensitive membrane material and analyte sensor containing the same”. Background Art

[0002] The detection of various analytes in an individual body may be crucial for monitoring its health status sometimes. Deviations from normal analyte levels can often indicate many physiological conditions. For example, glucose levels may be particularly important for detecting and monitoring diabetic individuals. By monitoring glucose levels with enough regularity, diabetic individuals may be able to take corrective measures (such as by injecting insulin to reduce glucose levels or by eating to raise glucose levels) before significant physiological damage occurs. Other analytes that may similarly wish to monitor that physiological disorders may occur include but are not limited to lactic acid, oxygen, pH, Ale, ketones, drug levels, etc.

[0003] Analyte monitoring in an individual can be performed periodically or continuously over a period of time. Regular analyte monitoring can be performed by extracting samples of body fluids such as blood at set time intervals and performing ex vivo analysis. Continuous analyte monitoring can be performed using one or more sensors that are maintained at least partially implanted in the tissue of an individual, such as the skin, subcutaneously, or intravenously, so that the analysis can be performed in vivo. Implanted sensors can collect analyte data continuously or sporadically, depending on the individual's specific health needs and / or previously measured analyte levels.

[0004] Regular ex vivo analyte monitoring is sufficient to determine the physiological status of many individuals. However, ex vivo analyte monitoring may be inconvenient or painful for some people. In addition, if the analyte measurement is not obtained at the appropriate time, the lost data cannot be recovered.

[0005] For individuals with severe analyte imbalances and / or rapidly changing analyte levels, continuous analyte monitoring using an implanted sensor may be a more ideal approach, although this may also be beneficial for other individuals. Although continuous analyte monitoring using an implanted sensor may be advantageous, challenges associated with these types of measurements remain. Intravenous analyte sensors have the advantage of providing analyte concentrations directly from the blood, but they are invasive and can sometimes be painful for individuals to wear for long periods of time. Subcutaneous and cutaneous analyte sensors are generally not painful to the individual wearing them and can provide adequate measurement accuracy in many cases.

[0006] Although the entirety of the sensor may be implanted within an individual (e.g., by surgery), it is often more desirable to implant primarily the active portion of the sensor internally (e.g., by skin penetration) within the body while one or more additional sensor components remain external to the individual. In some cases, sensors suitable for measuring analyte levels in vivo may extend for extended periods of time from a sensor housing designed to be worn "on the body," such as on the skin. Such on-body analyte sensors may be particularly desirable because they can often be applied directly by the wearer, rather than relying on a medical professional to perform an invasive sensor implantation procedure.

[0007] The sensor may include a membrane disposed on at least the implanted portion of the sensor. On the one hand, the membrane may improve the biocompatibility of the sensor in vivo. On the other hand, the membrane may be permeable or semi-permeable to the analyte of interest, but limits the total flux of the analyte to the active sensing portion of the sensor. Limiting the analyte to enter the active sensing portion of the sensor can help avoid overloading (saturation) of the active sensing component, thereby improving sensor performance and accuracy. For example, in the case of a sensor using enzyme-based detection, limiting the analyte to enter the sensor can make the chemical kinetics of the sensing process limited by the analyte, rather than the enzyme. In the case where the enzymatic reaction is limited by the analyte, the ready calibration of the analyte sensor as a function of the sensor output can be achieved. That is, when the enzymatic reaction is limited by the analyte, the sensor output can be related to the amount of the analyte in some way. In many cases, when the enzymatic reaction is limited by the analyte, the sensor response may change linearly with the concentration of the analyte in the biological fluid of interest.

[0008] One problem associated with attaching a membrane to an analyte sensor is that the analyte flux through the membrane may vary significantly with temperature. Although calibration factors or formulas can be used to compensate for the variation of analyte flux with temperature, doing so may add considerable complexity to the use of the sensor, especially in cases where the analyte flux is nonlinear with respect to temperature. In addition, thermistors used to apply calibration equations may be complex to operate, and their size may hinder the miniaturization of the sensor. Another difficulty is that the calibration temperature measurement location may not necessarily have the same temperature as the membrane covering the active portion of the sensor. Other components of the sensor may similarly exhibit performance differences with temperature (e.g., enzymatic reaction rate in the case of enzyme-based sensors), which may make the separation and application of calibration factors or formulas for the membrane quite difficult. With the increase of component complexity and performance variability, higher costs and increasing measurement errors may result. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The following drawings are included to illustrate certain aspects of the present disclosure and should not be considered to be exclusive embodiments. The disclosed subject matter is capable of numerous modifications, alterations, combinations, and equivalent substitutions in form and function without departing from the scope of the present disclosure.

[0011] Figure 1 A diagram of an illustrative analyte monitoring system that may incorporate the analyte sensors of the present disclosure is shown.

[0012] Figure 2 A diagram of an illustrative two-electrode sensor configuration compatible with the disclosure herein is shown.

[0013] Figure 3A A diagram of an illustrative three-electrode sensor configuration compatible with the disclosure herein is shown. Figure 3B A diagram showing another configuration of an illustrative three-electrode sensor that is compatible with the disclosure herein is shown.

[0014] Figure 4 Illustrative graphs of sensor response over a temperature range of 17°C to 42°C at fixed glucose concentration are shown, wherein the sensing area is covered with a polymer film composition described herein.

[0015] Figure 5 An illustrative bar graph is shown showing the temperature change in 5°C sensor operation increments over a temperature range of 17°C to 42°C at a fixed glucose concentration, wherein the sensing area is covered with a polymer film composition described herein.

[0016] Figure 6 An illustrative graph of sensor response versus glucose concentration at constant temperature is shown, wherein the sensing area is covered with a polymer film composition described herein. Detailed Description

[0018] The present disclosure generally describes analyte sensors suitable for in vivo use, and more particularly describes membrane materials that exhibit limited analyte permeability that varies with temperature and analyte sensors incorporating such membrane materials.

[0019] As discussed above, in vivo analyte sensors can incorporate membrane materials to improve biocompatibility and limit analyte access to the active sensing area of ​​the sensor. Limiting analyte access to the sensing area can help avoid sensor saturation, thereby improving sensor performance and accuracy. For example, in the case of an enzyme sensor, the membrane material can promote an analyte-limited detection process rather than an enzyme-limited detection process. In the case where the detection process is limited by the analyte, a ready sensor calibration can be achieved. In some cases, the sensor response can vary linearly with the analyte concentration during the analyte-limited detection process.

[0020] One difficulty associated with many membrane materials is that their analyte permeability may vary with temperature to a clinically significant degree. Variations in analyte permeability with temperature can cause problems with sensor calibration, especially if the permeability change is nonlinear with respect to temperature. Although some membrane materials are known to exhibit limited analyte permeability variation with temperature, their biocompatibility may need further improvement. In addition, some membrane materials may be difficult to purify after synthesis.

[0021] The present disclosure provides polymer film compositions, which can provide limited analyte permeability with temperature variation and an ideal combination of favorable biocompatibility properties in certain embodiments. More specifically, the polymer film compositions disclosed herein include a polymer backbone (also referred to herein as heterocyclic polymer) with one or more side chains comprising a heterocycle, and an amine-free polyether arm connected to at least a portion of the one or more side chains, particularly connected to at least a portion of the heterocycle. The amine-free polyether arm can be combined with one or more polyethylene glycol moieties (blocks) and one or more polypropylene glycol moieties (blocks), which can be connected to the heterocycle by an alkyl spacer or a hydroxy-functionalized alkyl spacer. In some embodiments, other spacers such as carbonyl, carboxylate or carboxamide may also be suitable. In some embodiments, in an amine-free polyether arm, a single polyethylene glycol moiety can be bonded to a single polypropylene glycol moiety to form a diblock arrangement (e.g., in an AB block pattern or a BA block pattern, wherein A is a polyethylene glycol block and B is a polypropylene glycol). In other more specific embodiments, one or more polyethylene glycol moieties and one or more polypropylene glycol moieties may be present in alternating blocks without intermediate functional groups (e.g., in an ABA pattern according to some embodiments, or in a BAB pattern according to other embodiments, wherein A is a polyethylene glycol block and B is a polypropylene glycol block). According to other embodiments of the present disclosure, the amine-free polyether arm may also include more than three alternating blocks. In the polymer film compositions disclosed herein, the block pattern and the number of ether units in each block may vary. In some embodiments, the terminal polyethylene glycol unit in the amine-free polyether arm may be connected to a heterocycle or other side chain in the heterocyclic polymer by an alkyl spacer or a hydroxy-functionalized alkyl spacer or an alternative spacer such as a carbonyl, a carboxylate or a carboxamide. In other embodiments, the terminal polypropylene glycol unit in the amine-free polyether arm may be connected to a heterocycle or other side chain in the heterocyclic polymer by an alkyl spacer or a hydroxy-functionalized alkyl spacer or an alternative spacer such as a carbonyl, a carboxylate or a carboxamide.

[0022] The polymer film compositions of the present disclosure can be synthesized by reacting a heterocyclic polymer with a polyether arm precursor bearing a reactive functional group such as a terminal leaving group (particularly a haloalkyl group) or a terminal epoxide. More specifically, a halo primary alkyl group such as a brominated primary alkyl group can be at the end of the amine-free polyether arm precursor and result in an alkyl spacer that connects the amine-free polyether arm to the heterocycle. In contrast, the epoxide end of the amine-free polyether arm precursor results in the amine-free polyether arm being connected to the heterocycle via a hydroxyl-functionalized alkyl group, particularly an alkyl group with secondary hydroxyl functionality. The selection of a specific amine-free polyether arm precursor, including the selection of reactive functionality, can be based on factors such as ease of synthesis, in vivo properties of the resulting polymer, and the like. In a more specific configuration, a primary alkyl halide or epoxide can be bonded to the polyethylene glycol portion of the amine-free polyether arm precursor (i.e., via a terminal ether bond and an intervening spacer). In other specific configurations, a primary alkyl halide or epoxide can be bonded to the polypropylene glycol portion of the amine-free polyether arm precursor (ie, via a terminal ether linkage and an intervening spacer).

[0023] Advantageously, the amine-free polyether arm precursors described herein can be independently synthesized prior to reaction with the heterocyclic polymer. Independent synthesis of the amine-free polyether arm precursors can provide greater side chain composition uniformity in the resulting polymer film composition than can be obtained by stepwise growth of arms from a polymer backbone, where different arm lengths may be produced. Moreover, by reacting the amine-free polyether arm precursors with the polymer backbone in one step, improved yields, greater synthetic convergence, and higher throughput can be achieved, which can make changes in film properties more easily correlated to structural changes. Another advantage of the polymer film compositions disclosed herein is that, in many cases, they can be synthesized with higher purity and compositional uniformity than comparable polymer compositions with amine functionality in the polyether arms.

[0024] Another advantage of the present disclosure is that the ratio of polyethylene oxide to polypropylene oxide in the polymer film composition of the present disclosure can be much more easily varied than similar polymer compositions with amine functionality in the polyether arms. More specifically, the distribution and ratio of polyethylene oxide to polypropylene oxide can be fixed in the amine-free polyether arm precursor prior to bonding to the heterocyclic polymer. Advantageously and surprisingly, this feature can allow the ratio of polyethylene glycol to polypropylene glycol to be adjusted to promote a desired biological response in vivo, as further discussed herein.

[0025] At least some of the polymer film compositions disclosed herein can exhibit low or non-existent cytotoxicity in vivo, as well as other favorable biocompatibility. In some specific embodiments, the ratio of polyethylene oxide to polypropylene oxide can adjust the biocompatibility obtained, so that the polymer film composition can be characterized by having a cytotoxicity score of 2 or less, as measured by the minimum essential elution medium test. In some or other specific embodiments, when evaluated according to the test protocol described therein, the polymer film compositions described herein meet the biocompatibility requirements specified in the International Organization for Standardization (ISO) 10993-1.

[0026] Like this, polymer film composition disclosed herein can be particularly advantageously used in various in vivo analyte sensors, particularly when the analyte sensor is intended to be worn for a long time. However, it should be understood that polymer film composition disclosed herein can also be used in isolated analyte sensors, without departing from the scope of the present disclosure. In specific embodiments, the polymer film composition described herein can be temperature insensitive to the permeability of glucose. Other analytes such as lactate can also penetrate through the polymer film composition at a rate that is insensitive to temperature, and this rate can be different from the rate of glucose.

[0027] Thus, in some embodiments, the polymer film composition of the present disclosure may include a polymer backbone comprising one or more side chains comprising a heterocycle and an amine-free polyether arm connected to the heterocycle of at least a portion of the one or more side chains via an alkyl spacer or a hydroxyl-functionalized alkyl spacer. Such an amine-free polyether arm is distinguished from a crosslinker (i.e., a group that covalently links two or more polymer backbones together) in that the amine-free polyether arm is bonded to a single polymer backbone.

[0028] Polymers suitable for use in various embodiments of the present disclosure may include a polymer backbone that is branched or unbranched and is a homopolymer or a heteropolymer. Homopolymers can be formed by polymerization of a single type of monomer. Heteropolymers (also referred to as copolymers) include two or more different types of monomers bonded in a single polymer chain. According to various embodiments, copolymers may have a random, alternating or block distribution of different monomer units.

[0029] Heterocycles suitable for incorporation into the polymer film compositions of the present disclosure may include any cyclic moiety containing any combination of one or more carbon atoms and N, P, O, S or Si atoms, wherein the cyclic moiety may be aromatic or aliphatic. Suitable functional groups incorporating heteroatoms within aliphatic or heteroaromatic cyclic moieties may include, for example, -O-, -S-, -SS-, -OS-, -NR- 1 R 2 ,=N-,=NN=,-N=N-,-N=N-NR1 R 2 , -PR 3 -,-P(O)2-,-P(O)R 3 -, -0-P(O)2-, -SO-, -S(O)-, -S(O)2-, etc., where R 1 -R 3 R is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl. Where applicable, R 1 -R 3 Any one of R may be straight chain or branched. 1 -R 3 Substitution variants of may include any of the above groups in which a carbon atom or a hydrogen atom has been replaced by a heteroatom such as F, Cl, Br, I, N, P, O, S or Si. In illustrative but non-limiting embodiments, suitable substituents may include, for example, halogen groups, alcohol groups, ketone groups, ether groups, thioether groups, disulfide groups, and the like.

[0030] In some more specific embodiments, the polymer backbone may include a heterocyclic or heteroaromatic nitrogen moiety in one or more side chains. In some more specific embodiments, the polymer backbone may include a heteroaromatic nitrogen moiety in one or more side chains. Suitable heteroaromatic nitrogen moieties may include, for example, acridine, carbazole, carboline, cinnoline, imidazole, indazole, indole, dihydroindole, indolizine, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimelin, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolazine, quinazoline, quinoline, quinolineazine, quinoxaline, tetrazole, thiadiazole, thiazole, triazole, their derivatives, etc.

[0031] According to some embodiments, one or more comonomers may be present in combination with monomer units bearing heteroaromatic nitrogen moieties. Suitable comonomers for incorporation into the polymer film compositions of the present disclosure include, for example, styrene compounds, which optionally bear substituents on the aromatic rings. Possibly suitable substituted styrene compounds include, for example, alkyl-substituted styrenes, halogen-substituted styrenes, hydroxyl-substituted styrenes, or any combination thereof.

[0032] In some more specific embodiments, the polymer film composition of the present disclosure may include polyvinyl pyridine or polyvinyl imidazole, including any copolymer thereof. In some specific embodiments, the polymer film composition of the present disclosure may include polyvinyl pyridine, in particular a copolymer of vinyl pyridine (in particular 4-vinyl pyridine) and styrene, or polyvinyl imidazole, in particular a copolymer of vinyl imidazole (in particular 2-vinyl imidazole) and styrene. In some embodiments, substituted styrenes may be used.

[0033] According to certain embodiments, suitable copolymers of 4-vinylpyridine and styrene may comprise repeating units of Formula 1:

[0034]

[0035] wherein the variables a and b are positive integers, and Q is an optional functionality.

[0036] In some embodiments, the variables a and b may independently range from about 1 to about 1000, including from about 2 to about 950, or from about 5 to about 900, or from about 10 to about 850, or from about 15 to about 800, or from about 20 to about 750, or from about 25 to about 700, or from about 30 to about 650, or from about 35 to about 600, or from about 40 to about 550, or from about 50 to about 500, or from 1 to about 10. In some embodiments, a may be greater than b. In other embodiments, a may be less than b. Depending on the desired film properties, the ratio of a to b can range from about 1:1 to about 1:100, or from about 1:1 to about 1:95, or from 1:1 to about 1:80, or from 1:1 to about 1:75, or from about 1:1 to about 1:50, or from about 1:1 to about 1:25, or from about 1:1 to about 1:10, or from about 1:1 to about 1:5, or from about 1:1 to about 1:3, or from about 1:1 to about 1:2, or from about 1:1 to about 100:1, or from about 1:1 to about 95:1, or from about 1:1 to about 80:1, or from about 1:1 to about 75:1, or from about 1:1 to about 50:1, or from about 1:1 to about 25:1, or from about 1:1 to about 10:1, or from about 1:1 to about 5:1, or from about 1:1 to about 3:1, or from about 1:1 to about 2:1.

[0037] In some or other embodiments, suitable copolymers of 4-vinylpyridine and styrene may have a styrene content ranging from about 0.01% to about 50%, or from about 0.05% to about 45%, or from about 0.1% to about 40%, or from about 0.5% to about 35%, or from about 1% to about 30%, or from about 2% to about 25%, or from about 5% to about 20% by mole. Substituted styrenes may be used similarly and in similar amounts.

[0038] According to some or other various embodiments, the copolymer of suitable 4-vinylpyridine and styrene can have 5kDa or more, or about 10kDa or more, or about 15kDa or more, or about 20kDa or more, or about 25kDa or more, or about 30kDa or more, or about 40kDa or more, or about 50kDa or more, or about 75kDa or more, or about 90kDa or more, or about 100kDa or more molecular weight. In some more specific embodiments, the copolymer of suitable 4-vinylpyridine and styrene can have a molecular weight in the range of about 5kDa to about 150kDa, or about 10kDa to about 125kDa, or about 15kDa to about 100kDa, or about 20kDa to about 80kDa, or about 25kDa to about 75kDa, or about 30kDa to about 60kDa. Other polymers suitable for polymer film compositions of the present disclosure can have molecular weight values ​​falling into similar ranges.

[0039] In the polymer film composition of the present disclosure, the amine-free polyether arm can be attached to the heterocycle of at least a portion of the side chains in the heterocyclic polymer. For example, in the case of polyvinylpyridine, the amine-free polyether arm can be covalently bonded to the pyridine ring, particularly through the pyridine nitrogen atom. The fraction of side chains in the polymer film composition having the amine-free polyether arm attached thereto can be about 0.1% or more of the available heterocycles in the heterocyclic polymer, or about 0.2% or more of the available heterocycles in the heterocyclic polymer, or about 0.3% or more of the available heterocycles in the heterocyclic polymer, or about 0.4% or more of the available heterocycles in the heterocyclic polymer, or about 0.5% or more of the available heterocycles in the heterocyclic polymer, or about 0.6% or more of the available heterocycles in the heterocyclic polymer, or about 0.7% or more of the available heterocycles in the heterocyclic polymer, or about 0.8% or more of the available heterocycles in the heterocyclic polymer. The heterocyclic polymer comprises about 0.8% or more of the available heterocyclic rings, or about 0.9% or more of the available heterocyclic rings in the heterocyclic polymer, or about 1.0% or more of the available heterocyclic rings in the heterocyclic polymer, or about 1.2% or more of the available heterocyclic rings in the heterocyclic polymer, or about 1.4% or more of the available heterocyclic rings in the heterocyclic polymer, or about 1.6% or more of the available heterocyclic rings in the heterocyclic polymer, or about 1.8% or more of the available heterocyclic rings in the heterocyclic polymer, or about 2.0% or more of the available heterocyclic rings in the heterocyclic polymer, or about 2.2% or more of the available heterocyclic rings in the heterocyclic polymer, or about 1.5% or more of the available heterocyclic rings in the heterocyclic polymer. about 2.4% or more of the available heterocycles, or about 2.6% or more of the available heterocycles in the heterocyclic polymer, or about 2.8% or more of the available heterocycles in the heterocyclic polymer, or about 3.0% or more of the available heterocycles in the heterocyclic polymer, or about 3.5% or more of the available heterocycles in the heterocyclic polymer, or about 4.0% or more of the available heterocycles in the heterocyclic polymer, or about 4.5% or more of the available heterocycles in the heterocyclic polymer, or about 5.0% or more of the available heterocycles in the heterocyclic polymer, or about 5.5% or more of the available heterocycles in the heterocyclic polymer, or About 6.0% or more of the available heterocycles in the polymer, or about 6.5% or more of the available heterocycles in the heterocyclic polymer, or about 7.0% or more of the available heterocycles in the heterocyclic polymer, or about 7.5% or more of the available heterocycles in the heterocyclic polymer, or about 8.0% or more of the available heterocycles in the heterocyclic polymer, or about 8.5% or more of the available heterocycles in the heterocyclic polymer, or about 9.0% or more of the available heterocycles in the heterocyclic polymer, or about 9.5% or more of the available heterocycles in the heterocyclic polymer, or about 10% or more of the available heterocycles in the heterocyclic polymer.In some more specific embodiments, the amine-free polyether arms can be attached to about 0.1% to about 5% of the available heterocycles in the heterocyclic polymer, or about 0.5% to about 4.5% of the available heterocycles in the heterocyclic polymer, or about 1.0% to about 4.0% of the available heterocycles in the heterocyclic polymer, or about 1.5% to about 3.0% of the available heterocycles in the heterocyclic polymer, or about 1.5% to about 2.5% of the available heterocycles in the heterocyclic polymer.

[0040] In some alternative embodiments, the amine-free polyether arms may be attached to non-heterocyclic side chains of the heterocyclic polymer, for example by covalent bonding to an optionally substituted phenyl group.

[0041] In some embodiments, at least a portion of the heterocyclic polymers may utilize heterocycles and may also have a crosslinker attached thereto. That is, in some embodiments, the polymer film composition of the present disclosure may further include a crosslinker, which is connected to at least a portion of the one or more side chains and binds the first polymer backbone to the second polymer backbone. In addition to the amine-free polyether arm, the crosslinker may also be connected to the heterocyclic polymer. In some embodiments, the crosslinker itself may be a polyether, such as polyethylene glycol or a copolymer of ethylene glycol and propylene glycol. Such a crosslinker is not limited in terms of the number of polyethylene glycol units that may exist. In some more specific embodiments, the amount of heterocycles functionalized by the crosslinker may be greater than the amount of heterocycles functionalized by the amine-free polyether arm. In other embodiments, the amount of heterocycles functionalized by the crosslinker may be less than the amount of heterocycles functionalized by the amine-free polyether arm. In illustrative embodiments, a diepoxy polyethylene glycol compound may be used to form a polymer film composition with a crosslinker.

[0042] In some more specific embodiments, the fraction of side chains that can have a crosslinker attached thereto can be about 0.1% or more of the available heterocycles in the heterocyclic polymer, or about 0.2% or more of the available heterocycles in the heterocyclic polymer, or about 0.3% or more of the available heterocycles in the heterocyclic polymer, or about 0.4% or more of the available heterocycles in the heterocyclic polymer, or about 0.5% or more of the available heterocycles in the heterocyclic polymer, or about 0.6% or more of the available heterocycles in the heterocyclic polymer, or about 0.7% or more of the available heterocycles in the heterocyclic polymer, or about 0.8% or more of the available heterocycles in the heterocyclic polymer. About 0.8% or more of the available heterocycles, or about 0.9% or more of the available heterocycles in the heterocyclic polymer, or about 1.0% or more of the available heterocycles in the heterocyclic polymer, or about 1.2% or more of the available heterocycles in the heterocyclic polymer, or about 1.4% or more of the available heterocycles in the heterocyclic polymer, or about 1.6% or more of the available heterocycles in the heterocyclic polymer, or about 1.8% or more of the available heterocycles in the heterocyclic polymer, or about 2.0% or more of the available heterocycles in the heterocyclic polymer, or about 2.2 ...6% or more of the available heterocycles in the heterocyclic polymer, or about 1.8% or more of the available hetero about 2.4% or more of the available heterocycles in the heterocyclic polymer, or about 2.6% or more of the available heterocycles in the heterocyclic polymer, or about 2.8% or more of the available heterocycles in the heterocyclic polymer, or about 3.0% or more of the available heterocycles in the heterocyclic polymer, or about 3.5% or more of the available heterocycles in the heterocyclic polymer, or about 4.0% or more of the available heterocycles in the heterocyclic polymer, or about 4.5% or more of the available heterocycles in the heterocyclic polymer, or about 5.0% or more of the available heterocycles in the heterocyclic polymer, or about 5.5% or more of the available heterocycles in the heterocyclic polymer, or About 6.0% or more of the available heterocycles in the heterocyclic polymer, or about 6.5% or more of the available heterocycles in the heterocyclic polymer, or about 7.0% or more of the available heterocycles in the heterocyclic polymer, or about 7.5% or more of the available heterocycles in the heterocyclic polymer, or about 8.0% or more of the available heterocycles in the heterocyclic polymer, or about 8.5% or more of the available heterocycles in the heterocyclic polymer, or about 9.0% or more of the available heterocycles in the heterocyclic polymer, or about 9.5% or more of the available heterocycles in the heterocyclic polymer, or about 10% or more of the available heterocycles in the heterocyclic polymer. In some more specific embodiments, the crosslinker can be attached to about 1% to about 20% of the available heterocycles in the heterocyclic polymer, or about 2% to about 10% of the available heterocycles in the heterocyclic polymer, or about 3% to about 8% of the available heterocycles in the heterocyclic polymer, or about 4% to about 9% of the available heterocycles in the heterocyclic polymer, or about 5% to about 12% of the available heterocycles in the heterocyclic polymer.

[0043] Alternatively, in some embodiments, at least a portion of the non-heterocyclic side chains of the heterocyclic polymer, such as optionally substituted phenyl groups, can have a crosslinker attached thereto.

[0044] According to various embodiments, the amine-free polyether arm can be combined with the polymer backbone in the polymer film composition disclosed herein via a heteroatom in at least a portion of the heterocycles in one or more side chains of the heterocyclic polymer. Alternative embodiments may include those in which the amine-free polyether arm is combined with the polymer backbone via carbon atoms in at least a portion of the heterocycles in the one or more side chains and / or via carbon atoms in the optionally substituted phenyl in the polymer backbone. In some more specific embodiments, the amine-free polyether arm can be combined to the polymer backbone through heterocycles or heteroaromatic nitrogen atoms in the one or more side chains. For example, in the case where the polymer backbone is polyvinylpyridine or its copolymer, the amine-free polyether arm can be connected to the side chain through a pyridine nitrogen atom. When functionalized with an amine-free polyether arm or a crosslinking agent, the pyridine nitrogen atom is in a quaternized form.

[0045] Thus, in some more specific embodiments, the polymer film compositions of the present disclosure wherein the amine-free polyether arms are bonded to the pyridinic nitrogen atoms may have repeating units defined by the following Formulas 2 and 3:

[0046]

[0047] wherein variables a, b and Q are as defined above, c is a positive integer not greater than a, and Z is an amine-free polyether arm, a crosslinker, or any combination thereof. When both the amine-free polyether arm and the crosslinker are present, the polymer film composition may have a structure defined by one or more of Formulas 4-7:

[0048]

[0049]

[0050] where variables a, b, and Q are defined as above,

[0051] c1 and c2 are positive integers whose sum is not greater than a,

[0052] d is given by Equation 1: d = a-cl-c2 (Equation 1)

[0053] Z1 is an amine-free polyether arm, and

[0054] Z2 is a cross-linking agent.

[0055] Thus, in various polymer film composition embodiments of the present disclosure, the heteroaromatic (pyridine) rings in the heterocyclic polymers can be functionalized in any combination or pattern with Z1 and Z2. That is, in defining heterocyclic polymers suitable for incorporation into the polymer film compositions of the present disclosure, the repeating units defined by Formulae 2-7 can be present in any combination with each other.

[0056] In other specific embodiments, the polymer film composition having amine-free polyether arms bonded to the pyridine moiety but not bonded via the pyridine nitrogen atom can be defined by the following Formulas 8 and 9:

[0057]

[0058] wherein the variables a, b, c, Q and Z are as defined above.

[0059] Optionally, when the amine-free polyether arm is bonded to a pyridine carbon atom, any pyridine nitrogen atom in Formulas 8 and 9 may be quaternized by an alkyl group (e.g., by reaction with an alkyl halide). According to the embodiments described herein, any unsubstituted carbon atom in the pyridine group may be bonded to the amine-free polyether arm and / or the crosslinker. When both the amine-free polyether arm and the crosslinker are present, the amine-free polyether arm and the crosslinker may be present on the same pyridine group or on different pyridine groups.

[0060] In various embodiments, the amine-free polyether arm may include at least one polyethylene oxide block and at least one polypropylene oxide block. According to some embodiments, the amine-free polyether arm may include a diblock arrangement of polyethylene oxide and polypropylene oxide. That is, in some embodiments, the amine-free polyether arm may include an alkyl spacer or a hydroxyl-functionalized alkyl spacer, a polyethylene oxide block, and a polypropylene oxide block in sequence, and in other embodiments, the amine-free polyether arm may include an alkyl spacer or a hydroxyl-functionalized alkyl spacer, a polypropylene oxide block, and a polyethylene oxide block in sequence. In some other more specific embodiments, the amine-free polyether arm may include an alkyl spacer or a hydroxyl-functionalized alkyl spacer, a first polyethylene oxide block, a polypropylene oxide block, and a second polyethylene oxide block (i.e., an ABA repeating pattern) in sequence. In some other more specific embodiments, the amine-free polyether arm may sequentially comprise an alkyl spacer or a hydroxy-functionalized alkyl spacer, a first polypropylene oxide block, a polyethylene oxide block, and a second polypropylene oxide block (i.e., a BAB repeating pattern). According to various embodiments, the alkyl spacer or the hydroxy-functionalized alkyl spacer may be bonded to a heterocyclic or heteroaromatic nitrogen atom in a side chain of the polymer backbone. In some cases, it is also possible to bond to any carbon atom of a heterocyclic side chain or any carbon atom of a side chain phenyl. According to various embodiments, the alkyl spacer or the hydroxy-functionalized alkyl spacer may also be bonded to the first polyethylene oxide block in the amine-free polyether arm, for example, through a terminal ether bond. According to some embodiments, the second polyethylene oxide block may be terminated by methoxy. Alternatively, according to some embodiments, the alkyl spacer or the hydroxy-functionalized alkyl spacer may also be bonded to the first polypropylene oxide block in the amine-free polyether arm, and the second polypropylene oxide block may be terminated by methoxy.

[0061] Therefore, in various embodiments of the present disclosure, the amine-free polyether arm may have a structure defined by the following Formula 10 or 11:

[0062]

[0063] Wherein PE represents a polyethylene oxide block, PP represents a polypropylene oxide block, and L is a spacer. Suitable spacers may include, but are not limited to, alkyl, hydroxyl-functionalized alkyl, carbonyl, carboxylate, carboxamide, and the like. The variables q, r, s, and t are positive integers defining the number of monomer units in each block and the number of block repetitions, provided that in the polyethylene oxide and polypropylene oxide diblock arrangements applicable to Formulas 10 and 11, the variable t may be 0. In Formula 10 where t≠0, the terminal polyethylene oxide monomer unit may be substituted with an alkoxy group such as a methoxy group. Similarly, in Formula 11 where t≠0, the terminal polypropylene oxide monomer unit may be substituted with an alkoxy group such as a methoxy group. The diblock arrangements associated with Formulas 10 and 11 where t=0 may similarly have alkoxy terminal groups. According to some embodiments, the variable q is an integer between about 2 and about 50 or between about 6 and about 20, the variable r is an integer between about 2 and about 60 or between about 10 and about 40, and the variable t is an integer between about 2 and about 50 or between about 10 and about 30. According to some or other various embodiments, the variable s is an integer between 1 and about 20 or between 1 and about 10. In some embodiments, the variable s is equal to 1. The diblock arrangement of polyethylene oxide and polypropylene oxide may include the variables q and r in the same ranges as above, but the variable s is equal to 1 and the variable t is equal to 0.

[0064] In some more specific embodiments of the present disclosure, the amine-free polyether arm may have a structure defined by Formula 12:

[0065]

[0066] Wherein variable w is 0 or 1, variable x is an integer between about 4 and about 24 or between about 6 and about 20, variable y is an integer between about 8 and about 60 or between about 10 and about 40, and variable z is an integer between about 6 and about 36 or between about 10 and about 30. Alternatively, in a diblock arrangement, variable z can be 0, while the other variables are in the same range. In some more specific embodiments, variable x can be between about 8 and about 16 or between about 9 and about 12, variable y can be between about 10 and about 32 or between about 16 and about 30 or between about 12 and about 20, and variable z can be between about 10 and about 20 or between about 14 and about 18. In some other more specific embodiments, x can be 10, y can be 20, and z can be 14; or x can be 12, y can be 16, and z can be 16; or x can be 14, y can be 12, and z can be 18. In some embodiments, x can be less than z, such that the second polyethylene oxide block is longer (larger) than the first polyethylene oxide block.

[0067] In some embodiments, the ratio of (x+z):y in Formula 12 can be at least about 1.4:1, or at least about 1.7:1, or at least about 2:1, or at least about 2.5:1, or at least about 3:1, or at least about 3.5:1. In more specific embodiments, the ratio of (x+z):y in Formula 12 can be in the range of about 1.4:1 to about 5:1, or in the range of about 1.7:1 to about 3.2:1, or in the range of about 2.2:1 to 3.0:1, or in the range of about 2.6:1 to about 2.9:1, or in the range of about 3:1 to about 5:1.

[0068] In some embodiments of the present disclosure, the amine-free polyether arm may have a structure defined by Formula 13:

[0069]

[0070] Wherein variable w is 0 or 1, variable x is an integer between about 4 and about 24 or between about 6 and about 20, variable y is an integer between about 8 and about 60 or between about 10 and about 40, and variable z is an integer between about 6 and about 36 or between about 10 and about 30. Alternatively, in a diblock arrangement, variable z can be 0, while the other variables are in the same range. In more specific embodiments, variable x can be between about 6 and about 16 or between about 9 and about 12, variable y can be between about 10 and about 40 or between about 16 and about 30 or between about 14 and about 32, and variable z can be between about 8 and about 20 or between about 12 and about 16.

[0071] The amine-free polyether arms described herein can be bonded to the heterocycle in the side chain of the heterocyclic polymer through the reactive functional group in the amine-free polyether arm precursor. Suitable reactive functional groups can include, for example, halogens or epoxides, which can react via nucleophilic attack from the side chain of the heterocyclic polymer. Halogen-functionalized amine-free polyether arm precursors lead to amine-free polyether arms in which n is 0 (i.e., the spacer is an alkyl group), while epoxide-functionalized amine-free polyether arm precursors lead to amine-free polyether arms in which n is 1 (i.e., the spacer is a propyl group with a secondary alcohol). In a more specific embodiment, the alkyl spacer generated by the halogen-functionalized amine-free polyether arm precursor can include a linear or branched alkyl group containing 2 to about 20 carbon atoms. In a more specific embodiment, the halogen that can be suitably included in the halogen-functionalized amine-free polyether arm precursor includes chlorine or bromine, wherein bromine is selected in a more specific embodiment.

[0072] Formulas 14 and 15 show the structures of exemplary amine-free polyether arm precursors that may be suitably reacted with heterocyclic polymers to form certain polymer film compositions disclosed herein, wherein the variables x, y, and z are as defined above.

[0073]

[0074] In Formula 14, variable A1 represents an alkyl group having 2 to about 20 carbon atoms, such as 2 to about 4 carbon atoms, or 2 to about 6 carbon atoms, or 2 to about 8 carbon atoms, and X is a halogen, such as chlorine or bromine. The alkyl group of A1 can be branched or straight-chain, and optionally contains heteroatom substitution. According to various embodiments, the halogen X can be a primary alkyl halogen. In Formula 15, variable A2 represents an alkyl group having 1 to about 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. In some embodiments, the alkyl group of A2 can be straight-chain, and in other embodiments, the alkyl group A2 can contain a branched chain.

[0075] In more specific embodiments, suitable amine-free polyether arm precursors for forming the polymeric film compositions disclosed herein can include those represented by Formulas 16 and 17, wherein the various variables are as defined above.

[0076]

[0077] In some embodiments, the sulfonate-containing arms may be attached to at least a portion of one or more side chains in the heterocyclic polymer disclosed herein. The sulfonate-containing arms may be combined with any amine-free polyether arms disclosed herein and present in any suitable ratio. In some embodiments, the polymer film composition disclosed herein may include a higher amount of amine-free polyether arms than sulfonate-containing arms.

[0078] According to some more specific embodiments, the sulfonate-containing arm can be connected to the heterocycle of the heterocyclic polymer via an alkyl group. According to various embodiments, the alkyl group can contain 1 to about 6 carbon atoms or 2 to about 4 carbon atoms. Suitable reagents for introducing the sulfonate-containing arm into the heterocyclic polymer disclosed herein can include halogenated sulfonic acid compounds such as chloromethanesulfonic acid, bromoethanesulfonic acid, etc., or cyclic sulfonate esters (sultones).

[0079] In some embodiments, an amine-free polyether arm comprising a single type of repeating ether unit can be attached to at least a portion of one or more side chains in the heterocyclic polymer disclosed herein. Such an amine-free polyether arm can be present in combination with a sulfonate-containing arm and / or an amine-free polyether arm having two or more different types of ether unit blocks, such as those described in Formulas 10-13.

[0080] According to a more specific embodiment, the amine-free polyether arm comprising a single type of repeating ether unit can be a polyethylene oxide arm or a polypropylene oxide arm. In a more particular embodiment, the amine-free polyether arm can be an amine-free polyethylene oxide arm connected to a heterocycle of at least a portion of the one or more side chains via an alkyl spacer or a hydroxyl-functionalized alkyl spacer. There can be about 8 to about 25, or about 10 to about 22, or about 12 to about 20 repeating ether units in the amine-free polyether arm comprising a single type of repeating ether unit. The repeated polyethylene oxide or polypropylene oxide ether unit can be connected to one or more side chains of the heterocyclic polymer via an alkyl or hydroxyl-functionalized alkyl. According to various embodiments, the alkyl group can contain 1 to about 6 carbon atoms, or 2 to about 4 carbon atoms. The hydroxyl-functionalized alkyl group can contain 3 carbon atoms with a hydroxyl group on the central carbon atom. At the end opposite to the point of attachment to the heterocyclic polymer, an alkoxy group, particularly a methoxy group, can terminate the amine-free polyether arm. Such amine-free polyether arms can be introduced into the heterocyclic polymer by reacting the heterocyclic polymer with an alkyl halide or epoxide terminated polyether.

[0081] In some embodiments, the polymer film compositions of the present disclosure may be cross-linked, as briefly mentioned above. A cross-linked polymer suitable for incorporation into the polymer film composition may include a cross-linking agent that connects two or more polymer backbones to each other (intermolecular cross-linking) or connects different parts of the same polymer backbone to each other (intramolecular cross-linking). A "cross-linking agent" containing two or more reactive functional groups can promote such cross-linking. Once cross-linking occurs, a portion of the cross-linking agent can remain as a cross-linking agent that connects one or more polymer chains to each other intermolecularly or intramolecularly.

[0082] In some embodiments, suitable cross-linking agents may include polyether imines and glycidyl ethers such as diglycidyl ether. Such combinations of agents form cross-linked structures containing amine groups. In other embodiments, suitable cross-linking agents may include polyethers and glycidyl ethers such as diglycidyl ethers, which result in cross-linked structures without amine groups. In more particular embodiments, suitable cross-linking agents for forming cross-linked structures without amines may include polyethylene oxide / polypropylene oxide copolymers and glycidyl ethers such as diglycidyl ether, or polyethylene oxide and glycidyl ethers such as diglycidyl ether.

[0083] In some or other embodiments, a suitable crosslinking agent may include a polyethylene oxide block having a terminal propylene oxide unit at each end of the polyethylene oxide block. Such a crosslinking agent may have a structure as shown in Formula 18:

[0084]

[0085] Wherein the variable n is between about 10 and about 500, or between about 10 and about 100, or between about 10 and about 50, or between about 12 and about 36, or between about 12 and about 30, or between about 12 and about 28, or between about 12 and about 26, or between about 12 and about 24, or between about 12 and about 22, or between about 12 and about 20, or between about 14 and about 28, or between about 14 and about 24, or between about 16 and about 30, or between about 16 and about 24. As will be appreciated by one of ordinary skill in the art, the crosslinking agent of Formula 18 reacts to form a crosslinked structure in which a polyethylene oxide block is bonded to the polymer backbone at each end via a hydroxyl-functionalized alkyl group. Specifically, the crosslinking agent of Formula 18 produces a crosslinking agent of Formula 19 upon nucleophilic opening of the epoxide ring in each terminal propylene oxide unit, wherein n is as defined above.

[0086]

[0087] Thus, in more specific embodiments of the present disclosure, a suitable cross-linked structure may include at least one polyethylene oxide block, each bonded to a first heterocycle of a first polymer backbone and a second heterocycle of a second polymer backbone at opposite ends through a hydroxyl-functionalized alkyl group. In such embodiments, the cross-linking is intermolecular cross-linking. In some or other embodiments of the present disclosure, such a cross-linking agent may be bonded to a first and a second heterocycle within the same polymer backbone at opposite ends through a hydroxyl-functionalized alkyl group, in which case the cross-linking is intramolecular cross-linking.

[0088] In some embodiments, crosslinking agents having additional epoxy groups may also be used, such as the illustrative triepoxide compound shown in Formula 20. Such crosslinking agents may result in the formation of crosslinked structures between more than two polymer backbones.

[0089]

[0090] Optionally, such crosslinking agents may be further reacted with polyethylene glycol, polypropylene glycol or ethylene glycol / propylene glycol copolymers to form given crosslinks.

[0091] Advantageously, according to various embodiments, the polymer film composition of the present disclosure can form a temperature-insensitive film. The term "temperature-insensitive" as used herein refers to a condition in a given range of a parameter of interest that changes with temperature in a clinically or statistically insignificant manner. In a more specific embodiment, the temperature-insensitive film of the present disclosure can be temperature-insensitive with respect to analyte permeability, particularly glucose permeability. Other analytes may also exhibit temperature-insensitive membrane permeability, with a permeation rate that is the same or different from that of glucose. Like this, when analyzing a fixed concentration of analyte within a given temperature range that is temperature-insensitive to the polymer film composition, the limited change in analyte permeability can result in little or no change in sensor response.

[0092] In more specific embodiments, the polymer film compositions of the present disclosure may be temperature insensitive with respect to analyte permeability (e.g., glucose permeability) within a temperature range of about 10°C to about 70°C, or about 15°C to about 65°C, or about 20°C to about 60°C, or about 25°C to about 50°C, or about 15°C to about 45°C, or about 15°C to about 40°C, or about 20°C to about 45°C, or about 25°C to about 40°C. In some or other more specific embodiments, the change in analyte permeability (e.g., glucose permeability) of the polymer film composition may be about 10% or less within the temperature range, or about 5% or less within the temperature range, or about 2% or less within the temperature range, or about 1% or less within the temperature range, or about 0.5% or less within the temperature range, or about 0.1% or less within the temperature range, or about 0.05% or less within the temperature range, or about 0.01% or less within the temperature range. Within a sub-range of a broader temperature range (e.g., about 15° C. to about 45° C.), the change in analyte permeability of the polymer film composition can be about 2% or less or about 1% or less within a given temperature increment of 5° C. The change in analyte permeability of the polymer film composition can be determined by measuring the difference in sensor response over a specified temperature range at a fixed analyte concentration (see Figure 4 ).

[0093] The polymer film compositions described herein can be further characterized by their biocompatibility. In various embodiments, the polymer film compositions can be characterized by having a cytotoxicity score of 2, or a cytotoxicity score of 1, or a cytotoxicity score of 0. Such cytotoxicity scores can be present in combination with features such as no hemolysis, mutagenicity, irritation, and similar properties. In some embodiments, the polymer film compositions of the present disclosure meet or exceed the ISO 10993-1 standard. The ISO 10993-1 standard for tissue implant devices includes the following clinical deficiencies: cytotoxicity, sensitization, irritation or intradermal reactivity, acute systemic toxicity, pyrogenicity, subacute or subchronic toxicity, genotoxicity, and implantation problems.

[0094] According to various embodiments, the polymer film composition disclosed above can be present in an analyte sensor. Therefore, the analyte sensor of the present disclosure can include a sensing region (i.e., the active portion of the sensor) and a polymer film composition covering the sensing region. The polymer film composition can include a polymer backbone and an amine-free polyether arm, wherein the polymer backbone includes one or more side chains containing a heterocycle, and the amine-free polyether arm is connected to the heterocycle of at least a portion of the one or more side chains through an alkyl spacer or a hydroxyl-functionalized alkyl spacer. As further discussed herein, any of the polymer film compositions can be used in conjunction with an analyte sensor.

[0095] In some embodiments, the sensing region of the analyte sensor of the present disclosure may include an enzyme. The enzyme may catalyze a reaction that consumes the target analyte or produces a product that can be detected by the analyte sensor. According to some embodiments, the enzyme may be covalently bonded to a polymer that comprises at least a portion of the sensing region. The selection of a specific enzyme may be determined by the target analyte to be detected. When the target analyte is glucose, glucose oxidase or glucose dehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucose dehydrogenase, flavin adenine dinucleotide (FAD) dependent glucose dehydrogenase, or nicotinamide adenine dinucleotide (NAD) dependent glucose dehydrogenase) may be used. When the target analyte is lactic acid, lactate oxidase or lactate dehydrogenase may be used. When the target analyte is oxygen or when oxygen is produced or consumed in response to a reaction of an analyte, laccase may be used. As will be appreciated by those of ordinary skill in the art who understand the benefits of the present disclosure, other enzymes may be similarly used to detect other target analytes. Any substrate acted upon by the aforementioned enzymes or other enzymes may be an analyte suitable for analysis by the analyte sensor disclosed herein.

[0096] Additional details of illustrative analyte sensors that may be used in conjunction with the disclosed polymer film compositions are discussed in further detail below. However, it should be understood that analyte sensors having structures and components different from those explicitly disclosed herein may also be suitably used.

[0097] Figure 1 Shown is a figure of an illustrative analyte monitoring system that can be combined with an analyte sensor of the present disclosure.As shown in the figure, analyte monitoring system 100 includes sensor control device 102 and reader device 120, which are constructed to communicate with each other through local communication paths or links, and this local communication path or link can be wired or wireless, unidirectional or bidirectional and encrypted or non-encrypted.Reader device 120 can also communicate with remote terminal 170 and / or trusted computer system 180 via communication path / link 141 and / or 142 respectively, and the communication path / link 141 and / or 142 can also be wired or wireless, unidirectional or bidirectional and encrypted or unencrypted.Any suitable electronic communication protocol can be used for each local communication path or link.Reader device 120 can include display 122 and optional input assembly 121.

[0098] Sensor control device 102 includes sensor housing 103, which may include circuitry and a power source for operating sensor 104. Sensor 104 protrudes from sensor housing 103 and extends through adhesive layer 105. Suitable adhesives included in adhesive layer 105 are familiar to those of ordinary skill in the art.

[0099] Sensor 104 is suitable for at least partially inserting into a tissue of interest, such as the dermis of the skin. Sensor 104 may include a sensor tail having a sufficient length to be inserted into the desired depth in a given tissue. According to one or more embodiments, the sensor tail may include a sensing region that is effective for sensing and may include an enzyme. According to various embodiments, the sensing region includes a polymer film composition of the present disclosure. According to one or more embodiments, sensor 104 can be used to determine one or more analyte levels and communicate with a reader device 120. Analytes can be monitored in any biological fluid such as dermal fluid, plasma, blood, lymph, etc. Analytes that can be monitored are not considered to be particularly limited. In certain embodiments, the analyte can be glucose. Other analytes of interest regarding human physiology can include, for example, lactic acid, oxygen, pH, Ale, ketones, drug levels, etc. Any of these analytes can exhibit temperature-insensitive permeability through the polymer film composition disclosed herein. Any combination of a single analyte and the aforementioned analytes can be analyzed.

[0100] An inserter may be present briefly to facilitate insertion of sensor 104 into tissue. In an illustrative embodiment, the inserter may include a needle 109. It should be appreciated that other types of inserters such as sheaths or blades may be present in alternative embodiments. More specifically, the needle or similar inserter may reside briefly near sensor 104 before insertion and then withdrawn thereafter. When present, the needle or other inserter may facilitate insertion of sensor 104 into tissue by opening an entry path for sensor 104 to follow. For example, according to one or more embodiments, the needle may facilitate puncture of the epidermis as a pathway to the dermis to allow implantation of sensor 104 to occur. After opening the entry channel, the needle or other inserter may be pulled out so that it does not become a sharp hazard. In an illustrative embodiment, the needle may be solid or hollow, beveled or non-beveled and / or circular or non-circular in cross section. In a more specific embodiment, the cross-sectional diameter and / or tip design of the needle may be comparable to an acupuncture needle, which may have a cross-sectional diameter of approximately 250 microns. However, it will be appreciated that a suitable needle may have a larger or smaller cross-sectional diameter if desired for a particular application. In alternative embodiments, needle 109 or similar inserter may not be present, provided that sensor 104 is sufficiently robust to penetrate tissue and establish communication with the bodily fluid of interest.

[0101] In some embodiments, the tip of the needle may be angled on the end of the sensor 104 so that the needle first penetrates the tissue and opens an entry path for the sensor 104. In other illustrative embodiments, the sensor 104 may reside within a lumen or groove of the needle 109, which similarly opens an entry path for the sensor 104. In both cases, the needle is withdrawn after facilitating insertion.

[0102] It should be appreciated that the analyte monitoring system 100 may include additional features and functionality that are not necessarily described herein for the sake of brevity.Accordingly, the foregoing description of the analyte monitoring system 100 should be regarded as illustrative in nature rather than limiting.

[0103] According to various embodiments, the analyte sensor of the present disclosure may include two electrodes or three electrode detection modes. The three electrode mode may include a working electrode, a counter electrode and a reference electrode. The two-electrode mode may include a working electrode and a second electrode, wherein the second electrode is used as both a counter electrode and a reference electrode (i.e., a pair / reference electrode). In the two-electrode and three-electrode detection modes, the sensing area of ​​the analyte sensor described herein may contact the working electrode. In various embodiments, various electrodes may be at least partially stacked on each other, as described in further detail below. In alternative embodiments, various electrodes may be spaced apart from each other on the insertion tail of the analyte sensor.

[0104] Figure 2 A diagram of an illustrative two-electrode sensor configuration compatible with the present disclosure is shown. As shown, the analyte sensor 200 includes a substrate 212 disposed between a working electrode 214 and a counter / reference electrode 216. Alternatively, the working electrode 214 and the counter / reference electrode 216 can be located on the same side of the substrate 212, with a dielectric material interposed therebetween. A sensing region 218 is disposed at least at one point on at least a portion of the working electrode 214. In some embodiments, a membrane 220 covers at least the sensing region 218, and may optionally cover some or all of the working electrode 214 and / or the counter / reference electrode 216. One or both surfaces of the sensor 200 may be covered with a membrane 220. The membrane 220 may comprise any polymer membrane composition disclosed herein.

[0105] The three-electrode sensor configuration may be similar to analyte sensor 200 ( Figure 3A and 3B ). In the case where the additional electrode 217 is used, the counter / reference electrode 216 is used as a counter electrode or a reference electrode, and the additional electrode 217 ( Figure 3A and 3B ) realizes another function that is not realized. The additional electrode 217 can be arranged on the working electrode 214 or the counter / reference electrode 216, with an isolation layer of dielectric material therebetween. Figure 3A As shown in FIG. 2 , dielectric layers 219a, 219b, and 219c separate electrodes 214, 216, and 217 from each other. Alternatively, at least one of electrodes 214, 216, and 217 may be located on an opposite side of substrate 212 ( Figure 3B ). Thus, in some embodiments, electrode 214 (working electrode) and electrode 216 (counter electrode) can be located on opposite sides of substrate 212, while electrode 217 (reference electrode) is located on one of electrodes 214 or 216 and separated therefrom by a dielectric material. According to some embodiments, a conductive layer 222 such as a silver / silver chloride reference can be located on electrode 217 (reference electrode). Figure 2 Similar to the sensor 200 shown in FIG. 2 , the sensing region 218 may include one or more spots configured to detect a target analyte.

[0106] In some embodiments, the additional electrode 217 may optionally be covered with a membrane 220. Although Figure 3A and 3B All electrodes 214, 216 and 217 have been depicted as being covered by film 220, but it should be appreciated that only the sensing area 218 must be covered in order to achieve the benefits described herein. Figure 3A and 3BThe configuration shown in is a non-limiting embodiment disclosed herein. As in the two-electrode configuration, one or both sides of the sensor 200 can be covered with a membrane 220.

[0107] When overlying the sensing region 218 , the film 220 may have a thickness between about 0.1 micrometers and about 1000 micrometers, or between about 1 micrometer and about 500 micrometers, or between about 10 micrometers and about 100 micrometers.

[0108] In some embodiments, the sensing region 218 may include a polymer bound to glucose oxidase or another enzyme and a low potential osmium complex electron transfer mediator, such as disclosed in, for example, U.S. Pat. No. 6,134,461, which is incorporated herein by reference in its entirety. Other suitable electron transfer mediators may include, for example, metal compounds or complexes of ruthenium, iron, or cobalt. Suitable ligands for the metal complex may include, for example, bidentate or higher dentate ligands, such as bipyridine, biimidazole, or pyridyl (imidazole). Other suitable bidentate ligands may include, for example, amino acids, oxalic acid, acetylacetone, diaminoalkanes, or ortho-diaminoarene. Any combination of monodentate, bidentate, tridentate, tetradentate, or higher dentate ligands may be present in the metal complex to achieve a complete coordination sphere.

[0109] The enzyme in the sensing region 218 can be covalently bonded to a polymer or other suitable matrix via a crosslinker. Suitable crosslinkers for reacting with free amino groups in the enzyme (e.g., with free amines in lysine) can include crosslinkers such as polyethylene glycol diglycidyl ether (PEGDGE) or other polyepoxides, cyanuric chloride, N-hydroxysuccinimide, imino esters, or derivatives thereof. Suitable crosslinkers for reacting with free carboxyl groups in the enzyme can include, for example, carbodiimides.

[0110] Various methods may be employed to determine the concentration of an analyte using the analyte sensor 200. For example, the concentration of the analyte may be monitored using any of coulometric, amperometric, voltammetric, or potentiometric electrochemical detection techniques.

[0111] Embodiments disclosed herein include:

[0112] A. Polymer film composition. The polymer film composition comprises: a polymer backbone comprising one or more side chains comprising a heterocyclic ring; and an amine-free polyether arm connected to the heterocyclic ring of at least a portion of the one or more side chains through an alkyl spacer or a hydroxyl-functionalized alkyl spacer.

[0113] B. Analyte sensor. The analyte sensor comprises: a sensing region; and a polymer film composition covering the sensing region; wherein the polymer film composition comprises a polymer backbone and an amine-free polyether arm, the polymer backbone comprises one or more side chains comprising a heterocycle, and the amine-free polyether arm is connected to the heterocycle of at least a portion of the one or more side chains through an alkyl spacer or a hydroxyl-functionalized alkyl spacer.

[0114] C. A polymer film composition having temperature insensitivity to glucose or other potential analytes. The polymer film composition is temperature insensitive, at least with respect to glucose permeability, within a temperature range of about 15°C to about 45°C and meets or exceeds ISO 10993-1 standards.

[0115] Each of embodiments A and B may have multiple additional elements of one or any combination of the following:

[0116] Element 1: wherein the polymer backbone comprises polyvinylpyridine or polyvinylimidazole.

[0117] Element 2: wherein the polymer backbone comprises a copolymer of vinylpyridine and styrene.

[0118] Element 3: wherein the amine-free polyether arm comprises at least one polyethylene oxide block and at least one polypropylene oxide block, and the amine-free polyether arm is bonded to a heterocyclic or heteroaromatic nitrogen atom in a side chain of the polymer backbone.

[0119] Element 4: wherein the amine-free polyether arm has the following structure:

[0120]

[0121] wherein w is 0 or 1, x is between about 4 and about 24, y is between about 8 and about 60, and z is between about 6 and about 36.

[0122] Element 5: wherein x is between about 8 and about 16, y is between about 10 and about 32, and z is between about 10 and about 20.

[0123] Element 6: Where x≤z.

[0124] Element 7: wherein the ratio of (x+z):y is at least about 1.7:1.

[0125] Element 8: wherein the ratio of (x+z):y is between about 1.7:1 and about 5:1.

[0126] Element 9: wherein the polymer film composition further comprises an arm containing a sulfonate group attached to at least a portion of the one or more side chains.

[0127] Element 10: wherein the polymer film composition further comprises a cross-linking agent that is linked to at least a portion of the one or more side chains and binds the first polymer backbone to the second polymer backbone.

[0128] Element 11: wherein the sensing region comprises an enzyme.

[0129] Element 12: wherein the polymer film composition further comprises an amine-free polyethylene oxide arm connected to the heterocyclic ring of at least a portion of the one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0130] As non-limiting examples, exemplary combinations suitable for A and B include:

[0131] A composition in combination with: 1 and 2; 1 and 3; 1 and 4; 1, 4 and 5; 1, 4 and 6; 1, 4, 5 and 6; 1, 4 and 7; 1, 4, 5 and 7; 1, 4 and 8; 1, 4, 5 and 8; 1 and 9; 1 and 10; 1 and 12; 1, 9 and 10; 2 and 3; 2 and 4; 2, 4 and 5; 2, 4 and 6; 2, 4, 5 and 6; 2, 4 and 7; 2, 4, 5 and 7; 2, 4 and 8; 2, 4, 5 and 8; 2 and 9; 2 and 10; 2, 9 and 10; 3 and 4; 3, 4 and 5; 3, 4 and 6; 3, 4, 5 and 6; 3, 4 and 7; 3, 4, 5 and 7; 3, 4 and 8; 3, 4, 5 and 9; 3 and 9; 3 and 10; 3, 9 and 10; 4 and 5; 4 and 6; 4, 5 and 6; 4 and 7; 4, 5 and 7; 4 and 8; 4, 5 and 8; 4 and 9; 4 and 10; 4, 9 and 10; 4 and 12; 9 and 10; 10 and 12; and 11 and 12. B Analyte sensor in combination with: 1 and 2; 1 and 3; 1 and 4; 1, 4 and 5; 1, 4 and 6; 1, 4, 5 and 6; 1, 4 and 7; 1, 4, 5 and 7; 1, 4 and 8; 1, 4, 5 and 8; 1 and 9; 1 and 10; 1, 9 and 10; 1 and 12; 2 and 3; 2 and 4; 2, 4 and 5; 2, 4 and 6; 2, 4, 5 and 6; 2, 4 and 7; 2, 4, 5 and 7; 2, 4 and 8; 2, 4, 5 and 8; 2 and 9; 2 and 10; 2, 9 and any of which may be further combined with element 11. The composition of C may be used in combination with any element applicable to A.

[0132] The present disclosure also provides the following embodiments:

[0133] Embodiment 1. A polymer film composition comprising:

[0134] a polymer backbone comprising one or more side chains comprising a heterocyclic ring; and

[0135] The amine-free polyether arms are connected to the heterocyclic ring of at least a portion of the one or more side chains through an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0136] Embodiment 2. The polymer film composition of Embodiment 1, wherein the polymer backbone comprises polyvinylpyridine or polyvinylimidazole.

[0137] Embodiment 3. The polymer film composition of Embodiment 2, wherein the polymer backbone comprises a copolymer of vinylpyridine and styrene.

[0138] Embodiment 4. The polymer film composition of Embodiment 1, wherein the amine-free polyether arm comprises at least one polyethylene oxide block and at least one polypropylene oxide block, and the amine-free polyether arm is bonded to a heterocyclic or heteroaromatic nitrogen atom in a side chain of the polymer backbone.

[0139] Embodiment 5. The polymer film composition of Embodiment 4, wherein the amine-free polyether arm has the following structure:

[0140]

[0141] wherein w is 0 or 1, x is between about 4 and about 24, y is between about 8 and about 60, and z is between about 6 and about 36.

[0142] Embodiment 6. The polymer film composition of Embodiment 5, wherein x is between about 8 and about 16, y is between about 10 and about 32, and z is between about 10 and about 20.

[0143] Embodiment 7. The polymer film composition of Embodiment 5, wherein x≤z.

[0144] Embodiment 8. The polymer film composition of Embodiment 5, wherein the ratio of (x+z):y is at least about 1.7:1.

[0145] Embodiment 9. The polymer film composition of Embodiment 5, wherein the ratio of (x+z):y is between about 1.7:1 and about 5:1.

[0146] Embodiment 10. The polymer film composition of Embodiment 1, further comprising a sulfonate-containing arm attached to at least a portion of the one or more side chains.

[0147] Embodiment 11. The polymer film composition of Embodiment 1 further comprises an amine-free polyethylene oxide arm connected to the heterocyclic ring of at least a portion of the one or more side chains through an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0148] Embodiment 12. The polymer film composition of embodiment 1, further comprising a crosslinker that is attached to at least a portion of the one or more side chains and binds the first polymer backbone to the second polymer backbone.

[0149] Embodiment 13. The polymer film composition of Embodiment 1, wherein the polymer film composition meets or exceeds ISO 10993-1 standard.

[0150] Embodiment 14. An analyte sensor comprising:

[0151] Sensing area; and

[0152] a polymer film composition covering the sensing area;

[0153] The polymer film composition comprises a polymer backbone and an amine-free polyether arm, wherein the polymer backbone comprises one or more side chains comprising a heterocycle, and the amine-free polyether arm is connected to the heterocycle of at least a portion of the one or more side chains through an alkyl spacer or a hydroxyl-functionalized alkyl spacer.

[0154] Embodiment 15. The analyte sensor of Embodiment 14, wherein the sensing region comprises an enzyme.

[0155] Embodiment 16. The analyte sensor of Embodiment 14, wherein the polymer backbone comprises polyvinylpyridine or polyvinylimidazole.

[0156] Embodiment 17. The analyte sensor of Embodiment 16, wherein the polymer backbone comprises a copolymer of vinylpyridine and styrene.

[0157] Embodiment 18. The analyte sensor of Embodiment 14, wherein the amine-free polyether arms comprise at least one polyethylene oxide block and at least one polypropylene oxide block, the amine-free polyether arms being bonded to heterocyclic or heteroaromatic nitrogen atoms in the side chains of the polymer backbone.

[0158] Embodiment 19. The analyte sensor of Embodiment 14, wherein the amine-free polyether arm has the following structure:

[0159]

[0160] wherein w is 0 or 1, x is between about 4 and about 24, y is between about 8 and about 60, and z is between about 6 and about 36.

[0161] Embodiment 20. The analyte sensor of Embodiment 19, wherein x is between about 8 and about 16, y is between about 10 and about 32, and z is between about 10 and about 20.

[0162] Embodiment 21. The analyte sensor of Embodiment 19, wherein x≤z.

[0163] Embodiment 22. The analyte sensor of Embodiment 19, wherein the ratio of (x+z):y is at least about 1.7:1.

[0164] Embodiment 23. The analyte sensor of Embodiment 19, wherein the ratio of (x+z):y is between about 1.7:1 and about 5:1.

[0165] Embodiment 24. The analyte sensor of Embodiment 14, further comprising a sulfonate-containing arm attached to at least a portion of the one or more side chains.

[0166] Embodiment 25. The analyte sensor of Embodiment 14, further comprising an amine-free polyethylene oxide arm connected to the heterocyclic ring of at least a portion of the one or more side chains via an alkyl spacer or a hydroxyl-functionalized alkyl spacer.

[0167] Embodiment 26. The analyte sensor of Embodiment 14, further comprising a crosslinker attached to at least a portion of the one or more side chains and binding the first polymer backbone to the second polymer backbone.

[0168] Embodiment 27. A polymer film composition that is temperature insensitive, at least with respect to glucose permeability, within a temperature range of about 15°C to about 45°C and that meets or exceeds ISO 10993-1 standards.

[0169] To aid a better understanding of the embodiments described herein, the following examples of various representative embodiments are given. The following examples should in no way be construed as limiting or defining the scope of the invention. Example

[0170] Example 1: Temperature variation.

[0171] A copolymer of vinylpyridine and styrene having an amine-free polyether arm having a structure corresponding to Formula 12 (w=1, x=14, y=12, z=18) was coated on a glucose-responsive sensor. The coated sensor was then exposed to a fixed concentration of glucose solution, and the sensor response was measured over a range of temperatures. Figure 4 A graph showing sensor response data over the temperature range of 17°C to 42°C is shown. Figure 4As shown in Figure 1, the sensor response shows minimal variation over a fairly large temperature range that covers the normal physiological temperature of humans. Even at temperatures where the response variation starts to be observed (i.e., greater than 37°C), the response variation is still less than 2% over a 5°C measurement interval, as shown in Figure 1. Figure 5 as shown in the bar graph.

[0172] Example 2: Glucose response.

[0173] The coated sensor of Example 1 was tested at room temperature under variable glucose concentrations. Figure 6 As shown in , at a fixed temperature, the sensor response as a function of glucose concentration is approximately linear.

[0174] Example 3: Biocompatibility testing.

[0175] Copolymers of vinylpyridine and styrene having amine-free polyether arms corresponding to general formula 12 (w=1, and variables x, y and z are as defined in Table 1 below) were subjected to several biocompatibility tests. The tests were performed according to ISO 10993-1 protocol and may be briefly described below.

[0176] Cytotoxicity: The cytotoxicity of polymers with amine-free polyether arms was tested under standard conditions using the minimal essential media test. The results are shown in Table 1. Cytotoxicity testing was performed by applying an extract of the polymer (minimal essential media without glucose) to a test cell monolayer, incubating and scoring based on the extent of monolayer disruption and the amount of cell lysis. A score of 0 represents no observable monolayer disruption or cell lysis. Mild cytotoxicity is classified as 2 points or less (<50% monolayer disruption, no extensive cell lysis). According to current USP and National Formulary requirements (<USP 87> ), for some purposes, a score of 2 or lower is considered an acceptable standard.

[0177] Table 1

[0178] experiment x y z (x+z):y Cytotoxicity score 1 10 20 14 1.2 2 2 12 16 16 1.75 0 3 14 12 18 2.67 0

[0179] As shown in Table 1, increasing the ratio of polyethylene oxide to polypropylene oxide improved the cytotoxic response.

[0180] Hemolysis: Hemolysis studies were performed on the polymer of Experiment 3 using the extraction method (phosphate buffered saline) specified in ASTM F 756. There was no difference in hemolysis between the extract and the negative control, which means that the polymer of Experiment 3 was non-hemolytic with a hemolytic index of 2 or less.

[0181] Mutagenicity: The polymer from Experiment 3 was subjected to mutagenicity studies using the Ames test. In this test, the extracts of the polymer did not meet the requirements for mutagenicity.

[0182] Single-dose systemic irritation study: The extracts of the polymers of Experiment 3 were injected intravenously or intraperitoneally. During the observation period, no signs of toxicity were observed compared to the control.

[0183] Skin Irritation Studies. Skin irritation studies of the extract of the polymer of Experiment 3 resulted in a sensitization response score of 0, meaning that there was no visible erythema or edema.

[0184] Intradermal irritation study: Intradermal irritation study of the polymer extract of Experiment 3 did not produce abnormal clinical signs during the 72-hour observation period compared to vehicle control. The calculated erythema and edema scores were less than 1 (almost no perceptible erythema or edema) compared to the control group.

[0185] Implantation Studies: When implanted, the polymer from Experiment 3 produced an irritation score of 0.2, thus classifying it as non-irritating.

[0186] Unless otherwise indicated, all numbers expressing quantities and the like in this specification and the associated claims 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 in the following specification and the attached claims are approximations that may vary depending upon the desired properties sought to be obtained by embodiments of the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0187] One or more illustrative embodiments incorporating various features are presented herein. For the sake of clarity, all features of physical implementation are not described or shown in this application. It should be understood that in the development of the physical implementation scheme in conjunction with the embodiment of the present invention, many implementation scheme-specific decisions must be made to achieve the developer's goal, such as complying with system-related, business-related, government-related and other constraints, which depend on implementation and change from time to time. Although the work of the developer may be time-consuming, such work remains routine work for those of ordinary skill in the art who benefit from the disclosure.

[0188] Although various systems, tools, and methods are described herein in terms of “comprising” various components or steps, the systems, tools, and methods may also “consist essentially of” or “consist of” the various components and steps.

[0189] As used herein, the phrase "at least one" preceding a series of items with the terms "and" or "or" to isolate any item modifies the entire list rather than each member of the list (i.e., each item). The phrase "at least one" allows for a meaning that includes at least one of any one of the items, and / or at least one of any combination of the items, and / or at least one of each item. For example, the phrases "at least one of A, B, and C" or "at least one of A, B, or C" each refer to only A, only B, or only C; any combination of A, B, and C; and / or at least one of each of A, B, and C.

[0190] Therefore, the disclosed systems, tools and methods are well suited to obtain the mentioned purposes and advantages and the purposes and advantages inherent therein. The specific embodiments disclosed above are illustrative only, because the teachings of the present disclosure can be modified and practiced in different but equivalent ways that are obvious to those skilled in the art who benefit from the teachings herein. In addition, except as described in the claims below, there is no intention to limit the details of the construction or design shown herein. It is therefore obvious that the specific illustrative embodiments disclosed above can be changed, combined or modified, and all such variations are considered to be within the scope of the present disclosure. The systems, tools and methods disclosed illustratively herein can be appropriately practiced in the absence of any element not specifically disclosed herein and / or any optional element disclosed herein. Although systems, tools and methods are described according to "comprising", "containing" or "including" various components or steps, these systems, tools and methods can also be "essentially composed of the various components and steps" or "composed of the various components and steps". All numbers and ranges disclosed above can vary to some extent. Whenever a numerical range with a lower limit and an upper limit is disclosed, any number and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of "from about a to about b", or equivalently "from about a to b", or equivalently "about ab") should be understood to list every number and range encompassed within the broader numerical range. In addition, the terms in the claims have their ordinary, common meaning unless otherwise explicitly and clearly defined by the patentee. Moreover, the indefinite articles "a" or "an" used in the claims are defined herein to mean one or more of the elements they introduce. If there is any conflict in the use of a word or term in this specification and in one or more patents or other documents that may be incorporated herein by reference, the definition consistent with this specification should be adopted.

Claims

1. A polymer film composition comprising: a polymer backbone comprising one or more side chains comprising a heterocyclic ring; and The amine-free polyether arms are connected to the heterocyclic ring of at least a portion of the one or more side chains through an alkyl spacer or a hydroxy-functionalized alkyl spacer.

2. The polymer film composition of claim 1, wherein the polymer backbone comprises polyvinylpyridine or polyvinylimidazole, preferably the polymer backbone comprises a copolymer of vinylpyridine and styrene.

3. The polymer film composition of claim 1, wherein the amine-free polyether arm comprises at least one polyethylene oxide block and at least one polypropylene oxide block, the amine-free polyether arm being bonded to a heterocyclic or heteroaromatic nitrogen atom in a side chain of the polymer backbone, Preferably, the amine-free polyether arm has the following structure: wherein w is 0 or 1, x is between about 4 and about 24, y is between about 8 and about 60, and z is between about 6 and about 36, Preferably, wherein x is between about 8 and about 16, y is between about 10 and about 32, and z is between about 10 and about 20.

4. The polymer film composition of claim 3, wherein x≤z; and / or wherein the ratio of (x+z):y is at least about 1.7:1, preferably the ratio of (x+z):y is between about 1.7:1 and about 5:

1.

5. The polymer film composition of claim 1, having at least one of the following characteristics: - which further comprises a sulfonate-containing arm attached to at least a portion of said one or more side chains, - which further comprises an amine-free polyethylene oxide arm connected to the heterocyclic ring of at least a portion of the one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer, - it further comprises a cross-linking agent which is attached to at least a portion of the one or more side chains and binds the first polymer backbone to the second polymer backbone, - wherein the polymer film composition meets or exceeds ISO 10993-1 standard.

6. An analyte sensor comprising: Sensing area; and a polymer film composition covering the sensing area; The polymer film composition comprises a polymer backbone and an amine-free polyether arm, wherein the polymer backbone comprises one or more side chains comprising a heterocycle, and the amine-free polyether arm is connected to the heterocycle of at least a portion of the one or more side chains through an alkyl spacer or a hydroxyl-functionalized alkyl spacer.

7. The analyte sensor of claim 6, having at least one of the following features: - the sensing region comprises an enzyme, - the polymer backbone comprises polyvinylpyridine or polyvinylimidazole, or the polymer backbone comprises a copolymer of vinylpyridine and styrene, The amine-free polyether arm comprises at least one polyethylene oxide block and at least one polypropylene oxide block, and the amine-free polyether arm is bonded to a heterocyclic or heteroaromatic nitrogen atom in a side chain of the polymer backbone.

8. The analyte sensor of claim 6, wherein the amine-free polyether arm has the following structure: wherein w is 0 or 1, x is between about 4 and about 24, y is between about 8 and about 60, and z is between about 6 and about 36, preferably wherein x is between about 8 and about 16, y is between about 10 and about 32, and z is between about 10 and about 20. Preferably, wherein x≤z; and / or wherein the ratio of (x+z):y is at least about 1.7:1, preferably the ratio of (x+z):y is between about 1.7:1 and about 5:

1.

9. The analyte sensor of claim 6, having at least one of the following features: - the polymer film composition further comprises a sulfonate-containing arm attached to at least a portion of the one or more side chains, - the polymer film composition further comprises an amine-free polyethylene oxide arm connected to the heterocyclic ring of at least a portion of the one or more side chains via an alkyl spacer or a hydroxyl-functionalized alkyl spacer, - The polymer film composition further comprises a crosslinker that is linked to at least a portion of the one or more side chains and binds the first polymer backbone to the second polymer backbone.

10. A polymer film composition which is temperature insensitive, at least with respect to glucose permeability, within a temperature range of about 15°C to about 45°C and which meets or exceeds ISO 10993-1 standards.

Images