Sensor assembly

Abstract

A sensor assembly (124) comprising at least one in-vivo analyte sensor (110) is proposed. The analyte sensor (110) comprises at least one at least partly implantable portion. The analyte sensor (110) comprises at least two subcutaneous electrodes (116, 118) arranged at least partially at the implantable portion. At least one of the subcutaneous electrodes (116, 118) comprises at least one membrane element (120) exhibiting at least one physical property. The sensor assembly (124) comprises at least one on-skin electrode (126). The sensor assembly (124) comprises at least one electronics unit connectable to the analyte sensor (110) and the on-skin electrode (126). The electronics unit comprises at least one reference resistance. The electronics unit is configured for determining the physical property of the membrane element (120) by measuring a voltage distribution between the reference resistance and a circuit comprising the subcutaneous electrode (116, 118) comprising the membrane element (120) and the on-skin electrode (126).

Description

[0001] Sensor assembly

[0002] Technical Field

[0003] The invention relates to a sensor assembly and a method for determining a concentration of at least one analyte in a bodily fluid. The sensor assembly may specifically be configured for detecting at least one analyte in a body fluid of a subject. The devices may be applied in the field of continuous monitoring of the analyte, e.g. glucose, specifically in the field of home care and in the field of professional care, such as in hospitals. Other applications, however, are also feasible.

[0004] Background art

[0005] Monitoring one or more analyte concentrations such as one or more metabolite concentrations in a body fluid of a subject plays an important role in the prevention and treatment of various diseases. Such analytes can include by way of example, but not exclusively, glucose, lactate, cholesterol or other types of analytes and metabolites. Without restricting further possible applications, the invention will be described in the following text with reference to glucose monitoring. However, additionally or alternatively, the invention can also be applied to other types of analytes.

[0006] For measuring the concentration of an analyte, several electrode configurations are known by the skilled person, e.g. from US 2011 / 0040163 Al, US 8,868,151 B2, US 2015 / 0230739 Al, US 2018 / 0103878 Al, US 9,844,329 B2 or US 9,775,543 B2.

[0007] A typical subcutaneous analyte sensor comprises a membrane element, which has several functions. One important function is limiting the flux of the analyte towards the analyte sensitive part of the layer with a known damping factor, in other words, the permeability of the membrane element must be known in order to properly measure the analyte. The permeability of the membrane element can be influenced by e.g. temperature or chemical environment. Furthermore, some deposits at the surface of the membrane element may additionally block analyte transport.

[0008] In order to compensate for these membrane effects, different techniques are implemented. The most common technique is acquisition of the skin surface temperature in order to at least roughly estimate the temperature of the sensors sensitive part. The set-up may comprise even more, than one temperature sensor. While this method may work sufficiently well for compensating the membrane effects caused by temperature variations, it is, clearly, not sensitive towards influence by changes in chemical environment.

[0009] As the main membrane property is its diffusion limiting properties, it can be evaluated by means of such electrochemical techniques, as electrochemical impedance spectroscopy or some pulse techniques. This is possible, as the typical electrochemical sensor can be roughly represented as Randle’s circuit, which comprises a capacitor (Cdl, double layer capacitor) in parallel to the charge transfer resistance (Ret), and ESR, which is equivalent series resistance, comprising all serially connected resistances including the variable membrane resistance, which does correlate with the membrane permeability. Applying sufficiently high- frequency of the excitation signal in EIS or applying a short voltage pulse, allows bypassing the Ret and the whole measurement corresponds to measurement of ESR. Since the ESR also includes such electrodes coatings as hydrogel membrane, its permeability can be measured selectively.

[0010] In the field of continuous glucose monitoring (CGM) the so-called fast-transient method is a novel method, which roughly corresponds to a classic electrochemical impedance measurement at high frequency and is, therefore, selective for equivalent serial resistance (ESR). The fast-transient method is described e.g. in WO 2021 / 180619, WO 2022 / 180130, or WO 2022 / 233966. An advantage of the fast-transient method is much more simple electric design.

[0011] A fast-transient signal may be applied to two- or more electrodes of an analyte sensor. The analyte sensor may have a biological end, e.g. having, in case of a two electrodes sensor, at one side a sensing electrode and at the other side a combined counter-reference electrode. Each of both electrodes can be described as Randle’s circuit in the first approximation. The Randle’s circuit of the sensing electrode comprises double layer capacitance Cdl in parallel to the charge transfer resistance Ret and ESR, comprising resistance of the conductive coating on the insulating substrate, sensing chemistry and membrane resistance Rmem. The combined counter-reference electrode also may comprise a substrate resistance, the own double layer capacitance in parallel to the charge transfer resistance, resistance of the Ag / AgCl layer and the membrane resistance Rmem. Furthermore, there is solution resistance between both electrodes Rsol. Since both Cdl act as shunts during the application of the fast-transient voltage, the charge transfer resistances are short circuited and do not contribute to the measured impedance. Thus, all remaining serially connected resistances, in particular resistance of the conductive layer of each electrode, resistance of the chemistry layers, resistance of the membrane, resistance of the electrolyte, e.g. interstitial fluid (ISF), are measured by fast-transient as ESR. Since fast-transient measures all the ESR comprising resistances, for sensor with high resistance of the conductive layer, such as carbon, the Rmem is one quite small portion of this, the ratio of usable signal to the background signal can be non-optimal. Furthermore, since the Cdl acts as a shunt protecting Ret from polarization by the fast-transient pulse, its capacity has to be large enough in order to avoid faradaic current flow.

[0012] While the Cdl at the sensing electrode is usually sufficiently large, at the counter reference electrode (CERE) is this typically not the case, as the AgCl layer is usually covered by a polymer with low permeability leaving only small open area for mass transfer in order to maintain its biocompatibility. This open area defines Cdl of the CERE and since it is usually quite small, the fast-transient pulse may induce some faradaic currents, and, depending on polarity, eventually consumes AgCl, which is not desired. Finally, since the Cdl of the sensing electrode and that of the CERE are connected serially, the overall capacitance is calculated as reciprocal sum of both. This, in turn, means, that deficit of capacity at either electrode leads to including corresponding Ret in the ESR, which distorts the result. Cdl of the CERE is, as mentioned above, is usually the limiting one. Furthermore, if the open area of the CERE is not covered by the diffusion limiting membrane, it does not contribute to the useful signal amplitude and the signal / background ratio gets worse.

[0013] Another aspect of the fast-transient measurement is the distribution of the electrical field lines during the pulse. Depending on the sensor design, these lines may be mostly concentrated within the coating membrane, thus the measurement is rather sensitive for the membrane bulk properties, or these can also, partially, penetrate electrolyte surrounding the coating membrane. In the latter case, the measurement would be not only sensitive for membrane bulk properties, but also for some deposits, which can eventually emerge at the sensor surface due to some protein deposition or bleeding. There is evidence based on experimental data, that the fast-transient measurement at a flat two-electrodes sensors with coating membrane of 10-20 pm thickness is almost insensitive towards some deposits at the membrane surface, as long as these deposited are not so dense, that these are mostly blocking mass transport across the membrane, for instance, if there is a huge blood clot arose. Such case can be artificially provoked in-vitro, but of extremely low probability in-vivo. The density of the deposit in-vivo is much lower and cannot be detected by the current set-up of the fast- transient measurement. It is, nevertheless vary valuable information, as even small density deposits may influence the sensitivity of the sensor very much, since these are limiting the analyte diffusion through the membrane towards the sensing layer at the working electrode.

[0014] Problem to be solved

[0015] It is therefore desirable to provide a sensor assembly and a method for determining a concentration of at least one analyte in a bodily fluid which at least partially address the above- mentioned technical challenges. Specifically, improvement of fast transient measurement for continuous glucose monitoring is desirable.

[0016] Summary

[0017] This problem is addressed by a sensor assembly and a method for determining a concentration of at least one analyte in a bodily fluid with the features of the independent claims. Advantageous embodiments which might be realized in an isolated fashion or in any arbitrary combinations are listed in the dependent claims as well as throughout the specification.

[0018] 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.

[0019] 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 any restriction regarding the possibility of combining the features introduced in such way with other optional or non-optional features of the invention.

[0020] In a first aspect, a sensor assembly comprising at least one in-vivo analyte sensor, is disclosed. The analyte sensor comprises at least two subcutaneous electrodes arranged at least partially at the implantable portion. At least one of the subcutaneous electrodes comprises at least one membrane element exhibiting at least one physical property. The sensor assembly further comprises at least one on-skin electrode. The sensor assembly comprises at least one electronics unit connectable to the analyte sensor and the on-skin electrode. The electronics unit comprises at least one reference resistance. The electronics unit is configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the subcutaneous electrode, which comprises the membrane element, and the on-skin electrode, e.g. during application of at least one voltage pulse such as at least one fast-transient (FT) voltage signal.

[0021] A processing unit may be configured for determining by using a known value of the applied voltage pulse and the voltage distribution the impedance. The impedance can be determined using different suitable techniques, such as electrochemical impedance spectroscopy (EIS) or FT or other.

[0022] The term “sensor assembly” 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 system comprising at least one sensor. As further used herein, the term “system” may refer to an arbitrary set of interacting or interdependent component parts forming a whole. Specifically, the components may interact with each other in order to fulfill at least one common function. The at least two components may be handled independently or may be coupled or connectable. The term “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 at least one condition or for measuring at least one measurement variable.

[0023] The term “analyte 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 a sensor which is capable of qualitatively or quantitatively detecting the presence and / or the concentration of the at least one analyte. The term “detecting” 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 process of determining a presence and / or a quantity and / or a concentration of the at least one analyte. Thus, the detection may be or may comprise a qualitative detection, simply determining the presence of the at least one analyte or the absence of the at least one analyte, and / or may be or may comprise a quantitative detection, which determines the quantity and / or the concentration of the at least one analyte.

[0024] The analyte sensor may be an electrochemical sensor. The term “electrochemical 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 analyte sensor which is adapted for a detection of an electrochemically detectable property of the analyte, such as an electrochemical detection reaction. Thus, for example, the electrochemical detection reaction may be detected by applying and comparing one or more electrode potentials. Specifically, the electrochemical sensor may be adapted to generate the at least one measurement signal which may, directly or indirectly, indicate a presence and / or an extent of the electrochemical detection reaction, such as at least one current signal and / or at least one voltage signal. The measurement may be a qualitative and / or a quantitative measurement. Still, other embodiments are feasible. As a result of the detection, at least one signal may be produced which characterizes an outcome of the detection, such as at least one measurement signal. The at least one measurement signal specifically may be or may comprise at least one electronic signal such as at least one voltage and / or at least one current. The at least one signal may be or may comprise at least one analogue signal and / or may be or may comprise at least one digital signal. The analyte sensor may be configured for generating and evaluating a plurality of measurement signals, wherefrom the desired information is determined. Herein, the plurality of measurement signals may be recorded within fixed or variable time intervals or, alternatively or in addition, at an occurrence of at least one prespecified event. In particular, the analyte sensor as used herein may, especially, be configured for a continuous monitoring of one or more analytes, in particular of glucose, such as for managing, monitoring, and controlling a diabetes state. As further used herein, the term "monitoring" refers to a process of continuously acquiring data and deriving desired information therefrom without user interaction.

[0025] 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 a chemical and / or biological substance which takes part in the metabolism of the body of a subject. The analyte can be any electrochemically detectable species, including simple ions, such as potassium (potentiometric measurement), but also much more complex structures, like creatinine. Exemplarily, the analyte may be a metabolite or a combination of two or more metabolites. As an example, the analyte may be selected from the group consisting of: glucose, ascorbate, ketones, lactate, triglycerides, cholesterol. A preferred analyte is glucose. Still, other analytes or combinations of two or more analytes may be detected.

[0026] 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 relates 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. The subject may be a patient. As an example, the subject may be a human being or an animal suffering from diabetes. The subject may be a user, e.g. a patient, intending to monitor an analyte value, such as a glucose value, in the user’s body tissue and / or to deliver medication, such as insulin, into the user’s body tissue. However, in an embodiment, the user of the insertion device may be different from the subject. Additionally or alternatively, the invention may be applied to other types of users or patients.

[0027] The analyte sensor is an in-vivo sensor. The term “in-vivo 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 a sensor which is configured for being at least partially implanted into a body tissue of a user. The analyte sensor may be configured for transdermal detecting the at least one analyte. The term “transdermal” 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 suitability of the analyte sensor for being fully or at least partly arranged within the body tissue of a subject. The analyte sensor may be a fully or partially implantable analyte sensor. The analyte sensor may be a transcutaneous analyte sensor. The analyte sensor may be adapted for performing the detection of the analyte in a bodily fluid of the subject in a subcutaneous tissue, e.g. in an interstitial fluid. As further used herein, the term “bodily fluid”, generally, refers to a fluid, in particular a liquid, which is typically present in a body or a body tissue of the subject and / or may be produced by the body of the subject. The bodily fluid may be selected from the group consisting of blood and interstitial fluid. However, additionally or alternatively, one or more other types of bodily fluids may be used, such as saliva, tear fluid, urine or other body fluids.

[0028] The analyte sensor may comprise at least one at least partly implantable portion. The term “implantable portion”, also denoted as “insertable portion”, 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 part or component of an element configured to be insertable into an arbitrary body tissue. Other parts or components of the analyte sensor may remain outside of the body tissue, e.g. some parts of a counter electrode and / or reference electrode or combined counter / reference electrode may remain outside of the body tissue. The portion of the analyte sensor which is inserted is also called the in-vivo portion, the portion of the analyte sensor which may stay outside of the body tissue is also called the ex-vivo portion. For example, the in-vivo portion has a length in the range from 3 mm to 12 mm. The implantable portion may fully or partially comprise a biocompatible surface, which may have as little detrimental effects on the user or the body tissue as possible, at least during typical durations of use. For this purpose, the implantable portion may be fully or partially covered with at least one biocompatibility membrane layer, such as at least one polymer membrane or a gel membrane, which, on one hand, may be permeable for the body fluid or at least for the analyte as comprised therein and which, on the other hand, may retain sensor substances, such as one or more test chemicals within the analyte sensor, thus preventing a migration thereof into the body tissue.

[0029] The analyte sensor may comprise a carrier, e.g. a substrate. The term “carrier” 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 which is suitable to carry one or more other elements disposed thereon or therein. 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 specifically may refer, without limitation, to an arbitrary flat element which has 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. The substrate may have an elongated shape, such as a strip-shape and / or a bar-shape. The substrate, as an example, may comprise a shaft, specifically a shaft having an elongate shape. For example the shaft may have a shape selected from the group consisting of a strip, a needle, a tape. Also other shapes may be feasible. The substrate, may be a flexible substrate, i.e. a substrate which may be bent or deformed by forces which usually occur during wearing and insertion into the body tissue, such as forces of 10 N or less. The substrate may be made of or may comprise a deformable material, such as a plastic or malleable material and / or an elastic material. As an example, the substrate may be or may comprise a foil, such as a foil made of one or more of a paper material, a cardboard material, a plastic material, a metal material, a ceramic material or a glass material. As an example, the carrier or the substrate may comprise a polyimide foil. The substrate may comprise an electrically insulating material, such as an electrically insulating plastic foil. The substrate may be or comprise at least partially, preferably completely, at least one electrically insulating material, especially in order to avoid unwanted currents between electrically conducting elements as carried by the substrate. For example, the at least one electrically insulating material may be selected from the group consisting of an insulating epoxy resin, a polycarbonate, a polyester, a polyvinylchloride, a polyurethane, a polyether, a polyethylene, a polyamide, a polyimide, a polyacrylate, a polymethacrylate, a polytetrafluoroethylene or a copolymer thereof, and alumina; however, other kinds of electrically insulating materials may also be feasible. For example, a suitable polyester may be polyethylene terephthalate (PET).

[0030] For example, the analyte sensor may be a needle-shaped or a strip-shaped analyte sensor having a flexible substrate and the electrodes disposed thereon. As an example, the analyte sensor may have a total length of 5 mm to 50 mm, specifically a total length of 7 mm to 30 mm. The term “total length” within the context of the present invention relates to the overall length of the analyte sensor which means a portion of the analyte sensor which is inserted and the portion of the analyte sensor which may stay outside of the body tissue.

[0031] The sensor assembly specifically may be a unitary system which may be handled as one single piece before use. For example, elements of the sensor assembly, such as the analyte sensor, an insertion cannula, an electronics unit, a housing and connector elements, may form a pre-assembled single unit. The term “preassembled” 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 fact that an assembly process has already taken place. The components of the sensor assembly may be assembled, such as by being mechanically interconnected, thereby being mechanically ready for use, such as for being inserted into the body tissue of the subject for detection of the analyte. The pre-assembling may take place in a factory, thereby rendering the sensor assembly a factory-assembled functional module.

[0032] The analyte sensor may be inserted into the body tissue of the subject by using at least one insertion device, also denoted as inserter. The sensor assembly may comprise the insertion device. The sensor assembly may be configured for inserting the analyte sensor into the body tissue of the subject. The insertion may take place in such a way that the analyte sensor is fully or partially placed under the skin after insertion. The insertion may take place also in such a way that a part of the analyte sensor may protrude from the body tissue, through the skin, in order to be contacted on the outside of the body, such as electrically and / or fluidi- cally. After insertion of the analyte sensor into the body tissue, the sensor assembly may disassemble into a disposable handling component, e.g. including an inserter in a used state, and the analyte sensor with a body mount, wherein the body mount may be attached to the skin of the subject and wherein the analyte sensor may protrude into the body tissue.

[0033] The term “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 an, generally arbitrary shaped, electrical conductor.

[0034] The term “subcutaneous 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 an electrode configured to be placed at least partially subcutaneously, e.g. some parts or components of the electrode may be placed subcutaneously and other parts e.g. analyte sensor may remain outside of the body tissue, e.g. contact pads. The parts or components of the electrode to be placed subcutaneously may be part of the implantable portion of the analyte sensor. The subcutaneous electrode may comprise at least one metallic wire, e.g. a platinum or platinum alloy wire. Platinum has a high electrochemical stability. Additionally or alternatively, a carbon paste on insulating substrate may be used.

[0035] An electrode immersed in an electrolyte solution can be simplified described by means of so-called Randle’s circuit. The simplest Randle’s circuit is described by two in series connected resistors Rl, R2 and one capacitor Cl in parallel to R2. The resistor R1 may represent so-called equivalent series resistance and includes resistance of the electrode itself, resistance of the electrolyte solution between the given electrode and another one against which these resistance values are being measured. The resistor R2 represents so-called charge-transfer resistance (RCT) and describes roughly the DC current, which flows through the interface electrode / electrolyte during a potentiostatic chronoamperometric measurement. The Cl is so-called double layer capacitor and is formed by interface electrode / electrolyte. Physically, having an electrode immersed in the electrolyte solution, it is impossible to contact a connection point between R1 and R2 by some measuring device. The only accessible contacting points are at the one left from R1 and at the right from R2 / C1. For resistance measurement, a voltage may be applied at the contacting points, which would lead to some current flow which can be measured. The resistance may be determined by dividing the applied DC voltage over the measured DC current and calculate the DC resistance according to Ohm’s law. The calculated resistance is the sum of the R1 and R2, as the DC current cannot flow through the Cl and, thus, it flows through the R1 and R2. If there is a need to measure R1 selectively, this can be done by measuring impedance. The impedance may be determined as a ratio of an AC excitation voltage over an AC current caused by the AC excitation voltage at different frequencies. The classic resistance measurement can be considered as part of an impedance measurement with frequency of the excitation signal approaching 0 Hz. The impedance measured at very high frequencies, such as the fast-transient signal which will be described below in more detail, would correspond to the value of Rl, as the AC current would mainly flow through the Cl, thus avoiding R2 and the R2 would not contribute to the determined impedance.

[0036] The subcutaneous electrodes may comprise at least one sensing electrode. The subcutaneous electrodes further may comprise at least one counter electrode and at least one reference electrode, or at least one counter-reference electrode.

[0037] The term “sensing electrode”, also denoted as “detection electrode” or “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 an electrode configured for performing at least one electrochemical detection reaction for detecting the at least one analyte. The working electrode may have an analyte detection agent being sensitive to the analyte to be detected. The term “analyte detection agent” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary material or a composition of materials adapted to change a detectable property in a presence of an analyte. This property may be an electrochemically detectable property. Specifically, the analyte detection agent may be a highly selective analyte detection agent, which only changes the property if the analyte is present in the body fluid whereas no change occurs if the analyte is not present. The degree or change of the property is dependent on the concentration of the analyte in the body fluid, in order to allow a quantitative detection of the analyte. As an example, the analyte detection agent may comprise an enzyme, such as glucose oxidase and / or glucose dehydrogenase. The working electrode may further comprise a conductive working electrode pad. The conductive working electrode pad may be in contact with the analyte detection agent. Thus, the analyte detection agent may be coated onto the conductive working electrode pad. The analyte detection agent may form an analyte detection agent surface which may be in contact with the body fluid. As an example, the analyte detection agent surface may be an open analyte detection agent surface or may be covered by the above-mentioned membrane which is permeable to the analyte to be detected and / or to the body fluid or a part thereof, such that the analyte may interact with the analyte detection agent. For potential analyte detection agents and / or materials for the conductive working electrode pad, reference may be made to WO 2007 / 071562 Al and / or the prior art documents disclosed therein. Other embodiments, however, are feasible. The one or more working electrode pads specifically may be formed by a dot, line or grid which each can form a coherent area of an electrode material. If more than one dot, line or grid of the electrode material is superimposed, the sensor may provide more than one electrode pad. All electrode pads together may build the working electrode. The analyte sensor may comprise the working electrode with a number of electrode pads in a range from 1 to 50, preferably from 2 to 30, preferably from 5 to 20 electrode pads.

[0038] The sensing electrode may be designed as a continuous conductive surface, e.g. a carbon (paste), having one or more spots, lines or the like of sensitive material thereon. The conductive material may be structured and / or at least partially isolated with a non-conductive material on top. The sensing electrode may comprise one or more exposed surfaces on which the sensitive material is applied.

[0039] The term “counter 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 an electrode configured for performing at least one electrochemical counter reaction adapted for balancing a current flow required by the detection reaction at the detection electrode. The term “reference 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 an electrode adapted for providing a constant electrode potential as a reference potential, in particular at least within tolerances, such as by providing a redox system having a constant electrode potential. The counter electrode and the reference electrode may be one of a common electrode or two separate electrodes. For potential materials usable for the counter electrode and / or the reference electrode, reference may be made to WO 2022 / 008394 and / or the prior art documents disclosed therein. Other embodiments, however, are feasible.

[0040] The working electrode may be sensitive for the analyte of interest at a polarization voltage which may be applied between the working and reference electrode and which may be regulated by a potentiostat. A measurement signal may be provided as an electric current between the working electrode and the counter electrode.

[0041] Each of the subcutaneous electrodes may comprise a conductive pad or conductive element, such as a metal pad and / or a metal element and / or a pad or element made of a conductive inorganic or organic material such as carbon and / or a conductive polymer. The conductive pad or conductive element may be uncovered and / or may be covered with an additional material, such as a sensing chemistry also denoted as test chemical. The working electrode may comprise a working electrode pad and, optionally, at least one test chemical disposed thereon. The counter electrode may comprise a counter electrode pad. Additionally and optionally, one or more redox materials may be disposed thereon. The at least two electrodes of the analyte sensor may be embodied such that an electrochemical reaction may take place at one or more of the electrodes, such as one or more working electrodes. Thus, the electrodes may be embodied such that an oxidation reaction and / or reduction reaction may take place at one or more of the electrodes. The electrochemical detection reaction may be detected by measuring electric current between a working electrode and one further electrode such as a counter electrode or a counter-reference electrode.

[0042] The two or more subcutaneous electrodes may be used for one or more of an amperometric or potentiometric measurement. The potentiometric measurement may comprise measuring a potential by setting current, e.g. galvanostatic, where the current is kept constant, or gal- vanodynamic, where the current in time is intentionally change. The amperometric measurement may comprise measuring a current by setting a potential, e.g. potentiostatic, where the potential is kept constant, or potentiodynamic, where the potential in time is intentionally changed. An impedance measurement can be performed as potentiostatic method or as galvanostatic method, depending, on what is defined and what is measured. Moreover, OCP (open circuit potentiometry) may be used. In this case no current flow may be intentionally induced by the measurement electronics. These types of measurements generally are known to the skilled person in the art of analyte detection, such as from WO 2007 / 071562 Al and / or the prior art documents disclosed therein. For potential setups of the electrodes, electrode materials or measurement setups, reference may be made to this document. Analyte sensors are generally known in the art and include continuous glucose sensor systems or for example continuous ketone measurement. It shall be noted, however, that other setups, electrode materials or measurement setups may be used within the present invention.

[0043] For example, the working electrode and the at least one further electrode may be located on opposing sides of the substrate in a manner that a geometrical projection of the site of the working electrode onto the side of the substrate on which the at least one further electrode may be located does not result in overlap between the geometrical projection of the site of the working electrode and the site of the at least one further electrode. However, placing the working electrode and the at least one further electrode on different sites on the same side of the substrate, such as both on the first side or the second side of the substrate, may also be feasible.

[0044] The sensor assembly comprises at least one electronics unit connectable to the analyte sensor. The analyte sensor may be operably connected to the electronics unit. The term “electronics unit” 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 unit, such as a unit which may be handled as a single piece, which is configured for performing at least one electronic function. For example, the electronics unit may have at least one interface for being connected to the analyte sensor. The analyte sensor may comprise one or more leads for electrically contacting the electrodes. The leads may, during insertion or at a later point in time, be connected to one or more electronic components. For example, the leads may already be connected to the electronics unit before insertion of the analyte sensor. The electronics unit may provide at least one electronic function interacting with the analyte sensor, such as at least one measurement function. The electronics unit may be configured for one or more of determining and / or controlling a detection of the analyte and / or transmitting measurement data to another component. Specifically, the electronics unit may be configured for one or more of performing a measurement with the analyte sensor, performing a voltage measurement, performing a current measurement, recording sensor signals, storing measurement signals and / or measurement data, transmitting sensor signals to another component. Thus, the electronics unit specifically may comprise at least one of: a voltmeter, an ammeter, a potentiostat, a voltage source, a current source, a signal receiver, a signal transmitter, an analog-digital converter, an electronic filter, a data storage device, an energy storage. For example, the electronics unit may be embodied as a transmitter or may comprise at least one transmitter configured for transmitting data to a remote computer or to a remote device. The sensor assembly further may comprise at least one electronic remote device configured to communicate and / or control with the sensor assembly. The electronic remote device may be selected from a personal computer, a wearable, a smartphone, a proprietary remote control, a tablet or a server.

[0045] The sensor assembly may comprise an electrical energy reservoir, such as at least one battery. The term “battery” 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 relates to an arbitrary source of electric power comprising one or more electrochemical cells with external connections for powering an electrical device. When a battery supplies power, its positive terminal may be referred to as cathode and its negative terminal may be referred to as anode. The battery may specifically be a primary battery. The primary battery may be configured for being used once. The primary battery may also be referred to as single-use or disposable battery. The sensor assembly may comprise at least one connector element configured for establishing an electrical contact between the electrical energy reservoir and electronic components of the sensor assembly. For example, the battery may be a 3V or 1.5V battery.

[0046] At least one of the subcutaneous electrodes comprises at least one membrane element exhibiting at least one physical property, e.g. depending on temperature. One of the subcutaneous electrodes may be the sensing electrode comprising the membrane element.

[0047] The term “membrane element” 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 at least one element configured for controlling and / or limiting diffusion of the analyte to the electrode to which the membrane element is applied. Thus, the membrane element may be configured as diffusion limiting membrane. However, the membrane element may have even more functionalities, such as providing biocompatibility. The membrane element may have further functions such as blocking of leakage of components below the membrane element such as of the enzyme or other components comprised in any one of the at least two measurement electrodes. The membrane element may also be configured as a blocking membrane. As used herein, the term “blocking” may refer to preventing leakage of inner components of a sensitive layer of the working electrode but not to the analyte. The membrane element may be configured for maintaining of sensor integrity, by for instance keeping the enzyme or redox mediator from leaching, thus gradation of the whole sensor. Independently on the role of the membrane element, its altering may be compensated.

[0048] The membrane element may comprise at least one polymer. The membrane element may be applied to the working electrode as thin polymer film. For example, the membrane element may be or may comprise Poly-(4-(N-(3-sulfonatopropyl) pyridinium)-co-(4vinyl-pyridine)- co- styrene (5% / 90% / 5%) or hydrophilic Polyurethane such as HP60D20 available from Lubrizol®. For example, the membrane element may comprise at least one of the following polymer classes and / or their copolymer: Poly(4 vinyl pyridine), Polymethacrylate, Polyacrylate, Polyvinyl pyrrolidone, Polyvinyl alcohol (PVA), Polyethylene glycol. For further details concerning the membrane element, specifically with regard to its properties and composition, reference may be made to WO 2022 / 058255.

[0049] The membrane element has at least one physical property depending on at least one parameter such as temperature, pH, composition of electrolyte and others. The term “physical property” 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 physical property of the membrane element, e.g. depending on environmental conditions, e.g. in vicinity of the membrane element. The physical property may be e.g. dependent on the temperature, e.g. may be proportional to the temperature. The physical property may be ionic conductivity.

[0050] The determined physical property may be evaluated into one value by at least one processing unit, e.g. by using at least one predetermined relationship between this value and the physical property. The term “to evaluate”, 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 process of processing at least one first item of information in order to generate at least one second item of information thereby.

[0051] For example, the physical property may be an ionic conductivity of the membrane element. The ionic conductivity of the membrane may correlate with a permeability of the membrane element for an analyte to be determined. The term “permeability” 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 material parameter characterizing transmission properties of the membrane element, specifically passing of substances through the membrane element. Further specifically, permeability may refer to permeability for a specific analyte since molecules and ions of the analytes may have different sizes, shapes and charge. The physical property, in particular permeability, may depend on different parameters such as temperature, composition of interstitial fluid, thickness of the membrane element, aging, swelling degree, mechanical stresses and the like. In an embodiment, the permeability refers to the permeability of the membrane for glucose. Permeability of the membrane element can be measurable by determining an ionic conductivity of the membrane element, which is reverse of electrical resistance of the membrane and is denoted as membrane resistance. Permeability of the membrane element for a specific analyte pAnaiyt may be determined by pAnaiyt = f*p, wherein p is the permeability determined via the electrical resistance of the membrane element and f is a conversion factor. The conversion factor may be determined in calibration experiments using known glucose values.

[0052] Permeability of the membrane element for certain compounds may be proportional to the membrane’s swelling degree. The swelling degree may correspond to the degree of water uptake. The swelling degree of the membrane may depend on its hydrophilicity. The membrane’s swelling degree may directly affect the amount and / or mobility and, thus, the permeability of the membrane for certain compounds. The conductivity of an electrolyte like water or bodily fluid, such as interstitial fluid is directly linked to so-called total dissolved solids whereby ions, such as H+, OH-, Na+, K+, Cl- and other have the most contribution. Therefore, also the conductivity of the membrane element which has taken up water or bodily fluid such as interstitial fluid also is directly linked to the total dissolved solids. The more charge carriers are present and the more mobile they are, the lower is the measured electrical resistance, by otherwise constant conditions, such as e.g. cell geometry. Thus, the electrical resistance, or reversely, electric conductivity of the membrane element may depend on quantity and mobility of ions present in the membrane element.

[0053] The sensor assembly comprises at least one on-skin electrode. The term “on-skin 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 an electrode which is mountable and / or attachable to an outer skin surface and / or that the electrode is at least partially in contact with an outer skin surface. In comparison to the subcutaneous electrodes, the on-skin electrode may be an electrode external from but on the user’s body. The outer skin surface may be the epidermis. The on-skin electrode may be brought in contact with the outer skin surface, e.g. such that the on-skin electrode can have direct contact with sweat pores on the epidermis. The on-skin electrode may be mountable and / or attachable to an outer skin surface by using at least one patch and / or the on-skin electrode may be a part of a patch.

[0054] The on-skin electrode may have a low impedance, e.g. < 500 Q, preferably < 250 Q, more preferably < 100 Q. The on-skin electrode may have a skin contacting surface. The term “skin contacting surface” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a surface of the respective electrode configured for contacting the electrode with the skin of the user, either directly or indirectly. For example, the skin contacting surface may be the skin-contacting layer directly in contact with the skin of the user. Alternatively, additional layers between the skin contacting surface and the skin may be used, e.g. the skin contacting surface may be contacted indirectly via at least one additional element such as at least one additional hydrogel layer e.g. for increasing skin compatibility, and the like. The on-skin electrode may have a high skin surface area for contacting the skin. The term “skin surface area” 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 geometrical area covered by the skin contacting surface. The skin surface area may be from a few square millimeters up to several hundreds of square millimeters, e.g. from 1 mm2to 1000 mm2, preferably from 10 mm2to 500 mm2. Other values are feasible. The skin contacting surface, and thus the skin surface area, may be a continuous area or may comprise a plurality of areas. The skin contacting surface, and thus the skin surface area, may allow for forming a solid-liquid-interface.

[0055] The present invention proposes implementing of an on-skin electrode in addition to the at least two-subcutaneous electrodes. The ESR between said on-skin electrode and at least one of the subcutaneous electrode comprising the membrane element, e.g. the working electrode, may be measured. This can allow excluding the counter or counter reference electrode (CERE) with its low Cdl and corresponding portion of ESR from the ESR measurement circuit. The on-skin electrode therefore may possess a low impedance and a high surface area. This can represent a Randles circuit with extremely high Cdl and extremely low ESR. Due to this effect, the measured ESR will mostly consist of the ESR of the working electrode.

[0056] Furthermore, since the ESR is measured between one electrode on the sensor and the external electrode, the ESR will be mandatory measured across the membrane / free electrolyte (ISF) interface, which will also unavoidably include eventually existing deposit. Thus, the blockage of the membrane surface may be detected as growth of the measured ESR.

[0057] The on-skin electrode may be realized in many different ways, having a high surface area and ionic contact with the skin surface area in order to form a solid to liquid interface. The on-skin electrode may comprise at least one electrically insulating substrate. The substrate may have a circular and / or disc-like shape. However, other shapes are possible. The substrate may comprise an electrically insulating material, such as an electrically insulating plastic foil. For example, the electrically insulating material may be selected from the group consisting of at least one a polyester such as Polyethylene terephthalate (PET), an insulating epoxy resin, a polycarbonate, a polyvinylchloride, a polyurethane, a polyether, a polyethylene, a polyamide, a polyimide, a polyacrylate, a polymethacrylate, a polytetrafluoroethylene or a copolymer thereof, and alumina; however, other kinds of electrically insulating materials may also be feasible. The substrate may be a housing of the sensor assembly, e.g. of a sensor patch casing.

[0058] The on-skin electrode may comprise at least one electrically conductive layer. The electrically conductive layer comprises at least one material selected from the group consisting of carbon, gold, or Ag, AgCl, at least one conductive polymer such as PEDOT, at least one conductive oxide such as ITO or FTO. However, other materials may be possible. For example, the on-skin electrode may comprise at least one at least one layer of Ag / AgCl or a, e.g. thin, layer of AgCl on an Ag layer. This can allow forming a reference electrode (RE) and / or a counter-reference electrode (CERE).

[0059] The on-skin electrode may comprise at least one hydrogel layer and / or may be separated from the skin by at least one hydrogel. The hydrogel layer may be an additional layer between the skin contacting surface and the skin. The hydrogel may comprise ions for providing conductivity. The hydrogel may allow for increasing skin compatibility, e.g. allowing reducing risk of allergic reaction. For example, the hydrogel may be a Cl-soaked hydrogel. The hydrogel layer may comprise chloride, e.g. in case Ag / AgCl is used. In this case, the chloride may provide a potential for the reference and / or counter reference electrode. However, in case of using other materials for the electrically conductive layer using of other ions in the hydrogel may be possible.

[0060] For example, the on-skin electrode may be part of a sensor patch casing contacting the skin. The on-skin electrode may be manufactured by screen-printing or another coating techniques, e.g. using conductive pastes, e.g. carbon or silver based, directly on the bottom part of the casing.

[0061] The on-skin electrode may be rigid or flexible - for example, the on-skin electrode may be part of sensor patch adhesive. For example, the on-skin electrode is a rigid electrode comprising Ag / AgCl and at least one electrolyte gel for contacting with the skin. For example, the on-skin electrode may be a standard Ag / AgCl electrode, e.g. as used for ECG, EMG, and EEG. For example, the Ag / AgCl and the electrolyte gel may be part of the sensor patch casing, e.g. may be applied to a bottom of the sensor patch casing. For example, the on-skin electrode may be part of sensor patch adhesive (e.g. carbon fibres)

[0062] For example, the on-skin electrode comprises an insulating substrate such as a Polyethylene terephthalate (PET) substrate coated with a carbon layer which is coated by the Ag / AgCl.

[0063] For example, the on-skin electrode is a flexible electrode. The on-skin electrode may be a textile electrode or may comprise at least one conductive polymer, e.g. in the adhesive. The on-skin electrode may comprise conductive fibers or particles comprising the adhesive, e.g. made of carbon. For example, the on-skin electrode may be designed as a textile electrode described in Lee et al, “ECG Monitoring Garment Using Conductive Carbon Paste for Reduced Motion Artifacts”, Polymers (Basel), 2017 Sep; 9(9): 439, doi:

[0064] 10.3390 / polym9090439.

[0065] For example, the on-skin electrode is a patch electrode comprising a conductive carbonbased paste. For example, the on-skin electrode may be designed as a patch electrode as described in Lee et al, “ECG Monitoring Garment Using Conductive Carbon Paste for Reduced Motion Artifacts”, Polymers (Basel), 2017 Sep; 9(9): 439, doi:

[0066] 10.3390 / polym9090439. For example, the on-skin electrode may be integrated in the adhesive in form of a sticky layer of a multilayer adhesive (e.g. available under 3M 9713 Electrically Conductive Adhesive Transfer Tape) or in the form of a whole adhesive, e.g. as described in 10.1021 / acsnano.6b01355.

[0067] The on-skin electrode may have a circular and / or disc-like shape.

[0068] The electronics unit is connectable to the analyte sensor and the on-skin electrode. For example, the electronics unit may comprise at least one electronic connection to the on-skin electrode and / or the analyte sensor such a wire, cable, lead and the like. For example, the on-skin electrode may be formed integral to sensor patch casing housing the electronics unit.

[0069] The electronics unit is configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance, the subcutaneous electrode comprising the membrane element and the on-skin electrode. The voltage distribution may be measured during application of at least one pulse. For example, the voltage distribution may be measured by one or more of: during application of at least one fasttransient signal, electrochemical impedance spectroscopy (EIS), or another pulse with a pulse duration t(pulse) » 10 ps, e.g. 100 ms and more. For example, the EIS may comprise using frequencies > 50 kHz. However, other embodiments are possible.

[0070] For example, the electronics unit is configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance, the subcutaneous electrode comprising the membrane element and the on-skin electrode and determining impedance. The processing unit may be configured for determining the impedance by using a known value of the applied voltage pulse and the voltage distribution. The determined impedance consists of and / or corresponds to the physical property of the membrane element.

[0071] The electronics unit may comprise at least one built-in reference resistance which is used for determining a voltage distribution between the reference resistance and a circuit comprising the subcutaneous electrode, which comprises the membrane element, and the on-skin electrode and / or between the reference resistance and two subcutaneous electrodes, one or both comprising the membrane element. The built-in reference resistance (also denoted as reference resistance Rref herein) may be in series with a circuit comprising the subcutaneous electrode, which comprises the membrane element, and the on-skin electrode. The reference resistance may be in series with the two subcutaneous electrodes.

[0072] The electronics unit may be configured for applying at least one voltage pulse, e.g. a fast transient voltage, to the circuit comprising the subcutaneous electrode, which comprises the membrane element, and the on-skin electrode and the reference resistance. The electronics unit may be configured for measuring a voltage distribution between the reference resistance and the circuit. A processing unit may be configured for determining by using the known value of the applied voltage pulse and the voltage distribution the impedance.

[0073] The electronics unit may comprise at least one pulse generator configured for generating the voltage pulse such as a fast-transient voltage signal. The electronics unit is configured for applying the fast-transient voltage signal to the serially connected subcutaneous electrode comprising the membrane element and the on-skin electrode.

[0074] The electronics unit may comprise a reference resistance arranged between the subcutaneous electrode comprising the membrane element and the on-skin electrode. In the circuit, there are two resistances, the one between the internal and the external electrodes, which has to be determined, and the known built-in reference resistance. The voltage distribution is measured at these two and the unknown resistance is calculated. The electronics unit may be configured for determining the voltage distribution at the reference resistance Rref during the fast transient voltage signal. For example, a voltage measurement may be performed at the reference resistance. A relation between the applied and the measured voltage may be determined under consideration of the reference resistance.

[0075] The term “reference resistance” 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 resistor having a known resistance value such as an average value determined, specifically predetermined, from a plurality of reference measurements. The reference resistance may be selected suitable for determining the ionic conductivity, such as similar to the membrane resistance Rmem. The term “built-in reference resistance” 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 reference resistance existing as part of the electronics unit.

[0076] The term “fast-transient voltage signal” 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 at least one arbitrary voltage signal, in particular an arbitrary voltage change in between two electrodes. The fast-transient voltage signal may have at least one fast transient signal flank, such as two very steep edges. The fast-transient voltage signal may comprise a square waveform and / or a sine wave form. For example, the fast-transient voltage signal may have a square waveform.

[0077] The fast-transient voltage signal may comprise a non-continuous signal such as a pulse. The term “pulse” 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 signal having a transient change in the amplitude of the signal from a first value, also denoted baseline value, to a second value, followed by a return to the baseline value or at least approximately to the baseline value. The second value may be a higher or lower value than the baseline value. A pulse duration may be < 20 ps, more preferably < 10 ps. The duration of the single pulse must be sufficiently long to be able to record its propagation. The fast-transient voltage signal may comprise a pulse having two edges: a leading edge or front edge, which is a first edge of the pulse and a trailing edge or back edge, which is a second edge of the pulse. The term “fast-transient” 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 time range between first and second values of the signal flank. The terms first and second “value” may refer to regions or points of the fast-transient voltage, in particular its amplitude. The first value may be the baseline value. The first value may be a local and / or overall minimum of the fast-transient voltage. The first value may be a first plateau of the fast-transient voltage. The first value may refer to a time point with no voltage is applied to the electrodes. The second value may be a local and / or overall extremum of the fast-transient voltage. The second value may be a second plateau of the fast-transient voltage, which may be reached during application of the fast-transient voltage. The second value may be extremum of the fasttransient voltage signal.

[0078] The term “signal flank” 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 transition of a signal amplitude from low to high signal value or from high to low signal value. The signal flank may be a rising signal flank or a falling signal flank. The signal flank of the fasttransient voltage signal may have a change in signal from the first value of the signal flank to the second value of the signal flank in a microsecond to nanosecond range. The signal flank may also be referred to as edge. The fast-transient voltage signal may have a low-to- high transition of a signal amplitude, which is equivalent to rising or positive signal flank, or high-to-low transition of a signal amplitude, which is equivalent to falling or negative signal flank. The fast-transient voltage signal may have steep edges. Specifically, the fast transition square wave may have a change in voltage from the first value to the second value below or equal 20 ns. The change in voltage from the first value to the second value may be even faster and may be only limited by electronics such as by the pulse generator (DAC, DO or others) or a read-out unit (voltage amplifier, ADC, or others). The duration of the single fast-transient voltage must be sufficiently long to record a response.

[0079] The fast-transient voltage signal may be applied to the reference resistance and the electrodes with a known amplitude. The amplitude of the fast-transient voltage signal may vary in a broad range and must be optimized for a given set-up. Generally, the lower limit may be limited by the readout technique, which must record the response voltage, mostly by its input range and resolution and may require an additional sufficiently fast voltage amplifier. The resistance of the membrane element Rmem may be determined as follows, the pulse generator may apply the fast-transient voltage signal with a known amplitude Ui to the electrodes. Simultaneously a voltage drop U2 may be measured at the reference resistance Rref. Knowing the amplitude of the applied voltage and the amplitude measured at the Rref, as well as the value of the Rref, Rmem can be calculated as:

[0080] The sensor assembly may comprise at least one processing unit. The processing unit may be configured for determining the physical property of the membrane element from the measured voltage distribution.

[0081] The term “processing unit”, also denoted as “processing device” or “processor”, 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 logic circuitry configured for performing basic operations of a computer or system, and / or, generally, to a device which is configured for performing calculations or logic operations. The processing unit may be configured for processing basic instructions that drive the computer or system. As an example, the processing device may comprise at least one arithmetic logic unit (ALU), at least one floating-point unit (FPU), such as a math co-processor or a numeric co-processor, a plurality of registers, specifically registers configured for supplying operands to the ALU and storing results of operations, and a memory, such as an LI and L2 cache memory. The processing unit may be a multi-core processor. The processing unit may be or may comprise a central processing unit (CPU). Additionally or alternatively, the processing device may be or may comprise a microprocessor, thus specifically the processor’s elements may be contained in one single integrated circuitry (IC) chip. Additionally or alternatively, the processing device may be or may comprise one or more application-specific integrated circuits (ASICs) and / or one or more field-programmable gate arrays (FPGAs) and / or one or more tensor processing unit (TPU) and / or one or more chip, such as a dedicated machine learning optimized chip, or the like. The processing unit may be configured, such as by software programming, for performing one or more evaluation operations. The processing unit may be configured for performing the named step(s). Thus, as an example, the processing unit may comprise a software code stored thereon comprising a number of computer instructions. The processing unit may provide one or more hardware elements for performing one or more of the indicated operations and / or may provide one or more processors with software running thereon for performing one or more of steps. The fast-transient voltage signal may be applied at least once. The fast-transient voltage signal may be applied after a certain time after contacting the on-skin electrode with the skin. The fast-transient voltage signal may be applied repeatedly, e.g. periodically. The fast-transient voltage may be applied repeatedly, in particular in time intervals from minutes to seconds. A measurement frequency may depend on how often measurement values are required. The electronics unit may be configured for determining a combined measurement value for reducing a measurement uncertainty. The determining of a combined measurement value may comprise determining of one or more of an average value, a mean value, a median, using a more complex filter such as a Kalman filter. For example, measurement values may be obtained every second and the measurement results may be averaged to a minute-value. The measurement frequency may depend on the application of the analyte sensor.

[0082] The measurement result of the fast-transient measurement may be used for determining the analyte concentration, e.g. for correction of an analyte signal, e.g. as part of an algorithm for determining the analyte concentration from a measured analyte signal.

[0083] Additionally or alternatively, the fast-transient measurement may be used for failsafe. The fast-transient may imply measuring in addition lead resistance(s) of the implanted analyte sensor. Thus, the fast-transient measurement can be used for detecting breaking of the analyte sensor and / or partial or complete explantation of the analyte sensor and / or detaching of the patch, e.g. in case the on-skin electrode detaches from the skin. The sensor assembly may be configured for determining and / or performing at least one failsafe action. For example, the failsafe action may comprise issuing and / or displaying an error message. For example, the failsafe action may comprise preventing issuing and / or displaying the analytical result.

[0084] Measuring of impedance using one or more of a fast-transient signal, electrochemical impedance spectroscopy (EIS), or another pulse with a pulse duration t(pulse) » 10 ps, e.g. 100 ms and more can be performed, e.g. between two internal electrodes of an in-vivo analyte sensor. In particular, using a fast-transient signal can allow a high selectivity for intrinsic membrane properties such as conductivity (bulk). Moreover, a simple circuit can be used. However, this technique may only be sensitive for deposits on or at the membrane if these are massive, noticeable blocking the mass-transport between the membrane bulk and the surrounding electrolyte. Signal to background ratio may be worse in case the second electrode has no membrane and contributes to the background (e.g. constant lead resistance), but not to the signal (variable membrane resistance). The second electrode can be limiting (e.g. small capacity). The present invention proposes to use at least one on-skin electrode in addition. This can allow solving the named problems. In case of using an on-skin electrode with a small resistance and a high capacity the second electrode is not limiting, the signal to background ration increases and the AgCl in CERE is not consumed by the fast-transient signal. Sensitivity for depositions on and at the membrane is significantly increased, because the electric field lines propagate through the membrane electrolyte interface.

[0085] As outlined above, the electronics unit may be configured for measuring the voltage distribution between the reference resistance, and a circuit comprising the subcutaneous electrode and the on-skin electrode. In addition, the sensor assembly may be configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the two subcutaneous electrodes. The processing unit may be configured for determining impedance, as outlined above, from the voltage distribution. The processing unit may be configured for combining both determined physical properties, e.g. by combining the determined impedances. This can allow determining if the impedance change relates to depositions on the membrane surface or to changes of intrinsic membrane conductivity or from both and / or in what ratio.

[0086] In a further aspect of the present invention, a sensor assembly comprising at least one in- vivo analyte sensor is disclosed. The analyte sensor comprises at least one at least partly implantable portion. The analyte sensor comprises at least two subcutaneous electrodes arranged at least partially at the implantable portion. At least one of the subcutaneous electrodes comprises at least one membrane element exhibiting at least one physical property. The sensor assembly comprises at least one on-skin electrode. The sensor assembly comprises at least one electronics unit connectable to the analyte sensor and the on-skin electrode. The electronics unit comprises at least one reference resistance.

[0087] The electronics unit is configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the subcutaneous electrode, which comprises the membrane element, and the on- skin electrode.

[0088] The electronics unit is further is configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the two subcutaneous electrodes.

[0089] The sensor assembly comprises at least one processing unit configured for combining the determined physical properties.

[0090] With respect to embodiments and definitions of the sensor assembly reference is made to the sensor assembly described in a first aspect of the present invention. In a further aspect of the present invention, a method for determining a concentration of an analyte in a bodily fluid is disclosed. The method comprises using at least one sensor assembly according to the present invention, such as described in one or more of the embodiments enclosed herein. With respect to definitions and embodiments reference is made to the description of the sensor assembly described in a further aspect or as described in more detail below.

[0091] The method comprises the method steps as given in the corresponding independent claim and as listed as follows. The method steps may be performed in the given order. Further, one or more of the method steps may be performed in parallel and / or in a time overlapping fashion. Further, one or more of the method steps may be performed repeatedly. Further, additional method steps may be present which are not listed.

[0092] The method comprises the following steps: i. applying a polarization potential and measuring a DC current between the subcutaneous electrodes; ii. applying at least one voltage pulse to the reference resistance and a circuit comprising the subcutaneous electrode comprising the membrane element and the on-skin electrode and determining the physical property of the membrane element during application of the voltage pulse by measuring a voltage distribution between the reference resistance and the circuit comprising subcutaneous electrode comprising the membrane element and the on-skin electrode and determining impedance from the voltage distribution; and iii. determining the concentration of the analyte by evaluating the DC current considering the physical property of the membrane element.

[0093] The DC current may be measured by using the in-vivo analyte sensor. The DC current may be a raw analyte signal. The raw analyte signal may be evaluated by using at least one algorithm for determining the analyte concentration. The algorithm may comprise using a relationship, e.g. a pre-determined relationship such as a linear relationship, between the analyte concentration and the raw analyte signal.

[0094] Step ii may comprise a fast transient measurement and / or an EIS measurement. For example, the method comprises performing at least one fast-transient measurement, wherein step ii comprises: applying at least one fast-transient voltage signal to the reference resistance and the circuit comprising the subcutaneous electrode comprising the membrane element and the on-skin electrode and determining the physical property of the membrane element during application of the fast-transient voltage signal by measuring the voltage distribution between the reference resistance and the circuit comprising subcutaneous electrode comprising the membrane element and the on-skin electrode and determining impedance from the voltage distribution.

[0095] The algorithm for determining the analyte concentration may take into account the physical property of the membrane element. The algorithm may comprise correcting the raw analyte signal by using the determined physical property. The algorithm may take into account additional parameters for corrections such as temperature. Additionally or alternatively, the determined physical property may be used as a fail-safe, e.g. indicating a malfunction of the analyte sensor. For example, the analyte concentration may be flagged and / or dismissed depending on the determined physical property.

[0096] The method may further comprise applying at least one voltage pulse, such as a fast-transient voltage signal, to the reference resistance and the circuit comprising the two subcutaneous electrodes, one or both comprising the membrane element and determining the physical property of the membrane element during application of the voltage pulse by measuring the voltage distribution between the reference resistance and the circuit comprising two subcutaneous electrodes, one or both comprising the membrane element, and determining impedance from the voltage distribution

[0097] The method, e.g. by using the processing unit, may comprise additionally considering the membrane property determined between the subcutaneous electrodes, e.g. the membrane property determined between the subcutaneous electrodes and the membrane property determined between the subcutaneous electrode and the on-skin electrode may be combined. This can allow determining if the impedance change relates to depositions on the membrane surface or to changes of intrinsic membrane conductivity or from both and / or in what ratio.

[0098] The method may be computer-implemented. The term "computer implemented method" 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 method involving at least one computer and / or at least one computer network. The computer and / or computer network may comprise at least one processor which is configured for performing at least one of the method steps of the method according to the present invention. Specifically, each of the method steps is performed by the computer and / or computer network. The method may be performed completely automatically, specifically without user interaction. Further disclosed and proposed herein is a computer program including computer-executable instructions for performing the method according to the present invention in one or more of the embodiments enclosed herein when the instructions are executed on a computer or computer network. Specifically, the computer program may be stored on a computer-readable data carrier and / or on a computer-readable storage medium.

[0099] As used herein, the terms “computer-readable data carrier” and “computer-readable storage medium” specifically may refer to non-transitory data storage means, such as a hardware storage medium having stored thereon computer-executable instructions. The computer- readable data carrier or storage medium specifically may be or may comprise a storage medium such as a random-access memory (RAM) and / or a read-only memory (ROM).

[0100] Thus, specifically, one, more than one or even all of method steps i) to iii) as indicated above may be performed by using a computer or a computer network, preferably by using a computer program.

[0101] Further disclosed and proposed herein is a computer program product having program code means, in order to perform the method according to the present invention in one or more of the embodiments enclosed herein when the program is executed on a computer or computer network. Specifically, the program code means may be stored on a computer-readable data carrier and / or on a computer-readable storage medium.

[0102] Further disclosed and proposed herein is a data carrier having a data structure stored thereon, which, after loading into a computer or computer network, such as into a working memory or main memory of the computer or computer network, may execute the method according to one or more of the embodiments disclosed herein.

[0103] Further disclosed and proposed herein is a non-transient computer-readable medium including instructions that, when executed by one or more processors, cause the one or more processors to perform the method according to one or more of the embodiments disclosed herein.

[0104] Further disclosed and proposed herein is a computer program product with program code means stored on a machine-readable carrier, in order to perform the method according to one or more of the embodiments disclosed herein, when the program is executed on a computer or computer network. As used herein, a computer program product refers to the program as a tradable product. The product may generally exist in an arbitrary format, such as in a paper format, or on a computer-readable data carrier and / or on a computer-readable storage medium. Specifically, the computer program product may be distributed over a data network.

[0105] Finally, disclosed and proposed herein is a modulated data signal which contains instructions readable by a computer system or computer network, for performing the method according to one or more of the embodiments disclosed herein.

[0106] Referring to the computer-implemented aspects of the invention, one or more of the method steps or even all of the method steps of the method according to one or more of the embodiments disclosed herein may be performed by using a computer or computer network. Thus, generally, any of the method steps including provision and / or manipulation of data may be performed by using a computer or computer network. Generally, these method steps may include any of the method steps, typically except for method steps requiring manual work, such as providing the samples and / or certain aspects of performing the actual measurements.

[0107] Specifically, further disclosed herein are:

[0108] - a computer or computer network comprising at least one processor, wherein the processor is adapted to perform the method according to one of the embodiments described in this description,

[0109] - a computer loadable data structure that is adapted to perform the method according to one of the embodiments described in this description while the data structure is being executed on a computer,

[0110] - a computer program, wherein the computer program is adapted to perform the method according to one of the embodiments described in this description while the program is being executed on a computer,

[0111] - a computer program comprising program means for performing the method according to one of the embodiments described in this description while the computer program is being executed on a computer or on a computer network,

[0112] - a computer program comprising program means according to the preceding embodiment, wherein the program means are stored on a storage medium readable to a computer,

[0113] - a storage medium, wherein a data structure is stored on the storage medium and wherein the data structure is adapted to perform the method according to one of the embodiments described in this description after having been loaded into a main and / or working storage of a computer or of a computer network, and

[0114] - a computer program product having program code means, wherein the program code means can be stored or are stored on a storage medium, for performing the method according to one of the embodiments described in this description, if the program code means are executed on a computer or on a computer network.

[0115] Summarizing and without excluding further possible embodiments, the following embodiments may be envisaged:

[0116] Embodiment 1. A sensor assembly comprising at least one in-vivo analyte sensor, wherein the analyte sensor comprises at least one at least partly implantable portion, wherein the analyte sensor comprises at least two subcutaneous electrodes arranged at least partially at the implantable portion, wherein at least one of the subcutaneous electrodes comprises at least one membrane element exhibiting at least one physical property, wherein the sensor assembly comprises at least one on-skin electrode, wherein the sensor assembly comprises at least one electronics unit connectable to the analyte sensor and the on-skin electrode, wherein the electronics unit comprises at least one reference resistance, wherein the electronics unit is configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the subcutaneous electrode, which comprises the membrane element, and the on-skin electrode.

[0117] Embodiment 2. The sensor assembly according to the preceding embodiment, wherein the on-skin electrode has low impedance and a high skin surface area for contacting the skin.

[0118] Embodiment s. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode is flexible or rigid.

[0119] Embodiment 4. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode is a rigid electrode comprising Ag / AgCl and at least one electrolyte gel for contacting with the skin.

[0120] Embodiment 5. The sensor assembly according to any one of the preceding embodiments, wherein on-skin electrode may comprise at least one electrically insulating substrate, wherein the electrically insulating substrate comprises an electrically insulating material, wherein the electrically insulating material is be selected from the group consisting of at least one a polyester such as Polyethylene terephthalate (PET), an insulating epoxy resin, a polycarbonate, a polyvinylchloride, a polyurethane, a polyether, a polyethylene, a polyamide, a polyimide, a polyacrylate, a polymethacrylate, a polytetrafluoroethylene or a copolymer thereof, and alumina. Embodiment 6. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode comprises at least one electrically conductive layer, wherein the electrically conductive layer comprises at least one material selected from the group consisting of carbon, gold, or silver, at least one conductive polymer such as PEDOT, at least one conductive oxide such as ITO or FTO.

[0121] Embodiment 7. The sensor assembly according to any one of the two preceding embodiments, wherein the on-skin electrode comprises and / or is separated from the skin by at least one hydrogel.

[0122] Embodiment 8. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode comprises an insulating substrate such as a Polyethylene terephthalate (PET) substrate coated with a carbon layer which is coated by the Ag / AgCl.

[0123] Embodiment 9. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode is a flexible electrode, wherein the on-skin electrode is a textile electrode and / or wherein the on-skin electrode comprises at least one conductive polymer and / or wherein the on-skin electrode comprises conductive fibers or particles comprising the adhesive such as carbon fibers or particles.

[0124] Embodiment 10. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode is a patch electrode comprising a conductive carbon-based paste.

[0125] Embodiment 11. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode is integrated in an adhesive.

[0126] Embodiment 12. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode is part of a sensor patch casing contacting the skin.

[0127] Embodiment 13. The sensor assembly according to any one of the preceding embodiments, wherein the on-skin electrode has a circular and / or disc-like shape.

[0128] Embodiment 14. The sensor assembly according to any one of the preceding embodiments, wherein the physical property is an ionic conductivity of the membrane element. Embodiment 15. The sensor assembly according to any one of the preceding embodiments, wherein the electronics unit comprises at least one pulse generator configured for generating a voltage pulse, wherein the electronics unit is configured for applying the voltage pulse to the reference resistance and the circuit comprising the subcutaneous electrode comprising the membrane element and the on-skin electrode, wherein the electronics unit is configured for determining a voltage distribution at the reference resistance R during the voltage pulse.

[0129] Embodiment 16. The sensor assembly according to any one of the preceding embodiments, wherein the voltage pulse is a fast transient voltage signal, wherein the fast-transient voltage signal comprises a single pulse or series of pulses, wherein a duration of each pulse is < 20 ps, preferably < 10 ps.

[0130] Embodiment 17. The sensor assembly according to any one of the preceding embodiments, wherein one of the subcutaneous electrodes is a sensing electrode comprising the membrane element, wherein the subcutaneous electrodes further comprises at least one counter electrode and at least one reference electrode, or at least one counter-reference electrode.

[0131] Embodiment 18. The sensor assembly according to any one of the preceding embodiments, wherein the electronics unit is further be configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the two subcutaneous electrodes, wherein the processing unit is configured for combining the determined physical properties.

[0132] Embodiment 19. A sensor assembly comprising at least one in-vivo analyte sensor, wherein the analyte sensor comprises at least one at least partly implantable portion, wherein the analyte sensor comprises at least two subcutaneous electrodes arranged at least partially at the implantable portion, wherein at least one of the subcutaneous electrodes comprises at least one membrane element exhibiting at least one physical property, wherein the sensor assembly comprises at least one on-skin electrode, wherein the sensor assembly comprises at least one electronics unit connectable to the analyte sensor and the on-skin electrode, wherein the electronics unit comprises at least one reference resistance, wherein the electronics unit is configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the subcutaneous electrode, which comprises the membrane element, and the on-skin electrode, wherein the electronics unit is further is configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the two subcutaneous electrodes, wherein the sensor assembly comprises at least one processing unit configured for combining the determined physical properties.

[0133] Embodiment 20. A method for determining a concentration of at least one analyte in a bodily fluid, wherein the method comprises using at least one sensor assembly according to any one of the preceding embodiments, wherein the method comprises the following steps: i. applying a polarization potential and measuring a DC current between the subcutaneous electrodes; ii. applying at least one voltage pulse to the reference resistance and a circuit comprising the subcutaneous electrode comprising the membrane element and the on-skin electrode and determining the physical property of the membrane element during application of the voltage pulse by measuring a voltage distribution between the reference resistance and the circuit comprising subcutaneous electrode comprising the membrane element and the on-skin electrode and determining impedance from the voltage distribution; and iii. determining the concentration of the analyte by evaluating the DC current considering the physical property of the membrane element.

[0134] Embodiment 21. The according to the preceding embodiment, wherein the step ii comprises applying at least one fast-transient voltage signal to the reference resistance and the circuit comprising the subcutaneous electrode comprising the membrane element and the on-skin electrode and determining the physical property of the membrane element during application of at least one fast-transient voltage signal by measuring a voltage distribution between the reference resistance and the circuit comprising the subcutaneous electrode comprising the membrane element and the on-skin electrode.

[0135] Embodiment 22. The method according to any one of the preceding embodiments referring to a method, wherein the method comprises applying at least one fast-transient voltage signal to the reference resistance and the circuit comprising the subcutaneous electrodes and determining the physical property of the membrane element during application of at least one fast-transient voltage signal by measuring a voltage distribution between the reference resistance and the circuit comprising the subcutaneous electrodes. Embodiment 23. The method according to any one of the preceding method embodiments, wherein the method is computer-implemented.

[0136] Embodiment 24. A computer program comprising instructions which, when the program is executed by the sensor assembly according to any one of the preceding embodiments referring to a sensor assembly, cause the sensor assembly to perform the method according to any one of the preceding embodiments referring to a method.

[0137] Embodiment 25. A computer-readable storage medium comprising instructions which, when the instructions are executed by the sensor assembly according to any one of the preceding embodiments referring to a sensor assembly, cause the sensor assembly to perform the method according to any one of the preceding embodiments referring to a method.

[0138] Embodiment 26. A non-transient computer-readable medium including instructions that, when executed by one or more processors, cause the one or more processors to perform the method according to any one of the preceding embodiments referring to a method.

[0139] Short description of the Figures

[0140] 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. The embodiments are schematically depicted in the Figures. Therein, identical reference numbers in these Figures refer to identical or functionally comparable elements.

[0141] In the Figures:

[0142] Figure 1 shows schematically a biological end of an in-vivo analyte sensor of a sensor assembly according to the present invention;

[0143] Figure 2 shows an exemplary embodiment of an on-skin electrode of a sensor assembly according to the present invention; and Figure 3 shows a flowchart of an embodiment of a method for determining a concentration of at least one analyte in a bodily fluid according to the present invention.

[0144] Detailed description of the embodiments

[0145] In Figure 1, upper part, highly schematically, a biological end of an implantable portion of an in-vivo analyte sensor 110 is shown. The analyte sensor 110 is an element of a sensor assembly 124. The analyte sensor 110 may be configured for transdermal detecting at least one analyte. The analyte sensor 110 comprises at least two subcutaneous electrodes 116, 118 arranged at least partially at the implantable portion. The analyte sensor 110 may comprise a carrier, e.g. a substrate 114. The substrate 114 may have an elongated shape, such as a strip-shape and / or a bar-shape. The substrate 114 may comprise an electrically insulating material, e.g. as shown in Figure 1 a plastic foil. Each side of the substrate 114 may be coated by some conductive layer 115, e.g. carbon. The electrodes 116, 118 may comprise at least one working electrode (WE) 116 and at least one further electrode (CE / RE) 118, e.g. a counter electrode and / or a reference electrode or a combined counter / reference electrode. In Figure 1, one side is the working electrode 116 and the other side is a combined counter-reference electrode 118. Sensing chemistry 112 may be applied at the working electrode 116 and some Ag / AgCl 113 may be applied at the counter / reference electrode 118. An insulating layer 122 may be applied.

[0146] At least one of the subcutaneous electrodes 116, 118 comprises at least one membrane element 120. For example, a diffusion limiting membrane 120 may be arranged at the top on at least one of the subcutaneous electrodes 116, 118. The membrane element may comprise at least one polymer. The membrane element 120 may be applied to the subcutaneous electrodes 116, 118 as thin polymer film. For example, the membrane element 120 may be or may comprise Poly-(4-(N-(3-sulfonatopropyl) pyridinium)-co-(4vinyl-pyridine)-co- styrene (5% / 90% / 5%) or hydrophilic Polyurethane such as HP60D20 available from Lubrizol®. For example, the membrane element 120 may comprise at least one of the following polymer classes and / or their copolymer: Poly(4 vinyl pyridine), Polymethacrylate, Polyacrylate, Polyvinyl pyrrolidone, Polyvinyl alcohol (PVA), Polyethylene glycol. For further details concerning the membrane element 120, specifically with regard to its properties and composition, reference may be made to WO 2022 / 058255. The membrane element 120 has at least one physical property, e.g. depending on at least one parameter such as temperature, pH, composition of electrolyte and others. The physical property may be an arbitrary physical property of the membrane element 120, e.g. depending on environmental conditions, e.g. in vicinity of the membrane element 120. The physical property may be e.g. dependent on the temperature, e.g. may be proportional to the temperature.

[0147] An electrode immersed in an electrolyte solution can be simplified described by means of so-called Randle’s circuit. The simplest Randle’s circuit is described by two resistors and one capacitor interconnected. Each of both electrodes 116, 118 can be described as Randle’s circuit in the first approximation. The simplest Randle’s circuit is described by two in series connected resistors Rl, R2 and one capacitor Cl in parallel to R2. The resistor R1 may represent so-called equivalent series resistance and includes resistance of the electrode itself, resistance of the electrolyte solution between the given electrode and another one against which these resistance values are being measured. The resistor R2 represents so-called charge-transfer resistance (RCT) and describes roughly the DC current, which flows through the interface electrode / electrolyte. Cl is the so-called double layer capacitor and is formed by interface electrode / electrolyte. Physically, having an electrode immersed in the electrolyte solution, it is impossible to contact a connection point between Rl and R2 by some measuring device. The only accessible contacting points are at the one left from Rl and at the right from R2 / C 1. For resistance measurement, a voltage may be applied at the contacting points, which would lead to some current flow which may be measured. The resistance may be determined by dividing the applied DC voltage over the measured DC current and calculate the DC resistance according to Ohm’s law. The calculated resistance is the sum of the Rl and R2, as the DC current cannot flow through the Cl and, thus, it flows through the Rl and R2. If there is a need to measure Rl selectively, this can be done by measuring impedance. The impedance measured at some very high frequencies would correspond to the value of Rl, as the AC current would flow through the Cl, thus avoiding R2 and the R2 would not contribute to the determined impedance. The Rl is so-called equivalent series resistance (ESR) and it comprises all serially connected high-frequency impedances as those cannot be separately measured by impedance measurement.

[0148] In the lower part of Figure 1 a simplified equivalent circuit of such the analyte sensor 110 is depicted, comprising corresponding charge transfer resistances at the both sensor sides, substrate, membrane and electrolyte resistivity as well as double layer capacitances. The working electrode 116 comprises the substrate resistance Rsub, double layer capacitance CDL in parallel to the charge transfer resistance RCT and membrane resistance Rmem. The combined counter-reference electrode 118 also comprises substrate resistance Rsub’, the own double layer capacitance CDL’ in parallel to the charge transfer resistance RCT’ and the membrane resistance Rmem’. Furthermore, there is solution resistance Rsoi between both electrodes 116, 118. The ESR can be determined as follows

[0149] ESR Rsub F Esubr F EmemRmemr F Rsol-

[0150] The sensor assembly 124 further comprises at least one on-skin electrode 126. An exemplary embodiment of the on-skin electrode 126 is shown in Figure 2. The on-skin electrode 126 may be mountable and / or attachable to an outer skin surface and / or is at least partially in contact with an outer skin surface. In comparison to the subcutaneous electrodes 116, 118, the on-skin electrode 126 may be an electrode external from but on the user’s body. The outer skin surface may be the epidermis. The on-skin electrode 126 may be brought in contact with the outer skin surface, e.g. such that the on-skin electrode can have direct contact with sweat pores on the epidermis. The on-skin electrode 126 may be mountable and / or attachable to an outer skin surface by using at least one patch and / or the on-skin electrode 126 may be a part of a patch.

[0151] The on-skin electrode 126 may have a low impedance, e.g. < 500 Q, preferably < 250 Q, more preferably < 100 Q.

[0152] The on-skin electrode 126 may have a high skin surface area for contacting the skin. The skin surface area may be a geometrical area covered by a skin contacting surface of the on- skin electrode 126. The skin surface area may be from a few square millimeters up to several hundreds of square millimeters, e.g. from 1 mm2to 1000 mm2, preferably from 10 mm2to 500 mm2. The skin contacting surface, and thus the skin surface area, may be a continuous area or may comprise a plurality of areas. The skin contacting surface, and thus the skin surface area, may allow for forming a solid-liquid-interface.

[0153] The present invention proposes implementing of an on-skin electrode 126 in addition to the at least two-subcutaneous electrodes 116, 118. The ESR between said on-skin electrode 126 and the working electrode 116 may be measured. This can allow excluding the counter or counter reference electrode (CERE) 118 with its low Cdl and corresponding portion of ESR from the ESR measurement circuit. The on-skin electrode 126 therefore may possess a low impedance and a high surface area. This can represent a Randles circuit with extremely high Cdl and extremely low ESR. Due to this effect, the measured ESR will mostly consist of the ESR of the working electrode 116.

[0154] The on-skin electrode 126 may be realized in many different ways, having a high surface area and ionic contact with the skin surface area in order to form a solid to liquid interface. As shown in Figure 2, the on-skin electrode 126 may comprise at least one electrically insulating substrate 128. The substrate 128 may have a circular and / or disc-like shape. However, other shapes are possible. The substrate 128 may comprise an electrically insulating material, such as an electrically insulating plastic foil. For example, the electrically insulating material may be selected from the group consisting of at least one a polyester such as Polyethylene terephthalate (PET), an insulating epoxy resin, a polycarbonate, a polyvinylchloride, a polyurethane, a polyether, a polyethylene, a polyamide, a polyimide, a polyacrylate, a polymethacrylate, a polytetrafluoroethylene or a copolymer thereof, and alumina; however, other kinds of electrically insulating materials may also be feasible. The substrate 128 may be a housing of the sensor assembly 124, e.g. of a sensor patch casing.

[0155] The on-skin electrode 126 may comprise at least one electrically conductive layer 130. The electrically conductive layer 130 comprises at least one material selected from the group consisting of carbon, gold, or Ag, AgCl, at least one conductive polymer such as PEDOT, at least one conductive oxide such as ITO or FTO. However, other materials may be possible. For example, the on-skin electrode may comprise at least one at least one layer of Ag / AgCl or a, e.g. thin, layer of AgCl on an Ag layer. This can allow forming a reference electrode (RE) and / or a counter-reference electrode (CERE).

[0156] The on-skin electrode 126 may comprise at least one hydrogel layer 132 and / or may be separated from the skin by at least one hydrogel 132. The hydrogel layer 132 may be an additional layer between the skin contacting surface and the skin. The hydrogel 132 may comprise ions for providing conductivity. The hydrogel 132 may allow for increasing skin compatibility, e.g. allowing reducing risk of allergic reaction. For example, the hydrogel may be a Cl-soaked hydrogel. The hydrogel layer 132 may comprise chloride, e.g. in case Ag / AgCl is used. In this case, the chloride may provide a potential for the reference and / or counter reference electrode. However, in case of using other materials for the electrically conductive layer 130 using of other ions in the hydrogel 132 may be possible.

[0157] The on-skin electrode 126 may be flexible or rigid. For example, the on-skin electrode 126 may be designed analogous to a medical ECG pad. However, other options are possible.

[0158] In the embodiment show in Figure 2, the components of the on-skin electrode 126 may be as follows. The on-skin electrode 126 may be designed analogous to a medical ECG pad typically comprising a plastic disc about 9.8 mm in diameter. The plastic disc (substrate 128) may be coated by a carbon layer 127 and a layer of Ag / AgCl 129 and a Cl- soaked hydrogel 132. For understanding the measurement principle, in the equivalent circuit shown in the lower part of Figure 1, the on-skin electrode 126 would replace the CERE as follows: The chloride containing hydrogel can be represented by Rmem’ as shown in the Figure 1, the Ag / AgCl layer is, thus, Rcere, and the carbon coating is Rsub’.

[0159] The sensor assembly 124 comprises at least one electronics unit (not shown in the Figures) which is connectable to the analyte sensor 110 and the on-skin electrode 126. For example, the electronics unit may comprise at least one electronic connection to the on-skin electrode 126 such a wire, cable, lead and the like. For example, the on-skin electrode 126 may be formed integral to sensor patch casing housing the electronics unit.

[0160] The electronics unit comprises a reference resistance arranged serially to a circuit comprising the subcutaneous electrode 116 comprising the membrane element 120 and the on-skin electrode.

[0161] The electronics unit is configured for determining the physical property of the membrane element 120 by measuring a voltage distribution between the reference resistance and the circuit comprising the subcutaneous electrode 116 comprising the membrane element 120 and the on-skin electrode 126. The voltage distribution may be measured during application of at least one pulse. For example, the voltage distribution may be measured by one or more of: during application of at least one fast-transient signal, electrochemical impedance spectroscopy (EIS), or another pulse with a pulse duration t(puls) » 10 ps, e.g. 100 ms and more.

[0162] For example, the electronics unit is configured for determining the physical property of the membrane element 120 by measuring a voltage distribution between the reference resistance and the circuit comprising the subcutaneous electrode 116 comprising the membrane element 120 and the on-skin electrode 126 during application of at least one fast-transient voltage signal. The electronics unit may comprise at least one pulse generator configured for generating the fast-transient voltage signal. The electronics unit is configured for applying the fast-transient voltage signal to the serially connected subcutaneous electrode 116 comprising the membrane element and the on-skin electrode 126.

[0163] As outlined above, the electronics unit comprises a reference resistance arranged serially to external circuit comprising the subcutaneous electrode 116 comprising the membrane element 120 and the on-skin electrode. Thus, the circuit, comprises two resistances, the one formed by the internal and the external electrodes, which has to be determined, and the known built-in reference resistance. The voltage distribution is measured at these two and the unknown resistance is calculated. The reference resistance may have a known resistance value such as an average value determined, specifically pre-determined, from a plurality of reference measurements. The reference resistance may be selected suitable for determining the ionic conductivity, such as similar to the membrane resistance Rmem.

[0164] The electronics unit may be configured for determining a voltage distribution at the reference resistance Rref during the fast transient voltage signal. For example, a voltage measurement may be performed at the reference resistance. A relation between the applied and the measured voltage may be determined under consideration of the reference resistance. The resistance of the membrane element Rmem may be determined as follows, the pulse generator may apply the fast-transient voltage signal with a known amplitude Ui to the electrodes. Simultaneously a voltage drop U2 may be measured at the reference resistance Rref. Knowing the amplitude of the applied voltage and the amplitude measured at the Rref, as well as the value of the Rref, Rmem can be calculated as:

[0165] The sensor assembly 124 may comprise at least one processing unit. The processing unit may be configured for determining the physical property of the membrane element from the measured voltage distribution.

[0166] For example, with the embodiment of Figure 2, the measured ESR between two such pads sticking at the abdomen after subtraction of the wiring and ISF resistances may amount to 710 Q. Thus, a circular pad with the external diameter of e.g. 20 mm and the inner diameter of 4 mm would show an ESR of solely 178 Q compared to about 5-10 kQ for a typical carbon paste based CGM electrode. The capacitance of such pad may be at around 280 nF, which is around one order of magnitude more, that that of the CERE.

[0167] The fast-transient measurement may be used for determining the physical property of the membrane element.

[0168] Additionally or alternatively, the fast-transient measurement may be used for failsafe. The fast-transient may imply measuring in addition lead resistance(s) of the implanted anlyte sensor 110. Thus, the fast-transient measurement can be used for detecting breaking of the analyte sensor 110 and / or partial or complete explantation of the analyte sensor 110 and / or detaching of the patch, e.g. in case the on-skin electrode detaches from the skin. Figure 3 shows an exemplary flowchart of a method for determining a concentration of an analyte in a bodily fluid. The method comprises using at least one sensor assembly according to the present invention, such as described with respect to Figures 1 and 2.

[0169] The method comprises the method steps as given in the corresponding independent claim and as listed as follows. The method steps may be performed in the given order. Further, one or more of the method steps may be performed in parallel and / or in a time overlapping fashion. Further, one or more of the method steps may be performed repeatedly. Further, additional method steps may be present which are not listed.

[0170] The method comprises the following steps: i. (134) applying a polarization potential and measuring a DC current between the subcutaneous electrodes 116, 118; ii. (136) applying at least one voltage pulse to the reference resistance and a circuit comprising the subcutaneous electrode 116, 118 comprising the membrane element 120 and the on-skin electrode 126 and determining the physical property of the membrane element 120 during application of the voltage pulse by measuring a voltage distribution between the reference resistance and the circuit comprising the subcutaneous electrode 116, 118 comprising the membrane element 120 and the on-skin electrode 126; and iii. (138) determining the concentration of the analyte by evaluating the DC current considering the physical property of the membrane element 120.

[0171] As an experimental setup, continuous glucose monitoring sensors have been measured in- vitro simultaneously recording glucose signal measured as DC current at nominal polarization potential and sensor impedance was measured by means of fast-transient. The glucose signal was represented as sensor sensitivity in nA / mg / dl calculated by division of the DC current over the glucose concentration. The impedance was normalized using the initial impedance value of the fully conditioned sensor. During the measurement different electrolyte mediums have been used sequentially: first a glucose containing PBS electrolyte was used, followed by a special growth medium, inducing deposit formation at the sensors surface, followed by the same glucose containing PBS electrolyte as at the beginning, for control measurement.

[0172] Two independent measurement sets have been performed: during the first one, the impedance was measured between two internal electrodes of the sensor, during the second one, the impedance was measured between one sensors electrode and one external electrode. The averaged data is shown in the table. In the table the numbers recorded during the second measurement set are indicted, where the impedance was measured against an external electrode. It can be seen, that for both measurements, the initial sensor sensitivity of 0.088 nA / mg / dl dropped to the 0.073 nA / mg / dl in the growth medium which is explained by both, altered chemical environment, which influences bulk membrane properties, as well as formed deposit at the membrane property, further limiting glucose diffusion. After switching back to the glucose containing PBS electrolyte, the sensor sensitivity increased again to 0.078 nA / mg / dl, but did not restore to the initial value 0.088 nA / mg / dl. The reason for the sensitivity growth is restored chemical environment, which allowed recovery of the bulk membrane properties and the reason for the non-complete restoring of the sensors sensitivity is the formed deposit at the membrane surface.

[0173] List of reference numbers analyte sensor sensing chemistry

[0174] Ag / AgCl substrate conductive layer working electrode, WE further electrode membrane insulating layer sensor assemby on-skin electrode carbon layer substrate layer of Ag / AgCl electrically conductive layer hydrogel layer applying at least one voltage pulse measuring a voltage distribution determining the concentration of the analyte

Claims

Claims1. A sensor assembly (124) comprising at least one in-vivo analyte sensor (110), wherein the analyte sensor (110) comprises at least one at least partly implantable portion, wherein the analyte sensor (110) comprises at least two subcutaneous electrodes (116, 118) arranged at least partially at the implantable portion, wherein at least one of the subcutaneous electrodes (116, 118) comprises at least one membrane element (120) exhibiting at least one physical property, wherein the sensor assembly (124) comprises at least one on-skin electrode (126), wherein the sensor assembly (124) comprises at least one electronics unit connectable to the analyte sensor (110) and the on-skin electrode (126), wherein the electronics unit comprises at least one reference resistance, wherein the electronics unit is configured for determining the physical property of the membrane element (120) by measuring a voltage distribution between the reference resistance and a circuit comprising the subcutaneous electrode (116, 118), which comprises the membrane element (120), and the on-skin electrode (126).

2. The sensor assembly (124) according to the preceding claim, wherein the on-skin electrode (126) has low impedance and a high skin surface area for contacting the skin.

3. The sensor assembly (124) according to any one of the preceding claims, wherein on- skin electrode (126) may comprise at least one electrically insulating substrate (128), wherein the electrically insulating substrate (128) comprises an electrically insulating material, wherein the electrically insulating material is be selected from the group consisting of at least one a polyester such as Polyethylene terephthalate (PET), an insulating epoxy resin, a polycarbonate, a polyvinylchloride, a polyurethane, a polyether, a polyethylene, a polyamide, a polyimide, a polyacrylate, a polymethacrylate, a polytetrafluoroethylene or a copolymer thereof, and alumina.

4. The sensor assembly (124) according to any one of the preceding claims, wherein the on-skin electrode (126) comprises at least one electrically conductive layer (130), wherein the electrically conductive layer (130) comprises at least one material selected from the group consisting of carbon, gold, or silver, at least one conductive polymer such as PEDOT, at least one conductive oxide such as ITO or FTO.

5. The sensor assembly (124) according to any one of the two preceding claims, wherein the on-skin electrode (126) comprises and / or is separated from the skin by at least one hydrogel (132).

6. The sensor assembly (124) according to any one of the preceding claims, wherein the on-skin electrode (126) comprises an insulating substrate coated with a carbon layer (127) which is coated by Ag / AgCl (129).

7. The sensor assembly (124) according to any one of the preceding claims, wherein the on-skin electrode (126) is a flexible electrode, wherein the on-skin electrode (126) is a textile electrode and / or wherein the on-skin electrode (126) comprises at least one conductive polymer and / or wherein the on-skin electrode (126) comprises conductive fibers or particles comprising the adhesive such as carbon fibers or particles.

8. The sensor assembly (124) according to any one of the preceding claims, wherein the on-skin electrode (126) is a patch electrode comprising a conductive carbon-based paste, and / or wherein the on-skin electrode (126) is integrated in an adhesive.

9. The sensor assembly (124) according to any one of the preceding claims, wherein the physical property is an ionic conductivity of the membrane element (120).

10. The sensor assembly (124) according to any one of the preceding claims, wherein the electronics unit is further be configured for determining the physical property of the membrane element by measuring a voltage distribution between the reference resistance and a circuit comprising the two subcutaneous electrodes, wherein the sensor assembly (124) comprises at least one processing unit configured for combining the determined physical properties.

11. A method for determining a concentration of at least one analyte in a bodily fluid, wherein the method comprises using at least one sensor assembly (124) according to any one of the preceding claims, wherein the method comprises the following steps: i. (134) applying a polarization potential and measuring a DC current between the subcutaneous electrodes (116, 118); ii. applying at least one voltage pulse to the reference resistance and a circuit comprising the subcutaneous electrode (116, 118) comprising the membrane element (120) and the on-skin electrode (126) and determining the physical property of the membrane element (120) during application of the voltage pulse bymeasuring a voltage distribution between the reference resistance and the circuit comprising subcutaneous electrode (116, 118) comprising the membrane element (120) and the on-skin electrode (126) and determining impedance from the voltage distribution; and iii. (138) determining the concentration of the analyte by evaluating the DC current considering the physical property of the membrane element (120).

12. The method according to the preceding claim, wherein the step ii comprises applying at least one fast-transient voltage signal to the reference resistance and the circuit comprising the subcutaneous electrode (116, 118) comprising the membrane element and the on- skin electrode and determining the physical property of the membrane element during application of at least one fast-transient voltage signal by measuring a voltage distribution between the reference resistance and the circuit comprising the subcutaneous electrode (116, 118) comprising the membrane element (120) and the on-skin electrode (126).

13. The method according to any one of the preceding method claims, wherein the method comprises applying at least one fast-transient voltage signal to the reference resistance and the circuit comprising the subcutaneous electrodes (116, 118) and determining the physical property of the membrane element (120) during application of at least one fasttransient voltage signal by measuring a voltage distribution between the reference resistance and the circuit comprising the subcutaneous electrodes (116, 118).

14. A computer program comprising instructions which, when the program is executed by the sensor assembly (124) according to any one of the preceding claims referring to a sensor assembly (124), cause the sensor assembly (124) to perform the method according to any one of the preceding claims referring to a method.

15. A computer-readable storage medium comprising instructions which, when the instructions are executed by the sensor assembly (124) according to any one of the preceding claims referring to a sensor assembly (124), cause the sensor assembly (124) to perform the method according to any one of the preceding claims referring to a method.

Images