A continuous analyte sensor having improved bending properties

Abstract

The present invention relates to an analyte sensor comprising an in-vivo portion for insertion into the body of a user and an ex-vivo portion for attachment to the external part of an analyte monitoring device. The in-vivo portion and the ex-vivo portion of the sensor are bent in an angle to each other thereby defining a bending area which is coated with a flexible thermoplastic polymer material. Further, the present invention relates to a method of manufacturing the new analyte sensor and a continuous analyte monitoring system comprising the new analyte sensor.

Description

[0001]P38943 A continuous analyte sensor having improved bending properties Description Field of the Invention The present invention relates to an analyte sensor comprising an in-vivo portion for insertion into the body of a user and an ex-vivo portion for attachment to the external part of an analyte monitoring device. The in-vivo portion and the ex-vivo portion of the sensor are bent in an angle to each other thereby defining a bending area which is coated with a flexible thermoplastic polymer material. Further, the present invention relates to a method of manufacturing the new analyte sensor and a continuous analyte monitoring system comprising the new analyte sensor. Background of the invention Monitoring the concentrations of physiologically relevant analytes in body fluids or body tissues plays an important role in the prevention, control, and treatment of various diseases such as diabetes mellitus. Diabetes mellitus is a disorder in which the beta cells of the pancreas cannot produce sufficient amounts of insulin (type I) or in which insulin is not effective (type II). Without appropriate medication, the blood glucose level cannot be regulated adequately, which in turn may lead to serious pathological conditions. In order to avoid the occurrence of these pathological conditions and the damages associated therewith, the blood glucose level of diabetic subjects needs to be monitored, thereby enabling effective therapeutic intervention, e.g. administration of insulin or other medicaments. For this purpose, continuous glucose monitoring (CGM) devices have been developed. Typically, a CGM device includes an external part comprising a housing including an electronics unit which is positioned outside of the skin and attached thereto, e.g. using a plaster. The CGM device further comprises an P38943 in-vivo glucose sensor. An in-vivo portion of the sensor may be inserted into the user's body and is sensitive for the level of glucose in the surrounding body fluid or tissue. An ex-vivo portion of the sensor is situated outside of the user's body and attached to the external part of the CGM device for providing electrical contact with the electronics unit which is adapted for analyzing the sensor signal. Typically, the sensor of a GCM device comprises a support to which multiple layers functioning as electrode areas, conductive paths, and resistive covers are applied. In order to obtain a reasonable small design of the device the in-vivo portion of the sensor, i.e., the portion inserted into the body, and the ex-vivo portion of the sensor attached to the external part of the CGM device are bent in an angle to each other, e.g., in an angle of about 90°. The bend defines a bending area where the sensor material is put under a mechanical stress which is a challenge for laminated structures comprising layers with varying flexibilities., e.g., rigid resistive coatings typically made from UV curable resist inks on the one hand and flexible conductive carbon coatings on the other hand. This mechanical stress may cause delamination or breakage of the sensor during its time of use which is of course highly undesirable for a patient wearing the CGM device. US 10,863,944 B2 discloses an analyte sensor for inserting into the body including a strain relief feature configured to limit the sensor from bending at a bend radius smaller than a predetermined bend radius. The strain relief feature may include an elastomeric material. US 2023 / 0139158 A1 discloses a sensor comprising a diffusion resistance layer of a blend of PVP and a polyurethane urea-polycarbonate block copolymer to improve the mechanical properties. US 8,527,024 B2 discloses a sensor comprising a diffusion barrier and a polymer layer, e.g., form polyurethane, for protecting a sensor from mechanical damage. WO 2022 / 008394 A1 discloses a sensor having a membrane, e.g., thermoplastic urethane membrane located on the top of a counter- and / or reference electrode for preventing the sensor from damage when it is bent. P38943 It is an object of the present invention to overcome the risk of sensor breakage in the bending area and to provide a sensor structure with improved mechanical stability, which at least partially overcomes the problems of the prior art as described above. Summary of the invention This object is addressed by an analyte sensor, a method for manufacturing an analyte sensor and a continuous analyte monitoring system comprising the new analyte sensor comprising the features of the independent claims. Advantageous embodiments, which might be realized in an isolated fashion or in any arbitrary combination, are listed in the dependent claims and throughout the specification. The analyte sensor of the present invention shows improved robustness against delamination and / or breakage in the bending area while maintaining excellent insulation characteristics. A first aspect of the invention relates to an analyte sensor comprising: - a substrate, - an electrically conductive layer positioned on the top of the substrate, - at least one working electrode, - at least one further electrode, - an electrically insulating layer comprising a rigid polymer material, - a protection layer comprising a flexible thermoplastic polymer material, and - an outer diffusion membrane, wherein the analyte sensor comprises an in-vivo portion configured for insertion in the body of a user, and an ex-vivo portion configured for attachment to an external part of an analyte monitoring device, wherein the in-vivo portion and the ex-vivo portion of the analyte sensor are bent in an angle to each other thereby defining a bending area positioned between the in-vivo portion and the ex-vivo portion, P38943 wherein the electrically insulating layer covers the electrically conductive layer excluding the area of the at least one working electrode and optionally excluding the area of the at least further electrode, and further excluding the bending area, and wherein the protection layer covers the bending area and optionally the area of the at least one further electrode. In certain embodiments, the analyte sensor is glucose sensor. A further aspect of the present invention relates to a method of manufacturing an analyte sensor comprising applying to a substrate: - an electrically conductive layer, - at least one working electrode, - at least one further electrode, - an electrically insulating layer comprising a rigid polymer material, - a protection layer comprising a flexible thermoplastic polymer material, and - an outer diffusion membrane, wherein the analyte sensor comprises an in-vivo portion configured for insertion in the body of a user, and an ex-vivo portion configured for attachment to an external part of an analyte monitoring device, wherein the in-vivo portion and the ex-vivo portion of the analyte sensor are bent in an angle to each other thereby defining a bending area positioned between the in-vivo portion and the ex-vivo portion, wherein the electrically insulating layer is applied on top of the electrically conductive layer excluding the area of the at least one working electrode and optionally excluding the area of the at least further electrode, and further excluding the bending area, and wherein the protection layer is applied on top of the electrically conductive layer in the bending area and optionally in the area of the at least one further electrode. Still a further aspect of the present invention relates to an analyte monitoring system comprising the analyte sensor as herein described. In certain embodiments, the analyte monitoring system sensor is a continuous glucose monitoring system. P38943 Still a further aspect of the present invention relates to a method of determining an analyte in a tissue and / or body fluid of a subject comprising using an analyte sensor, or an analyte monitoring system as herein described. In certain embodiments, the analyte is glucose. Definitions As used in the following, the terms “have”, “comprise” or “include” or any arbitrary grammatical variations thereof are used in a non-exclusive way. Thus, these terms may both refer to a situation in which, besides the feature 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 further features are present. As an example, the expressions “A has B”, “A comprises B” and “A includes B” may both refer to a situation in which, besides B, no other element is present in A (i.e. a situation in which A solely and exclusively consists of B) and to a situation in which, besides B, one or more further elements are present in entity A, such as element C, elements C and D or even further elements. Further, it shall be noted that the terms “at least one”, “one or more” or similar expressions indicating that a feature or element may be present once or more than once typically will be used only once when introducing the respective feature or element. In the following, in most cases, when referring to the respective feature or element, the expressions “at least one” or “one or more” will not be repeated, non- withstanding the fact that the respective feature or element may be present once or more than once. Further, as used in the following, the terms "preferably", "more preferably", "particularly", "more particularly", "specifically", "more specifically" or similar terms are used in conjunction with optional features, without restricting alternative possibilities. Thus, features introduced by these terms are optional features and are not intended to restrict the scope of the claims in any way. The invention may, as the skilled person will recognize, be performed by using alternative features. Similarly, features introduced by "in an embodiment of the invention" or similar expressions are intended to be optional features, without any restriction regarding alternative embodiments of the invention, without any restrictions regarding the scope of the invention and without P38943 any restriction regarding the possibility of combining the features introduced in such way with other optional or non-optional features of the invention. Detailed description The analyte sensor A first aspect of the present invention relates to an analyte sensor. The term “analyte sensor” or “sensor” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element or device configured for detecting or for measuring the concentration of the at least one analyte. The term “analyte” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element, component or compound which may be present in a body fluid and the concentration of which may be of interest for a user. Specifically, the analyte may be or may comprise an arbitrary chemical substance or chemical compound, which may take part in the metabolism of the user, such as at least one metabolite. As an example, the at least one metabolite may be selected from the group consisting of glucose, cholesterol, triglycerides, lactate; more specifically the analyte may be glucose. Additionally or alternatively, however, other types of analytes and / or any combination of analytes may be determined. The analyte sensor of the present invention is adapted for use in an analyte monitoring device, particularly in continuous analyte monitoring device and more particularly in a CGM device. The analyte sensor is configured for at least partial implantation, specifically transcutaneous insertion, into the body tissue of a user. Thus, the sensor may be adapted for performing the detection of the analyte in the body fluid of a subcutaneous tissue, in particular, in an interstitial fluid. More specifically, the analyte sensor may be configured for continuous monitoring of an analyte, even more specifically the analyte sensor may be configured for continuous glucose monitoring. P38943 The terms “user” and “subject” are used interchangeably herein. The terms may in particular relate to a human being. Other parts or components of the sensor may remain outside of the body tissue. For example, as used herein, the terms "implantable" or "subcutaneous" refer to be fully or at least partly arranged within the body tissue of the user. According to the present invention, the analyte sensor comprises an insertable in-vivo portion and an ex-vivo portion. The term “in-vivo” portion refers to the portion or component of the analyte sensor configured to be insertable into an arbitrary body tissue. The term “ex-vivo” portion refers to the portion or component configured to remain outside of the body. Typically, the ex-vivo portion of the sensor is adapted for attachment to the external part of an analyte monitoring device that typically comprises a housing and an electronics unit for evaluating and optionally displaying a signal from the analyte sensor. Typically, the analyte sensor has an elongate structure and comprises a substrate as a base material on which a plurality of different layers of different materials are positioned. According to the present invention, the in-vivo portion and the ex-vivo portion of the analyte sensor are bent in an angle to each other thereby defining a bending area between the in-vivo portion and the ex-vivo portion. The angle between the in-vivo sensor portion and the ex-vivo sensor portion may be the range of about 45 to 135°, of about 60° to 120°, of about 70-110°, particularly of about 75° to about 105° and more particularly about 90°. Typically, the bending area has a length of about 1 mm to about 3 mm and particularly 2 mm. In certain embodiments, the bending area forms a neck, i.e., an area wherein the thickness and / or width of the analyte sensor is reduced compared to the thickness and / or width of the in-vivo portion and the ex-vivo portion. For example, the width of the sensor in the bending area is reduced by about 30% to about 50%, e.g., about 40 % compared to an adjacent portion of the analyte sensor, i.e., the in-vivo portion and / or the in vitro portion. For example, the sensor may have a width of about 600 µm to about 750 µm, e.g. about 660 µm in the in-vivo portion and the ex-vivo portion and a width of about 200 µm to about 500 µm, e.g. about 400 µm in the bending area. P38943 On the in-vivo portion of the analyte sensor a working electrode and typically at least one further electrode, e.g. a counter, reference and / or counter / reference electrode is applied. They are in contact with an electrically conductive material which provides electrical connection to the external part of the analyte monitoring device via the ex- vivo portion of the analyte sensor. The analyte sensor further comprises an electrically insulating layer for providing electrical insulation from undesired external influences. According to the present invention, the electrically insulating layer comprises a rigid polymer material and covers the electrically conductive layer on the substrate excluding the area of the at least one working electrode and optionally excluding the area of the at least further electrode, and further excluding the bending area. In certain embodiments, the electrically insulating layer does not cover the area of the at least one further electrode. The analyte sensor further comprises a protection layer that covers the bending area and optionally the area of the at least one further electrode. The protection layer comprises a flexible thermoplastic polymer material. By omitting the rigid insulation layer in the bending area, the sensor becomes more flexible and better withstands breakage and / or delamination. Further, the protection layer may minimize leakage of Ag+ions from the area of the at least one further electrode and provide an area for impedance measurement. On its outside, the analyte sensor comprises a diffusion membrane layer that controls and limits analyte, e.g., glucose diffusion from the interstitial fluid to the working electrode for allowing a controlled enzymatic reaction taking place and for ensuring the generation of a signal sensor which has a linear dependency on the analyte concentration, e.g., the glucose concentration. It further prevents leakage of enzyme and any water-soluble component from the sensor into the body, reduces the concentration of interfering substances at the working electrode, and provides biocompatibility. The analyte sensor may be manufactured by a coating method, e.g., a roll-to-roll coating procedure wherein the materials of individual the individual layers are applied to the substrate according to known methods, e.g., as described in WO 2023 / 283096 A1, the content of which is herein incorporated by reference. According to the present invention, in the sensor roll material of the present invention, the rigid polymer material P38943 of the electrically insulating layer is omitted in the area that will be later the bending area of the assembled analyte sensor. At this position, an electrically insulating flexible polymer material will be later applied, e.g., via slot die coating. In preferred embodiments, the electrically insulating flexible polymer material is applied such that an overlap with the rigid polymer material of the electrically insulating layer is avoided as much as possible. The substrate The analyte sensor of the present invention comprises a substrate as a base material which serves as backbone ensuring mechanical stability during insertion and application and on which a plurality of layers of different materials are positioned. In particular, the substrate is a carrier for an electrically conductive layer, electrodes, an electrically insulating layer and membranes. The term "substrate" as used herein, is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term "substrate" is synonymously used with the term "sensor substrate" and specifically may refer, without limitation, to any kind of material or combination of materials, which is suitable to form a carrier to support the layers of material as described herein. In particular, a "sensor substrate" as understood herein may comprise electrically insulating material. In certain embodiments, the sensor substrate is a polymer material, particularly a mechanical stable and rigid polymer material such as polyester such as polyethylene terephthalate (PET). The term "layer", as used herein, is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an element of a layer setup of the analyte sensor. Specifically, the term "layer" may refer to an arbitrary covering of an arbitrary substrate, specifically of a flat substrate. The layer may specifically have a lateral extension exceeding its thickness by at least a factor of 2, at least a factor of 5, at least a factor of 10, or even at least a factor of 20 or more. Specifically, the analyte sensor may have a layer setup. The analyte sensor may comprise a plurality of layers such as the at least one conductive material, the at least one layer of the at least one sensing material, and optionally at least one membrane layer. One or more of the layers of the analyte sensor may comprise sub- layers. For example, a layer comprising the conductive material may comprise at least one further layer. P38943 The substrate may have a first side and a second side which is opposite to the first side. In certain embodiments, the layers of material applied on the first side and the second side are different. The electrically conductive material The sensor comprises a layer of electrically conductive material applied on the top of the substrate. The electrically conductive material provides electrically conductive tracks between the electrodes of the sensor and the electronics unit to which the sensor is attached. Further, the electrically conductive material may serve as a carrier for the sensor electrodes, e.g., a working electrode and a combined counter and reference electrode as described below. The term “electrically conductive material” is synonymously used with the term “conductive material” and is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art. It is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a conductive strip, layer, wire or other type of elongated electrical conductor. More specifically, the term “conductive material” may refer, without limitation, to a material, which is conductive and hence capable of sustaining an electrical current, for example the conductive material may comprise at least one material selected from the group consisting of: carbon; carbon paste; gold; copper; silver; nickel; platinum; palladium. Specifically, the conductive material may be or may comprise at least one metal, such as one or more of gold, copper, silver, nickel, palladium, or platinum. Additionally or alternatively, the at least one conductive material may be or may comprise at least one conductive compound, such as at least one conductive organic or inorganic compound. Additionally or alternatively, the at least one conductive material may be or may comprise at least one nonmetallic conductive material, e.g. polyaniline, poly-3, 4- ethylenedioxythiophene (PEDOT), carbon or carbon paste. Carbon paste specifically may relate to a material comprising carbon, a solvent such as diethylene glycol butyl ether, and at least a binder such as vinyl chloride co-and terpolymers. Preferably, the conductive material according to the present invention may comprise gold and / or carbon; more preferably, the conductive material may consist of gold and / or carbon P38943 and / or carbon paste. Specifically, the conductive material may comprise gold and a further material, for example carbon. Moreover, the conductive material may comprise at least one further layer of at least one further material; specifically, the further layer may comprise a further conductive material. More specifically the further layer of the conductive material may comprise or may consist of carbon. The further material may be disposed on the first side. Using a further layer, in particular carbon, may contribute to efficient electron transfer by the conductive material. The working electrode The analyte sensor of the invention is an electrochemical sensor comprising at least one working electrode. The term “working electrode” as used herein, is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to the electrode of the analyte sensor that is sensitive for the analyte. The working electrode may be disposed on a first side of the at least one sensor substrate. In particular, the working electrode comprises at least one sensing material which is sensitive for the analyte to be determined, e.g., glucose. The at least one sensing material is applied to an application area on the substrate. In certain embodiments, the sensing material is applied on top of a layer of an electrically conductive material. The working electrode of the sensor comprises at least one sensing material which is sensitive for the analyte to be determined, e.g., glucose. The term “sensing material”, as used herein, is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The sensing material comprises at least one enzyme; e.g., an enzyme that is capable of catalyzing a chemical reaction consuming at least the analyte. Specifically the enzyme may be an H2O2generating and / or consuming enzyme; even more specifically a glucose oxidase (EC 1.1.3.4), a hexose oxidase (EC 1.1.3.5), an (S)-2-hydroxy acid oxidase (EC 1.1.3.15), a cholesterol oxidase (EC 1.1.3.6), a glucose dehydrogenase (EC 1.1.1.47), a galactose oxidase (EC 1.1.3.9), an alcohol oxidase (EC 1.1.3.13), an L-glutamate oxidase (EC 1.4.3.11 ) or an L-aspartate oxidase (EC 1.4.3.16); even more specifically a glucose oxidase (GOx) including any modification thereof. P38943 Moreover, the sensing material comprises at least one crosslinker; the crosslinker may for example be capable of crosslinking at least part of the sensing material. Specifically, the sensing material may comprise at least one crosslinker selected from UV-curable crosslinkers and chemical crosslinkers; more specifically the sensing material comprises a chemical crosslinker. Suitable chemical and UV-curable crosslinkers are well known in the art. Further, the sensing material may comprise at least one polymeric transition metal complex. The term “polymeric transition metal complex” specifically may refer, without limitation, to a material that may be or may comprise at least a polymeric material; specifically it may be or may comprise at least a polymeric material and at least a metal containing complex. The metal containing complex may be selected from the group of transition metal element complexes, specifically the metal containing complex may be selected from osmium-complexes, ruthenium-complexes, vanadium-complexes, cobalt-complexes, and iron-complexes, such as ferrocenes, such as 2- aminoethylferrocene. Even more specifically, the sensing material may comprise a polymeric transition metal complex as described for example in WO 01 / 36660 A2, the content of which is included by reference. In particular, the sensing material may comprise a modified poly (vinyl pyridine) backbone loaded with poly(biimidizyl) Os complexes covalently coupled through a bidentate linkage. Suitable further sensing materials are further described in Feldmann et al, Diabetes Technology & Therapeutics, 5 (5), 2003, 769-779, the content of which is included by reference. Suitable sensing materials further may include ferrocene-containing polyacrylamide- based viologen-modified redox polymer, pyrrole-2,2'-azino-bis(3-ethylbenzthiazoline- 6-sulfonic acid) (ABTS)-pyrene, naphthoquinone-LPEI. The polymeric transition metal complex may represent a redox mediator incorporated into a cross-linked redox polymer network. This is advantageous as it may facilitate electron transfer between the at least one enzyme or analyte and the conductive material. In order to avoid a sensor drift, the redox mediator and the enzyme may be covalently incorporated into a polymeric structure. ln certain embodiments, the at least one enzyme comprised in the sensing material comprises an enzyme capable of catalyzing a chemical reaction consuming at least the analyte, particularly an H2O2 generating and / or consuming enzyme, a crosslinker P38943 and a polymeric transition metal complex. Specifically, the sensing material may comprise at least a polymeric transition metal complex and GOx and a chemical crosslinker. More specifically, the sensing material may comprise a modified poly(vinyl pyridine) backbone loaded with poly(biimidizyl) Os complexes covalently coupled through a bidentate linkage, GOx and a chemical crosslinker like poly(ethylene glycol) diglycidylether (PEG-DGE). Suitable further sensing materials are known to the person skilled in the art. In an embodiment, the sensing material may comprise a polymeric material and MnO2- particles. The sensing material may for example comprise about 40-60 wt% of a polymeric transition metal complex; about 30-40 wt% of an enzyme capable of catalyzing a chemical reaction consuming at least the analyte, particularly a H2O2 generating and / or consuming enzyme, 20 and about 0.5 -25 wt% of a crosslinker based on the dry total weight of the sensing material. The counter and / or reference electrode The analyte sensor of the invention is an electrochemical sensor comprising a working electrode and at least one further electrode, particularly a counter electrode and / or a reference electrode or a combined counter / reference electrode. Even more particularly, the sensor comprises precisely one further electrode. Even more particularly, the sensor is a two-electrode sensor comprising precisely one working electrode and precisely one combined counter / reference electrode. In certain embodiments, the working electrode is sensitive for the analyte to be measured at a polarization voltage which may be applied between working and reference electrodes, and which may be regulated by a potentiostat. A measurement signal may be provided as an electric current between the counter electrode and the working electrode. A separate counter electrode may be absent, and a pseudo reference electrode may be present, which may also work as a counter electrode. Thus, an analyte sensor typically may comprise a set of at least two, in an embodiment a set of three electrodes. Particularly, the sensing material is present in the working electrode only. P38943 In certain embodiments, the working electrode is applied on a first side of the sensor substrate and the at least one further electrode, e.g., the combined counter / reference electrode is applied to a second side of the substrate which is opposite to the first side of the substrate. The reference electrode, the counter electrode and the combined counter / reference electrode of the sensor comprise a “reference electrode conductive material” or a “counter electrode conductive material”, respectively. These terms as used herein, are broad terms and are to be given its ordinary and customary meaning to a person of ordinary skill in the art and are not to be limited to a special or customized meaning. The terms specifically may refer, without limitation, to a conductive strip, layer, wire or other type of elongated electrical conductor present on a reference electrode or a counter electrode, respectively. More specifically, the terms may refer, without limitation, to a material, which is conductive, and hence capable of sustaining an electrical current, for example the reference electrode conductive material and / or the counter electrode conductive material may comprise at least one material as specified herein above with respect to the conductive material. In addition to the materials listed above, the reference electrode conductive material and / or the counter electrode conductive material may specifically comprise Ag / AgCl. The electrically insulating layer The sensor of the present invention comprises at least one electrically insulating layer of a rigid polymer material that covers the electrically conductive material applied to the substrate of the analyte sensor, at least the electrically conductive material applied to the in-vivo sensor portion excluding the area where the working electrode is positioned and optionally excluding the area where the at least one further electrode is positioned. Further, according to the present invention, the electrically insulating layer is absent in the bending area. The layer of electrically insulating material acts as an electrical insulator between the analyte sensor and the interstitial fluid into which it is inserted. The electrically insulating material provides protection of the electrically conductive layer on the substrate from external influences and prevents crosstalk of signals and electric short P38943 circuits. It also provides adhesion for further membrane layers, e.g. a diffusion layer, applied on top thereof and it works as glue for adhering the sensor to the external part of the analyte monitoring device. The term "electrically insulating material", as used herein, is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. "Electrically insulating material" may also refer to a dielectric material. The term specifically may refer, without limitation, to a material or combination of materials which prevent the transfer of electrical charges, and which do not sustain a significant electrical current. In the sensor of the present invention, the electrically insulating material layer is formed from a rigid polymer material which provides mechanical stability for the sensor and has the benefit that it can be applied via screen printing allowing application of a set of parallel lines within a single production step. In certain embodiments, the rigid polymer material has relatively high Young’s-modulus and / or high sheet resistance. In certain embodiments, the Young´s modulus of the rigid polymer is about 1 GPa to about 5 GPa. Specifically, without limiting other possibilities, the rigid polymer material may be or may comprise at least one insulating resin, e.g., a resistive cover made from a curable, e.g., UV curable resist ink such as an insulating epoxy resin used in manufacturing electronic printed circuit boards. In certain embodiments the rigid polymer material is selected from a curable, e.g., UV curable acrylic polymer or copolymer. In certain embodiments, the layer of the rigid polymer material has a thickness of about 10 to about 25 µm, more precisely 15-20 µm. The protection layer In the bending area between the in-vivo portion and the ex-vivo portion of the analyte sensor, the rigid insulating material is absent. This area is covered by a layer of flexible polymer material, e.g., flexible thermoplastic polymer material which provides resistance against breakage and / or delamination of the analyte sensor. In certain embodiments, the flexible polymer material has relatively low Young’s modulus and / or P38943 high sheet resistance. In certain embodiments, the Young´s modulus of the flexible thermoplastic polymer is about 5 MPa to about 500 MPa. Specifically, without limiting other possibilities, the at least one flexible electrically insulating material may be or may comprise or be a thermoplastic material. In certain embodiments the rigid polymer material is selected from a thermoplastic polyurethane, e.g., Pathway™ TPU excipients, a polydimethylsiloxane (PDMS) or a styrene polymer or copolymer, e.g., a styrene ethylene butylene styrene block copolymer (SEBS). In certain embodiments, the protection layer of the flexible electrically insulating polymer material has a thickness of about 5 to about 15 µm, more precisely about 10 µm. In certain embodiments, the portion of the sensor covered by the flexible thermoplastic polymer in the bending area has a length of at least 1 mm and up to about 3 mm. In certain embodiments, the electrically insulating layer and the protection layer substantially have no overlap along the edges of the bending area. The protection layer has also electrically insulating properties to protect the electrically conductive material in the bending area from electrical contact with the environment, e.g. the interstitial body fluid. In certain embodiments, the protection layer may also be present in the area of the at least one further electrode where it may be the same as the bending area or different. The diffusion membrane The analyte sensor of the present invention further comprises at least one outer diffusion membrane layer at least partially covering the working electrode. The membrane layer generally may selectively allow for one or more molecules and / or compounds to pass, whereas other molecules and / or compounds are stopped by the membrane layer. Thus, the membrane layer is permeable for the at least one analyte to be detected. Thus, as an example, the membrane layer may be permeable for one or more of glucose, lactate, cholesterol or other types of analytes. The at least one membrane layer may hence function as a diffusion barrier that controls diffusion of the analyte from the exterior, e.g. the body fluid surrounding the analyte sensor, to the P38943 sensing material, i. e. the enzyme molecules in the sensing material. In addition, the at least one membrane layer may function as a biocompatibility membrane layer. The diffusion membrane layer, as an example, may have a thickness sufficient for providing mechanical stability. The at least one membrane layer specifically may have a thickness of about 1 pm to about 150 pm. For the at least one membrane layer, as outlined herein, several materials may be used, standalone or in combination. Thus, as an example, the membrane layer specifically may comprise one or more of a polymeric material, specifically a polyvinyl pyridine based copolymer, a polyurethane; a hydrogel; a polyacrylate; a methacrylate- acrylate copolymer or block-copolymer; among which polyvinyl pyridine based copolymers are particularly suitable. These types of membranes are generally known in the art. Moreover, the membrane layer may comprise a crosslinker, specifically a chemical crosslinker or a UV-curable crosslinker, e.g. as described above. Further, the outer diffusion membrane may comprise at least a second membrane layer which may be a biocompatibility membrane layer. The biocompatibility layer may have a thickness of from about 1 pm to about 10 pm, in an embodiment of from about 3 pm to about 6 pm. More specifically, the biocompatibility layer covers the analyte sensor at least partly or completely. Even more specifically, the biocompatibility layer may be the outmost layer of the analyte sensor. The biocompatibility membrane layer may be or may comprise the following materials: methacrylate based polymers and copolymers, acrylamide-methacrylate based copolymers, biodegradable polysaccharides such as hyaluronic acid (HA), agarose, dextran, chitosan and a poly(vinylpyridine) based polymer. Moreover, the present invention relates to the use of the analyte sensor for detecting at least one analyte in a sample; specifically in a sample of a body fluid. More particularly, the analyte sensor is a sensor for continuous glucose measurement. As used herein, the term "body fluid" relates to all bodily fluids of a subject known to comprise or suspected to comprise the analyte of the present invention, including interstitial fluid, blood, plasma, lacrimal fluid, urine, lymph, cerebrospinal fluid, bile, stool, sweat, and saliva. Generally, an arbitrary type of body fluid may be used. Preferably, the body fluid is a bodily fluid which is present in a body tissue of a user, P38943 such as in the interstitial tissue. Thus, as an example, the body fluid may be selected from the group consisting of blood and interstitial fluid. However, additionally or alternatively, one or more other types of body fluids may be used. The body fluid generally may be contained in a body tissue. Thus, generally, the detection of the at least one analyte in the body fluid may preferably be determined in-vivo. The term "sample" is understood by the skilled person and relates to any sub-portion of a bodily fluid. Samples can be obtained by well-known techniques including, e.g., venous or arterial puncture, epidermal puncture, and the like. The term “subject” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a human being or an animal, independent from the fact that the human being or animal, respectively, may be in a healthy condition or may suffer from one or more diseases. As an example, the subject may be a human being or an animal suffering from diabetes. However, additionally or alternatively, the invention may be applied to other types of subjects. Moreover, the present invention relates to a method for measuring an analyte in a sample comprising the analyte sensor or a continuous analyte monitoring device described herein above. The methods for measuring of an analyte of the present invention, in particular, may be in-vivo methods. Alternatively, the method of the invention may also encompass measuring of an analyte under in vitro conditions, e.g. in a sample of a body fluid obtained from a subject, particularly from a human subject. Specifically, said method may not comprise diagnosis of disease based on said measurement. Description of Embodiments Further optional features and embodiments will be disclosed in more detail in the subsequent description of embodiments, preferably in conjunction with the dependent claims. Therein, the respective optional features may be realized in an isolated fashion as well as in any arbitrary feasible combination, as the skilled person will realize. The scope of the invention is not restricted by the preferred embodiments. P38943 Summarizing and without excluding further possible embodiments, the following embodiments may be envisaged: 1. An analyte sensor comprising: - a substrate, - an electrically conductive layer positioned on the top of the substrate, - at least one working electrode, - at least one further electrode, - an electrically insulating layer comprising a rigid polymer material, - a protection layer comprising a flexible thermoplastic polymer material, and - an outer diffusion membrane, wherein the analyte sensor comprises an in-vivo portion configured for insertion in the body of a user, and an ex-vivo portion configured for attachment to an external part of an analyte monitoring device, wherein the in-vivo portion and the ex-vivo portion of the analyte sensor are bent in an angle to each other thereby defining a bending area positioned between the in-vivo portion and the ex-vivo portion, wherein the electrically insulating layer covers the electrically conductive layer excluding the area of the at least one working electrode and optionally excluding the area of the at least further electrode, and further excluding the bending area, and wherein the protection layer covers the bending area and optionally the area of the at least one further electrode. 2. The analyte sensor of embodiment 1, wherein the angle between the in-vivo portion and ex-vivo portion in the bending area is about 45 to 135°. P38943 3. The analyte sensor of embodiment 1 or 2, wherein the angle between the in-vivo portion and ex-vivo portion in the bending area is about 90°. 4. The analyte sensor of any one of embodiments 1-3, wherein the bending area forms a neck between the in-vivo portion and the ex-vivo portion. 5. The analyte sensor of any one of embodiments 1-4, wherein the bending area has a length of at least 1 mm and up to about 3 mm. 6. The analyte sensor of any one of embodiments 1-5, wherein the rigid polymer material of the electrically insulating layer is characterized by a relatively high Young´s modulus. 7. The analyte sensor of any one of embodiments 1-6, wherein the rigid polymer material of the electrically insulating layer is selected from a curable epoxy resin or a curable acrylic polymer or copolymer. 8. The analyte sensor of any one of embodiments 1-7, wherein the flexible thermoplastic polymer material of the protection layer is characterized by a relatively low Young´s modulus. 9. The analyte sensor of any one of claims 1-8, wherein the flexible thermoplastic polymer material of the protection layer is selected from a thermoplastic polyurethane, a polydimethylsiloxane or a styrene polymer or copolymer. 10. The analyte sensor of any one of embodiments 1-9, wherein the portion of the sensor covered by the flexible thermoplastic polymer in the bending area has a length of at least 1 mm and up to about 3 mm. P38943 11. The analyte sensor of any one of embodiments 1-10, wherein the electrically insulating layer and the protection layer substantially have no overlap along the edges of the bending area. 12. The analyte sensor of any one of embodiments 1-11, which is a continuous analyte sensor. 13. The analyte sensor of any one of embodiments 1-12, which is a glucose sensor. 14. A method of manufacturing an analyte sensor of any one of embodiments 1-13 comprising applying to a substrate: - an electrically conductive layer, - at least one working electrode, - at least one further electrode, - an electrically insulating layer comprising a rigid polymer material, - a protection layer comprising a flexible thermoplastic polymer material, and - an outer diffusion membrane, wherein the analyte sensor comprises an in-vivo portion configured for insertion in the body of a user, and an ex-vivo portion configured for attachment to an external part of an analyte monitoring device, wherein the in-vivo portion and the ex-vivo portion of the analyte sensor are bent in an angle to each other thereby defining a bending area positioned between the in-vivo portion and the ex-vivo portion, wherein the electrically insulating layer is applied on top of the electrically conductive layer excluding the area of the at least one working electrode and optionally excluding the area of the at least further electrode, and further excluding the bending area, and P38943 wherein the protection layer is applied on top of the electrically conductive layer in the bending area and optionally in the area of the at least one further electrode. 15. The method of embodiment 14, which is a roll-to-roll coating procedure. 16. The method of embodiment 14 or 15, wherein the protection layer is applied to the bending area by slot die coating. 17. An analyte monitoring system comprising an analyte sensor of any one of embodiments 1-13. 18. The analyte monitoring system of embodiment 17 which is a continuous analyte monitoring system. 19. The analyte monitoring system of embodiment 17 or 18 which is a continuous glucose monitoring system. 20. A method of determining an analyte in a tissue and / or body fluid of a subject comprising using an analyte sensor of any one of embodiments 1-13 or an analyte monitoring system of embodiment 18 or 19. 21. The method of embodiment 20, wherein the subject is a human. 22. The method of embodiment 20 or 21, wherein the analyte is glucose. P38943 Description of the Figures Fig.1 is a schematic depiction of a continuous analyte monitoring device adapted for attachment to the skin of a user, e.g., by means of a tape or a plaster. The continuous analyte monitoring device comprises an external part 10 comprising an electronics unit and an analyte sensor 20. The analyte sensor 20 comprises an in-vivo portion 22 adapted for insertion into the skin of the user, and an ex-vivo portion 24 adapted for providing contact to the external part 10. The in-vivo portion 22 and the ex-vivo portion 24 of the analyte sensor are connected by a bending area 26 defining an angle of about 90° between the in-vivo portion 22 and the ex-vivo portion 24. In the bending area 26, the analyte sensor of the present invention is coated with a protection layer of a thermoplastic flexible polymer material (not shown). Fig.2 is a depiction of an analyte sensor 30 comprising an insulation layer of a rigid polymer material in the bending area 32 after a bending test. A delamination was observed. Fig, 3 is a depiction of an analyte sensor 30 without an insulation layer of a rigid polymer material in the bending area 32 after a bending test. No delamination was observed. Fig. 4 shows the results of a bending test with a sensor having a thermoplastic polyurethane coating in the bending area according to the present invention (samples 01 and 02, type B) and a sensor having a UV-curable resist-ink coating in the bending area (samples 01 and 02, type A). Examples On a flexible, polymeric base film (PET) a carbon layer was applied which functions as conductive electrode path. Subsequently a resist layer was coated on top of the conductive layer where required as well as any further functional coatings necessary for the electrochemical function of the in-vivo sensor (e.g. working or reference electrode materials). Geometrical structuring of these materials via laser or mechanical cutting then provided individual sensors. Both Figures 2 and 3 show a side view of P38943 sensor bending areas. In the example shown in Fig.2 an UV-curable resist-ink covers the required surface of the conductive layer, referred to herein with sample type A. This is also the case for the example shown in Fig. 3 but here the UV-curable ink was omitted in the bending area, referred to herein with sample type B. Instead, this section has a thermoplastic polyurethane coating. Both configurations underwent testing in a bending test stand allowing reproducible strain of sensors in the bending area. In this test a sensor was bent to 90° analogous to Figure 1 and then bent forward and backward by + / - 30° multiple times per minute for several thousand cycles or until severe damage was detected electronically. During this test, the resistance of the sensor was continuously measured via an electrical short at the sensor tip. The working and counter / reference electrode were directly contacted by cutting of ca.1 mm of the sensor tip and applying a drop of conductive paste. Figure 4 compares the behavior of two specimens each from sample types A and B in the bending test stand during 4000 bending cycles. Initially all sensors showed a resistance < 10 kOhm. The resistance for sample type A increased drastically to the GOhm region after few or at least not more than 1000 cycles. This correlates to observed destruction of the conductive path as shown in Figure 2. The sensor resistance for specimens of sample type B remained constant in the kOhm range however and no damage in the sensor material was observed.

Claims

P38943 Claims 1. An analyte sensor comprising: - a substrate, - an electrically conductive layer positioned on the top of the substrate, - at least one working electrode, - at least one further electrode, - an electrically insulating layer comprising a rigid polymer material, - a protection layer comprising a flexible thermoplastic polymer material, and - an outer diffusion membrane, wherein the analyte sensor comprises an in-vivo portion configured for insertion in the body of a user, and an ex-vivo portion configured for attachment to an external part of an analyte monitoring device, wherein the in-vivo portion and the ex-vivo portion of the analyte sensor are bent in an angle to each other thereby defining a bending area positioned between the in-vivo portion and the ex-vivo portion, wherein the electrically insulating layer covers the electrically conductive layer excluding the area of the at least one working electrode and optionally excluding the area of the at least further electrode, and further excluding the bending area, and wherein the protection layer covers the bending area and optionally the area of the at least one further electrode.

2. The analyte sensor of claim 1, wherein the angle between the vivo portion and ex- vivo portion in the bending area is about 90°.

3. The analyte sensor of claim 1 or 2, wherein the rigid polymer material of the electrically insulating layer is characterized by a relatively high Young´s modulus.P38943 4. The analyte sensor of any one of claims 1-3, wherein the rigid polymer material of the electrically insulating layer is selected from a curable epoxy resin or a curable acrylic polymer or copolymer.

5. The analyte sensor of any one of claims 1-4, wherein the flexible thermoplastic polymer material of the protection layer is characterized by a relatively low Young´s modulus.

6. The analyte sensor of any one of claims 1-5, wherein the flexible thermoplastic polymer material of the protection layer is selected from a thermoplastic polyurethane, a polydimethylsiloxane or a styrene polymer or copolymer.

7. The analyte sensor of any one of claims 1-6, wherein the portion of the sensor covered by the flexible thermoplastic polymer has a length of at least 1 mm and up to about 3 mm.

8. The analyte sensor of any one of claims 1-7, which is a glucose sensor.

9. A method of manufacturing an analyte sensor of any one of claims 1-8 comprising applying to a substrate: - an electrically conductive layer, - at least one working electrode, - at least one further electrode, - an electrically insulating layer comprising a rigid polymer material, - a protection layer comprising a flexible thermoplastic polymer material, and - an outer diffusion membrane,P38943 wherein the analyte sensor comprises an in-vivo portion configured for insertion in the body of a user, and an ex-vivo portion configured for attachment to an external part of an analyte monitoring device, wherein the in-vivo portion and the ex-vivo portion of the analyte sensor are bent in an angle to each other thereby defining a bending area positioned between the in-vivo portion and the ex-vivo portion, wherein the electrically insulating layer is applied on top of the electrically conductive layer excluding the area of the at least one working electrode and optionally excluding the area of the at least further electrode, and further excluding the bending area, and wherein the protection layer is applied on top of the electrically conductive layer in the bending area and optionally in the area of the at least one further electrode.

10. The method of claim 9, which is a roll-to-roll coating procedure.

11. The method of claim 9 or 10, wherein the protection layer is applied by slot die coating.

12. An analyte monitoring system comprising an analyte sensor of any one of claims 1-8.

13. The analyte monitoring system of claim 12 which is a continuous glucose monitoring system.

14. A method of determining an analyte in a tissue and / or body fluid of a subject comprising using an analyte sensor of any one of claims 1-8 or an analyte monitoring system of claim 12 or 13.P38943 15. The method of claim 14 wherein the analyte is glucose.

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