Analyte sensors and their manufacture

Abstract

The present invention relates to an analyte sensor comprising a substrate, at least one working electrode, at least one second electrode, and a membrane, wherein the membrane is located on the at least one second electrode. The present invention further relates to a process for manufacturing the analyte sensor of the present invention, and an analyte sensor system comprising the analyte sensor of the present invention and an electronic unit. The analyte sensor of the present invention can be primarily used to perform measurements of an analyte in a user's body fluid.

Description

[Technical Field]

[0001] The present invention relates to an analyte sensor comprising a substrate, at least one working electrode, at least one second electrode, and a membrane, wherein the membrane is located on the at least one second electrode. The present invention further relates to a process for manufacturing the analyte sensor of the present invention, and an analyte sensor system comprising the analyte sensor of the present invention and an electronic unit. The analyte sensor of the present invention can be primarily used to perform measurements of an analyte in a user's body fluid. [Background technology]

[0002] Biosensors for measuring analytes in biological fluids, especially those designed for implantation or subcutaneous insertion, must fulfill a variety of functions. On the one hand, the sensor must provide specific, highly sensitive measurements without interference from specific components of the biological fluid. To this end, biosensors are often covered with a membrane that excludes certain compounds, allowing only low-molecular-weight compounds access to the actual sensing site. While the specificity of a biosensor is achieved by using a biorecognition element such as an enzyme, sensitivity is often tuned by using a diffusion-limiting membrane. Finally, the implanted sensor must be biocompatible, so it does not trigger an inflammatory response in the body; for this purpose, an additional biocompatible membrane may be added.

[0003] Additionally, with implanted sensors, it is desirable to have sensors that can remain in place for extended periods of time without degrading measurements, to avoid the patient having to frequently replace the sensor.

[0004] Implanted sensors comprise an electrode system that facilitates the measurement of physiologically important analytes, such as glucose, in a patient's body. The working electrode of such sensors has a conductive enzyme layer with attached enzyme molecules that release charge carriers upon catalytic conversion of analyte molecules. In this process, a current is generated as a measurement signal whose amplitude correlates to the analyte concentration. These types of sensors are also called electrochemical sensors.

[0005] U.S. Patent No. 9,895,091 discloses electrochemical sensors. These electrochemical sensors can include an impermeable dielectric layer on top of the Ag / AgCl reference electrode. This coating is used to extend the life of the reference electrode. The disclosed electrochemical sensors have a layered structure in which the reference electrode is disposed on top of the working electrode. The working electrode is separated from the reference electrode by an insulating layer.

[0006] U.S. Patent No. 1,047,0691 discloses an analyte sensor including a working electrode and a reference electrode. The sensor may include an insulator formed from an insulating material. A portion of the insulator may be removed to expose the working electrode and / or the reference electrode.

[0007] The production of the sensors disclosed in the prior art is very time-consuming and costly, and furthermore they have drawbacks with regard to their long-term stability. Summary of the Invention

[0008] Issues to be resolved It is therefore an object of the present invention to provide an analyte sensor that at least partially avoids certain drawbacks of the prior art, in particular with regard to its manufacturability and with regard to its long-term stability.

[0009] Summary of the Invention This problem is solved by an analyte sensor according to independent claims 1 and 13, as well as by a method for manufacturing this sensor according to independent claim 11, and by an analyte sensor system according to independent claim 14. Preferred embodiments of the invention, which can be realized in a single way or in any combination, are disclosed in the dependent claims and in the entire specification.

[0010] The analyte sensors of the present invention are particularly easy to manufacture. Furthermore, they exhibit excellent long-term stability and consistent sensitivity. In particular, the analyte sensors of the present invention allow the analyte sensors to have only two electrodes instead of three, making the analyte sensors of the present invention particularly cost-effective. Furthermore, they have improved biocompatibility.

[0011] When used below, the terms "have," "comprise," or "include," or any grammatical variations thereof, are used in an exclusive manner. Thus, these terms may refer both to a situation in which, in addition to the features introduced by these terms, no further features are present in the entity described in this context, and to a situation in which one or more additional features are present. For example, the expressions "A has B," "A comprises B," and "A includes B" may both refer to a situation in which, apart from B, no other elements are present in A (i.e., a situation in which A consists solely and exclusively of B), and to a situation in which, apart from B, one or more further elements are present in entity A, such as element C, elements C and D, and even further elements.

[0012] Furthermore, it should be noted that the terms "at least one" or "one or more," or similar expressions, indicating that a feature or element can be present one or more times, are typically used only once when introducing each feature or element. Hereinafter, in most cases, when referring to each feature or element, the expressions "at least one" or "one or more" will not be repeated, despite the fact that each feature or element can be present one or more times.

[0013] Furthermore, when used hereinafter, the terms "preferably," "more preferably," "particularly," "more particularly," "particularly," or "more particularly," or similar terms, are used in connection with any feature without limiting its alternative possibilities. Therefore, features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. The present invention may also be implemented by using alternative features, as recognized by those skilled in the art. Similarly, features introduced by "in an embodiment of the present invention" or similar expressions are intended to be optional features without any limitations on alternative embodiments of the invention, without any limitations on the scope of the invention, and without any limitations on the possibility of combining features introduced in such a way with optional or non-functional features of the invention.

[0014] In a first aspect of the present invention there is provided an analyte sensor comprising: a substrate including a first side and a second side; at least one working electrode disposed on the first surface of the substrate, at least one electrically conductive material; at least one working electrode comprising at least one enzyme; at least one second electrode disposed on a second surface of the substrate, the at least one second electrode comprising silver; a membrane comprising a polymer composition comprising a hydrophobic polymer; Equipped with An analyte sensor is disclosed in which the membrane is positioned over at least one second electrode.

[0015] The term "analyte sensor" within the context of the present invention may refer to any device configured for the detection of an analyte.

[0016] The term "analyte" can refer to any element, component, or compound that may be present in a bodily fluid and whose concentration may be of interest to a user. Preferably, the analyte may be or include any chemical or chemical compound that may be involved in a user's metabolism, such as at least one metabolite. By way of example, the analyte may be selected from the group consisting of glucose, cholesterol, triglycerides, and lactate. However, additionally or alternatively, other types of analytes and / or any combination of analytes may be determined. Preferably, the analyte is glucose.

[0017] Therefore, the analyte sensor is preferably a biosensor. More preferably, the analyte sensor is an electrochemical sensor. The term "electrochemical sensor" refers to a sensor configured to perform at least one electrochemical measurement, particularly a plurality or series of electrochemical measurements, to detect an analyte contained in a body fluid using an amperometric method. In particular, the term "electrochemical measurement" refers to the detection of an electrochemically detectable property of an analyte, such as an electrochemical detection reaction, by using an amperometric method. Thus, for example, electrochemical detection can be performed by applying and comparing one or more potentials. Specifically, the electrochemical sensor can be configured to generate at least one electrical measurement signal, such as at least one current signal and / or at least one voltage signal, that can directly or indirectly indicate the presence and / or absence of an electrochemical detection reaction. The measurement can be quantitative and / or qualitative.

[0018] In particularly preferred embodiments of the present invention, the analyte sensor can be fully or partially implantable and thus configured to perform detection of analytes in bodily fluids, particularly in subcutaneous tissue, and particularly in interstitial fluid. As used herein, the terms “implantable” or “subcutaneous” refer to being disposed fully or at least partially within a user's bodily tissue, preferably partially within a user's bodily tissue. To this end, the analyte sensor can comprise an insertable portion, and the term “insertable portion” can generally refer to a portion or component of an element configured to be insertable into any bodily tissue, while other portions or components can remain outside the bodily tissue. Preferably, the insertable portion can comprise, in whole or in part, a biocompatible membrane, i.e., a surface that can cause as little harmful effects as possible to a user, patient, or bodily tissue, at least during a typical period of use.

[0019] Thus, preferably, the analyte sensors of the present invention are implantable sensors.

[0020] As commonly used, the term "body fluid" can refer to a fluid, particularly a liquid, that can typically be present in and / or produced by a user's or patient's body or body tissue. Preferably, the body fluid can be selected from the group consisting of blood and interstitial fluid. However, additionally or alternatively, one or more other types of body fluids, such as saliva, tears, urine, or other body fluids, can be used. During analyte detection, the body fluid can be present within the body or body tissue. Thus, the analyte sensor can be configured to detect an analyte within body tissue. In one embodiment, the analyte sensor is suitable for short-term application, e.g., 3 to 21 days, or long-term application, e.g., 1 to 12 months. During the application, the analyte can be determined by continuous or discontinuous measurements.

[0021] The analyte sensor of the present invention is an electrochemical sensor comprising at least one working electrode and at least one second electrode. More specifically, the sensor is an amperometric electrochemical sensor comprising at least one working electrode and at least one second electrode. The working electrode is sensitive to the analyte to be measured at a polarization voltage that may be applied between the at least one working electrode and the at least one second electrode and may be adjusted by a potentiostat. The measurement signal may be provided as a current between the at least one working electrode and the at least one second electrode.

[0022] The analyte sensors of the present invention comprise a substrate including a first surface and a second surface.

[0023] Within the context of the present invention, the term "substrate" can specifically refer to, but is not limited to, any type of material or combination of materials suitable for forming a carrier layer for supporting at least one working electrode and at least one second electrode. In particular, the substrate can include an electrically insulating material. Within the context of the present invention, "electrically insulating material" is a broad term and is given its ordinary and customary meaning to those skilled in the art. The term "electrically insulating material" can also encompass dielectric materials. This term can specifically refer to, but is not limited to, a material or combination of materials that prevents the transfer of electric charges and does not support a large current. Specifically, without limiting other possibilities, the at least one electrically insulating material can be or include at least one insulating resin, such as an insulating epoxy resin used in the manufacture of electronic printed circuit boards. In particular, it can include or be at least one thermoplastic material, such as polycarbonate, polyester, polyvinyl chloride, polyurethane, polyethylene, polypropylene, polystyrene, polyether, polyamide, polyimide, polytetrafluoroethylene, or a copolymer thereof. In an embodiment, the at least one electrically insulating material can include or be alumina. Suitable polyesters are, for example, selected from the group consisting of polyethylene terephthalate (PET), glycol-modified polyethylene terephthalate, and polyethylene naphthalate. Suitable polyethylenes are, for example, selected from the group consisting of high-density polyethylene (HDPE) and low-density polyethylene (LDPE).

[0024] Thus, in a preferred embodiment, the substrate comprises at least one electrically insulating material selected from the group consisting of insulating epoxy resin, polycarbonate, polyester, polyvinyl chloride, polyurethane, polyethylene, polypropylene, polystyrene, polyether, polyamide, polyimide, polytetrafluoroethylene or copolymers thereof, and alumina.

[0025] The substrate comprises a first side and a second side, and it will be apparent to one skilled in the art that the first side and the second side are different from each other.

[0026] In an embodiment, the first surface and the second surface are disposed opposite each other. Thus, in an embodiment, the substrate comprises two opposing surfaces, a first surface and a second surface opposite the first surface.

[0027] Therefore, in the analyte sensor according to the present invention, the first and second surfaces of the substrate are preferably arranged facing inversely to each other.

[0028] The substrate may be a flat substrate. Specifically, the substrate may be flexible and / or deformable. In particular, the substrate may be bendable. Thus, for example, the substrate may be a thin, flexible substrate. For example, the substrate may have a thickness of 50 μm to 1 mm, specifically 80 μm to 500 μm, for example 110 μm to 250 μm.

[0029] The substrate may preferably have a length of less than 50 mm, for example a length of 30 mm or less, for example a length of 5 mm to 30 mm.

[0030] When the analyte sensor is an implantable sensor, preferably a partially implantable sensor, the length of the substrate is measured in the direction of insertion of the analyte sensor. The length of the substrate refers to the entire length of the substrate. The "entire length of the substrate" is the entire length of the substrate, including the insertable portion of the substrate that is in the body tissue of a user and on the main portion of the substrate during use of the analyte sensor. The "on the main portion of the substrate" is the portion of the substrate that can be connected to, for example, an electronic unit.

[0031] The analyte sensor comprises at least one working electrode disposed on a first surface of the substrate. Preferably, the at least one working electrode is disposed only on the first surface of the substrate. In the context of the present invention, this means that, in embodiments, the second surface does not comprise at least one working electrode.

[0032] The at least one working electrode is preferably configured to detect an analyte, and in particular the at least one working electrode is an electrode of an analyte sensor that is sensitive to the analyte.

[0033] The at least one working electrode comprises at least one conductive material. In the context of the present invention, "conductive material" refers to a material capable of supporting an electric current. Thus, the at least one conductive material may be selected from the group consisting of metallic and non-metallic conductive materials.

[0034] Suitable metals are known per se and are, for example, selected from the group consisting of gold, nickel, platinum and palladium, with gold being particularly preferred.

[0035] Suitable non-metallic conductive materials are, for example, selected from the group consisting of carbon, carbon paste, gold paste, or conductive polymers. Suitable conductive polymers are, for example, polyaniline and / or poly-3,4-ethylenedioxythiophene (PEDOT). Carbon paste may, for example, contain carbon, a solvent such as diethylene glycol butyl ether, and at least one binder such as vinyl chloride copolymers and terpolymers. Carbon paste itself is known.

[0036] Therefore, the at least one conductive material of the at least one working electrode is preferably selected from the group consisting of gold, nickel, platinum, palladium, carbon, carbon paste, polyaniline, and poly-3,4-ethylenedioxythiophene (PEDOT), and particularly preferably selected from the group consisting of gold, carbon, and carbon paste. More preferably, the at least one conductive material essentially consists of gold and / or carbon and / or carbon paste. In one embodiment, the at least one conductive material has a layered structure in which a first layer consists of gold and a second layer consists of carbon and / or carbon paste. In this embodiment, preferably, gold is disposed on the first surface of the substrate, and is disposed on top of the gold, carbon, and / or carbon paste.

[0037] In particular, at least one working electrode can include at least one conductive material in the form of at least one conductive trace. The term "conductive trace" in the context of the present invention refers to, but is not limited to, a conductive strip, layer, wire, or other type of conductor. The conductive trace can have a thickness of at least 0.05 μm, preferably at least 0.5 μm, more preferably at least 5 μm, specifically at least 7 μm, or at least 10 μm. When the conductive trace includes or is carbon, the conductive trace can have a thickness of at least 7 μm, more specifically at least 10 μm. Specifically, when the conductive trace is gold, the conductive trace can have a thickness of at least 50 nm, more specifically at least 900 nm.

[0038] The at least one conductive material may be disposed on the first surface of the substrate by any known method, such as chemical vapor deposition (CVD), physical vapor deposition (PVD), or a wet coating process. Wet coating processes are known per se. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing.

[0039] At least one working electrode contains at least one enzyme. The at least one working electrode can contain exactly one enzyme or a mixture of two or more enzymes. Exactly one enzyme is preferred. Specifically, the enzyme can catalyze a chemical reaction that converts the analyte. Even more specifically, the at least one enzyme is selected from the group consisting of glucose oxidase (EC 1.1.3.4), hexose oxidase (EC 1.1.3.5), (S)-2-hydroxyacid oxidase (EC 1.1.3.15), cholesterol oxidase (EC 1.1.3.6), glucose dehydrogenase, galactose oxidase (EC 1.1.3.9), alcohol oxidase (EC 1.1.3.13), L-glutamate oxidase (EC 1.4.3.11), and L-aspartate oxidase (EC 1.4.3.16). In particular, the at least one enzyme is glucose oxidase (GOx) and / or a variant thereof.

[0040] At least one enzyme may be included in the sensing material. The sensing material including the at least one enzyme may be at least partially disposed on the conductive material of at least one working electrode. In particular, the sensing material may cover at least a portion of at least one conductive trace. The sensing material together with the conductive trace forms at least one working electrode. In particular, the sensing material preferably forms a layer on at least one conductive material.

[0041] The sensing material may be applied to the at least one conductive material by any known method, for example, by a wet coating process. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing. After the wet coating process, the layer of sensing material may be further processed. Such processing is, for example, a drying process, a curing process, and / or a laser ablation process. Such processing is known per se.

[0042] The term "sensing material" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to any special or customized meaning. This term can specifically refer to, but is not limited to, a material that may be or include at least one polymeric material. Specifically, it can be or include at least one polymeric material and at least one metal-containing complex. The metal-containing complex can be selected from the group of transition metal element complexes, specifically, the metal-containing complex can be selected from osmium complexes, ruthenium complexes, vanadium complexes, cobalt complexes, and iron complexes, such as ferrocene, e.g., 2-aminoethylferrocene. Even more specifically, the sensing material can be a polymeric transition metal complex, such as those described in WO 01 / 36660, the contents of which are incorporated by reference. In particular, the sensing material can include a modified poly(vinylpyridine) backbone carrying a poly(biimidyl)Os complex covalently bonded via a bidentate bond. Suitable sensing materials are further described in Feldmann et al., Diabetes Technology & Therapeutics, 5(5), 2003, 769-779, the contents of which are incorporated by reference. Suitable sensing materials may further include ferrocene-containing polyacrylamide-based viologen-modified redox polymers, pyrrole-2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS)-pyrene, and naphthoquinone-LPEI. The polymeric transition metal complex may represent a redox mediator incorporated into a crosslinked redox polymer network. This is advantageous because it can facilitate electron transfer between at least one enzyme or analyte and the conductive trace. To avoid sensor drift, the redox mediator and enzyme may be covalently incorporated into the polymer structure.

[0043] In embodiments, the sensing material may include a polymeric material and MnO2 particles or any other material that catalyzes the hydrogen peroxide oxidation reaction and at least one enzyme. Another material that catalyzes the hydrogen peroxide oxidation reaction is Pt (platinum).

[0044] Furthermore, the sensing material may further include at least one crosslinker. The crosslinker can, for example, crosslink at least a portion of the sensing material. Specifically, the sensing material may include at least one crosslinker selected from a UV-curable crosslinker and a chemical crosslinker. More specifically, the sensing material includes a chemical crosslinker. Alternatively, the sensing material may not include a crosslinker. As used herein, "free of any crosslinker" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. Specifically, this term can refer to a crosslinker concentration ranging from 0 to 0.5 wt % based on the dry weight of the sensing material. As used herein, the term "dry weight" refers to the dry weight of the respective material, e.g., the material without the addition of water or other solvents.

[0045] Suitable chemical crosslinkers according to the present invention are preferably epoxide-based crosslinkers, for example diglycidyl ethers such as poly(ethylene glycol) diglycidyl ether (PEG-DGE) and poly(propylene glycol) diglycidyl ether; trifunctional short chain epoxides; anhydrides; resorcinol diglycidyl ether, bisphenol A diglycidyl ether, diglycidyl 1,2-cyclohexanedicarboxylate, poly(ethylene glycol) diglycidyl ether, glycerol diglycidyl ether, 1,4-butanediol diglycidyl ether, poly(propylene glycol) diglycidyl ether, bisphenol diglycidyl ether, diglycidyl ethers such as N,N-diglycidyl-4-glycidyloxyaniline and trimethylolpropane triglycidyl ether; and tetraglycidyl ethers such as tetrakisepoxycyclosiloxane, pentaerythritol tetraglycidyl ether, and tetraglycidyl-4,4'-methylenebisbenzeneamine.

[0046] The term "chemical crosslinker" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to any special or customized meaning. Specifically, the term can refer to, but is not limited to, a crosslinker that can initiate a chemical reaction to produce a crosslinked molecular network and / or crosslinked polymer when exposed to heat. "Exposed to heat" can refer to exposure to temperatures greater than 15°C, specifically greater than 20°C, more specifically, temperatures in the range of 20°C to 50°C, and even more specifically, temperatures in the range of 20°C to 25°C. More specifically, the chemical crosslinker can initiate crosslinking of the sensing material when exposed to heat.

[0047] As used herein, the term "UV-curable crosslinker" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to any special or customized meaning. Specifically, the term can refer, but is not limited to, the ability of a chemical to initiate a photochemical reaction that produces a crosslinked molecular network and / or crosslinked polymer when irradiated with light in the UV spectral range. More specifically, the UV-curable crosslinker can initiate crosslinking of a layer of sensing material when irradiated with UV light.

[0048] Suitable UV-curable crosslinkers according to the present invention include benzophenones, diazirines, and azides. Particularly suitable UV-curable crosslinkers are selected from the group consisting of benzophenone-containing crosslinkers, poly(di(2-hydroxy-3-aminobenzophenonepropylene)glycol), dibenzophenone 1,2-cyclohexanedicarboxylate, bis[2-(4-azidosalicylamido)ethyl]disulfide, and the reaction products of 4-aminobenzophenone with any one of the diglycidyl crosslinkers, triglycidyl crosslinkers, and tetraglycidyl crosslinkers mentioned above. Examples of such reaction products include 2,4,6,8-tetramethyl-2,4,6,8-tetrakis(2-hydroxy-3-aminopropylbenzophenone)-cyclotetrasiloxane, and the reaction products of 4-benzoylbenzoic acid N-succinimidyl ester with diamines or Jeffamine.

[0049] The analyte sensor further comprises at least one second electrode disposed on the second surface of the substrate. Preferably, the at least one second electrode is disposed only on the second surface of the substrate. Within the context of the present invention, this means that in an embodiment, the first surface does not comprise at least one second electrode. In an embodiment, exactly one second electrode is disposed on the second surface of the substrate. Preferably, the at least one second electrode does not comprise an enzyme. Thus, preferably, the at least one second electrode does not comprise at least one enzyme. Preferably, the second surface of the substrate does not comprise an enzyme.

[0050] The at least one second electrode may be selected from the group consisting of a counter electrode, a reference electrode, and a combined counter / reference electrode. Preferably, the at least one second electrode is a combined counter / reference electrode.

[0051] Thus, the at least one second electrode of the analyte sensor is preferably selected from the group consisting of a counter electrode, a reference electrode and a combination counter / reference electrode.

[0052] At least one second electrode comprises silver. "Silver" within the context of the present invention encompasses not only elemental silver but also any silver-containing compound. Thus, at least one second electrode comprises elemental silver and / or at least one silver-containing compound. A preferred silver-containing compound is silver chloride (AgCl). For example, at least one second electrode comprises elemental silver and / or silver chloride. In particular, at least one second electrode comprises elemental silver and silver chloride. In particular, at least one second electrode comprises silver / silver chloride (Ag / AgCl). In an embodiment, at least one second electrode comprises only AgCl when the analyte sensor is manufactured. No elemental Ag is added when the analyte sensor is manufactured. During use of the analyte sensor, elemental Ag may be formed from AgCl, so that the analyte sensor comprises Ag / AgCl during use. The reaction of AgCl to form elemental Ag is known per se to those skilled in the art.

[0053] Therefore, analyte sensors that include at least one second electrode that comprises Ag / AgCl are preferred.

[0054] For example, the weight of AgCl in the at least one second electrode is in the range of 20 μg to 150 μg. When two or more second electrodes are included, the weight of AgCl in the at least one second electrode refers to the sum of the weights of AgCl in the two or more second electrodes. The weight of AgCl in the at least one second electrode refers to the weight when the analyte sensor is manufactured. It will be apparent to those skilled in the art that the weight may change during use of the analyte sensor due, for example, to the formation of elemental Ag from AgCl.

[0055] Therefore, an analyte sensor in which the weight of AgCl in at least one second electrode is in the range of 20 μg to 150 μg is preferred.

[0056] The minimum weight of AgCl in the at least one second electrode can be calculated according to the following formula:

[0057]

number

[0058] The Ag / AgCl contained in at least one second electrode in the embodiment may be contained in a binder. Suitable binders are known per se and are selected, for example, from the group consisting of metal binders, ceramic binders, and polymer binders. Polymer binders, particularly physically and / or chemically bonded polymer binders, are preferred.

[0059] For example, the at least one second electrode comprises Ag / AgCl in the range of 50 to 70 wt. % Ag, 20 to 40 wt. % AgCl, and 1 to 20 wt. % binder, the weight percentages being in each case based on the sum of the weight percentages of Ag, AgCl, and binder.

[0060] The at least one second electrode can include at least one second conductive trace, preferably disposed on the second side of the substrate. In particular, the first side of the substrate preferably does not include a second conductive trace.

[0061] The term "second conductive trace" can specifically refer to, but is not limited to, a conductive strip, layer, wire, or other type of elongated conductor. In particular, this term can refer to at least one second conductive material. Therefore, the at least one second conductive trace is preferably capable of supporting an electric current. For example, the at least one second conductive material may be selected from the group consisting of gold, nickel, platinum, palladium, carbon, carbon paste, polyaniline, and poly-3,4-ethylenedioxythiophene (PEDOT). Particularly preferably, the at least one second conductive material of the at least one second electrode is selected from the group consisting of gold, carbon, and carbon paste. More preferably, the at least one second conductive material consists essentially of gold and / or carbon and / or carbon paste. In an embodiment, the at least one second conductive material has a layered structure in which a first layer consists of gold and a second layer consists of carbon and / or carbon paste. In this embodiment, preferably, gold is disposed on the second surface of the substrate, and is disposed on top of the gold, carbon, and / or carbon paste.

[0062] The at least one second electrode preferably comprises silver disposed on at least one second conductive trace. Thus, Ag / AgCl is preferably at least partially disposed on at least one second conductive trace, particularly on at least one layered structure of a second conductive material. The silver, preferably Ag / AgCl, and the at least one second conductive trace, particularly the at least one layered structure of a second conductive material, form the at least one second electrode.

[0063] Thus, the silver contained in the at least one second electrode typically forms a layer, the thickness of which is, for example, in the range of 5 μm to 30 μm.

[0064] The at least one second conductive trace and at least one second conductive material may be applied to the second side of the substrate by the same method as the at least one conductive trace and at least one conductive material of the at least one working electrode are applied to the first side of the substrate. Accordingly, the above-described embodiments and preferences apply. The method of applying the at least one second conductive trace and at least one second conductive material of the second electrode and the method of applying the at least one conductive trace and at least one conductive material of the working electrode can be selected independently of each other.

[0065] The silver, particularly Ag / AgCl, contained in the at least one second electrode may be applied at least partially to the second surface of the substrate, particularly onto the at least one second conductive trace, by the same method as the method by which the sensing material of the at least one working electrode is applied to the first surface of the substrate. Accordingly, the above-described embodiments and preferences apply. The method of applying the silver, particularly Ag / AgCl, contained in the at least one second electrode and the method of applying the sensing material, preferably contained in the at least one working electrode, can be selected independently of each other.

[0066] The analyte sensor of the present invention includes a membrane, the membrane comprising a polymer composition comprising a hydrophobic polymer and positioned over at least one second electrode.

[0067] In embodiments, the term "membrane" within the context of the present invention refers to at least one layer of material that provides a selective barrier. Thus, such membranes generally can selectively allow one or more molecules and / or compounds to pass through the membrane, while other molecules and / or compounds are blocked by the membrane. For example, a membrane may allow the movement of water and / or chloride anions through the membrane while restricting the movement of silver cations and / or silver chloride through the membrane.

[0068] For example, in this embodiment, the membrane may have a thickness in the range of 1 μm to 100 μm, preferably in the range of 5 μm to 20 μm.

[0069] In another particularly preferred embodiment, the term "membrane" within the context of the present invention refers to at least one layer of material that is essentially impermeable, where "essentially impermeable" means that the membrane has a water absorption rate of less than 1% by weight, based on the total weight of the membrane.

[0070] For example, the membrane may have a thickness in the range of 1 μm to 100 μm, preferably in the range of 5 μm to 15 μm.

[0071] Embodiments described below with respect to membranes apply to both membrane embodiments, preferably membrane embodiments that refer to at least one layer of material that is essentially impermeable.

[0072] The membrane overlies at least one second electrode.

[0073] "Overlying at least one second electrode" means that the membrane covers the at least one second electrode. In embodiments, the membrane completely covers the at least one second electrode. Within the context of the present invention, the term "completely covers" means that the at least one second electrode does not come into direct contact with the patient's bodily fluids when the analyte sensor is implanted in a user. Instead, only the membrane comes into direct contact with the bodily fluids.

[0074] In a further embodiment, the membrane partially covers the at least one second electrode. Within the context of the present invention, the term "partially covers" means that the at least one second electrode is in direct contact with bodily fluids when the analyte sensor is implanted in a user. In particular, the at least one second electrode is in direct contact with bodily fluids through pores in the membrane. This embodiment is particularly preferred when the term "membrane" refers to at least one layer of material that is essentially impermeable.

[0075] Thus, in an embodiment, the membrane comprises a hole. The membrane may comprise exactly one hole or two or more holes.

[0076] The term "pore" in the context of the present invention is given its ordinary and customary meaning to those skilled in the art. In particular, it refers to any opening and / or perforation in a membrane. The pore allows the passage of one or more molecules and / or compounds therethrough. Thus, the pore provides a fluid channel between at least one second electrode and body fluid.

[0077] The holes can have any shape and any size. The holes can be located anywhere within the membrane. For example, the holes can be located at the edge of the membrane and / or essentially in the center of the membrane.

[0078] For example, the membrane may contain pores, and the total area of ​​the pores in the membrane may be up to 0.15 square millimeters (mm 2 ), preferably up to 0.05 mm 2 In an embodiment, the total area of ​​the pores in the membrane is between 0.005 and 0.15 mm 2 in the range of 0.005 to 0.05 mm 2 is within the range.

[0079] Therefore, if the membrane contains holes and the total area of ​​the holes is up to 0.15 mm 2 Analyte sensors having a size of .gtoreq.100.mu.m are preferred.

[0080] Within the context of the present invention, "total pore area" relates to the sum of the surface areas of the pores.

[0081] In a preferred embodiment of the present invention, at least one working electrode does not include a membrane comprising a polymer composition that includes a hydrophobic polymer.

[0082] Thus, analyte sensors in which at least one working electrode does not include a membrane comprising a polymer composition that includes a hydrophobic polymer are preferred.

[0083] The membrane comprises a polymer composition that includes a hydrophobic polymer.

[0084] "Hydrophobic" within the context of the present invention means that the polymer has a water absorption in the range of 0 to 5% by weight, in embodiments less than 1% by weight, based on the total weight of the polymer.

[0085] Therefore, an analyte sensor in which the hydrophobic polymer has a water absorption rate of less than 1 wt %, based on the total weight of the hydrophobic polymer, is preferred.

[0086] The hydrophobic polymer is preferably a thermoplastic hydrophobic polymer.

[0087] The hydrophobic polymer may have a glass transition temperature, for example, in the range of -100°C to 0°C, preferably in the range of -70°C to -50°C. The glass transition temperature can be measured by differential scanning calorimetry using a 10°C / min ramp for heating and cooling. The glass transition temperature is measured during the second heating cycle. This means that the hydrophobic polymer is first heated at a 10°C / min ramp, then cooled at a 10°C / min ramp, and then heated again at a 10°C / min ramp to determine the glass transition temperature.

[0088] The hydrophobic polymer may have, for example, a crystallization temperature in the range of 50° C. to 100° C., such as in the range of 75° C. to 85° C. The crystallization temperature is measured by differential scanning calorimetry using the same parameters as the glass transition temperature.

[0089] Therefore, an analyte sensor in which the hydrophobic polymer has a glass transition temperature, the glass transition temperature being within the range of -100°C to 0°C, is preferred.

[0090] This glass transition temperature is particularly advantageous as it results in a sufficiently high stability of the membrane, so that the membrane is not damaged, or is damaged to only a small extent, especially if the sensor is bent during use.

[0091] The hydrophobic polymer can be any hydrophobic polymer known to those skilled in the art.Preferably, the hydrophobic polymer is selected from the group consisting of thermoplastic polyurethane (TPU), thermoplastic polyurea, polyethylene, polypropylene, polystyrene, butyl methacrylate polymer (BUMA), polyethylene terephthalate (PET), and UV-curable resin, such as acrylated silicone, acrylated urethane, acrylated polyester, and / or acrylated epoxide.Preferably, the hydrophobic polymer is thermoplastic polyurethane.

[0092] Therefore, an analyte sensor in which the polymer composition comprises a hydrophobic thermoplastic polyurethane is preferred.

[0093] The hydrophobic thermoplastic polyurethane can contain various ratios of hard and soft segments. Suitable hard segments typically comprise the polymerization product of a diisocyanate and a polyol. Suitable diisocyanates can be aliphatic or aromatic diisocyanates, preferably aliphatic diisocyanates.

[0094] Suitable aromatic diisocyanates are, for example, 4,4'-methylenediphenyl diisocyanate and / or toluene-2,4-diisocyanate.

[0095] Suitable aliphatic diisocyanates are, for example, hexamethylene diisocyanate and / or isophorone diisocyanate.

[0096] Suitable polyols are preferably diols, such as 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol and / or 1,10-decanediol.

[0097] Suitable soft segments may include polyethers and / or polyesters. Suitable polyethers are, for example, polyethylene oxide and / or polytetrahydrofuran, while suitable polyesters are, for example, polyethylene terephthalate and / or polyethylene naphthalate.

[0098] The polymer composition may include additional components.

[0099] The analyte sensor may comprise at least one third electrode. Preferably, the analyte sensor does not comprise at least one third electrode.

[0100] When at least one third electrode is included in the analyte sensor, the at least one second electrode is preferably selected from the group consisting of a counter electrode and a reference electrode. In this case, the at least one third electrode is preferably also selected from the group consisting of a counter electrode and a reference electrode. When the at least one second electrode is a counter electrode, the at least one third electrode is a reference electrode, and vice versa.

[0101] The analyte sensor may further comprise at least one flux-limiting membrane.

[0102] At least one flux-limiting membrane is specifically disposed at least above at least one working electrode, and preferably also above a membrane comprising a polymer composition comprising a hydrophobic polymer.

[0103] The term "flux-limiting membrane" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to any special or customized meaning. Specifically, the term can refer, but is not limited to, at least one layer of material that provides a selective barrier. Thus, a flux-limiting membrane generally selectively allows one or more molecules and / or compounds to pass through, while other molecules and / or compounds are blocked by the flux-limiting membrane. Thus, the flux-limiting membrane is permeable to at least one analyte to be detected. Thus, by way of example, the flux-limiting membrane can be permeable to one or more of glucose, lactate, cholesterol, or other types of analytes. Thus, the at least one flux-limiting membrane can function as a diffusion barrier that controls the diffusion of analytes from the outside, e.g., the bodily fluid surrounding the analyte sensor, to the sensing material, i.e., the at least one enzyme contained in the at least one working electrode. Furthermore, the at least one flux-limiting membrane can function as a biocompatible membrane layer, as referred to elsewhere herein.

[0104] For example, the at least one flux-limiting membrane may have a thickness sufficient to provide mechanical stability. The at least one flux-limiting membrane may specifically have a thickness of 1 μm to 150 μm. For the at least one flux-limiting membrane, several materials may be used alone or in combination, as outlined herein. Thus, for example, the flux-limiting membrane may specifically comprise at least one polymer material. Suitable polymer materials may be selected from the group consisting of, for example, polyvinylpyridine-based copolymers, polyurethanes, and hydrogels. Polyvinylpyridine-based copolymers are particularly suitable.

[0105] Suitable hydrogels are, in particular, polyethylene glycol copolymers (PEG copolymers), polyvinyl acetate copolymers (PVA copolymers), poly(2-alkyl-2-oxazolone) copolymers, polyacrylate and / or methacrylate-acrylate copolymers or block copolymers, especially polyacrylate and / or methacrylate-acrylate copolymers or block copolymers containing hydrophilic side groups. Thus, by way of example, suitable hydrogels can be selected from the group consisting of (hydroxyethyl)methacrylate (HEMA) homopolymers, HEMA copolymers, silicone hydrogels, and HEMA-co-N-vinylpyrrolidone polymers, each of which can contain side groups selected from the group consisting of methacrylic acid, glycerol methacrylate, N,N-dimethylacrylamide, and phosphoarylcholine.

[0106] These types of flux-limiting membranes are generally known in the art. For example, flux-limiting membranes such as those disclosed in EP 2697388, WO 2007 / 071562, and / or WO 2005 / 078424 can be used. Specifically, the polymer material can have a weight-average molecular weight (MW) of more than 10,000 kDa. More specifically, the polymer material can have a weight-average molecular weight (MW) of more than 50,000 kDa, or even more than 100,000 kDa. Polymer materials with a weight-average molecular weight (MW) of 10,000 to 500,000 kDa are particularly suitable. The polymer material of the flux-limiting membrane can be the same as or different from the polymer material of the sensing material.

[0107] The analyte sensor may further include at least one biocompatible membrane.

[0108] The at least one biocompatible membrane is specifically disposed on at least one working electrode. Preferably, the at least one biocompatible membrane is also disposed on a membrane comprising a polymer composition including a hydrophobic polymer. In particular, the at least one biocompatible membrane is disposed on a flux-limiting membrane in an embodiment of the present invention included in an analyte sensor. Specifically, the biocompatible membrane completely covers the at least one flux-limiting membrane. In the context of the present invention, the term "completely covers" specifically means that when the analyte sensor is in use, the flux-limiting membrane is not in direct contact with body fluids, but only the biocompatible membrane is in direct contact with body fluids. This means that at least the implantable portion of the analyte sensor is preferably completely covered by the at least one biocompatible membrane.

[0109] As used herein, the term "biocompatible membrane," also referred to as a biocompatible layer, refers to a layer made of a biocompatible material, particularly the outermost layer or a portion thereof of an analyte sensor. Specifically, the biocompatible layer has a thickness of 1 μm to 10 μm, in embodiments 3 μm to 6 μm. More specifically, the biocompatible layer at least partially or completely covers the analyte sensor. Even more specifically, the biocompatible layer may be the outermost layer of the analyte sensor. Thus, more specifically, at least a portion of the biocompatible layer contacts the subject's bodily fluid. For example, the biocompatible layer may not be diffusion-limiting for the analyte, as specified elsewhere herein. For example, the biocompatible layer may not be diffusion-limiting for small molecules having a molecular weight of less than 2,000 Da, in embodiments less than 1,000 Da. For example, the biocompatible layer may not include added enzymes. For example, the biocompatible layer may not include added polypeptides. As will be appreciated by those skilled in the art, this does not preclude the diffusion of enzyme or polypeptide molecules into the biocompatible layer from adjacent layers, tissues or bodily fluids.

[0110] The term "biocompatible material" as used herein refers to a material suitable for use in a living tissue or system by not being toxic, damaging, or physiologically reactive, or by not causing a reduced degree of toxicity, damaging, or physiologically reactive, or by not causing immune rejection. In embodiments, the biocompatible material is a material that does not induce a bodily response, such as an inert material or a material containing chemical compounds that prevent a bodily response from occurring in the vicinity of the biocompatible layer. In another embodiment, the biocompatible material is a material that prevents cells from attaching to the biocompatible layer. The biocompatible membrane can be or include at least one material selected from the group consisting of methacrylate-based polymers and copolymers, such as acrylamide-methacrylate-based copolymers, biodegradable polysaccharides, such as hyaluronic acid (HA), agarose, dextran, and chitosan. Additional biocompatible materials are disclosed in WO 2019 / 166394 and include non-biodegradable synthetic hydrogels, such as hydrogels prepared from the copolymerization of 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl methacrylate (HPMA), acrylamide (AAm), acrylic acid (AAc), N-isopropylacrylamide (NIPAm), and methoxyl poly(ethylene glycol) (PEG) monoacrylate (mPEGMA or PEGMA) with crosslinkers such as N,N'-methylenebis(acrylamide) (MBA), ethylene glycol diacrylate (EGDA), and PEG diacrylate (PEGDA), Pluronic® polymers having the structure poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO)-PEO, modified poly(vinyl alcohol) (PVA), poly(4-vinylpyridine), and PEG.

[0111] Another object of the present invention is to provide a method for producing an analyte sensor, in particular an analyte sensor of the present invention, comprising the steps of: a) providing a feedstock substrate including a first side and a second side; b) preparing a working electrode area on a first surface of the source substrate, the step of preparing the working electrode area comprising: b1) applying a conductive material to a first surface of a raw substrate; b2) applying a sensing material comprising at least one enzyme at least partially onto a conductive material; c) preparing a second electrode region on a second surface of the source substrate, the step of preparing the second electrode region comprising: c1) preparing a second electrode region, comprising applying a silver composition onto a second surface of the source substrate; d) applying a polymer composition over the second electrode region to obtain a membrane, the polymer composition comprising a hydrophobic polymer; e) cutting the starting substrate containing the working electrode region, the second electrode region, and the membrane to obtain an analyte sensor; A method comprising:

[0112] The process steps a) to e) can be performed in a given order. However, it is also possible to perform the steps in a different order. In particular, the order of steps b) and c) can be different. For example, it is possible to perform step b1) first, then step c1), and then step b2). Further process steps can be performed. It is also possible to perform at least one of the process steps a) to e) multiple times. For example, step c1) can be performed more than once, so as to obtain two or more layers of the silver composition.

[0113] In step a) of the method of manufacturing an analyte sensor of the present invention, a starting substrate is provided.

[0114] Within the context of the present invention, the term "raw substrate" can specifically refer to, but is not limited to, any type of material or combination of materials suitable for forming a carrier layer for supporting at least one working electrode and at least one second electrode. From the raw substrate, the substrate of the analyte sensor of the present invention can be manufactured, for example, by cutting the raw substrate. In particular, the raw substrate can include an electrically insulating material. For the electrically insulating material, the embodiments and preferences described above for the electrically insulating material of the substrate apply.

[0115] Thus, in a preferred embodiment, the raw material substrate comprises at least one electrically insulating material selected from the group consisting of insulating epoxy resin, polycarbonate, polyester, polyvinyl chloride, polyurethane, polyether, polyethylene, polyamide, polyimide, polyacrylate, polymethacrylate, polytetrafluoroethylene or copolymers thereof, and alumina.

[0116] A suitable polyester is, for example, polyethylene terephthalate.

[0117] The raw substrate comprises a first side and a second side, and it will be apparent to one skilled in the art that the first side and the second side are different from each other.

[0118] In an embodiment, the first surface and the second surface are disposed opposite each other, and thus, in an embodiment, the feedstock substrate includes two opposing surfaces, a first surface and a second surface opposite the first surface.

[0119] The base substrate may be a flat substrate. Specifically, the base substrate may be flexible and / or deformable. Thus, for example, the base substrate may be a thin, flexible base substrate. For example, the base substrate may have a thickness of 50 μm to 1 mm, specifically 80 μm to 500 μm, for example 110 μm to 250 μm.

[0120] The raw substrate may preferably have a length in the range of a few centimetres to a few metres, for example in the range of 10 cm to 100 m.

[0121] The raw substrate may preferably have a width ranging from 2 centimeters (cm) to 8 cm.

[0122] In an embodiment, the source substrate may include a conductive material on at least one of the first and second sides, preferably the first and second sides.

[0123] In embodiments of the present invention, the source substrate may be suitable for use in a roll-to-roll process.

[0124] The source substrate can be provided by any method known to those skilled in the art. For example, the source substrate may be provided as a roll. This is particularly advantageous because the source substrate can then be used in a roll-to-roll process.

[0125] In embodiments, the raw substrate is cut into sheets before the working electrode area is prepared. The sheets can have any length, for example, within the range of 100 mm to 300 mm.

[0126] In step b), a working electrode area is prepared on a first surface of the starting substrate.

[0127] The working electrode region specifically includes all components that form part of at least one working electrode of the analyte sensor.

[0128] In step b1), a conductive material is applied to the first side of the raw substrate, for which the above-mentioned embodiments and preferences apply.

[0129] The conductive material can be applied to the first surface of the raw substrate by any known method, such as chemical vapor deposition (CVD), physical vapor deposition (PVD), or a wet coating process. Wet coating processes are known per se. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing.

[0130] In step b2), a sensing material comprising at least one enzyme is applied at least partially onto the conductive material, with respect to the sensing material and the at least one enzyme the above-mentioned embodiments and preferences apply.

[0131] The sensing material may be applied to the at least one conductive material by any known method, for example, by a wet coating process. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing. After the wet coating process, the layer of sensing material may be further processed. Such processing is, for example, a drying process, a curing process, and / or a laser ablation process. Such processing is known per se.

[0132] The sensing material may be applied to the conductive material so as to completely or partially cover the conductive material, or may overlap the conductive material. The sensing material may be applied to the conductive material in any shape, such as one or more lines, one or more dots, or one or more strips. It is also possible to partially remove the sensing material from at least one conductive material after its application. Methods for partially removing the sensing material from at least one conductive material are known per se. For example, a portion of the sensing material can be irradiated with light, in particular with a laser, thereby partially removing the sensing material. It is also possible to irradiate a portion of the sensing material, thereby crosslinking the sensing material, and then wash away the unirradiated portion.

[0133] In step c), a second electrode region is prepared on the second side of the source substrate.

[0134] The second electrode region specifically includes all components that form part of at least one second electrode of the analyte sensor.

[0135] In step c1), a silver composition is applied to the second surface of the source substrate. In an embodiment, the silver composition is applied directly to the second surface of the source substrate. The silver composition may be applied to the second surface of the source substrate so as to at least partially cover the second surface of the source substrate. In another embodiment, the silver composition is applied at least partially to the second conductive trace.

[0136] The silver composition can be any composition known to those skilled in the art. In particular, the silver composition comprises silver. "Silver" in the context of the silver composition of the present invention encompasses not only elemental silver but also silver compounds. In particular, the silver composition comprises Ag / AgCl and a polymer binder. For the polymer binder and Ag / AgCl, the preferences and embodiments described above apply.

[0137] The silver composition may be applied to the second surface of the raw substrate by any known method, such as a wet coating process. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing. After the wet coating process, the layer of silver composition may be further processed. Such processing may be, for example, a drying process, a curing process, and / or a laser ablation process. Such processing is known per se.

[0138] In an embodiment, prior to step c1), a second conductive trace is applied to the raw substrate. For the second conductive trace, the above-described embodiments and preferences apply. Therefore, the second conductive trace can refer to a second conductive material. For the second conductive material, the above-described embodiments and preferences apply.

[0139] The second conductive material can be applied to the first surface of the source substrate by any known method, such as chemical vapor deposition (CVD), physical vapor deposition (PVD), or a wet coating process. Wet coating processes are known per se. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing.

[0140] In step d), a polymer composition is applied onto the second electrode region. For the polymer composition, the above-mentioned embodiments and preferences apply. A film is obtained. The film is obtained on the second electrode region. In particular, in step d), a film is formed on the second electrode region.

[0141] In embodiments, during the method of the present invention, a polymer composition comprising a hydrophobic polymer is not applied to the first side of the substrate.

[0142] The polymer composition may be applied onto the second electrode region by any known method, for example, by a wet coating process. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing. After the wet coating process, the layer of polymer composition may be further processed. Such processing may be, for example, a drying process, a curing process, and / or a laser ablation process. Such processing is known per se.

[0143] In embodiments, the polymer composition can be applied to the second side of the raw substrate, preferably the membrane obtained in step d), and then irradiated with a laser to form pores, for which the preferences and embodiments described above for membrane pores apply.

[0144] In step e), the raw substrate comprising the working electrode area, the second electrode area and the membrane is cut to obtain the analyte sensor.

[0145] The source substrate is preferably cut along its width to form strips. These strips can correspond to analyte sensors. It is also possible for the source substrate to be cut at least once along its length before or after it is cut along its width.

[0146] The raw substrate is preferably cut by a laser.

[0147] Thus, preferably, in the method of manufacturing an analyte sensor, the cutting in step e) comprises laser cutting.

[0148] When cutting the raw substrate in step e), holes can be formed in the membrane in the cut areas.

[0149] Further process steps may be performed, for example in step f) a flux limiting membrane may be added. Therefore, in an embodiment of the method of the present invention, the following step f) is performed:

[0150] f) Adding a flux-limiting membrane to the analyte sensor obtained in step e) to obtain a coated analyte sensor.

[0151] The above-mentioned preferences and embodiments are applicable to the flux-limiting membrane. In particular, the flux-limiting membrane, preferably the at least one polymer material contained in the flux-limiting membrane, may be applied by, for example, a wet coating process. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing.

[0152] For example, in step g), a biocompatible membrane may be added.

[0153] Therefore, in an embodiment of the method of the present invention, the following step g) is performed: g) applying a biocompatible membrane to the analyte sensor obtained in step e).

[0154] If step f) is performed, a biocompatible membrane is typically applied to the coated analyte sensor obtained in step f).

[0155] Therefore, when step f) is performed, in an embodiment the following step g) is performed: g) applying a biocompatible membrane to the coated analyte sensor obtained in step f).

[0156] The biocompatible membrane is generally made of a biocompatible material. Therefore, in step g), the biocompatible membrane is preferably applied by any known process, particularly a wet coating process. Suitable wet coating processes are, for example, selected from the group consisting of spin coating, spray coating, doctor blade, printing, dispensing, slot coating, dip coating, and screen printing.

[0157] Therefore, another object of the present invention is also an analyte sensor obtainable by the method for manufacturing an analyte sensor of the present invention.

[0158] A further object of the present invention is to provide an analyte sensor system comprising: an analyte sensor of the present invention; an electronics unit electronically connected to the analyte sensor.

[0159] For analyte sensors included in the analyte sensor system, the embodiments and preferences described above for the analyte sensors of the present invention apply.

[0160] The term "electronic unit" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically refer to, but is not limited to, a unit configured to perform at least one electronic function, such as a unit that can be treated as a single component. Specifically, the electronic unit may have at least one interface for connecting to an analyte sensor, and the electronic unit may provide at least one electronic function for interacting with the analyte sensor, such as at least one measurement function. The electronic unit may specifically be configured to measure at least one voltage and / or measure at least one current, thereby interacting with the analyte sensor. The electronic unit may further comprise at least one integrated circuit, such as a processor and / or a battery. The term "processor," as generally used herein, is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically refer to, but is not limited to, any logic circuit configured to perform the basic operations of a computer or system, and / or generally to a device configured to perform calculations or logical operations. In particular, the processor may be configured to process electronic signals, such as current or voltage, particularly electronic signals from the analyte sensor. Specifically, the processor may be or include a microcontroller unit (MCU). Additionally or alternatively, the processor may be or include a microprocessor; thus, specifically, elements of the processor may be included in one single integrated circuit (IC) chip. Additionally or alternatively, the processor may be or include one or more application-specific integrated circuits (ASICs) and / or one or more field-programmable gate arrays (FPGAs), etc.The processor can be specifically configured to perform one or more evaluation operations, such as by software programming. Thus, the processor can be configured to process and / or evaluate electronic signals from the analyte sensor and, for example, output a signal indicative of the analyte concentration measured by the analyte sensor. The electronic unit may further include at least one measuring device, such as a potentiostat, for measuring at least one of voltage and current. Additionally, the electronic unit can include a microcontroller specifically configured to control one or more electronic functions of the electronic unit.

[0161] The electronic unit may specifically include at least one electronic unit housing, and the analyte sensor may have, for example, a proximal end and / or an end providing electrical contacts for contacting the analyte sensor, protruding into the electronic unit housing and electrically connected to at least one electronic component within the electronic unit housing. By way of example, the proximal end and / or at least one contact portion of the analyte sensor may protrude into the electronic unit housing and be electrically connected therein to at least one electronic component, such as at least one printed circuit board and / or at least one contact portion of the electronic unit, for example, by one or more of a soldered connection, a bonded connection, a plug, a clamp connection, etc. The electronic unit may specifically be used and / or configured as a transmitter for transmitting measurement data, for example wirelessly, to at least one external device, for example, at least one receiver.

[0162] The electronic unit is electronically connected to the analyte sensor. Thus, an electrical connection exists between the analyte sensor and the electronic unit. The electronics included in the analyte sensor system are in contact with the analyte sensor. For example, the conductive trace and the second conductive trace of the analyte sensor can each form an electrical connection with the electronic unit. Typically, the analyte sensor comprises a contact portion at a proximal end and a working electrode and a second electrode at a distal end. Thus, an electrical signal, such as a current and / or a voltage, can be transmitted from the analyte sensor to the electronic unit via the electronic connection. Through the electrical connection, the electronic unit can interact with the analyte sensor to perform at least one electrochemical measurement. The electrical connection may be specifically established by at least one connection portion of the analyte sensor protruding into the housing of the electronic unit, as outlined above.

[0163] The diagram is as follows: [Brief explanation of the drawings]

[0164] [Figure 1] The experimental results are shown. DETAILED DESCRIPTION OF THE INVENTION

[0165] <Example> The following examples serve to illustrate the invention and should not be construed as limiting with regard to the scope of protection.

[0166] For in vivo testing, an analyte sensor was prepared, which comprised the following: -Base material: PET, thickness 130 μm -Working electrode: -Conductive material: A layer of gold (100 nm thick) with a layer of carbon paste on top -Enzyme: glucose oxidase included in the sensing chemistry (Os complex modified polymer) - Second electrode: counter / reference electrode combination -Conductive material: Gold layer (100nm thick) -Silver: Ag / AgCl paste

[0167] A membrane comprising a hydrophobic polymer (hydrophobic thermoplastic polyurethane) was placed on top of the second electrode. The analyte sensor was laser cut. Holes were formed in the hydrophobic polymer of the analyte sensor depending on the laser cutting conditions. A flux-limiting membrane and a biocompatible membrane covered the sensor.

[0168] Analyte sensors were prepared with the following total pore areas in the hydrophobic polymer: Sensor 1: 0mm 2 Sensor 2: 0.03 mm 2 Sensor 3: 0.1 mm 2 Sensor 4: 0.32 mm 2

[0169] Analyte sensors were implanted in vivo in the same subjects, and current was measured over an 8-day period. In parallel, normal blood glucose (BG) levels were measured by a BG meter using a finger prick. Figure 1 shows the normalized current for measurements using sensors 2, 3, and 4. Zero on the x-axis indicates the start of the measurement period, which occurred after approximately 1 hour of run-in time. The measurement curve for sensor 1 is not shown because no current was obtained.

[0170] From the start of the measurement, sensor 2 shows a sufficiently high current that remains constant over the entire measurement period (8 days). There are several peaks indicating high and low glucose values ​​during the measurement period. These peaks correspond to those seen in normal blood glucose measurements. Therefore, measurements with sensor 2 are particularly reliable and stable over longer periods. Furthermore, they allow calibration with normal blood glucose measurements.

[0171] Sensor 3 had a significantly longer run-in time, during which the current did not correlate with the BG value. From Figure 1, it can be seen that the expected current was reached only after one day of measurement. Thereafter, the measurements were comparable in reliability and stability to those of sensor 2.

[0172] Sensor 4 showed an even longer run-in time, during which the current was significantly lower than expected. Although there were several peaks in the visible current, they did not correlate with BG values, and the sensitivity of the sensor (ratio of current to BG values) was too low and unstable. After 7 days, the current was significantly higher and correlated with BG values, and the sensitivity increased.

Claims

1. 1. An analyte sensor comprising: a substrate including a first side and a second side; at least one working electrode disposed on the first surface of the substrate, at least one electrically conductive material; at least one working electrode comprising at least one enzyme; at least one second electrode disposed on the second surface of the substrate, the at least one second electrode comprising silver; a membrane comprising a polymer composition comprising a hydrophobic polymer; Equipped with the hydrophobic polymer has a water absorption rate of less than 1 wt. %, based on the total weight of the hydrophobic polymer; The membrane is located on the at least one second electrode, the membrane includes a plurality of holes, and the total area of ​​the holes is 0.03 to 0.1 mm 2 The analyte sensor has a size of

2. The analyte sensor of claim 1 , wherein the analyte sensor is an implantable sensor.

3. 3. The analyte sensor of claim 1, wherein the at least one second electrode is selected from the group consisting of a counter electrode, a reference electrode, and a combined counter / reference electrode.

4. The analyte sensor of claim 1 , wherein the first and second surfaces of the substrate are disposed opposite each other.

5. The analyte sensor of claim 1 , wherein the at least one second electrode comprises Ag / AgCl.

6. 6. The analyte sensor of claim 5, wherein the weight of AgCl in the at least one second electrode is in the range of 20 μg to 150 μg.

7. The analyte sensor of claim 1 , wherein the polymer composition comprises a hydrophobic thermoplastic polyurethane.

8. The analyte sensor of any one of claims 1 to 7, wherein the hydrophobic polymer has a glass transition temperature in the range of -100°C to 0°C.

9. The analyte sensor of claim 1 , wherein the at least one working electrode does not include the membrane comprising the polymer composition that includes the hydrophobic polymer.

10. 1. A method of manufacturing an analyte sensor, comprising: a) providing a feedstock substrate comprising a first side and a second side; b) preparing a working electrode area on the first surface of the base substrate, the preparing the working electrode area comprising: b1) applying a conductive material to the first surface of the source substrate; b2) applying a sensing material comprising at least one enzyme at least partially over the conductive material; c) preparing a second electrode region on the second surface of the source substrate, the step of preparing the second electrode region comprising: c1) preparing a second electrode region, comprising: applying a silver composition onto the second surface of the base substrate; d) applying a polymer composition over the second electrode region to obtain a membrane, the polymer composition comprising a hydrophobic polymer; e) cutting the starting substrate containing the working electrode region, the second electrode region, and the membrane to obtain the analyte sensor; Including, the hydrophobic polymer has a water absorption rate of less than 1 wt. %, based on the total weight of the hydrophobic polymer; the membrane is located above the second electrode region, the membrane includes a plurality of holes, and the total area of ​​the holes has a size of 0.03 to 0.1 mm 2 ; method.

11. The method of claim 10 , wherein the cutting in step e) comprises laser cutting.

12. 1. An analyte sensor system comprising: - an analyte sensor according to any one of claims 1 to 9; an electronic unit configured to electronically connect to said analyte sensor; 1. An analyte sensor system comprising:

Images