Non-invasive analyte sensor

Abstract

A non-invasive analyte sensor (112) is presented, comprising at least two electrodes (114), each electrode (114) having a skin-contacting surface (116). At least one of the electrodes (114) is a detection electrode (120). The detection electrode (120) includes at least one analyte-responsive layer (124) and at least one conversion layer (126). At least one other of the electrodes (114) is configured as an auxiliary electrode (128), which is configured as a counter electrode or a combined counter-reference electrode.

Description

Technical Field

[0001] This invention discloses a non-invasive analyte sensor, a non-invasive continuous monitoring system for skin-worn applications including at least one non-invasive analyte sensor, a method for determining the concentration of an analyte in a sample using the non-invasive analyte sensor, and a computer program. The method and apparatus according to the invention can be used to detect at least one analyte present in bodily exudates. In particular, the method and apparatus are applicable to the detection of one or more analytes (such as glucose or other analytes) in bodily exudates (such as sweat), and can be applied in professional diagnostics, hospital bedside care, personal care, and home monitoring. However, other applications are also possible. Background Technology

[0002] Non-invasive continuous monitoring systems for the detection of analytes (such as for glucose detection) are generally known, for example, see US10034625B1, EP3641633A1, US20180368743A1, or US11609163B2. Such systems can be worn close to the skin, such as by applying them to the skin using at least one patch, or they can be worn, such as as a wristwatch.

[0003] For example, non-invasive monitoring systems for analyte detection are known, which detect analytes without actively removing them from the detection volume. However, these non-invasive monitoring systems suffer from the problem of slow reabsorption of glucose by the skin, causing the system to display a cumulative glucose concentration that does not correspond to the actual glucose level in, for example, interstitial fluid (ISF).

[0004] Furthermore, balance sensors for invasive glucose monitoring are known. However, balance sensors do not actively consume glucose and can only operate under conditions where the body's glucose concentration actively changes, such as in vivo or in some reactors, where glucose levels can be monitored and altered by external factors. Accordingly, such arrangements are not suitable for non-invasive skin-tight sensors that measure glucose levels in bodily exudates such as sweat.

[0005] Problems to be solved Therefore, the object of the present invention is to provide a non-invasive analyte sensor, a non-invasive continuous monitoring system for skin-worn application, and a method for determining the concentration of an analyte in a sample, which at least partially avoids the disadvantages of such known devices and methods and at least partially solves the aforementioned challenges. Specifically, devices and methods that allow for the accurate and non-invasive determination of analyte concentrations should be provided. Summary of the Invention

[0006] This problem is solved by: a non-invasive analyte sensor for skin-worn application, comprising at least one non-invasive analyte sensor; a method for determining the concentration of an analyte in a sample using a non-invasive continuous monitoring system; and a computer program having the features of the independent claim. Advantageous embodiments that can be implemented individually or in any arbitrary combination are enumerated in the dependent claims and throughout the specification.

[0007] As used below, the terms “have,” “contain,” or “include,” or any grammatical variation thereof, are used in a non-exclusive manner. Thus, these terms can refer either to a situation where no further features exist in the entity described herein besides those introduced by these terms, or to a situation where one or more further features exist. For example, the statements “A has B,” “A contains B,” and “A includes B” can refer to a situation where no other element exists in A besides B (i.e., where A consists solely and exclusively of B) and can also refer to a situation where one or more further elements (such as element C, element D, or even further elements) exist in entity A besides B.

[0008] Furthermore, it should be noted that the terms "at least one," "one or more," or similar expressions indicating that a feature or element may exist once or more are generally used only once when introducing the corresponding feature or element. In the following text, in most cases, when referring to the corresponding feature or element, the expressions "at least one" or "one or more" will not be used repeatedly, even though the corresponding feature or element may exist only once or more.

[0009] Furthermore, as used below, the terms “preferably,” “morepreferably,” “particularly,” “more particularly,” “specifically,” “more specifically,” or similar terms are used with optional features without limiting the possibility of alternatives. Therefore, features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. As those skilled in the art will recognize, the invention can be carried out by using alternative features. Similarly, features introduced by phrases such as “in embodiments of the invention” or similar expressions are intended to be optional features, without limiting alternative embodiments of the invention, without limiting the scope of the invention, and without limiting the possibility of combining features introduced in this manner with other optional or non-optional features of the invention.

[0010] In a first aspect of the invention, a non-invasive analyte sensor is disclosed. The non-invasive analyte sensor includes at least two electrodes, each having a skin contact surface. At least one electrode is a detection electrode. The detection electrode includes at least one analyte-response layer and at least one conversion layer. At least one other electrode is configured as an auxiliary electrode, which is configured as a counter electrode or a combined counter-reference electrode.

[0011] As used herein, the term "analyte" is a broad term and should be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) any element, component, or compound that is present in a fluid, specifically a bodily fluid, and whose concentration may be of interest to the user. Specifically, an analyte can be, or may contain, any chemical substance or chemical compound that can participate in the user's metabolism, such as at least one metabolite. As an example, at least one analyte may be selected from the group consisting of glucose, lactate, ascorbate, and any other analyte, which may be a designed analyte response layer and can subsequently be converted by a suitable conversion layer. For example, the analyte is glucose. However, additionally or alternatively, other types of analytes and / or any combination of analytes may be identified. As used herein, the term "fluid" is a broad term and should be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) a biological fluid of interest that is known to contain or is suspected of containing an analyte. The fluid can be a bodily fluid, such as bodily exudates like sweat, tears, and saliva. Bodily fluids are typically contained in body tissues. Detection of at least one analyte in the bodily fluid can preferably be determined on the skin. The analyte sensor can be a skin-touch sensor. As used herein, the term "skin-touch sensor" is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term can refer to (but is not limited to) a sensor configured for the detection of analytes on living tissue at the surface of the skin.

[0012] As used herein, the term "sensor" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. Specifically, the term may refer to (but is not limited to) any element or device configured to detect at least one condition or to measure at least one variable. Similarly, as used herein, the term "analyte sensor" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. Specifically, the term may refer to (but is not limited to) a sensor configured to quantitatively or qualitatively detect at least one analyte. Non-invasive analyte sensors may be configured for continuous analyte monitoring.

[0013] As used herein, the term "non-invasive" is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. Specifically, the term may refer to (but is not limited to) analyte sensors that operate outside the user's body, particularly analyte sensors that do not penetrate and / or penetrate the skin.

[0014] The analyte sensor is configured for skin-worn wear. As used herein, the term "skin-worn wear" is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to any particular or custom meaning. Specifically, the term may refer to (but is not limited to) the fact that the analyte sensor is mountable and / or attachable to an external skin surface and / or that the analyte sensor is at least partially in contact with an external skin surface. The external skin surface may be the epidermis. For analyte detection, the analyte sensor may be made in contact with the external skin surface, for example, by making the analyte sensor directly contact sweat pores on the epidermis. The analyte sensor may be mounted and / or attachable to an external skin surface using at least one patch, and / or the analyte sensor may be part of a patch. The analyte sensor may be the skin worn by the user. The analyte sensor may be worn as a watch, bracelet, etc. For example, the analyte sensor may be a patch that is firmly in contact with the skin surface. The analyte sensor may be an element of a non-invasive monitoring system, as will be outlined in more detail below. The non-invasive monitoring system may include at least one readout device, such as at least one optical readout device. For example, the readout device can be a dedicated, securely attached transmitter for high-quality continuous reading. For example, the readout device can be, or may be comprised of, a smartwatch or a fitness band for continuous monitoring. The readout device can also be an external device for single reading, such as for rapid glucose monitoring.

[0015] As used herein, the term "user" is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to (but is not limited to) a human or animal, regardless of whether the human or animal may be in a healthy state or may suffer from one or more diseases. For example, a user may be a human or animal suffering from diabetes. However, additionally or alternatively, the invention may be applied to other types of users.

[0016] An analyte sensor comprises at least two electrodes. As used herein, the term "electrode" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) an electrical conductor that is generally of any shape. An analyte sensor may be a two-electrode sensor. However, in possible embodiments, an analyte sensor comprises more than two electrodes. An analyte sensor may comprise more than two electrodes. For example, an analyte sensor may comprise one or more electrodes of the same type.

[0017] Each electrode of an analyte sensor may have a skin contact surface. As used herein, the term "skin contact surface" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. Specifically, the term may refer to (but is not limited to) the surface of a respective electrode configured to make the electrode directly or indirectly contact the user's skin. For example, a skin contact surface may be a skin contact layer that directly contacts the user's skin. Alternatively, an additional layer may be used between the skin contact surface and the skin, for example, the skin contact surface may indirectly contact the skin contact surface via at least one additional element (such as at least one additional hydrogel layer), for example, to increase skin compatibility, etc.

[0018] At least one electrode is a detection electrode. As used herein, the term "detection electrode" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or customary meaning. Specifically, the term may refer to (but is not limited to) an electrode configured to perform at least one electrochemical detection reaction for the detection of at least one analyte.

[0019] The detection electrodes can consist of multiple layers.

[0020] The detection electrode may comprise a conductive layer on a substrate, which may comprise one or more of Au, carbon, gold-plated copper, or other electrically conductive materials. For example, the conductive layer may be sputtered, screen-printed, or coated onto the substrate. For instance, the conductive layer may be screen-printed, in which silver-based ink for forming conductive traces may be applied, as described in Amay J. Bandodkar et al., “Tattoo-Based Noninvasive Glucose Monitoring: A Proof-of-Concept Study”, Anal. Chem. 2015, 87, 394−398, dx.doi.org / 10.1021 / ac504300n.

[0021] The detection electrode comprises at least one analyte-responsive layer. As used herein, the term "analyte-responsive layer" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. Specifically, the term may refer to (but is not limited to) a layer configured to exhibit at least one physical property depending on the amount of analyte, for example, changing at least one chemical and / or physical property, such as its ionic conductivity, hydrophilicity, and / or volume, depending on the analyte concentration. For example, the analyte may be glucose, and the analyte-responsive layer may be a glucose-responsive layer.

[0022] An analyte response layer can be an equilibrium analyte response layer. As used herein, the term "equilibrium analyte response layer" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to a specific or custom-defined meaning. Specifically, the term may refer to (but is not limited to) an analyte response layer containing an equilibrium within the detected chemical substance. In an analyte response layer, an equilibrium exists between the analyte-bound molecules and the uncharged and charged forms of the p-ions. Upon addition of an analyte, the charged form binds to it, leaving the p-ions. The equilibrium between the uncharged and charged forms is continuously re-established. Therefore, the amount of free p-ions is proportional to the amount of analyte. The concentration of free p-ions affects the physicochemical properties of the analyte response layer. For example, the equilibrium can be associated with two forms of a boric acid-based analyte response layer. However, embodiments in which the analyte response layer is not an equilibrium analyte response layer but operates in a different manner are conceivable.

[0023] Non-invasive analyte sensors can be equilibrated sensors. Therefore, non-invasive analyte sensors do not actively consume the analyte (e.g., glucose) and can only operate under conditions where the bulk glucose concentration actively changes, such as in vivo. Accordingly, such equilibrated sensors are generally not suitable for non-invasive skin-tight sensors that measure glucose levels in bodily exudates (such as sweat). This is because the skin reabsorbs glucose slowly, causing the sensor to display an accumulated glucose concentration that does not correspond to the actual glucose level in, for example, ISF. This invention allows for a configuration in which the glucose concentration within the detection volume corresponds to the bulk glucose concentration. The term "equilibrated sensor" as used herein is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) an analyte sensor with axial balance. In particular, axial balance is related to the bulk concentration of the sample (e.g., exudate) being between zero (within tolerance) and zero (within tolerance) of the analyte concentration, as the entire analyte is consumed by the conversion layer. Therefore, along the axial direction from proximal to distal, the analyte concentration decreases from its maximum value delivered by the sample to zero, where the analyte concentration is consumed by the conversion layer. The analyte-responsive layer can be positioned somewhere along this axis, and its measurement is proportional to the signal input at the proximal end. For example, the detection electrode can contain an analyte-responsive layer at its proximal end and a conversion layer further away from the skin.

[0024] For example, an analyte-responsive layer comprises at least one analyte-responsive hydrogel layer. As used herein, the term "hydrogel" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. Specifically, the term may refer to (but is not limited to) solid materials comprising a three-dimensional polymeric matrix or network in a liquid medium.

[0025] Non-invasive analyte sensors can operate based on the detection principle of glucose reactive hydrogels (GRH) loaded with phenylboronic acid derivatives. However, embodiments of non-invasive analyte sensors are not limited to the use of GRH based on phenylboronic acid ester derivatives, and therefore are not limited to diol detection. Phenylboronic acid and its derivatives are known to form reversible covalent complexes with diol units such as glucose.

[0026] For example, the analyte-responsive polymer gel layer contains boric acid. For example, the analyte-responsive polymer gel may contain phenylboronic acid esters. For example, the analyte-responsive polymer gel may contain 3-(acrylamido)phenylboronic acid, 4-vinylpyridine and divinylbenzene, or acrylamide and 3-acrylamidophenylboronic acid, or ethyl acrylate, 3-(acrylamido)phenylboronic acid, N-vinylpyrrolidone and ethylene glycol dimethacrylate. Analyte-responsive polymer gels may typically contain boric acid groups or concanavalin A groups (Matthew J. Webber1, 2015) doi:10.3109 / 1061186X.2015.1055749.

[0027] For example, analyte-responsive polymer gels may contain poly(N-isopropylacrylamide). Analyte-responsive polymer gels are generally known. For example, glucose-responsive polymer gels are described in “Glucose-Responsive Polymer Gel Bearing Phenylborate Derivative as a Glucose-Sensing Moiety Operating at the Physiological pH”, Matsumoto et al., Biomacromolecules 2004, 5, 1038-1045, which is incorporated herein by reference. Not limited by theory, it is known that phenylboronic acid and its derivatives can form reversible covalent complexes with diol units, such as glucose. Phenylboronic acid compounds in water exist in equilibrium between their uncharged and charged forms. Only the charged form can form a relatively stable complex with glucose via reversible covalent bonding, while the complex between the uncharged form and glucose is unstable in water due to its high hydrolytic sensitivity. Because the complex between charged phenylboronic esters and glucose also carries an anionic charge, further addition of glucose induces an equilibrium shift towards increasing the charged form portion, and vice versa. Therefore, introducing phenylboronic acid ester groups into amphiphilic polymer gel structures (such as poly(N-isopropylacrylamide) (PNIPAAm) gel structures) induces a reversible volume transition in the gel, primarily because the osmotic pressure of ions also changes with the glucose concentration. Analyte-responsive polymer gels can be configured to change their volume and / or charge in the presence of an analyte (e.g., glucose), particularly continuously. Changes in total gel charge and volume can alter the ionic conductivity of the analyte-responsive polymer gel, which can be measured as described in more detail below. For example, an analyte sensor could be a glucose sensor comprising a boric acid-based glucose-responsive polymer gel. The glucose concentration can be determined using an excitation signal (e.g., a fast transient voltage) used to measure the ionic conductivity in relation to the analyte (e.g., glucose) concentration.

[0028] For example, in the embodiments, the analyte-responsive polymer may have the following composition:

[0029] As used herein, the term "conversion layer" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. Specifically, the term may refer to (but is not limited to) a layer configured for the chemical or electrochemical conversion of analytes. The conversion layer can actively remove analytes from the equilibrium analyte response layer, thereby continuously restoring the equilibrium analyte concentration. The analyte concentration may lie somewhere on an axis between a continuously varying analyte concentration and "zero" on the exudate, where the analyte is completely converted. The equilibrium analyte response layer can be used for analyte detection, but may require a conversion layer as an additional mechanism capable of continuously restoring equilibrium.

[0030] The conversion layer can be designed as a single stack of at least one or more functional layers. However, other embodiments are also conceivable. For example, the conversion layer may contain two or more horizontally distributed functional layers.

[0031] The transformation layer can be enzyme-containing or non-enzymatic.

[0032] For example, the conversion layer can contain enzyme molecules for the conversion of analytes. The conversion layer can contain glucose oxidase (GOx) or glucose dehydrogenase (GDH). In the case of GOx, molecular oxygen from ambient air can act as a natural electron acceptor. In this case, all layers above the conversion layer can be designed to be at least partially oxygen-permeable to supply oxygen to GOx. The reaction product, hydrogen peroxide, can preferably be directly decomposed to avoid its oxidative effect on the enzyme. The conversion layer can contain some catalytic material, such as manganese oxide or platinum nanoparticles. In the case of GDH, GDH is an oxygen-independent enzyme that requires another electron acceptor, such as silver chloride. To transfer electrons from the enzyme (cofactor), another medium can be used. Therefore, the enzyme can be chemically linked by at least one redox hydrogel (e.g., at least one Os complex-modified hydrogel).

[0033] The conversion layer can be non-enzymatic. For example, the conversion layer is non-enzymatic and contains at least one material selected from the following material categories: metal-organic frameworks; low-solubility nanoparticle metal salts, such as tin-nickel sulfides; graphene oxide; carbon nanotubes; and other material categories.

[0034] For example, the conversion layer is configured for chemical or electrochemical operation, wherein in the latter case, an additional polarization voltage is applied to the auxiliary electrode.

[0035] The conversion layer can have further functions, such as being used for additional detection of analytes.

[0036] The detection electrode can comprise a stack of at least two functional layers to form a balanced sensor. The proximal functional layer can form an analyte-responsive layer, and the distal functional layer can form a conversion layer. The proximal functional layer can be closer to the user's skin than the distal functional layer. For example, the analyte first passes through the analyte-responsive layer, thereby altering at least one of its physicochemical properties, and then flows to the conversion layer, where the analyte is chemically or electrochemically converted. Non-invasive analyte sensors can allow for the combination of an electrical biosensor and a balanced sensor. The two sensors are stacked axially relative to the skin surface, with bodily exudates first passing through the analyte-responsive layer, altering its conductivity, and further flowing to the conversion layer, such as an enzyme layer, where the analyte and potential interfering substances are electrochemically converted / consumed.

[0037] The detection electrode and auxiliary electrode can operate as a two-(or more)-electrode potentiostat. The potentiostat measures the electrons generated in the conversion layer (e.g., by a suitable enzyme) and their shuttle from the conversion layer to the conductive layer of the detection electrode via a suitable medium, and / or transports electrons from the conversion layer to the conductive layer of the detection electrode by applying a potential to the electrode. If the medium is intrinsic, such as an Os-complex-modified polymer, it may be a mixture of the medium and the enzyme, i.e., the enzyme is trapped within the Os-polymer network. When the enzyme generates electrons, their density can increase in the vicinity of the enzyme. Due to the statistical distribution of electrons in the medium, electron transport toward the electrode surface can be effectively present. This process can be enhanced by applying a potential to the electrode. This can induce typical current detection.

[0038] The current flowing from the conversion laminar flow to the auxiliary electrode can be proportional to the analyte concentration. The conversion layer and potentiostat can be configured to ensure continuous quantitative conversion of the analyte, keeping the analyte response layer in equilibrium.

[0039] The determination of analyte concentrations can involve various electrochemical techniques, such as electrochemical impedance spectroscopy (EIS), potentiometric techniques, and current-based techniques, or a combination thereof. For example, current-based analysis can be used to drive the conversion layer. As described below, EIS can be used in place of or in parallel with fast transient voltages for analyte detection. In addition to current-based analysis, potentiometric analysis can be used to elucidate further properties of the measurement system. Additional voltage modes can be added to induce electrophoresis.

[0040] Furthermore, as will be outlined in more detail below, an excitation signal in the form of a fast transient voltage can be applied to the electrodes to measure the ionic conductivity of the analyte response layer, which is correlated with the analyte concentration (e.g., glucose). Because the resistance of the conversion layer is very low, this does not negatively impact fast transient measurements across the entire stack.

[0041] For example, the detection electrode may include an additional layer between the analyte response layer and the conversion layer. For example, the detection electrode may include one or more separation layers, such as gels, meshes, etc. For example, the detection electrode may include at least one breathable water-permeable protective layer, such as a polytetrafluoroethylene layer, on the conversion layer.

[0042] For example, the detection electrode may include an additional gel layer such as a hydrogel, for example to increase skin compatibility, and / or an additional membrane, such as a microporous or nanoporous membrane of PTFE, for example, used as a filter. The detection electrode may be coated with an additional hydrogel layer on the skin-facing side. The hydrogel may be permeable to the analyte. The hydrogel may act as an adhesive. As described above, the analyte-responsive layer may be configured to form part of the skin-contact surface. However, an additional layer may exist between the analyte-responsive layer and the skin.

[0043] At least one other electrode in the electrode array is configured as an auxiliary electrode. As used herein, the term "auxiliary electrode" is a broad term and should be given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) another electrode configured to perform at least one auxiliary function for detecting an analyte using a detection electrode. The auxiliary electrode is configured as a counter electrode or a combined counter-reference electrode. As used herein, the term "counter electrode" is a broad term and should be given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) an electrode configured to perform at least one electrochemical pair reaction, the at least one electrochemical pair reaction being adjusted to be suitable for balancing the current required for the detection reaction at the detection electrode. As used herein, the term "reference electrode" is a broad term and should be given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) an electrode adjusted to provide a constant electrode potential as a reference potential, particularly at least within tolerances, such as by providing a redox system with a constant electrode potential.

[0044] The auxiliary electrode may comprise a conductive layer on a substrate, comprising one or more of Au, Ag, carbon, gold, copper plating, or other conductive materials. The auxiliary electrode may comprise at least one layer comprising one or more of Ag and / or AgCl. The auxiliary electrode may be coated with a hydrogel on the skin-facing side, wherein the hydrogel coating of the auxiliary electrode may contain chloride ions. For example, the auxiliary electrode (e.g., as a counter electrode) may comprise a conductive surface, such as carbon, gold, or silver-coated PET or other substrates. When a combined counter / reference function is required, the auxiliary electrode may have an additional Ag / AgCl layer or AgCl layer only if the Ag layer is used as the conductive layer. A hydrogel containing a defined, preferably physiological, Cl- concentration may be coated on top of these layers for conductivity and reference potential setting of the counter-reference electrode. The hydrogel may also separate silver from the skin.

[0045] An analyte response layer can be configured to form part of a skin contact surface. A detection electrode can be configured to contact a first skin surface. An auxiliary electrode can be configured to contact a second skin surface different from the first skin surface. For example, the auxiliary electrode is designed as a concentric ring around the detection electrode.

[0046] Non-invasive analyte sensors may include temperature sensors. Temperature can affect diffusion and kinetic processes, or even equilibrium, and needs to be considered through data evaluation.

[0047] In a further aspect, a non-invasive continuous monitoring system for skin-tight wear is disclosed. The non-invasive continuous monitoring system includes at least one non-invasive analyte sensor according to the invention, such as those described in one or more embodiments covered herein, measurement electronics configured to distribute an excitation signal to the analyte sensor, and a reference resistor connected in series with the analyte sensor, and measuring at least one voltage distribution across the analyte sensor and the reference resistor during the excitation signal. The measurement electronics are further configured to determine the analyte concentration in the analyte response layer by evaluating the measured voltage distribution.

[0048] In a further aspect, a non-invasive continuous monitoring system for skin-tight wear is disclosed. The non-invasive continuous monitoring system includes at least one non-invasive analyte sensor according to the invention, such as those described in one or more embodiments covered herein, and measurement electronics configured to apply an excitation signal to the analyte sensor and measure at least one current response. The measurement electronics are further configured to determine the analyte concentration in the analyte response layer by evaluating the measured current response and correlating it with the excitation signal.

[0049] For example, the amplitude and frequency of the AC excitation signal are related to the amplitude and phase of the response signal.

[0050] For the definition and embodiments of non-invasive analyte sensors, refer to the description of non-invasive analyte sensors as described in the first aspect or as outlined in more detail below.

[0051] As used further herein, the term "system" refers to any group of interacting or interdependent components that form a whole. Specifically, components can interact with each other to achieve at least one common function. At least two components can be processed independently or can be coupled or connected. Therefore, the term "monitoring system" generally refers to a group of at least two elements or components capable of interacting to perform at least one analytical detection, specifically at least one analytical detection of at least one sample analyte. A monitoring system can specifically be a device comprising at least two components.

[0052] As used herein, the term "measurement electronics" is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. Specifically, the term may refer to (but is not limited to) any electronic device or unit configured to measure at least one voltage distribution across an analyte sensor and a reference resistor during an excitation signal and for further evaluation.

[0053] Measurement electronics may include at least one processing device for evaluating response signals. As used herein, the term "processing device" is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, any logic circuit configured to perform basic operations of a computer or system; and / or, generally, a device configured to perform computation or logical operations. The processing device may be configured to process basic instructions that drive the computer or system. As an example, the processing device may include at least one arithmetic logic unit (ALU), at least one floating-point unit (FPU) (such as a math coprocessor or numerical coprocessor), multiple registers (specifically registers configured to supply operands to the ALU and store the results of operations), and memory (such as L1 and L2 caches). The processing device may be a multi-core processor. The processing device may be or may include a central processing unit (CPU). Additionally or alternatively, the processing device may be or may include a microprocessor; therefore, specifically, the elements of the processor may be contained within a single integrated circuit (IC) chip. Additionally or alternatively, the processing device may be or may include 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 units (TPUs) and / or one or more chips, such as dedicated machine learning optimization chips. The processing device may be specifically configured (e.g., via software programming) to perform one or more evaluation operations. The processing device may be configured to perform named steps. Thus, as an example, the processing device may contain software code stored thereon, which includes a number of computer instructions. The processing device may provide one or more hardware elements for performing one or more of the indicated operations and / or may provide one or more processors on which software runs for performing one or more of the steps.

[0054] As mentioned above, non-invasive analyte sensors can allow for the combination of current biosensors and balance sensors.

[0055] To operate the non-invasive analyte sensor as a balanced sensor, the detection electrode and auxiliary electrode can be operated as two (or more) electrode potentiostats. The potentiostats can measure the electrons generated in the conversion layer (e.g., by a suitable enzyme) and their shuttle from the conversion layer to the conductive layer of the detection electrode via a suitable medium and / or transport electrons from the conversion layer to the conductive layer of the detection electrode by applying a potential to the electrode. As mentioned above, if the medium is intrinsic, such as an Os-complex-modified polymer, it may be a mixture of the medium and the enzyme, i.e., the enzyme is trapped in the Os-polymer network. When the enzyme generates electrons, their density can increase in the vicinity of the enzyme. Due to the statistical distribution of electrons in the medium, electron transport toward the electrode surface can be effectively present. This process can be enhanced by applying a potential to the electrode. This can induce typical current detection.

[0056] The current can be proportional to the analyte concentration and can be recorded and evaluated as a concentration value by measuring electronics (e.g., using at least one predetermined relationship between the analyte concentration and the measured current). A conversion layer and potentiostat can be configured to ensure continuous quantitative conversion of the analyte, keeping the analyte sensor always in equilibrium.

[0057] To operate the non-invasive analyte sensor as a current biosensor, the measurement electronics can generate an excitation signal and apply it to the electrodes, determining the analyte concentration in the analyte-response layer by evaluating the response signal, as will be outlined in more detail below. Specifically, the ionic conductivity of the analyte-response layer is measured to determine the analyte concentration. Due to the large surface area of ​​the auxiliary electrode and the relatively low ionic resistivity of the skin, the majority of the measured resistance is due to the conductivity of the analyte-response layer, which varies with the analyte concentration. The measurement electronics can be configured to record the impedance value between the two electrodes by applying the excitation signal and determining the response signal.

[0058] The advantage of combining a balance sensor and a current biosensor may be that impedance measurements are sensitive to diols, while electrochemical measurements can be distorted by the non-selective oxidation of other electrochemically active substances, such as lactate. Therefore, having both signals in the algorithm and using them appropriately can allow for improved overall selectivity of the measurement system.

[0059] As used herein, the term "excitation signal" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. Specifically, the term may refer to (but is not limited to) any voltage signal. Non-invasive continuous monitoring systems (e.g., measurement electronics) may include at least one signal generator device for generating an excitation signal.

[0060] As used herein, the term "signal generator device" is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. Specifically, the term may refer to (but is not limited to) a device configured to generate a voltage signal, such as a voltage source. A signal generator device may be and / or may include at least one voltage source. A signal generator device may include at least one functional generator selected from the group consisting of at least one square wave generator and at least one sine wave generator. A signal generator device may also generate a single pulse that may be asymmetrical. In this context, "asymmetrical" means that the first pulse may differ from the second pulse and / or the third pulse and / or any other subsequent pulse. A signal generator device may be part of measurement electronics. A signal generator device may be configured to apply an excitation signal to electrodes.

[0061] The excitation signal can be a fast transient voltage. As used herein, the term "fast transient voltage" is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term can refer to (but is not limited to) at least one arbitrary voltage signal, particularly an arbitrary voltage change between two electrodes. A fast transient voltage may have at least one fast transient signal flank, such as two very steep edges. A fast transient voltage may comprise a square waveform and / or a sinusoidal waveform. For example, a fast transient voltage may have a square waveform.

[0062] Fast transient voltages can include discontinuous signals, such as pulses. The term "pulse" as used herein is a broad term and should be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or customary meaning. Specifically, the term can refer to (but is not limited to) a signal whose amplitude instantaneously changes from a first value (also representing a baseline value) to a second value, and then returns to the baseline value or is at least approximately equal to the baseline value. The second value can be a value higher or lower than the baseline value. The pulse duration can be ≤ 20 µs, more preferably ≤ 10 µs. The duration of a single pulse must be long enough to record its propagation. Fast transient voltages can include pulses with two edges: a leading or positive edge of the first edge of the pulse, and a trailing or back edge of the second edge of the pulse.

[0063] The term "fast transient" as used herein is a broad term and should be given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) the time range between a first signal edge value and a second signal edge value.

[0064] The terms "first" and "second" can refer to regions or points of a fast transient voltage, particularly its amplitude. The first value can be a baseline value. The first value can be a local and / or global minimum of the fast transient voltage. The first value can be the first plateau of the fast transient voltage. The first value can refer to a point in time when no voltage is applied to the electrodes. The second value can be a local and / or global extreme value of the fast transient voltage. The second value can be the second plateau of the fast transient voltage, which can be reached during the application of the fast transient voltage. The second value can be an extreme value of the fast transient voltage.

[0065] The term "signal edge" as used herein is a broad term and should be given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to (but is not limited to) a transition in signal amplitude from a low signal value to a high signal value or from a high signal value to a low signal value. A signal edge can be a rising signal edge or a falling signal edge. The signal edge of a fast transient voltage can vary from a first signal edge value to a second signal edge value in the range of microseconds to nanoseconds. A signal edge may also be referred to as an edge. A fast transient voltage can have a low-to-high signal amplitude transition equivalent to a rising or positive signal edge or a high-to-low signal amplitude transition equivalent to a falling or negative signal edge. A fast transient voltage can have a steep edge. Specifically, a fast-switching square wave can have a voltage change from a first value to a second value within 20 ns or less. The voltage change from the first value to the second value can be even faster and can be limited only by electronic devices, such as fast transient voltage generators (DACs, DOs, or others) or readout units (voltage amplifiers, ADCs, or others). The faster the voltage change (higher conversion rate) and the sharper the transition to plateau, the more accurately the analyte concentration can be determined. The duration of a single fast transient voltage must be long enough to record the response voltage.

[0066] A fast transient voltage with a known amplitude can be applied. The amplitude of the fast transient voltage can vary over a wide range and must be optimized for a given setup. Typically, the lower limit may be limited by the readout technique (which must record the response voltage, primarily limited by its input range and resolution) and may require an additional sufficiently fast voltage amplifier.

[0067] A rapid transient voltage can be applied at least once. A rapid transient voltage can be applied some time after the analyte sensor has been in contact with the skin. A rapid transient voltage can be applied repeatedly, for example, periodically. A rapid transient voltage can be applied repeatedly, particularly at intervals of several minutes to several seconds. The measurement frequency can depend on the required frequency of the measurements. The measurement electronics can be configured to determine combined measurements to reduce measurement uncertainty. Determining combined measurements can involve using sophisticated filters (such as Kalman filters) to determine one or more of the mean, average, and median. For example, measurements can be acquired every second, and the average of 60 measurements can be taken as a value per minute. The measurement frequency can depend on the application of the analyte sensor.

[0068] Furthermore, the excitation signal can comprise a continuously variable voltage signal, for example, in the form of a sinusoidal signal. The continuously variable voltage signal can be applied continuously or periodically. The continuously variable voltage signal can be, or may contain, a voltage pattern, particularly for operating the conversion layer.

[0069] Furthermore, the analyte sensor may include at least one pair of electrodes for electrophoresis. Measurement electronics may be configured to apply an additional voltage mode between the electrodes for electrophoresis. This voltage mode can induce an electrophoretic effect and accelerate the extraction of bodily exudates.

[0070] Measurement electronics are configured to measure the voltage distribution across the analyte sensor and reference resistor during an excitation signal. Specifically, the measurement electronics are configured to measure at least one response signal. The term "response signal" as used herein is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. The term may specifically refer to (but is not limited to) the measured propagation of an applied excitation signal. The response signal may be a current or a voltage. The response signal may be measured during the duration of the excitation signal. The measurement electronics may be configured to record at least one impedance value between electrodes in response to the applied excitation signal.

[0071] The response signal can be measured at a reference resistor. A non-invasive continuous monitoring system may include at least one reference resistor connected in series with the ionic resistivity of the analyte response layer. A reference resistor suitable for determining the ionic resistivity of the analyte response layer can be selected, for example, using Z... GRH Indicates the value of the reference resistor R. ref Can be prioritized in Z GRH Within a certain range. The reference resistance can be a known value, such as an average value determined from multiple reference measurements (specifically, predetermined). The reference resistance can reflect the measurement range of the analyte response layer. The reference resistance can reflect the required measurement tolerance. In determining Z... GRHDuring the defined period, the signal generator device can apply a fast transient voltage with a known amplitude U1 to the electrodes. Simultaneously, a reference resistor R can be used... ref The voltage drop U2 is measured at point R. The magnitude of the applied voltage and its value at R are known. ref The measured amplitude and R ref Value, Z GRH It can be calculated as: .

[0072] The evaluation of the response signal can be performed using a processing device. The evaluation may further include using at least one predetermined relation from the analyte response layer Z. GRH The concentration of the analyte is determined by the ionic resistivity. For example, the predetermined relationship can be linear. For example, the predetermined relationship can be stored in at least one database of the processing device.

[0073] In a further aspect of the invention, a method for determining the concentration of an analyte in a sample using a non-invasive continuous monitoring system according to the invention, as described in one or more embodiments appended herein. For a definition and embodiment of a non-invasive continuous monitoring system, refer to the description of non-invasive analyte sensors and non-invasive continuous monitoring systems described in further aspects or as described in more detail below. The method comprises the method steps as set forth in the corresponding independent claims and listed below. The method steps may be performed in a given order. Further, one or more of the method steps may be performed in parallel and / or in a time-overlapping manner. Further, one or more of the method steps may be performed repeatedly. Further, additional method steps not listed may be present.

[0074] The method includes the following steps: i. Ensure that the skin contact surfaces of the detection electrode and the auxiliary electrode are in contact with the skin surface. ii. Distribute an excitation signal to the analyte sensor and a reference resistor connected in series with the analyte sensor, and measure at least one voltage distribution across the analyte sensor and the reference resistor during the excitation signal period. iii. The concentration of the analyte is determined by evaluating the measured voltage distribution.

[0075] Alternatively or additionally, the method includes the following steps: I. Ensure that the skin contact surfaces of the detection electrode and auxiliary electrode are in contact with the skin surface. II. Apply an excitation signal to the analyte sensor and measure at least one current response. III. The analyte concentration in the analyte response layer is determined by evaluating the measured current response and correlating it with the excitation signal.

[0076] As used herein, the term "contact" is a broad term and should be given the common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. Specifically, the term may refer to (but is not limited to) the process of exposing a detection electrode to a fluid (e.g., via attaching and / or mounting the detection electrode to the skin).

[0077] This method may include measuring the current between the conversion layer and the auxiliary electrode and using the measured current to additionally determine the analyte concentration.

[0078] The method may include applying at least one additional excitation signal for sample generation and / or extraction, such as using electrophoresis.

[0079] This document further discloses and proposes a computer program comprising computer-executable instructions that, when executed on a computer or computer network, are used to perform the method according to the invention in one or more embodiments appended herein. Specifically, the computer program may be stored on a computer-readable data carrier and / or a computer-readable storage medium.

[0080] As used herein, the terms "computer-readable data carrier" and "computer-readable storage medium" can specifically refer to non-transitory data storage instruments, such as hardware storage media having computer-executable instructions stored thereon. Computer-readable data carriers or storage media can specifically be or can include storage media such as random access memory (RAM) and / or read-only memory (ROM).

[0081] Therefore, one, more than one, or even all of the method steps i to iii specifically described above can be performed using a computer or computer network, preferably using a computer program. In particular, the computer program can execute and / or trigger the execution of method steps ii, iii, II, and III.

[0082] This document further discloses and proposes a computer program product with program code tools so that, when the program is executed on a computer or computer network, the method according to the invention can be performed in one or more embodiments appended herein. Specifically, the program code tools may be stored on a computer-readable data carrier and / or a computer-readable storage medium.

[0083] This document further discloses and proposes a data carrier having a data structure stored thereon, which, after being loaded into a computer or computer network (such as after being loaded into the working memory or main memory of the computer or computer network), can perform methods according to one or more embodiments disclosed herein.

[0084] This document further discloses and proposes a non-transitory computer-readable medium comprising instructions that, when executed by one or more processors, cause one or more processors to perform the method according to the invention.

[0085] This document further discloses and proposes a computer program product having program code tools stored on a machine-readable medium, so that when the program is executed on a computer or computer network, it performs methods according to one or more embodiments disclosed herein. As used herein, a computer program product refers to a program that is a tradable product. The product can typically exist in any format (such as in paper format) or reside on a computer-readable data carrier and / or a computer-readable storage medium. Specifically, the computer program product can be distributed on a data network.

[0086] This document further discloses and proposes a modulated data signal containing instructions that can be read by a computer system or computer network for performing a method according to one or more embodiments disclosed herein.

[0087] Referring to the computer implementation aspects of the present invention, one or more method steps, or even all method steps, of the methods according to one or more embodiments disclosed herein can be performed using a computer or computer network. Therefore, generally, any method step, including the manipulation of providing and / or data, can be performed using a computer or computer network. Typically, these method steps can include any method steps other than those requiring manual work (such as providing samples and / or performing actual measurements).

[0088] Specifically, this article further discloses the following: - A computer or computer network including at least one processor, wherein the processor is adapted to perform a method according to one of the embodiments described in this specification. - A computer-loadable data structure, adapted to perform one of the methods described in this specification when the data structure is executed on the computer. - A computer program, wherein the computer program is adapted, when executed on a computer, to perform a method according to one of the embodiments described in this specification. - A computer program including program tools for performing a method according to one of the embodiments described herein, when executed on a computer or on a computer network. - A computer program that includes program tools according to the foregoing embodiments, wherein the program tools are stored on a computer-readable storage medium. - A storage medium on which a data structure is stored and wherein the data structure is adapted to be loaded into the main memory and / or working memory of a computer or computer network, and to be subjected to a method according to one of the embodiments described herein. - A computer program product having program code tools, wherein the program code tools can be stored or stored on a storage medium for use in performing a method according to an embodiment described herein if the program code tools are executed on a computer or computer network.

[0089] In summary, and without excluding further possible embodiments, the following embodiments are conceivable.

[0090] Example 1. A non-invasive analyte sensor comprising at least two electrodes, each having a skin contact surface, wherein at least one electrode is a detection electrode, wherein the detection electrode comprises at least one analyte response layer and at least one conversion layer, wherein at least one other electrode is configured as an auxiliary electrode, the auxiliary electrode being configured as a counter electrode or a combined counter-reference electrode.

[0091] Example 2. A non-invasive analyte sensor according to the foregoing embodiments, wherein the detection electrode comprises a stack of at least two functional layers, wherein the proximal functional layer forms an analyte response layer and the distal functional layer forms a conversion layer.

[0092] Example 3. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the analyte response layer is configured to form part of a skin contact surface.

[0093] Example 4. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the analyte first passes through the analyte response layer, thereby altering at least one of its physicochemical properties, and then flows to the conversion layer, wherein the analyte is chemically or electrochemically converted.

[0094] Example 5. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the analyte response layer comprises at least one analyte response hydrogel layer.

[0095] Example 6. A non-invasive analyte sensor according to the foregoing embodiments, wherein the analyte-responsive hydrogel layer comprises boric acid.

[0096] Example 7. A non-invasive analyte sensor according to the foregoing embodiments, wherein the analyte-responsive hydrogel layer comprises a phenylboronic acid derivative.

[0097] Example 8. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the conversion layer is enzymatic or non-enzymatic.

[0098] Example 9. A non-invasive analyte sensor according to any of the foregoing examples, wherein the conversion layer contains enzyme molecules for converting the analyte.

[0099] Example 10. A non-invasive analyte sensor according to any of the foregoing examples, wherein the conversion layer comprises glucose oxidase (GOx) or glucose dehydrogenase (GDH).

[0100] Example 11. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the conversion layer is non-enzymatic and comprises at least one material selected from the following material categories: metal-organic frameworks; low-solubility nanoparticle metal salts, such as tin-nickel sulfides; graphene oxide; carbon nanotubes; and other material categories.

[0101] Example 12. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the conversion layer is configured for chemical or electrochemical operation.

[0102] Example 13. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the detection electrode comprises a conductive layer on a substrate, the conductive layer comprising one or more of Au, carbon, gold-plated copper or other conductive materials.

[0103] Example 14. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the detection electrode is coated with hydrogel on the skin-facing side.

[0104] Example 15. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the auxiliary electrode comprises a conductive layer on a substrate, the conductive layer comprising one or more of Au, Ag, carbon or gold, copper plating or other conductive materials.

[0105] Example 16. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the auxiliary electrode comprises at least one layer comprising one or more of Ag and / or AgCl.

[0106] Example 17. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the auxiliary electrode is coated with hydrogel on the skin-facing side, and wherein the hydrogel coating of the auxiliary electrode contains chloride ions.

[0107] Example 18. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein a detection electrode is configured to contact a first skin surface, and an auxiliary electrode is configured to contact a second skin surface different from the first skin surface.

[0108] Example 19. A non-invasive analyte sensor according to the foregoing embodiments, wherein the auxiliary electrode is designed as a concentric ring around the detection electrode.

[0109] Example 20. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the analyte is glucose.

[0110] Example 21. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the non-invasive analyte sensor is a dual-electrode sensor.

[0111] Example 22. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the non-invasive analyte sensor is configured for continuous analyte monitoring.

[0112] Example 23. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the non-invasive analyte sensor is configured for skin-tight wear.

[0113] Example 24. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the non-invasive analyte sensor includes a temperature sensor.

[0114] Example 25. A non-invasive analyte sensor according to any of the foregoing embodiments, wherein the sample is a bodily exudate such as sweat.

[0115] Example 26. A non-invasive continuous monitoring system for skin-worn applications, comprising: at least one non-invasive analyte sensor as described in any of the preceding embodiments, and measurement electronics configured for use with - An excitation signal is distributed to the analyte sensor and a reference resistor connected in series with the analyte sensor, and at least one voltage distribution across the analyte sensor and the reference resistor is measured during the excitation signal, wherein the measurement electronics are further configured to determine the analyte concentration in the analyte response layer by evaluating the measured voltage distribution; and / or - An excitation signal is applied to an analyte sensor and at least one current response is measured, wherein measurement electronics are configured to determine the analyte concentration in the analyte response layer by evaluating the measured current response and correlating it with the excitation signal.

[0116] Example 27. A non-invasive continuous monitoring system according to the foregoing embodiments, wherein the excitation signal is a fast transient voltage and the voltage distribution is measured as a current or voltage response signal.

[0117] Example 28. A non-invasive continuous monitoring system according to the foregoing embodiments, wherein the fast transient voltage comprises a discontinuous signal such as a pulse, wherein the pulse duration is ≤ 20 µs, preferably ≤ 10 µs.

[0118] Example 29. A non-intrusive continuous monitoring system according to any one of the three preceding embodiments, wherein the excitation signal is a continuously variable voltage signal and the response signal is current or voltage.

[0119] Example 30. A non-invasive continuous monitoring system according to the foregoing embodiments, wherein voltage distribution is measured during the duration of the excitation signal.

[0120] Example 31. A non-invasive continuous monitoring system according to any of the foregoing embodiments relating to a non-invasive continuous monitoring system, wherein measuring electronics are configured to record at least one impedance value between electrodes in response to an applied excitation signal.

[0121] Example 32. A non-invasive continuous monitoring system according to any of the foregoing embodiments relating to a non-invasive continuous monitoring system, wherein the measuring electronics are configured to apply an additional voltage pattern between electrodes in order to operate the conversion layer.

[0122] Example 33. A method for determining the concentration of an analyte in a sample using a non-invasive continuous monitoring system according to any of the foregoing embodiments involving a non-invasive continuous monitoring system, the method comprising the steps of: i. Ensure that the skin contact surfaces of the detection electrode and the auxiliary electrode are in contact with the skin surface. ii. Distribute an excitation signal to the analyte sensor and a reference resistor connected in series with the analyte sensor, and measure at least one voltage distribution across the analyte sensor and the reference resistor during the excitation signal period. iii. The analyte concentration is determined by evaluating the measured voltage distribution; And / or the method includes the following steps: I. Ensure that the skin contact surfaces of the detection electrode and auxiliary electrode are in contact with the skin surface. II. Apply an excitation signal to the analyte sensor and measure at least one current response. III. The analyte concentration in the analyte response layer is determined by evaluating the measured current response and correlating it with the excitation signal.

[0123] Example 34. The method according to the foregoing embodiments, wherein the method includes measuring the current between the conversion layer and the auxiliary electrode and using the measured current to additionally determine the analyte concentration.

[0124] Example 35. The method according to any of the foregoing embodiments of the method, wherein the method comprises applying at least one additional excitation signal for sample generation and / or extraction.

[0125] Example 36. A computer program including program tools for performing the methods described in the foregoing embodiments when the computer program is executed on a computer or on a computer network. Attached Figure Description

[0126] Further optional features and embodiments will be disclosed in more detail in the following description of the embodiments, preferably in conjunction with the dependent claims. As will be appreciated by those skilled in the art, each optional feature can be implemented individually and in any feasible combination. The scope of the invention is not limited to the preferred embodiments. Embodiments are schematically depicted in the accompanying drawings. In these drawings, the same reference numerals refer to the same or functionally equivalent elements.

[0127] In the attached diagram: Figure 1 illustrates an embodiment of a non-invasive continuous monitoring system comprising a non-invasive analyte sensor according to the present invention; and Figure 2 illustrates an embodiment of a method for determining the concentration of an analyte in a sample. Detailed Implementation

[0128] Figure 1 illustrates, in a highly schematic manner, an exemplary embodiment of a non-invasive continuous monitoring system 110 including a non-invasive analyte sensor 112 according to the present invention.

[0129] The non-invasive analyte sensor 112 includes at least two electrodes 114. The analyte sensor 112 may be a dual-electrode sensor. However, in possible embodiments, the analyte sensor includes more than two electrodes 114.

[0130] Each electrode 114 may have a skin contact surface 116. An analyte sensor 112 may be mounted and / or attached to an external skin surface 118 using at least one patch, and / or the analyte sensor 112 may be part of a patch. The analyte sensor 112 may be skin worn by a user. The analyte sensor 112 may be worn as a watch, bracelet, etc. The skin contact surface 116 may be configured to allow the electrode 114 to contact the user's skin directly or indirectly. For example, the skin contact surface 116 may be a skin contact layer that directly contacts the user's skin. Alternatively, an additional layer may be used between the skin contact surface 116 and the skin, for example, indirectly contacting the skin contact surface via at least one additional element (such as at least one additional hydrogel layer), for example, to increase skin compatibility, etc.

[0131] At least one electrode of electrode 114 is a detection electrode 120. Detection electrode 120 may comprise multiple layers.

[0132] The detection electrode 120 may include a conductive layer 122 on a substrate, which comprises one or more of Au, carbon, gold-plated copper, or other conductive materials. For example, the conductive layer may be sputtered, screen-printed, or coated onto the substrate.

[0133] The detection electrode 120 includes at least one analyte-responsive layer 124. The analyte-responsive layer 124 can be configured to change at least one chemical and / or physical property, such as its ionic conductivity, hydrophilicity, and / or volume, according to the analyte concentration. For example, the analyte may be glucose, and the analyte-responsive layer 124 may be a glucose reaction layer.

[0134] The analyte response layer 124 can be an equilibrium analyte response layer. The analyte response layer 124 contains an equilibrium within the detected chemical substance used. In the analyte response layer 124, an equilibrium exists between the analyte-bound molecules and the uncharged and charged forms of the p-ions. Upon addition of analyte, the charged form binds to it, leaving the p-ions. The equilibrium between the uncharged and charged forms is continuously re-established. Therefore, the amount of free p-ions is proportional to the amount of analyte. The concentration of free p-ions affects the physicochemical properties of the analyte response layer. For example, the equilibrium can be associated with both forms of a boric acid-based analyte response layer. However, it is conceivable that an embodiment in which the analyte response layer 124 is not an equilibrium analyte response layer but operates in a different manner is possible.

[0135] The non-invasive analyte sensor 112 can be a balanced sensor. Therefore, the non-invasive analyte sensor does not actively consume the analyte (e.g., glucose) and can only operate under conditions where the bulk glucose concentration actively changes, such as in vivo. Accordingly, such balanced sensors are generally not suitable for non-invasive skin-touch sensors that measure glucose levels in bodily exudates (such as sweat). This is because the skin reabsorbs glucose slowly, causing the sensor to display a cumulative glucose concentration that does not correspond to the actual glucose level in, for example, ISF. The present invention allows for a configuration in which the glucose concentration within the detection volume corresponds to the bulk glucose concentration. The non-invasive analyte sensor 112 has an axial balance. In particular, the axial balance is related to the bulk concentration of the sample (e.g., exudate) and the analyte concentration between zero (within tolerance), as the entire analyte is consumed by the conversion layer. Thus, along the axial axis from proximal to distal, the analyte concentration decreases from a maximum value during sample delivery to zero, where the analyte concentration is consumed by the conversion layer 126. The analyte-responsive layer 124 can be positioned at a point on the axis, and its measurement is proportional to the signal input at the proximal end. For example, the detection electrode 120 may include the analyte-responsive layer 124 at its proximal end and a conversion layer 126 further away from the skin.

[0136] For example, the analyte-responsive layer 124 comprises at least one analyte-responsive hydrogel layer. The non-invasive analyte sensor 112 can operate based on the detection principle of using a glucose reactive hydrogel (GRH) based on a phenylboronic acid ester derivative. However, embodiments of the non-invasive analyte sensor 112 are not limited to using GRH based on phenylboronic acid ester derivatives, and therefore are not limited to diol detection. Phenylated acid and its derivatives are known to form reversible covalent complexes with diol units such as glucose.

[0137] For example, the analyte-responsive hydrogel layer contains boric acid. For example, the analyte-responsive hydrogel may contain phenylboronic acid esters. For example, the analyte-responsive hydrogel may contain 3-(acrylamido)phenylboronic acid, 4-vinylpyridine and divinylbenzene, or acrylamide and 3-acrylamidophenylboronic acid, or ethyl acrylate, 3-(acrylamido)phenylboronic acid, N-vinylpyrrolidone and ethylene glycol dimethacrylate. Analyte-responsive hydrogels may typically contain boric acid groups or concanavalin A groups (Matthew J. Webber1, 2015) doi:10.3109 / 1061186X.2015.1055749.

[0138] For example, analyte-responsive hydrogels can contain poly(N-isopropylacrylamide). Analyte-responsive hydrogels are generally known. For example, glucose-responsive hydrogels are described in “Glucose-Responsive Polymer Gel Bearing Phenylborate Derivative as a Glucose-Sensing Moiety Operating at the Physiological pH”, Matsumoto et al., Biomacromolecules 2004, 5, 1038-1045, which is incorporated herein by reference. Not limited by theory, it is known that phenylboronic acid and its derivatives can form reversible covalent complexes with diol units, such as glucose. Phenylboronic acid compounds in water exist in an equilibrium between their uncharged and charged forms. Only the charged form can form a relatively stable complex with glucose via reversible covalent bonding, while the complex between the uncharged form and glucose is unstable in water due to its high hydrolytic sensitivity. Because the complex between charged phenylboronic esters and glucose also carries an anionic charge, further addition of glucose induces an equilibrium shift towards increasing the charged form portion, and vice versa. Therefore, introducing phenylboronic acid ester groups into amphiphilic polymer gel structures (such as poly(N-isopropylacrylamide) (PNIPAAm) gel structures) induces a reversible volume transition in the gel, primarily because the osmotic pressure of ions also changes with the glucose concentration. Analyte-responsive hydrogels can be configured to change their volume and / or charge in the presence of an analyte (e.g., glucose), particularly in a continuous manner. Changes in total gel charge and volume can alter the ionic conductivity of the analyte-responsive hydrogel, which can be measured as described in more detail below. For example, an analyte sensor could be a glucose sensor comprising a boric acid-based glucose-responsive hydrogel. The glucose concentration can be determined using an excitation signal (e.g., a fast transient voltage) used to measure the ionic conductivity in relation to the analyte (e.g., glucose) concentration.

[0139] The detection electrode 120 further includes at least one conversion layer 126. The conversion layer 126 can be configured for chemical or electrochemical conversion of the analyte. The analyte response layer 124 can be used for analyte detection, but requires the conversion layer 126 as an additional mechanism, which is capable of continuously reconstructing equilibrium.

[0140] The conversion layer 126 can be enzyme-containing or non-enzymatic. For example, the conversion layer 126 can contain enzyme molecules for converting analytes. The conversion layer 126 can contain glucose oxidase (GOx) or glucose dehydrogenase (GDH). For example, the conversion layer 126 is enzyme-free and contains at least one material selected from the following material classes: metal-organic frameworks; low-solubility nanoparticle metal salts, such as tin-nickel sulfides; graphene oxide; carbon nanotubes; and other material classes. For example, the conversion layer 126 is configured for chemical or electrochemical operations, wherein in the latter case, an additional polarization voltage is applied to the auxiliary electrode 128.

[0141] The detection electrode 120 may comprise a stack of at least two functional layers. A proximal functional layer may form an analyte-responsive layer 124, and a distal functional layer may form a conversion layer 126. The proximal functional layer may be closer to the user's skin than the distal functional layer. For example, the analyte first passes through the analyte-responsive layer 124, thereby altering at least one of its physicochemical properties, and then flows to the conversion layer 126, where the analyte is chemically or electrochemically converted. The non-invasive analyte sensor 112 may allow for the combination of an electrical biosensor and a balance sensor. Both sensors are stacked axially relative to the skin surface, with bodily exudates first passing through the analyte-responsive layer 124, altering its conductivity, and further flowing to the conversion layer 126 (e.g., an enzyme layer), where the analyte and potential interfering substances are electrochemically converted / consumed.

[0142] For example, the detection electrode 120 may include an additional layer between the analyte response layer 124 and the conversion layer 126. For example, the detection electrode 120 may include one or more separation layers, such as gels, meshes, etc. For example, the detection electrode 120 may include at least one breathable water-permeable protective layer, such as a polytetrafluoroethylene layer, on the conversion layer.

[0143] For example, the detection electrode 120 may include an additional gel layer (such as a hydrogel) for example to increase skin compatibility, and / or an additional membrane (such as a microporous or nanoporous membrane of, for example, PTFE) for example as a filter. The detection electrode 120 may be coated with an additional hydrogel layer on the skin-facing side. The hydrogel may be permeable to the analyte. The hydrogel may act as an adhesive. As described above, the analyte-responsive layer 124 may be configured to form part of the skin contact surface 116. However, an additional layer may exist between the analyte-responsive layer 124 and the skin.

[0144] At least one other electrode among electrodes 114 is configured as an auxiliary electrode 128. The auxiliary electrode 128 is configured as a counter electrode or a combined counter-reference electrode. In this embodiment, the auxiliary electrode 128 may include a conductive layer 130 comprising carbon. The auxiliary electrode 128 may include at least one layer 132 comprising one or more of Ag and / or AgCl. The auxiliary electrode 128 may be coated with a hydrogel 134 on the skin-facing side, wherein the hydrogel coating of the auxiliary electrode may contain chloride ions.

[0145] The detection electrode 120 can be configured to contact a first skin surface. The auxiliary electrode 128 can be configured to contact a second skin surface different from the first skin surface. For example, the auxiliary electrode 128 is designed as a concentric ring around the detection electrode 120.

[0146] The non-invasive continuous monitoring system 110 further includes measurement electronics 136 configured to distribute an excitation signal to an analyte sensor 112 and a reference resistor connected in series with the analyte sensor 112, and to measure at least one voltage distribution across the analyte sensor 112 and the reference resistor during the excitation signal. Measurement electronics 136 is further configured to determine the analyte concentration in the analyte response layer by evaluating the measured voltage distribution (e.g., a response signal). Measurement electronics 136 may include at least one processing means for evaluating the response signal.

[0147] The non-invasive continuous monitoring system 110 can combine an electric current biosensor and a balance sensor.

[0148] To operate the non-invasive analyte sensor 112 as a balanced sensor, the detection electrode 120 and auxiliary electrode 128 can be operated as two (or more) electrode potentiostats. The potentiostats can measure electrons generated in the conversion layer 126, for example by a suitable enzyme, and shuttled from the conversion layer 126 to the conductive layer 122 of the detection electrode 120 via a suitable medium, and / or by applying a potential to the electrode 114 to transport electrons from the conversion layer 126 to the conductive layer 122 of the detection electrode 120. If the medium is intrinsic, such as an Os-complex-modified polymer, it may be a mixture of the medium and the enzyme, i.e., the enzyme is trapped in the Os-polymer network. When the enzyme generates electrons, its density can increase in the vicinity of the enzyme. Due to the statistical distribution of electrons in the medium, electron transport toward the electrode surface can be effectively present. This process can be enhanced by applying a potential to the electrode. This can induce typical current detection. The current can be proportional to the analyte concentration and can be recorded and evaluated as a concentration value by measuring electronics 136 (e.g., by using at least one predetermined relationship between the analyte concentration and the measured current).

[0149] The conversion layer 126 and the potentiostat can be configured to ensure continuous quantitative conversion of the analyte, so that the analyte response layer 124 is always in equilibrium.

[0150] To operate the non-invasive analyte sensor 112 as a current biosensor, the measurement electronics 136 can generate an excitation signal and apply it to the electrodes 114, determining the analyte concentration in the analyte-response layer 124 by evaluating the response signal. Specifically, the ionic conductivity of the analyte-response layer 124 is measured to determine the analyte concentration. Due to the large surface area of ​​the auxiliary electrode 128 and the relatively low ionic resistivity of the skin, the majority of the measured resistance is due to the conductivity of the analyte-response layer 124, which varies with the analyte concentration. The measurement electronics 136 can be configured to record the impedance value between the two electrodes 114 by applying the excitation signal and determining the response signal.

[0151] The non-invasive continuous monitoring system 110 (e.g., measurement electronics 136) may include at least one signal generator device for generating an excitation signal. The excitation signal may be a fast transient voltage. For example, the fast transient voltage may have a square waveform. The fast transient voltage may contain a discontinuous signal, such as a pulse. The pulse duration may be ≤ 20 µs, more preferably ≤ 10 µs. The fast transient voltage may be applied to the electrode at least once. The fast transient voltage may be applied after a certain period of time following contact between the analyte sensor and the skin. The fast transient voltage may be repeatedly applied to the electrode, for example, periodically. The fast transient voltage signal may be repeatedly applied to the electrode, particularly at time intervals of several minutes to several seconds.

[0152] Furthermore, the excitation signal can comprise a continuously variable voltage signal, for example, in the form of a sinusoidal signal. The continuously variable voltage signal can be applied continuously or periodically. The continuously variable voltage signal can be, or may comprise, a voltage pattern, particularly for operating the conversion layer 126.

[0153] Furthermore, the analyte sensor 112 may include at least one pair of electrodes for electrophoresis. The measurement electronics 136 may be configured to apply an additional voltage mode between the electrodes for electrophoresis. This voltage mode may induce an electrophoretic effect and accelerate the extraction of bodily exudates.

[0154] The response signal can be a current or a voltage. The response signal can be measured during the duration of the excitation signal. The measuring electronics 136 can be configured to record at least one impedance value between the electrodes in response to the application of the excitation signal.

[0155] The response signal can be measured at a reference resistor, which could be a component of measuring electronics 136. The reference resistor can be connected in series with the ionic resistivity of the analyte response layer 124. A reference resistor suitable for determining the ionic resistivity of the analyte response layer can be selected, for example, using Z... GRH Indicates the value of the reference resistor R. ref Can be prioritized in Z GRH Within a certain range. The reference resistance can be correlated with known values, such as a predetermined average value determined from multiple reference measurements. The reference resistance can reflect the measurement range of the analyte response layer 124. The reference resistance can reflect the required measurement tolerance. In determining Z... GRH During the defined period, the signal generator device can apply a fast transient voltage with a known amplitude U1 to the electrodes. Simultaneously, a reference resistor R can be used... ref The voltage drop U2 is measured at point R. The magnitude of the applied voltage and its value at R are known. ref The measured amplitude and R ref Value, ZGRH It can be calculated as: .

[0156] The evaluation of the response signal can be performed using a processing device. The evaluation may further include using at least one predetermined relation from the analyte response layer Z. GRH The concentration of the analyte is determined by the ionic resistivity. For example, the predetermined relationship can be linear. For example, the predetermined relationship can be stored in at least one database of the processing device.

[0157] Figure 2 shows a flowchart of an exemplary embodiment of a method for determining the concentration of an analyte in a sample using, for example, a non-invasive continuous monitoring system 110 as described with respect to Figure 1. The method steps can be performed in a given order. Further, one or more of the method steps can be performed in parallel and / or in a time-overlapping manner. Further, one or more of the method steps can be repeated. Further, additional method steps not listed may be present. The method includes the following steps: i. (138) Bring the skin contact surface 116 of the detection electrode 120 and the auxiliary electrode 128 into contact with the skin surface 118. ii. (140) Distribute an excitation signal to the analyte sensor 112 and a reference resistor connected in series with the analyte sensor 112, and measure at least one voltage distribution across the analyte sensor 112 and the reference resistor during the excitation signal period. iii. (142) Determine the analyte concentration by evaluating the measured voltage distribution.

[0158] The method may include measuring the current between the conversion layer 126 and the auxiliary electrode 128, and using the measured current to additionally determine the analyte concentration.

[0159] List of reference numerals

Claims

1. A non-invasive analyte sensor (112) comprising at least two electrodes (114), each electrode (114) having a skin contact surface (116), wherein at least one of the electrodes (114) is a detection electrode (120), wherein the detection electrode (120) comprises at least one analyte response layer (124) and at least one conversion layer (126), wherein at least one other electrode of the electrodes (114) is configured as an auxiliary electrode (128), the auxiliary electrode (128) being configured as a counter electrode or a combined counter-reference electrode, wherein the detection electrode (120) comprises a stack of at least two functional layers, wherein a proximal functional layer forms a balanced sensor and a distal functional layer forms a conversion layer (126).

2. The non-invasive analyte sensor (112) according to any one of the preceding claims, wherein the analyte-responsive layer (124) comprises at least one analyte-responsive hydrogel layer, wherein the analyte-responsive hydrogel layer comprises boric acid, wherein the analyte-responsive hydrogel layer comprises a phenylboronic acid derivative.

3. The non-invasive analyte sensor (112) according to any one of the preceding claims, wherein the conversion layer (126) is enzyme-containing or non-enzymatic.

4. The non-invasive analyte sensor (112) according to any one of the preceding claims, wherein the conversion layer (126) comprises glucose oxidase (GOx) or glucose dehydrogenase (GDH).

5. The non-invasive analyte sensor (112) according to any one of the preceding claims, wherein the conversion layer (126) is enzyme-free and comprises at least one material selected from the following material categories: metal-organic frameworks; low-solubility nanoparticle metal salts, such as tin-nickel sulfides; graphene oxide; carbon nanotubes; and other material categories.

6. The non-invasive analyte sensor (112) according to any one of the preceding claims, wherein the analyte is glucose.

7. The non-invasive analyte sensor (112) according to any one of the preceding claims, wherein the sample is bodily exudate, such as sweat.

8. A non-invasive continuous monitoring system (110) for skin-tight wear, comprising: At least one non-invasive analyte sensor (112) according to any one of the preceding claims, and a measurement electronics (136) configured for use with respect to the following: - Distribute an excitation signal to the analyte sensor (112) and a reference resistor connected in series with the analyte sensor (112), and measure at least one voltage distribution on the analyte sensor (112) and the reference resistor during the excitation signal, and determine the analyte concentration in the analyte response layer (124) by evaluating the measured voltage distribution; and / or - An excitation signal is applied to the analyte sensor (112) and at least one current response is measured, wherein the measurement electronics (136) is configured to determine the analyte concentration in the analyte response layer (124) by evaluating the measured current response and correlating it with the excitation signal.

9. The non-invasive continuous monitoring system (110) according to the preceding claim, wherein the excitation signal is a fast transient voltage and the voltage distribution is measured as a current or voltage response signal, wherein the fast transient voltage includes a discontinuous signal such as a pulse, wherein the pulse duration is ≤ 20 µs, preferably ≤ 10 µs.

10. The non-invasive continuous monitoring system (110) according to any of the preceding claims relating to a non-invasive continuous monitoring system, wherein the measuring electronics (136) is configured to record at least one impedance value between electrodes (114) in response to the application of the excitation signal.

11. The non-invasive continuous monitoring system (110) according to any of the preceding claims relating to a non-invasive continuous monitoring system, wherein the measurement electronics (136) is configured to apply an additional voltage pattern between electrodes (114) to operate the conversion layer (126) by induced electrophoresis.

12. A method for determining the concentration of an analyte in a sample using a non-invasive continuous monitoring system (110) according to any one of the preceding claims relating to a non-invasive continuous monitoring system, the method comprising the steps of: i. (138) Make the skin contact surface (116) of the detection electrode (120) and the auxiliary electrode (128) contact the skin surface (118), ii. (140) Distribute an excitation signal to the analyte sensor (112) and a reference resistor connected in series with the analyte sensor (112), and measure at least one voltage distribution on the analyte sensor (112) and the reference resistor during the excitation signal. iii. (142) Determine the analyte concentration by evaluating the measured voltage distribution; And / or the method includes the following steps: I. (138) Bring the skin contact surface (116) of the detection electrode (120) and the auxiliary electrode (128) into contact with the skin surface (118). II. Apply an excitation signal to the analyte sensor (112) and measure at least one current response. III. The analyte concentration in the analyte response layer (124) is determined by evaluating the measured current response and correlating it with the excitation signal.

13. The method according to the preceding claim, wherein the method comprises: The current between the conversion layer (126) and the auxiliary electrode (128) is measured, and the measured current is used to additionally determine the concentration of the analyte.

14. A computer program including program tools for performing the method according to any one of the preceding claims relating to the method when the computer program is executed on a computer or on a computer network.

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